Wetenschappelijk onderzoek in Medisch Spectrum Twente 2011
Inhoudsopgave Inhoudsopgave ........................................................................................................... 2 Voorwoord .................................................................................................................. 3 Overzicht publicaties en de Top 3 .............................................................................. 4 Overzicht aantal publicaties per vakgroep: ................................................................ 5 Promoties in MST in 2011 .......................................................................................... 6 Gastroenterologie ................................................................................................... 6 Heelkunde ............................................................................................................ 15 Heelkunde ............................................................................................................ 20 Klinische farmacie ................................................................................................ 26 Neurologie ............................................................................................................ 35 Thoraxchirurgie .................................................................................................... 41 PubMed publicaties per vakgroep ............................................................................ 44 Anesthesiologie .................................................................................................... 44 Cardiologie ........................................................................................................... 45 Gastroenterologie ................................................................................................. 58 Gynaecologie ....................................................................................................... 63 Heelkunde ............................................................................................................ 71 Intensive Care ...................................................................................................... 89 Interne Geneeskunde ........................................................................................... 97 Kindergeneeskunde ........................................................................................... 110 Klinische Chemie................................................................................................ 115 Klinische Farmacie ............................................................................................. 121 KNO .................................................................................................................... 124 Laboratorium voor Microbiologie ........................................................................ 125 Longziekten ........................................................................................................ 130 Medical School Twente ...................................................................................... 143 Neurologie .......................................................................................................... 153 Orthopedie .......................................................................................................... 166 Pathologie .......................................................................................................... 168 Plastische Chirurgie ........................................................................................... 175 Radiologie .......................................................................................................... 176 Radiotherapie ..................................................................................................... 181 Reumatologie ..................................................................................................... 186 Revalidatiegeneeskunde .................................................................................... 204 Spoedeisende Hulp ............................................................................................ 208 Tandheelkunde ................................................................................................... 209 Thoraxchirurgie .................................................................................................. 210
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Voorwoord Voor u ligt de derde editie van het jaarlijkse overzicht van het wetenschappelijk overzicht wat door medewerkers van Medisch Spectrum Twente in 2011 is gepubliceerd. Zoals u zult zien is het aantal publicaties dit jaar ongeveer gelijk aan dat van vorig jaar. Dit jaaroverzicht wordt ook buiten MST verspreid onder huisartsen, apothekers, fysiotherapeuten en andere wetenschappelijke instellingen in de regio. De publicaties zijn gegroepeerd op vakgroep of maatschap. Niet op volgorde van belangrijkheid maar alfabetisch. Hierbij is als criterium genomen dat de publicatie terug te vinden moet zijn op PubMed en de publicatiedatum moet ook in 2011 zijn. De zogenaamde “Epub Ahead of Print” artikelen komen in de volgende uitgave. Daarnaast worden ook peer-reviewed artikelen uit Nederlandstalige tijdschriften opgenomen. In 2011 zijn 190 unieke publicaties verschenen in peer-reviewed tijdschriften. Dit is weer meer als in 2010. Op naar 200! In 2007 werden er 89 gepubliceerd, in 2008 74, in 2009 109 en in 2010 177. De gemiddelde impact score van alle artikelen is 3,63. Dat is 1,49 punten lager dan in 2010 maar nog steeds een erg mooi gemiddelde. Er waren in 2011 zes promoties in MST. Een van de redenen voor het hoge aantal publicaties en de gemiddelde impact factor lijkt gelegen in een aantal nieuwe onderzoekers in MST. Blijkbaar slagen we er in om goede en veel publicerende onderzoekers naar “het Oosten” te lokken! Dit zal zeker bijdragen aan een nog vruchtbaarder onderzoeksklimaat. Om de almaar toenemende onderzoeksactiviteit ook adequaat te kunnen blijven ondersteunen heeft de Raad van Bestuur per 1 december 2011 een extra epidemioloog aangesteld: Marjolein Brusse-Keizer. Naast de Elsevier lijstjes en AD ranglijsten staan ook in deze uitgave lijstjes in de vorm van een Top 3. U vindt per gepubliceerd artikel de impact factor van het tijdschrift en per vakgroep of maatschap de totale en gemiddelde impact factor score van alle gepubliceerde artikelen. Om een indruk te krijgen van de bijdrage van eigen onderzoek is ook een overzicht gegeven van het aantal artikelen waarbij een onderzoeker uit MST 1e, 2e, of laatste auteur is. Daarvan wordt ook apart de totale en gemiddelde impact score weergegeven. Om de ontwikkeling te kunnen volgen zijn de ranglijsten van 2011 naast die van 2009 en 2010 weergegeven. Ik wens u veel leesplezier toe, Prof. dr. Job van der Palen Coördinator Wetenschappelijk Onderzoek Medical School Twente Medisch Spectrum Twente E-mail:
[email protected]
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Overzicht publicaties en de Top 3 Aantal unieke publicaties Gemiddelde impact factor score
2009 109 3,16
2009
2010 177 5,12
2010
2011 190 3,63
2011
Top 3: Aantal publicaties: 1
Heelkunde
16
1 Heelkunde
38 1 Heelkunde
26
2
Cardiologie
14
2 Neurologie
23 2 Reumatologie
25
2
Reumatologie
14
3 Reumatologie
17 3 Cardiologie
23
Top 3: Totale impact factor score: 1 Int. Geneeskunde 59.4
1 Heelkunde
213.9 1 Int. Geneeskunde 151.5
2 Reumatologie
54.2
2 Gynaecologie
140.4 2 Reumatologie
3 Neurologie
41.3
3 Int. Geneeskunde 110.1 3 Heelkunde
93.6 69.2
Top 3: Gemiddelde impact factor score: 1 Radiotherapie
10.9
1 Radiotherapie
10.4 1 Int. Geneeskunde
8.9
2 Int. Geneeskunde
5.0
2 Gynaecologie
9.4 2 Radiotherapie
7.3
3 Gastroenterologie
4.9
3 Int. Geneeskunde
8.5 3 Gastroenterologie
6.9
Top 3: Aantal publicaties als 1e, 2e of laatste auteur: 1 Cardiologie
12 1 Heelkunde
20 1 Heelkunde
18
2 Heelkunde
7 2 Cardiologie
12 2 Cardiologie
17
3 Int. Geneeskunde
5 2 Reumatologie
12 3 Reumatologie
15
3 Longziekten
5
3 Medical School
5
Top 3: Totale impact factor score als 1e, 2e of laatste auteur: 1 Longziekten
27.8 1 Radiologie
54.2 1 Reumatologie
47.9
2 Medical School
20.5 2 Klinische Chemie
44.5 2 Longziekten
33.1
3 Neurologie
16.3 3 Neurologie
43.2 3 Cardiologie
32.2
Top 3: Gemiddelde impact factor score als 1e, 2e of laatste auteur: 1 Neurologie
8.2 1 Int. Geneeskunde
2 Longziekten
5.6 2 Klinische Farmacie
6.6 2 Radiotherapie
4.4
3 Gastroenterologie
4.7 3 Klinische Chemie
5.6 3 Intensive Care
3.8
4
17.8 1 Gastroenterologie 17.8
Overzicht aantal publicaties per vakgroep: 2009
2010
2011
1
2
1
14
14
23
4
5
4
Anesthesiologie Cardiologie Gastroenterologie Gynaecologie
2
15
7
16
38
26
1
2
12
12
13
17
Kaakchirurgie
0
1
0
Kindergeneeskunde
5
4
7
Klinische Chemie
4
14
10
Klinische Farmacie
4
3
4
Klinische Fysica
0
1
0
KNO
0
1
1
Laboratorium voor Microbiologie
4
6
8
Longziekten
8
5
17
12
13
13
3
0
0
Heelkunde Intensive Care Interne Geneeskunde
Medical School Twente Neurochirurgie Neurologie
11
23
21
Nucleaire Geneeskunde
1
1
0
Orthopedie
1
2
3
Pathologie
1
6
9
Plastische Chirurgie
4
1
1
Psychiatrie
1
0
0
Radiologie
2
11
6
Radiotherapie
2
4
5
Reumatologie
14
17
25
Revalidatiegeneeskunde
2
5
4
Spoedeisende Hulp
0
2
1
Tandheelkunde
0
0
1
Thoraxchirurgie
4
2
5
5
Promoties in MST in 2011 Gastroenterologie Studies on smoking in patients with inflammatory bowel disease and liver transplant recipients Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. E. Sterken, in het openbaar te verdedigen op woensdag 30 november 2011 om 12.45 uur door Frans van der Heide geboren op 1 oktober 1981 te Ternaard
Promotores: Prof. dr. J.H. Kleibeuker Prof. dr. K.N. Faber Co-promotor: Dr. G. Dijkstra Dr. E.B. Haagsma Beoordelingscommissie: Prof. dr. A. Dijkstra Prof. dr. J.P.H. Drenth Prof. dr. H.A.M. Kerstjens
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Samenvatting Twee belangrijke groepen patiënten voor de maag-darm-leverarts zijn patiënten met chronische inflammatoire darmziekten (inflammatory bowel diseases – IBD) en met leverziekten. De twee belangrijkste chronische inflammatoire darmziekten zijn de ziekte van Crohn (ZvC) en colitis ulcerosa (CU); beide worden gekenmerkt door terugkerende episodes van ontsteking van het maagdarmkanaal. Bij de ZvC kan het gehele maagdarmkanaal zijn aangedaan, terwijl bij CU de ontsteking zich beperkt tot de dikke darm. Een ander opmerkelijk verschil tussen de ZvC en CU is het tegengestelde effect van roken; roken lijkt nadelig te zijn voor de ZvC, maar gunstig voor CU. Waarschijnlijk door dit opmerkelijk tegengestelde effect zijn er veel studies gedaan naar de rol van roken in IBD. De rol van actief roken op het ontwikkelen van IBD is duidelijk: het is een risicofactor voor het ontwikkelen van de ZvC, maar beschermt tegen CU. In tegenstelling tot de duidelijke rol van actief roken, is het onduidelijk wat de rol van passief roken op het ontwikkelen van IBD is. Verder zijn studies over de effecten van actief roken op het beloop van de ZvC en CU niet eenduidig. Meerdere studies toonden een nadelig effect van actief roken op het beloop van de ZvC en een gunstig effect op dat van CU, maar voor beide ziektes konden andere studies dit niet bevestigen. Ten slotte is de rol van passief roken op het beloop van de ZvC en CU onbekend. Het is onbekend waarom roken nadelig is voor de ZvC en gunstig voor CU. Mogelijk betrokken mechanismen zijn de Toll-like receptor-4-afhankelijke pathway in macrofagen, de heme-oxygenase-1 (HO-1) pathway en trombogene effecten van tabak op de intestinale microvasculatuur. Het begrijpen van het mechanisme wordt gecompliceerd door de vele componenten in sigarettenrook. De meest bestudeerde componenten zijn nicotine en koolstofmonoxide, en beide hebben nadelige en gunstige effecten op darmontsteking. Patiënten met leverziekten zijn een andere belangrijke groep. Levertransplantatie (LT) is een geaccepteerde behandeling voor eindstadium leverziekte. De prognose van de ontvangers van een LT is de laatste decennia verbeterd. De belangrijkste oorzaken van morbiditeit en mortaliteit na LT zijn maligniteiten en hart- en vaatziekten. Roken is een beruchte risicofactor voor verschillende maligniteiten en hart- en vaatziekten in de algemene populatie, maar studies over de rol van roken in ontvangers van een LT zijn schaars. De paar studies die er zijn over de effecten van roken na LT laten zien dat roken een risicofactor is voor verschillende complicaties en ernstige aandoeningen na LT. Helaas is er weinig bekend over het rookgedrag van ontvangers van een LT. Dit proefschrift is gefocust op de rol van actief en passief roken in IBD, en op de rol van roken in ontvangers van een LT. Hoofdstuk 1 begint met een introductie over de rol van roken bij mensen met IBD en ontvangers van een LT, en geeft een overzicht van de onderzoeksdoelen van dit proefschrift. Gezien het tegengestelde effect van roken op de ZvC en CU, treden er na diagnose bij patiënten met de ZvC en CU waarschijnlijk verschillende veranderingen op in rookgedrag. In hoofdstuk 2 hebben we veranderingen in actief roken, stopplannen en passief roken bestudeerd in 380 patiënten met de ZvC en 295 met CU. Hiervoor
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gebruikten we een schriftelijke enquête. Van de ooit rokende UC patiënten stopten meer met roken voor de diagnose dan ZvC patiënten (63 vs. 22%; p<0.001), wat leidde tot 30% ex-rokers ten tijde van diagnose bij CU en 13% bij de ZvC (p<0.001). Het percentage dat stopte met roken ten tijde van en na diagnose was gelijk voor de ZvC en CU. De helft van de ZvC patiënten stopte met roken na de diagnose wat leidde tot minder huidige rokers bij de ZvC dan in een controle populatie (26 (95% betrouwbaarheidsinterval: 21–30%) vs. 33%). In geval van zowel de ZvC (22 vs. 35%; p=0.044) als CU (24 vs. 53%; p=0.024) waren patiënten die na diagnose doorrookten minder vaak hoogopgeleid dan de stoppers. Stopplannen (89%), blootstelling aan sigarettenrook in de kindertijd en huidig passief roken waren niet verschillend tussen ZvC en CU patiënten. Wij concluderen dat er geen verschillen zijn in veranderingen in rookgedrag tussen ZvC en CU patiënten ten tijde van en na diagnose, wat suggereert dat deze patiënten niet goed op de hoogte zijn van de link tussen hun ziekte en rookgedrag. Toch lijken ZvC patiënten vatbaarder voor het stoppen met roken dan de algemene populatie aangezien de helft van de ZvC patiënten stopte met roken na diagnose. Dus is het geen verspilde energie ZvC patiënten te helpen met het stoppen met roken. Bij zowel ZvC als CU patiënten is een hogere opleiding geassocieerd met stoppen met roken na diagnose. Studies over de rol van roken op het ziektebeloop van zowel de ZvC als CU laten tegenstrijdige resultaten zien, en studies over de effecten van passief roken op het beloop van IBD zijn zeldzaam of afwezig. In hoofdstuk 3 hebben we retrospectief de effecten van actief en passief roken bestudeerd in 380 patiënten met de ZvC en 295 met CU uit een academisch ziekenhuis cohort. Voor het definiëren van rookgedrag gebruikten we dezelfde enquête als in hoofdstuk 2, en data over het ziektebeloop werden verkregen door statusonderzoek. Ten tijde van diagnose rookte 52% van de ZvC patiënten, 41% in een controlepopulatie, en 28% van de CU patiënten. Het aantal huidige rokers bij de ZvC is lager dan in de algemene populatie (26 vs. 35%). Er werden geen nadelige effecten van actief roken op het beloop van de ZvC gezien, maar passieve rokers hadden vaker immuunsuppressiva en infliximab nodig dan patiënten zonder blootstelling aan passief roken. Actief roken had gunstige effecten op CU, wat bleek uit een lager aantal colectomieën, en minder vaak primaire scleroserende cholangitis en backwash-ileitis in actieve rokers dan in nooit-rokers. Daarnaast was een hoger aantal sigaretten per dag gecorreleerd met een minder uitgebreide ontsteking van de dikke darm en een geringere behoefte aan therapie. Stoppen met roken na diagnose was nadelig voor CU patiënten aangezien patiënten die na diagnose stopten vaker steroïden en opnames nodig hadden dan patiënten die voor diagnose stopten. De conclusie van deze studie is dat actief roken een risicofactor is voor het krijgen van de ZvC, maar het ziektebeloop niet beïnvloedt. Passief roken is nadelig voor het beloop van ZvC patiënten. Voor CU heeft actief roken dosisafhankelijke gunstige effecten op het beloop. Onze data suggereren dat passief roken een nieuwe risicofactor is voor de ZvC. De resultaten van hoofdstuk 3 waren enigszins onverwacht, vooral doordat het nadelige effect van actief roken op de ZvC niet werd bevestigd, maar ook door de tegengestelde effecten van actief en passief roken. Deels zou dit veroorzaakt kunnen zijn door het bestuderen van patiënten uit een academisch ziekenhuis met een belangrijke referentiefunctie. Het bestuderen van patiënten die verwezen zijn vanuit andere ziekenhuizen kan leiden tot een selectiebias, want patiënten met een
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gunstiger ziektebeloop kunnen ondervertegenwoordigd zijn. De effecten van roken op het beloop kunnen zo subtiel zijn, dat zij meer uitgesproken zijn in patiënten met een gunstig beloop. Het doel van hoofdstuk 4 was om te zien of de bevindingen van hoofdstuk 3 bevestigd konden worden in een IBD cohort uit een regionaal ziekenhuis. We hebben retrospectief de effecten van actief en passief roken onderzocht in 128 patiënten met ZvC en 192 met CU uit een regionaal ziekenhuis. Hiervoor werden dezelfde methoden als in hoofdstuk 3 gebruikt. Ten tijde van diagnose rookte 52% (95% betrouwbaarheidsinterval: 43–60%) van de ZvC patiënten, 40% in een controle populatie en 25% (95% betrouwbaarheidsinterval: 18–31%) van de CU patiënten. Er waren minder ex-rokers (19 vs. 31%, p=0.013) en nooit-rokers ten tijde van diagnose (30 vs. 44%, p=0.009) bij ZvC dan bij CU. Er werden geen nadelige effecten van actief en passief roken op de ZvC gezien. CU patiënten die doorrookten na diagnose hadden minder vaak twee of meer opnames nodig dan nooit rokers (5 vs. 25%, p=0.036). Voor de rest werden er geen duidelijke gunstige effecten van roken op CU gezien. Passief rokende CU patiënten hadden vaker extra-intestinale manifestaties (25 vs. 7%, p=0.029) dan patiënten zonder blootstelling aan passief roken. We concluderen dat ook in een IBD populatie van een regionaal ziekenhuis roken een risicofactor is voor het ontwikkelen van de ZvC en beschermt tegen CU. We vonden geen nadelige effecten van roken op het ziektebeloop van de ZvC en geen eenduidig gunstige effecten op het beloop van CU. Naast rookgedrag is de genetische aanleg ook een andere belangrijke factor voor het ontwikkelen van de ZvC. Het laatste decennium is een nog steeds groeiend aantal genetische varianten gevonden die geassocieerd zijn met IBD en vooral de ZvC. Het is waarschijnlijk dat de ontwikkeling van de ZvC wordt beïnvloedt door een interactie tussen deze genetische varianten en roken, maar er zijn weinig studies die dit hebben onderzocht. In hoofdstuk 5 hebben we verschillen in ziektegeassocieerde genetische varianten onderzocht tussen ZvC patiënten gestratificeerd voor actief roken bij diagnose en voor passief roken in de kindertijd. We selecteerden 19 bevestigde genetische varianten in 14 ZvC-geassocieerde genen of loci inclusief drie NOD2 varianten. Genotype data van deze 19 ZvCgeassocieerde zogenaamde “single-nucleotide” polymorfismen (SNPs) waren beschikbaar van 310 ZvC patiënten en 976 controles uit eerdere studies door onze groep. We bestudeerden de allelische associatie van deze 19 SNPs in ZvC patiënten gestratificeerd voor actief roken bij diagnose en voor passief roken in de kindertijd. Data over actief roken bij diagnose en passief roken in de kindertijd werden verkregen door de eerder genoemde schriftelijke enquête en statusonderzoek. De loci geassocieerd in rokende, maar niet in niet-rokende, ZvC patiënten waren 5p13.1 (rs17234657), DLG5 (rs2165047), NKX2-3 (rs10883365) en NOD2 (R702W). De loci geassocieerd in niet-rokende, maar niet in rokende, ZvC patiënten waren IL23R (rs7517847), 5p13.1 (rs9292777), IRGM (rs13361189 en rs4958847), IL12B (rs6887695) en CCNY (rs3936503). PTPN2 (rs2542151) was alleen geassocieerd in het rokende ZvC cohort (p=0.04), en niet in het gehele ZvC cohort (p=0.23) of in het niet-rokende ZvC cohort (p=0.80). In passief rokende ZvC patiënten werden associaties met 13 SNPs in 9 loci gevonden, inclusief PTPN2. In ZvC patiënten niet blootgesteld aan passief roken werden alleen associaties gevonden met NOD2 (1007fsinsC en G908R). Concluderend vonden we verschillende genetische associaties in verschillende groepen, die zich van elkaar
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onderscheidden door al dan niet actief roken ten tijde van diagnose en al dan niet passief roken in de kinderleeftijd. Een deel van dit verschil kan verklaard worden door een gebrek aan “power” in dit relatieve kleine ZvC cohort. Toch impliceert het verschil in geassocieerde genen tussen rokende en niet-rokende ZvC patiënten een complexe gen-omgevingsinteractie. Daarom moeten genetische studies in de ZvC gestratificeerd worden voor rookgedrag, want anders kunnen minder sterk geassocieerde genen zoals PTPN2 gemist worden. Het is onbekend waarom roken gunstig is voor CU. Eén van de mogelijk betrokken pathways is de heme-oxygenase-1 (HO-1) pathway. HO-1 is het snelheidsbeperkende enzym betrokken bij de afbraak van haem, wat leidt tot de eindproducten biliverdine, Fe2+ en koolstofmonoxide. Haem veroorzaakt oxidatieve stress, terwijl alle drie de eindproducten antioxidatieve, antiapoptotische en antiinflammatoire eigenschappen hebben. Inductie van HO-1 had een gunstig effect in diermodellen met darmschade. Sigarettenrook (SR) is in staat tot het induceren van HO-1 in verschillende humane cellen, maar het effect van roken op HO-1 expressie in de dikke darm is onbekend. Inductie van HO-1 in de dikke darm zou gunstig kunnen zijn voor CU patiënten door bescherming te bieden tegen de ontwikkeling van CU en/of door ontsteking in geval van actieve CU te verminderen. In hoofdstuk 6 hebben we een laboratoriumonderzoek verricht naar de effecten van roken op de expressie van HO-1 in de dikke darm in vitro, in dieren en in mensen. Voor de in vitro proeven werden DLD-1 cellen geïncubeerd met sigarettenrook extract (SRE), voor de dierproeven werden muizen blootgesteld aan SR en voor het humane deel werden dikke darmbiopten verzameld van gezonde niet-rokers en rokers. HO-1 expressie werd beoordeeld met quantitative polymerase chain reaction (qPCR), western blotting en immunohistochemie. Cytochroom P450 1A1 (CYP1A1) expressie (qPCR) werd gebruikt als een positieve controle voor blootstelling van de dikke darm aan SR. SRE induceerde dosisafhankelijk HO-1 en CYP1A1 expressie in DLD-1 cellen. In muizen en mensen was de CYP1A1 mRNA expressie in de dikke darm verhoogd bij expositie aan SR, maar HO-1 mRNA en eiwit expressie in de dikke darm was gelijk tussen controles en aan SR geëxposeerden. In de humane studie was de expositie aan SR in de therapeutische bandbreedte voor CU. De conclusie van deze studie is dat SR een CYP1A1 respons induceert, maar geen HO-1 stress respons in epitheel cellen van de dikke darm. Dit wijst erop dat het gunstige effect van SR op UC niet verloopt via opregulatie van HO-1 in de dikke darm, maar SR zou wel andere beschermingsmechanismen lokaal in de dikke darm in gang kunnen zetten. Literatuur betreffende de rol van roken in ontvangers van een levertransplantatie (LT) is schaars. De paar beschikbare studies over de effecten van roken in LT ontvangers tonen dat roken een risicofactor is voor verschillende complicaties en ernstige aandoeningen na LT. Gezien dit schadelijke effect van roken na LT is het teleurstellend dat slechts twee transplantatiecentra het rookgedrag van LT ontvangers hebben onderzocht. In hoofdstuk 7 beschrijven we het rookgedrag van LT ontvangers voor en na transplantatie, en de associatie tussen roken en het optreden van maligniteiten en cardiovasculaire ziekten na LT. Eén van de doelen was het definiëren van groepen die vatbaar zijn voor herstarten van roken na LT. Alle 401 volwassen patiënten met een follow-up van minimaal twee jaar na LT werden geïncludeerd. Data werden verzameld vanuit medische statussen en naar
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alle 326 levende patiënten werd een enquête gestuurd over het rookgedrag op vier momenten voor en na LT. Op de enquête reageerden 301 (92%) patiënten. Zowel voor als na LT gebruikte 53% van de patiënten nooit tabak en ongeveer 17% was actief roker. Ter vergelijk, in 2007 rookte 28% van de Nederlandse bevolking. Bijna een derde van de actieve rokers tijdens evaluatie voor LT lukte het om te stoppen met roken, meestal tijdens de wachtlijstperiode voor LT. Twaalf procent van de exrokers begon opnieuw met roken, vooral na LT. Vooral ex-rokers die nog maar een relatief korte tijd geleden gestopt waren, waren vatbaar voor een terugval. Tabakgebruik was het hoogst in patiënten met een alcoholische leverziekte (52% was actief roker voor LT en 44% na LT) en het laagst in patiënten met primaire scleroserende cholangitis (1,4% was actief roker voor LT). Tien jaar na LT was het cumulatieve aantal maligniteiten 12,7% in actieve rokers tegen 2,1% in niet-rokers (P=0.02). Er werd geen associatie gevonden met huidkanker of cardiovasculaire ziekten. Concluderend, voor en na LT zijn ongeveer 17% van de patiënten actief roker. Na LT omvat dit percentage ex-rokers die weer zijn begonnen en een afname van actieve rokers bij patiënten met een alcoholische leverziekte. Preventieprogramma’s moeten zich niet alleen focussen op actieve rokers, maar ook op ex-rokers en dan vooral ex-rokers die recent zijn gestopt. Gezien het hoge aantal maligniteiten in actieve rokers na LT zijn een interventieprogramma na LT en frequente screening voor maligniteiten nodig. Toekomstperspectieven Ondanks de enorme hoeveelheid studies over de effecten van roken op het ziektebeloop van de ZvC en CU is het nog steeds onduidelijk welke rol roken precies speelt in het beloop van beide ziekten. In dit proefschrift konden wij geen nadelig effect van roken vinden op het beloop van de ZvC, terwijl andere studies wel een duidelijk nadelig effect vonden. Waarschijnlijk is roken alleen nadelig voor bepaalde patiënten met de ZvC. Dit zou afhankelijk kunnen zijn van geslacht, en lokalisatie en ernst van de ziekte. Eerder is al gesuggereerd dat roken vooral voor vrouwelijke ZvC patiënten nadelig is, maar dit konden wij in dit proefschrift niet bevestigen. Toekomstige studies zouden meer moeten focussen op het identificeren van specifieke patiëntgroepen die vatbaar zijn voor de effecten van roken. Wij hebben als eerste de effecten van passief roken op het beloop van IBD onderzocht, en hebben dit gedaan in zowel een cohort van een academisch als van een regionaal ziekenhuis. In het academische cohort vonden we een nadelig effect van passief roken bij ZvC patiënten, maar konden dit niet bevestigen in het regionale cohort. Er zijn dan ook meer studies over de effecten van passief roken op het beloop van IBD nodig om de precieze rol van passief roken te bepalen. In dit proefschrift hebben we laten zien dat de ontwikkeling van de ZvC mede afhankelijk is van een interactie tussen roken en de genetische aanleg. Ook de effecten van rook op het ziektebeloop zouden weleens afhankelijk kunnen zijn van de genetische aanleg. Hopelijk lukt het in de toekomst genetische varianten te selecteren die patiënten vatbaar maken voor de effecten van roken. Op dit moment is het nog niet mogelijk het beloop van de ZvC te voorspellen, maar er gloort hoop. Onderzoekers van onze groep toonden aan dat het misschien mogelijk wordt subgroepen van ZvC patiënten met een ernstige prognose te identificeren op basis van de genetische varianten. Zij vonden een associatie tussen een toenemend
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aantal risicoallelen en een ernstiger ziektebeloop.1 Komende studies moeten zich richten op het classificeren van ZvC patiënten gebaseerd op genetische aanleg in combinatie met rookgedrag. Hopelijk kunnen we hierdoor specifieke patiëntgroepen identificeren en hierop de behandeling aanpassen; sommige patiënten kunnen baat hebben bij vroege interventie en agressieve medicatie, terwijl andere patiënten juist de bijwerkingen van onnodige medicatie bespaard kan blijven. Uit onze studie naar de interactie tussen roken en genetische aanleg blijkt duidelijk dat specifieke omgevingsfactoren nodig zijn om bepaalde genetische varianten te laten bijdragen aan het ontwikkelen van ziekte. Dit is een belangrijke bevinding, omdat de meeste genetische patiënt-controle studies niet gestratificeerd zijn voor omgevingsfactoren en niet gecorreleerd zijn aan omgevingsfactoren in de controle cohorten. Als deze studies wel gaan stratificeren voor rookgedrag en/of andere omgevingsfactoren is het misschien mogelijk om nog meer ZvC-geassocieerde genen te vinden en waarschijnlijk ook meer CU-geassocieerde genen. Dit zal vooral het geval zijn voor geassocieerde genen met lage odds ratio’s. Hoewel de effecten van roken op het ontstaan en beloop van IBD al decennia worden bestudeerd, is het nog steeds onbekend welke pathways beïnvloed worden door roken en welke component(en) in sigarettenrook verantwoordelijk is/zijn. In dit proefschrift hebben we de heme-oxygenase 1 (HO-1) pathway bestudeerd. Hoewel sigarettenrook HO-1 expressie induceerde in in vitro experimenten met DLD-1 cellen, vonden we geen effect van roken op de expressie van HO-1 in de dikke darm van muizen en mensen. Dit betekent echter niet dat de HO-1 pathway niet betrokken is bij de gunstige effecten van roken op CU, want roken zou zijn gunstige effecten ook kunnen uitoefenen door opregulatie van HO-1 in de longen met als gevolg verhoogde koolstofmonoxide concentraties. Verschillende interventiestudies in muizen hebben gunstige effecten van koolstofmonoxide aangetoond bij darmschade.2-4 Wellicht blijkt uit toekomstige interventiestudies dat koolstofmonoxide ook gunstig is voor CU patiënten. In dit proefschrift hebben we aangetoond dat sigarettenrook de dikke darm bereikt gezien de verhoogde CYP1A1 expressie in de dikke darm van rokers. Dit betekent dat sigarettenrook andere lokale beschermingsmechanismen dan HO-1 in de dikke darm kan beïnvloeden. Om deze te vinden, zijn meer studies nodig. Gezien de mogelijk nadelige effecten van roken op de ZvC moet stoppen met roken één van de therapeutische doelen zijn. In dit proefschrift toonden we aan dat de helft van de bij diagnose rokende ZvC patiënten stopte met roken na de diagnose en we concludeerden dat ZvC patiënten vatbaarder zijn voor het stoppen met roken dan de algemene populatie. Een Franse studie vond dat na interventie het slechts 12% van de rokers lukte om meer dan een jaar te stoppen en slechts 10% lukte het om langdurig te stoppen.5 Een recente studie suggereerde dat de meeste ZvC patiënten succesvol in de IBD kliniek geholpen kunnen worden bij het stoppen met roken zonder specialistische hulp, aangezien ZvC patiënten een hoog kennisniveau over de risico’s van roken op de gezondheid hadden en een lage nicotineafhankelijkheid.6 In tegenstelling tot deze studie toonde een andere studie aan dat ZvC patiënten vaker het rookgerelateerde persoonlijkheidskenmerk “impulsive sensation seeking” hadden, wat juist geassocieerd is met een geringe neiging tot stoppen.7 De auteurs van deze studie suggereren dat ZvC patiënten met “impulsive sensation seeking” specifieke strategieën voor het stoppen met roken nodig hebben. Bovenstaande studies zijn dus niet eenduidig en er zijn meer studies
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nodig om opheldering te krijgen of ZvC patiënten speciale stopprogramma’s nodig hebben en hoe deze er dan uit moeten zien. Elke maag-darm-leverarts is het er mee eens dat het advies aan ZvC patiënten is om te stoppen met roken. De situatie voor CU is gecompliceerder. Zolang we niet weten welke component in sigarettenrook de gunstige effecten veroorzaakt, blijft het moeilijk wat we CU patiënten moeten adviseren. Het is wel belangrijk dat we CU patiënten die willen stoppen met roken niet ontmoedigen, want op de lange termijn worden ze beschermd tegen rookgerelateerde ziekten; CU patiënten hadden een verminderd risico op longkanker 8,9 en hart- en vaatziekten 8,10 vergeleken met ZvC patiënten. De tweede focus van dit proefschrift is de rol van roken in LT ontvangers. Voor patiënten die geëvalueerd worden voor LT is stoppen met alcohol een voorwaarde om in aanmerking te komen voor LT, vooral voor diegenen met een alcoholische leverziekte. De vraag is of stoppen met roken ook ingevoerd moet worden als een voorwaarde om in aanmerking te komen voor LT. In dit proefschrift vonden wij dat voor en na LT ongeveer 17% van de patiënten actief roken en dat actieve rokers na LT zes keer vaker maligniteiten hebben. Andere studies hebben ook ongunstige effecten van roken op de lange termijn na LT aangetoond en dus moet (blijvend) stoppen met roken een belangrijk doel na LT zijn. Of stoppen met roken ook een belangrijk doel vóór LT moet zijn, zal moeten blijken uit toekomstige studies over de effecten van roken op acute complicaties na LT, zoals trombose van de leverslagader 11 en transplantaatfalen. Interessant is een recente studie waarin actieve rokers een 92% hoger aantal galwegcomplicaties hadden na LT dan nooitrokers.12 Mede gezien deze laatste studie en het opmerkelijk lage aantal van 1,4% actieve rokers bij primaire scleroserende cholangitis zoals aangetoond in dit proefschrift, zou het interessant zijn om te bestuderen wat het effect van roken is op recidief van primaire scleroserende cholangitis na LT. Dit zal echter alleen mogelijk zijn in een multicenter studie gezien het lage aantal rokers in deze patiënt groep. Concluderend kan worden gesteld dat studies, inclusief die in dit proefschrift, ons hebben voorzien van enorm veel kennis over de effecten van roken op de ZvC en CU. De ware rol van roken bij ZvC en CU is echter nog steeds niet duidelijk en nog belangrijker, we weten nog steeds niet welke mechanismen door roken worden beïnvloed. Het laatste decennium is een nog steeds groeiend aantal genetische varianten gevonden die geassocieerd zijn met IBD. In dit proefschrift hebben we een interactie aangetoond tussen deze genetische varianten en rookgedrag op de ontwikkeling van de ZvC. Deze bevindingen bewijzen dat toekomstige genetische studies in de ZvC en CU gestratificeerd moeten worden voor rookgedrag. In LT ontvangers zijn hart- en vaatziekten en maligniteiten belangrijke oorzaken van morbiditeit en mortaliteit. In dit proefschrift toonden we een hoog en constant aantal rokers voor en na LT, en een associatie tussen roken en maligniteiten na LT. Dit maakt dat een interventieprogramma voor het stoppen met roken en frequente screening op maligniteiten bij rokers nodig zijn in LT ontvangers. Referenties 1.
Weersma RK, Stokkers PC, van Bodegraven AA et al. Dutch Initiative on Crohn and Colitis (ICC). Molecular prediction of disease risk and severity in a large Dutch Crohn's disease cohort. Gut 2009;58:388-95.
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Hegazi RA, Rao KN, Mayle A et al. Carbon monoxide ameliorates chronic murine colitis through a heme oxygenase 1-dependent pathway. J Exp Med 2005;202:1703–13. 3. Takagi T, Naito Y, Mizushima K et al. Inhalation of carbon monoxide ameliorates TNBS-induced colitis in mice through the inhibition of TNF-α expression. Dig Dis Sci 2010;55:2797-804. 4. Takagi T, Naito Y, Uchiyama K et al. Carbon monoxide liberated from carbon monoxide-releasing molecule exerts an anti-inflammatory effect on dextran sulfate sodium-induced colitis in mice. Dig Dis Sci 2011;56:1663-71. 5. Cosnes J, Beaugerie L, Carbonnel F, Gendre JP. Smoking cessation and the course of Crohn's disease: an intervention study. Gastroenterology 2001;120:1093–9. 6. Wahed M, Goodhand JR, West O et al. Tobacco dependence and awareness of health risks of smoking in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 2011;23:90-4. 7. Hyphantis T, Antoniou K, Tomenson B et al. Is the personality characteristic "impulsive sensation seeking" correlated to differences in current smoking between ulcerative colitis and Crohn's disease patients? Gen Hosp Psychiatry 2010;32:57-65. 8. Palli D, Trallori G, Saieva C et al. General and cancer specific mortality of a population based cohort of patients with inflammatory bowel disease: The Florence study. Gut 1998;42:175–9. 9. Pedersen N, Duricova D, Elkjaer M et al. Risk of extra-intestinal cancer in inflammatory bowel disease: meta-analysis of population-based cohort studies. Am J Gastroenterol 2010;105:1480-7. 10. Jess T, Gamborg M, Munkholm P et al. Overall and cause-specific mortality in ulcerative colitis: meta-analysis of population-based inception cohort studies. Am J Gastroenterol 2007;102:609–17. 11. Pungpapong S, Manzarbeitia C, Ortiz J et al. Cigarette smoking is associated with an increased incidence of vascular complications after liver transplantation. Liver Transplantation 2002;8:582-7. 12. Mathur AK, Ranney DN, Patel SP et al. The effect of smoking on biliary complications following liver transplantation. Transpl Int 2011;24:58-66. 2.
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Heelkunde Searching for metastases in colorectal cancer Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op woensdag 2 februari 2011 om 14.45 uur door Irene Grossmann geboren op 12 maart 1973 te Schwäbisch Hall, Duitsland
Promotoren: Prof. dr. T. Wiggers Prof. dr. G.H. de Bock Co-promotor: Dr. J.M. Klaase Beoordelingscommissie: Prof. dr. J.T.M. Plukker Prof. dr. J.H.W. de Wilt Prof. dr. R.G.H. Beets-Tan
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Samenvatting Stadiëren voorafgaand aan de behandeling De relevantie van stadiëren voorafgaand aan de behandeling wordt ondersteund door de uitkomsten van het eerste onderzoek (hoofdstuk 2). In de beschreven populatie van 612 patiënten werd een hoge incidentie van gemetastaseerd colorectaal carcinoom (CRC) gevonden (31%). Met een CT van het abdomen bleek het goed mogelijk om lever metastasen te vinden, echter was de gevoeligheid voor peritoneale carcinomatosis (PC) slecht. Inschatting van het T stadium bij colon carcinomen was redelijk goed. Lokaal uitgebreide colon carcinomen en PC zijn gecorreleerd; mogelijk zou het T stadium als een alternatieve indicator voor verdenking op PC kunnen dienen. De belangrijkste verandering in het behandelplan, als een gevolg van de bevindingen bij de stadiëring, werd gezien bij patiënten met gemetastaseerd colon carcinoom met een spoedeisende presentatie. Bij deze patiënten werd er minder vaak een resectie verricht naar aanleiding van het vinden van ongenezelijke ziekte. Dit, en de aanwezigheid van afstandsmetastasen bij bijna de helft van de patiënten met een spoedeisende presentatie, onderstreept de relevantie van stadiëren bij alle urgenties. Echter bleek dat stadiëren juist bij spoedeisende presentaties vaker achterwege werd gelaten, voornamelijk om logistieke redenen. Meer alertheid op het gegeven dat vooraf stadiëren het behandelplan kan veranderen naar minder uitgebreide procedures, heeft mogelijk een gunstig effect op de operatie morbiditeit en mortaliteit. Ook bij patiënten met lever metastasen werden veranderingen in het behandelplan gezien, echter niet bij patiënten met PC. Dit is voornamelijk een gevolg van het onvermogen van de CT van het abdomen om PC af te beelden, niet vanwege het ontbreken van eventuele consequenties voor de behandeling. Het zoeken naar afstandsmetastasen kan de oncologische uitkomsten verbeteren, waarin de uiteindelijke verbetering net zo afhankelijk is van logistiek en organisatie als van de accuratesse van de beeldvormende techniek. Stadiëring met een CT van de thorax werd niet ondersteund door de bevindingen van de tweede studie (hoofdstuk 3). De incidentie van longmetastasen was laag (7%), met name van metastasen die beperkt zijn tot de long (3%). Vanwege diagnostische onzekerheden werd ook slechts een kleine minderheid van de longmetastasen gediagnosticeerd vóór de behandeling van de pimaire tumor (2.5%). Indifferente afwijkingen werden vaak gezien (25%) en het maken van een onderscheid tussen goedaardige en kwaadaardige afwijkingen blijkt heel lastig. Slechts een klein deel van de indifferente afwijkingen bleek kwaadaardig (16%). Stadiëren met een CT van de thorax resulteerde niet in een verandering van het behandelplan van de primaire tumor en heeft niet geleid tot meer curatieve behandelingen. Wel gaf het aanleiding tot diagnostische dilemma’s, veel aanvullend onderzoek en langdurige onzekerheid. Stadiëring van de longen was het meest relevant bij patiënten met metastasen elders die in aanmerking kwamen voor curatieve behandeling hiervan. Het beperken van een CT van de thorax tot deze doelgroep resulteert al in een aanzienlijk besparing van kosten. Echter blijven ook in deze patiëntengroep dezelfde problememen met indifferente afwijkingen bestaan. Concluderend werd het stadiëren van de thorax met een CT scan niet geadviseerd als een routine procedure.
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Follow-up De nationale enquete over de follow-up liet zien dat een verbetering van follow-up gebaseerd op wetenschappelijk bewijs gewenst is en er voldoende draagvlak is voor een landelijke studie (hoofdstuk 4). Deze uitkomst heeft geleid tot een uitgebreide literatuurstudie met als doel indien, en waar mogelijk, een nieuwe follow-up strategie te ontwerpen (hoofdstuk 5 en 6). Follow-up en daarmee ook het CEA, lijkt niet veel effect te hebben op de overleving, zoals werd geconcludeerd in 5 meta-analyses. Wanneer er geen bewijs is, kunnen veronderstellingen al snel verworden tot feiten. Een voorbeeld van zo’n veelgehoord ‘feit’, is dat als er een normale CEA waarde is voorafgaand aan resectie van de primaire tumor, het CEA ook niet zal stijgen wanneer de ziekte terug komt. Dit bleek onjuist (hoofdstuk 5). De uitgebreide literatuurstudie over het CEA in de follow-up over een periode van 30 jaar (hoofdstuk 5), toonde aan dat eerdere studies wel lieten zien dat follow-up op zichzelf een minimaal effect had, maar niet dat de toegevoegde waarde van het CEA als een effectieve tumormarker kon worden verworpen. Integendeel zelfs; het CEA was de enige diagnostische methode in follow-up studies met een aangetoond positief effect op de overleving, ook al waren de gemeten effecten klein. De aanvankelijke belofte van het CEA als tumormarker zijn -ten onrechte- langdurig ondermijnd door slecht opgezette en te kleine studies in het verleden. Onze conclusie was dat een herevaluatie van het potentieel van serum CEA bepalingen in de follow-up de moeite waard is (hoofdstuk 5). In de tijd dat het serum CEA werd ontdekt als een tumor marker bij gastro-intestinale maligniteiten en de klinische toepassing werd ontwikkeld (Staab, 1978-1982), werd beredeneerd dat een tweemaandelijkse bepaling en een dynamische afkapwaarde de meest optimale accuratesse bewerkstelligen. Deze hypothese werd heroverwogen door de onderliggende bewijzen te analyseren. In de eerste plaats hebben we gekeken naar de voorspellende waarde van een dynamische afkapwaarde van het serum CEA voor recidief ziekte in de follow-up. De klinisch optimale afkapwaarde is afhankelijk van de gewenste sensitiviteit en specificteit in de beoogde populatie. De sensitiviteit moet hoog zijn om recidief ziekte adequaat te kunnen ontdekken. De specificiteit moet hoog zijn, om onnodig aanvullende onderzoek te voorkomen wanneer de test wordt gebruikt als een screenings methode. In follow-up, wat een screening in een hoog risico populatie in houdt, zijn beide nodig. De analyse liet zien dat het serum CEA de laagste accuratesse heeft in het gebied van 2.5 tot 10 ng/ml (sensitiviteit 70-90%, specificiteit 30-65%). Dit wordt grotendeels veroorzaakt door de overlap van verhoogd serum CEA waarden door inflammatoire aandoeningen en roken in dit meetgebied. Tegelijkertijd is dit het geprefereerde meetgebied om recidief ziekte te ontdekken, met het oog op de kans een genezende behandeling te kunnen bieden. Een dynamische afkwapwaarde kan de verstoring in dit meetgebied sterk verminderen. Het verschil tussen maligniteiten en inflammatoire aandoeningen is dat maligniteiten blijven groeien waar ontstekingen meestal weer vanzelf overgaan. De aanzienlijke inter-individuele variatie (55%) kan (deels) worden gecorrigeerd door de gebruikte afkapwaarde te verhogen (normaal 2.0-2.5 ng/ml) naar 5 ng/ml, zoals dat tegenwoordig gebruikelijk is. Het nadeel van deze benadering is dat de sensitiviteit daardoor lager wordt. Het alternatief om de intra-individuele stijging te beoordelen, elimineert de interindividuele variatie volledig en toont daarbij ook het potentiële onderscheidende stijgingspatroon. Deze benadering vereist frequente metingen. Een dynamische
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afkapwaarde werd slechts in één prospectieve cohort studie toegepast (Staab, 1985), maar is nooit getest in een vergelijkende of gerandomiseerde studie. De voorspellende capaciteit van de CEA stijging werd wel geëvalueerd; al deze studies lieten zien dat de stijging van CEA een veel betere indicator is van recidief ziekte dan de hoogte van het CEA. Deze bevindingen ondersteunen de originele hypothese, die in een gereviseerde versie -rekening houdend met de huidige klinische context-, de basis is geworden van een nieuw follow-up ontwerp. Deze gereviseerde benadering is ‘high-frequency dynamic threshold’ (HiDT) [hoge frequentie dynamische afkapwaarde] serum CEA bepalingen genoemd. Deze hernieuwde poging na verscheidene voorafgaande mislukkingen om de effectiviteit van de oncologische follow-up te verbeteren, ontmoette veel skeptische reacties. Niettemin bestonden er ook andere redenen om een nieuwe poging te doen de follow-up gericht op de detectie van recidief ziekte te verbeteren; in de aanzienlijke verbeteringen in de behandeling van gemetastaseerde ziekte, in de snelle technische vooruitgang van de beeldvormende technieken die non-invasieve localisatie van recidief ziekte mogelijk maken en in de mogelijkheden van geautomatiseerde ondersteuning. In 2008 werd een prospectieve cohort studie gestart gericht op de haalbaarheid van het protocol, waarin 241 patienten werden geincludeerd in twee centra (UMCG en MST). Tot nu toe zijn 28 patiënten gediagnosticeerd met recidief ziekte (12%). De sensitiviteit van HiDT serum CEA bepalingen in het meetgebied van 2.5-10 ng/ml was 79% en de specificiteit 88%. De uitkomsten wat betreft de mogelijkheid tot een genezende behandeling in de interim analyse was 43%. De studie toonde aan dat het protocol uitvoerbaar is en ondersteunt de hypothese op de onderliggende theoretische gronden. Een belangrijk deel van deze fase II studie was het analyseren van de psychologische effecten van het nieuwe follow-up ontwerp (hoofdstuk 7). Om frequente serum CEA bepalingen mogelijk te maken zonder een onwerkbare overbelasting van de polikliniek te veroorzaken, werden de maandelijkse CEA bepalingen middels brieven of, bij een relevante stijging, middels telefonisch contact met de patient gecommuniceerd. Het aantal geplande polikliniek bezoeken was daarbij minder dan momenteel gebruikelijk. Uit deze studie werd duidelijk dat het protocol niet alleen goed uitvoerbaar was (geen verschil in depressie -, angst en kanker zorgen uitkomsten, en een hogere tevredenheid in de interventiegroep), het werd zelfs geprefereerd door de patiënten boven direct contact met de arts. De emotionele aspecten van follow-up in gedachten nemend, was deze uitkomst onverwacht vanuit het oogpunt van de medische stand. De uitkomsten van de fase II studie wat betreft de eerste inschattingen op mogelijkheden tot een in opzet genezende behandeling, de uitvoerbaarheid van het protocol wat betreft de computer ondersteuning en de psychologische effecten, hebben geresulteerd in een aankomende nationale gerandomiseerde fase III studie. Follow-up op maat (hoofdstuk 8) De incidentie van recidief ziekte binnen één jaar na genezende behandeling van niet-gemetastaseerde ziekte, mits patiënten voor de behandeling goed waren gestadieerd, bleek laag (6%). Vroege recidieven waren beperkt tot de groep patiënten met locaal uitgebreide primaire tumoren; in deze geselecteerde populatie was de incidentie van recidief ziekte 17%. Het T-stadium bleek de belangrijkste risicofactor voor een vroeg recidief. Bij locaal beperkte ziekte kan de follow-up veilig
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worden gereduceerd tot de begeleiding ten aanzien van functionele uitkomsten en psychologische ondersteuning, aangepast aan de behoefte van de patiënt. Deze uitkomst stelt de huidige nadruk van de oncologische controle in het eerste jaar, zoals gerapporteerd werd in de enquete (hoofdstuk 4), ter discussie. Deze studie was een eerste stap in het beschrijven van hedendaagse recidiefpatronen en de relevantie hiervan in het verbeteren van de effectiviteit en efficiëntie van toekomstige op maat gemaakte follow-up.
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Heelkunde Nodal metastases and biomarkers in melanoma Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. E. Sterken, in het openbaar te verdedigen op maandag 12 december 2011 om 12.45 uur door Schelto Kruijff geboren op 18 mei 1977 te Rijpwetering
Promotoren: Prof. dr. H.J. Hoekstra Co-promotor: Dr. J.M. Klaase Beoordelingscommissie: Prof. dr. E. Heineman Prof. dr. I.H.M. Borel rinkes Prof. dr. G.A.P. Hospers
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Samenvatting Melanoma causes more than 75% of all deaths related to skin cancer and melanoma incidence rates have increased rapidly worldwide and are expected to keep on rising in the future. The absolute total number of new cases in the Netherlands is estimated to be well over 4800 in 2015.1 Despite being diagnosed in an earlier phase of disease as a result of increased awareness and better surveillance, melanoma patients presenting with palpable nodal metastases today still have a poor 5-year survival (59% and 40% for stage IIIB and IIIC respectively) but a tremendous heterogeneity in 5-year survival rates is observed (23%-87% 5year survival).2,3 Biomarkers measured preoperatively in stage III melanoma patients could both be highly specific indicators of early recurrence after surgical treatment and could optimize and refine the staging of melanoma patients with palpable nodes.4 In this thesis the main focus on stage III melanoma and how to identify stage III melanoma patients who may benefit from adjuvant systematic treatment with the aid of biomarkers as S-100B (fig.1) and FDG- SUV in order to improve, in the long run, survival.
Figure 1 : Structure of the protein S-100B Part I : Detection and treatment of nodal melanoma metastases In chapter two the role of the method of detection in nodal disease in the prognosis of melanoma patients who underwent therapeutic lymph node dissection (TLND) was evaluated. International consensus on the follow-up of melanoma patients has
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not been achieved and high-frequency follow-up still practiced in many countries around the world. It was found that the method of detection of lymph node recurrence in melanoma patients by patient or physician has no impact on survival. 45 % of lymph node metastases in Stage I-II melanoma patients are physician detected. Younger patients detect their own lymph node metastases significantly more often than elderly patients. However, neither the method of detection nor age correlates with DSS. More frequent follow-up would not alter DFS and DSS significantly. The data of this study will ad to the controversy about the value of high frequency follow-up regimens in melanoma. A prospective, randomized, high quality methodological research has been started in order to develop meaningful applicable guidelines (MELFO).In the third chapter we conducted an extensive retrospective study to assess the present morbidity of therapeutic or completion lymph node dissection to determine risk factors for short term morbidity and to evaluate recommendations on peri-operative treatment. Therapeutic groin dissection for melanoma remains a surgical procedure with a high morbidity. Presently, more complications occur after therapeutic ilio-inguinal lymph node dissection than 20 years ago. Analysing our data it was found that a high BMI was significantly correlated with the occurrence of wound infections. Bed rest and flexion of the hip and knee in flexion using a Bohler splint (fig. 2) improved wound healing after therapeutic ilio-inguinal lymph node dissection.
Figure 2: Bed rest and flexion of the hip and knee in flexion using a Bohler splint Part II : Prognostic markers in melanoma When compared with other markers and tumor characteristics as ulceration, Clark level and Mitosis index , Breslow thickness is the most important biomarker and predictor for mortality. In chapter four, patients diagnosed with invasive melanoma between 1994 and 2008 were selected from the Netherlands Cancer Registry (NCR). Incidence (per 100 000) over time was calculated for young (<65 years) and elderly patients (≥65 years). Distribution of Breslow thickness for young and elderly males and females was assessed. Regression analysis of the log-transformed Breslow thickness was used to assess changes over time. Relative survival was calculated as the ratio of observed survival to expected survival. We found that melanoma incidence increased more rapidly among the elderly (5·4% Estimated Annual Percent Change (EAPC), p <0,0001) than among younger patients (3·9% EAPC, p <0,0001) (fig. 3) and the overall Breslow thickness declined significantly over time (p<0·001).However, the decline in Breslow thickness is less prominent among elderly patients than among young patients with a relative survival
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of elderly patients that was worse compared with that of younger patients (p<0·001). Campaigns in the Netherlands must focus more on early melanoma detection in the elderly. 400
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Figure 3 Incidence of invasive melanoma among young and elderly patients Up to today the role of S-100B for patients with palpable lymph node metastases before undergoing therapeutic lymph node dissection was still unknown. In chapter five the role of S-100B for disease-free survival (DFS) was evaluated and compared with the tumor marker LDH. Ppreoperative S-100B elevation in patients with optimally staged clinical stage III melanoma was correlated with shortened diseasefree survival (fig.4). The new serum tumour marker S-100B has the potential to identify stage III melanoma patients who may benefit from adjuvant systematic treatment. In the stratification of new adjuvant therapeutic trials in patients with loco regional recurrence stage III melanoma, we would recommend the incorporation of S-100B in the stratification instead of the more commonly used LDH tumour marker. Preoperative S-100B levels provide information for stage III melanoma patients who want to be optimal informed with respect to their disease prognosis. In chapter six S-100B values and Standardized Uptake Value (SUV) in FDG-PET for clinically stage III melanoma patients were analysed as indicators of early recurrence in stage III disease. S-100B and SUV in stage III melanoma seemed to have no correlation and both markers have different associations with various histopathological factors. However as also was conclude in chapter five, S-100B, in contrast with SUV, is associated with nodal tumor load, and when elevated, predicts a shorter DFS.
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Figure 4 : Disease specific survival(DSS) correlated to S-100B in AJCC stadium IIIB. In chapter seven to investigate the feasibility of using bevacizumab to improve the survival of AJCC stage III melanoma patients, we analyzed how a single bevacizumab treatment affected nodal disease and a panel of biomarkers in clinically FDG-PET/CT staged, stage III melanoma patients, prior to therapeutic lymph node dissection (TLND). Four weeks before TLND, nine patients with palpable lymph node metastases received 7.5 mg/kg bevacizumab. Before and after this treatment, all patients were assessed by measurements of the maximum standardized uptake value (SUVmax) by FDG-PET scan, and serum S-100B and LDH. After TLND, the dissection specimen was analyzed for the number of removed lymph nodes, the amount of metastatic lymph nodes, and tumor necrosis. Tumor necrosis in dissection specimens was associated with declining S-100B levels, while elevated S-100B was only found in cases with no necrosis. Bevacizumab might be useful in treating AJCC stage III melanoma patients prior to TLND, and S100-B appears to be a useful marker for assessment of treatment effects. Future research, preferably in a randomized controlled trial using serum S-100B for response monitoring, should determine the effect of (neoadjuvant) Bevacizumab, and adjuvant Ipilimumab and/or BRAF pathway inhibitors as a new combined treatment strategy of systemic treatment with TLND to improve disease free and overall survival in clinically stage III melanoma patients. The current status of S-100B in treatment of melanoma is described in chapter eight. A review was composed describing the role of S-100B for the different tumor stages in melanoma and how the protein could be used by a practicing surgical oncologist. S-100B was already known as a marker in stage IV palliative melanoma treatment, however in the future it could be used for high risk stage III melanoma to perform better staging. S-100B can be used to perform a individualized risk assessment before administering adjuvant treatment on the one hand and on the other hand to 24
measure response to induction therapy for nodal disease.4,5Despite these described prognostic values, S-100B is not suitable for routine screening purposes in stage I– III melanoma patients or or for the early detection of recurrence in the follow-up of melanoma patients; that is, early detection of recurrences in follow-up as the results of these measurements do not yet translate into an adequate therapeutic intervention nor survival benefit due to limited treatment options in advanced melanoma. However, maybe, since an effective (adjuvant) therapy for loco-regional metastatic and disseminated melanoma seems to be discovered, the routine use of biomarkers as S-100B seems about to alter dramatically in the future.6-9 References 1. de Vries E, van de Poll-Franse LV, Louwman WJ et al. Predictions of skin cancer incidence in the Netherlands up to 2015. Br J Dermatol 2005; 152:481488. 2. Balch CM, Greshenwald JE, Soong SJ et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27:6199-206. 3. Balch CM, Gershenwald JE, Soong S et al. Multivariate Analysis of Prognostic Factors Among 2,313 Patients With Stage III Melanoma: Comparison of Nodal Micrometastases Versus Macrometastases. J Clin Oncol. 2010;28:2452-9. 4. Kruijff S, Bastiaannet E, Muller-Kobold AC et al. S-100B concentrations predict disease-free survival in stage III melanoma patients. Ann Surg Oncol 2009;16:3455-62. 5. S. Kruijff, E Bastiaannet, A.H. Brouwers, et al. The use of S-100B to evaluate therapy effects during bevacizumab induction treatment in AJCC stage III melanoma. Ann Surg Oncol. 2011; accepted for publication. 6. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. New Engl J Med. 2010;363:711-23. a. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809-19. 7. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-16. 8. Garbe C, Peris K, Hauschild A, et al. Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline. Eur. J. Cancer 2010: 46:270-283.
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Klinische farmacie Risk management of biologicals: A regulatory and clinical perspective Risico management van biologicals vanuit een regulatoir en een klinisch perspectief Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. J.C. Stoof, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen maandag 21 maart 2011 des middags te 2.30 uur
door Thijs Jan Giezen geboren op 15 juni 1982 te Rotterdam Promotoren: Prof. dr. H.G.M. Leufkens Prof. dr. A.C.G. Egberts Co-promotor: Dr. A.K. Mantel-Teeuwisse Dr. S.M.J.M. Straus
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Samenvatting Biologicals worden door de European Medicines Agency (EMA), het Europese geneesmiddelenbureau, gedefinieerd als producten waarbij een (gedeelte van een) organisme wordt gebruikt voor de productie van het uiteindelijke geneesmiddel. Dit betekent dat geneesmiddelen die geëxtraheerd worden uit menselijk of dierlijk materiaal tot de biologicals worden gerekend. Een voorbeeld hiervan zijn stollingsfactoren die geëxtraheerd worden uit humaan plasma. De meeste biologicals worden echter geproduceerd met behulp van recombinant DNA technologieën. Hiervoor worden cellijnen gebruikt van bijvoorbeeld hamsters of gisten die gemodificeerd zijn en daardoor in staat zijn tot de productie van bepaalde eiwitten. Een bekend biological is insuline dat al vele jaren wordt gebruikt voor de behandeling van diabetes mellitus. In de jaren twintig van de vorige eeuw werd insuline voor het eerst geëxtraheerd vanuit de alvleesklier van varkens. Sinds de introductie van de recombinant DNA technologieën in de jaren tachtig van de vorige eeuw wordt insuline op grote schaal geproduceerd met behulp van deze techniek. Naast insuline is er momenteel een groot aantal geneesmiddelen beschikbaar die tot de biologicals behoren. Biologicals nemen op dit moment onder andere een belangrijke plaats in bij de behandeling van patiënten met kanker en autoimmuunziekten. In vergelijking met de traditionele, chemisch gesynthetiseerde geneesmiddelen, zoals bijvoorbeeld paracetamol, hebben biologicals specifieke karakteristieken die van invloed kunnen zijn op hun veiligheid. Waar de chemisch gesynthetiseerde geneesmiddelen vaak een relatief eenvoudig productieproces hebben, hebben biologicals vaak een zeer complex productieproces. Daarnaast hebben biologicals een groot risico voor immunogeniciteit. Immunogeniciteit houdt in dat er antilichamen worden geproduceerd als reactie op de toediening van een biological. Het biological kan verschillen van het humaan aanwezige eiwit waardoor het lichaam het toegediende biological als lichaamsvreemd beschouwt en een immuunreactie op gang brengt. In veel gevallen is de vorming van antilichamen niet klinisch relevant. De antilichamen kunnen het effect van het toegediende biological echter neutraliseren waardoor de effectiviteit afneemt. Er zijn gevallen beschreven waar de vorming van antilichamen tot ernstige veiligheidsproblemen hebben geleid. De voorspelbaarheid van preklinische onderzoeken (dierstudies) voor de klinische praktijk is tevens beperkt voor biologicals. Bepaalde biologicals gedragen zich namelijk anders bij de verschillende organismen en dieren vormen vaak antilichamen aangezien een menselijk eiwit als lichaamsvreemd wordt beschouwd. Bijwerkingen van biologicals kunnen tenslotte vaak worden gerelateerd aan een versterkt farmacologisch effect. Het is bekend dat onderzoeken uitgevoerd voor de registratie van een geneesmiddel bepaalde beperkingen hebben ten aanzien van het identificeren van (zeldzame) bijwerkingen. Deze beperkingen bestaan onder andere uit een relatief kleine groep patiënten die bovendien streng geselecteerd is. Gegevens over bijwerkingen geïdentificeerd na registratie van een geneesmiddel vormt daardoor een belangrijke aanvulling op de informatie zoals verzameld tijdens de onderzoeken uitgevoerd voor registratie. De farmacovigilantie (geneesmiddelenbewaking) is de wetenschap die zich hiermee bezig houdt. Farmacovigilantie wordt gedefinieerd als de wetenschap die zich bezighoudt met de detectie, beoordeling en preventie van bijwerkingen van
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geneesmiddelen nadat deze zijn toegelaten tot de markt. De methodes die worden gebruikt voor de detectie van bijwerkingen kunnen grofweg in twee methoden worden onderverdeeld: 1) afwachtend, gebaseerd op de verzameling van bijwerkingen die spontaan gemeld worden door artsen, apothekers en patiënten en 2) de meer proactieve benadering waarbij specifieke onderzoeken worden opgezet voor de identificatie en kwantificering van bijwerkingen. De proactieve benadering is in de Europese Unie (EU) in 2005 geïmplementeerd met de verplichte indiening van een zogenaamd EU-Risk Management Plan (EU-RMP) voor de registratieaanvraag van nieuwe geneesmiddelen, inclusief biologicals. In het EU-RMP worden onder andere aanvullende activiteiten beschreven om het bijwerkingenprofiel verder in kaart te brengen op het moment dat het geneesmiddel op de markt komt. Naast het verzamelen van spontane meldingen van bijwerkingen kunnen aanvullende activiteiten bestaan uit epidemiologische onderzoeken (zogenaamde postauthorisation safety studies [PASS]) waarbij een groep patiënten wordt gevolgd in de tijd en bijwerkingen worden verzameld. Echter, zoals eerder beschreven verschillen biologicals van de chemisch gesynthetiseerde geneesmiddelen en deze verschillen kunnen ook tot uitdrukking komen in de farmacovigilantie van deze producten. In dit proefschrift is de farmacovigilantie van de biologicals bestudeerd vanuit een regulatoir en een klinisch perspectief. Regulatoire activiteiten in het beheersen van risico’s van biologicals In hoofdstuk 2 zijn drie onderzoeken gepresenteerd. Deze onderzoeken richtten zich op de regulatoire activiteiten in de beheersing van de risico’s van biologicals. Zoals reeds beschreven in de introductie dienen farmaceutische bedrijven een EU-RMP in te dienen als onderdeel van de registratieaanvraag van onder andere biologicals. In hoofdstuk 2.1 hebben we de activiteiten bestudeerd die zijn voorgesteld door farmaceutische bedrijven om het veiligheidsprofiel na registratie verder in kaart te brengen en is de methode die is gebruikt voor PASS bestudeerd. Daarnaast zijn problemen met PASS geïdentificeerd en zijn voorstellen gedaan om de geïdentificeerde problemen te verbeteren. Binnen dit onderzoek zijn de karakteristieken van biologicals en chemisch gesynthetiseerde geneesmiddelen vergeleken. In totaal zijn achttien EU-RMPs (9 voor biologicals en 9 voor chemisch gesynthetiseerde geneesmiddelen) bestudeerd. De EU-RMPs waren van producten die goedgekeurd waren door het wetenschappelijk comité voor geneesmiddelen voor humaan gebruik (CHMP) tussen november 2005 en mei 2007. Binnen het EURMP worden mogelijke veiligheidsproblemen geclassificeerd als a) belangrijk geïdentificeerd risico (er is een causaal verband tussen het veiligheidsprobleem en het geneesmiddel), b) belangrijk potentieel risico (er bestaat potentieel een veiligheidsprobleem op basis van bijvoorbeeld het werkingsmechanisme van het geneesmiddel) en c) belangrijke informatie die ontbreekt en het veiligheidsprofiel van het geneesmiddel kan beïnvloeden. De classificatie van de mogelijke veiligheidsproblemen geeft inzicht in de kennis van het veiligheidsprofiel op een bepaald moment in de tijd. Een vergelijking van de classificatie van de mogelijke veiligheidsproblemen liet zien dat veiligheidsproblemen voor biologicals minder frequent geclassificeerd waren als belangrijk geïdentificeerd risico (relatief risico [RR] 0.6; 95% betrouwbaarheidsinterval [95% BI] 0.3-1.0) en vaker als belangrijke informatie die ontbrak (RR 1.6; 95% BI 1.0-2.7) in vergelijking met de chemisch
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gesynthetiseerde geneesmiddelen. Voor PASS zijn verschillende karakteristieken bestudeerd: de database gebruikt voor de onderzoeken (registers [waarbij patiënten met een bepaalde ziekte en/-of behandeling wordt geïncludeerd], populatie gebaseerde database [waarbij patiënten in een bepaald gebied automatisch worden geïncludeerd], een database die gegevens van klinisch onderzoek bevat), landen in de wereld van waaruit patiënten zijn geïncludeerd in PASS en volledigheid van het studieprotocol van PASS (volledig studieprotocol, beperkt studieprotocol, studie synopsis, korte beschrijving van het onderzoek, toezegging zonder verdere informatie). In totaal werden 47 PASS beschreven in de 18 EU-RMPs; 31 voor biologicals en 16 voor chemisch gesynthetiseerde geneesmiddelen. PASS voor biologicals werden vaker voorgesteld om te worden uitgevoerd in registers in vergelijking met PASS voor chemisch gesynthetiseerde geneesmiddelen die frequenter werden uitgevoerd in populatie gebaseerde databases. Ongeveer 60% van de PASS includeren inwoners van de EU. In 40% van de PASS worden dus geen inwoners van de EU meegenomen wat kan leiden tot problemen in de generaliseerbaarheid van de resultaten verkregen met deze onderzoeken naar de populatie binnen de EU. De beperkte generaliseerbaarheid kan veroorzaakt worden door verschillen tussen patiënten in verschillende werelddelen, verschillen in goedgekeurde indicaties en verschillen in de gezondheidszorg. Met betrekking tot de studieprotocollen is gevonden dat er geen volledige studieprotocollen zijn ingediend; 26% betrof een beperkt studieprotocol; 33% een synopsis van het onderzoek, 37% een korte beschrijving en 4% een toezegging zonder verdere informatie. Op basis van dit onderzoek is geconcludeerd dat indiening van incomplete studieprotocollen bij de regulatoire autoriteiten een afdoende wetenschappelijke beoordeling stoort. Het indienen van meer volledige studieprotocollen is daarom noodzakelijk. Daarnaast zijn verschillen gezien tussen biologicals en de chemisch gesynthetiseerde geneesmiddelen met betrekking tot de kennis omtrent het veiligheidsprofiel op het moment van registratie en de gebruikte database. Dit benadrukt de noodzaak dat PASS product specifiek moet worden opgezet. Hoofdstuk 2.2 en 2.3 richten zich op het ingrijpen door regulatoire autoriteiten in verband met veiligheid van geneesmiddelen. In deze hoofdstukken is gekeken naar het type bijwerking, de frequentie van ingrijpen door de regulatoire autoriteiten en de tijd tussen goedkeuring van de registratie aanvraag en het ingrijpen door de regulatoire autoriteiten. De volgende maatregelen zijn meegenomen: (1) brieven die gestuurd zijn aan artsen en apothekers in de Verenigde Staten (VS) en de EU, (2) black box warnings in de VS (black box warnings zijn veiligheidswaarschuwingen die bovenaan de bijsluiter worden vermeld in een zwart kader) en (3) terugtrekking van de markt van het geneesmiddel in de VS of de EU als gevolg van één of meerdere bijwerkingen. In hoofdstuk 2.2 zijn alle in de VS en de EU tussen januari 1995 en juni 2007 goedgekeurde biologicals meegenomen. Vaccins, allergenen en producten die voor verdere bewerking en transfusie worden gebruikt zijn geëxcludeerd. Voor het totaal aantal van 174 goedgekeurde biologicals werd er tussen januari 1995 en juni 2008 82 maal ingegrepen door de regulatoire autoriteiten. Dit betrof 41 verschillende biologicals. De kans op een eerste regulatoir ingrijpen was 3 jaar na registratie 14%
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(95% BI 9%-19%) voor biologicals en 10 jaar na registratie 29% (95% BI 20%-37%). Regulatoir ingrijpen was vaker nodig voor biologicals die als eerste zijn goedgekeurd in een Anatomische Therapeutisch Chemische (ATC) subklasse in vergelijking tot biologicals die later zijn goedgekeurd (hazard ratio 3.7; 95% BI 1.5-9.5). Dit onderlijnt de noodzaak dat biologicals die als eerste worden goedgekeurd in een klasse nauwlettend in de gaten moeten worden gehouden na registratie. De veiligheidswaarschuwingen betroffen voornamelijk de categorieën Algemene waarschuwingen en toedieningsplaatsstoornissen, Infecties en parasitaire aandoeningen, Immuunsysteemaandoeningen en Neoplasmata, benigne, maligne en niet gespecificeerd (inclusief cysten en poliepen). Op basis van deze resultaten hebben we geconcludeerd dat veiligheidswaarschuwingen voor biologicals vaak gerelateerd zijn aan het farmacologische werkingsmechanisme (bijvoorbeeld infecties). In het onderzoek beschreven in hoofdstuk 2.3 zijn alle 95 tussen januari 2000 en december 2008 goegekeurde geneesmiddelen voor de behandeling van zeldzame aandoeningen – zogenaamde weesgeneesmiddelen – meegenomen. In totaal was er tussen januari 2000 en juni 2009 16 keer regulatoir ingrijpen nodig voor tien verschillende geneesmiddelen. De kans op een eerste regulatoir ingrijpen was 8 jaar na goedkeuring 20.3%. In dit onderzoek zijn biologicals vergeleken met chemisch gesynthetiseerde geneesmiddelen. Biologicals hebben een niet-significant hoger risico op regulatoir ingrijpen (relatief risico [RR] 1.7; 95% BI 0.5-5.5). Geneesmiddelen goedgekeurd via een versnelde registratie procedure (RR 3.3; 95% BI 1.1-10.4) alsmede geneesmiddelen goedgekeurd voor oncologische indicaties (RR 7.8; 95% BI 1.0-63.8) en voor indicaties gerelateerd aan het maagdarmstelsel en het metabolisme (RR 10.4; 95% BI 1.-87.3) hebben een hoger risico op regulatoir ingrijpen. Op basis van deze gegevens is geconcludeerd dat geneesmiddelen voor zeldzame aandoeningen een lagere kans hadden op regulatoir ingrijpen in vergelijking tot datgene beschreven in de literatuur en in hoofdstuk 2.2 van dit proefschrift. Echter, identificatie van veiligheidsproblemen is waarschijnlijk lastiger voor geneesmiddelen die goedgekeurd zijn voor zeldzame aandoeningen vanwege de zeldzaamheid van de aandoeningen en daarmee samenhangend een beperkt gebruik waardoor zeldzame bijwerkingen minder snel kunnen worden ontdekt. Artsen en apothekers dienen daarom te waken voor veiligheidsproblemen die gerelateerd zijn aan deze groep geneesmiddelen. Evaluatie en classificatie van bijwerkingen van biologicals in de klinische praktijk Hoofdstuk 3 richt zich op spontane meldingen van bijwerkingen van biologicals zoals verzameld gedurende gebruik in de klinische praktijk. Hiervoor is de database van de WHO, VigiBase, gebruikt waarin wereldwijd spontane bijwerkingen van geneesmiddelen worden verzameld. In hoofdstuk 3.1 hebben we getracht het bijwerkingenprofiel van de biologicals in kaart te brengen en dit te vergelijken met het profiel van de chemisch gesynthetiseerde geneesmiddelen. Daarnaast zijn verschillende groepen van biologicals onderling vergeleken. Hiervoor zijn biologicals geclassificeerd op basis van eigenschappen gerelateerd aan hun structuur en/ of werkingsmechanisme.
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Vaccines zijn niet meegenomen in dit onderzoek. Tussen januari 1995 en december 2008 zijn 191.004 rapporten van bijwerkingen gerapporteerd voor 62 biologicals. Dit betrof 546.474 verschillende bijwerkingen. In de referentiegroep (voornamelijk betaande uit chemisch gesynthetiseerde geneesmiddelen) zijn 2.556.209 rapporten van bijwerkingen ontvangen. Dit betrof 8.761.522 verschillende bijwerkingen. Voor de biologicals is gevonden dat 2/3 van alle bijwerkingen gemeld zijn voor slechts vijf actieve bestanddelen: etanercept, interferon- -1a, infliximab, teriparatide en adalimumab. Vergelijking van het bijwerkingenprofiel van de biologicals met de referentiegroep laat zien dat bijwerkingen van biologicals die geïdentificeerd zijn gedurende gebruik in de klinische praktijk voornamelijk gerelateerd waren aan ‘Infecties en parasitaire aandoeningen’ (proportional reporting ratio [PRR] 4.5), ‘Chirurgische en medische verrichtingen’ (PRR 2.4) en en Neoplasmata, benigne, maligne en niet gespecificeerd (inclusief cysten en poliepen) (PRR 2.1). Bijwerkingen van biologicals die geïdentificeerd zijn tijdens gebruik in de klinische praktijk betroffen minder vaak bijwerkingen gerelateerd aan ‘Psychische aandoeningen’ (PRR 0.4), ‘Bloedvataandoeningen’ (PRR 0.4) en ‘Zwangerschap, perinatale periode en puerperium’ (PRR 0.4). Een vergelijking binnen de groep van de biologicals liet zien dat ook binnen de biologicals verschillen bestaan in het bijwerkingenprofiel. Er werd onder andere gevonden dat bijwerkingen gerelateerd aan ‘Infecties en parasitaire aandoeningen’ frequenter gerapporteerd zijn voor antilichamen en receptoren in vergelijking met de hormonen. We hebben geconcludeerd dat er voor de kwantitatieve signaaldetectie zorgvuldig moet worden gekeken naar de referentiegroep aangezien 2/3 van alle meldingen voor de biologicals slechts vijf actieve bestanddelen betrof. Inclusie van deze vijf biologicals in de referentiegroep kan mogelijke associaties ernstig verstoren. Dit onderzoek liet nogmaals zien dat biologicals een ander bijwerkingenprofiel hebben dan de chemisch gesynthetiseerde geneesmiddelen en dat er ook binnen de groep van de biologicals verschillen bestaan. Dit onderzoek liet bijvoorbeeld zien dat infecties frequenter zijn gemeld voor biologicals met een immuunsuppressieve werking. Voorspellen van het bijwerkingenprofiel aan de hand van het werkingsmechanisme is belangrijk voor biologicals. Op basis daarvan kunnen bepaalde bijwerkingen specifiek in de gaten worden gehouden na registratie. Echter, aangezien niet alle bijwerkingen kunnen worden voorspeld blijft spontane rapportage van bijwerkingen noodzakelijk. In hoofdstuk 3.2 is VigiBase gebruikt om een nieuw classificatiesysteem van bijwerkingen specifiek voor drie groepen biologicals – cytokines, antilichamen en fusie-eiwitten – te kwalificeren en te kwantificeren. Traditioneel worden bijwerkingen ingedeeld in type A ( bijwerkingen gerelateerd aan het werkingsmechanisme en bijwerkingen die dosisafhankelijk zijn) en type B (zeldzame, niet voorspelbare bijwerkingen zoals bijvoorbeeld immuunreacties) bijwerkingen. Aan de toepasbaarheid van dit classificatiesysteem voor biologicals wordt getwijfeld aangezien immuunreacties, bijvoorbeeld, gerelateerd kunnen worden aan de karakteristieken van biologicals en daardoor wellicht als type A bijwerking geclassificeerd dienen te worden. In het nieuwe classificatiesysteem voor biologicals worden vijf groepen bijwerkingen onderscheiden: bijwerkingen gerelateerd aan een hoog aantal cytokines en cytokine release syndrome (type α), overgevoeligheidsreacties (type β), bijwerkingen gerelateerd aan het
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immuunsysteem en/ of een disbalans in het cytokine gehalte (type γ), crossreactiviteit met een receptor die zich op een andere plaats in het lichaam bevindt en daar een bijwerking veroorzaakt (type δ) en bijwerkingen die niet gerelateerd zijn aan immunologische reacties (type ε). Binnen VigiBase zijn 17 type β, 21 type γ en 24 type ε bijwerkingen geselecteerd. Er konden slechts twee type α en geen type δ bijwerkingen worden geïdentificeerd. Deze groepen zijn daarom niet meegenomen. Voor elke combinatie van een bijwerking en een biological is een reporting odds ratio (ROR) berekend. Op basis van de RORs zijn clusters van bijwerkingen geïdentificeerd. Deze analyse is gebaseerd op de aanname dat gerelateerde bijwerkingen een vergelijkbaar rapportageprofiel hebben en dientengevolge een vergelijkbare ROR, waardoor deze samen worden geclusterd. Hierdoor kan een combinatie van gerelateerde bijwerkingen worden vastgestelde. De combinatie van bijwerkingen is zinvol in het geval van signaaldetectie. De clusteranalyse resulteerde in zeven clusters; cluster 1 bestond uit 2 β en 22 ε bijwerkingen, cluster 2 bevatte 1 β, 13 γ en 2 ε bijwerkingen, cluster 3 bevatte 2 β en 4 γ bijwerkingen, cluster 4 bevatte 3 γ bijwerkingen en clusters 5, 6, en 7 bestonden respectievelijk uit 5, 2 en 4 type β bijwerkingen. Naast de clusteranalyse is de relatie tussen bijwerkingen ook kwantitatief bepaald. Hiervoor is voor elke combinatie van twee bijwerkingen een waarde uitgerekend die een maat is voor de (on)gelijkheid van de bijwerkingen. Op basis van deze berekeningen hebben we bijvoorbeeld laten zien dat de immunologische bijwerkingen geclassificeerd als type β en γ bijwerkingen onderling een meer vergelijkbaar rapportageprofiel hebben dan de type ε bijwerkingen die alle niet-immunologische bijwerkingen omvatten. Daarnaast hebben binnen de type β bijwerkingen, reacties die samenhangen met hetzelfde stadium van de overgevoeligheidsreactie (type I en type IV overgevoeligheidsreacties) een vergelijkbaar rapportageprofiel. Op basis van deze resultaten is geconcludeerd dat het voorgestelde classificatiesysteem voor bijwerkingen van biologicals in staat is te differentiëren tussen de immunologische type β en γ bijwerkingen en de nietimmunologische type ε bijwerkingen. Binnen de type β bijwerkingen toonden gerelateerde bijwerkingen op basis van het stadium van de overgevoeligheidsreacties een vergelijkbaar rapportageprofiel. Beheersing van risico’s van biologicals in de klinische praktijk: het voorbeeld van rituximab De onderzoeken beschreven in hoofdstuk 4 richten zich op het identificeren van risicofactoren en markers waarmee patiënten met een verhoogd risico op een bepaalde bijwerking in een vroeg stadium kunnen worden geïdentificeerd. In de onderzoeken beschreven in dit hoofdstuk wordt gebruik gemaakt van een groep patiënten die behandeld zijn met rituximab. Gebruikers van rituximab zijn geïdentificeerd in de Utrecht Patient Oriented Database (UPOD). UPOD is tot stand gekomen door het koppelen van databases waardoor complete informatie beschikbaar is met betrekking tot patiëntkarakteristieken, diagnoses, medicatiegebruik en laboratoriumgegevens. UPOD omvat deze data voor alle patiënten die behandeld zijn in het Universitair Medisch Centrum Utrecht sinds 2004. In hoofdstuk 4.1 hebben we een onderzoek gepresenteerd waarin we de incidentie en risicofactoren hebben bestudeerd voor het optreden van invasieve Aspergillose
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(IA) – een ernstige schimmelinfectie – bij patiënten die behandeld zijn met rituximab tussen 2005 en 2008 voor hematologische maligniteiten. IA is een belangrijke doodsoorzaak in patiënten met maligniteiten. Hoewel een specifieke rol voor rituximab nog niet is aangetoond, suggereren twee patiëntbeschrijvingen en één epidemiologisch onderzoek een rol voor rituximab. Het is bekend dat een vroege diagnose en dientengevolge een vroege behandeling de uitkomst voor de patiënt sterk verbetert. Dit benadrukt het belang van een vroege identificatie van patiënten met een verhoogd risico op IA. In totaal zijn 104 patiënten behandeld met rituximab voor hematologische maligniteiten tussen 2005 en 2008 waarvan zeven zijn gediagnosticeerd met IA (cumulatieve incidentie: 6.7%). Binnen deze groep is een case-control onderzoek uitgevoerd waarin alleen de patiënten die een allogene stamceltransplantatie hadden`ondergaan zijn meegenomen. We hebben gevonden dat patiënten die IA ontwikkelden behandeld waren met een hogere cumulatieve dosis van rituximab (<1500 mg versus 1500 mg; odds ratio [OR] 25.5; 95% BI 2.4275.7) en dat deze patiënten frequenter waren gediagnosticeerd met andere schimmelinfecties in de 30 dagen voor de diagnose IA (OR 15.0; 95% BI 1.2-183.6). Op basis van deze data hebben we geconcludeerd dat de cumulatieve incidenctie in deze groep rituximabgebruikers vergelijkbaar is met de incidenties zoals gevonden in andere onderzoeken waarin patiënten met hematologische maligniteiten zijn bestudeerd. Patiënten die behandeld zijn met een hogere cumulatieve dosis rituximab alsmede patiënten die gediagnosticeerd zijn met schimmelinfecties in de 30 dagen voor de diagnose IA hebben een verhoogd risico op het ontwikkelen van IA. In hoofdstuk 4.2 hebben we de incidentie van rituximab-geïnduceerde trombocytopenie – te lage hoeveelheid bloedplaatjes – bestudeerd alsmede risicofactoren en bloedwaarden die kunnen worden gebruikt voor een vroege identificatie van patiënten met een verhoogd risico op trombocytopenie. Trombocytopenie is een bekende bijwerking van rituximab maar informatie met betrekking tot incidentie, risicofactoren en hematologische markers is beperkt. Negentig patiënten die behandeld zijn met rituximab tussen 2005 en 2009 zijn meegenomen in dit onderzoek waarvan 27 patiënten trombocytopenie ontwikkelden (cumulatieve incidentie: 30%) binnen 30 dagen na toediening van de rituximab en 18 patiënten graad 3/4 trombocytopenie ontwikkelden. Patiënten met trombocytopenie zijn vergeleken met patiënten die geen trombocytopenie ontwikkelden. In deze analyse is een relatief laag aantal bloedplaatjes voor toediening van rituximab (217.5 versus 324.4x109 bloedplaatjes/L; p=0.011) geïdentificeerd als risicofactor voor trombocytopenie. Daarnaast zijn behandeling met rituximab voor maligniteiten in vergelijking met behandeling voor autoimmuunziekten (OR 4.7; 95% BI: 1.0-23.3) en een grotere spreiding in het volume van de trombocyten voor toediening van rituximab (16.1 versus 15.8; p=0.051) geïdentificeerd als risicofactoren voor trombocytopenie. Daarnaast zagen wij dat patiënten die trombocytopenie ontwikkelden een lager aantal trombocyten hadden in de week voor dat de diagnose trombocytopenie werd gesteld in vergelijking tot patiënten die geen trombocytopenie ontwikkelden. We hebben geconcludeerd dat trombocytopenie in de klinische praktijk vaker voorkomt dan in klinische onderzoeken die uitgevoerd zijn voor registratie van rituximab. Artsen en apothekers dienen derhalve rekening te houden met trombocytopenie als een relevante
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bijwerking na toediening van rituximab. Frequentere meting van het aantal trombocyten wordt aangeraden voor patiënten die behandeld worden met rituximab voor maligniteiten en/ of patiënten met een relatief laag aantal trombocyten voor toediening van rituximab. Discussie In hoofdstuk 6 zijn vier onderwerpen besproken in relatie tot de farmacovigilantie en farmacoepidemiologie van biologicals. Daarnaast worden aanbevelingen gedaan voor de regulatoire en klinische praktijk. Concluderend, we hebben ons in dit proefschrift gericht op de farmacovigilantie van biologicals met een sterke focus op de regulatoire en klinische praktijk. Kennis omtrent het bijwerkingenprofiel en de karakteristieken van de biologicals is belangrijk in beheersing van de risico’s in de regulatoire en klinische praktijk. In het regulatoire veld verschuift de insteek meer en meer van een afwachtende naar een proactieve aanpak. Het werkingsmechanisme van een nieuw biological en de daarmee samenhangende verwachte bijwerkingen dienen nauwkeurig te worden beoordeeld voor registratie en dienen na registratie nauwlettend in de gaten te worden gehouden. In de klinische praktijk wordt verwacht dat informatie met betrekking tot de bijwerkingen van biologicals en kennis omtrent patiënten met een verhoogd risico voor een bepaalde bijwerking zal leiden tot een veiliger gebruik van geneesmiddelen en dientengevolge een afname van het risico van een bijwerking voor de patiënt.
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Neurologie Circadian Rhythmicity and Epilepsy: the Significance of Chronobiological Time Proefschrift
ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. L.M. Bouter, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de faculteit der Geneeskunde op vrijdag 4 maart 2011 om 11.45 uur in de aula van de universiteit, De Boelelaan 1105 door
Wytske Ætske Hofstra geboren te Bedum
Promotor: prof.dr. C.J. Stam Co-promotor: dr. A.W. de Weerd
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Samenvatting Circadiane Ritmiek en Epilepsie: het Belang van Chronobiologische Tijd In de studies beschreven in dit proefschrift hebben we de interactie tussen circadiane ritmiek en epilepsie onderzocht. Circadiane ritmen zijn endogeen bepaalde cycli van ongeveer 24 uur. Deze cycli worden in veel fysiologische en psychologische ritmen gevonden, zoals slaap-waak ritme, kernlichaamstemperatuur, bloeddruk, het uitvoeren van taken en hormoonproductie. Circadiane ritmen worden in zoogdieren gegenereerd en onderhouden door een biologische klok waarvan het hoofdbestanddeel wordt gevormd door cellen in de suprachiasmatische kernen of nuclei (SCN). Naast de SCN worden er ook perifere circadiane oscillatoren in het menselijk lichaam gevonden, die min of meer onafhankelijk van de SCN werken. Deze oscillatoren zijn onder andere aangetoond in de lever, skeletspieren en testis en staan allemaal onder invloed van de SCN (Lamont et al., 2007). Om het circadiane systeem gelijk te laten lopen aan de 24-uurs dag, moeten de SCN zich elke dag aanpassen of ‘resetten’. Dit wordt ‘entrainment’ genoemd en wordt bereikt door externe aanwijzingen, die ook wel Zeitgebers (“tijdgevers”) worden genoemd. Zeitgebers zijn bijvoorbeeld geplande slaap, activiteiten en temperatuur. Verreweg de belangrijkste Zeitgeber is de licht-donkercyclus door de zon (Duffy and Wright, Jr., 2005). Er zijn diverse genen ontdekt die, tenminste deels, verantwoordelijk zijn voor de karakteristieke activiteit van de individuele SCN en de verschillen tussen individuen. De activiteit hangt af van de expressie van zelf-regulatoire translatie-transcriptie feedback loops van genen zoals de Period genes (Per1, Per2, Per3), het Clock gen en twee Cryptochrome genen (Cry1, Cry2). In verschillende dierstudies is aangetoond dat deletie of mutatie in deze genen tot ritmen met abnormale perioden leidt of zelfs tot aritmische fenotypen, als je de diermodellen onder constante condities test. Bovendien wordt gedacht dat dysfunctie van deze genen een belangrijke rol speelt in de ontwikkeling van verschillende ziekten, waaronder kanker (Lamont et al., 2007). De onderzoeken in dit proefschrift hebben zich gericht op de interactie tussen circadiane ritmiek en epilepsie. Epilepsie is een veelvoorkomende neurologische aandoening. Bij een epileptische aanval raakt het normale activatiepatroon van neuronen verstoord. Hierdoor kunnen aanvallen ontstaan met vreemde sensaties, emoties, spierverkramping en/ of verlaging van het bewustzijn. Volgens de Wereld Gezondheids Organisatie (World Health Organisation, WHO) is epilepsie de meest voorkomende ernstige hersenaandoening wereldwijd met vandaag de dag 40 tot 50 miljoen patiënten. Geschat wordt dat er wereldwijd twee miljoen nieuwe gevallen per jaar bijkomen. In Nederland wordt het aantal epilepsiepatiënten geschat op 121000, dit in vergelijking met bijvoorbeeld 16000 patiënten met multipele sclerose en 26000 patiënten met de ziekte van Parkinson (cijfers uit 2008 (Gommer and Poos, 2010a, b en c)). In hoofdstuk 2 wordt de bestaande kennis over de interactie tussen circadiane ritmiek en epilepsie bij mensen uiteen gezet. Als er inderdaad een relatie is, kan de interactie van belang zijn voor een beter begrip van de pathofysiologie van epilepsie
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en ook voor het tijdstip waarop diagnostiek en behandeling plaatsvinden. Het zou bijvoorbeeld zo kunnen zijn dat het aanpassen van de behandeling aan het individuele circadiane ritme (een voorbeeld van chronotherapie) de controle over aanvallen kan verbeteren. Het lijkt erop dat het voorkomen van epileptische aanvallen bij de mens een 24-uurs ritme volgt, afhankelijk van uit welke hersenkwab de aanval komt. Deze bevindingen worden ondersteund door resultaten van onderzoeken in dieren. Ratten die in continue duisternis geplaatst werden, lieten spontane limbische aanvallen zien, die in een endogeen bepaald circadiaan ritme voorkwamen. Daarnaast zijn er verschillende studies verricht naar de invloed van epilepsie op circadiane ritmen. Significante verschillen in chronotypen werden gevonden tussen twee groepen patiënten met verschillende epilepsiesyndromen. Talloze studies beschrijven de invloed van epilepsie en epileptische aanvallen op de slaap en vice versa. De kennis over kernlichaamstemperatuur en klokgenen in patiënten is echter (nog) minimaal. Wel is er in diverse studies gevonden dat er een verminderde variabiliteit in hartritme (een circadiaan ritme) bestaat in epilepsiepatiënten. Ook kunnen de spiegels van hormonen, die onder invloed staan van de 24-uurs biologische klok, anders zijn bij epilepsiepatiënten. Kortom, er zijn nog steeds grote hiaten in de kennis over de interactie tussen circadiane ritmiek en epilepsie. In hoofdstuk 3 wordt beschreven hoe je circadiane ritmiek kunt meten bij mensen. Er wordt een overzicht gegeven van vaak gebruikte meetmethoden. Zo zijn er bepaalde belangrijke protocollen nodig om circadiane ritmiek in kaart te brengen. Een voorbeeld is een desynchronisatieprotocol waarin circadiane ritmiek en de slaap-waak cyclus uiteen kunnen worden gehaald of een ‘constante routine’protocol, waarin factoren die circadiane ritmiek kunnen beïnvloeden zo minimaal of constant mogelijk worden gehouden. Tevens worden biologische markers besproken, die de fase van het circadiane ritme kunnen bepalen. Voorbeelden hiervan zijn het moment dat de melatoninespiegel toeneemt (bij gedimd licht, in het Engels dim light melatonin onset, DLMO genoemd), de kernlichaamstemperatuur en de cortisolspiegel. Slaapparameters worden ook vaak gebruikt, maar schieten tekort in vergelijking met de hierboven beschreven methoden. Vragenlijsten zijn behulpzaam in het bepalen van chronotypen en slaapparameters. Verder is actigrafie een van de meest gebruikte methoden in dieronderzoek naar circadiane ritmiek. In de mens is het echter niet een kernmethode, maar meer een goede aanvulling. Concluderend is de DLMO de meest robuuste en meest gebruikte methode om het circadiane ritme in mensen in kaart te brengen. Slechts weinig studies hebben het vóórkomen van epileptische aanvallen over de 24-uurs dag geëvalueerd. Met name gegevens over aanvallen bij kinderen zijn schaars. In de studie die in hoofdstuk 4 beschreven wordt, hebben we klinische aanvallen bij 176 patiënten (76 kinderen, 100 volwassenen) geanalyseerd. Deze patiënten waren opgenomen voor continue electro-encefalografie- (EEG) en videoregistratie met een duur van tenminste 22 uur. Verscheidene kenmerken van de aanvallen werden meegenomen in het onderzoek: classificatie, tijdstip, origine en in welk slaapstadium de aanval voorkwam. Aantallen aanvallen werden vergeleken met aantallen die verwacht kunnen worden als aanvallen willekeurig zouden
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plaatsvinden (binomiale test). Er werden meer dan 800 aanvallen geregistreerd. Beduidend meer aanvallen werden geobserveerd tussen 11 en 17 uur en tussen 23 en 5 uur werden significant minder aanvallen gezien dan je zou verwachten als aanvallen willekeurig zouden voorkomen. Pieken in voorkomen midden op de dag (11-17u) werden gezien in alle aanvallen bijeengenomen, maar ook in subgroepen met complex partiële aanvallen (in zowel kinderen als volwassen), aanvallen uit extratemporale gebieden (in kinderen) en aanvallen uit de temporaalkwabben (in volwassenen). Significant minder aanvallen dan verwacht werden geobserveerd tussen 23 en 5 uur bij alle aanvallen bijeengenomen, complex partiële aanvallen (zowel kinderen als volwassen) en bij tonische aanvallen in kinderen. Tevens werden veel minder aanvallen uit de temporaalkwab (in zowel kinderen als volwassen) en van extratemporale origine (bij kinderen) dan verwacht gezien in deze periode. Met deze resultaten lijkt het erop dat verschillende typen aanvallen in een bepaald ritme over de dag voorkomen. Deze patronen worden gekarakteriseerd door een piek midden op de dag en een dal aan het begin van de nacht. Zoals hierboven genoemd, zijn er weinig studies die zich hebben gericht op het patroon van vóórkomen van aanvallen over de 24-uurs dag. Slechts één onderzoeksgroep heeft hierbij gebruik gemaakt van intracraniële EEG-metingen om aanvallen te registreren. Wij hebben de spontane aanvallen van 33 patiënten geanalyseerd die voor langdurige meting kwamen met intracraniële EEG en video. Deze studie wordt beschreven in hoofdstuk 5. Verscheidene kenmerken van de aanvallen werden meegenomen in het onderzoek: classificatie, tijdstip, origine en of de aanval voorkwam in waak of slaap. Er werden 450 aanvallen geregistreerd die ongelijk verdeeld over de dag voorkwamen, afhankelijk van origine van de aanval: temporale aanvallen werden vooral tussen 11 en 17 uur gezien, frontale aanvallen het meest tussen 23 en 5 uur en pariëtale aanvallen vooral tussen 17 en 23 uur. Tijdens waak kwam het grootste gedeelte van de aanvallen voor tussen 5 en 11 uur en 17 tot 23 uur. Als de patiënt in slaap was, werd het grootste gedeelte van de aanvallen geobserveerd van 11 tot 17 uur en 23 tot 5 uur. Deze resultaten lijken er op te wijzen dat aanvallen uit verschillende hersenkwabben een sterke tendens hebben voor te komen in verschillende patronen over de dag. Het is denkbaar dat het moment waarop epileptische aanvallen voorkomen, invloed heeft op wanneer men slaapt, wakker is, dagelijkse activiteiten plant en doet (oftewel het chronotype). Daarom hebben we een studie uitgevoerd met vragenlijsten die de verdeling van chronotypen en slaapparameters bij 200 patiënten met epilepsie vergelijkt met de verdeling in de algemene bevolking. Deze studie wordt beschreven in hoofdstuk 6. Om het chronotype en de subjectieve slaapparameters te bepalen werden de Morningness Eveningness Questionnaire en de Munich Chronotype Questionnaire gebruikt. Er werden significante verschillen gevonden tussen epilepsiepatiënten en controles. Epilepsiepatiënten waren meer ochtend georiënteerd, hadden een vroegere midslaap (=tijdstip tussen in slaap vallen en wakker worden) op vrije dagen en de slaapduur op vrije dagen was langer (p<0.001). De verdeling van chronotypen en subjectieve slaapparameters echter, was niet verschillend tussen patiënten met temporale epilepsie, frontale epilepsie of juveniele myoclonische epilepsie. Tevens hadden patiënten die geopereerd waren
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voor temporaal epilepsie dezelfde verdeling in chronotypen en slaapduur wanneer ze vergeleken werden met niet-geopereerde patiënten. Midslaap was echter eerder in geopereerde patiënten (p=0.035). Dit is de eerste studie die zich richt op chronotypen in epilepsiepatiënten. We hebben laten zien dat de verdeling van chronotypen en subjectieve slaapparameters verschillend is wanneer epilepsiepatiënten en controles vergeleken worden. Niettemin hebben we geen verschil geconstateerd tussen patiënten met verschillende epilepsiesyndromen, ook al worden hierbij verschillende aanvalspatronen over de 24-uurs dag gezien. Onze resultaten suggereren dat epilepsie op zich, maar niet de tijdstippen waarop aanvallen voorkomen, invloed heeft op chronotypen en subjectieve slaapparameters. Bijna een derde van de patiënten met epilepsie houdt aanvallen ondanks adequate behandeling met medicijnen. Chronotherapie (gebaseerd op dynamische verandering in de farmacologie van medicijnen en ziekte gerelateerde processen) zou een veelbelovende nieuwe optie kunnen zijn in de behandeling van epilepsie. In de studie die wordt beschreven in hoofdstuk 7, was het doel te bestuderen of verschillende circadiane types (oftewel ochtend- en avondtypes en tussenliggende types) de tijden dat ze medicatie innemen aanpassen aan hun circadiane type of niet. Deze studie werd uitgevoerd als een eerste stap in het exploreren van chronotherapeutische opties. Om dit te onderzoeken hebben we een vragenlijststudie verricht, die de tijden van inname van anti-epileptische medicatie vergelijkt tussen patiënten met verschillende circadiane types. Het circadiane type werd bepaald door de Morningness/Eveningness Questionnaire. Resultaten laten duidelijk zien dat ochtendtypes hun medicatie op vrije dagen significant eerder innemen dan avondtypen met een verschil van wel 100 minuten bij het nemen van de ochtenddosis (p<0.001) en 55 minuten bij de avonddosis (p=0.019). Ook op werkdagen worden verschillen gezien: zo nemen ochtendtypen de ochtenddosis significant eerder in dan avondtypes (55 minuten, p<0.001). Onafhankelijk van het circadiane type werd medicatie op vrije dagen beduidend later ingenomen dan op werkdagen. Dit verschil is het grootst in de groep avondtypen (verschil van 90 minuten, p=0.005). Leeftijd en geslacht hadden geen invloed op hoe laat medicatie werd ingenomen. Concluderend kunnen we zeggen dat dit de eerste studie is die laat zien dat patiënten de tijden waarop ze medicatie innemen aanpassen aan hun circadiane type. Zoals genoemd is er sterk bewijs dat epileptische aanvallen in diurnale patronen voorkomen. Een studie in een rattenmodel van partiële epilepsie liet circadiane aanvalspatronen zien en in mensen is circadiane ritmiek in interictale ontladingen gevonden. Dit suggereert dat circadiane ritmiek mogelijk een rol speelt in epilepsie. Circadiane invloed op aanvalspatronen in de mens is nog nooit bestudeerd. In hoofdstuk 8 wordt de pilot studie beschreven die we hebben verricht om vast te stellen of circadiane ritmiek aanvalspatronen beïnvloedt. We hebben circadiane ritmes van patiënten, die werden opgenomen voor EEG en videoregistratie, prospectief bepaald. Hierbij hebben we gebruik gemaakt van de melatoninespiegel (het moment dat de spiegel stijgt onder gedimd-lichtcondities (dim light melatonin onset, DLMO)). Aanvallen die optraden tijdens de opname werden geregistreerd door EEG en video. De DLMO varieerde van 18:46u tot 23:13u (gemiddeld 21:22u).
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Honderdvierentwintig aanvallen van 21 patiënten werden geanalyseerd. Aanvallen uit de temporaalkwab kwamen met name tussen 23 en 5 uur voor. Als het tijdstip van aanvallen gecorreleerd werd aan de individuele circadiane fase (zoals gemeten met de DLMO) werd het volgende gezien: temporale aanvallen kwamen het meest voor in de zes uur voor DLMO en frontale aanvallen met name tussen zes en twaalf uur na DLMO. De resultaten van deze pilot studie suggereren dat temporale en frontale aanvallen niet alleen in diurnale patronen voorkomen, maar verbonden lijken te zijn met de circadiane fase.
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Thoraxchirurgie Delirium in Cardiac Surgery A Study on Risk-Assessment and Long-Term Consequences Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Twente, op gezag van de rector magnificus, prof. dr. H. Brinksma, volgens besluit van het College voor Promoties in het openbaar te verdedigen op vrijdag 14 oktober 2011 om 14.45 uur door Sandra Koster geboren op 12 november 1977 te Rotterdam
Promotoren: Prof. dr. J.A.M. van der Palen Prof. dr. M.J. Schuurmans Overige leden: Prof. dr. E.T. Bohlmeijer Prof. dr. G.C.M. Kusters Prof. dr. R.C. van der Mast Prof. dr. B. van Rompaey Dr. J.G. Grandjean
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Samenvatting In dit proefschrift staat het identificeren van patiënten met een verhoogd risico op een delirium centraal, in het bijzonder wordt het risico op een delirium bij de cardiochirurgische patiënt onderzocht. Hoofdstuk 1 gaat in op de achtergrondinformatie van een delirium en beschrijft de aanleiding tot het onderzoek. Een delirium is een veelvoorkomend psychiatrisch ziektebeeld bij vooral oudere patiënten die opgenomen zijn in het ziekenhuis. Gemiddeld wordt een incidentie van 25% aangenomen bij oudere patiënten die zijn opgenomen in het ziekenhuis. Als gevolg van de vergrijzing zal de incidentie delirium in de toekomst toenemen. Een delirium gaat gepaard met veel negatieve gevolgen zoals verlengde opnameduur, opname in een verpleeghuis, verminderd cognitief en functioneel herstel en een verhoogde morbiditeit en mortaliteit. Preventie of vroegtijdige identificatie van een delirium is daarom van groot belang. In dit onderzoek wordt met het ontwikkelen van een eerste delirium risicochecklist getracht om patiënten met een verhoogd risico op een postoperatief delirium na een hartoperatie te identificeren, zodat vroegtijdige herkenning en wellicht preventie van een delirium mogelijk is. Hoofdstuk 2 beschrijft de validatie van de Delirium Observatie Screening (DOS) schaal door de uitkomst van de DOS schaal te vergelijken met de gouden standaard: het oordeel van de psychiater die de DSM-IV criteria hanteert. Bij 27 van de 112 patiënten werd een DOS score van ≥3 gevonden, wat duidt op een delirium. Deze uitkomst was nagenoeg vergelijkbaar met het oordeel van de psychiater. De sensitiviteit en specificiteit van de DOS schaal waren respectievelijk 100% en 96.6%. De AUC was 0.98. Geconcludeerd wordt dat de DOS schaal een zeer goed instrument is om vroegtijdige herkenning van een delirium door verpleegkundigen te bewerkstelligen bij patiënten die een hartoperatie moeten ondergaan. Vroegtijdige herkenning zal bijdragen aan een goed postoperatief management, zoals implementatie van interventies en zal zo de negatieve gevolgen die gepaard gaan met een delirium kunnen verminderen. Hoofdstuk 3 geeft een overzicht van de onderzoeken die zijn verricht op het gebied van risicofactoren en delirium, en dan hoofdzakelijk binnen de cardio-thoracale chirurgie. De review kwam tot 27 risicofactoren, waarvan 12 predisponerende en 15 precipiterende risicofactoren. De meest voorkomende predisponerende risicofactoren van een delirium bij de cardiochirurgische patiënt zijn atriumfibrilleren, cognitieve disfunctie, depressie, een CVA in de voorgeschiedenis, oudere leeftijd en perifeer vaatlijden. De meest voorkomende precipiterende risicofactor is een bloedtransfusie. Onder de laboratoriumwaarden was een afwijkende albumine waarde de meest voorkomende precipiterende risicofactor. Een model bestaande uit meerdere risicofactoren zou toegepast moeten worden om patiënten met een verhoogd risico op een delirium na een hartoperatie mee te kunnen identificeren. Bij deze patiënten zouden, indien mogelijk, preventieve maatregelen genomen kunnen worden en vroege identificatie van een delirium zou zo mogelijk worden. Dit zou wellicht kunnen bijdragen aan het verminderen van de incidentie delirium en de negatieve gevolgen die gepaard gaan met een delirium. Hoofdstuk 4 onderzoekt de predictieve validiteit van een delirium risicochecklist. De incidentie delirium na een hartoperatie was 21% en de gemiddelde duur van een delirium was twee en een halve dag. De opnameduur in het ziekenhuis was in geval van een delirium 11 dagen langer. De delirium risicochecklist, bestaande uit een afwijkende natrium- en kalium waarde en Euroscore, kan goed voorspellen welke
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patiënten een verhoogd risico hebben op een delirium na een electieve hartoperatie. Bij een mogelijkheid van een delirium van 50%, was de sensitiviteit van de risicochecklist delirium 25.0% en de specificiteit 95.5%. De predictieve waarde van een positieve testuitslag was 60% en de predictieve waarde van een negatieve testuitslag 82.4%. De Area Under the Receiver Operating Curve (AUC) was 0.75. Geconcludeerd wordt dat met de delirium risicochecklist electieve hartoperatie patiënten met een verhoogd risico op een delirium kunnen worden geïdentificeerd. Hoofdstuk 5 onderzoekt opnieuw de predictieve validiteit van de delirium risicochecklist in een grotere populatie en met meer risicofactoren. De incidentie delirium was 17.3%. Vergeleken met het eerdere voorspellingsmodel, bleek de Euroscore opnieuw een risicofactor te zijn van een postoperatief delirium, maar afwijkende waarden van de elektrolyten natrium en kalium niet. Bij een mogelijkheid van een delirium van 20% in het oorspronkelijke model, was de sensitiviteit van de risicochecklist delirium 40.4% en de specificiteit 82.7%. De Area Under the Receiver Operating Curve (AUC) was 0.71. Gebaseerd op deze nieuwe studie werd een nieuw voorspellingsmodel opgesteld bestaande uit de volgende risicofactoren: Euroscore, oudere leeftijd (≥ 70 jaar), cognitieve achteruitgang, co-morbiditeit, delirium in de voorgeschiedenis, gebruik van alcohol en de soort hartoperatie. Bij een mogelijkheid van een delirium van 20% in het nieuwe model, was de sensitiviteit van de risicochecklist delirium 80.8% en de specificiteit 82.2%. De Area Under the Receiver Operating Curve (AUC) was 0.89. Patiënten met een hogere Euroscore hebben een verhoogd risico op het ontwikkelen van een delirium na een hartoperatie. Met de toegevoegde voorspellers kunnen patiënten met een verhoogd risico op een postoperatief delirium nauwkeuriger worden geïdentificeerd. Hoofdstuk 6 beschrijft de cognitieve en functionele gevolgen van een delirium, 11.5 jaar na een hartoperatie. Een delirium na een hartoperatie lijkt geassocieerd met een verhoogde mortaliteit, meer heropnames, geheugen- en concentratieproblemen en een verstoord slaappatroon. Daarom moeten preventie en/of vroege herkenning van een delirium worden verbeterd. Patiënten en hun zorgverleners (familie en/of huisarts) zouden bijvoorbeeld beter geïnformeerd moeten worden over de lange termijn gevolgen van een delirium en wat ze hier eventueel aan kunnen doen. Hoofdstuk 7 beschrijft de gevolgen van een delirium zes maanden na een hartoperatie met meer patiënten en met gebruik van gevalideerde meetinstrumenten om de cognitieve functie en kwaliteit van leven te bepalen. Ook mortaliteit en heropnames in het ziekenhuis werden bepaald. Een delirium na een hartoperatie is geassocieerd met verhoogde mortaliteit, meer heropnames in het ziekenhuis, verminderde kwaliteit van leven en cognitieve functie en functionele achteruitgang, zoals afhankelijkheid in het dagelijkse leven en mobiliteit. Een delirium na een hartoperatie gaat gepaard met vele ingrijpende gevolgen. Deze bevindingen rechtvaardigen de uitvoer van interventiestudies om te beoordelen of het voorkómen, de vroege herkenning en de behandeling van een delirium de postoperatieve functionele en cognitieve functies kunnen verbeteren.
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PubMed publicaties per vakgroep Anesthesiologie 1. Thoracic Epidural Anesthesia for Cardiac Surgery: A Randomized Trial V Svircevic,1 AP Nierich,2 KG Moons,3 JC Diephuis,4 JJ Ennema,2 GJ Brandon Bravo Bruinsma,5 CJ Kalkman,6 D van Dijk7 1 UMC Utrecht, Utrecht, and Department of Anesthesiology, Isala Clinics, Zwolle; 2 Department of Anesthesiology, Isala Clinics, Zwolle; 3 Department of Anesthesiology, UMC Utrecht, and Julius Centre, UMC Utrecht. 4 Department of Anesthesiology, Medisch Spectrum Twente, Enschede; 5 Department of Cardiothoracic Surgery, Isala Clinics. 6 Department of Anesthesiology, UMC Utrecht. 7 Department of Anesthesiology and Department of Intensive Care, UMC Utrecht Background: The addition of thoracic epidural anesthesia (TEA) to general anesthesia (GA) during cardiac surgery may have a beneficial effect on clinical outcomes. TEA in cardiac surgery, however, is controversial because the insertion of an epidural catheter in patients requiring full heparinization for cardiopulmonary bypass may lead to an epidural hematoma. The clinical effects of fast-track GA plus TEA were compared with those of with fast-track GA alone. Methods: A randomized controlled trial was conducted in 654 elective cardiac surgical patients who were randomly assigned to combined GA and TEA versus GA alone. Follow-up was at 30 days and 1 yr after surgery. The primary endpoint was 30-day survival free from myocardial infarction, pulmonary complications, renal failure, and stroke. Results: Thirty-day survival free from myocardial infarction, pulmonary complications, renal failure, and stroke was 85.2% in the TEA group and 89.7% in the GA group (p=0.23). At 1 yr follow-up, survival free from myocardial infarction, pulmonary complications, renal failure, and stroke was 84.6% in the TEA group and 87.2% in the GA group (p=0.42). Postoperative pain scores were low in both groups. Conclusions: This study was unable to demonstrate a clinically relevant benefit of TEA on the frequency of major complications after elective cardiac surgery, compared with fast-track cardiac anesthesia without epidural anesthesia. Given the potentially devastating complications of an epidural hematoma after insertion of an epidural catheter, it is questionable whether this procedure should be applied routinely in cardiac surgical patients who require full heparinization. Gepubliceerd: Anesthesiology. 2011;114(2):262-70 Impact factor: 5.486
Totale impact factor: 5.486 Gemiddelde impact factor: 5.486 Aantal artikelen 1e, 2e of laatste auteur: 0 Totale impact factor: 0 Gemiddelde impact factor: 0
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Cardiologie 1. Associations between cardiovascular parameters and uteroplacental Doppler (blood) flow patterns during pregnancy in women with congenital heart disease: Rationale and design of the Zwangerschap bij Aangeboren Hartafwijking (ZAHARA) II study A Balcia, j, k, KM Sollieb, k, BJ Mulderd, k, MW de Laate, JW Roos-Hesselinkf, AP van Dijkg, EM Wajonh, HW Vliegeni, W Drenthena, HL Hillegea, c, JG Aarnoudseb, DJ van Veldhuisena, PG Piepera a Department of Cardiology, b Obstetrics, c Epidemiology, UMC Groningen, University of Groningen, Groningen d Department of Cardiology, e Obstetrics, AMC, University of Amsterdam, Amsterdam f Department of Cardiology, Erasmus MC, Erasmus University, Rotterdam g Department of Cardiology, Radboud University Nijmegen MC, Radboud University Nijmegen, Nijmegen h Department of Cardiology, Thoraxcentrum Twente, Medical Spectrum Twente, Enschede i Department of Cardiology, Leiden UMC, University of Leiden, Leiden j Interuniversity Cardiology Institute of the Netherlands (ICIN), Utrecht Previous research has shown that women with congenital heart disease (CHD) are more susceptible to cardiovascular, obstetric, and offspring events. The causative pathophysiologic mechanisms are incompletely understood. Inadequate uteroplacental circulation is an important denominator in adverse obstetric events and offspring outcome. The relation between cardiac function and uteroplacental perfusion has not been investigated in women with CHD. Moreover, the effects of physiologic changes on pregnancy-related events are unknown. In addition, longterm effects of pregnancy on cardiac function and exercise capacity are scarce. Gepubliceerd: Am Heart J. 2011;161(2):269-275 Impact factor: 5.052
2. Effect of Oversized Partial Postdilatation on Coatings of Contemporary Durable Polymer-Based Drug-Eluting Stents: A Scanning Electron Microscopy Study Basalus MW1, Tandjung K1, Van Apeldoorn AA2, Ankone MJ2, von Birgelen C1,2 1 Department of Cardiology, Thoraxcentrum Twente, Medical Spectrum Twente, Enschede 2 MIRA-Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede Background: Oversized postdilation of drug-eluting stents (DES) is often performed to avoid stent malapposition. In stents implanted in long lesion or major bifurcations, extremely oversized partial postdilation may be required, which exposes DES coating to extreme forces. This study aims to assess shape and incidence of coating
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irregularities on durable polymer-based DES following extremely oversized partial postdilatation. Methods: Fifteen DES samples (3 3.5 mm stents of Cypher Select plus [Cordis Europa, Roden, the Netherlands], Taxus Liberté[Boston Scientific Corp., Natick, MA, USA], Endeavor Sprint [Medtronic Vascular, Santa Rosa, CA, USA], Endeavor Resolute [Medtronic Vascular, Santa Rosa, CA, USA], and Xience V [Abbott Vascular, Santa Clara, CA, USA]) were deployed in sterile water (37 °C) at 14 atm, followed by a proximal postdilation with noncompliant 5.0-mm balloons at 18 atm. Stents were then examined with scanning electron microscopy. Results: Thorough examination of a total of 660 scanning electron microscopic images demonstrated that shape and incidence of coating irregularities in the postdilated and/or transitional DES regions differed only mildly from the nonpostdilated regions. Cypher Select plus showed more peeling without bare metal aspect in the postdilated and transitional regions, and cracks were wider (P < 0.001) in the postdilated and transitional regions; in Taxus Liberté one additional irregularity (torn webbing) and more wrinkles were observed (P < 0.05 for both); in Endeavor Resolute wider cracks were found in the extremely postdilated region only (P < 0.001). Endeavor Sprint and Xience V showed no differences in shape or incidence of coating irregularities between oversized and nonoversized stent regions. Conclusions: Bench side assessment of five contemporary durable polymer-based DES with scanning electron microscopy suggests that even very aggressive stent postdilatation results in no more than mild differences in coating irregularities between postdilated and nonpostdilated stent regions. Gepubliceerd: J Interv Cardiol. 2011;24(2):149-161 Impact factor: 1.387
3. Clinical and diagnostic features of partially anomalous pulmonary venous connection in an adult female patient: a case report and review of the literature Basalus MW1, Said SA2, Stassen CM3, Fast JH2 1 Department of Cardiology, Medisch Spectrum Twente, Enschede 2 Department of Cardiology, Hospital Group Twente, Hengelo 3 Department of Radio-diagnostics, Hospital Group Twente, Hengelo A 40-year-old woman presented with dyspnoea, chest pain and fatigue. Her medical history was unremarkable. An early systolic ejection murmur was heard in the 3D left inter-costal space. Chest X-ray revealed normal cardiothoracic ratio with an anomalous vessel adjacent to the left pulmonary hilum. Echocardiography and exercise tolerance test were normal. Right heart catheterisation revealed normal pulmonary pressures with normal cardiac output. CT scan and MRI of the thorax were diagnostic for an aberrant pulmonary venous connection between the left lower lobe pulmonary vein and the left brachiocephalic vein without atrial septal defect. She was treated conservatively and remained well. Gepubliceerd: Neth Heart J. 2011;19(5):256-8 Impact factor: 1.447
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4. Serial intravascular ultrasound assessment of changes in coronary atherosclerotic plaque dimensions and composition: an update M Hartmann1, J Huisman1, D Böse2, LO Jensen3, P Schoenhagen4,5, GS Mintz6, R Erbel2, C von Birgelen1,7 1 Department of Cardiology, Thoraxcentrum Twente, Medical Spectrum Twente, Enschede 2 Department of Cardiology, University of Duisburg-Essen, Essen, Germany 3 Department of Cardiology, Odense University Hospital, Odense C, Denmark 4 Department of Cardiology, Cleveland Clinic Foundation, Cleveland, OH, USA 5 Department of Radiology, Cleveland Clinic Foundation, Cleveland, OH, USA 6 Cardiovascular Research Foundation, New York, NY, USA 7 MIRA, Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede This manuscript reviews the use of serial intravascular ultrasound (IVUS) examination of coronary atherosclerosis in recent observational studies and randomized trials that revealed the effects of cholesterol-lowering and lipidmodifying therapies and offered novel insight into plaque progression and regression. We discuss the value of plaque progression–regression as complementary imaging endpoint and potential surrogate marker of cardiovascular event risk. In addition, the progress in serial assessment of coronary plaque composition and plaque vulnerability by radiofrequency-based analyses is reviewed. Finally, we report on the evaluation of true vessel remodelling in recent serial IVUS trials and discuss the future perspective of serial invasive imaging of coronary atherosclerosis. Gepubliceerd: Eur J Echocardiogr. 2011;12(4):313-321 Impact factor: 2.117
5. Tako-Tsubo Cardiomyopathy Triggered by Paroxysmal Supraventricular Tachycardia in an Octogenarian M Hartmann1, GK van Houwelingen1, HP Lambregts2, PM Verhorst1, C von Birgelen1,2 1 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede 2 MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede Gepubliceerd: Neth Heart J 2011;19:52–54 Impact factor: 1.447
6. Acute left ventricular failure in a patient with hydroxychloroquine-induced cardiomyopathy Hartmann M1, Meek IL2, van Houwelingen GK1, Lambregts HP1, Toes GJ3, van der Wal AC4, von Birgelen C1,5
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Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede 3 Department of Pathology, Medisch Spectrum Twente, Enschede 4 Department of Pathology, AMC, University Amsterdam, Amsterdam 5 University of Twente, MIRA Institute for Biomedical Technology and Technical Medicine, Enschede We present the case of a 75-year-old woman with a medical history of rheumatoid arthritis treated with hydroxychloroquine, who was admitted with acute left-sided heart failure due to a hydroxychloroquine-induced cardiomyopathy as supported by endomyocardial biopsy. Gepubliceerd: Neth Heart J. 2011;19(11):482-5 Impact factor: 1.447
7. Ultrasound and light: friend or foe? On the role of intravascular ultrasound in the era of optical coherence tomography Huisman J, Hartmann M, von Birgelen C Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede More than 20 years after its introduction, intravascular ultrasound (IVUS) has outlived many other intracoronary techniques. IVUS was useful to solve many interventional problems and assisted us in understanding the dynamics of atherosclerosis. It serves as an established imaging endpoint in large progressionregression trial and as an important workhorse in many catheterization laboratories. Nowadays, increasingly complex lesions are treated with drug-eluting stents. The application of IVUS during such interventions can be very useful. Recently, optical coherence tomography (OCT), a light-based imaging technique, has entered the clinical arena. The "omnipresence" of OCT during scientific sessions and live courses with PCI may raise in many the question: Does IVUS have a future in the "era of OCT"? Three review articles, highlighted by this editorial, demonstrate the broad spectrum of current IVUS applications and underline the significant role of IVUS during the last two decades. OCT, the much younger technique, still has to prove its value. Yet OCT is likely to take over some of the current indications of IVUS as a research tool. In addition, OCT is currently gaining clinical significance for stent optimization during complex interventional procedures. Nevertheless, there is little doubt that IVUS still has a major role in studies on coronary atherosclerosis and for guidance of coronary stenting. Thus, ultrasound and light-are they friend or foe? In fact, both methods are good in their own rights. They are complementary rather than competitive. Moreover, in combination, at least for certain indications, they could be even better. Gepubliceerd: Int J Cardiovasc Imaging. 2011;27(2):209-214 Impact factor: 2.539
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8. Impact of analyzing fewer image frames per segment during offline volumetric radiofrequency-based intravascular ultrasound measurements of target lesions prior to percutaneous coronary interventions Huisman J1, Hartmann M1, Mintz GS, van Houwelingen GK1, Stoel MG1, de Man FH1, Louwerenburg HW1, von Birgelen C1,3 1 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede 2 Cardiovascular Research Foundation, New York, NY, USA 3 MIRA, Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede In the present study, we evaluated the impact of a 50% reduction in number of image frames (every second frame) on the analysis time and variability of offline volumetric radiofrequency-based intravascular ultrasound (RF-IVUS) measurements in target lesions prior to percutaneous coronary interventions (PCI). Volumetric RFIVUS data of vessel geometry and plaque composition are generally obtained by a semi-automated analysis process that includes time-consuming manual contour editing. A reduction in the number of frames used for volumetric analysis may speed up the analysis, but could increase measurement variability. We repeatedly performed offline volumetric analyses in RF-IVUS image sets of 20 mm-long coronary segments that contained 30 de novo lesions prior to PCI. A 50% reduction in frames decreased the analysis time significantly (from 57.5 ± 7.3 to 35.7 ± 3.7 min; P < 0.0001) while geometric and compositional RF-IVUS measurements did not differ significantly from measurements obtained from all frames. The variability between measurements on the reduced number of frames versus all frames was comparable to the intra-observer measurement variability. In target lesions prior to PCI, offline volumetric RF-IVUS analyses can be performed using a reduced number of image frames (every second frame). This reduces the time of analysis without substantially increasing measurement variability. Gepubliceerd: Int J Cardiovasc Imaging. 2011;26(5):487-97 Impact factor: 2.539
9. Is T-wave alternans testing feasible in candidates for prophylactic implantable defibrillators? Kraaier K1, McCracken T1, van der Palen J2, Wilde AA3, Scholten MF1 1 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede 2 Department of Epidemiology, Medisch Spectrum Twente, Enschede 3 Department of Cardiology, AMC Amsterdam, Amsterdam Aims: Previous studies have demonstrated that microvolt T-wave alternans (TWA) screening in patients with ischaemic and dilated cardiomyopathy is effective in identifying patients at high or low risk of sudden cardiac death. It remains unclear which percentage of potential recipients of an implantable cardioverter defibrillator (ICD) are able to perform TWA testing using an exercise protocol which is, at this
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moment, the golden standard. In this study, we evaluated the feasibility of TWA in the risk stratification of potential ICD recipients with ischaemic or dilated cardiomyopathy. Methods and results: Medical charts of 165 primary prevention ICD recipients were reviewed to decide if patients were able to perform a TWA exercise test or not. Reasons to waiver a test were: atrial fibrillation or flutter, pacemaker dependency, recent (cardiovascular) surgery (<1 month) and inability to exercise. Of the potential ICD recipients 35% had one or more of these contraindications and were therefore not suitable for testing. Conclusion: In several studies, TWA is a promising risk stratifier for predicting sudden cardiac death; however, in our population, 35% of the potential ICD candidates could not be tested. In order to fulfil its promise as a predictor for SCD, an alternative means to measure TWA needs to be evaluated. Gepubliceerd: Neth Heart J. 2011 Jan;19(1):6-9 Impact factor: 1.447
10. Contrast-enhancement cardiac magnetic resonance imaging beyond the scope of viability Olimulder MA1, Galjee MA1, van Es J1, Wagenaar LJ1, von Birgelen C1,2 1 Department of Cardiology, Thorax Center Twente, Medisch Spectrum Twente, Enschede 2 MIRA–Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede The clinical applications of cardiovascular magnetic resonance imaging with contrast enhancement are expanding. Besides the direct visualisation of viable and nonviable myocardium, this technique is increasingly used in a variety of cardiac disorders to determine the exact aetiology, guide proper treatment, and predict outcome and prognosis. In this review, we discuss the value of cardiovascular magnetic resonance imaging with contrast enhancement in a range of cardiac disorders, in which this technique may provide insights beyond the scope of myocardial viability. Gepubliceerd: Neth Heart J. 2011;19(5):236-45 Impact factor: 1.447
11. Concomitant off-pump modified maze and coronary surgery MA Mariania , T Stokera, MF Scholtenb, A Addisc, D Corradid, O Alfierie, S Benussie a Department of Cardiothoracic Surgery, UMC Groningen, University of Groningen, Groningen b Department of Cardiology, Thoracic Centre Twente, Medisch Spectrum Twente, Enschede c Centre for Research and Applications of Biotechnique in Cardiovascular Surgery, CRABCC–Lazzaro Spallanzani Institute, Milan, Italy d Pathology Section, University of Parma, Parma, Italy
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e
Cardiac Surgery, San Raffaele Hospital, Milan, Italy
We describe a modification of the Cox-Maze III using bipolar radiofrequency combined with off-pump coronary artery surgery for the treatment of patients with coronary artery disease and long-standing permanent atrial fibrillation. This study reports the midterm outcome of 12 patients with coronary artery disease and longstanding permanent atrial fibrillation who underwent off-pump coronary artery surgery and concomitant modified Maze with bipolar radiofrequency. At a mean follow-up of 23 months, all patients were alive, and 75% (9 of 12) had sinus rhythm. Our modified Maze can be safely and effectively combined with coronary artery surgery in an off-pump setting. Gepubliceerd: Ann Thorac Surg. 2011;91(6):e96-8 Impact factor: 3.558
12. Obstructive intramyocardial haematoma after percutaneous coronary intervention Slootweg AP1, Louwerenburg JW1, Mecozzi G2, Wagenaar LJ1, Verhorst PM1 1 Department of Cardiology, Medisch Spectrum Twente, Enschede 2 Department of Cardiothoracic Surgery, Medisch Spectrum Twente, Enschede Gepubliceerd: Neth Heart J. 2011;DOI 10.1007/s12471-011-0163-8 Impact factor: 1.447
13. Severe regurgitation due to perforation of the mitral-aortic intervalvular fibrosa 3 years after aortic valve replacement van Gorselen E1,2, Nihoyannopoulos P2, Verhorst P1, von Birgelen C1, Prendergast B3, Bellamy M2 1 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede 2 Department of Cardiology, Hammersmith Hospital, Imperial College London, London, UK 3 Department of Cardiology, John Radcliffe Hospital, Oxford, UK We report the case of a 91-year-old man with severe symptomatic mitral regurgitation (MR), referred for assessment of percutaneous edge-to-edge repair 3 years after bioprosthetic aortic valve replacement (AVR). Detailed transthoracic, trans-oesophageal (TEE), and three-dimensional (3D) echocardiography showed a perforation in the subaortic curtain leading to severe regurgitation from the left ventricular outflow tract to the left atrium, which was undiagnosed on previous twodimensional echocardiography. This regurgitation might be iatrogenic in origin after AVR in the absence of previous known endocarditis. This case highlights the utility and added value of 3D TEE in identifying the mechanism of MR. Gepubliceerd: Eur J Echocardiogr. 2011;12(4):E30 Impact factor: 2.117
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14 . A crackling handshake van Gorselen EO1, Gerding MN2 1 Department of Cardiology, Medisch Spectrum Twente, Enschede 2 Department of Internal Medicine, Deventer Hospital, Deventer Gepubliceerd: Neth J Med. 2011;69(2):83-86 Impact factor: 1.842
15. High-dose tirofiban pretreatment reduces the need for bail-out study medication in patients with ST-segment elevation myocardial infarction: results of a subgroup analysis of the On-TIME 2 trial RS Hermanides1, AA Heestermans2, JM ten Berg3, AT Gosselink1, JP Ottervanger1, KG van Houwelingen4, JJ Kolkman5, PR Stella6, T Dill7, C Hamm7, AW van 't Hof1 Department of Cardiology, 1Isala Klinieken, Zwolle, 2Medisch Centrum Alkmaar, Alkmaar, 3St. Antonius Ziekenhuis, Nieuwegein, 4Medisch Spectrum Twente, Enschede, 5Diagram BV, Zwolle, 6UMC, Utrecht, 7Kerckhoff-Klinik, Bad Nauheim, Germany Objective This study investigated the outcome of patients who received bail-out study medication and evaluated whether high-dose tirofiban (HDT) pretreatment may reduce the need for bail-out study medication. Design A prespecified analysis of the multicentre, double-blind, placebo controlled, randomised On-TIME 2 trial. Bail-out use of study medication was predefined and part of the combined clinical end point. Patients 984 patients excluded from many coronary intervention hospitals in different countries were randomly assigned to HDT or placebo. In the subgroup who received blinded bail-out treatment, patients pretreated with placebo who received bail-out HDT were compared with those pretreated with HDT who received bail-out placebo. Interventions Routine prehospital initiation of HDT versus bail-out use of HDT. Main Outcome Measures Electrocardiographic and clinical outcome. Results Blinded bail-out study medication was used in 24% (237/980) of patients, with a higher rate in patients pretreated with placebo: 29% (140/492) versus 20% (97/488), p=0.002. Bail-out versus no bail-out use of study medication was associated with more residual ST deviation (5.5±7.2 vs 3.7±4.8 mm, p=0.005), and worse clinical outcome (major adverse cardiac events (MACE) at 30 days 12.2% vs 5.6%, p<0.001), mainly due to poor outcome in patients who received HDT bail-out. In patients pretreated with HDT who received placebo bail-out study medication, residual ST deviation and clinical outcome did not differ significantly compared with patients who did not receive bail-out medication (4.0±4.6 vs 3.7± 4.8 mm, p=0.703, MACE 7.2% vs 5.6%, p=0.535). Conclusions Routine prehospital treatment with HDT significantly reduced the use of blinded bail-out study medication. The need for bail-out therapy was associated with a less favourable outcome. This analysis suggests that routine pretreatment is superior to provisional use of HDT in patients with ST-segment elevation myocardial infarction. Gepubliceerd: Heart. 2011;97(2):106-11
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Impact factor: 4.706
16. Facilitated reperfusion with prehospital glycoprotein IIb/IIIa inhibition: predictors of complete ST-segment resolution before primary percutaneous coronary intervention in the On-TIME 2 trial: correlates of reperfusion before primary PCI T Heestermansa, H Suryapranatab, JM ten Bergc, A Mosterddef, AT Gosselinkb, W Kochmang, T Dillh, G van Houwelingeni, E Kolkmanj, JW van Werkumc, F Zijlstrak, C Hammh, AW. van 't Hofb a Department of Cardiology, Medisch Centrum Alkmaar, Alkmaar b Department of Cardiology, Isala Klinieken, Zwolle c Department of Cardiology, St Antonius Hospital, Nieuwegein d Department of Cardiology, Meander Medisch Centrum, Amersfoort e Department of Cardiology, UMC Utrecht, Utrecht f Julius Centre for Health Sciences and Primary Care, UMC Utrecht, Utrecht g Department of Cardiology, Swissmed Centrum, Zdrowia S.A., Poland h Department of Cardiology, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany i Department of Cardiology, Medisch Spectrum Twente, Enschede j Department of Medical Statistics, Diagram BV, Zwolle k Department of Cardiology, UMC Centrum, Groningen Objective: The objective of this study is to evaluate the incidence, predictors, and outcome of complete ST-segment resolution (STR) during transportation after pretreatment with dual or triple antiplatelet therapy in the Ongoing Tirofiban in Myocardial Infarction Evaluation (On-TIME) 2 trial. Methods: Patients with ST-segment elevation myocardial infarction were randomized in the ambulance to pretreatment with high-dose tirofiban (HDT) or to a control pretreatment (placebo or no HDT) on top of 600-mg clopidogrel, 500-mg aspirin, and 5000-IU unfractionated heparin. Complete STR was defined as ≥70% STR on the electrocardiogram obtained before percutaneous coronary intervention (PCI) as compared with the inclusion electrocardiogram. Results: Complete STR before PCI occurred in 16.8% (n = 188/1121) and more frequently in the HDT group (19.0% vs 14.6%, P = .05). Independent predictors for complete STR before PCI were younger age (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.70-0.96, P = .01 per 10 year increase), fast diagnosis (OR, 0.97; 95% CI, 0.97-1.0, P = .004 per 15-minute increase time from symptom onset to diagnosis), longer pretreatment time (OR, 1.09; 95% CI, 1.03-1.16, P = .003 per 15minute increase time start study medication to angiography), and randomization to HDT (OR, 1.39; 95% CI, 1.0-1.9, P = .05). Complete STR before PCI was associated with very low 30-day (0.5% vs 2.8%, P = .07) and 1-year (1.1% vs 5.0%, P = .019) mortality. Conclusions: Dual or triple antiplatelet pretreatment in the ambulance results in complete STR before PCI in 17% of patients. Fast ST-segment elevation myocardial infarction diagnosis, prehospital initiation of pretreatment early after symptom onset, and HDT independently predicted STR before PCI. Complete STR is associated with improved clinical outcome. Gepubliceerd: J Electrocardiol. 2011;44(1):42-8
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Impact factor: 1.109
17. The Impact of Age on Effects of Pre-hospital Initiation of High Bolus Dose of Tirofiban Before Primary Angioplasty for ST-Elevation Myocardial Infarction Hermanides RS1, van Houwelingen G2, Ottervanger JP1, de Boer MJ1, Dill T3, Hamm C3, Stella PR4, Boersma E5, Ten Berg JM6, van 't Hof AW1 1 Department of Cardiology, Isala Klinieken, Zwolle 2 Department of Cardiology, Medisch Spectrum Twente, Enschede 3 Department of Cardiology, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany 4 Department of Cardiology, UMC Utrecht, Utrecht 5 Department of Epidemiology, Erasmus MC, Rotterdam 6 Department of Cardiology, St. Antonius Ziekenhuis, Nieuwegein Purpose: Glycoprotein IIb/IIIa inhibitors are favourable in ST-elevation myocardial infarction (STEMI) patients, and the additional value of early pre-hospital high bolus dose tirofiban has recently been established. The aim of this study was to determine the impact of age on myocardial reperfusion and clinical outcomes of pre-hospital administration of high bolus dose tirofiban. Methods: This is a pre-specified sub-analysis of the multicentre, double-blind, placebo-controlled, randomised On-TIME 2 trial and it's open label phase. The primary endpoint was mean residual ST segment deviation 1 h after primary PCI and was evaluated in three age groups. Results: Of the 466 patients in the highest tertile (≥68 years), median age was 74.4 years (IQR 71.3-78.6 years) and 231 (50%) were randomised to tirofiban. Mean residual ST segment deviation 1 h after PCI was significantly lower in elderly patients pre-treated with tirofiban compared to elderly patients without tirofiban pretreatment (4.2Ԝ±Ԝ5.2 mm vs 6.4Ԝ±Ԝ7.5 mm, pԜ=Ԝ0.001). Furthermore, elderly patients pre-treated with tirofiban had a non-significantly higher rate of 30-day major or minor bleeding compared to elderly patients without tirofiban pre-treatment (14.2% vs 9.0%, pԜ=Ԝ0.088). 30-day net adverse clinical events in elderly patients with- or without tirofiban was not significantly different (11.9% vs 15.2%, pԜ=Ԝ0.300). Conclusion: The effect of pre-hospital initiation of high bolus dose tirofiban on myocardial reperfusion, as determined by ST-segment resolution is highest in the elderly patients. However, this was associated with a trend towards more bleeding complications, resulting in a balanced clinical effect after 30-day follow-up. Future studies should evaluate whether the elderly STEMI patient may benefit from highly effective and safer antiplatelet therapy. Gepubliceerd: Cardiovasc Drug Ther. 2011;25(4):323-330 Impact factor: 3.098
18. Higher efficacy of pre-hospital tirofiban with longer pre-treatment time to primary PCI: protection for the negative impact of time delay Heestermans T1, de Boer MJ1, van Werkum JW2, Mosterd A3,4,5, Gosselink AT6, Dambrink JH6, van Houwelingen G7, Koopmans P6, Hamm C8, Zijlstra F8, ten Berg JM2, van 't Hof AW6 54
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Department of Cardiology, Medisch Centrum Alkmaar, Alkmaar Department of Cardiology, St Antonius Hospital, Nieuwegein 3 Department of Cardiology, Meander Medisch Centrum, Amersfoort 4 Department of Cardiology, UMC Utrecht, Utrecht 5 Julius Centre for Health Sciences and Primary Care, UMC Utrecht, Utrecht 6 Department of Cardiology, Isala Klinieken, Zwolle 7 Department of Cardiology, Medisch Spectrum Twente, Enschede 8 Department of Cardiology, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany 9 Department of Cardiology, UMC Groningen, Groningen 2
Aims: To evaluate the impact of longer duration of pre-hospital initiated antiplatelet and antithrombotic therapy on outcome in patients with ST-segment elevation myocardial infarction (STEMI). Methods and results: In this sub-analysis of the Ongoing Tirofiban in Myocardial Evaluation (On-TIME) 2 trial, we studied, in 1,370 patients, the effect of pretreatment time (time from administering study medication to time of angiography) on complete ST-segment resolution (STR), initial patency and 30-day mortality. Study medication consisted of high dose tirofiban (HDT) or control (placebo or no HDT) on top of high dose clopidogrel, aspirin and unfractionated heparin. Median pretreatment time was 55 min (44-70). Longer pre-treatment was associated with longer transportation times, longer in-hospital delay, longer total ischaemic time (all p<0.001) and higher 30-day mortality (3.6% vs. 1.8%, p=0.046). Longer HDT pretreatment time was independently associated with increased complete STR both before (odds ratio [OR] 1.51, 95%; confidence interval [CI] 0.98-2.32; p=0.06) and after PCI (OR 1.43, 95%; CI 1.02-2.02; p=0.039) and with a significantly improved initial TIMI 2 or 3 flow (51.4% vs. 43.4%, p=0.042) and reduced 30-day mortality (2.1% vs. 5.0%, p=0.047) as compared to longer control pre-treatment. Conclusions: Longer time delay before primary PCI is associated with increased mortality. Pre-treatment with high dose tirofiban, however, may compensate for this negative effect by improving ST-segment resolution and initial patency and by reducing mortality. Further studies should be performed to confirm that this is an attractive therapy for patients with longer delays to reperfusion. Gepubliceerd: EuroIntervention. 2011;7(4):442-8 Impact factor: 2.716
19. Diagnostic and therapeutic approach of congenital solitary coronary artery fistulas in adults: Dutch case series and review of literature Said SA1, Nijhuis RL1, Op den Akker JW2, Kimman GP3, Van Houwelingen KG4, Gerrits D5, Huisman AB5, Slart RH6, Nicastia DM7, Koomen EM7, Tans AC8, AlWindy NY8, Sonker U9, Slagboom T10, Pronk AC11 1 Department of Cardiology, ZGT location Hengelo, Hengelo 2 Department of Radiology, ZGT location Almelo, Almelo 3 Department of Cardiology, Medical Center Alkmaar, Alkmaar 4 Department of Cardiology, Medical Spectrum Twente, Enschede 5 Department of Radiology, Medical Spectrum Twente, Enschede 6 Department of Nuclear Medicine and Molecular Imaging, UMC, Groningen
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Department of Cardiology, Gelre Hospitals, Apeldoorn Department of Cardiology, Gelre Hospitals, Zutphen 9 Department of Cardiac Surgery, St. Antonius Hospital, Nieuwegein 10 Department of Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam 11 Department of Cardiology, St. Elisabeth Hospital, Tilburg 8
Background: Coronary artery fistulas (CAFs) are infrequent anomalies, coincidentally detected during coronary angiography (CAG). Aim: To elucidate the currently used diagnostic imaging modalities and applied therapeutic approaches. Materials and methods: Five Dutch patients were found to have CAFs. A total of 170 reviewed subjects were subdivided into two comparable groups of 85 each, treated with either percutaneous 'therapeutic' embolisation (PTE group) or surgical ligation (SL group). Results: In our series, the fistulas were visualised with several diagnostic imaging tests using echocardiography, multidetector computed tomography, and CAG. Four fistulas were unilateral and one was bilateral; five originated from the left and one originated from the right coronary artery. Among the reviewed subjects, high success rates were found in both treatment groups (SL: 97% and PTE: 93%). Associated congenital or acquired cardiovascular disorders were frequently present in the SL group (23%). Bilateral fistulas were present in 11% of the SL group versus 1% of the PTE group. The fistula was ligated surgically in one and abolished percutaneously in another. Medical treatment including metoprolol was conducted in two, and watchful waiting follow-up was performed in one. Conclusions: Several diagnostic imaging techniques are available for assessment of the anatomical and functional characteristics of CAFs. Gepubliceerd: Neth Heart J. 2011;19(4):183-91 Impact factor: 1.447
20. Bronchial erosion and hemoptysis after pulmonary vein isolation by cryoballoon ablation van Opstal JM1, Timmermans C2, Blaauw Y2, Pison L2 1 Department of Cardiology, Thorax Center Twente, Enschede 2 Department of Cardiology, Maastricht UMC, Maastricht Gepubliceerd: Heart Rhythm. 2011 Sep;8(9):1459 Impact factor: 4.246
21. Beyond the lumen border: on the use of intravascular ultrasound in the left main coronary artery von Birgelen C, Hartmann M Department of Cardiology, Medisch spectrum Twente, Enschede Gepubliceerd: EuroIntervention. 2011;7(3):300-302 Impact factor: 2.716
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22. Percutaneous tricuspid valve implantation in a fontan patient with congestive heart failure and protein-losing enteropathy Straver B1, Wagenaar LJ2,3, Blom NA1,4, Mulder BJ2, Bouma BJ2, Hazekamp MG2, de Winter RJ2 1 Department of Pediatric Cardiology, Emma Children's Hospital, AMC, Amsterdam; 2 Department of Cardiology and the Department of Cardiothoracic Surgery, AMC, Amsterdam; 3 Department of Cardiology, Medisch Spectrum Twente, Enschede; 4 Department of Pediatric Cardiology, Leiden University Medical Center, Leiden Gepubliceerd: Circ Cardiovasc Interv. 2011;4(1):112-3 Impact factor: 0
23. Rare prosthesis failure after aortic valve replacement with a Freedom Solo Giordano V1, Hermens JA2, Wajon EM2, Grandjean JG1 1 Department of Cardio-Thoracic Surgery, Thoraxcentrum Twente, Enschede 2 Department of Cardiology, Thoraxcentrum Twente, Enschede We report an unusual case of a 78-year-old man readmitted to our Cardiac Surgery Division due to a severe regurgitation of the stentless bioprosthesis Freedom Solo implanted, strictly following the manufacturer's recommendations, approximately six months before for aortic stenosis of native valve. Although different possible etiologies may be determined for the subacute aortic regurgitation of a bioprosthesis, a partial adhesion of a leaflet to the aortic wall represents an exceptional event. The device was explanted, a new different bioprosthesis model was implanted and the patient recovered uneventfully. But no evidence of aortic or leaflet vegetations suggesting for abscess was found, neither atheromatous or calcified plaques, nor signs of inflammation of the aortic wall were detected. In the end, it is believed that the cause of the cuspal adhesion to the aortic sinus was primary tissue failure. Gepubliceerd: Interact Cardiovasc Thorac Surg. 2011;12(2):273-5 Impact factor: 0.943
Totale impact factor: 50.814 Gemiddelde impact factor: 2.209 Aantal artikelen 1e, 2e of laatste auteur: 17 Totale impact factor: 32.236 Gemiddelde impact factor: 1.896
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Gastroenterologie 1.Colonic stenting versus emergency surgery for acute left-sided malignant colonic obstruction: a multicentre randomised trial JE van Hoofta, e, WA Bemelmanb, Bas Oldenburgg, AW Marinellih, MF Lutke Holzikf, MJ Grubbeni, MA Sprangersc, MG Dijkgraafd, P Fockensa for the collaborative Dutch Stent-In study group a Department of Gastroenterology and Hepatology, AMC, University of Amsterdam, Amsterdam b Department of Surgery, AMC, University of Amsterdam, Amsterdam c Department of Medical Psychology, AMC, University of Amsterdam, Amsterdam d Clinical Research Unit, AMC, University of Amsterdam, Amsterdam e Department of Gastroenterology, Medisch Spectrum Twente, Enschede f Department of Surgery, Medisch Spectrum Twente, Enschede g Department of Gastroenterology and Hepatology, UMC, Utrecht h Department of Surgery, Medical Centre Haaglanden, Den Haag i Department of Gastroenterology, Sint Elisabeth Hospital, Tilburg Background: Colonic stenting as a bridge to elective surgery is an alternative for emergency surgery in patients with acute malignant colonic obstruction, but its benefits are uncertain. We aimed to establish whether colonic stenting has better health outcomes than does emergency surgery. Methods: Patients with acute obstructive left-sided colorectal cancer were enrolled from 25 hospitals in the Netherlands and randomly assigned (1:1 ratio) to receive colonic stenting as a bridge to elective surgery or emergency surgery. The randomisation sequence was computer generated with permuted blocks and was stratified by centre; treatment allocation was concealed by use of a web-based application. Investigators and patients were unmasked to treatment assignment. The primary outcome was mean global health status during a 6-month follow-up, which was assessed with the QL2 subscale of the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (EORTC QLQ-C30). Analysis was by intention to treat. This study is registered, number ISRCTN46462267. Findings: Between March 9, 2007, and Aug 27, 2009, 98 patients were assigned to receive colonic stenting (n=47 patients) or emergency surgery (n=51). Two successive interim analyses showed increased 30-day morbidity in the colonic stenting group, with an absolute risk increase of 0·19 (95% CI -0·06 to 0·41) in analysis of the first 60 patients (14 of 28 patients receiving colonic stenting vs 10 of 32 receiving emergency surgery), and an absolute risk increase of 0·19 (-0·01 to 0·37) in analysis of the first 90 patients (23 of 47 patients vs 13 of 43). In accordance with the advice of the data safety monitoring committee, the study was suspended on Sept 18, 2009, and ended on March 12, 2010. At the final analysis of 98 patients, mean global health status during follow-up was 63·0 (SD 23·8) in the colonic stenting group and 61·4 (SD 21·9) in the emergency surgery group; after adjustment for baseline values, mean global health status did not differ between treatment groups (-4·7, 95% CI -14·8 to 5·5, p=0·36). No difference was recorded between treatment groups in 30-day mortality (absolute risk difference -0·01, 95% CI -0·14 to 0·12, p=0·89), overall mortality (-0·02, -0·17 to 0·14, p=0·84), morbidity (-0·08, -0·27
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to 0·11, p=0·43), and stoma rates at latest follow-up (0·09, -0·10 to 0·27, p=0·35). However, the emergency surgery group had an increased stoma rate directly after initial intervention (0·23, 0·04 to 0·40, p=0·016) and a reduced frequency of stomarelated problems (between-group difference -12·0, -23·7 to -0·2, p=0·046). The most common serious adverse events were abscess (three in the colonic stenting group vs four in the emergency surgery group), perforations (six vs none), and anastomotic leakage (five vs one), and the most common adverse events were pneumonia (three vs one) and wound infection (one vs three). Interpretation: Colonic stenting has no decisive clinical advantages to emergency surgery. It could be used as an alternative treatment in as yet undefined subsets of patients, although with caution because of concerns about tumour spread caused by perforations. Gepubliceerd: Lancet Oncol. 2011;12(4):344-52 Impact factor: 17.764
2. The long-term effect of ursodeoxycholic acid on laboratory liver parameters in biochemically non-advanced primary biliary cirrhosis EM Kuipera, BE Hansena, b, W Lesterhuisc, RJ Robijnd, JC Thijse, LGJB Engelsf, GH Koekg, MN Aparicioh, MJ Kerbert-Dreteleri, HR van Buurena and for the Dutch PBC study group a Department of Gastroenterology and Hepatology, Rotterdam b Department of Epidemiology and Biostatistics, Erasmus UMC, Rotterdam c Department of Gastroenterology and Hepatology, Albert Schweitzer Hospital, Dordrecht d Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem e Department of Internal Medicine, Bethesda Hospital, Hoogeveen f Department of Gastroenterology and Hepatology, Orbis Medical Center, Sittard g Department of Gastroenterology and Hepatology, Maastricht UMC, Maastricht h Department of Gastroenterology and Hepatology, Canisius Wilhelmina Hospital, Nijmegen i Department of Internal Medicine, Medical Spectrum Twente, Enschede Background and aims: Ursodeoxycholic acid (UDCA) has an established effect on liver biochemistries in primary biliary cirrhosis (PBC). Few studies have evaluated long-term laboratory treatment effects and data beyond 6 years are not available. The aim of this study was to assess the long-term evolution of liver biochemistries during prolonged treatment with UDCA in biochemically non-advanced PBC. Patients and methods: Prospective multicenter cohort study of patients with PBC with pretreatment normal bilirubin and albumin, treated with UDCA 13-15mg/kg/day. At yearly intervals, follow-up data including serum bilirubin, alkaline phosphatase (ALP), transaminases, albumin and IgM were collected. Data were analyzed with a repeated measurement model. Results: Two hundred and twenty-five patients were included and followed during a median period of 10.3 years. Following 1-year treatment with UDCA 36-100% of the total biochemical improvement was achieved, the maximum response was observed after 3 years. After initial improvements, bilirubin and AST levels increased and
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albumin levels significantly decreased after 6-10 years. However, these changes were of limited magnitude. The beneficial effects on ALT and ALP were maintained while IgM continued to decrease. Conclusion: In non-advanced PBC the biochemical response to UDCA is maintained up to 15 years. The long-term evolution of bilirubin, albumin and ALT differs from that of ALP and AST. The mean IgM level normalised and levels continued to decrease during the period of follow-up. Gepubliceerd: Clin Res Hepatol Gastroenterol. 2011;35(1):29-33 Impact factor: 0
3. Predictors for Neoplastic Progression in Patients With Barrett's Esophagus: A Prospective Cohort Study M Sikkema1,22, CW Looman2, EW Steyerberg2, M Kerkhof1, F Kastelein1, H van Dekken3, AJ van Vuuren1, WA Bode4, H van der Valk5, RJ Ouwendijk6, R Giard7, W Lesterhuis8, R Heinhuis9, EC Klinkenberg10, GA Meijer11, F ter Borg12, JW Arends13, JJ Kolkman14, J van Baarlen15, RA de Vries16, AH Mulder17, AJ van Tilburg18, GJ Offerhaus19, FJ ten Kate19, JG Kusters1, EJ Kuipers1,20, PD Siersema1,21 1 Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam 2 Department of Public Health, Erasmus MC, Rotterdam 3 Department of Pathology, Erasmus MC, Rotterdam 4 Department of Gastroenterology, IJsselland Hospital, Capelle a/d IJssel 5 Pathology Laboratory, PATHAN, Rotterdam 6 Department of Gastroenterology, Ikazia Hospital, Rotterdam 7 Department of Pathology, Maasstad Hospital, Rotterdam 8 Department of Gastroenterology, Albert Schweitzer Hospital, Dordrecht 9 Department of Pathology, Albert Schweitzer Hospital, Dordrecht 10 Department of Gastroenterology and Hepatology, VU Medical Center, Amsterdam 11 Department of Pathology, VU MC, Amsterdam 12 Department of Gastroenterology, Deventer Hospital, Deventer 13 Department of Pathology, Deventer Hospital, Deventer 14 Department of Gastroenterology, Medisch Spectrum Twente, Enschede 15 Laboratorium Pathologie Oost Nederland, Enschede 16 Department of Gastroenterology, Rijnstate Hospital, Arnhem 17 Department of Pathology, Rijnstate Hospital, Arnhem 18 Department of Gastroenterology, Sint Franciscus Gasthuis, Rotterdam 19 Department of Pathology, UMC Utrecht, Utrecht 20 Internal Medicine, Erasmus MC, Rotterdam 21 Department of Gastroenterology, UMC Utrecht, Utrecht 22 Department of Gastroenterology and Hepatology, UMC Utrecht, Utrecht Objectives: Patients with Barrett's esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of
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progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors. Methods: We included 713 patients with BE (≥2Ԝcm) with no dysplasia (ND) or lowgrade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance. Results: After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of ≥10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3-7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01-1.2), esophagitis (RR 3.5; 95% CI 1.3-9.5), and LGD (RR 9.7; 95% CI 4.4-21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (<1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18-40%). Conclusions: In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE. Gepubliceerd: Am J Gastroenterol. 2011;106:1231-8 Impact factor: 6.882
4. Prolonged thioguanine therapy is well tolerated and safe in the treatment of ulcerative colitis van Asseldonk DP1, Jharap B1, Kuik DJ2, de Boer NK1, Westerveld BD3, Russel MG4, Kubben FJ5, van Bodegraven AA1, Mulder CJ1 1 Department of Gastroenterology and Hepatology, VU UMC, Amsterdam 2 Department of Epidemiology and Biostatistics, VU UMC, Amsterdam 3 Department of Gastroenterology and Hepatology, Isala Clinics, Zwolle 4 Department of Gastroenterology and Hepatology, Medical Spectrum Twente, Enschede 5 Department of Gastroenterology and Hepatology, Maasstad Hospital, Rotterdam Background: Thioguanine has been used for the treatment of inflammatory bowel disease, in particular for patients who failed conventional thiopurine therapy. To date, thioguanine has been infrequently studied in ulcerative colitis. AIM: To evaluate the tolerability, safety and efficacy of thioguanine in the treatment of ulcerative colitis. Methods: A database analysis was performed on inflammatory bowel disease patients who had failed conventional thiopurine therapy and were treated with
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thioguanine. Rates and reasons for treatment failure were assessed. Laboratory values, abdominal ultrasonography, liver biopsy and endoscopic remission rates were evaluated. Results: Forty-six patients were included and median treatment duration was 22 months (range 0.3-72.0). Nine patients failed thioguanine therapy: six due to adverse events, three due to therapy resistance. Concomitant treatment with aminosalicylates protected against thioguanine failure (hazard ratio (HR) 0.11, 95% CI 0.03-0.48). When performed, ultrasonography (n=21) revealed no suspected therapy-related pathology in all but one patient, in whom hepatomegaly was observed. Liver histology (n=12) predominantly revealed no abnormalities (n=4) or non-specific regeneration (n=4); none showed nodular regenerative hyperplasia. At follow-up, 40% of colonoscopies revealed endoscopic remission as compared with 10% at baseline (P=0.180). Conclusions: Long-term use of thioguanine appears to be well tolerated and relatively safe in ulcerative colitis patients who failed conventional thiopurine therapy. Gepubliceerd: Digest Liver Dis. 2011;43(2):110-5 Impact factor: 2.805
Totale impact factor: 27.451 Gemiddelde impact factor: 6.863 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 17.764 Gemiddelde impact factor: 17.764
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Gynaecologie 1. Cancer prevalence in osteoporotic women with low serum vitamin D levels Veldhuis S1, Wolbers F2, Brouckaert O1, Vermes I2,3, Franke HR1 1 Department of Obstetrics and Gynecology, Medisch Spectrum Twente, Enschede 2 Department of Polymer Chemistry and Biomaterials, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 3 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede Objective:: The aim of this study was to assess the role of vitamin D in cancer development in postmenopausal osteoporotic women. Methods:: A cross-sectional and in vitro study was carried out, with statistical analysis with odds ratios and 95% CIs presented. Human estrogen receptor-positive breast cancer cells (MCF-7) were studied in vitro. The apoptosis-to-proliferation (A/P) ratio was also determined. Results:: A total of 885 women were included in this study. Any kind of cancer was found in 112 (12.7%) of all women. Breast cancer was the most prevalent malignancy, representing half of the cases (n = 56, 50%). The prevalence of any kind of cancer and breast cancer in women with low 25-hydroxyvitamin D3 levels (25OHD; <50 nmol/L) was higher than in women with high 25OHD levels (≥50 nmol/L). The in vitro study demonstrated a statistically significant increased A/P ratio of 5.27 (95% CI, 4.054-6.493) with a high concentration of 1α,25-dihydroxyvitamin D (10 μM) after 96 hours. Conclusions:: Osteoporotic women with low serum levels of 25OHD (<50 nmol/L) have an increased prevalence of any kind of cancer and breast cancer; however, these differences are not statistically significant. 1α,25-dihydroxyvitamin D induced an increased A/P ratio in MCF-7 breast cancer cells in vitro. Gepubliceerd: Menopause. 2011;18(3):319-22 Impact factor: 3.318
2. Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia between 34 and 37 weeks' gestation (HYPITAT-II): a multicentre, open-label randomised controlled trial J Langenveld,1 K Broekhuijsen,2 GJ van Baaren,3 MG van Pampus,4 AH van Kaam,5 H Groen,6 M Porath,7 MA Oudijk,8 KW Bloemenkamp,9 CJ de Groot,10 E van Beek,11 ME van Huizen,12 HP Oosterbaan,13 C Willekes,1 EJ Wijnen-Duvekot,14 MT Franssen,6 DA Perquin,15 JM Sporken,16 MD Woiski,17 HA Bremer,18 DN Papatsonis,19 JT Brons,20 M Kaplan,21 BW Nij Bijvanck,22 BW Mol3, HYPITAT-II study group 1 Department of Obstetrics and Gynecology, Maastricht University Medical Centre. GROW - School for Oncology and Developmental Biology 2 Department of Obstetrics and Gynecology, Martini hospital, Groningen 3 Department of Obstetrics and Gynecology, AMC, Amsterdam 4 Department of Obstetrics and Gynecology, Onze Lieve Vrouwe Gasthuis Amsterdam
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Department of Neonatology, Emma Children's Hospital, AMC, Amsterdam Department of Epidemiology, UMC Groningen 7 Department of Obstetrics and Gynecology, Maxima Medical Centre, Veldhoven 8 Department of Obstetrics and Gynecology, UMC Utrecht 9 Department of Obstetrics and Gynecology, Leiden University Medical Centre 10 Department of Obstetrics and Gynecology, VU MC Amsterdam 11 Department of Obstetrics and Gynecology, St. Antonius Hospital Nieuwegein 12 Department of Obstetrics and Gynecology, Haga Hospital Den Haag 13 Department of Obstetrics and Gynecology, Jeroen Bosch Hospital, s’Hertogenbosch 14 Department of Obstetrics and Gynecology, VieCuri Medical Centre, Venlo 15 Department of Obstetrics and Gynecology, Medical Centre Leeuwarden, Leeuwarden 16 Department of Obstetrics and Gynecology, Canisius-Wilhelmina Hospital, Nijmegen 17 Department of Obstetrics and Gynecology, Radboud Univeristy Nijmegen, Nijmegen 18 Department of Obstetrics and Gynecology, Reinier de Graaf Hospital, Delft 19 Department of Obstetrics and Gynecology, Amphia Hospital Breda 20 Department of Obstetrics and Gynecology, Medical Spectrum Twente, Enschede 21 Department of Obstetrics and Gynecology, Saxenburgh Group, Hardenberg 22 Department of Obstetrics and Gynecology, Isala Hospital, Zwolle 6
Background: Gestational hypertension (GH) and pre-eclampsia (PE) can result in severe complications such as eclampsia, placental abruption, syndrome of Hemolysis, Elevated Liver enzymes and Low Platelets (HELLP) and ultimately even neonatal or maternal death. We recently showed that in women with GH or mild PE at term induction of labour reduces both high risk situations for mothers as well as the caesarean section rate. In view of this knowledge, one can raise the question whether women with severe hypertension, pre-eclampsia or deterioration chronic hypertension between 34 and 37 weeks of gestation should be delivered or monitored expectantly. Induction of labour might prevent maternal complications. However, induction of labour in late pre-term pregnancy might increase neonatal morbidity and mortality compared with delivery at term. Methods/design: Pregnant women with severe gestational hypertension, mild preeclampsia or deteriorating chronic hypertension at a gestational age between 34+0 and 36+6 weeks will be asked to participate in a multi-centre randomised controlled trial. Women will be randomised to either induction of labour or expectant monitoring. In the expectant monitoring arm, women will be induced only when the maternal or fetal condition detoriates or at 37+0 weeks of gestation. The primary outcome measure is a composite endpoint of maternal mortality, severe maternal complications (eclampsia, HELLP syndrome, pulmonary oedema and thromboembolic disease) and progression to severe pre-eclampsia. Secondary outcomes measures are respiratory distress syndrome (RDS), neonatal morbidity and mortality, caesarean section and vaginal instrumental delivery rates, maternal quality of life and costs. Analysis will be intention to treat. The power calculation is based on an expectant reduction of the maternal composite endpoint from 5% to 1%
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for an expected increase in neonatal RDS from 1% at 37 weeks to 10% at 34 weeks. This implies that 680 women have to be randomised. Discussion: This trial will provide insight as to whether in women with hypertensive disorders late pre-term, induction of labour is an effective treatment to prevent severe maternal complications without compromising the neonatal morbidity. Gepubliceerd: BMC Pregnancy Childbirth. 2011;11:50 Impact factor: 0
3. Recommendations to Prevent Urinary Tract Injuries during Laparoscopic Hysterectomy: A Systematic Delphi Procedure among Experts Janssen PF1,2, Brölmann HA2, Huirne JA2 1 Department of Obstetrics and Gynecology, Medisch Spectrum Twente, Enschede 2 Department of Gynaecology, VU UMC, Amsterdam Study objective: To reach consensus among experts in the field of laparoscopic gynaecology in uniform recommendations on the prevention and early detection of urinary tract injuries during laparoscopic hysterectomy (LH). Design: A systematic Delphi consensus procedure (Canadian Task Force Classification III). Setting: A tertiary-care university hospital. Population: International gynecologic experts in the field of LH. Methods: Experts were selected according to standard criteria with regard to surgical experience and research. Twenty of 40 experts were willing to participate. Three questionnaires were sent. Each questionnaire was formulated and based on the answers of the previous one. Results: Fourteen experts completed the third questionnaire. In 40 of 65 proposed recommendations, consensus was achieved. Consensus was achieved with respect to required education, learning curve, equipment, restoration of distorted anatomy and on the application of diagnostic tools in early detection of urinary tract injuries. Conclusion: The Delphi technique is a useful tool to achieve consensus regarding urologic complications in LH. Recommendations may serve as a basis for further research and the development of educational programs. Gepubliceerd: J Minim Invasive Gynecol. 2011;18(3):314-321 Impact factor: 1.556
4. Perioperative outcomes using LigaSure compared with conventional bipolar instruments in laparoscopic hysterectomy: a randomised controlled trial Janssen P1,6, Brölmann H1, van Kesteren P2, Bongers M3, Thurkow A4, Heymans M5, Huirne J1 1 Department of Obstetrics and Gynaecology, VU UMC, Amsterdam 2 Department of Obstetrics and Gynaecology, Onze Lieve Vrouwe Gasthuis, Amsterdam 3 Department of Obstetrics and Gynaecology, Maxima Medisch Centrum, Veldhoven
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Department of Obstetrics and Gynaecology, Sint Lucas Andreas Ziekenhuis, Amsterdam 5 Department of Epidemiology and Biostatistics, VU UMC, Amsterdam 6 Department of Obstetrics and Gynaecology, Medisch Spectrum Twente, Enschede Objective To compare the effects of LigaSure versus the conventional bipolar technique on operating time and blood loss during laparoscopic hysterectomy. Design A randomised controlled trial. Setting Three teaching hospitals. Population Women undergoing a laparoscopic hysterectomy for benign indications. Methods 140 women undergoing a laparoscopic hysterectomy were randomised for LigaSure or conventional bipolar instruments. Main outcome measures Primary outcome was operating time from initial skin incision till detachment of the uterus. Secondary outcome measures were total operating time (from initial skin incision till final skin closure), time to dissect the adnexal ligaments, intra-operative blood loss and subjective evaluation by the surgeon of the instrument used. Results No differences in operating time (from initial skin incision till uterine detachment and initial skin incision till final skin closure) using LigaSure versus conventional bipolar instruments: 97.6 versus 91.8 minutes (P = 0.39, 95% CI - 7.6 to 19.2), and 148.1 versus 142.1 minutes (P = 0.46, 95% CI - 10.1 to 22.3), respectively. The mean blood loss using LigaSure versus conventional bipolar was 234.1 versus 273.1 ml (P = 0.46, 95% CI -39.1 to 52.7). Various subjective efficacy and instrument handling parameters were significantly different between the two instruments and between the different participating centres. Conclusions There were no significant differences in operating time and blood loss between the use of LigaSure and the use of conventional bipolar instruments during laparoscopic hysterectomy, even after correction for potential confounders. User satisfaction parameters were assessed as significantly different by surgeons of the participating centres. Gepubliceerd: BJOG. 2011;118(13):1568-75 Impact factor: 3.349
5. Long-term outcomes in women with polycystic ovary syndrome initially randomized to receive laparoscopic electrocautery of the ovaries or ovulation induction with gonadotrophins MJ Nahuis1,2,3, N Kose1, N Bayram4, HJ van Dessel5, DD Braat6, CJ Hamilton7, PG Hompes2, PM Bossuyt8, BW Mol1, F van der Veen1, M van Wely1 1 Center for Reproductive Medicine, Department of Obstetrics and Gynaecology, AMC, University of Amsterdam, Amsterdam 2 Center for Reproductive Medicine, Department of Obstetrics and Gynaecology, VU MC, University of Amsterdam, Amsterdam 3 Department of Obstetrics and Gynaecology, Medisch Spectrum Twente, Enschede 4 Department of Obstetrics and Gynaecology, Zaans Medisch Centrum, Zaandam 5 Department of Obstetrics and Gynaecology, Twee Steden Ziekenhuis, Tilburg
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Center for Reproductive Medicine, Department of Obstetrics and Gynaecology, Radboud University Nijmegen MC, Nijmegen 7 Department of Obstetrics and Gynaecology, Jeroen Bosch ziekenhuis, Den Bosch 8 Department of Clinical Epidemiology and Biostatistics, AMC, University of Amsterdam, Amsterdam Background Long-term effects of laparoscopic electrocautery of the ovaries are unknown. To study the long-term effects of laparoscopic electrocautery of the ovaries and gonadotrophins, we followed women with clomiphene-resistant polycystic ovary syndrome (PCOS) randomly allocated to one of these treatments until 8–12 years after their initial treatment. Methods Between February 1998 and October 2001 168 women with clomiphene citrate-resistant PCOS were included in a randomized controlled trial comparing an electrocautery strategy to a strategy starting with rFSH. In 2009 these women were contacted about their reproductive outcome and menstrual cycle regularity. Analysis was by intention-to-treat. We compared time to conception resulting in live birth, subsequent pregnancies, ectopic and multiple pregnancies, menopause, as well as minimal and maximal menstrual cycle length. Results After 8–12 years, the cumulative proportion of women with a first child was 86% in women who had been allocated to electrocautery versus 81% in women who had been allocated to immediate rFSH [relative ratio (RR): 1.1; 95% confidence interval (CI): 0.92–1.2]. Treatment with electrocautery resulted in a significantly lower need for stimulated cycles to reach a live birth; 53% after electrocautery versus 76% after rFSH (RR: 0.69; 95% CI: 0.55–0.88).The cumulative proportion of women with a second child was 61% after electrocautery versus 46% after immediate rFSH (RR: 1.4; 95% CI: 1.00–1.9). Overall, there were 7 twins out of 134 deliveries (5%) after electrocautery versus 10 twins out of 124 deliveries (8%) in the rFSH group (RR: 0.65; 95% CI: 0.25–1.6). Fifty-four per cent of the women allocated to electrocautery had a regular menstrual cycle 8–12 years after randomization versus 36% in those allocated to rFSH (RR: 1.5; 95% CI: 0.87–2.6). Conclusion In women with clomiphene-resistant PCOS, laparoscopic electrocautery of the ovaries is as effective as ovulation induction with FSH treatment in terms of live births, but reduces the need for ovulation induction or ART in a significantly higher proportion of women and increases the chance for a second child. Clinicians may use these data when informing clomiphene-resistant anovulatory women about treatment options. Gepubliceerd: Hum Reprod. 2011; 26(7):1899-1904 Impact factor: 4.357
6. Hysterectomy, endometrial ablation and Mirena® for heavy menstrual bleeding: a systematic review of clinical effectiveness and cost-effectiveness analysis S Bhattacharya,1 LJ Middleton,2 A Tsourapas,2 AJ Lee,1 R Champaneria,2 JP Daniels,2 T Roberts,2 NH Hilken,2 P Barton,2 R Gray,2 KS Khan,2 P Chien,3 P O’Donovan,4 KG Cooper5 and the International Heavy Menstrual Bleeding Individual Patient Data Meta-analysis Collaborative Group * Includes IA van Zon-Rabelink
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University of Aberdeen, Aberdeen, UK University of Birmingham, Birmingham, UK 3 Ninewells Hospital, Dundee, UK 4 Bradford Royal Infirmary, Bradford, UK 5 Aberdeen Royal Infirmary, Aberdeen, UK * Department of Gynaecology, Medisch Spectrum Twente, Enschede 2
Objective: The aim of this project was to determine the clinical effectiveness and cost-effectiveness of hysterectomy, first- and second-generation endometrial ablation (EA), and Mirena® (Bayer Healthcare Pharmaceuticals, Pittsburgh, PA, USA) for the treatment of heavy menstrual bleeding. Design: Individual patient data (IPD) meta-analysis of existing randomised controlled trials to determine the short- to medium-term effects of hysterectomy, EA and Mirena. A population-based retrospective cohort study based on record linkage to investigate the long-term effects of ablative techniques and hysterectomy in terms of failure rates and complications. Cost-effectiveness analysis of hysterectomy versus first- and second-generation ablative techniques and Mirena. Setting: Data from women treated for heavy menstrual bleeding were obtained from national and international trials. Scottish national data were obtained from the Scottish Information Services Division. Participants: Women who were undergoing treatment for heavy menstrual bleeding were included. Interventions: Hysterectomy, first- and second-generation EA, and Mirena. Main outcome measures: Satisfaction, recurrence of symptoms, further surgery and costs. Results: Data from randomised trials indicated that at 12 months more women were dissatisfied with first-generation EA than hysterectomy [odds ratio (OR): 2.46, 95% confidence interval (CI) 1.54 to 3.93; p = 0.0002), but hospital stay [WMD (weighted mean difference) 3.0 days, 95% CI 2.9 to 3.1 days; p < 0.00001] and time to resumption of normal activities (WMD 5.2 days, 95% CI 4.7 to 5.7 days; p < 0.00001) were longer for hysterectomy. Unsatisfactory outcomes associated with first- and second-generation techniques were comparable [12.2% (123/1006) vs 10.6% (110/1034); OR 1.20, 95% CI 0.88 to 1.62; p = 0.2). Rates of dissatisfaction with Mirena and second-generation EA were similar [18.1% (17/94) vs 22.5% (23/102); OR 0.76, 95% CI 0.38 to 1.53; p = 0.4]. Indirect estimates suggested that hysterectomy was also preferable to second-generation EA (OR 2.32, 95% CI 1.27 to 4.24; p = 0.006) in terms of patient dissatisfaction. The evidence to suggest that hysterectomy is preferable to Mirena was weaker (OR 2.22, 95% CI 0.94 to 5.29; p = 0.07). In women treated by EA or hysterectomy and followed up for a median [interquartile range (IQR)] duration of 6.2 (2.7-10.8) and 11.6 (7.9-14.8) years, respectively, 962/11,299 (8.5%) women originally treated by EA underwent further gynaecological surgery. While the risk of adnexal surgery was similar in both groups [adjusted hazards ratio 0.80 (95% CI 0.56 to 1.15)], women who had undergone ablation were less likely to need pelvic floor repair [adjusted hazards ratio 0.62 (95% CI 0.50 to 0.77)] and tension-free vaginal tape surgery for stress urinary incontinence [adjusted hazards ratio 0.55 (95% CI 0.41 to 0.74)]. Abdominal hysterectomy led to a lower chance of pelvic floor repair surgery [hazards ratio 0.54 (95% CI 0.45 to 0.64)] than vaginal hysterectomy. The incidence of endometrial
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cancer following EA was 0.02%. Hysterectomy was the most cost-effective treatment. It dominated first-generation EA and, although more expensive, produced more quality-adjusted life-years (QALYs) than second-generation EA and Mirena. The incremental cost-effectiveness ratios for hysterectomy compared with Mirena and hysterectomy compared with second-generation ablation were £1440 per additional QALY and £970 per additional QALY, respectively. Conclusions: Despite longer hospital stay and time to resumption of normal activities, more women were satisfied after hysterectomy than after EA. The few data available suggest that Mirena is potentially cheaper and more effective than first-generation ablation techniques, with rates of satisfaction that are similar to second-generation techniques. Owing to a paucity of trials, there is limited evidence to suggest that hysterectomy is preferable to Mirena. The risk of pelvic floor surgery is higher in women treated by hysterectomy than by ablation. Although the most cost-effective strategy, hysterectomy may not be considered an initial option owing to its invasive nature and higher risk of complications. Future research should focus on evaluation of the clinical effectivesness and cost-effectiveness of the best second-generation EA technique under local anaesthetic versus Mirena and types of hysterectomy such as laparoscopic supracervical hysterectomy versus conventional hysterectomy and second-generation EA. Gepubliceerd: Health Technol Assess. 2011;15(19):iii-xvi, 1-252 Impact factor: 4.197
7. Outcome of Endometrial Cancer Stage IIIA with Adnexa or Serosal Involvement Only Jobsen JJ1, Naudin Ten Cate L2, Lybeert ML3, Scholten A4, van der Steen-Banasik EM5, van der Palen J6,7, Stenfert Kroese MC8, Slot A9, Schutter EM10, Siesling S11 1 Department of Radiation Oncology, Medisch Spectrum Twente, Enschede 2 Laboratorium Pathologie Oost Nederland, Enschede 3 Department of Radiation Oncology, Catharina Hospital, Eindhoven 4 Department of Clinical Oncology, Leiden University Medical Center, Leiden 5 Arnhem Radiotherapeutic Institute, Arnhem 6 Department of Research Methodology, Measurement, and Data Analysis, Faculty of Behavioral Science, University of Twente, Enschede 7 Department of Clinical Epidemiology, Medisch Spectrum Twente, Enschede 8 Radiotherapy Institute Steden en Omstreken, Deventer 9 Radiotherapy Institute Friesland, Leeuwarden 10 Department of Obstetrics and Gynaecology, Medisch Spectrum Twente, Enschede 11 Comprehensive Cancer Centre North East, Enschede/Groningen Objective. The aim of this study is to look at possible differences in outcome between serosa and adnexal involvement stage IIIA endometrial carcinoma. Methods. 67 patients with stage IIIA endometrial carcinoma were included, 46 with adnexal involvement and 21 with serosa. A central histopathological review was performed.
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Results. The 7-year locoregional failure rate was (LRFR) 2.2% for adnexal involvement and 16.0% for involvement of the serosa (P = .0522). The 7-year distant metastasis-free survival was 72.7% for adnexal involvement and 58.7% for serosa (P = .3994). The 7-year disease-specific survival (DSS) was 71.8% for patients with adnexal involvement and 75.4% for patients with serosa. Conclusion. Endometrial carcinoma stage IIIA with involvement of the adnexa or serosa showed to have a comparable disease-specific survival. Locoregional control was worse for serosa involvement compared to adnexa. Gepubliceerd: Obstet Gynecol Int.;2011:962518 Impact factor: 4.392
Totale impact factor: 21.169 Gemiddelde impact factor: 3.024 Aantal artikelen 1e, 2e of laatste auteur: 4 Totale impact factor: 12.580 Gemiddelde impact factor: 3.145
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Heelkunde 1. A woman with bilateral linear striations in femur and tibia Winkelhorst T, Raber MH Department of Surgery, Medisch Spectrum Twente, Enschede A 20-year-old woman was referred to our hospital with complaints of both knees due to patellofemoral pain. Osteopathia striata, a rare radiographic skeletal disorder, manifested by fine, linear striations primarily in the long bones, was a chance finding. Gepubliceerd: Ned Tijdschr Geneeskd. 2011;155(18):A1659. Impact factor: 0
2. Regarding “Infrapopliteal balloon angioplasty for the treatment of chronic occlusive disease” T Boelstra1, R Meerwaldt1, RH Geelkerken1, CJ Zeebregts2 1 Department of Surgery, Medical Spectrum Twente, Enschede 2 Department of Surgery, Division of Vascular Surgery, UMC Groningen, Groningen Critical limb ischemia (CLI) usually represents extensive multilevel arterial occlusive disease, often requiring infrapopliteal revascularization. Angioplasty also seems very promising in this segment. Previous studies on the effect of infrapopliteal angioplasty in CLI were often limited by a lack of description of patient and lesion characteristics. In a recent article in the Journal of Vascular Surgery, Conrad et al1 described their results with infrapopliteal angioplasty in a large study with 144 patients and with well-described CLI and lesion characteristics. The limb salvage rate at 40 months of follow-up was 86%, despite inferior patency rates. The authors concluded that infrapopliteal angioplasty should be considered the initial therapy for these patients. Important information is missing in their report, however. Almost 70% of their patients had diabetes mellitus, and claiming a success in limb salvage as a result of angioplasty in such patients seems somehow inappropriate. Tissue loss and healing of ulcers in diabetic patients is strongly related to diabetic neuropathy, infections, and microvascular diabetic complications, besides peripheral arterial occlusive disease.2 Many of these patients often have an ankle-brachial index of about 50 mm Hg or higher (subcritical ischemia), and limb loss rates are relatively low whether they undergo revascularization or not.3,4 Information on the presence of neuropathy and other microvascular complications, as well as the actual ankle-brachial index, are needed to adequately interpret the results reported by Conrad et al. Furthermore, multilevel treatment was necessary in 74% of their patients. Dilatation of inflow lesions was performed in 40% to 88% of the patients in infrapopliteal angioplasty studies. Experience with combined multisegment occlusive disease indicates that treatment of the more proximal lesion alone was appropriate in_40% to 75% of the patients to relieve CLI.5 The concurrent angioplasty of inflow lesions may explain the observed high gap between infrapopliteal lesion patency and limb salvage rates. What were the proximal lesions (ie, TransAtlantic InterSociety
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Consensus classification and level), what procedures were performed for these more proximal lesions (angioplasty or bypass surgery), and what were the patency rates of these procedures in the Conrad et al study? This information is needed to understand their success in treating these patients. Finally, indicating angioplasty as the initial therapy in patients with CLI needs some caution after the results of the Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial.6 Approximately 75% of the BASIL cohort survived _2 years, and an angioplasty-first strategy in these patients did not fare as well as a bypass surgery-first strategy. Improvements in endovascular therapy allow an increasing subset of patients to be treated with angioplasty. Angioplasty and open surgery are, however, complementary, and therapy must be individualized. More information is needed from Conrad et al to fully appreciate their study. References 1. Conrad MF, Kang J, Cambria RP, Brewster DC, Watkins MT, Kwolek CJ, et al. Infrapopliteal balloon angioplasty for the treatment of chronic occlusive disease. J Vasc Surg 2009;50:799-805. 2. Adam DJ, Raptis S, Fitridge RA. Trends in the presentation and surgical management of the acute diabetic foot. Eur J Vasc Endovasc Surg 2006;31:151-6. 3. Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet 2005;366:1925-34. 4. Wolfe JH, Wyatt MG. Critical and subcritical ischaemia. Eur J Vasc Endovasc Surg 1997;13:578-82. 5. Bakal CW, Cynamon J, Sprayregen S. Infrapopliteal percutaneous transluminal angioplasty: what we know. Radiology 1996;200:36-43. 6. Bradbury AW. Bypass versus angioplasty in severe ischaemia of the leg (BASIL) trial: what are its implications? Semin Vasc Surg 2009;22:267-74. Gepubliceerd: J Vasc Surg. 2011 Mar;53(3):884 Impact factor: 3.851
3. A conservative and minimally invasive approach to necrotizing pancreatitis improves outcome HC van Santvoort1, OJ Bakker1, TL Bollen2, MG Besselink1, U Ahmed Ali1, AM Schrijver1, MA Boermeester3, H van Goor4, CH Dejong5, CH van Eijck6, B van Ramshorst7, AF Schaapherder8, E van der Harst9, S Hofker10, VB Nieuwenhuijs10, MA Brink11, PM Kruyt12, ER Manusama13, GP van der Schelling14, T Karsten15, EJ Hesselink16, CJ van Laarhoven17, C Rosman18, K Bosscha19, RJ de Wit20, AP Houdijk21, MA Cuesta22, PJ Wahab23, HG Gooszen1 1 Dept. of Surgery, UMC Utrecht, Utrecht 2 Dept. of Radiology St. Antonius Hospital, Nieuwegein 3 Dept. of Surgery, AMC Center, Amsterdam 4 Dept. of Surgery, Radboud University Nijmegen MC, Nijmegen 5 Dept. of Surgery and NUTRIM, Maastricht UMC, Maastricht 6 Dept. of Surgery, St. Antonius Hospital, Nieuwegein 7 Dept. of Surgery, Erasmus MC, Rotterdam
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Dept. of Surgery, Leiden UMC, Leiden Dept. of Surgery, Maasstad Hospital, Rotterdam 10 Dept. of Surgery, UMC Groningen, Groningen 11 Dept. of Gastroenterology, Meander Medical Center, Amersfoort 12 Dept. of Surgery, Gelderse Vallei Hospital, Ede 13 Dept. of Surgery, Leeuwarden Medical Center 14 Dept. of Surgery, Amphia Medical Center, Breda 15 Dept. of Surgery, Reinier de Graaf Hospital, Delft 16 Dept. of Surgery, Gelre Hospital, Apeldoorn 17 Dept. of Surgery, St. Elisabeth Hospital, Tilburg (currently: Dept. of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen) 18 Dept. of Surgery, Canisius Wilhelmina Hospital, Nijmegen 19 Dept. of Surgery, Jeroen Bosch Hospital, Den Bosch 20 Dept. of Surgery, Medisch Spectrum Twente, Enschede 21 Dept. of Surgery, Medical Center Alkmaar, Alkmaar 22 Dept. of Surgery, Vrije Universiteit MC, Amsterdam 23 Dept. of Gastroenterology, Rijnstate Hospital, Arnhem 9
Background & aims: Treatment of necrotizing pancreatitis has become more conservative and less invasive, but there are few data from prospective studies to support the efficacy of this change. We performed a prospective, multicenter study of treatment outcomes among patients with necrotizing pancreatitis. Methods: We collected data from 639 consecutive patients with necrotizing pancreatitis, from 2004 to 2008, treated at 21 Dutch hospitals. Data were analyzed for disease severity, interventions (radiological, endoscopic, surgical), and outcome. Results: Overall mortality was 15% (n=93). Organ failure occurred in 240 patients (38%), with 35% mortality. Treatment was conservative in 397 patients (62%), with 7% mortality. An intervention was performed in 242 patients (38%), with 27% mortality; this included early emergency laparotomy in 32 patients (5%), with 78% mortality. Patients with longer times between admission and intervention had lower mortality: 0-14 days, 56%; 14-29 days, 26%; and >29 days, 15%,P <.001. Twohundred eight patients (33%) received interventions for infected necrosis, with 19% mortality. Catheter drainage was most often performed as the first intervention (63% of cases), without additional necrosectomy in 35% of patients. Primary catheter drainage had fewer complications than primary necrosectomy (42% vs. 64%,P =.003). Patients with pancreatic parenchymal necrosis (n=324), compared to patients with only peripancreatic necrosis (n=315), had a higher risk of organ failure (50% vs. 24%,P <.001) and mortality (20% vs. 9%,P <.001). Conclusions: Approximately 62% of patients with necrotizing pancreatitis can be treated without an intervention and with low mortality. In patients with infected necrosis, delayed intervention and catheter drainage as first treatment improves outcome. Gepubliceerd: Gastroenterology. 2011;141(4):1254-63 Impact factor: 12.032
4. Case Report: Bilateral PAES As Cause of Lower Leg Pain in Young Athlete
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Kamphuis D, Raber M, Meerwaldt R Department of Surgery, Medisch Spectrum Twente, Enschede Gepubliceerd: Am Fam Physician 2011;84(11):1195-8 Impact factor: 1.547
5. Viable Tumor Tissue Adherent to Needle Applicators after Local Ablation: A Risk Factor for Local Tumor Progression Snoeren N1, Huiskens J2, Rijken AM3, van Hillegersberg R1, van Erkel AR4, Slooter GD5, Klaase JM6, van den Tol PM7, Ten Kate FJ2, Jansen MC2, van Gulik TM2 1 Department of Surgery, UMC Utrecht, Utrecht; 2 AMC, Amsterdam; 3 Amphia Hospital, Breda; 4 Leiden UMC, Leiden; 5 Maxima Medical Centre, Veldhoven; 6 Medisch Spectrum Twente, Enschede; 7 VU MC, Amsterdam Background: Local tumor progression (LTP) is a serious complication after local ablation of malignant liver tumors, negatively influencing patient survival. LTP may be the result of incomplete ablation of the treated tumor. In this study, we determined whether viable tumor cells attached to the needle applicator after ablation was associated with LTP and disease-free survival. Methods: In this prospective study, tissue was collected of 96 consecutive patients who underwent local liver ablations for 130 liver malignancies. Cells and tissue attached to the needle applicators were analyzed for viability using glucose-6phosphate-dehydrogenase staining and autofluorescence intensity levels of H&E stained sections. Patients were followed-up until disease progression. Results: Viable tumor cells were found on the needle applicators after local ablation in 26.7% of patients. The type of needle applicator used, an open approach, and the omission of track ablation were significantly correlated with viable tumor tissue adherent to the needle applicator. The presence of viable cells was an independent predictor of LTP. The attachment of viable cells to the needle applicators was associated with a shorter time to LTP. Conclusions: Viable tumor cells adherent to the needle applicators were found after ablation of 26.7% of patients. An independent risk factor for viable cells adherent to the needle applicators is the omission of track ablation. We recommend using only RFA devices that have track ablation functionality. Adherence of viable tumor cells to the needle applicator after local ablation was an independent risk factor for LTP. Gepubliceerd: Ann Surg Oncol. 2011;18(13):3702-10 Impact factor: 4.182
6. The Role of High Frequency Dynamic Threshold (HiDT) Serum Carcinoembryonic Antigen (CEA) Measurements in Colorectal Cancer Surveillance: A (Revisited) Hypothesis Paper I Grossmann1,2, C Verberne2, G De Bock3, K Havenga3, I Kema4, J Klaase5, A Renehan6, T Wiggers2 1 Department of Surgery, Catharina Hospital, Eindhoven 2 Department of Surgery, UMC Groningen, Groningen
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Department Epidemiology and Biostatistics, UMC Groningen, Groningen Department of Clinical Chemistry, UMC Groningen, Groningen 5 Department of Surgery, Medical Spectrum Twente, Enschede 6 The Christie NHS Foundation Trust, School of Cancer, Enabling Sciences and Technology, University of Manchester, Manchester, UK 4
Following curative treatment for colorectal cancer (CRC), 30% to 50% of patients will develop recurrent disease. For CRC there are several lines of evidence supporting the hypothesis that early detection of metachronous disease offers a second opportunity for cure. This paper revisits the potential role of serum carcinoembryonic antigen (CEA) in follow-up. A comprehensive review of the literature (1978–2008) demonstrates that the initial promise of serum CEA as an effective surveillance tool has been tarnished through perpetuation of poorly designed studies. Specific limitations included: testing CEA as only an ‘add-on’ diagnostic tool; lack of standardization of threshold values; use of static thresholds; too low measurement frequency. Major changes in localizing imaging techniques and treatment of metastatic CRC further cause a decrease of clinical applicability of past trial outcomes. In 1982, Staab hypothesized that the optimal benefit of serum CEA as a surveillance tool is through high-frequency triage using a dynamic threshold (HiDT). Evidence supporting this hypothesis was found in the biochemical characteristics of serum CEA and retrospective studies showing the superior predictive value of a dynamic threshold. A multi-centred randomized phase III study optimizing the usage of HiDT against resectability of recurrent disease is commencing recruitment in the Netherlands. Gepubliceerd: Cancers 2011, 3(2), 2302-2315 Impact factor: 0
7. The strengths and limitations of routine staging before treatment with abdominal CT in colorectal cancer I Grossmann1,2, JM Klaase2, JK Avenarius3, IH de Hingh4, WJ Mastboom2, T Wiggers1 1 Department of surgery, University Medical Center Groningen, Groningen 2 Department of surgery, Medical Spectrum Twente, Enschede 3 Department of radiology, Medical Spectrum Twente, Enschede 4 Department of Surgery, Catharina Hospital, Eindhoven Background: Advanced colorectal cancer (CRC), either locally advanced (LA), metastasized (mCRC) or both, is present in a relevant proportion of patients. The chances on curation of advanced CRC are continuously improving with modern multi-modality treatment options. Less invasive procedures in incurable CRC may improve short term outcomes and the quality of life. Both situations motivate adequate staging before treatment in CRC. This prospective observational study evaluates the outcomes after the introduction of routine staging with abdominal CT before treatment.
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Methods: In a prospective observational study of 612 consecutive patients (20072009), the ability of abdominal CT to find liver metastases (LM), peritoneal carcinomatosis (PC) and T4 stage in colon cancer (LACC) was analyzed. Results: Advanced CRC was present in 58% of patients, mCRC in 31%. The ability to find LM was excellent (99%), cT4 stage CC good (86%) and PC poor (33%). In the group of surgical patients with emergency presentations, the incidences of both mCRC (51%) and LACC (69%) were higher than in the elective group (20% and 26% respectively). Staging tended to be omitted more often in the emergency group (35% versus 12% in elective surgery). Conclusion: The strengths of staging with abdominal CT are to find LM and LACC, however it fails in diagnosing PC. On grounds of the incidence of advanced CRC, staging is warranted as well in patients with emergency presentations. Gepubliceerd: BMC Cancer. 2011 Oct 7;11(1):433 Impact factor: 3.153
8. Imaging tumor vascularization for detection and diagnosis of breast cancer M Heijblom1,2; JM Klaase2; FM van den Engh4; TG van Leeuwen1,3; W Steenbergen1; S Manohar1 1 Biomedical Photonic Imaging Group, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 2 Department of Surgery, Center for Breast Care, Medisch Spectrum Twente, Enschede 3 Biomedical Engineering and Physics, AMC, University of Amsterdam, Amsterdam 4 Department of Radiology, Medisch Spectrum Twente, Enschede Breast cancer is one of the major causes of morbidity and mortality in western women. Current screening and diagnostic imaging modalities, like x-ray mammography and ultrasonography, focus on morphological changes of breast tissue. However, these techniques still miss some cancers and often falsely detect cancer. The sensitivity and specificity for detecting the disease can probably be improved by focusing on the consequences of tumor angiogenesis: the increased microvessel density with altered vascular characteristics. In this review, various techniques for imaging breast tumor vasculature are discussed. Dynamic contrast enhanced magnetic resonance imaging is the most-used imaging modality in this field. It has a proven high sensitivity, but a low specificity and cannot be applied in all women. Moreover, it has problems with detecting ductal carcinoma in situ (DCIS). On the contrary, contrast enhanced digital mammography can detect DCIS, but requires the use of ionizing radiation. Contrast enhanced ultrasound provides realtime information about true intravascular blood volume and flow. However, this technique still has difficulties with discriminating benign from malignant tissue. Moreover, these three imaging modalities all require the injection of contrast agents. Two relatively new techniques that do not use external contrast agents are diffuse optical imaging and photoacoustic imaging. Both visualize the increased concentration of hemoglobin in malignant tissue and thereby provide a high intrinsic contrast.
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Gepubliceerd: Technol Cancer Res Treat. 2011;10(6):607-23 Impact factor: 1.814
9. Medical treatment in carotid artery intervention Kolkert JL1,2, Meerwaldt R1, Lefrandt JD2, Geelkerken RH1, Zeebregts CJ2 1 Department of Surgery, Medisch Spectrum Twente Enschede 2 Department of Surgery, UMC Groningen, University of Groningen, Groningen Medical treatment has a pivotal role in the treatment of patients with occlusive carotid artery disease. Large trials have provided the justification for operative treatment besides medical treatment in patients with recent significant carotid artery stenosis two decades ago. Since then, medical therapy has evolved tremendously. Next to aspirin, antiplatelet regimens acting on a different level in the modulation of platelet aggregation have made their entry. Moreover, statin therapy has been introduced. These changes among others in secondary stroke prevention, along with better understanding in life-style adjustments and perioperative medical management, have led to a decrease in stroke recurrence. Secondary prevention is therefore now the most important pillar of medical therapy. It consists of antiplatelet therapy, statins and blood pressure lowering agents in all patients. Small adjustments are recommended for those patients referred for invasive treatment. Moreover, long-term medical treatment is imperative. In this article, we summarize current evidence in literature regarding medical management in patients with previous stroke or TIA. Gepubliceerd: J Cardiovasc Surg (Torino). 2011;52(6):803-19 Impact factor: 1.352
10. Protection of stapled colorectal anastomoses with a biodegradable device: the C-Seal feasibility study Kolkert JL1,2, Havenga K2, ten Cate Hoedemaker HO2, Zuidema J3, Ploeg RJ2 1 Department of Surgery, Medisch Spectrum Twente Enschede 2 Department of Surgery, UMC Groningen, University of Groningen, Groningen 3 Polyganics BV, Groningen Background: A colorectal anastomotic leak can be life-threatening. We have assessed the feasibility of a new intraluminal biodegradable bypass device that we designed to avoid anastomotic leakage and the necessity of a temporary stoma. Methods: Fifteen patients underwent colorectal surgery. Before performing the anastomosis in a standard way, the C-Seal (Polyganics BV, Groningen, The Netherlands) was glued to the anvil of the circular stapler. Consequently, the bypass was fixated in the staple row just proximal of the simultaneously made anastomosis. A water-soluble contrast enema was performed after 1 week. Results: The sheath was well compatible with the standard stapler device and easy to use. All donuts remained intact. No radiologic or clinical leaks were observed after surgery.
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Conclusions: This pilot study shows that the C-Seal can be applied successfully in colorectal surgery. Further investigation with large numbers of patients is now necessary to assess the efficacy of the C-Seal as a protective device. Gepubliceerd: Am J Surg. 2011;201(6):754-8 Impact factor: 2.680
11. Overestimation of contralateral internal carotid artery stenosis before ipsilateral surgical endarterectomy Kolkert JL1,2, van den Dungen JJ2, Loonstra J2, Tielliu IF2, Verhoeven EL2, Beck AW2, Zeebregts CJ2 1 Department of Surgery, Medisch Spectrum Twente, Enschede 2 Department of Surgery, Division of Vascular Surgery, UMC Groningen, Groningen Objective: The aim of this study was to investigate a possible overestimation of the degree of contralateral carotid artery stenosis by duplex in patients with significant bilateral carotid stenoses who are to undergo carotid endarterectomy (CEA). Methods: A retrospective analysis was performed of all patients undergoing CEA in our center over a period of 11 years. Pre- and postoperative duplex ultrasonography measurements of peak systolic velocity (PSV) and end diastolic velocity (EDV) were compared and used to classify the degree of stenosis. Univariate analysis was performed to indicate possible predictors for contralateral stenosis overestimation. Results: A total of 384 CEA procedures in 357 patients were performed in our hospital. Pre- and postoperative bilateral duplex measurements were available in 135 patients. Forty-four out of 135 patients (33%) were preoperatively identified as having significant stenosis (>60%) of the internal carotid artery on both sides. In these patients, postoperative duplex measurements of the contralateral carotid showed a decrease in mean (SD) PSV from 2.53 (1.11) m s(-1) to 1.97 (0.87) m s(1) (P<0.01) and a decrease in EDV from 0.87 (0.60) m s(-1) to 0.60 (0.36) m s(-1) (P<0.01). The absolute changes in contralateral PSV and EDV after CEA were larger among patients with a higher degree of stenosis preoperatively. These changes led to reclassification of stenosis to a lesser degree in 24 (55%) patients. In 16 cases (36%), this resulted in a measured stenosis on the contralateral side of less than 60%. Conclusions: One-third of the patients with duplex measurements consistent with bilateral significant carotid stenosis did not have a significant contralateral stenosis by duplex after CEA. Therefore, additional postoperative duplex measurement is advisable before planning contralateral CEA. Gepubliceerd: Eur J Radiol. 2011;77(1):68-72 Impact factor: 2.941
12. Salvage surgery for a giant melanoma on the back Kruijff S, Vink R, Klaase J Department of Surgery, Medisch Spectrum Twente, Enschede
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We report a case of a giant melanoma on the back with a very extreme Breslow thickness. On physical examination a large odorous and ulcerating tumour was seen adjacent to two large crusted lesions, probably in transit metastases. In the right and left axilla enlarged lymph nodes were palpated. The patient underwent salvage surgery consisting of a complete wide excision of the tumors on the back as well as axillary lymph node dissection on both sides. Histopathology showed a malignant melanoma with a Breslow thickness of 48 mm. Four of fifteen nodes in the right axilla and one of nine nodes in the left axilla, were positive for metastatic disease. Also various in transit and subcutaneous metastases were found in the wide excision specimen. The interest of our observation relies in the rarity of a melanoma with such an extreme Breslow thickness and the difficulty in performing adequate palliative therapy that offers quality of life by means of tumor control. Gepubliceerd: Rare Tumors. 2011;3(3):e28 Impact factor: 0
13. Endarterectomy more favourable than stenting in symptomatic significant carotid stenosis: higher risk of ischaemic stroke or death following stenting Meerwaldt R1, Beuk RJ1, Huisman AB2, Manschot S3, Zeebregts CJ4, Geelkerken RH1 1 Afd. Chirurgie,2 Radiologie, 3 Neurologie, Medisch Spectrum Twente, Enschede 4 Afd. Chirurgie, UMC Groningen, Groningen. Carotid endarterectomy (CEA) has proven its value in the treatment of patients with recent significant carotid artery stenosis.- Percutaneous transluminal angioplasty with carotid artery stenting ('stenting' in short) is an alternative to CEA.- The results of stenting and CEA in patients with symptomatic significant carotid artery stenosis were evaluated in 9 prospective randomized controlled trials and 11 meta-analyses. Almost all of these trials failed to show superiority of stenting to CEA.- According to the 4 largest and most recent studies in this field the risk of a stroke or death within 30 days after the intervention is considerably higher following stenting than following CEA.- In the long run the results of stenting and CEA seem to be comparable.- CEA remains the gold standard in treatment of significant carotid artery stenosis, in particular in patients older than 70. Gepubliceerd: Ned Tijdschr Geneeskd. 2011;155(5):A2411 Impact factor: 0
14. Increased skin autofluorescence after colorectal operation reflects surgical stress and postoperative outcome Pol HW1, Sibma E1, Zeebregts CJ2, Pierik EG1, Meerwaldt R3 1 Department of Surgery, Isala Clinics, Zwolle 2 Department of Surgery, Division of Vascular Surgery, UMC Groningen, University of Groningen 3 Department of Surgery, Medisch Spectrum Twente, Enschede
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Background: Abdominal surgery is a major oxidative stress effector. The increase in oxidative stress has been related to postoperative complications. Oxidative stress leads to the formation and accumulation of oxidation protein end products, which exhibit autofluorescence (AF) and induce inflammatory reactions. Methods: Skin AF was assessed perioperatively in 40 consecutive colorectal surgery patients until discharge. Duration of surgery, estimated blood loss, and urinary production per hour were analyzed as measures of surgical stress. The clinical occurrence of anastomotic leakage, systemic infections, and cardiopulmonary complications within 30 days of surgery were analyzed. Results: A perioperative increase in skin AF of 19 ± .2% was observed. Duration of operation and blood loss were independently associated with the perioperative increase in skin AF. Skin AF correlated with C-reactive protein levels postoperatively. American Society of Anesthesiologists classification, duration of operation, and preoperative and perioperative increases in AF were independently associated with postoperative complications. Conclusions: This is the first study to demonstrate an association between skin AF and surgical stress and outcomes, which may rate the condition of a patient after operation. Gepubliceerd: Am J Surg. 2011;202(5):583-9 Impact factor: 2.680
15. A man with a lesion on the palate Muller Kobold JP1, Nijdam ES2 1 Afdeling chirurgie, Medisch Spectrum Twente, Enschede 2 Afdeling kaakchirurgie, Medisch Spectrum Twente, Enschede A 77-year-old man had a dark lesion on the palate. The lesion was found when fitting a new set of dentures. Except ill-fitting false teeth, the man had no complaints. Examination of a biopsy revealed a melanoma. The palatum was surgically removed. Gepubliceerd: Ned Tijdschr Geneeskd. 2011;155(18):A2135 Impact factor: 0
16. A woman with a mass in her abdomen Muller Kobold JP, Raber MH Department of Surgery, Medisch Spectrum Twente, Enschede A 43-year-old woman was referred; she had felt an abdominal mass on her left side. Imaging showed a cystic lesion. The lesion was removed via laparotomy. Pathological examination showed a benign mucinous cyst. Gepubliceerd: Ned Tijdschr Geneeskd 2011;155(18):A2162 Impact factor: 0
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17. A young man with intimomedial mucoid degeneration of the brachial artery Raber MH, Meerwaldt R, van Det RJ Department of Surgery, Medisch Spectrum Twente, Enschede Intimomedial mucoid degeneration is a rare disorder and has been described as a distinctly different entity from Erdheim's cystic medial necrosis. Most studies show a strong predominance in African American females with hypertension. In our case report, we describe the presence of a large brachial aneurysm in a young white male with intimomedial mucoid degeneration. Gepubliceerd: J Vasc Surg. 2011;53(3):822-824 Impact factor: 3.851
18. Delayed Primary Closure of the Septic Open Abdomen with a Dynamic Closure System Verdam FJ1,2, Dolmans DE1,3, Loos MJ4, Raber MH5, de Wit RJ5, Charbon JA4, Vroemen JP1 1 Department of General Surgery, Amphia Hospital, Breda 2 Department of General Surgery, Maastricht UMC, Maastricht 3 Department of General Surgery, Atrium Medical Center, Heerlen M. J. Loos _ J. A. Charbon 4 Department of General Surgery, Maxima Medical Centre, Veldhoven 5 Department of General Surgery, Medical Spectrum Twente, Enschede Background: The major challenge in the management of patients with an infected open abdomen (OA) is to control septic peritonitis and intra-abdominal fluid secretion, and to facilitate repeated abdominal exploration, while preserving the fascia for delayed primary closure. We here present a novel method for closure of the infected OA, based on continuous dynamic tension, in order to achieve reapproximation of the fascial edges of the abdominal wall. Methods: Eighteen cases with severe peritonitis of various origin (e.g., gastrointestinal perforations, anastomotic leakage) were primarily stabilized by laparostomy, sealed with either the vacuum-assisted closure abdominal dressing or the Bogotá bag. After hemodynamic stabilization and control of the sepsis, the Abdominal Re-approximation Anchor System (ABRA; Canica Design, Almonte, Ontario, Canada) was applied. This system approximates the wound margins through dynamic traction exerted by transfascial elastomers. Before ABRA application, 5/18 patients had a grade 2B, 2/18 a grade 3, and 11/18 a grade or 4 status according to the open abdomen classification of Björck. Results: In this severely ill population the mean time before ABRA system application was 12 days (range: 2-39 days). Two of 18 patients died of non-ABRArelated causes within three weeks. In 14 of the remaining 16 patients (88%) primary abdominal closure of the midline was accomplished in 15 days (range: 7-30 days). The other two patients needed a component separation technique according to Ramirez to reach closure. However, secondary wound dehiscence occurred in both these patients. Two thirds of patients (12/18) developed pressure sores to the skin
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and/or dermis, but all healed without further complications. During outpatient clinic follow-up, 4/14 successfully closed patients still developed a midline hernia. Conclusions: Delayed primary closure of OA in septic patients could be achieved in 88% with this new approximation system. However, the risk of hernia development remained. We consider this system a useful tool in the treatment of septic patients with an open abdomen. Gepubliceerd: World J Surg. 2011;35(10):2348-55 Impact factor: 2.693
19. Stomal mucocutaneous dehiscence as a complication of a dynamic wound closure system following laparostomy: a case report Raber MH, Steenvoorde P, de Wit R Department of Surgery, Medisch Spectrum Twente, Enschede Dynamic retention suture techniques that allow gradual reapproximation of abdominal midline muscles and fascia as well as sufficient freedom of movement for breathing and patient care commonly are used to prevent lateral retraction of the abdominal fascia in patients whose abdominal wound closure must be delayed. A 58-year-old otherwise healthy man was admitted with severe abdominal sepsis and following surgery, which included the creation of a stoma, a dynamic wound closure system was applied. Mucocutaneous stomal dehiscence was observed a few days after starting the treatment. The complication was believed to have occurred as a result of traction on the proximal end of the stoma (the bowel inside the abdomen) due to tension on the sutures of the small part of the bowel outside the abdomen. Definite, primary closure of the abdominal fascia was achieved after 16 days, at which point the stoma was reinserted with good results. Since using a modified procedure that involves cutting a groove in the protective drape and carefully placing two flaps around the stoma, this complication has not been observed with similar patients in the authors' facility. This complication is not unique to this wound closure system; it also has been reported with other treatment modalities such as negative pressure wound therapy. The relatively small number of patients requiring delayed closure of the abdomen, coupled with the uniqueness of each case due to a wide variety of indications and comorbidities, hampers the development of evidencebased guidelines of care for these patients. A worldwide data exchange that includes patient experiences and descriptions of successful and failed attempts to address problems and complications in these patients is necessary. In the meantime, experiences with these types of wounds need to be shared in the literature. Gepubliceerd: Ostomy Wound Manage 2011;57:34-37 Impact factor: 0.800
20. Initial promising results of the dynamic locking blade plate, a new implant for the fixation of intracapsular hip fractures: results of a pilot study Roerdink WH1, Aalsma AM2, Nijenbanning G2, van Walsum AD1
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1 2
Department of Traumatology, Medisch Spectrum Twente, Enschede BAAT Medical Engineering, Hengelo
The osteosynthesis of intracapsular hip fractures results in a 19-48% failure rate. Only when the anatomical reduction is secured by stable fixation, revascularisation of the femoral head can take place and the fracture can heal by primary osteonal reconstruction. The common implants lack rotational and/or angular stability. Also the relative large volume of the implants within the femoral head compromises the (re)vascularisation. The combination of an anatomical reduction and a low volume, dynamic implant, providing angular and rotational stability seem to be crucial factors in the treatment of intracapsular hip fractures. This assumption formed the starting point for the development of the dynamic locking blade plate (DLBP), a new implant for the internal fixation of intracapsular hip fractures. This report describes the first clinical results of the new implant. Gepubliceerd: Arch Orthop Trauma Surg. 2011;131(4):519-24 Impact factor: 1.196
21. Surgical options for the management of visceral artery aneurysms Van Petersen A1, Meerwaldt R1, Geelkerken R1, Zeebregts C2 1 Department of Surgery, Medisch Spectrum Twente, Enschede 2 Department of Surgery, Division of Vascular Surgery, UMC Groningen, University of Groningen, Groningen Visceral artery aneurysm (VAA) is a rare entity but increased use of abdominal imaging has led to an increased prevalence. Rupture is related to a high mortality rate. Open repair, endovascular treatment and laparoscopic techniques have been described as treatment options. In this systematic review we describe the surgical options for treating VAA. A literature search identified articles focussing on the key issues of visceral artery aneurysms and surgical options using the Pubmed and Cochrane databases. Case reports dominate the literature about VAA. Twentyseven small case series and ten review articles have been published in the last 20 years concerning the surgical options for VAA. The evidence does not exceed level 3. Surgical treatment is dictated by both patient and aneurysm characteristics. Whether VAA should be treated largely depends upon age, gender, presence of hypertension (e.g. in renal aneurysm), aneurysm size and presentation. Aneurysm size and characteristics, anatomical location and presence of collateral circulation dictate the surgical option to be chosen. The mortality and morbidity rates after elective open repair are low. Literature about surgical options for treating VAA remains scarce. Only a few clinical trials have shown the possibilities and results of open surgical repair. In general, there is no consensus on the surgical treatment of VAA and the highest level of evidence is based upon expert opinions. Gepubliceerd: J Cardiovasc Surg (Torino). 2011;52(3):333-43 Impact factor: 1.352
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22. A man with thoracic pain van Veen MJ, Klaase JM Department of Surgery, Medisch Spectrum Twente, Enschede A 46-year-old man had pain between the shoulders and at the sternum. Two and a half months earlier he had fallen when cycling. It appeared the pain was caused by fractures of thoracic vertebrae v and vi and a dislocation of the manubrium and body of the sternum. Ned Tijdschr Geneeskd. 2011;155(18):A1426 Impact factor: 0
23. A hinged external fixator for complex elbow dislocations: A multicenter prospective cohort study Schep NW1, De Haan J2, Iordens GI1, Tuinebreijer WE1, Bronkhorst MW3, De Vries MR4, Goslings JC5, Ham SJ6, Rhemrev S7, Roukema G8, Schipper IB9, Sintenie JB10, Van der Meulen HG11, Van Thiel TP12, Van Vugt AB13, Verleisdonk EJ14, Vroemen JP15, Wittich P16, Patka P1, Van Lieshout EM1, Den Hartog D1 1 Department of Surgery-Traumatology, Erasmus MC, UMC Rotterdam, Rotterdam 2 Department of Surgery-Traumatology, Westfriesgasthuis, Hoorn 3 Department of Surgery-Traumatology, Bronovo Hospital, The Hague 4 Department of Surgery-Traumatology, Reinier de Graaf Gasthuis, Delft 5 Trauma Unit Department of Surgery, AMC, Amsterdam 6 Department of Orthopaedic Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam 7 Department of Surgery-Traumatology, Medical Center Haaglanden, ‘s-Gravenhage 8 Department of Surgery-Traumatology, Maasstad Hospital, Rotterdam 9 Department of Surgery-Traumatology, Leiden UMC, Leiden 10 Department of Surgery-Traumatology, Elkerliek Hospital, Helmond 11 Department of Surgery-Traumatology, Haga Hospital, ‘s-Gravenhage 12 Department of Surgery-Traumatology, Hospital Queen Beatrix, Winterswijk 13 Department of Surgery-Traumatology, Medical Spectrum Twente, Enschede 14 Department of Surgery-Traumatology, Diakonessenhuis, Utrecht 15 Department of Surgery-Traumatology, Amphia Hospital, Breda 16 Department of Surgery-Traumatology, Sint Antonius Hospital, Nieuwegein Background: Elbow dislocations can be classified as simple or complex. Simple dislocations are characterized by the absence of fractures, while complex dislocations are associated with fractures of the radial head, olecranon, or coronoid process. The majority of patients with these complex dislocations are treated with open reduction and internal fixation (ORIF), or arthroplasty in case of a nonreconstructable radial head fracture. If the elbow joint remains unstable after fracture fixation, a hinged elbow fixator can be applied. The fixator provides stability to the elbow joint, and allows for early mobilization. The latter may be important for preventing stiffness of the joint. The aim of this study is to determine the effect of early mobilization with a hinged external elbow fixator on clinical outcome in patients with complex elbow dislocations with residual instability following fracture fixation.
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Methods: The design of the study will be a multicenter prospective cohort study of 30 patients who have sustained a complex elbow dislocation and are treated with a hinged elbow fixator following fracture fixation because of residual instability. Early active motion exercises within the limits of pain will be started immediately after surgery under supervision of a physical therapist. Outcome will be evaluated at regular intervals over the subsequent 12 months. The primary outcome is the Quick Disabilities of the Arm, Shoulder, and Hand score. The secondary outcome measures are the Mayo Elbow Performance Index, Oxford Elbow Score, pain level at both sides, range of motion of the elbow joint at both sides, radiographic healing of the fractures and formation of periarticular ossifications, rate of secondary interventions and complications, and health-related quality of life (Short-Form 36). Discussion: The outcome of this study will yield quantitative data on the functional outcome in patients with a complex elbow dislocation and who are treated with ORIF and additional stabilization with a hinged elbow fixator. Gepubliceerd: BMC Musculoskelet Disord. 2011;12(1):130 Impact factor: 1.941
24. Influence of routine computed tomography on predicted survival from blunt thoracoabdominal trauma R van Vugt1, J Deunk1, M Brink2, HM Dekker2, DR Kool2, AB van Vugt3,4, MJ Edwards1 1 Departments of Surgery and Trauma, Radboud University Nijmegen MC, Nijmegen 2 Department of Radiology, Radboud University Nijmegen MC, Nijmegen 3 Department of Emergency Medicine, Radboud University Nijmegen MC, Nijmegen 4 Department of Surgery, Medisch Spectrum Twente, Enschede Introduction: Many scoring systems have been proposed to predict the survival of trauma patients. This study was performed to evaluate the influence of routine thoracoabdominal computed tomography (CT) on the predicted survival according to the trauma injury severity score (TRISS). Patients and methods: 1,047 patients who had sustained a high-energy blunt trauma over a 3-year period were prospectively included in the study. All patients underwent physical examination, conventional radiography of the chest, thoracolumbar spine and pelvis, abdominal sonography, and routine thoracoabdominal CT. From this group with routine CT, we prospectively defined a selective CT (sub)group for cases with abnormal physical examination and/or conventional radiography and/or sonography. Type and extent of injuries were recorded for both the selective and the routine CT groups. Based on the injuries found by the two different CT algorithms, we calculated the injury severity scores (ISS) and predicted survivals according to the TRISS methodology for the routine and the selective CT algorithms. Results: Based on injuries detected by the selective CT algorithm, the mean ISS was 14.6, resulting in a predicted mortality of 12.5%. Because additional injuries were found by the routine CT algorithm, the mean ISS increased to 16.9, resulting in a predicted mortality of 13.7%. The actual observed mortality was 5.4%.
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Conclusion: Routine thoracoabdominal CT in high-energy blunt trauma patients reveals more injuries than a selective CT algorithm, resulting in a higher ISS. According to the TRISS, this results in higher predicted mortalities. Observed mortality, however, was significantly lower than predicted. The predicted survival according to MTOS seems to underestimate the actual survival when routine CT is used. Gepubliceerd: Eur J Trauma Emerg Surg. 2011;37(2):185-190 Impact factor: 0.257
25. Prevalence and Relief of Pain in Trauma Patients in Emergency Medical Services Berben SA1, Schoonhoven L2, Meijs TH3,4, van Vugt AB5, van Grunsven PM1 1 Emergency Department and Emergency Healthcare Network; 2Nursing Science, Scientific Institute for Quality of Healthcare, Radboud University Nijmegen Medical Centre 3 Critical Care, HAN University; 4 Ambulance Emergency Medical Service GelderlandZuid, Nijmegen 5 Department of Surgery, Medical Spectrum Twente Hospital, Enschede Objectives: The aim of this study was to give insight in the prevalence of pain, and the (effect of) pain management according to the national emergency medical services analgesia protocol in trauma patients in the Netherlands. Methods: The retrospective document study included adult and alert trauma patients. Data collection concerned patient characteristics, prevalence of pain, and the (effect of) pain management. Actual pain management was compared with the national emergency medical services analgesia protocol for paramedics. Pain relief was defined as a decrease on the Numeric Rating Scale. Results: One thousand four hundred and seven trauma patients were included. A report on pain was missing in 28% of the patients (n=393), 2% of the patients (n=34) reported no pain, and the prevalence of pain was reported by 70% of the patients (n=980). Of the patients in pain, 31% (n=311) had a systematic pain assessment (Numeric Rating Scale) at the scene of accident and the median pain score was 6 (interquartile range=3 to 8). Pharmacological pain treatment was administered to 42% of the patients in pain (n=410), and consisted mainly of intravenous fentanyl. Nonpharmacological pain treatments were cleaning of wounds (n=189), and application of splints or immobilizing bandages (n=130). Pain relief on arrival in the emergency department could only be evaluated in 15% of the patients in pain (n=149). Discussion: Prevalence of pain in trauma was high, and without consistent "objective" reporting of pain it is difficult to evaluate the effectiveness of pain management, despite the adherence to clinical practice guideline or protocol. Paramedics need to elicit and report validated pain measurements. Gepubliceerd: Clin J Pain. 2011;27(7):587-92 Impact factor: 3.114
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26. Colonic stenting versus emergency surgery for acute left-sided malignant colonic obstruction: a multicentre randomised trial JE van Hoofta, e, WA Bemelmanb, Bas Oldenburgg, AW Marinellih, MF Lutke Holzikf, MJ Grubbeni, MA Sprangersc, MG Dijkgraafd, P Fockensa for the collaborative Dutch Stent-In study group a Department of Gastroenterology and Hepatology, AMC, University of Amsterdam, Amsterdam b Department of Surgery, AMC, University of Amsterdam, Amsterdam c Department of Medical Psychology, AMC, University of Amsterdam, Amsterdam d Clinical Research Unit, AMC, University of Amsterdam, Amsterdam e Department of Gastroenterology, Medisch Spectrum Twente, Enschede f Department of Surgery, Medisch Spectrum Twente, Enschede g Department of Gastroenterology and Hepatology, UMC, Utrecht h Department of Surgery, Medical Centre Haaglanden, Den Haag i Department of Gastroenterology, Sint Elisabeth Hospital, Tilburg Background: Colonic stenting as a bridge to elective surgery is an alternative for emergency surgery in patients with acute malignant colonic obstruction, but its benefits are uncertain. We aimed to establish whether colonic stenting has better health outcomes than does emergency surgery. Methods: Patients with acute obstructive left-sided colorectal cancer were enrolled from 25 hospitals in the Netherlands and randomly assigned (1:1 ratio) to receive colonic stenting as a bridge to elective surgery or emergency surgery. The randomisation sequence was computer generated with permuted blocks and was stratified by centre; treatment allocation was concealed by use of a web-based application. Investigators and patients were unmasked to treatment assignment. The primary outcome was mean global health status during a 6-month follow-up, which was assessed with the QL2 subscale of the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (EORTC QLQ-C30). Analysis was by intention to treat. This study is registered, number ISRCTN46462267. Findings: Between March 9, 2007, and Aug 27, 2009, 98 patients were assigned to receive colonic stenting (n=47 patients) or emergency surgery (n=51). Two successive interim analyses showed increased 30-day morbidity in the colonic stenting group, with an absolute risk increase of 0·19 (95% CI -0·06 to 0·41) in analysis of the first 60 patients (14 of 28 patients receiving colonic stenting vs 10 of 32 receiving emergency surgery), and an absolute risk increase of 0·19 (-0·01 to 0·37) in analysis of the first 90 patients (23 of 47 patients vs 13 of 43). In accordance with the advice of the data safety monitoring committee, the study was suspended on Sept 18, 2009, and ended on March 12, 2010. At the final analysis of 98 patients, mean global health status during follow-up was 63·0 (SD 23·8) in the colonic stenting group and 61·4 (SD 21·9) in the emergency surgery group; after adjustment for baseline values, mean global health status did not differ between treatment groups (-4·7, 95% CI -14·8 to 5·5, p=0·36). No difference was recorded between treatment groups in 30-day mortality (absolute risk difference -0·01, 95% CI -0·14 to 0·12, p=0·89), overall mortality (-0·02, -0·17 to 0·14, p=0·84), morbidity (-0·08, -0·27 to 0·11, p=0·43), and stoma rates at latest follow-up (0·09, -0·10 to 0·27, p=0·35). However, the emergency surgery group had an increased stoma rate directly after
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initial intervention (0·23, 0·04 to 0·40, p=0·016) and a reduced frequency of stomarelated problems (between-group difference -12·0, -23·7 to -0·2, p=0·046). The most common serious adverse events were abscess (three in the colonic stenting group vs four in the emergency surgery group), perforations (six vs none), and anastomotic leakage (five vs one), and the most common adverse events were pneumonia (three vs one) and wound infection (one vs three). Interpretation: Colonic stenting has no decisive clinical advantages to emergency surgery. It could be used as an alternative treatment in as yet undefined subsets of patients, although with caution because of concerns about tumour spread caused by perforations. Gepubliceerd: Lancet Oncol. 2011;12(4):344-52 Impact factor: 17.764
Totale impact factor: 69.200 Gemiddelde impact factor: 2.662 Aantal artikelen 1e, 2e of laatste auteur: 18 Totale impact factor: 27.217 Gemiddelde impact factor: 1.512
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Intensive Care 1. Cardiac filling volumes versus pressures for predicting fluid responsiveness after cardiovascular surgery: the role of systolic cardiac function RJ Trof1,2, I Danad1, MW Reilingh1, RM Breukers1, AB Groeneveld1 1 Vrije Universiteit MC, Department of Intensive Care, Amsterdam 2 Department of Intensive Care, Medisch Spectrum Twente, Enschede Introduction: Static cardiac filling volumes have been suggested to better predict fluid responsiveness than filling pressures, but this may not apply to hearts with systolic dysfunction and dilatation. We evaluated the relative value of cardiac filling volume and pressures for predicting and monitoring fluid responsiveness, according to systolic cardiac function, estimated by global ejection fraction (GEF, normal 25 to 35%) from transpulmonary thermodilution. Methods: We studied hypovolemic, mechanically ventilated patients after coronary (n = 18) or major vascular (n = 14) surgery in the intensive care unit. We evaluated 96 colloid fluid loading events (200 to 600 mL given in three consecutive 30-minute intervals, guided by increases in filling pressures), divided into groups of responding events (fluid responsiveness) and non-responding events, in patients with low GEF (<20%) or near-normal GEF (≥20%). Patients were monitored by transpulmonary dilution and central venous (n = 9)/pulmonary artery (n = 23) catheters to obtain cardiac index (CI), global end-diastolic volume index (GEDVI), central venous (CVP) and pulmonary artery occlusion pressure (PAOP). Results: Fluid responsiveness occurred in 8 (≥15% increase in CI) and 17 (≥10% increase in CI) of 36 fluid loading events when GEF was <20%, and 7 (≥15% increase in CI) and 17 (≥10% increase in CI) of 60 fluid loading events when GEF was ≥20%. Whereas a low baseline GEDVI predicted fluid responsiveness particularly when GEF was ≥20% (P = 0.002 or lower), a low PAOP was of predictive value particularly when GEF was <20% (P = 0.004 or lower). The baseline CVP was lower in responding events regardless of GEF. Changes in CVP and PAOP paralleled changes in CI particularly when GEF was <20%, whereas changes in GEDVI paralleled CI regardless of GEF. Conclusions: Regardless of GEF, CVP may be useful for predicting fluid responsiveness in patients after coronary and major vascular surgery provided that positive end-expiratory pressure is low. When GEF is low (<20%), PAOP is more useful than GEDVI for predicting fluid responsiveness, but when GEF is near-normal (≥20%) GEDVI is more useful than PAOP. This favors predicting and monitoring fluid responsiveness by pulmonary artery catheter-derived filling pressures in surgical patients with systolic left ventricular dysfunction and by transpulmonary thermodilution-derived GEDVI when systolic left ventricular function is relatively normal. Gepubliceerd: Crit Care. 2011;15(1):R73 Impact factor: 4.595
2. Scvo2 is not a universal indicator of fluid responsiveness
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Kuiper AN1, Trof RJ1,2, Groeneveld AB1 Department of Intensive Care, VU UMC, Amsterdam 2 Department of Intensive Care, Medisch Spectrum Twente, Enschede 1
Gepubliceerd: J Trauma. 2011 Aug;71(2):518-9 Impact factor: 3.129
3. Use of synthetic colloids in sepsis: a critical review on efficacy, safety and patient benefits Trof RJ1, Groeneveld AB2 1 Department of Intensive Care, Medisch Spectrum Twente, Enschede 2 Department of Intensive Care, VU UMC, Amsterdam In this narrative review, the studies and analyses are discussed that pertain to benefits and detriments of synthetic colloids versus natural colloids or crystalloids used for fluid resuscitation in sepsis and septic shock. The relative amount of fluid infusions used to reach clinical or hemodynamic end-points are reviewed, as well as potential toxicity of starch solutions and on the kidney. Hence, it cannot be excluded that adverse effects partly offset beneficial hemodynamic effects that are similar to that of natural colloids, so that in most analyses a mortality benefit of synthetic colloid fluid resuscitation in sepsis and septic shock cannot be demonstrated. Gepubliceerd: Minerva Anestesiol. 2011; 77(12):1216-23 Impact factor: 2.581
4. Quantitative imaging of microcirculatory response during nitroglycerin-induced hypotension Atasever B1, Boer C2, van der Kuil M2, Lust E2, Beishuizen A2,3, Speekenbrink R4, Seyffert J5, de Mol B6, Ince C1 1 Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Amsterdam 2 Department of Anesthesiology/Intensive Care, VUMC, Amsterdam 3 Department of Intensive Care, Medisch Spectrum Twente, Enschede 4 Department of Cardiothoracic Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam 5 Department of Anesthesiology, Onze Lieve Vrouwe Gasthuis, Amsterdam 6 Department of Cardiothoracic Surgery, AMC, University of Amsterdam, Amsterdam Gepubliceerd: J Cardiothorac Vasc Anesth 2011;25(1):140-4 Impact factor: 1.596
5. Predilution versus postdilution continuous venovenous hemofiltration: no effect on filter life and azotemic control in critically ill patients on heparin Nurmohamed SA1, Jallah BP2, Vervloet MG1, Beishuizen A2,3, Groeneveld AB2 1 Department of Nephrology, VU University Medical Centre, Amsterdam, The Netherlands.
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2 3
Department of Anesthesiology/Intensive Care, VUMC, Amsterdam Department of Intensive Care, Medisch Spectrum Twente, Enschede
In continuous venovenous hemofiltration (CVVH), the delivery of replacement fluid in pre- or postdilution mode remains the subject of controversy. We compared both modes in terms of filter life, dose, and azotemic control. All patients admitted to the intensive care units of a university hospital between November 2004 and December 2006 receiving CVVH and systemic anticoagulation with heparin were retrospectively studied. Thirty-six patients treated by CVVH in predilution and 27 in postdilution mode were studied, with 132 filters in the former and 111 in the latter. The filter life [median ± interquartile range (IQR)] was 24 ± 38 hours and 29 ± 46 hours (p = 0.58) in the pre- and postdilution modes, respectively. Although the fall in creatinine and urea depended on the dose, 19% greater delivered dose in the postthan predilution mode did not impact on azotemic control. In critically ill, heparinized patients on CVVH, filter life and azotemic control are similar in pre- and postdilution modes and underscore the clinical applicability of the predilution mode. Gepubliceerd: ASAIO J. 2011;57(1):48-52 Impact factor: 1.221
6. Acute and delayed mild coagulopathy are related to outcome in patients with isolated traumatic brain injury S Greuters,1 A van den Berg,1 G Franschman,1 VA Viersen,1 A Beishuizen,2,3 SM Peerdeman,4 C Boer1, ALARM-BLEEDING investigators 1 Department of Anesthesiology, Institute for Cardiovascular Research, VUMC, Amsterdam 2 Department of Intensive Care Medicine, Institute for Cardiovascular Research, VUMC, Amsterdam 3 Department of Intensive Care, Medisch Spectrum Twente, Enschede 4 Department of Neurosurgery, VUMC, Amsterdam Introduction: The relationship between isolated traumatic brain injury (TBI) associated coagulopathy and patient prognosis frequently lacks information regarding the time course of coagulation disorders throughout the post-traumatic period. This study was conducted to assess the prevalence and time course of posttraumatic coagulopathy in patients with isolated TBI and the relationship of these hemostatic disorders with outcome. Methods: The local Human Subjects Committee approved the study. We retrospectively studied the medical records of computed tomography (CT)-confirmed isolated TBI patients with an extracranial abbreviated injury scale (AIS) <3 who were primarily referred to a Level 1 trauma centre in Amsterdam (n = 107). Hemostatic parameters including activated partial thromboplastin time (aPTT), prothrombin time (PT), platelet count, hemoglobin, hematocrit, glucose, pH and lactate levels were recorded throughout a 72-hour period as part of a routine standardized follow-up of TBI. Coagulopathy was defined as a aPPT >40 seconds and/or a PTT in International Normalized Ratio (INR) >1.2 and/or a platelet count <120*109/l.
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Results: Patients were mostly male, aged 48 ± 20 years with a median injury severity score of 25 (range 20 to 25). Early coagulopathy as diagnosed in the emergency department (ED) occurred in 24% of all patients. The occurrence of TBIrelated coagulopathy increased to 54% in the first 24 hours post-trauma. In addition to an increased age and disturbed pupillary reflex, both coagulopathy upon ED arrival and during the first 24 hours post-trauma provided an independent prognostic factor for unfavorable outcome (odds ratio (OR) 3.75 (95% CI 1.07 to 12.51; P = 0.04) and OR 11.61 (2.79 to 48.34); P = 0.003). Conclusions: Our study confirms a high prevalence of early and delayed coagulopathy in patients with isolated TBI, which is strongly associated with an unfavorable outcome. These data support close monitoring of hemostasis after TBI and indicate that correction of coagulation disturbances might need to be considered. Gepubliceerd: Crit Care. 2011;15(1):R2 Impact factor: 4.595
7. Blood transfusion during cardiac surgery is associated with inflammation and coagulation in the lung: a case control study PR Tuinman, 1 AP Vlaar,1 AD Cornet,4 JJ Hofstra,1 M Levi,2 JC Meijers,3 A Beishuizen,4,5 MJ Schultz,1 AB Groeneveld,4 NP Juffermans1 1 Department of Intensive Care Medicine and Laboratory of Experimental Intensive Care and Anesthesiology (LEICA), AMC, Amsterdam 2 Department of Internal Medicine, AMC, Amsterdam 3 Department of Experimental Vascular Medicine, AMC, Amsterdam 4 Department of Intensive Care Medicine, VUMC, Amsterdam 5 Department of Intensive Care, Medisch Spectrum Twente, Enschede Introduction: Blood transfusion is associated with increased morbidity and mortality in cardiac surgery patients, but cause-and-effect relations remain unknown. We hypothesized that blood transfusion is associated with changes in pulmonary and systemic inflammation and coagulation occurring in patients who do not meet the clinical diagnosis of transfusion-related acute lung injury (TRALI). Methods: We performed a case control study in a mixed medical-surgical intensive care unit of a university hospital in the Netherlands. Cardiac surgery patients (n = 45) were grouped as follows: those who received no transfusion, those who received a restrictive transfusion (one two units of blood) or those who received multiple transfusions (at least five units of blood). Nondirected bronchoalveolar lavage fluid (BALF) and blood were obtained within 3 hours postoperatively. Normal distributed data were analyzed using analysis of variance and Dunnett's post hoc test. Nonparametric data were analyzed using the Kruskal-Wallis and Mann-Whitney U tests. Results: Restrictive transfusion increased BALF levels of interleukin (IL)-1β and Ddimer compared to nontransfused controls (P < 0.05 for all), and IL-1β levels were further enhanced by multiple transfusions (P < 0.01). BALF levels of IL-8, tumor necrosis factor α (TNFα) and thrombin-antithrombin complex (TATc) were increased after multiple transfusions (P < 0.01, P < 0.001 and P < 0.01, respectively)
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compared to nontransfused controls, but not after restrictive transfusions. Restrictive transfusions were associated with increased pulmonary levels of plasminogen activator inhibitor 1 compared to nontransfused controls with a further increase after multiple transfusions (P < 0.001). Concomitantly, levels of plasminogen activator activity (PAA%) were lower (P < 0.001), indicating impaired fibrinolysis. In the systemic compartment, transfusion was associated with a significant increase in levels of TNFα, TATc and PAA% (P < 0.05). Conclusions: Transfusion during cardiac surgery is associated with activation of inflammation and coagulation in the pulmonary compartment of patients who do not meet TRALI criteria, an effect that was partly dose-dependent, suggesting transfusion as a mediator of acute lung injury. These pulmonary changes were accompanied by systemic derangement of coagulation. Gepubliceerd: Crit Care. 2011;15(1):R59 Impact factor: 4.595
8. Assessment of small bowel function in critical illness: potential role of citrulline metabolism Peters JH1, Beishuizen A2,5, Keur MB2, Dobrowolski L2, Wierdsma NJ3, van Bodegraven AA4 1 Department of Gastroenterology, Red Cross Hospital, Beverwijk 2 Intensive Care Unit, VUMC, Amsterdam 3 Department of Nutrition and Dietetics, VUMC, Amsterdam 4 Department of Gastroenterology, VUMC, Amsterdam 5 Department of Intensive Care, Medisch Spectrum Twente, Enschede Small intestinal function in critically ill patients should ideally be assessed in order to determine the preferred feeding route, timing, and composition of enteral nutrition. Additionally, evaluation of small bowel function may lead to new insights aimed to maintain enterocyte integrity. Critically ill patients are likely to have impaired enterocyte function mainly as a consequence of diminished splanchnic blood flow associated with mucosal hyperpermeability and bacterial translocation, a pathological state believed to be pivotal in the development of sepsis and multiple organ dysfunction syndrome (MODS). However, feasible and validated clinical tools to reliably assess enterocyte function are lacking. This explorative review discusses the promising role of citrulline, a nonprotein amino acid almost exclusively generated by the enterocyte, as a biomarker reflecting enterocyte function in critically ill patients. Citrulline metabolism, its potential as enterocyte biomarker, and literature on citrulline in critically illness will be discussed. Finally, a novel test for enterocyte function, the citrulline generation test (enterocytic citrulline production upon stimulation with enteral or intravenous glutamine) will be considered briefly. Gepubliceerd: J Intensive Care Med. 2011;26(2):105-10 Impact factor: 4.996
9. Intravenous fat emulsion therapy for intentional propafenone intoxication
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ten Tusscher BL1, Beishuizen A1,4, Girbes AR1, Swart EL2, van Leeuwen RW3 Department of Intensive Care, VUMC, Amsterdam 2 Department of Clinical Pharmacy and Toxicology, VUMC, Amsterdam 3 Department of Clinical Pharmacy and Toxicology, Maastricht UMC, Maastricht 4 Department of Intensive Care, Medisch Spectrum Twente, Enschede 1
Gepubliceerd: Clin Toxicol (Phila). 2011;49(7):701 Impact factor: 1.623
10. Assessing adrenal insufficiency of corticosteroid secretion using free versus total cortisol levels in critical illness Molenaar N1, Groeneveld AB1, Dijstelbloem HM2, de Jong MF1, Girbes AR1, Heijboer AC2, Beishuizen A1,3 1 Department of Intensive Care, VUMC, Amsterdam 2 Department of Clinical Chemistry, VUMC, Amsterdam 3 Department of Intensive Care, Medisch Spectrum Twente, Enschede Purpose: To study the value of free versus total cortisol levels in assessing relative adrenal insufficiency during critical illness-related corticosteroid insufficiency. Methods: A prospective study in a mixed intensive care unit from 2004 to 2007. We consecutively included 49 septic and 63 non-septic patients with treatmentinsensitive hypotension in whom an adrenocorticotropic hormone (ACTH) test (250 μg) was performed. Serum total and free cortisol (equilibrium dialysis), corticosteroid-binding globulin (CBG) and albumin were assessed. Results: Although a low CBG resulted in a high free cortisol level relative to total cortisol, free and total cortisol and their increases were well correlated (r = 0.770.79, P < 0.001). In sepsis, hypoalbuminemia did not affect total and free cortisol, and increases in total cortisol upon ACTH predicted increases in free cortisol regardless of low binding proteins. In non-sepsis, total cortisol was lower with than without hypoalbuminemia; free cortisol did not differ, since hypoalbuminemia concurred with a low CBG. Increases in total cortisol depended less on binding proteins than on raw levels. The areas under the receiver operating characteristic curve for predicting increases in free from total cortisol were 0.93-0.97 in sepsis and 0.79-0.85 in non-sepsis (P = 0.044 or lower for sepsis vs. non-sepsis). Conclusions: Although the biologically active free cortisol fraction depends on binding proteins, total cortisol correlates to free cortisol in treatment-insensitive hypotension during critical illness. In sepsis, albumin is not an important binding molecule. Subnormal increments in total cortisol upon ACTH suffice in assessing relative adrenal insufficiency, particularly in sepsis. Gepubliceerd: Intensive Care Med. 2011;37(12):1986-93 Impact factor: 4.996
11. Malabsorption and nutritional balance in the ICU: fecal weight as a biomarker: a prospective observational pilot study
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NJ Wierdsma1, JH Peters2, PJ Weijs1, MB Keur3, AR Girbes3, AA van Bodegraven4, A Beishuizen3,5 1 Department of Nutrition and Dietetics, VUMC, Amsterdam 2 Department of Gastroenterology and Hepatology, Red Cross Hospital, Beverwijk 3 Department of Intensive Care, VUMC, Amsterdam 4 Department of Gastroenterology, Small Bowel Unit, VUMC, Amsterdam 5 Department of Intensive Care, Medisch Spectrum Twente, Enschede Introduction: Malabsorption, which is frequently underdiagnosed in critically ill patients, is clinically relevant with regard to nutritional balance and nutritional management. We aimed to validate the diagnostic accuracy of fecal weight as a biomarker for fecal loss and additionally to assess fecal macronutrient contents and intestinal absorption capacity in ICU patients. Methods: This was an observational pilot study in a tertiary mixed medical-surgical ICU in hemodynamically stable adult ICU patients, without clinically evident gastrointestinal malfunction. Fecal weight (grams/day), fecal energy (by bomb calorimetry in kcal/day), and macronutrient content (fat, protein, and carbohydrate in grams/day) were measured. Diagnostic accuracy expressed in terms of test sensitivity, specificity, positive (PPV) and negative predictive value (NPV), and receiver operator curves (ROCs) were calculated for fecal weight as a marker for energy malabsorption. Malabsorption was a priori defined as < 85% intestinal absorption capacity. Results: Forty-eight patients (63 ± 15 years; 58% men) receiving full enteral feeding were included. A cut-off fecal production of > 350 g/day (that is, diarrhea) was linked to the optimal ROC (0.879), showing a sensitivity and PPV of 80%, respectively. Specificity and NPV were both 96%. Fecal weight (grams/day) and intestinal energyabsorption capacity were inversely correlated (r = -0.69; P < 0.001). Patients with > 350 g feces/day had a significantly more-negative energy balance compared with patients with < 350 g feces/day (loss of 627 kcal/day versus neutral balance; P = 0.012). Conclusions: A fecal weight > 350 g/day in ICU patients is a biomarker applicable in daily practice, which can act as a surrogate for fecal energy loss and intestinal energy absorption. Daily measurement of fecal weight is a feasible means of monitoring the nutritional status of critically ill patients and, in those identified as having malabsorption, can monitor responses to changes in dietary management. Gepubliceerd: Crit Care. 2011;15(6):R264 Impact factor: 4.595
12. Patiënte met kruisproblemen door antistoffen tegen k bij een hemorragische shock Lukens MV, Bossink R, Huistede-Oude Heuvel AH, Adema E, Winkelhorst JT, Ozdemir A, Slomp J Department of Clinical chemistry, Medisch Spectrum Twente, Enschede Gepubliceerd: Tijdschrift Bloedtransfusie 2011;4:106-10 Impact factor: 0
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Totale impact factor: 39.743 Gemiddelde impact factor: 3.312 Aantal artikelen 1e, 2e of laatste auteur: 7 Totale impact factor: 26.515 Gemiddelde impact factor: 3.789
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Interne Geneeskunde 1. Quality of life, geriatric assessment and survival in elderly patients with non-smallcell lung cancer treated with carboplatin-gemcitabine or carboplatin-paclitaxel: NVALT-3 a phase III study Biesma B1, Wymenga AN2, Vincent A3, Dalesio O3, Smit HJ4, Stigt JA5, Smit EF6, van Felius CL7, van Putten JW8, Slaets JP9, Groen HJ10 on behalf of the Dutch Chest Physician Study Group 1 Department of Pulmonology, Jeroen Bosch Hospital, ’s-Hertogenbosch 2 Department of Internal Medicine, Medisch Spectrum Twente, Enschede 3 Biometrics Department, Netherlands Cancer Institute, Amsterdam 4 Department of Pulmonology, Alysis Zorggroep, Location Rijnstate Hospital, Arnhem 5 Department of Pulmonology, Isala Clinics, Zwolle 6 Department of Pulmonology, VU Medical Center, Amsterdam 7 Department of Pulmonology, Twenteborg Hospital, Almelo 8 Department of Pulmonology, Martini Hospital 9 Department of Internal Medicine 10 Department of Pulmonology, UMC, Groningen Background: Elderly patients with advanced non-small-cell lung cancer (NSCLC) may derive similar benefit from platinum-based chemotherapy as younger patients. Quality of life (QoL) and comprehensive geriatric assessment (CGA) is often advocated to assess benefits and risks. Patients and methods: A total of 181 chemotherapy-naive patients [≥70 years, performance score (PS) of 0-2] with stage III-IV NSCLC received carboplatin and gemcitabine (CG) (n = 90) or carboplatin and paclitaxel (CP) (n = 91) every 3 weeks for up to four cycles. Primary end point was change in global QoL from baseline compared with week 18. Pretreatment CGA and mini geriatric assessment during and after treatment were undertaken. A principal component (PC) analysis was carried out to determine the underlying dimensions of CGA and QoL and subsequently related to survival. Results: There were no changes in QoL after treatment. The number of QoL responders (CG arm, 12%; CP arm, 5%) was not significantly different. CGA items were only associated with neuropsychiatric toxicity. Quality-adjusted survival was not different between treatment arms. The PC analysis derived from nine CGA, six QoL and one PS score indicated only one dominant dimension. This dimension was strongly prognostic, and physical and role functioning, Groningen Frailty Indicator and Geriatric Depression Scale were its largest contributors. Conclusions: Paclitaxel or gemcitabine added to carboplatin did not have a differential effect on global QoL. CGA was associated with toxic effects in a very limited manner. CGA and QoL items measure one underlying dimension, which is highly prognostic. Gepubliceerd: Ann Oncol. 2011;22(7):1520-7 Impact factor: 6.452
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2. Low prevalence of hypopituitarism after traumatic brain injury - a multi-center study Kokshoorn N1, Smit JW1, Nieuwlaat WA2, Tiemensma J1, Bisschop P3, Groote Veldman R4, Roelfsema F1, Franken AA5, Wassenaar M1, Biermasz NR1, Romijn JA1, Pereira AM1 1 Department of Endocrinology and Metabolic Diseases, Leiden UMC, Leiden 2 Department of Internal Medicine, St Elisabeth Hospital, Tilburg 3 Department of Endocrinology and Metabolism, AMC, Amsterdam 4 Department of Internal Medicine, Medical Spectrum Twente, Enschede 5 Department of Internal Medicine, Isala Clinics, Zwolle Objective: Hypopituitarism after traumatic brain injury (TBI) is considered to be a prevalent condition. However, prevalence rates differ considerably among reported studies, due to differences in definitions, endocrine assessments of hypopituitarism, and confounding factors, like timing of evaluation and the severity of the trauma. Aim: To evaluate the prevalence of hypopituitarism in a large cohort of TBI patients after long-term follow-up using a standardized endocrine evaluation. Study design: Cross-sectional study Patients and Methods: We included 112 patients with TBI, hospitalized for at least 3 days and a duration of follow up > 1 yr after TBI from 5 (neurosurgical) referral centers. Evaluation of pituitary function included fasting morning hormone measurements and insulin tolerance test (ITT n=90) or, when contraindicated, ACTH-stimulation and/or CRH-stimulation test and a GHRH-arginine test (n=22). Clinical evaluation included quality of life questionnaires. Results: We studied 112 patients (75 males), with median age 48 yr, and mean BMI 26.7+/-4.8 kg/m2. Mean duration of hospitalization was 11 days (3-105) and 33% had a severe trauma (Glasgow Coma Scale < 9) after TBI. The mean duration of follow-up was 4 (1-12) years. Hypopituitarism was diagnosed in 5.4% (6/112) of patients: severe growth hormone deficiency (n=3), hypogonadism (n=1), adrenal insufficiency (n=2). Patients diagnosed with pituitary insufficiency had significantly higher BMI (p=0.002). Conclusion: In this study, the prevalence of hypopituitarism during long-term followup after TBI was low. Prospective studies are urgently needed to find reliable predictive tools for the identification of patients with a significant pre-test likelihood for hypopituitarism after TBI. Gepublicerd: Eur J Endocrinol. 2011;165(2):225-31 Impact factor: 3.482
3. Intensified chemotherapy inspired by a pediatric regimen combined with allogeneic transplantation in adult patients with acute lymphoblastic leukemia up to the age of 40 AW Rijneveld1, B van der Holt1, SM Daenen2, BJ Biemond3, O de Weerdt4, P Muus5, J Maertens6, V Mattijssen7, H Demuynck8, MC Legdeur9, PW Wijermans10, S Wittebol11, FM Spoelstra1, AW Dekker12, GJ Ossenkoppele13, R Willemze14, JJ Cornelissen1 on behalf of the Dutch-Belgian HOVON Cooperative group 1 Erasmus UMC, Department of Hematology, Rotterdam
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2
UMC Groningen, Department of Hematology, Groningen AMC, Department of Hematology, Amsterdam 4 Sint Antonius Hospital, Department of Hematology, Nieuwegein 5 UMC Nijmegen, Department of Hematology, Nijmegen 6 University Hospital Gasthuisberg, Department of Hematology, Leuven, Belgium 7 Rijnstate Hospital, Department of Hematology, Arnhem 8 Heilig Hart Hospital, Department of Hematology, Roeselaere, Belgium 9 Medisch Spectrum Twente, Department of Hematology, Enschede 10 Haga Hospital, Department of Hematology, Den Haag 11 Meander Medical Center, Department of Hematology, Amersfoort 12 UMC Utrecht, Department of Hematology, Utrecht 13 Vrije Universiteit MC, Department of Hematology, Amsterdam 14 Leiden UMC, Department of Hematology, Leiden 3
Event-free survival (EFS) at 5 years in pediatric acute lymphoblastic leukemia (ALL) is >80%. Outcome in adult ALL is still unsatisfactory, which is due to less cumulative dosing of chemotherapy and less strict adherence to timing of successive cycles. In the present phase II trial, we evaluated a pediatric regimen in adult patients with ALL under the age of 40. Treatment was according to the pediatric FRALLE approach for high-risk ALL patients and characterized by increased dosages of asparaginase, steroids, methotrexate and vincristin. However, allogeneic stem cell transplantation was offered to standard risk patients with a sibling donor and to all high-risk patients in contrast to the pediatric protocol. Feasibility was defined by achieving complete remission (CR) and completion of treatment within a strict timeframe in at least 60% of patients. In all, 54 patients were included with a median age of 26. CR was achieved in 49 patients (91%), of whom 33 completed treatment as scheduled (61%). Side effects primarily consisted of infections and occurred in 40% of patients. With a median follow-up of 32 months, EFS estimated 66% at 24 months and overall survival 72%. These data show that a dose-intensive pediatric regimen is feasible in adult ALL patients up to the age of 40. Gepubliceerd: Leukemia. 2011;25(11):1697-703 Impact factor: 8.966
4. Cytarabine dose for acute myeloid leukemia Löwenberg B1, Pabst T9, Vellenga E3, van Putten W2, Schouten HC4, Graux C13, Ferrant A14, Sonneveld P1, Biemond BJ5, Gratwohl A10, de Greef GE1, Verdonck LF6, Schaafsma MR7, Gregor M11, Theobald M16, Schanz U12, Maertens J15, Ossenkoppele GJ8 1 Erasmus UMC and the 2 HOVON Data Center and Department of Trials and Statistics, Erasmus UMC, Rotterdam; 3 UMC, Groningen; 4 UMC, Maastricht; 5 AMC, University of Amsterdam, Amsterdam ; 6 UMC, Utrecht; 7 Medisch Spectrum Twente, Enschede; 8 VU MC, Amsterdam; 9 Inselspital, Bern, Switzerland; 10 University Hospital, Basel, Switzerland; 11 Kantonsspital, Lucerne, Switzerland; 12 University Hospital, Zurich and Lucerne, Switzerland; 13 Hôpital Mont-Godinne, Yvoir,Belgium; 14 Hôpital Saint-Luc, Brussels,Belgium; 15 University Hospital Gasthuisberg,
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Leuven,Belgium; 16 Department of Internal Medicine III, University Hospital, Mainz, Germany Cytarabine (ara-C) is an important drug in the treatment of acute myeloid leukemia (AML). High-dose cytarabine (2000 to 3000 mg per square meter of body-surface area) is toxic but results in higher rates of relapse-free survival than does the conventional dose of 100 to 400 mg per square meter. Intermediate dose levels have not been thoroughly evaluated. Gepubliceerd: N Engl J Med. 2011;364(11):1027-36 Impact factor: 53.484
5. Effect of thalidomide with melphalan and prednisone on health-related quality of life (HRQoL) in elderly patients with newly diagnosed multiple myeloma: a prospective analysis in a randomized trial Verelst SG1, Termorshuizen F2, Uyl-de Groot CA3, Schaafsma MR4, Ammerlaan AH2, Wittebol S5, Sinnige HA6, Zweegman S7, van Marwijk Kooy M8, van der Griend R9, Lokhorst HM10, Sonneveld P1, Wijermans PW11 1 Department of Hematology, Erasmus MC Rotterdam, Rotterdam 2 Department of Trials and Statistics, Erasmus MC Rotterdam, Rotterdam 3 Institute for Medical Technology Assessment, Erasmus University Rotterdam, RotterdamM. 4 Department Internal Medicine, Medical Spectrum Twente, Enschede 5 Department of Internal Medicine, Meander MC, Amersfoort 6 Department of Internal Medicine, Jeroen Bosch Hospital, ‘s-Hertogenbosch 7 Department of Hematology, VU MC Amsterdam, Amsterdam 8 Department of Internal Medicine, Isala Kliniek, Zwolle 9 Department of Internal Medicine, Diakonessenhuis Utrecht, Utrecht 10 Department of Hematology, UMC Utrecht, Utrecht 11 Department of Hematology, Haga Hospital, The Hague Thalidomide with melphalan/prednisone (MPT) was defined as standard treatment in elderly patients with multiple myeloma (MM) based on five randomized trials. In one of these trials, HOVON49, a prospective health-related quality-of-life (HRQoL) study was initiated in order to assess the impact of thalidomide on QoL. Patients aged >65 years with newly diagnosed MM were randomized to receive melphalan plus prednisone (MP) or MPT, followed by thalidomide maintenance in the MPT arm. Two hundred eighty-four patients were included in this side study (MP, nԜ=Ԝ149; MPT nԜ=Ԝ135). HRQoL was assessed with the EORTC Core QoL Questionnaire (QLQC30) and the myeloma-specific module (QLQ-MY24) at baseline and at predetermined intervals during treatment. The QLQ-C30 subscales physical function (PԜ=Ԝ0.044) and constipation (PԜ<Ԝ0.001) showed an improvement during induction in favour of the MP arm. During thalidomide maintenance, the scores for the QLQMY24 paraesthesia became significantly higher in the MPT arm (P<0.001). The QLQ-C30 subscales pain (PԜ=Ԝ0.12), insomnia (PԜ=Ԝ0.068), appetite loss (PԜ=Ԝ0.074) and the QLQ-MY24 item sick (PԜ=Ԝ0.086) scored marginally better during thalidomide maintenance. The overall QoL-scale QLQ-C30-HRQoL showed a significant time
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trend towards more favourable mean values during protocol treatment without differences between MP and MPT. For the QLQ-C30 subscales emotional function and future perspectives, difference in favour of the MPT arm from the start of treatment was observed (PԜ=Ԝ0.018 and PԜ=Ԝ0.045, respectively) with no significant 'timeԜ×Ԝarm' interaction, indicating a persistent better patient perspective with MPT treatment. This study shows that the higher frequency of toxicity associated with MPT does not translate into a negative effect on HRQoL and that MPT holds a better patient perspective. Gepubliceerd: Ann Hematol. 2011;90(12):1427-39 Impact factor: 2.688
6. Prognostic factors and outcome in relapsed multiple myeloma after nonmyeloablative allo-SCT: a single center experience MC Minnema1, S van Dorp2, NW van de Donk1, F Schouten1, MJ Kersten3, JL Coenen4, H Schouten5, S Zweegman6, R Schaafsma7, HM Lokhorst1 1 Department of Hematology, UMC Utrecht, Utrecht 2 Department of Immunology, UMC Utrecht, Utrecht 3 Department of Hematology, AMC, Amsterdam 4 Department of Internal Medicine, Isala Klinieken, Zwolle 5 Department of Internal Medicine, UHM, Maastricht 6 Department of Hematology, VU UMC, Amsterdam 7 Department of Internal Medicine, MST, Enschede For relapsed multiple myeloma (MM) patients, allo-SCT is a possible treatment option, but recent data obtained using a nonmyeloablative (NMA) conditioning regimen are scarce. We retrospectively collected data from 38 relapsed MM patients who received a NMA allo-SCT from October 2001 to January 2008. In total, 18 patients (48%) were transplanted using a matched unrelated donor. The median follow-up is 2.3 years. In 16 patients (42%) the response improved and eight patients (21%) were rapidly progressive within 6 months after allo-SCT. In total, 15 patients (39%) were in CR after allo-SCT. The median PFS was 1.4 years (range, 0.1-4.9), and having a CR after allo-SCT or having chronic GVHD resulted in longer PFS. Median OS was 3.1 years (range, 0.2-7.2) and again having a CR after alloSCT or chronic GVHD was associated with a better OS. Six patients (16%) have died from treatment-related diseases. These results indicate that NMA allo-SCT is a treatment option in relapsed MM patients and that results may be improved by strategies that enhance the CR rate after allo-SCT. Gepubliceerd: Bone Marrow Transplant 2011;46(2):244-9 Impact factor: 3.660
7. Complete response correlates with long-term progression-free and overall survival in elderly myeloma treated with novel agents: analysis of 1175 patients F Gay1, A Larocca1, P Wijermans2, F Cavallo1, D Rossi3, R Schaafsma4, M Genuardi1, A Romano5, A Marina Liberati6, A Siniscalchi7, MT Petrucci8, C Nozzoli9,
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F Patriarca10, M Offidani11, R Ria12, P Omedè1, B Bruno1, R Passera13, P Musto14, M Boccadoro1, P Sonneveld15, A Palumbo1 1 Myeloma Unit, Division of Hematology, University of Torino, AOU S. Giovanni Battista, Torino, Italy; 2Haga Hospital, The Hague; 3Division of Hematology, Department of Clinical and Experimental Medicine, Università del Piemonte Orientale Amedeo Avogadro, Novara, Italy; 4MST Hospital, Enschede; 5Division of Hematology, Ospedale Ferrarotto, University of Catania, Catania, Italy; 6Struttura Complessa di Oncoematologia con Autotrapianto, Azienda Ospedaliera S. Maria di Terni, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, Perugia, Italy; 7Department of Hematology, S. Eugenio Hospital, Tor Vergata University, Rome, Italy; 8Hematology, “Sapienza” University of Rome, Rome, Italy; 9Hematology Unit Careggi Hospital Florence, Florence, Italy; 10Clinica Ematologica, Azienda Ospedaliera-Universitaria di Udine, Udine, Italy; 11Clinica di Ematologia, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy; 12Università degli Studi di Bari “Aldo Moro,” Dipartimento di Scienze Biomediche e Oncologia Umana, Sezione di Medicina Interna e Oncologia Clinica Policlinico, Bari, Italy; 13Divisione di Medicina Nucleare 2, Università di Torino, AOU S. Giovanni Battista, Torino, Italy; 14Department of Onco-Hematology, Istituto di Ricovero e Cura a Carattere Scientifico, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy; 15Erasmus MC, Rotterdam Complete response (CR) was an uncommon event in elderly myeloma patients until novel agents were combined with standard oral melphalan-prednisone. This analysis assesses the impact of treatment response on progression-free survival (PFS) and overall survival (OS). We retrospectively analyzed 1175 newly diagnosed myeloma patients, enrolled in 3 multicenter trials, treated with melphalan-prednisone alone (n = 332), melphalan-prednisone-thalidomide (n = 332), melphalan-prednisonebortezomib (n = 257), or melphalan-prednisone-bortezomib-thalidomide (n = 254). After a median follow-up of 29 months, the 3-year PFS and OS were 67% and 27% (hazard ratio = 0.16; P < .001), and 91% and 70% (hazard ratio = 0.15; P < .001) in patients who obtained CR and in those who achieved very good partial response, respectively. Similar results were observed in patients older than 75 years. Multivariate analysis confirmed that the achievement of CR was an independent predictor of longer PFS and OS, regardless of age, International Staging System stage, and treatment. These findings highlight a significant association between the achievement of CR and long-term outcome, and support the use of novel agents to achieve maximal response in elderly patients, including those more than 75 years. Gepubliceerd: Blood 2011;117(11):3025-31 Impact factor: 10.558
8. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual-patient data from six randomized clinical trials PM Fayers1,2, A Palumbo3, C Hulin4, A Waage2,5, P Wijermans6, M Beksaç7, S Bringhen8, JY Mary9, P Gimsing10, F Termorshuizen11, R Haznedar12, T Caravita13, P Moreau14, I Turesson15, P Musto16, L Benboubker17, M Schaafsma18, P Sonneveld19, T Facon20 on
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behalf of NMSGa, GIMEMAb, TMSGc, HOVONd, IFMe, and European Myeloma Network 1 Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, United Kingdom; 2 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; 3Divisione di Ematologia dell'Università di Torino, A.O.U. S. Giovanni Battista, Torino, Italy; 4 Hematology Department, University Hospital, Nancy, France; 5Department of Hematology, St. Olavs University Hospital, Trondheim, Norway; 6Department of Hematology, Haga Hospital, The Hague; 7Department di Torino, A.O.U. S. Giovanni Battista, Torino, Italy; 9INSERM U717, Université Paris 7, Hôpital Saint-Louis, Paris, France; 10Department of Hematology, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark; 11Erasmus MC and University, Rotterdam; 12Department of Hematology , Gazi University School of Medicine, Ankara, Turkey; 13Cattedra e Divisione di Ematologia, Università Tor Vergata, Ospedale S. Eugenio, Roma, Italy; 14 Centre Hospitalier Universitaire, Nantes, France; 15Department of Hematology, Skane University Hospital, Malmö, Sweden; 16Department of Onco-Hematology, IRCCS "Centro di Riferimento Oncologico della Basilicata" Rionero in Vulture (Pz), Italy; 17Oncohématologie CHRU, Hôpital Bretonneau, Tours, France; 18Medical Spectrum Twente, Enschede; 19Erasmus MC and University, Rotterdam; 20 Department of Hematology, Hôpital Claude Huriez, Lille, France; aNordic Myeloma Study Group; bItalian Multiple Myeloma Network; cTurkish Myeloma Study Group; d Hemato-Oncologie voor Volwassenen Nederland eIntergroupe Francophone du Myélome. The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The effect on overall survival (OS) varied across trials. We carried out a metaanalysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and one-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (HR 0.83, 95% CI 0.73–0.94, p=0.004), representing increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also associated with superior PFS (HR 0.68, 95% CI 0.61–0.76, p<0.0001) and better one-year response rates (partial response or better was 59% on MPT and 37% on MP). Although the trials differed in terms of patient baseline characteristics and thalidomide regimens, there was no evidence that treatment affected OS differently according to levels of the prognostic factors. We conclude that thalidomide added to MP improves OS and PFS in previously untreated elderly patients with multiple myeloma, extending the median survival time by on average 20%. Gepubliceerd: Blood 2011;118(5):1239-1247 Impact factor: 10.558
9. Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia
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(CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme LH van der Helm1, C Alhan2, PW Wijermans3, M van Marwijk Kooy4, R Schaafsma5, BJ Biemond6, A Beeker7, M Hoogendoorn8, BP van Rees9, O de Weerdt10, J Wegman11, WJ Libourel12, SA Luykx-de Bakker13, MC Minnema14, RE Brouwer15, F Croon-de Boer16, M Eefting17, KS Jie18, AA van de Loosdrecht2, J Koedam19, NJ Veeger1, E Vellenga1, G Huls1 1 Department of Haematology, UMC Groningen, Groningen 2 Department of Haematology, VU UMC, Amsterdam 3 Department of Haematology, HagaZiekenhuis, Den Haag 4 Department of Internal Medicine, Isala Klinieken, Zwolle 5 Department of Internal Medicine, Medisch Spectrum Twente, Enschede 6 Department of Haematology, Amsterdam Medical Centre, Amsterdam 7 Department of Internal Medicine, Spaarne Ziekenhuis, Hoofddorp 8 Department of Haematology, Medical Centre Leeuwarden, Leeuwarden 9 Department of Internal Medicine, Ziekenhuis De Tjongerschans, Heerenveen 10 Department of Internal Medicine, Sint Antonius Hospital, Nieuwegein 11 Department of Internal Medicine, Deventer Ziekenhuizen, Deventer 12 Department of Internal Medicine, Erasmus Medical Centre, Rotterdam 13 Department of Internal Medicine, Tergooiziekenhuizen, Hilversum 14 Department of Haematology, UMC Utrecht, Utrecht 15 Department of Internal Medicine, Reinier de Graaf Groep, Delft 16 Department of Internal Medicine, Ikazia Hospital, Rotterdam 17 Department of Haematology, Leiden UMC, Leiden 18 Department of Internal Medicine, Atrium Medical Centre, Heerlen 19 Celgene BV, Utrecht The efficacy of azacitidine in the treatment of high-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) (20-30% blasts) has been demonstrated. To investigate the efficacy of azacitidine in daily clinical practice and to identify predictors for response, we analysed a cohort of 90 MDS, CMML and AML patients who have been treated in a Dutch compassionate named patient programme. Patients received azacitidine for a median of five cycles (range 1-19). The overall response rate (complete/partial/haematological improvement) was 57% in low risk MDS, 53% in high risk MDS, 50% in CMML, and 39% in AML patients. Median overall survival (OS) was 13·0 (9·8-16·2) months. Multivariate analysis confirmed circulating blasts [Hazard Ratio (HR) 0·48, 95% confidence interval (CI) 0·24-0·99; P = 0·05] and poor risk cytogenetics (HR 0·45, 95% CI 0·22-0·91; P = 0·03) as independent predictors for OS. Interestingly, this analysis also identified platelet doubling after the first cycle of azacitidine as a simple and independent positive predictor for OS (HR 5·4, 95% CI 0·73-39·9; P = 0·10). In conclusion, routine administration of azacitidine to patients with variable risk groups of MDS, CMML and AML is feasible, and subgroups with distinct efficacy of azacitidine treatment can be identified. Gepubliceerd: Br J Haematol. 2011;155(5):599-606 Impact factor: 4.942
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11. Autologous peripheral blood stem cell transplantation for acute myeloid leukemia E Vellenga1, W van Putten2, GJ Ossenkoppele3, LF Verdonck4, M Theobald5, JJ Cornelissen6, PC Huijgens3, J Maertens7, A Gratwohl8, R Schaafsma9, U Schanz10, C Graux11, HC Schouten12, A Ferrant13, M Bargetzi14, MF Fey15, B Löwenberg6 for the Dutch Belgian HOVON group and the Swiss SAKK group for the DutchBelgian Hemato-Oncology Cooperative Group (HOVON), and Swiss Group for Clinical Cancer Research Collaborative Group (SAKK) 1 Department of Hematology, University of Groningen and UMC Groningen; 2 Hovon Data Center and Department of Trials and Statistics, Erasmus UMC, Rotterdam; 3 Department of Hematology, VU UMC Amsterdam 4 Department of Hematology, UMC Utrecht; 5 Department of Internal Medicine III, University Hospital Mainz, Germany; 6 Department of Hematology, Erasmus UMC, Rotterdam 7 Department of Hematology, University Hospital Gasthuisberg, Leuven, Belgium; 8 Department of Hematology, University Hospital, Basel, Switzerland; 9 Department of Hematology, Medisch Spectrum Twente, Enschede; 10 Division of Hematology, University Hospital Zürich, Switzerland; 11 Division of Hematology, UCL, MontGodinne, Yvoir, Belgium; 12 Department of Hematology, UMC Maastricht; 13 Department of Hematology, Hospital St Luc, Bruxelles, Belgium; 14 Center of Hematology/Oncology and Transfusion Medicine Kantonsspittal Aarau, Switzerland; 15 Department of Medical Oncology, University and Inselspital, Berne, Switzerland We report the results of a prospective, randomized phase 3 trial evaluating the use of autologous peripheral blood stem cell transplantation (ASCT) vs. intensive consolidation chemotherapy in newly diagnosed AML patients in complete remission (CR1). Patients with AML between 16-60 yrs of age in CR1 after two cycles of intensive chemotherapy and not eligible for allogeneic SCT were randomized between intensive chemotherapy with etoposide and mitoxantrone or ASCT following high-dose cyclophosphamide and busulfan. Of patients randomized (chemotherapy n=259; ASCT n=258), more than 90% received their assigned treatment arm. The two groups were comparable as regards prognostic factors. The ASCT group showed a markedly reduced relapse rate (58% vs. 70%, p=0.02) and better relapse free survival (RFS) at five years (38% vs. 29%, p= 0.065, HR 0.82 (0.66-1.1) with non-relapse mortality of 4% vs. 1% in the chemotherapy arm (p=0.02). Overall survival (OS) was similar (44% vs. 41% at 5 years, p=0.86) due to more opportunities for salvage with second-line chemotherapy and stem cell transplantation in patients relapsing on the chemotherapy arm. This large study shows a relapse advantage for ASCT as post remission therapy but similar survival since more relapsing patients on the chemotherapy arm were salvaged with a late transplantation for relapse. Gepubliceerd: Blood 2011;118(23):6037-6042 Impact factor: 10.558
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12. Randomized Phase II Study Comparing Efficacy and Safety of CombinationTherapy Trastuzumab and Docetaxel vs. Sequential Therapy of Trastuzumab Followed by Docetaxel Alone at Progression As First-Line Chemotherapy in Patients with HER2(+) Metastatic Breast Cancer: HERTAX Trial P Hamberg1, MM Bos2, HJ Braun3, JM Stouthard4, GA van Deijk5, FL Erdkamp6, IN van der Stelt-Frissen7, M Bontenbal1, GJ Creemers8, JE Portielje5, JF Pruijt9, OJ Loosveld10, WM Smit11, EW Muller12, PI Schmitz7, C Seynaeve1, JG Klijn1 and Dutch Breast Cancer Trialists' Group (BOOG) 1 Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam; 2 Reinier de Graaf group, Delft; 3 Vlietland Hospital, Schiedam; 4 Maasstad Hospital, Rotterdam; 5 Haga Hospital, The Hague; 6 Maasland Hospital, Sittard; 7 Department of Trials and Statistics, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam; 8 Catharina Hospital, Eindhoven; 9 Jeroen Bosch Hospital, Den Bosch; 10 Amphia Hospital, Breda; 11 Medisch Spectrum Twente, Enschede; 12 Slingeland Hospital, Doetinchem Because chemotherapy for metastatic breast cancer (MBC) is associated with relevant toxicity, sequential monotherapy trastuzumab followed by cytotoxic therapy at disease progression might be an attractive approach. Gepubliceerd: Clin Breast Cancer. 2011;11(2):103-13 Impact factor: 2.790
13. Weekly docetaxel in metastatic breast cancer patients: No superior benefits compared to three-weekly docetaxel CP Schrödera, L de Munckb, AM Westermannc, WM Smitd, GJ Creemerse, H de Graaff, JM Stouthardg, G van Deijkh, Z Erjaveci, A van Bochovej, W Vaderk, PH Willemsea a Dept. of Medical Oncology, University of Groningen and UMC Groningen, Groningen b Dept. of Research, Comprehensive Cancer Centre North East, Groningen, Groningen c Dept. of Medical Oncology, AMC, Amsterdam, Amsterdam d Dept. of Medical Oncology, Medisch Spectrum Twente, Enschede e Dept. of Medical Oncology, Catharina Ziekenhuis, Eindhoven f Dept. of Medical Oncology, MCL Zuid, Leeuwarden g Dept. of Medical Oncology, Maasstad Ziekenhuis, Rotterdam h Dept. of Medical Oncology, HAGA Ziekenhuis-Rode Kruis, Den Haag i Dept. of Medical Oncology, Ommelander Ziekenhuis Groep, Delfzijl j Dept. of Medical Oncology, ZaansMC, Zaandam k Dept. of Medical Research, Sanofi-Aventis Netherlands B.V., Gouda In anthracycline-pretreated metastatic breast cancer (MBC) patients, it is unknown whether weekly single-agent docetaxel is preferable to 3-weekly docetaxel regarding its toxicity and efficacy profile. Gepubliceerd: Eur J Cancer. 2011;47(9):1355-62
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Impact factor: 4.944
14. Abacavir/lamivudine/zidovudine maintenance after standard induction in antiretroviral therapy-naïve patients: FREE randomized trial interim results HG Sprenger1, N Langebeek2, PG Mulder3, CH Ten Napel 4, R Vriesendorp 5, AI Hoepelman 6, JC Legrand7, PP Koopmans 8, ME Van Kasteren 9, B Bravenboer 10, RW Ten Kate 11, PH Groeneveld 12, TS van der Werf 1, EH Gisolf 2, C Richter2 Department of Internal Medicine, 1University Medical Center Groningen, Groningen; 2 Rijnstate Hospital, Arnhem; 3Erasmus Medical Center, Rotterdam; 4Medical Spectrum Twente, Enschede; 5Medical Center Haaglanden, The Hague; 6University Medical Center Utrecht, Utrecht; 7University Hospital Center, Charleroi, Belgium; 8 Radboud University Medical Center, Nijmegen; 9Elisabeth Hospital, Tilburg; 10 Catharina Hospital, Eindhoven; 11Kennemer Gasthuis, Haarlem; 12Isala Clinics, Zwolle Maintenance with a triple nucleoside reverse transcriptase Inhibitor (NRTI) regimen after successful induction with a dual NRTI/protease inhibitor (PI) combination may be advantageous, because of low pill burden, favorable lipids, and less drug interactions. This strategy to become free of PI-related problems without losing viral efficacy has not been formally tested. We performed a randomized, open-label, multicenter, 96-week comparative study in antiretroviral therapy (ART)-naïve patients with CD4
50 copies per milliliter). Two hundred seven patients had similar baseline (BL) characteristics: median CD4 180 cells/mm(3), median VL 5.19 log(10) copies per milliliter. One hundred twenty subjects (58%) met randomization criteria. Baseline VL differed significantly between dropouts and randomized subjects (median 5.41 versus 5.06 log(10) copies per milliliter, p = 0.017), as did CD4 cells (median 160 and 200 cells/mm(3), p = 0.044). Sixty-one subjects received TZV and 59 subjects continued NRTIs/PI. At week 48, 2 patients in the TZV group and 5 in the PI group did not have a sustained virologic suppression (log rank test; p = 0.379). CD4 counts increased significantly in both arms. In ART-naïve patients, TZV maintenance had similar antiviral efficacy compared to continued standard ART at 48 weeks after baseline. Patients on successful standard ART can be safely switched to a NRTI-only regimen, at least for the tested time period. Gepubliceerd: AIDS Patient Care STDS. 2010;24(6):361-6 Impact factor: 2.333
15. Dextromethorphan As a Phenotyping Test to Predict Endoxifen Exposure in Patients on Tamoxifen Treatment
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de Graan AJ1, Teunissen SF4, de Vos FY1, Loos WJ1, van Schaik RH2, de Jongh FE3, de Vos AI5, van Alphen RJ6, van der Holt B1, Verweij J1, Seynaeve C1, Beijnen JH4, Mathijssen RH1 1 Erasmus Medical Center-Daniel den Hoed Cancer Center, University Medical Center; 2 Department of Internal Medicine, Erasmus MC; 3 Department of Internal Medicine, Ikazia Hospital, Rotterdam; 4 Department of Internal Medicine, Slotervaart Hospital, Amsterdam; 5 Department of Internal Medicine, Admiraal De Ruyter Hospital, Goes; 6 Department of Internal Medicine, Medical Spectrum Twente, Enschede Purpose: Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the value of CYP2D6 genotyping to reduce the variable efficacy have been reported. In this pharmacokinetic study, we investigated the value of dextromethorphan, a known probe drug for both CYP2D6 and CYP3A enzymatic activity, as a potential phenotyping probe for tamoxifen pharmacokinetics. Methods: In this prospective study, 40 women using tamoxifen for invasive breast cancer received a single dose of dextromethorphan 2 hours after tamoxifen intake. Dextromethorphan, tamoxifen, and their respective metabolites were quantified. Exposure parameters of all compounds were estimated, log transformed, and subsequently correlated. Results: A strong and highly significant correlation (r = -0.72; P < .001) was found between the exposures of dextromethorphan (0 to 6 hours) and endoxifen (0 to 24 hours). Also, the area under the plasma concentration-time curve of dextromethorphan (0 to 6 hours) and daily trough endoxifen concentration was strongly correlated (r = -0.70; P < .001). In a single patient using the potent CYP2D6 inhibitor paroxetine, the low endoxifen concentration was accurately predicted by dextromethorphan exposure. Conclusion: Dextromethorphan exposure after a single administration adequately predicted endoxifen exposure in individual patients with breast cancer taking tamoxifen. This test could contribute to the personalization and optimization of tamoxifen treatment, but it needs additional validation and simplification before being applicable in future dosing strategies. Gepubliceerd: J Clin Oncol. 2011;29:3240-3246 Impact factor: 18.970
16. Impact on clinical decision making of quality control standards applied to sputum analysis in COPD MC Telgena, MG Brusse-Keizera,, PD van der Valka, J. van der Palena, d, HA Kerstjensb, MG Hendrixc a Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede b Department of Pulmonary Medicine, UMC Groningen, University of Groningen, Groningen c Regional Laboratory of Public Health, P.O Box 377, 7500 AJ Enschede
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d
Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede Purpose: Sputum analysis is important in COPD exacerbation management. We determined whether application of stringent quality control criteria for sputum samples had an impact on culture results. Methods: We analyzed sputum samples of 108 patients during stable COPD and during exacerbations. To all samples quality control standards and culture interpretation rules according to the American Society of Microbiologists (ASM) were applied. Results: In sputum exacerbation samples considered appropriate according to ASM quality standards, criteria for infection (40%) were met more often compared to inappropriate samples (13%) (p < 0.001). The same pattern was observed when applying these rules to sputum samples obtained during stable disease, (50% vs. 18%, p < 0.001). There was no difference in the percentage of infectious cultures obtained during the stable state and exacerbations. Conclusions: Applying stringent quality control criteria to sputum samples can have a profound effect on the labeling of sputum samples as infectious, and therefore on clinical decision making. Gepubliceerd: Resp Med 2011;105(3):371-376 Impact factor: 2.525
17. In critically ill patients the procalcitonin level can be misleading J Koeze1,4, MG Hendrix2, FA van den Bergh3, RM Brouwer4, JG Zijlstra1 1 Department of Critical Care, UMC Groningen, University of Groningen, Groningen 2 Laboratory of Microbiology, Twente Achterhoek, Enschede 3 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede 4 Department of Internal Medicine, Medisch Spectrum Twente, Enschede Gepubliceerd: Crit Care. 2011;15(2):422 Impact factor: 4.595
Totale impact factor: 151.505 Gemiddelde impact factor: 8.912 Aantal artikelen 1e, 2e of laatste auteur: 3 Totale impact factor: 13.572 Gemiddelde impact factor: 4.524
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Kindergeneeskunde 1. Monitoring pulmonary function during exercise in children with asthma van Leeuwen JC1, Driessen JM1, de Jongh FH2,3, van Aalderen WM3, Thio BJ1 1 Department of Pediatrics, Medisch Spectrum Twente, Enschede 2 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 3 Department of Pediatrics, AMC, Amsterdam Objective Exercise-induced bronchoconstriction (EIB) is defined as acute, reversible bronchoconstriction induced by physical exercise. It is widely believed that EIB occurs after exercise. However, in children with asthma the time to maximal bronchoconstriction after exercise is short, suggesting that the onset of EIB in such children occurs during exercise. Aim In this study the authors investigate pulmonary function during exercise in cold air in children with asthma. Methods 33 Children with asthma with a mean age of 12.3 years and a clinical history of exercise induced symptoms, underwent a prolonged, submaximal, exercise test of 12 min duration at approximately 80% of the predicted maximum heart rate. Pulmonary function was measured before and each minute during exercise. If EIB occurred (fall in forced expiratory volume in 1 s >15% from baseline), exercise was terminated and salbutamol was administered. Results 19 Children showed EIB. In 12 of these children bronchoconstriction occurred during exercise (breakthrough EIB), while seven children showed bronchoconstriction immediately after exercise (non-breakthrough EIB). Breakthrough EIB occurred between 6 and 10 min of exercise (mean 7.75 min). Conclusion In the majority of children with EIB in this study (ie, 12 out of 19), bronchoconstriction started during, and not after, a submaximal exercise test. Gepubliceerd: Arch Dis Child 2011;96(7):664-8 Impact factor: 2.616
2. Panhypopituitarism in one identical twin: the effect of hormone replacement Del Canho H1, van Alfen-van der Velden J2, Del Canho R3, Otten B2 1 Afdeling Kindergeneeskunde, Medisch Spectrum Twente, Enschede. 2 Afdeling Kindergeneeskunde, UMC St Radboud, subafd. Metabole en Endocriene Ziekten, Nijmegen. 3 Afdeling Kindergeneeskunde, Maasstad Ziekenhuis, Rotterdam. Background: Panhypopituitarism in childhood is rare. It is even rarer if the disorder appears in a boy with an identical but healthy twin brother. In such a patient it is useful to study the consequences of the hormone disorder and the effect of hormone replacement. Case description: A 6-year-old boy saw a paediatrician because of short stature. He was much shorter than his identical twin brother and he had more abdominal fat mass and a smaller penis. Laboratory tests identified hypothyroidism of central origin, in combination with hypocortisolism and growth hormone deficiency.
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Hormonal replacement resulted in an improvement in growth rate. At the age of 15 years, testosterone therapy was introduced because puberty had not occurred and his growth rate was low. Finally the patient grew a few centimetres taller than his twin brother. Conclusion: In the first year of life, panhypopituitarism has no negative consequences for growth. After this point, growth is clearly delayed. With sufficient replacement growth can completely catch up. Gepubliceerd: Ned Tijdschr Geneeskd. 2011;155(42):A3084 Impact factor: 0
3. The effect of stepping down combination therapy on airway hyperresponsiveness to mannitol Kersten ET1, Driessen JM1, Duiverman EJ2, Thio BJ1 1 Department of Pediatrics, Medisch Spectrum Twente, Enschede 2 Department of Pediatric Pulmonology, Beatrix Children’s Hospital, UMC Groningen, Groningen Rationale: Controversy exists about the safety of long acting beta2-agonist (LABA) treatment, in particular in children. Combination therapy with a LABA and an inhaled corticosteroid (ICS) is prescribed to children with moderate asthma and can be stepped down by withdrawal of the LABA when asthma is well controlled. Objective: To analyze the effect of stepping down from LABA/ICS combination therapy to monotherapy with the same dose of ICS on the airway response to mannitol in asthmatic children. Methods: 17 children, aged 12-17 years, with clinically stable asthma, receiving combination therapy, were analyzed in this observational prospective open-label study. Children performed a mannitol challenge at baseline and 30±4 days after their medication was stepped down to ICS monotherapy. The changes in the provoking dose of mannitol to cause a 15% fall in FEV(1) (PD(15)), response-dose ratio and recovery time following a short acting beta2-agonist to ≥95% of baseline FEV(1) were assessed. Results: Mannitol PD(15) and response-dose ratio did not significantly change after stepping down. The recovery time following a short acting beta2-agonist to ≥95% of baseline FEV(1) was significantly shorter (p=0.01) after the withdrawal of the LABA. Conclusions: In short-term follow-up, stepping down clinically stable asthmatic children from combination therapy to monotherapy with an ICS does not change airway hyperresponsiveness (AHR) to mannitol but does shorten recovery time to baseline lung function following a rescue short acting beta2-agonist. Gepubliceerd: Respir Med. 2011;105(5):691-697 Impact factor: 2.525
4. Association of the Asthma Control Questionnaire with Exercise-Induced Bronchoconstriction
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Madhuban AA1, Driessen JM1, Brusse-Keizer MG2, van Aalderen WM3, de Jongh FH2, Thio BJ1 1 Department of Pediatrics, Medisch Spectrum Twente, Enschede 2 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 3 Department of Pediatrics, AMC Amsterdam,Amsterdam Introduction. Asthma is a common chronic disease in childhood which features bronchial hyperresponsiveness to exercise (EIB). In daily clinical practice, the report of EIB is used to assess the level of control of asthma. The asthma control questionnaire (ACQ) is a tool to evaluate the control of asthma in children. The aim of this study was to evaluate the relationship between the ACQ and EIB. Materials and methods. Two hundred children, aged 12.5 ± 2.5 years, with a pediatrician-diagnosed mild-to-moderate asthma filled out an ACQ and performed an exercise provocation test in cold air. EIB was defined as a fall in FEV(1) of 15%. Results. Eighty six of the 200 children had a positive exercise challenge. There was no relationship between the categorical ACQ and the occurrence of EIB (p = .39). There was no difference in the occurrence of EIB between genders (p = .12). The positive predictive value of the ACQ for EIB was 51% and the negative predictive value for EIB was 59%. In comparison to the girls, the boys carried an odds ratio (OR) of 0.48 for having an indifferent control of asthma (p = .04; confidence interval (CI): 0.23-0.96), and an OR of 0.46 for having a not well-controlled asthma (p = .03; CI: 0.23-0.93). Conclusion. This study shows that the ACQ is not related to EIB in children with asthma. Remarkable is the percentage (41%) of children who, despite wellcontrolled asthma according to the ACQ, had EIB, which implies that their asthma is not well-controlled. Boys were more likely to report well-controlled asthma, although boys and girls were equally likely to have EIB. Gepubliceerd: J Asthma. 2011;48(3):275-8 Impact factor: 1.341
5. Effects of a single dose inhaled corticosteroid on the dynamics of airway obstruction after exercise Driessen JM1, Nieland H2, van der Palen JA3, van Aalderen WM4, Thio BJ1, de Jongh FH2 1 Department of Pediatrics, Medisch Spectrum Twente, Enschede 2 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 3 Medical School Twente, Medisch Spectrum Twente, Enschede 4 Department of Pediatrics, AMC, Amsterdam Rationale: Exercise-induced bronchoconstriction (EIB) is defined as a transient narrowing of the airways induced by exercise. Repetitive measurements of spirometric parameters, such as FEV(1) and expiratory flows, and forced oscillation technique (FOT) measurements can be used to analyze the dynamics of EIB. A single high dose of fluticasone propionate (FP) protects against EIB. The aim of the study was to analyze the effect of FP on the dynamics of exercise-induced airway narrowing as measured with FOT and spirometry.
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Methods: Twelve children performed an exercise challenge on 2 separate days, 4Ԝhr after inhalation of 1Ԝmg FP (pressurized metered dose inhaler) or a placebo. Before and after the exercise flow-volume loops as well as the FOT (frequency range: 432ԜHz) were measured. Results: The FEV(1) , and FEF(50) fell significantly after exercise within groups; the peak fall in FEV(1) after FP was significantly smaller than after placebo (respectively, 19.3Ԝ±Ԝ14.6% and 29.2Ԝ±Ԝ14.8%, PԜ=Ԝ0.03, 95% CI: 0.9-18.8%). The fall in FEV(1) and FEF(50) peaked 3Ԝmin after exercise and showed a subsequent partial recovery. The fall in the FEV(1) /FVC ratio showed a later peak fall (12Ԝmin after exercise). The resistance increased while the reactance decreased significantly after exercise. FP significantly decreased the maximal increase in Rrs(6) when compared to the placebo (respectively 176.5Ԝ±Ԝ59.1% and 201.0Ԝ±Ԝ63.8%, PԜ=Ԝ0.05, 95% CI: 0.5-48.7%). The maximal decrease in Xrs(6) was not significantly affected by FP (PԜ=Ԝ0.06). Conclusion: Repetitive spirometric and FOT measurements after exercise show a rapid narrowing and steady recovery of the patency of the conducting airways, and indicate a delayed and prolonged recovery of the smaller airways. A single high dose of inhaled FP seems to employ its effect mainly in the conducting airways. Gepubliceerd: Pediatr Pulmonol. 2011;46(9):849-856 Impact factor: 2.239
6. The role of endoscopy in the diagnostic assessment of childhood inflammatory bowel disease TZ Hummel1,2, MA Benninga2, A Kindermann2 1 Department of Pediatric Medicine, Medisch Spectrum Twente, Enschede 2 Emma Children’s Hospital/Academic Medical Center, Amsterdam Gepubliceerd: Eur Gastroenterol Hepatol Review. 2011;7(1):47-50 Impact factor: 1.598
7. The duration of effect of infliximab maintenance treatment in pediatric Crohn’s disease is limited CI De Bie1, TZ Hummel2,14, A Kindermann2, FT Kokke3, GM Damen4, CM Kneepkens5, PF Van Rheenen6, JJ Schweizer7, JH Hoekstra8, OF Norbruis9, WE Tjon a Ten10, AC Vreugdenhil11, JM Deckers-Kocken8,12, CF Gijsbers13, JC Escher1, L De Ridder1 1 Erasmus MC – Sophia Children’s Hospital, Rotterdam 2 Emma Children’s Hospital/Academic Medical Center, Amsterdam 3 Wilhelmina Children’s Hospital/Utrecht Medical Center, Utrecht 4 University Medical Center St Radboud, Nijmegen 5 VU University Medical Center, Amsterdam 6 Beatrix Children’s Hospital/University Medical Center Groningen, Groningen 7 Leiden University Medical Center, Leiden 8 Jeroen Bosch Medical Hospital, ’s-Hertogenbosch 9 Isala Klinieken, Zwolle 113
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Maxima Medical Center, Veldhoven University Hospital Maastricht, Maastricht 12 Flevoziekenhuis, Almere 13 Juliana Children’s Hospital/Haga Teaching Hospital, The Hague 14 Department of Pediatric Medicine, Medisch Spectrum Twente, Enschede 11
Background: Infliximab is effective for induction and maintenance of remission in children with moderately to severely active Crohn's disease (CD). Aim: To evaluate the long-term efficacy of infliximab treatment in paediatric CD. Methods: In this observational, multicentre study, all paediatric CD patients in The Netherlands treated with infliximab from October 1992 to November 2009 and with minimal follow-up of 3 months since start of infliximab, were studied. Results: One hundred and fifty-two CD patients [81M; median age at start of infliximab 15.0 years (IQR 13.1-16.4)] received a median number of 10.5 infliximab infusions (IQR 6-21). Median follow-up after start of infliximab was 25 months (IQR 13-40). Kaplan-Meier analysis showed that the cumulative probability of losing response to infliximab in patients who initially required repeated infusions was 13%, 40% and 50% after 1, 3 and 5 years, respectively. Seventy-four patients (49%) needed dose adjustments, with a median time to any adjustment of 6 months. Conclusions: Duration of effect of infliximab is limited as 50% of patients on infliximab maintenance treatment lose their therapeutic response after 5 years. Dose adjustments after start of infliximab are frequently needed to regain therapeutic benefit. These findings emphasise the need for effective, long-term treatment strategies for paediatric CD. Gepubliceerd: Aliment Pharmacol Ther. 2011;33(2):243-50 Impact factor: 3.861
Totale impact factor: 14.180 Gemiddelde impact factor: 2.026 Aantal artikelen 1e, 2e of laatste auteur: 7 Totale impact factor: 14.180 Gemiddelde impact factor: 2.026
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Klinische Chemie 1. On chip electrofusion of single human B cells and mouse myeloma cells for efficient hybridoma generation Kemna EW1, Wolbers F1, Vermes I1,2, van den Berg A1 1 BIOS, Lab on a Chip group, MESA+ Institute for Nanotechnology, University of Twente, Enschede 2 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede This article describes the development and full characterization of a microfluidic chip for electrofusion of human peripheral blood B-cells and mouse myeloma (NS-1) cells to generate hybridomas. The chip consists of an array of 783 traps, with dimensions that were optimized to obtain a final cell pairing efficiency of 33±6%. B cells were stained with a cytoplasmic stain CFDA to assess the different stages of cell fusion, i.e. dye transfer to NS-1 cells (initiating fusion) and membrane reorganization (advanced fusion). Six DC pulses of 100 Ԝμs (2.5 ԜkV/cm) combined with an AC field (30Ԝ s, 2Ԝ MHz, 500Ԝ V/cm) and pronase treatment resulted in the highest electrofusion efficiency of paired cells (51±11%). Hybridoma formation, with a yield of 0.33 and 1.2%, was observed after culturing the fused cells for 14 days in conditioned medium. This work provides valuable leads to improve the current electrofusion protocols for the production of human antibodies for diagnostic and therapeutic applications. Gepubliceerd: Electrophoresis 2011;32(22):3138-46 Impact factor: 3.569
2. Heterologous prime-boost immunizations with a virosomal and an alphavirus replicon vaccine result in higher CTL frequencies than homologous prime-boost immunizations but not in higher anti-tumor responses M Walczak1, A de Mare1,4, A Riezebos-Brilman1, M Fiedler2, P Jansen-Dürr2, AG van der Zee3, HW Nijman3, J Wilschut1, T Daemen1 1 Department of Medical Microbiology, Molecular Virology Section, UMC Groningen, University of Groningen, Groningen 2 Tumour Virology Group, Tyrolean Cancer Research Institute, Innsbruck, Austria 3 Department of Gynecology, UMC Groningen, University of Groningen, Groningen 4 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede Heterologous prime-boost immunization strategies in general establish higher frequencies of antigen-specific T lymphocytes than homologous prime-boost protocols or single immunizations. We developed virosomes and recombinant Semliki Forest Virus (rSFV) as antigen delivery systems, each capable of inducing strong CTL responses in homologous prime-boost protocols. Here, we demonstrate that a heterologous prime-boost with recombinant Semliki Forest Virus (rSFV) encoding a fusion protein of E6 and E7 of Human Papillomavirus (HPV) type 16 and virosomes containing the HPV16 E7 protein resulted in higher numbers of antigenspecific CTL in mice than homologous protocols. Evasion of vector-specific immunity
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appeared to play a role in establishing these high frequencies, as co-induction of vector-specific responses during the prime immunization reduced the frequency of antigen-specific CTL after a heterologous booster. However, the high numbers of CTL initially primed by the heterologous protocols did not correlate with enhanced responsiveness to in vitro antigenic stimulation, nor in improved cytolytic activity or anti-tumor responses in vivo compared to a homologous protocol with rSFV. This lack of correlation could not be explained by changes in numbers of regulatory T cells. However, we observed differences in the frequencies of T cell subsets within the E7-specific CD8+ T cell population, e.g. higher frequencies of central memory T cells upon homologous immunizations compared to heterologous immunizations. The induction of central memory T cells is crucial for a cancer vaccine as these cells are known to rapidly expand upon recall stimulation. This study demonstrates that the strongly increased number of antigen-specific CTL as induced by heterologous prime-boost immunizations, often used as a proof for the enhanced efficacy of such regimes, does not necessarily equal superior functional anti-tumor responses. Gepubliceerd: Molecular Pharmaceutics 2011:8(1):65-77 Impact factor: 5.400
3. Employing age-related cut-off values results in fewer patients with renal impairment in secondary care Drion I1, Joosten H2, van Hateren KJ1, Kleefstra N1,2,3, Krabbe JG4, Wetzels JF5, Bilo HJ1,2 1 Diabetes Kenniscentrum, Isala Klinieken, Zwolle. 2 Afdeling Interne Geneeskunde, UMC Groningen, Groningen 3 Langerhans Medical Research Group, Zwolle 4 Afdeling Klinische Chemie, Medisch Spectrum Twente, Enschede 5 Afdeling Nefrologie, UMC St Radboud, Nijmegen To describe the consequences on the burden for primary and secondary care in the Netherlands, of using age-related cut-off values for renal function which follow the Dutch national transmural agreement (LTA) for 'Chronic renal impairment', rather than the 'Kidney disease outcome quality initiative' (K/DOQI) guidelines. Gepubliceerd: Ned Tijdschr Geneeskd. 2011;155(18):A3091 Impact factor: 0
4. Local innate and adaptive immune responses regulate inflammatory cell influx into the lungs after vaccination with formalin inactivated RSV D Kruijsena, MA Schijfa, b,, MV Lukensa,d, NO van Udena, JL Kimpena, FE Coenjaertsc, GM van Bleeka a Department of Pediatrics, The Wilhelmina Children's Hospital, UMC, Utrecht b Department of Immunology, Danone Research - Centre for Specialised Nutrition, Wageningen c Department of Medical Microbiology, UMC, Utrecht d Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede
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Inactivated respiratory syncytial virus (RSV) vaccines tend to predispose for immune mediated enhanced disease, characterized by Th2 responses and airway hypersensitivity reactions. We show in a C57BL/6 mouse model that the early innate response elicited by the challenge virus (RSV versus influenza virus) influences the outcome of the Th1/Th2 balance in the lung after intramuscular priming with inactivated vaccine. Priming of CD4(+)/IFN-γ(+) T cells by mature dendritic cells administered intravenously and/or priming of a virus specific CD8(+) T cell response ameliorated the Th2-mediated inflammatory response in the lung, suggesting that vaccination procedures are feasible that prevent vaccine induced immune pathology. Gepubliceerd: Vaccine 2011;29(15):2730-41 Impact factor: 3.574
5. Dynamic Culturing of Smooth Muscle Cells in Tubular Poly(Trimethylene Carbonate) Scaffolds for Vascular Tissue Engineering Y Song1, JWH Wennink1, MMJ Kamphuis1,2, Sterk LM1, I Vermes1,2, AA Poot1, J Feijen1, DW Grijpma1,3 1 Department of Polymer Chemistry and Biomaterials, Faculty of Science and Technology, Institute for Biomedical Technology and Technical Medicine (MIRA), University of Twente, Enschede 2 Department of Clinical Chemistry, Medical Spectrum Twente, Enschede 3 Department of Biomedical Engineering, UMC Groningen, University of Groningen, Groningen Porous, tubular, flexible and elastic poly(trimethylene carbonate) (PTMC) scaffolds (length 8 cm, inner diameter 3 mm) for vascular tissue engineering were prepared by means of a dip-coating and particulate leaching procedure. Using NaCl as porogen, scaffolds with an average pore size of 110 mum and a porosity of 85% were obtained. Before leaching the salt, the structures were made creep-resistant by means of crosslinking at 25 kGy gamma irradiation. To increase the efficiency of cell seeding, the scaffolds were provided with a micro-porous outer layer of 0.2 mm with an average pore size of 28 mum and a porosity of 65% (total wall thickness 1 mm). Human smooth muscle cells (SMCs) were seeded in these scaffolds with an efficiency of 43%, as determined after 24 h cell adhesion. SMCs were cultured in the scaffolds up to 14 days under stationary conditions or under pulsatile flow conditions in a bioreactor (pressure 70-130 mmHg, 69 pulsations/min, average wall shear rate 320 s<sup>-1). Although SMCs proliferated under both conditions, cell numbers were 3-5 times higher in case of dynamic culturing. This was qualitatively confirmed by means of histology. Also in terms of mechanical properties, the dynamically cultured constructs performed better than the statically cultured constructs. After culturing for 14 days, the maximum tensile strengths of the constructs, determined in the radial direction, had increased from 0.16 MPa (unseeded scaffold) to 0.48 MPa (dynamic culturing) and 0.38 MPa (static culturing). The results of this study indicate that a potentially useful medial layer for tissue-
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engineered vascular grafts can be prepared by dynamic culturing of human SMCs seeded in porous tubular PTMC scaffolds. Gepubliceerd: Tissue Eng Part A 2011;17:381-7 Impact factor: 4.636
6. A new floating electrode structure for generating homogeneous electrical fields in microfluidic channels Segerink LI1, Sprenkels AJ1, Bomer JG1, Vermes I1,2, van den Berg A2 1 BIOS-Lab on a Chip group, MESA+ Institute for Nanotechnology, University of Twente, Enschede 2 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede In this article a new parallel electrode structure in a microfluidic channel is described that makes use of a floating electrode to get a homogeneous electrical field. Compared to existing parallel electrode structures, the new structure has an easier production process and there is no need for an electrical connection to both sides of the microfluidic chip. With the new chip design, polystyrene beads suspended in background electrolyte have been detected using electrical impedance measurements. The results of electrical impedance changes caused by beads passing the electrodes are compared with results in a similar planar electrode configuration. It is shown that in the new configuration the coefficient of variation of the impedance changes is lower compared to the planar configuration (0.39 versus 0.56) and less dependent on the position of the beads passage in the channel as a result of the homogeneous electrical field. To our knowledge this is the first time that a floating electrode is used for the realization of a parallel electrode structure. The proposed production method for parallel electrodes in microfluidic channels can easily be applied to other applications. Gepubliceerd: Lab Chip. 2011;11(12):1995-2001 Impact factor: 6.260
7. Evaluation of tubular poly(trimethylene carbonate) tissue engineering scaffolds in a circulating pulsatile flow system Song Y1, Wennink JW1, Poot AA1, Vermes I1,2, Feijen J1, Grijpma DW1 1 Institute for Biomedical Technology (BMTI) and Department of Polymer Chemistry and Biomaterials, Faculty of Science and Technology, University of Twente, Enschede 2 Department of Clinical chemistry, Medisch Spectrum Twente, Enschede Tubular scaffolds (internal diameter approximately 3 mm and wall thickness approximately 0.8 mm) with a porosity of approximately 83% and an average pore size of 116 µm were prepared from flexible poly(trimethylene carbonate) (PTMC) polymer by dip-coating and particulate leaching methods. PTMC is a flexible and biocompatible polymer that crosslinks upon irradiation; porous network structures were obtained by irradiating the specimens in vacuum at 25 kGy before leaching
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soluble salt particles. To assess the suitability of these scaffolds in dynamic cell culturing for cardiovascular tissue engineering, the scaffolds were coated with a thin (0.1 to 0.2 mm) non-porous PTMC layer and its performance was evaluated in a closed pulsatile flow system (PFS). For this, the PFS was operated at physiological conditions at liquid flows of 1.56 ml/s with pressures varying from 80-120 mmHg at a frequency of 70 pulsations per minute. ?The mechanical properties of these coated porous PTMC scaffolds were not significantly different than non-coated scaffolds. Typical tensile strengths in the radial direction were 0.15 MPa, initial stiffness values were close to 1.4 MPa. Their creep resistance in cyclic deformation experiments was excellent. In the pulsatile flow setup, the distention rates of these flexible and elastic scaffolds were approximately 0.10% per mmHg, which is comparable to that of a porcine carotid artery (0.11% per mmHg). The compliance and stiffness index values were close to those of natural arteries.?In long-term deformation studies, where the scaffolds were subjected to physiological pulsatile pressures for one week, the morphology and mechanical properties of the PTMC scaffolds did not change. This suggests their suitability for application in a dynamic cell culture bioreactor. Gepubliceerd: Int J Artif Organs. 2011;34(2):161-71 Impact factor: 1.503
8. In critically ill patients the procalcitonin level can be misleading J Koeze1, MG Hendrix2, FA van den Bergh3, RM Brouwer4, JG Zijlstra1 1 Department of Critical Care, UMC Groningen, University of Groningen, Groningen 2 Laboratory of Microbiology, Twente Achterhoek, Enschede 3 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede 4 Department of Internal Medicine, Medisch Spectrum Twente, Enschede Gepubliceerd: Crit Care. 2011;15(2):422 Impact factor: 4.595
9. Cancer prevalence in osteoporotic women with low serum vitamin D levels Veldhuis S1, Wolbers F2, Brouckaert O1, Vermes I2,3, Franke HR1 1 Department of Obstetrics and Gynecology, Medisch Spectrum Twente, Enschede 2 Department of Polymer Chemistry and Biomaterials, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 3 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede Objective:: The aim of this study was to assess the role of vitamin D in cancer development in postmenopausal osteoporotic women. Methods:: A cross-sectional and in vitro study was carried out, with statistical analysis with odds ratios and 95% CIs presented. Human estrogen receptor-positive breast cancer cells (MCF-7) were studied in vitro. The apoptosis-to-proliferation (A/P) ratio was also determined. Results:: A total of 885 women were included in this study. Any kind of cancer was found in 112 (12.7%) of all women. Breast cancer was the most prevalent
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malignancy, representing half of the cases (n = 56, 50%). The prevalence of any kind of cancer and breast cancer in women with low 25-hydroxyvitamin D3 levels (25OHD; <50 nmol/L) was higher than in women with high 25OHD levels (≥50 nmol/L). The in vitro study demonstrated a statistically significant increased A/P ratio of 5.27 (95% CI, 4.054-6.493) with a high concentration of 1α,25-dihydroxyvitamin D (10 μM) after 96 hours. Conclusions:: Osteoporotic women with low serum levels of 25OHD (<50 nmol/L) have an increased prevalence of any kind of cancer and breast cancer; however, these differences are not statistically significant. 1α,25-dihydroxyvitamin D induced an increased A/P ratio in MCF-7 breast cancer cells in vitro. Gepubliceerd: Menopause. 2011;18(3):319-22 Impact factor: 3.318
10. Patiënte met kruisproblemen door antistoffen tegen k bij een hemorragische shock Lukens MV, Bossink R, Huistede-Oude Heuvel AH, Adema E, Winkelhorst JT, Ozdemir A, Slomp J Department of Clinical chemistry, Medisch Spectrum Twente, Enschede Gepubliceerd: Tijdschrift Bloedtransfusie 2011;4:106-10 Impact factor: 0
Totale impact factor: 32.855 Gemiddelde impact factor: 3.286 Aantal artikelen 1e, 2e of laatste auteur: 2 Totale impact factor: 5.400 Gemiddelde impact factor: 2.700
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Klinische Farmacie 1. Dopaminergic drugs and the risk of hip or femur fracture: a population-based case-control study Arbouw ME1,2,3, Movig KL3, van Staa TP1,4, Egberts AC1,2, Souverein PC1, de Vries F1,4 1 Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Universiteit Utrecht, Utrecht 2 Department of Clinical Pharmacy, UMCUtrecht, Utrecht 3 Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede 4 MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton, UK The effect of dopaminergic medication on the risk of hip/femur fractures is not clear. Our results showed a nearly twofold increased risk of hip/femur fractures in current dopaminergic drug users. Concomitant use of antidepressants further increased this risk. Fracture risk assessment may be warranted in elderly users of dopaminergic drugs. Gepubliceerd: Osteoporosis Int. 2011;22(7):2197-204 Impact factor: 4.859
2. Relation between amoxicillin concentration in sputum of COPD patients and length of hospitalization Brusse-Keizer M1, ten Bokum L2, Movig K3, van der Valk P1, Kerstjens H5, van der Palen J1,5, Hendrix R6 1 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 2 Department of Clinical Pharmacy, Deventer Hospital, Deventer 3 Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede 4 Department of Pulmonary Medicine, UMC Groningen, and University of Groningen, Groningen 5 Department of Research Methodology, Measurement, and Data Analysis, University of Twente 6 Regional Laboratory of Public Health, Enschede Amoxicillin is a widely used antibiotic in COPD. Little is known about the transfer of amoxicillin into sputum of COPD patients. The objective was to investigate the relationship between the concentration of amoxicillin in sputum in hospitalized COPD patients and length of hospitalization. To be effective against bacterial pathogens, the amoxicillin concentration in target tissues should be higher than the Minimal Inhibiting Concentration (MIC) of 2 mg/l. Therefore, this was also used as the cut-off value for the amoxicillin concentration in sputum, as a marker for lung tissue concentration. Fifty-two COPD in-patients with an exacerbation, treated with amoxicillin clavulanic acid, were included in this cohort study. Of these patients 7 also had pneumonia. Patients were divided in patients with an amoxicillin sputum concentration ≥ 2 mg/l and < 2 mg/l. Furthermore, inflammation markers in sputum
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and serum and clinical parameters were obtained. Of the 33 patients with usable sputum, 11 had a concentration in sputum ≥ 2 mg/l. The mean length of hospitalization for patients with concentrations below the MIC90 to common respiratory pathogens was 11.0 days, while for patients with concentrations at or above the MIC90 this was 7.0 days (p = 0.005). COPD patients admitted for an acute exacerbation of COPD, with a sputum concentration of amoxicillin ≥ 2 mg/l had a markedly reduced length of hospitalization compared to patients with a concentration < 2 mg/l. It is worthwhile testing whether individualized treatment based on sputum amoxicillin concentrations of patients during hospitalization for acute exacerbations can effectively reduce hospital stay. Gepubliceerd: COPD. 2011 Apr;8(2):66-70 Impact factor: 2.250
3. Long-term administration of fluoxetine to improve motor recovery after stroke Berends HI1, IJzerman MJ2, Movig KL3, Van Putten MJ1,4 1 Department of Technical Medicine, University of Twente, Enschede 2 Department of Health Technology & Services Research, University of Twente, Enschede 3 Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede 4 Department of Neurology, Medisch Spectrum Twente, Enschede Evaluation of: Chollet F Tardy J, Albucher JF et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 10(2), 123–130 (2011). In this study, the authors examined the effects of administration of fluoxetine for 90 days on the recovery of motor function in acute stroke patients. They found that motor function in the group receiving fluoxetine improved significantly compared with the control group. Before administration of fluoxetine can be used as a new therapeutic treatment to improve the rehabilitation after stroke, the long-term effects in chronic stroke patients, as well as the physiological effects, have to be studied and compared with the results of other neuropharmacalogical agents. Gepubliceerd: Future Neurology 2011;6:455-457 Impact factor: 0
4. Sputum amoxicillin concentrations in relation to beta-lactamase activity in COPD patients Van Der Zanden RW1, Brusse-Keizer MG2, Van Der Valk PD2, Hendrix MG3, Van Der Palen J4, Movig KL1 1 Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede 2 Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede 3 Laboratory of Microbiology, Twente Achterhoek, Enschede 4 Medical School Twente, Medisch Spectrum Twente, Enschede Gepubliceerd: Pharmaceutisch Weekblad 2011;146:91-95
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Impact factor: 0
Totale impact factor: 7.109 Gemiddelde impact factor: 1.777 Aantal artikelen 1e, 2e of laatste auteur: 2 Totale impact factor: 4.859 Gemiddelde impact factor: 2.423
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KNO 1. Shared care for hearing complaints: guideline effects on patient flow Duijvestijn JA1, Grutters JP2, Chenault MN3, Joore MA2, Manni JJ4, Anteunis LJ5 1 Department of Otorhinolaryngology, Head and Neck Surgery, Medisch Spectrum Twente, Enschede 2 Department of Health Organisation, Policy and Economics, Maastricht University, Maastricht 3 Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Maastricht, Department of Methodology and Statistics, School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Science, Maastricht University, Maastricht 4 Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Maastricht, Maastricht 5 Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Maastricht, School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Science, Maastricht University, Maastricht Rationale, aims and objectives: A national guideline was proposed to enable shared care in hearing complaints and therefore to change patient flows. In this study the effect of this guideline is evaluated. Methods: From a total of 3500 patients with hearing complaints, consulting the Ear Nose and Throat Department of a large non-university hospital in the Netherlands in 2002, a random sample of 1000 patients was selected. Patient flow was simulated according to guideline criteria with as main outcome measures: the effect of the guideline on patient flow. Results: Simulation of the consensus guideline did not really alter patient flow, with 89% to 97% of the patients still being referred to the Ear Nose and Throat specialist or Audiological Centre. Age, ear operations in the past and asymmetric hearing loss are the most important factors determining whether a person is labelled as a patient in need of medical care. Conclusion: The present study emphasizes the importance of designing evidencebased guidelines for shared care. Gepubliceerd: J Eval Clin Pract. 2011;17(2):209-14 Impact factor: 1.003
Totale impact factor: 1.003 Gemiddelde impact factor: 1.003 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 1.003 Gemiddelde impact factor: 1.003
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Laboratorium voor Microbiologie 1. Human immune responses that reduce the transmission of Plasmodium falciparum in African populations Bousema T1, Sutherland CJ1, Churcher TS2, Mulder B3, Gouagna LC4, Riley EM1, Targett GA1, Drakeley CJ1 1 Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 2 Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College London, London, UK 3 Microbiology Laboratory Twente, Enschede 4 Institut de Recherche pour le Développement, Marseille, France Malaria-infected individuals can develop antibodies which reduce the infectiousness of Plasmodium gametocytes to biting Anopheles mosquitoes. When ingested in a bloodmeal together with gametocytes, these antibodies reduce or prevent subsequent parasite maturation in the insect host. This transmission-blocking immunity is usually measured in human sera by testing its effect on the infectivity of gametocytes grown in vitro. Here we evaluate evidence of transmission-blocking immunity in eight studies conducted in three African countries. Plasmodium falciparum gametocytes isolated from each individual were fed to mosquitoes in both autologous plasma collected with the parasites, and permissive serum from nonexposed donors. Evidence of transmission reducing effects of autologous plasma was found in all countries. Experiments involving 116 Gambian children (aged 0.515 years) were combined to determine which factors were associated with transmission reducing immune responses. The chances of infecting at least one mosquito and the average proportion of infected mosquitoes were negatively associated with recent exposure to gametocytes and sampling late in the season. These results suggest that effective malaria transmission-reducing antibodies do not commonly circulate in African children, and that recent gametocyte carriage is required to initiate and/or boost such responses. Gepubliceerd: Int J Parasitol. 2011;41(3-4):293-300 Impact factor: 3.822
2. Relation between amoxicillin concentration in sputum of COPD patients and length of hospitalization Brusse-Keizer M1, ten Bokum L2, Movig K3, van der Valk P1, Kerstjens H5, van der Palen J1,5, Hendrix R6 1 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 2 Department of Clinical Pharmacy, Deventer Hospital, Deventer 3 Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede 4 Department of Pulmonary Medicine, UMC Groningen, and University of Groningen, Groningen 5 Department of Research Methodology, Measurement, and Data Analysis, University of Twente
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6
Regional Laboratory of Public Health, Enschede
Amoxicillin is a widely used antibiotic in COPD. Little is known about the transfer of amoxicillin into sputum of COPD patients. The objective was to investigate the relationship between the concentration of amoxicillin in sputum in hospitalized COPD patients and length of hospitalization. To be effective against bacterial pathogens, the amoxicillin concentration in target tissues should be higher than the Minimal Inhibiting Concentration (MIC) of 2 mg/l. Therefore, this was also used as the cut-off value for the amoxicillin concentration in sputum, as a marker for lung tissue concentration. Fifty-two COPD in-patients with an exacerbation, treated with amoxicillin clavulanic acid, were included in this cohort study. Of these patients 7 also had pneumonia. Patients were divided in patients with an amoxicillin sputum concentration ≥ 2 mg/l and < 2 mg/l. Furthermore, inflammation markers in sputum and serum and clinical parameters were obtained. Of the 33 patients with usable sputum, 11 had a concentration in sputum ≥ 2 mg/l. The mean length of hospitalization for patients with concentrations below the MIC90 to common respiratory pathogens was 11.0 days, while for patients with concentrations at or above the MIC90 this was 7.0 days (p = 0.005). COPD patients admitted for an acute exacerbation of COPD, with a sputum concentration of amoxicillin ≥ 2 mg/l had a markedly reduced length of hospitalization compared to patients with a concentration < 2 mg/l. It is worthwhile testing whether individualized treatment based on sputum amoxicillin concentrations of patients during hospitalization for acute exacerbations can effectively reduce hospital stay. Gepubliceerd: COPD. 2011 Apr;8(2):66-70 Impact factor: 2.250
3. Clinical predictors of exacerbation frequency in chronic obstructive pulmonary disease Brusse-Keizer MG1, van der Palen J2,3, van der Valk PD1, Hendrix R4, Kerstjens H5 1 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 2 Medical School Twente, Medisch Spectrum Twente, Enschede 3 Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede 4 Regional Laboratory of Public Health, P.O Box 377, 7500 AJ Enschede 5 Department of Pulmonary Medicine, UMC Groningen, University of Groningen, Groningen Introduction: Reduction of exacerbation frequency plays an increasingly important role in interventions in COPD. To reduce this frequency efficiently, patients at risk for frequent exacerbations need to be identified. Objective: To identify predictors for frequent exacerbations from multiple domains of COPD during a stable phase of the disease. Methods: Data of multiple domains of COPD were collected of 121 patients with moderate to severe COPD. Patients were divided into infrequent (<2 exacerbations per year) and frequent (>2 exacerbations) exacerbators.
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Results: SGRQ total score and a course of oral corticosteroid within 3 months prior to the study together predicted best whether patients would be infrequent or frequent exacerbators over the course of the next year. Each unit increase in total SGRQ score was associated with a 3% higher risk of being a frequent exacerbator (OR = 1.03; 95% CI: 1.00 - 1.06; p = 0.047). Patients who received a course of oral corticosteroids in the period of 3 months prior to the study had a 3-fold increased risk of being a frequent exacerbator (OR = 3.17; 95% CI: 1.20 - 8.34; p = 0.02). Furthermore, we observed that a sizable number of patients switched from being a frequent to an infrequent exacerbator and vice versa. Conclusions: Health related quality of life and a course of oral corticosteroid in the past 3 months are the best predictors of future exacerbator status. The predictive value of the model is however still insufficient. Furthermore, our data suggest, in contrast to previous observations, that exacerbation frequency is not a constant feature. Gepubliceerd: Clin Respir J. 2011; 5(4):227-34 Impact factor: 0.512
4. Impact on clinical decision making of quality control standards applied to sputum analysis in COPD MC Telgena, MG Brusse-Keizera,, PD van der Valka, J. van der Palena, d, HA Kerstjensb, MG Hendrixc a Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede b Department of Pulmonary Medicine, UMC Groningen, University of Groningen, Groningen c Regional Laboratory of Public Health, P.O Box 377, 7500 AJ Enschede d Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede Purpose: Sputum analysis is important in COPD exacerbation management. We determined whether application of stringent quality control criteria for sputum samples had an impact on culture results. Methods: We analyzed sputum samples of 108 patients during stable COPD and during exacerbations. To all samples quality control standards and culture interpretation rules according to the American Society of Microbiologists (ASM) were applied. Results: In sputum exacerbation samples considered appropriate according to ASM quality standards, criteria for infection (40%) were met more often compared to inappropriate samples (13%) (p < 0.001). The same pattern was observed when applying these rules to sputum samples obtained during stable disease, (50% vs. 18%, p < 0.001). There was no difference in the percentage of infectious cultures obtained during the stable state and exacerbations. Conclusions: Applying stringent quality control criteria to sputum samples can have a profound effect on the labeling of sputum samples as infectious, and therefore on clinical decision making. Gepubliceerd: Resp Med 2011;105(3):371-376
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Impact factor: 2.525
5. In critically ill patients the procalcitonin level can be misleading J Koeze1, MG Hendrix2, FA van den Bergh3, RM Brouwer4, JG Zijlstra1 1 Department of Critical Care, UMC Groningen, University of Groningen, Groningen 2 Laboratory of Microbiology, Twente Achterhoek, Enschede 3 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede 4 Department of Internal Medicine, Medisch Spectrum Twente, Enschede Gepubliceerd: Crit Care. 2011;15(2):422 Impact factor: 4.595
6. Tenosynovitis Caused by a Pseudallescheria boydii Infection and Symptoms of Reflex Sympathetic Dystrophy After a Dog Bite Ruinemans GM1, Haagsma CJ1, Hendrix R2 1 Department of Rheumatology, Ziekenhuisgroep Twente, Twenteborg Hospital, Almelo 2 Laboratory of Microbiology, Twente Achterhoek, Enschede Tenosynovitis caused by a Pseudallescheria boydii infection is an extremely rare complication after a dog bite and is easily misdiagnosed, leading to a delay in treatment. Careful history taking and adequate cultures can lead to a timely diagnosis, and longstanding antimycotic treatment can successfully eradicate the fungus. Gepubliceerd: J Clin Rheumatol. 2011 Oct;17(7):363-4 Impact factor: 1.283
7. Xpert MTB/RIF®, a novel automated polymerase chain reaction-based tool for the diagnosis of tuberculosis Bowles EC1, Freyée B2, van Ingen J3, Mulder B4, Boeree MJ3, van Soolingen D5 1 Department of Clinical Microbiology, UMC Utrecht, Utrecht 2 Department of Medical Microbiology and Infection Prevention, Gelre Hospital, Apeldoorn 3 Department of Pulmonary Diseases, Radboud University Nijmegen MC, Nijmegen 4 Laboratory for Clinical Microbiology Twente-Achterhoek, Enschede 5 Department of Pulmonary Diseases and Department of Clinical Microbiology, Radboud University Nijmegen MC, Nijmegen There is an urgent need for new point of care tests for tuberculosis (TB). Xpert MTB/RIF® is a real-time polymerase chain reaction-based system that detects Mycobacterium tuberculosis DNA and rifampicin (RMP) resistance modulating mutations directly from clinical samples in 2 h. The sensitivity for detecting M. tuberculosis in culture-positive samples was 93.8% (60/64) and exceeded smear microscopy (40/64, 62.5%). The specificity for detecting M. tuberculosis was 92.0% 128
(23/25) and for RMP resistance it was 100% (8/8). The test is simple to conduct and requires basic sputum handling facilities only. These characteristics render it a promising close-to-patient test for TB in various settings. Gepubliceerd: Int J Tuberc Lung Dis. 2011;15(7):988-9 Impact factor: 2.557
8. Sputum amoxicillin concentrations in relation to beta-lactamase activity in COPD patients Van Der Zanden RW1, Brusse-Keizer MG2, Van Der Valk PD2, Hendrix MG3, Van Der Palen J4, Movig KL1 1 Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede 2 Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede 3 Laboratory of Microbiology, Twente Achterhoek, Enschede 4 Medical School Twente, Medisch Spectrum Twente, Enschede Gepubliceerd: Pharmaceutisch Weekblad 2011;146:91-95 Impact factor: 0
Totale impact factor: 17.544 Gemiddelde impact factor: 2.193 Aantal artikelen 1e, 2e of laatste auteur: 4 Totale impact factor: 10.653 Gemiddelde impact factor: 2.663
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Longziekten 1. Internet-based tapering of oral corticosteroids in severe asthma: a pragmatic randomised controlled trial Hashimoto S1, ten Brinke A2, Roldaan AC3, van Veen IH4, Möller GM5, Sont JK6, Weersink EJ1, van der Zee JS1, Braunstahl GJ7, Zwinderman AH8, Sterk PJ1, Bel EH1 1 Department of Respiratory Medicine, AMC, University of Amsterdam, Amsterdam 2 Department of Pulmonology, Medical Centre Leeuwarden, Leeuwarden 3 Department of Pulmonology, Haga Ziekenhuis, Den Haag 4 Department of Pulmonology, Medisch Spectrum Twente, Enschede 5 Department of Pulmonology, Leiden UMC, Leiden 6 Department of Medical Decision Making, Leiden UMC, Leiden 7 Department of Pulmonary Medicine, St Franciscus Gasthuis, Rotterdam 8 Department of Clinical Epidemiology and Biostatistics, AMC, University of Amsterdam Background In patients with prednisone-dependent asthma the dose of oral corticosteroids should be adjusted to the lowest possible level to reduce long-term adverse effects. However, the optimal strategy for tapering oral corticosteroids is unknown. Objective To investigate whether an internet-based management tool including home monitoring of symptoms, lung function and fraction of exhaled nitric oxide (FE(NO)) facilitates tapering of oral corticosteroids and leads to reduction of corticosteroid consumption without worsening asthma control or asthma-related quality of life. Methods In a 6-month pragmatic randomised prospective multicentre study, 95 adults with prednisone-dependent asthma from six pulmonary outpatient clinics were allocated to two tapering strategies: according to conventional treatment (n=43) or guided by a novel internet-based monitoring system (internet strategy) (n=52). Primary outcomes were cumulative sparing of prednisone, asthma control and asthma-related quality of life. Secondary outcomes were forced expiratory volume in 1 s (FEV(1)), exacerbations, hospitalisations and patient's satisfaction with the tapering strategy. Results Median cumulative sparing of prednisone was 205 (25-75th percentile -221 to 777) mg in the internet strategy group compared with 0 (-497 to 282) mg in the conventional treatment group (p=0.02). Changes in prednisone dose (mixed effect regression model) from baseline were 4.79 mg/day and +1.59 mg/day, respectively (p<0.001). Asthma control, asthma-related quality of life, FEV(1), exacerbations, hospitalisations and satisfaction with the strategy were not different between groups. Conclusions An internet-based management tool including home monitoring of symptoms, lung function and FE(NO) in severe asthma is superior to conventional treatment in reducing total corticosteroid consumption without compromising asthma control or asthma-related quality of life. Gepubliceerd: Thorax. 2011;66(6):514-20
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Impact factor: 6.525
2. Association of the Asthma Control Questionnaire with Exercise-Induced Bronchoconstriction Madhuban AA1, Driessen JM1, Brusse-Keizer MG2, van Aalderen WM3, de Jongh FH2, Thio BJ1 1 Department of Pediatrics, Medisch Spectrum Twente, Enschede 2 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 3 Department of Pediatrics, AMC Amsterdam,Amsterdam Introduction. Asthma is a common chronic disease in childhood which features bronchial hyperresponsiveness to exercise (EIB). In daily clinical practice, the report of EIB is used to assess the level of control of asthma. The asthma control questionnaire (ACQ) is a tool to evaluate the control of asthma in children. The aim of this study was to evaluate the relationship between the ACQ and EIB. Materials and methods. Two hundred children, aged 12.5 ± 2.5 years, with a pediatrician-diagnosed mild-to-moderate asthma filled out an ACQ and performed an exercise provocation test in cold air. EIB was defined as a fall in FEV(1) of 15%. Results. Eighty six of the 200 children had a positive exercise challenge. There was no relationship between the categorical ACQ and the occurrence of EIB (p = .39). There was no difference in the occurrence of EIB between genders (p = .12). The positive predictive value of the ACQ for EIB was 51% and the negative predictive value for EIB was 59%. In comparison to the girls, the boys carried an odds ratio (OR) of 0.48 for having an indifferent control of asthma (p = .04; confidence interval (CI): 0.23-0.96), and an OR of 0.46 for having a not well-controlled asthma (p = .03; CI: 0.23-0.93). Conclusion. This study shows that the ACQ is not related to EIB in children with asthma. Remarkable is the percentage (41%) of children who, despite wellcontrolled asthma according to the ACQ, had EIB, which implies that their asthma is not well-controlled. Boys were more likely to report well-controlled asthma, although boys and girls were equally likely to have EIB. Gepubliceerd: J Asthma. 2011;48(3):275-8 Impact factor: 1.341
3. Effects of a single dose inhaled corticosteroid on the dynamics of airway obstruction after exercise Driessen JM1, Nieland H2, van der Palen JA3, van Aalderen WM4, Thio BJ1, de Jongh FH2 1 Department of Pediatrics, Medisch Spectrum Twente, Enschede 2 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 3 Medical School Twente, Medisch Spectrum Twente, Enschede 4 Department of Pediatrics, AMC, Amsterdam Rationale: Exercise-induced bronchoconstriction (EIB) is defined as a transient narrowing of the airways induced by exercise. Repetitive measurements of
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spirometric parameters, such as FEV(1) and expiratory flows, and forced oscillation technique (FOT) measurements can be used to analyze the dynamics of EIB. A single high dose of fluticasone propionate (FP) protects against EIB. The aim of the study was to analyze the effect of FP on the dynamics of exercise-induced airway narrowing as measured with FOT and spirometry. Methods: Twelve children performed an exercise challenge on 2 separate days, 4Ԝhr after inhalation of 1Ԝmg FP (pressurized metered dose inhaler) or a placebo. Before and after the exercise flow-volume loops as well as the FOT (frequency range: 432ԜHz) were measured. Results: The FEV(1) , and FEF(50) fell significantly after exercise within groups; the peak fall in FEV(1) after FP was significantly smaller than after placebo (respectively, 19.3Ԝ±Ԝ14.6% and 29.2Ԝ±Ԝ14.8%, PԜ=Ԝ0.03, 95% CI: 0.9-18.8%). The fall in FEV(1) and FEF(50) peaked 3Ԝmin after exercise and showed a subsequent partial recovery. The fall in the FEV(1) /FVC ratio showed a later peak fall (12Ԝmin after exercise). The resistance increased while the reactance decreased significantly after exercise. FP significantly decreased the maximal increase in Rrs(6) when compared to the placebo (respectively 176.5Ԝ±Ԝ59.1% and 201.0Ԝ±Ԝ63.8%, PԜ=Ԝ0.05, 95% CI: 0.5-48.7%). The maximal decrease in Xrs(6) was not significantly affected by FP (PԜ=Ԝ0.06). Conclusion: Repetitive spirometric and FOT measurements after exercise show a rapid narrowing and steady recovery of the patency of the conducting airways, and indicate a delayed and prolonged recovery of the smaller airways. A single high dose of inhaled FP seems to employ its effect mainly in the conducting airways. Gepubliceerd: Pediatr Pulmonol. 2011;46(9):849-856 Impact factor: 2.239
4. Monitoring pulmonary function during exercise in children with asthma van Leeuwen JC1, Driessen JM1, de Jongh FH2,3, van Aalderen WM3, Thio BJ1 1 Department of Pediatrics, Medisch Spectrum Twente, Enschede 2 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 3 Department of Pediatrics, AMC, Amsterdam Objective Exercise-induced bronchoconstriction (EIB) is defined as acute, reversible bronchoconstriction induced by physical exercise. It is widely believed that EIB occurs after exercise. However, in children with asthma the time to maximal bronchoconstriction after exercise is short, suggesting that the onset of EIB in such children occurs during exercise. Aim In this study the authors investigate pulmonary function during exercise in cold air in children with asthma. Methods 33 Children with asthma with a mean age of 12.3 years and a clinical history of exercise induced symptoms, underwent a prolonged, submaximal, exercise test of 12 min duration at approximately 80% of the predicted maximum heart rate. Pulmonary function was measured before and each minute during exercise. If EIB occurred (fall in forced expiratory volume in 1 s >15% from baseline), exercise was terminated and salbutamol was administered.
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Results 19 Children showed EIB. In 12 of these children bronchoconstriction occurred during exercise (breakthrough EIB), while seven children showed bronchoconstriction immediately after exercise (non-breakthrough EIB). Breakthrough EIB occurred between 6 and 10 min of exercise (mean 7.75 min). Conclusion In the majority of children with EIB in this study (ie, 12 out of 19), bronchoconstriction started during, and not after, a submaximal exercise test. Gepubliceerd: Arch Dis Child 2011;96(7):664-8 Impact factor: 2.616
5. Fatigue in spinocerebellar ataxia: Patient self-assessment of an early and disabling symptom E Brusse1, MG Brusse-Keizer3, HJ Duivenvoorden2, JC van Swieten1 1 Departments of Neurology and 2 Medical Psychology and Psychotherapy, Erasmus MC UMC, Rotterdam 3 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede Objective: To identify the prevalence and severity of fatigue and predicting factors for severe fatigue in autosomal dominant spinocerebellar ataxia (SCA). Methods: We studied a cross-section of 123 patients with SCA. Six functional scales were used in a self-assessment: the Fatigue Severity Scale (FSS); the Beck Depression Inventory (BDI); the Rotterdam Handicap Scale (RHS); the Short Form– 36 health survey, distinguishing a norm-based physical and mental component score (Nb-PCS and Nb-MCS); the Pittsburgh Sleep Quality Index (PSQI); and the Epworth Sleepiness Scale (ESS). A subset of 58 patients was clinically evaluated, measuring severity of ataxia with the Scale for the Assessment and Rating of Ataxia and cognitive functioning with the Mini-Mental State Examination. Results: Severe fatigue (FSS ≥5) was present in 69% of patients and FSS value correlated with the scores on RHS, Nb-PCS, Nb-MCS, BDI, PSQI, and ESS. There was no relation with disease duration, gender, or medication use. Multivariate analysis revealed that Nb-PCS and BDI were the best independent predictors for severe fatigue. Interestingly, the presence of visual symptoms was related to FSS value in the clinically evaluated subgroup. Conclusion: Fatigue is a severe and disabling symptom in adult patients with SCA, even early in the course of disease. Physical functioning and depression are the strongest predictors of fatigue. In treatment strategies, all treatable factors for fatigue should be addressed, especially depression, visual symptoms, and sleeping disorders. Gepubliceerd: Neurology 2011;76(11):953-9 Impact factor: 8.017
6. Relation between amoxicillin concentration in sputum of COPD patients and length of hospitalization Brusse-Keizer M1, ten Bokum L2, Movig K3, van der Valk P1, Kerstjens H5, van der Palen J1,5, Hendrix R6
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Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede Department of Clinical Pharmacy, Deventer Hospital, Deventer 3 Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede 4 Department of Pulmonary Medicine, UMC Groningen, and University of Groningen, Groningen 5 Department of Research Methodology, Measurement, and Data Analysis, University of Twente 6 Regional Laboratory of Public Health, Enschede 2
Amoxicillin is a widely used antibiotic in COPD. Little is known about the transfer of amoxicillin into sputum of COPD patients. The objective was to investigate the relationship between the concentration of amoxicillin in sputum in hospitalized COPD patients and length of hospitalization. To be effective against bacterial pathogens, the amoxicillin concentration in target tissues should be higher than the Minimal Inhibiting Concentration (MIC) of 2 mg/l. Therefore, this was also used as the cut-off value for the amoxicillin concentration in sputum, as a marker for lung tissue concentration. Fifty-two COPD in-patients with an exacerbation, treated with amoxicillin clavulanic acid, were included in this cohort study. Of these patients 7 also had pneumonia. Patients were divided in patients with an amoxicillin sputum concentration ≥ 2 mg/l and < 2 mg/l. Furthermore, inflammation markers in sputum and serum and clinical parameters were obtained. Of the 33 patients with usable sputum, 11 had a concentration in sputum ≥ 2 mg/l. The mean length of hospitalization for patients with concentrations below the MIC90 to common respiratory pathogens was 11.0 days, while for patients with concentrations at or above the MIC90 this was 7.0 days (p = 0.005). COPD patients admitted for an acute exacerbation of COPD, with a sputum concentration of amoxicillin ≥ 2 mg/l had a markedly reduced length of hospitalization compared to patients with a concentration < 2 mg/l. It is worthwhile testing whether individualized treatment based on sputum amoxicillin concentrations of patients during hospitalization for acute exacerbations can effectively reduce hospital stay. Gepubliceerd: COPD. 2011 Apr;8(2):66-70 Impact factor: 2.250
7. Clinical predictors of exacerbation frequency in chronic obstructive pulmonary disease Brusse-Keizer MG1, Van Der Palen J2,3, Van Der Valk PD1, Hendrix R4, Kerstjens H5 1 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 2 Medical School Twente, Medisch Spectrum Twente, Enschede 3 Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede 4 Regional Laboratory of Public Health, P.O Box 377, 7500 AJ Enschede 5 Department of Pulmonary Medicine, UMC Groningen, University of Groningen, Groningen
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Introduction: Reduction of exacerbation frequency plays an increasingly important role in interventions in COPD. To reduce this frequency efficiently, patients at risk for frequent exacerbations need to be identified. Objective: To identify predictors for frequent exacerbations from multiple domains of COPD during a stable phase of the disease. Methods: Data of multiple domains of COPD were collected of 121 patients with moderate to severe COPD. Patients were divided into infrequent (<2 exacerbations per year) and frequent (>2 exacerbations) exacerbators. Results: SGRQ total score and a course of oral corticosteroid within 3 months prior to the study together predicted best whether patients would be infrequent or frequent exacerbators over the course of the next year. Each unit increase in total SGRQ score was associated with a 3% higher risk of being a frequent exacerbator (OR = 1.03; 95% CI: 1.00 - 1.06; p = 0.047). Patients who received a course of oral corticosteroids in the period of 3 months prior to the study had a 3-fold increased risk of being a frequent exacerbator (OR = 3.17; 95% CI: 1.20 - 8.34; p = 0.02). Furthermore, we observed that a sizable number of patients switched from being a frequent to an infrequent exacerbator and vice versa. Conclusions: Health related quality of life and a course of oral corticosteroid in the past 3 months are the best predictors of future exacerbator status. The predictive value of the model is however still insufficient. Furthermore, our data suggest, in contrast to previous observations, that exacerbation frequency is not a constant feature. Gepubliceerd: Clin Respir J. 2011; 5(4):227-34 Impact factor: 0.512
8. Pneumothorax in a Preterm Infant Monitored by Electrical Impedance Tomography: A Case Report Miedema M1, Frerichs I1, de Jongh FH1,2, van Veenendaal MB1, van Kaam AH1 1 Department of Neonatology, Emma Children's Hospital AMC, Amsterdam 2 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede Electrical impedance tomography (EIT) is a noninvasive bedside tool for monitoring regional changes in ventilation. We report, for the first time, the EIT images of a ventilated preterm infant with a unilateral pneumothorax, showing a loss of regional ventilation in the affected lung during both high-frequency oscillation and spontaneous ventilation. Gepubliceerd: Neonatology. 2011;99(1):10-13 Impact factor: 2.289
9. What the pulmonary specialist should know about the new inhalation therapies BL Laube1, HM Janssens2, FH de Jongh3, SG Devadason4, R Dhand5, P Diot6, ML Everard7, I Horvath8, P Navalesi9, T Voshaar10 H Chrystyn11 1 Department of Paediatrics, School of Medicine, Johns Hopkins University Baltimore, Maryland USA
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Paediatric Respiratory Medicine, ErasmusMC/ Sophia Children's Hospital Rotterdam 3 Pulmonology Medisch Spectrum Twente, Enschede 4 School of Paediatrics and Child Health, University of Western Australia Perth, Western Australia Australia 5 Internal Medicine, University of Missouri Columbia, Missouri USA 6 Pneumologie INSERM U618, Hôpital Bretonneau, 37044, Tours Cedex France 7 Respiratory Medicine, Sheffield Children's Hospital Sheffield, South Yorkshire UK 8 Department of Pulmonology, Semmelweis University Budapest, Hungary 9 Ospedale Sant'Andrea Anaesthesia and Intensive Care, Università del Piemonte Orientale “A. Avogadro” Vercelli Italy 10 Pulmonology Allergy, Sleep Medicine, Interdisciplinary Lung Centre, Krankenhaus Bethanien Moers, Moers Germany 11 Division of Pharmacy and Pharmaceutical Sciences, School of Applied Sciences, University of Huddersfield Huddersfield, West Yorkshire UK A collaboration of multidisciplinary experts on the delivery of pharmaceutical aerosols has been facilitated by the European Respiratory Society (ERS) and the International Society for Aerosols in Medicine (ISAM), in order to draw up a Consensus Statement with clear, up-to-date recommendations that enable the pulmonary physician to choose the type of aerosol delivery device that is most suitable for their patients. The focus of the Consensus Statement was the patientuse aspects of specific aerosol delivery devices that are currently available. The subject was divided into different topics, which were in turn assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. To achieve consensus, draft reports and recommendations were reviewed and voted on by the entire panel. Specific recommendations for use of the devices are found throughout the statement. Healthcare providers should ensure that their patients can and will use these devices correctly. This requires that the clinician is aware of the devices that are currently available to deliver the prescribed drugs, knows the various techniques that are appropriate for each device, is able to evaluate the patient's inhalation technique to be sure they are using the devices properly and to make sure that the inhalation method is appropriate for each patient. Gepubliceerd: Eur Respir J. 2011;37(6):1308-417 Impact factor: 5.922
10. Changes in Lung Volume and Ventilation during Lung Recruitment in HighFrequency Ventilated Preterm Infants with Respiratory Distress Syndrome Miedema M1, de Jongh FH1,2, Frerichs I3, van Veenendaal MB1, van Kaam AH1 1 Department of Neonatology, Emma Children’s Hospital, AMC, Amsterdam 2 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 3 Department of Anesthesiology and Intensive Care Medicine, UMC SchleswigHolstein, Kiel, Germany
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Objectives: To assess global and regional changes in lung volume and ventilation during lung recruitment in preterm infants with respiratory distress syndrome. Study design: Using electrical impedance tomography, changes in lung volume and ventilation were measured in 15 high-frequency oscillatory ventilated preterm infants during oxygenation-guided recruitment maneuvers. The inflation and deflation limbs were mapped, and the lower and upper inflection points were calculated using both oxygenation and impedance data. The impedance data were also used to determine recruitment-related changes in oscillation volume and distribution. Results: During inflation, lower and upper inflection points were identified in the majority of infants. The deflation limb showed clear lung hysteresis in all infants. The upper inflection point was significantly lower when comparing the pressure/oxygenation and pressure/impedance curves. Lung volume changes differed between the ventral and dorsal regions, but did not show a consistent pattern. Optimal recruitment increased the oscillation volume, but the distribution of ventilation was relatively homogeneous along the ventral-dorsal axis. Conclusions: Lung hysteresis is present in preterm infants with respiratory distress syndrome. Regional differences in lung volume changes and ventilation during highfrequency oscillatory ventilation with lung recruitment are relatively modest and do not follow a gravity-dependent distribution. Gepubliceerd: J Pediatr. 2011;159(2):199-205 Impact factor: 4.042
11. Changes in Lung Volume and Ventilation during Surfactant Treatment in Ventilated Preterm Infants Miedema M1, de Jongh FH1,3, Frerichs I2, van Veenendaal MB1, van Kaam AH1 1 Department of Neonatology, Emma Children's Hospital, AMC, Amsterdam 2 Department of Anesthesiology and Intensive Care Medicine, University MC Schleswig-Holstein, Campus Kiel, Germany 3 Department of Pulmonology, Medisch Spectrum Twente, Enschede Rationale: The immediate and regional effects of exogenous surfactant in open lung high-frequency oscillatory ventilated (HFOV) preterm infants are unknown. Objectives: To assess regional changes in lung volume, mechanics, and ventilation during and after surfactant administration in HFOV preterm infants with respiratory distress syndrome (RDS). Methods: Using electrical impedance tomography, changes in lung volume were continuously recorded during a stepwise recruitment procedure before, during, and after surfactant administration in 15 preterm infants (gestational age: 28.3 wk; birth weight: 1,000 g). Deflation limbs of the pressure-impedance curve before and after surfactant were mapped and the effect of surfactant on oscillation volumes and ventilation was determined. Data were analyzed for the whole cross-section and the left, right, ventral, and dorsal lung regions. Measurements and Main Results: Surfactant increased lung volume by 61 ± 39% within a median time of 241 seconds. The ventral to dorsal ratio in lung volume changed significantly from 1.16 before to 0.81 after surfactant administration. The upper inflection point of the deflation limb after surfactant (10.4 ± 2.4 cm H(2)O) was
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significantly lower compared with before surfactant (16.4 ± 3.1 cm H(2)O). Surfactant increased maximal compliance of the respiratory system, and this effect was reached at lower airway pressures. Surfactant caused a transient decrease in oscillatory volume but did not alter its regional distribution. Conclusions: Surfactant treatment in HFOV preterm infants with RDS causes a rapid increase and subsequent stabilization of lung volume, which is most prominent in dependent lung regions. It increased maximal compliance, but this effect is only reached at lower airway pressures. Gepubliceerd: Am J Respir Crit Care Med. 2011;184(1):100-5 Impact factor: 10.191
12. Community based physiotherapeutic exercise in COPD self-management: A randomised controlled trial Effing T1,2, Zielhuis G3, Kerstjens H4, van der Valk P1, van der Palen J1,5 1 Department of Pulmonology, Medisch Spectrum Twente, Enschede 2 Department of Respiratory Medicine, Repatriation General Hospital, Daw Park, South Australia, Australia 3 Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen, Nijmegen 4 Department of Pulmonology, UMC Groningen, and University of Groningen, Groningen 5 Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede Little is known about effects of community-based physiotherapeutic exercise programmes incorporated in COPD self-management programmes. In a randomised trial, the effect of such a programme (COPE-active) on exercise capacity and various secondary outcomes including daily activity as a marker of behaviour change was evaluated. All patients attended four 2-h self-management sessions. In addition the intervention group participated in the COPE-active programme offered by physiotherapists of private practices, consisting of a 6-month "compulsory" period (3 sessions/week) and subsequently a 5-month "optional" period (2 sessions/week). Because COPE-active was intended to change behaviour with regard to exercise, one session/week in both periods consisted of unsupervised home-based exercise training. Of 153 patients, 74 intervention and 68 control patients completed the oneyear follow-up. Statistically significant between-group differences in incremental shuttle walk test-distance (35.1 m; 95% CI (8.4; 61.8)) and daily activity (1190 steps/day; 95% CI (256; 2125)) were found in favour of the intervention group. Over the 12-month period a significant difference of the chronic respiratory questionnaire (CRQ) dyspnoea-score (0.33 points; 95% CI (0.01; 0.64)) and a non-significant difference of the endurance shuttle walk test (135 m (95% CI (-29; 298)) was found. No differences were found in the other CRQ-components, anxiety and depression scores and percentage of fat free mass. This study demonstrates that a communitybased reactivation programme improves exercise capacity in patients with moderately to severe COPD. Even more important, the programme improves actual
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daily activity after one-year which indicates behaviour change with regard to daily exercise. Gepubliceerd: Respir Med. 2011;105(3):418-26 Impact factor: 2.331
13. Management of obstructive sleep apnea in Europe I Fietzea, , T Penzela, A Alonderisb, F Barbec, MR Bonsignored, P Calverlye, W De Backerf, K Diefenbacha, V Donicg, MM Eijsvogelh, KA Franklini, T Gislasonj, L Grotek, J Hednerk, P Jennuml, L Laviem, P Laviem, P Levyn, C Lombardio, W Mallinp, O Marroneq, JM Montserratr, ES Papathanasious, G Paratio,af, R Plywaczewskit, M Pretlu, RL Rihav, D Rodensteinw, TW Saaresrantax, R Schulzy, P Sliwinskit, P Steiropoulosz, J Svazaaa, Z Tomorig, P Tonnesenab, G Varoneckasb, J Verbraeckenf,ag, J Veselyac, A Vitolsad, J Zielinskit, WT McNicholasae, On behalf of the COST Action B26 Group a Charité-Universitätsmedizin Berlin, Interdisciplinary Center for Sleep Medicine, Berlin, Germany; b Institute of Psychophysiology and Rehabilitation, Palanga, Lithuania; c Hospital Arnau de Vilanova, Lleida, Spain; d Biomedical Department of Internal ans Specialistic Medicine (DIBIMIS), Univ of Palermo, c/o Ospedale V Cervello, Palermo, Italy; e Univeristy Hospital Aintree, Aintree, UK; f University Hospital Antwerp, Edegem, Belgium; g Faculty of Medicine, Safarik University Kosice, Kosice, Slovak Republic; h Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede; i Department of Surgery, Umeå University, Umeå, Sweden; j University of Iceland, Medical Faculity, Reykjavik, Iceland; k Sleep Disorder Centre, Sahlgrenska University Hospital, Gothenburg, Sweden; l Danish Center for Sleep Medicine, Glostrup University, Glostrup, Denmark; m Diagnostic Sleep Laboratory, Faculty of Medicine, Technion, Haifa, Israel; n Grenoble University Hospital CHU Michallon, Grenoble, France; o Dept. Cardiology, S.Luca Hospital, Istituto Auxologico Italiano, Italy; p LKH Enzenbach, Hörgas 30, A-8112 Gratwein, Austria; q Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare, Palermo, Italy; r Hospital Clinico Respiratorio, Barcelona, Spain; s The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; t National Research Institute of Tuberculosis and Lung Diseases, Warsaw, Poland; u Department of Neurology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; v Royal Infirmary Edinburgh 51, Little France, UK; w Cliniques Universitaires Saint-Luc, Brussels, Belgium; x Department of Pulmonary Diseases and Clinical Allergolgy, Turku University Hospital and Sleep Research Unit, Department of Physiology, University of Turku, Turku, Finland; y University of Giessen, Lung Center, Giessen, Germany; z Department of Pneumonology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece; aa Riga Stradins University, Institute of Stomatology, Sleep laboratory, Riga, Latvia; ab Hospital Copenhagen, Opgang 3A, 2.sal, Hellerup, Denmark; ac Pathological Physiology Medical Faculty, Palacky University, Olomouc, Czech Republic; ad Institute of Cardiology, University of Latvia, Riga, Latvia; ae St. Vincent’s University Hospital, Dublin, Ireland; af Dept. Clinical Medicine and Prevention, University of MilanoBicocca, Milano, Italy; ag Maastricht University Medical Center+, Maastricht
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Objectives: In Europe, the services provided for the investigation and management of obstructive sleep apnoea (OSA) varies from country to country. The aim of this questionnaire-based study was to investigate the current status of diagnostic pathways and therapeutic approaches applied in the treatment of OSA in Europe, qualification requirements of physicians involved in diagnosis and treatment of OSA, and reimbursement of these services. Methods: Two questionnaires were sent to 39 physicians in 22 countries in Europe. In order to standardize the responses, the questionnaire was accompanied by an example. Results: Sleep centers from 21 countries (38 physicians) participated. A broad consistency among countries with respect to the following was found: pathways included referral to sleep physicians/sleep laboratories, necessity for objective diagnosis (primarily by polysomnography), use of polygraphic methods, analysis of polysomnography (PSG), indications for positive airway pressure (PAP) therapy, application of standard continuous PAP (CPAP) therapy (100% with an CPAP/APAP ratio of 2.24:1), and the need (90.5%) and management of follow-up. Differences were apparent in reimbursement of the diagnostic procedures and follow-up, in the procedures for PAP titration from home APAP titration with portable sleep apnea monitoring (38.1%) up to hospital monitoring with PSG and APAP (85.7%), and in the qualification requirements of sleep physicians. Conclusions: Management of OSA in different European countries is similar except for reimbursement rules, qualification of sleep specialists and procedures for titration of the CPAP treatment. A European network (such as the one accomplished by the European Cooperation in Science and Technology [COST] B26 Action) could be helpful for implementing these findings into health-service research in order to standardize management in a cost effective perspective. Gepubliceerd: Sleep Med. 2011;12(2):190-7 Impact factor: 3.430
14. Necrotizing sarcoid granulomatosis: A case report and review of progresses in this disease G Epping1, CA Schwengle1, RP Aliredjo2, M Wagenaar1 1 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 2 Department of Pathology, Medisch Spectrum Twente, Enschede We present the case of a young male who visited the emergency room with progressive dyspnea and left sided chest pain. A chest X-ray was performed which showed a pattern of diffuse nodular and reticular opacities. The diagnosis of Necrotizing Sarcoid Granulomatosis (NSG) was made by histopathological examination of a lung biopsy specimen and by excluding other causes of granulomatous disease. He was treated with corticosteroids. Because of persistent extrapulmonary (ocular) involvement a maintenance dose of prednisone was needed. Necrotizing Sarcoid Granulomatosis is a granulomatous disease with necrosis and vasculitis of unknown cause. The resemblance between NSG and (nodular) sarcoidosis is strong, but subtle differences exist. The prognosis is good and therapy is usually not necessary. However in some cases there is a need for
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therapy with corticosteroids, depending on the involved organs and/or the degree of impairment. Gepubliceerd: Health 2011;3(8):534-536 Impact factor: 0
15. Toxic alveolitis after inhalation of a water repellent Epping G1, Van Baarlen J2, Van Der Valk PD1 1 Department of Respiratory Medicine, Medisch Spectrum Twente, Enschede 2 Department of Pathology, Medisch Spectrum Twente, Enschede Inhalation of fluorocarbon polymers can cause pulmonary toxicity. Although multiple cases of lung injury have been reported, cellular characterization of the associated alveolitis occurring acutely after inhalation is limited. We report the case of a previously healthy woman who presented at our Emergency Department with an acute pneumonitis following inhalation of a fluorocarbon polymer-based rain-proofing spray. Bronchoalveolar lavage (BAL) performed shortly after the presentation showed an elevated total cell count, with a high proportion of neutrophils (58%) and eosinophils (9%). In addition, a lipid stain (Oil-Red-O-stain) showed a high level of lipid laden macrophages, a marker that could reflect a direct toxic effect of the spray on alveolar cells. The patient made a full recovery after four days of in-hospital observation with supportive care. Gepubliceerd: Int J Occup Med Environ Health. 2011;24(4):409-13 Impact factor: 1.000
16. Impact on clinical decision making of quality control standards applied to sputum analysis in COPD MC Telgena, MG Brusse-Keizera,, PD van der Valka, J. van der Palena, d, HA Kerstjensb, MG Hendrixc a Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede b Department of Pulmonary Medicine, UMC Groningen, University of Groningen, Groningen c Regional Laboratory of Public Health, P.O Box 377, 7500 AJ Enschede d Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede Purpose: Sputum analysis is important in COPD exacerbation management. We determined whether application of stringent quality control criteria for sputum samples had an impact on culture results. Methods: We analyzed sputum samples of 108 patients during stable COPD and during exacerbations. To all samples quality control standards and culture interpretation rules according to the American Society of Microbiologists (ASM) were applied. Results: In sputum exacerbation samples considered appropriate according to ASM quality standards, criteria for infection (40%) were met more often compared to
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inappropriate samples (13%) (p < 0.001). The same pattern was observed when applying these rules to sputum samples obtained during stable disease, (50% vs. 18%, p < 0.001). There was no difference in the percentage of infectious cultures obtained during the stable state and exacerbations. Conclusions: Applying stringent quality control criteria to sputum samples can have a profound effect on the labeling of sputum samples as infectious, and therefore on clinical decision making. Gepubliceerd: Resp Med 2011;105(3):371-376 Impact factor: 2.525
17. Sputum amoxicillin concentrations in relation to beta-lactamase activity in COPD patients Van Der Zanden RW1, Brusse-Keizer MG2, Van Der Valk PD2, Hendrix MG3, Van Der Palen J4, Movig KL1 1 Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede 2 Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede 3 Laboratory of Microbiology, Twente Achterhoek, Enschede 4 Medical School Twente, Medisch Spectrum Twente, Enschede Gepubliceerd: Pharmaceutisch Weekblad 2011;146:91-95 Impact factor: 0
Totale impact factor: 55.300 Gemiddelde impact factor: 3.259 Aantal artikelen 1e, 2e of laatste auteur: 11 Totale impact factor: 33.107 Gemiddelde impact factor: 3.010
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Medical School Twente 1. Risk factors of delirium after cardiac surgery A systematic review Koster S1, Hensens AG1, Schuurmans MJ2,3, van der Palen J4,5 1 Department of Cardio Thoracic Surgery, Medisch Spectrum Twente, Enschede 2 University of Professional Education Utrecht, Department of Healthcare, Utrecht 3 University Medical Center Utrecht, Nursing Science, Utrecht 4 Department of Epidemiology, Medisch Spectrum Twente, Enschede 5 Department of Research Methodology, Measurement and Data Analysis, Faculty of Behavioral Sciences, University of Twente, Enschede Background: Delirium or acute confusion is a temporary mental disorder that occurs frequently among hospitalized elderly patients, but also in younger patients a delirium can develop. Patients who undergo cardiac surgery have an increased risk of developing delirium that is associated with many negative consequences. Therefore, prevention of delirium is essential. Despite the high incidence of delirium, a paucity of data on risk factors for delirium exists. AIM: The aim of this study was to summarize the available information concerning these risk factors. Methods: A literature research was performed using the PubMed, Cinahl, and Cochrane Library databases and was limited to the last 10 years. Results: Our review revealed 27 risk factors; 12 predisposing and 15 precipitating factors for delirium after cardiac surgery. The most established predisposing risk factors were atrial fibrillation, cognitive impairment, depression, history of stroke, older age, and peripheral vascular disease. The most established precipitating risk factor was a red blood cell transfusion. An abnormal albumin level was reported as the most established precipitating risk factor among blood values tested. A low cardiac output and the use of an Intra Aortic Balloon Pump or inotropic medication seem to be the most relevant risk factors associated with a postoperative delirium. Conclusion: A multifactorial risk model should be applied to identify patients at an increased risk of developing delirium following elective cardiac surgery. In these patients, if possible, preventative interventions can be taken and early recognition of delirium can be realized. This could potentially decrease the incidence of delirium and negative consequences caused by a postoperative delirium. Gepubliceerd: Eur J Cardiovasc Nurs. 2011;10:197–204 Impact factor: 1.348
2. Is T-wave alternans testing feasible in candidates for prophylactic implantable defibrillators? Kraaier K1, McCracken T1, van der Palen J2, Wilde AA3, Scholten MF1 1 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede 2 Department of Epidemiology, Medisch Spectrum Twente, Enschede 3 Department of Cardiology, AMC Amsterdam, Amsterdam
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Aims: Previous studies have demonstrated that microvolt T-wave alternans (TWA) screening in patients with ischaemic and dilated cardiomyopathy is effective in identifying patients at high or low risk of sudden cardiac death. It remains unclear which percentage of potential recipients of an implantable cardioverter defibrillator (ICD) are able to perform TWA testing using an exercise protocol which is, at this moment, the golden standard. In this study, we evaluated the feasibility of TWA in the risk stratification of potential ICD recipients with ischaemic or dilated cardiomyopathy. Methods and results: Medical charts of 165 primary prevention ICD recipients were reviewed to decide if patients were able to perform a TWA exercise test or not. Reasons to waiver a test were: atrial fibrillation or flutter, pacemaker dependency, recent (cardiovascular) surgery (<1 month) and inability to exercise. Of the potential ICD recipients 35% had one or more of these contraindications and were therefore not suitable for testing. Conclusion: In several studies, TWA is a promising risk stratifier for predicting sudden cardiac death; however, in our population, 35% of the potential ICD candidates could not be tested. In order to fulfil its promise as a predictor for SCD, an alternative means to measure TWA needs to be evaluated. Gepubliceerd: Neth Heart J. 2011 Jan;19(1):6-9 Impact factor: 1.447
3. Cognitive Behavioural Treatment Is as Effective in High- as in Low-Scoring Alexithymic Patients with Substance-Related Disorders HA de Haana, b, EA Joostenb, c, AG Wijdeveldb, c, PB Boswinkela, b, J van der Palend, e , CA De Jonga a Tactus Addiction Treatment, Deventer, b Nijmegen Institute for Scientist-Practitioners in Addiction, Nijmegen, c Department of Addiction Treatment, GGZ Noord- and Midden-Limburg, Venray, d Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede e Medical School Twente, Medisch Spectrum Twente, Enschede, Gepubliceerd: Psychother Psychosom. 2011;80(4):254-255 Impact factor: 6.000
4. Relation between amoxicillin concentration in sputum of COPD patients and length of hospitalization Brusse-Keizer M1, ten Bokum L2, Movig K3, van der Valk P1, Kerstjens H5, van der Palen J1,5, Hendrix R6 1 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 2 Department of Clinical Pharmacy, Deventer Hospital, Deventer 3 Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede 4 Department of Pulmonary Medicine, UMC Groningen, and University of Groningen, Groningen
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Department of Research Methodology, Measurement, and Data Analysis, University of Twente 6 Regional Laboratory of Public Health, Enschede Amoxicillin is a widely used antibiotic in COPD. Little is known about the transfer of amoxicillin into sputum of COPD patients. The objective was to investigate the relationship between the concentration of amoxicillin in sputum in hospitalized COPD patients and length of hospitalization. To be effective against bacterial pathogens, the amoxicillin concentration in target tissues should be higher than the Minimal Inhibiting Concentration (MIC) of 2 mg/l. Therefore, this was also used as the cut-off value for the amoxicillin concentration in sputum, as a marker for lung tissue concentration. Fifty-two COPD in-patients with an exacerbation, treated with amoxicillin clavulanic acid, were included in this cohort study. Of these patients 7 also had pneumonia. Patients were divided in patients with an amoxicillin sputum concentration ≥ 2 mg/l and < 2 mg/l. Furthermore, inflammation markers in sputum and serum and clinical parameters were obtained. Of the 33 patients with usable sputum, 11 had a concentration in sputum ≥ 2 mg/l. The mean length of hospitalization for patients with concentrations below the MIC90 to common respiratory pathogens was 11.0 days, while for patients with concentrations at or above the MIC90 this was 7.0 days (p = 0.005). COPD patients admitted for an acute exacerbation of COPD, with a sputum concentration of amoxicillin ≥ 2 mg/l had a markedly reduced length of hospitalization compared to patients with a concentration < 2 mg/l. It is worthwhile testing whether individualized treatment based on sputum amoxicillin concentrations of patients during hospitalization for acute exacerbations can effectively reduce hospital stay. Gepubliceerd: COPD. 2011 Apr;8(2):66-70 Impact factor: 2.250
5. Clinical predictors of exacerbation frequency in chronic obstructive pulmonary disease Brusse-Keizer MG1, Van Der Palen J2,3, Van Der Valk PD1, Hendrix R4, Kerstjens H5 1 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 2 Medical School Twente, Medisch Spectrum Twente, Enschede 3 Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede 4 Regional Laboratory of Public Health, P.O Box 377, 7500 AJ Enschede 5 Department of Pulmonary Medicine, UMC Groningen, University of Groningen, Groningen Introduction: Reduction of exacerbation frequency plays an increasingly important role in interventions in COPD. To reduce this frequency efficiently, patients at risk for frequent exacerbations need to be identified. Objective: To identify predictors for frequent exacerbations from multiple domains of COPD during a stable phase of the disease.
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Methods: Data of multiple domains of COPD were collected of 121 patients with moderate to severe COPD. Patients were divided into infrequent (<2 exacerbations per year) and frequent (>2 exacerbations) exacerbators. Results: SGRQ total score and a course of oral corticosteroid within 3 months prior to the study together predicted best whether patients would be infrequent or frequent exacerbators over the course of the next year. Each unit increase in total SGRQ score was associated with a 3% higher risk of being a frequent exacerbator (OR = 1.03; 95% CI: 1.00 - 1.06; p = 0.047). Patients who received a course of oral corticosteroids in the period of 3 months prior to the study had a 3-fold increased risk of being a frequent exacerbator (OR = 3.17; 95% CI: 1.20 - 8.34; p = 0.02). Furthermore, we observed that a sizable number of patients switched from being a frequent to an infrequent exacerbator and vice versa. Conclusions: Health related quality of life and a course of oral corticosteroid in the past 3 months are the best predictors of future exacerbator status. The predictive value of the model is however still insufficient. Furthermore, our data suggest, in contrast to previous observations, that exacerbation frequency is not a constant feature. Gepubliceerd: Clin Respir J. 2011; 5(4):227-34 Impact factor: 0.512
6. Community based physiotherapeutic exercise in COPD self-management: A randomised controlled trial Effing T1,2, Zielhuis G3, Kerstjens H4, van der Valk P1, van der Palen J1,5 1 Department of Pulmonology, Medisch Spectrum Twente, Enschede 2 Department of Respiratory Medicine, Repatriation General Hospital, Daw Park, South Australia, Australia 3 Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen, Nijmegen 4 Department of Pulmonology, UMC Groningen, and University of Groningen, Groningen 5 Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede Little is known about effects of community-based physiotherapeutic exercise programmes incorporated in COPD self-management programmes. In a randomised trial, the effect of such a programme (COPE-active) on exercise capacity and various secondary outcomes including daily activity as a marker of behaviour change was evaluated. All patients attended four 2-h self-management sessions. In addition the intervention group participated in the COPE-active programme offered by physiotherapists of private practices, consisting of a 6-month "compulsory" period (3 sessions/week) and subsequently a 5-month "optional" period (2 sessions/week). Because COPE-active was intended to change behaviour with regard to exercise, one session/week in both periods consisted of unsupervised home-based exercise training. Of 153 patients, 74 intervention and 68 control patients completed the oneyear follow-up. Statistically significant between-group differences in incremental shuttle walk test-distance (35.1 m; 95% CI (8.4; 61.8)) and daily activity (1190
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steps/day; 95% CI (256; 2125)) were found in favour of the intervention group. Over the 12-month period a significant difference of the chronic respiratory questionnaire (CRQ) dyspnoea-score (0.33 points; 95% CI (0.01; 0.64)) and a non-significant difference of the endurance shuttle walk test (135 m (95% CI (-29; 298)) was found. No differences were found in the other CRQ-components, anxiety and depression scores and percentage of fat free mass. This study demonstrates that a communitybased reactivation programme improves exercise capacity in patients with moderately to severe COPD. Even more important, the programme improves actual daily activity after one-year which indicates behaviour change with regard to daily exercise. Gepubliceerd: Respir Med. 2011;105(3):418-26 Impact factor: 2.331
7. Impact on clinical decision making of quality control standards applied to sputum analysis in COPD MC Telgena, MG Brusse-Keizera,, PD van der Valka, J. van der Palena, d, HA Kerstjensb, MG Hendrixc a Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede b Department of Pulmonary Medicine, UMC Groningen, University of Groningen, Groningen c Regional Laboratory of Public Health, P.O Box 377, 7500 AJ Enschede d Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede Purpose: Sputum analysis is important in COPD exacerbation management. We determined whether application of stringent quality control criteria for sputum samples had an impact on culture results. Methods: We analyzed sputum samples of 108 patients during stable COPD and during exacerbations. To all samples quality control standards and culture interpretation rules according to the American Society of Microbiologists (ASM) were applied. Results: In sputum exacerbation samples considered appropriate according to ASM quality standards, criteria for infection (40%) were met more often compared to inappropriate samples (13%) (p < 0.001). The same pattern was observed when applying these rules to sputum samples obtained during stable disease, (50% vs. 18%, p < 0.001). There was no difference in the percentage of infectious cultures obtained during the stable state and exacerbations. Conclusions: Applying stringent quality control criteria to sputum samples can have a profound effect on the labeling of sputum samples as infectious, and therefore on clinical decision making. Gepubliceerd: Resp Med 2011;105(3):371-376 Impact factor: 2.525
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8. Timing of temporal and frontal seizures in relation to the circadian phase: A prospective pilot study Hofstra WA a,e, Gordijn MC b, van der Palen J c,d, van Regteren R a, Grootemarsink BE, de Weerd AW a a Department of Clinical Neurophysiology and Sleep Centre, SEIN, Zwolle b Department of Chronobiology, University of Groningen c Medical School Twente, Medisch Spectrum Twente, Enschede d Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede e Department of Neurology, Medisch Spectrum Twente, Enschede There is strong evidence that epileptic seizures occur in diurnal or 24-h patterns. A study in rat models of partial epilepsy showed circadian seizure patterns, and in humans circadian rhythmicity in interictal discharges has been found, suggesting that circadian rhythm may play a role in epilepsy. Circadian influences on human seizure patterns have not been investigated. We performed a pilot study to ascertain influences of the circadian rhythm on seizure occurrence. We prospectively outlined circadian rhythms of patients admitted for long term EEG and video monitoring, using measurement of the dim light melatonin onset (DLMO). Seizures during admission were recorded with continuous EEG and video monitoring. The DLMO ranged from 18:46h to 23:13h (mean 21:22h). One hundred and twenty-four seizures of 21 patients were analysed. Seizures of temporal lobe origin occurred mainly between 11:00 and 17:00h and frontal seizures were seen mostly between 23:00 and 05:00h. When correlating seizure timing to the individual's circadian phase as measured by the DLMO, the following was seen: temporal seizures occurred most frequently in the 6h before DLMO and frontal seizures mainly in 612h after the DLMO. The results of this pilot study suggest that temporal and frontal seizures occur in a non-random fashion synchronized to a hormonal marker of the circadian timing system. Gepubliceerd: Epilepsy Res. 2011;94(3):158-62 Impact factor: 2.302
9. Outcome of Endometrial Cancer Stage IIIA with Adnexa or Serosal Involvement Only Jobsen JJ1, Naudin Ten Cate L2, Lybeert ML3, Scholten A4, van der Steen-Banasik EM5, van der Palen J6,7, Stenfert Kroese MC8, Slot A9, Schutter EM10, Siesling S11 1 Department of Radiation Oncology, Medisch Spectrum Twente, Enschede 2 Laboratorium Pathologie Oost Nederland, Enschede 3 Department of Radiation Oncology, Catharina Hospital, Eindhoven 4 Department of Clinical Oncology, Leiden University Medical Center, Leiden 5 Arnhem Radiotherapeutic Institute, Arnhem 6 Department of Research Methodology, Measurement, and Data Analysis, Faculty of Behavioral Science, University of Twente, Enschede 7 Department of Clinical Epidemiology, Medisch Spectrum Twente, Enschede 8 Radiotherapy Institute Steden en Omstreken, Deventer 9 Radiotherapy Institute Friesland, Leeuwarden
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Department of Obstetrics and Gynaecology, Medisch Spectrum Twente, Enschede 11 Comprehensive Cancer Centre North East, Enschede/Groningen Objective. The aim of this study is to look at possible differences in outcome between serosa and adnexal involvement stage IIIA endometrial carcinoma. Methods. 67 patients with stage IIIA endometrial carcinoma were included, 46 with adnexal involvement and 21 with serosa. A central histopathological review was performed. Results. The 7-year locoregional failure rate was (LRFR) 2.2% for adnexal involvement and 16.0% for involvement of the serosa (P = .0522). The 7-year distant metastasis-free survival was 72.7% for adnexal involvement and 58.7% for serosa (P = .3994). The 7-year disease-specific survival (DSS) was 71.8% for patients with adnexal involvement and 75.4% for patients with serosa. Conclusion. Endometrial carcinoma stage IIIA with involvement of the adnexa or serosa showed to have a comparable disease-specific survival. Locoregional control was worse for serosa involvement compared to adnexa. Gepubliceerd: Obstet Gynecol Int.;2011:962518 Impact factor: 4.392
10. Attrition in web-based treatment for problem drinkers MG Postel1,2, HA de Haan1,2, ED ter Huurne1,2, J van der Palen3,4, ES Becker5, CA de Jong2,5 1Tactus Addiction Treatment, Enschede 2Nijmegen Institute for Scientist-Practitioners in Addiction, Nijmegen 3Department of Epidemiology, Medisch Spectrum Twente, Enschede 4Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede 5Behavioural Science Institute, Radboud University Nijmegen, Nijmegen Background: Web-based interventions for problem drinking are effective but characterized by high rates of attrition. There is a need to better understand attrition rates in order to improve the completion rates and the success of Web-based treatment programs. Objective: The objectives of our study were to (1) examine attrition prevalence and pretreatment predictors of attrition in a sample of open-access users of a Webbased program for problem drinkers, and (2) to further explore attrition data from our randomized controlled trial (RCT) of the Web-based program. Methods: Attrition data from two groups of Dutch-speaking problem drinkers were collected: (1) open-access participants enrolled in the program in 2009 (n = 885), and (2) RCT participants (n = 156). Participants were classified as noncompleters if they did not complete all 12 treatment sessions (9 assignments and 3 assessments). In both samples we assessed prevalence of attrition and pretreatment predictors of treatment completion. Logistic regression analysis was used to explore predictors of treatment completion. In the RCT sample, we additionally measured reasons for
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noncompletion and participants' suggestions to enhance treatment adherence. The qualitative data were analyzed using thematic analysis. Results: The open-access and RCT group differed significantly in the percentage of treatment completers (273/780, 35.0% vs 65/144, 45%, χ(2) (1) = 5.4, P = .02). Logistic regression analysis revealed a significant contribution of treatment readiness, gender, education level, age, baseline alcohol consumption, and readiness to change to predict treatment completion. The key reasons for noncompletion were personal reasons, dissatisfaction with the intervention, and satisfaction with their own improvement. The main suggestions for boosting strategies involved email notification and more flexibility in the intervention. Conclusions: The challenge of Web-based alcohol treatment programs no longer seems to be their effectiveness but keeping participants involved until the end of the treatment program. Further research should investigate whether the suggested strategies to improve adherence decrease attrition rates in Web-based interventions. If we can succeed in improving attrition rates, the success of Web-based alcohol interventions will also improve and, as a consequence, their public health impact will increase. Gepubliceerd: J Med Internet Res. 2011;13(4):e117 Impact factor: 4.663
11. Effects of a single dose inhaled corticosteroid on the dynamics of airway obstruction after exercise Driessen JM1, Nieland H2, van der Palen JA3, van Aalderen WM4, Thio BJ1, de Jongh FH2 1 Department of Pediatrics, Medisch Spectrum Twente, Enschede 2 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 3 Medical School Twente, Medisch Spectrum Twente, Enschede 4 Department of Pediatrics, AMC, Amsterdam Rationale: Exercise-induced bronchoconstriction (EIB) is defined as a transient narrowing of the airways induced by exercise. Repetitive measurements of spirometric parameters, such as FEV(1) and expiratory flows, and forced oscillation technique (FOT) measurements can be used to analyze the dynamics of EIB. A single high dose of fluticasone propionate (FP) protects against EIB. The aim of the study was to analyze the effect of FP on the dynamics of exercise-induced airway narrowing as measured with FOT and spirometry. Methods: Twelve children performed an exercise challenge on 2 separate days, 4Ԝhr after inhalation of 1Ԝmg FP (pressurized metered dose inhaler) or a placebo. Before and after the exercise flow-volume loops as well as the FOT (frequency range: 432ԜHz) were measured. Results: The FEV(1) , and FEF(50) fell significantly after exercise within groups; the peak fall in FEV(1) after FP was significantly smaller than after placebo (respectively, 19.3Ԝ±Ԝ14.6% and 29.2Ԝ±Ԝ14.8%, PԜ=Ԝ0.03, 95% CI: 0.9-18.8%). The fall in FEV(1) and FEF(50) peaked 3Ԝmin after exercise and showed a subsequent partial recovery. The fall in the FEV(1) /FVC ratio showed a later peak fall (12Ԝmin after exercise). The resistance increased while the reactance decreased significantly
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after exercise. FP significantly decreased the maximal increase in Rrs(6) when compared to the placebo (respectively 176.5Ԝ±Ԝ59.1% and 201.0Ԝ±Ԝ63.8%, PԜ=Ԝ0.05, 95% CI: 0.5-48.7%). The maximal decrease in Xrs(6) was not significantly affected by FP (PԜ=Ԝ0.06). Conclusion: Repetitive spirometric and FOT measurements after exercise show a rapid narrowing and steady recovery of the patency of the conducting airways, and indicate a delayed and prolonged recovery of the smaller airways. A single high dose of inhaled FP seems to employ its effect mainly in the conducting airways. Gepubliceerd: Pediatr Pulmonol. 2011;46(9):849-856 Impact factor: 2.239
12. Sensor materials for the detection of human neutrophil elastase and cathepsin G activity in wound fluid A Hasmann1, U Gewessler2, E Hulla1, KP Schneider2, B Binder4, A Francesko3, T Tzanov3, M Schintler5, J van der Palen6, GM Guebitz1, E Wehrschuetz-Sigl2 1 Institute for Environmental Biotechnology, Graz University of Technology, Petersgasse, Graz, Austria; 2 Austrian Center of Industrial Biotechnology, Petersgasse, Graz, Austria; 3 Department of Chemical Engineering, UPC Campus Terrassa, Spain; 4 Department of Dermatology, Medical University of Graz, Graz, Austria; 5 Department of Surgery, Medical University of Graz, Graz, Austria; 6 Department of Epidemiology, Medisch Spectrum Twente, Enschede Human neutrophil elastase (HNE) and cathepsin G (CatG) are involved in the pathogenesis of a number of inflammatory disorders. These serine proteinases are released by neutrophils and monocytes in case of infection. Wound infection is a severe complication regarding wound healing causing diagnostic and therapeutic problems. In this study we have shown the potential of HNE and CatG to be used as markers for early detection of infection. Significant differences in HNE and CatG levels in infected and non-infected wound fluids were observed. Peptide substrates for these two enzymes were successfully immobilised on different surfaces, including collagen, modified collagen, polyamide polyesters and silica gel. HNE and CatG activities were monitored directly in wound fluid via hydrolysis of the chromogenic substrates. Infected wound fluids led to significant higher substrate hydrolysis compared with non-infected ones. These different approaches could be used for the development of devices which are able to detect elevated enzyme activities before manifestation of infection directly on bandages. This would allow a timely intervention by medical doctors thus preventing severe infections. Gepubliceerd: Exp Dermatol 2011;20(6):508-13 Impact factor: 4.159
13. Sputum amoxicillin concentrations in relation to beta-lactamase activity in COPD patients Van Der Zanden RW1, Brusse-Keizer MG2, Van Der Valk PD2, Hendrix MG3, Van Der Palen J4, Movig KL1
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Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede 3 Laboratory of Microbiology, Twente Achterhoek, Enschede 4 Medical School Twente, Medisch Spectrum Twente, Enschede 2
Gepubliceerd: Pharmaceutisch Weekblad 2011;146:91-95 Impact factor: 0
Totale impact factor: 34.168 Gemiddelde impact factor: 2.628 Aantal artikelen 1e, 2e of laatste auteur: 3 Totale impact factor: 4.191 Gemiddelde impact factor: 1.397
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Neurologie 1. Drug adherence and multidisciplinary care in patients with multiple sclerosis: protocol of a prospective, web-based, patient-centred, nation-wide, Dutch cohort study in glatiramer acetate treated patients (CAIR study) PJ Jongen, 1 G Hengstman,2 R Hupperts,3 H Schrijver,4 J Gilhuis,5 JH Vliegen,6 E Hoogervorst,7 M van Huizen,8 E van Munster,9 J Samijn,10 E de Schryver,11 T Siepman,12 M Tonk,13 E Zandbergen,14 J ten Holter,15 R van der Kruijk,16 G Borm17 1 MS4 Research Institute, Nijmegen; 2 Department of Neurology, Catharina Ziekenhuis, Eindhoven; 3 Academic MS Centre Limburg, Orbis Medical Centre, Sittard; 4 Department of Neurology, Westfries Gasthuis, Hoorn; 5 Department of Neurology, Reinier de Graaf Gasthuis, Delft; 6 Medisch Spectrum Twente, Enschede; 7 St. Antonius Ziekenhuis, Nieuwegein; 8 Scheper Ziekenhuis, Emmen; 9 Jeroen Bosch Ziekenhuis, Den Bosch; 10 Maasstad Ziekenhuis, Rotterdam; 11 Rijnland Ziekenhuis, Leiderdorp; 12 Erasmus Medisch Centrum, Rotterdam; 13 Leids Universitair Medisch Centrum, Leiden; 14 Rijnstate Ziekenhuis, Arnhem; 15 Deventer Ziekenhuis, Deventer; 16 Slingeland Ziekenhuis, Doetinchem; 17 Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen MC, Nijmegen Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, for which no definitive treatment is available. Most patients start with a relapsing-remitting course (RRMS). Disease-modifying drugs (DMDs) reduce relapses and disability progression. First line DMDs include glatiramer acetate (GA), interferon-beta (INFb)-1a and INFb-1b, which are all administered via injections. Effectiveness of DMD treatment depends on adequate adherence, meaning year-long continuation of injections with a minimum of missed doses. In real-life practice DMD-treated patients miss 30% of doses. The 6-month discontinuation rate is up to 27% and most patients who discontinue do so in the first 12 months.Treatment adherence is influenced by the socio-economic situation, health care and caregivers, disease, treatment and patient characteristics. Only a few studies have dealt with adherence-related factors in DMD-treated patients. Selfefficacy expectations were found to be related to GA adherence. Patient education and optimal support improve adherence in general. Knowledge of the aspects of care that significantly relate to adherence could lead to adherence-improving measures. Moreover, identification of patients at risk of inadequate adherence could lead to more efficient care.In the near future new drugs will become available for RRMS. Detailed knowledge on factors prognostic of adherence and on care aspects that are associated with adequate adherence will improve the chances of these drugs becoming effective treatments. We investigate in RRMS patients the relationship between drug adherence and multidisciplinary care, as well as factors associated with adherence. Given the differences in the frequency of administration and in the side effects between the DMDs we decided to study patients treated with the same DMD, GA. Gepubliceerd: BMC Neurol. 2011;11:40 Impact factor: 2.797
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2. A novel approach for computer assisted EEG monitoring in the adult ICU Cloostermans MC1,2, de Vos CC1,2, van Putten MJ1,2 1 Department of Neurology and Clinical Neurophysiology, Medisch Spectrum Twente, Enschede 2 MIRA - Institute for Biomedical Technology and Technical Medicine, Twente University, Enschede Objective: The implementation of a computer assisted system for real-time classification of the electroencephalogram (EEG) in critically ill patients. Methods: Eight quantitative features were extracted from the raw EEG and combined into a single classifier. The system was trained with 41 EEG recordings and subsequently evaluated using an additional 20 recordings. Through visual analysis, each recording was assigned to one of the following categories: normal, iso-electric, low voltage, burst suppression, slowing, and EEGs with generalized periodic discharges or seizure activity. Results: 36 (88%) recordings from the training set and 17 (85%) recordings from the test set were classified correctly. A user interface was developed to present both trend-curves and a diagnostic output in text form. Implementation in a dedicated EEG monitor allowed real-time analysis in the intensive care unit (ICU) during pilot measurements in four patients. Conclusions: We present the first results from a computer assisted EEG interpretation system, based on a combination of eight quantitative features. Our system provided an initial, reasonably accurate interpretation by non-experts of the most common EEG patterns observed in neurological patients in the adult ICU. SIGNIFICANCE: Computer assisted EEG monitoring may improve early detection of seizure activity and ischemia in critically ill patients. Gepubliceerd: Clin Neurophysiol 2011;122:2100-2109 Impact factor:2.786
3. Predicting success of vagus nerve stimulation (VNS) from interictal EEG CC de Vosa, b, L Melchinga, J van Schoonhovena, JJ Ardeschb, AW de Weerdc, HC van Lambalgenc, MJ van Puttena, b a MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede b Department of Neurology, Medisch Spectrum Twente, Enschede c SEIN Epilepsie Instellingen, Zwolle Purpose: Vagus nerve stimulation (VNS) has shown to be an effective treatment for drug resistant epilepsy in numerous patients, however, not in all. It is still not possible to predict which patients will profit from VNS. In this pilot study, we explore predictive interictal EEG features for seizure reduction after VNS. Methods: 19 Patients with medically refractory epilepsy and an implanted VNS system were included. Interictal EEG registrations, recorded before implantation, were retrospectively analysed. A quantative symmetry measure, the pair wise derived brain symmetry index (pdBSI), was tested to predict VNS outcome. Reduction in seizure frequency was used to define the responders.
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Results: 10 Patients did respond to VNS, of whom 7 patients had a seizure reduction of at least 50% in a follow-up period of 2 years. On average, we find higher pdBSI values for delta, theta, alpha and beta bands for non-responders than for responders. The average pdBSI of the theta and alpha bands could significantly discriminate between responders and non-responders. Conclusion: In this study, quantifying EEG symmetry using the pdBSI shows promising results in predicting the reduction of seizure frequency after VNS treatment Gepubliceerd: Seizure 2011;20(7):541-545 Impact factor: 1.649
4. Screening Hodgkin lymphoma survivors for radiotherapy induced cardiovascular disease EM van Leeuwen-Segarceanua, WJ Bosa,, LD Dorresteijnb,, BJ Rensingc,, JA van der Heydenc, OJ Vogelsd, DH Biesmae a Department of Internal Medicine, St. Antonius Hospital, Nieuwegein b Department of Neurology, Medisch Spectrum Twente, Enschede c Department of Cardiology, St. Antonius Hospital, Nieuwegein d Department of Neurology, St. Antonius Hospital, Nieuwegein e Division of Internal Medicine and Dermatology, UMC Utrecht, Utrecht Long term prognosis of Hodgkin lymphoma (HL) survivors is affected by late toxicity of radiotherapy and chemotherapy. Cardiovascular complications of radiotherapy have been shown to have a great impact on the long term survival. The aim of this review is to summarize the available data on different screening modalities for cardiovascular disease and to suggest a screening program. Patients older than 45years at HL diagnosis should be screened for coronary artery disease (CAD) starting 5years after mediastinal radiotherapy; they are at increased risk of preexistent atherosclerosis which can be accelerated by radiotherapy. Screening for CAD should start 10years after radiotherapy in younger patients. The best screening modality for CAD is subject of discussion, based on the latest studies we suggest screening by Coronary artery calcium score measurements or CT-angiography. Valvular disorders should be looked for by echocardiography starting 10years after radiotherapy. Electrocardiograms should be performed at each cardiovascular screening moment in order to detect arrhythmia's or conduction abnormalities. We suggest repeating these screening tests every 5years or at onset of cardiovascular complaints; patients should be extensively instructed about signs and symptoms of cardiovascular disease. Furthermore traditional risk factors for cardiovascular disease should be carefully monitored and treated. We suggest determining a cardiovascular risk profile at diagnosis of HL in patients older than 45years. In case of a high risk, treating HL without RT should be considered. Gepubliceerd: Cancer Treat Rev. 2011;37(5):391-403 Impact factor: 6.811
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5. Risk factors and prognosis of young stroke. The FUTURE study: A prospective cohort study. Study rationale and protocol Rutten-Jacobs LC1, Maaijwee NA1, Arntz RM1, Van Alebeek ME1, Schaapsmeerders P2, Schoonderwaldt HC1, Dorresteijn LD3, Overeem S1, Drost G1, Janssen MC4, van Heerde WL5, Kessels RP2,6,7, Zwiers MP8,9, Norris DG9, van der Vlugt MJ10, van Dijk EJ1, de Leeuw FE1 1 Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Department of Neurology, Radboud University Nijmegen MC, Nijmegen 2 Department of Medical Psychology, Radboud University Nijmegen MC, Nijmegen 3 Medisch Spectrum Twente, Department of Neurology, Enschede 4 Department of Internal Medicine, Radboud University Nijmegen MC, Nijmegen 5 Central Laboratory for Haematology, Radboud University Nijmegen MC, Nijmegen 6 Department of Geriatrics, Radboud, Radboud University Nijmegen MC, Nijmegen 7 Donders Institute for Brain, Cognition and Behaviour, Centre for Cognition, Radboud University Nijmegen, Nijmegen 8 Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Department of Psychiatry, Radboud University Nijmegen MC, Nijmegen 9 Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging, Radboud University Nijmegen, Nijmegen 10 Department of Cardiology, Radboud University Nijmegen MC, Nijmegen Background: Young stroke can have devastating consequences with respect to quality of life, the ability to work, plan or run a family, and participate in social life. Better insight into risk factors and the long-term prognosis is extremely important, especially in young stroke patients with a life expectancy of decades. To date, detailed information on risk factors and the long-term prognosis in young stroke patients, and more specific risk of mortality or recurrent vascular events, remains scarce. Methods/Design: The FUTURE study is a prospective cohort study on risk factors and prognosis of young ischemic and hemorrhagic stroke among 1006 patients, aged 18-50 years, included in our study database between 1-1-1980 and 1-11-2010. Follow-up visits at our research centre take place from the end of 2009 until the end of 2011. Control subjects will be recruited among the patients' spouses, relatives or social environment. Information on mortality and incident vascular events will be retrieved via structured questionnaires. In addition, participants are invited to the research centre to undergo an extensive sub study including MRI. Discussion: The FUTURE study has the potential to make an important contribution to increase the knowledge on risk factors and long-term prognosis in young stroke patients. Our study differs from previous studies by having a maximal follow-up of more than 30 years, including not only TIA and ischemic stroke but also hemorrhagic stroke, the addition of healthy controls and prospectively collect data during an extensive follow-up visit. Completion of the FUTURE study may provide better information for treating physicians and patients with respect to the prognosis of young stroke. Gepubliceerd: BMC Neurol. 2011;11(1):109 Impact factor: 2.797
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6. Timing of temporal and frontal seizures in relation to the circadian phase: A prospective pilot study Hofstra WA a,e, Gordijn MC b, van der Palen J c,d, van Regteren R a, Grootemarsink BE, de Weerd AW a a Department of Clinical Neurophysiology and Sleep Centre, SEIN, Zwolle b Department of Chronobiology, University of Groningen c Medical School Twente, Medisch Spectrum Twente, Enschede d Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede e Department of Neurology, Medisch Spectrum Twente, Enschede There is strong evidence that epileptic seizures occur in diurnal or 24-h patterns. A study in rat models of partial epilepsy showed circadian seizure patterns, and in humans circadian rhythmicity in interictal discharges has been found, suggesting that circadian rhythm may play a role in epilepsy. Circadian influences on human seizure patterns have not been investigated. We performed a pilot study to ascertain influences of the circadian rhythm on seizure occurrence. We prospectively outlined circadian rhythms of patients admitted for long term EEG and video monitoring, using measurement of the dim light melatonin onset (DLMO). Seizures during admission were recorded with continuous EEG and video monitoring. The DLMO ranged from 18:46h to 23:13h (mean 21:22h). One hundred and twenty-four seizures of 21 patients were analysed. Seizures of temporal lobe origin occurred mainly between 11:00 and 17:00h and frontal seizures were seen mostly between 23:00 and 05:00h. When correlating seizure timing to the individual's circadian phase as measured by the DLMO, the following was seen: temporal seizures occurred most frequently in the 6h before DLMO and frontal seizures mainly in 612h after the DLMO. The results of this pilot study suggest that temporal and frontal seizures occur in a non-random fashion synchronized to a hormonal marker of the circadian timing system. Gepubliceerd: Epilepsy Res. 2011;94(3):158-62 Impact factor: 2.302
7. Family history of stroke is an independent risk factor for lacunar stroke subtype with asymptomatic lacunar infarcts at younger ages Knottnerus IL1,2,3, Gielen M4,5, Lodder J2,3, Rouhl RP2, Staals J2, Vlietinck R6, van Oostenbrugge RJ2,3 1 Department of Neurology, Medisch Spectrum Twente, Enschede 2 Department of Neurology Maastricht UMC, Maastricht 3 Cardiovascular Research Institute Maastricht, Maastricht UMC, Maastricht 4 Department of Genetics and Cell Biology, Section of Complex Genetics, Nutrition and Toxicology Research Institute Maastricht, Maastricht 5 Unit of Genetic Epidemiology, Department of Public Health, Epidemiology, and Biostatistics, University of Birmingham, Birmingham, England 6 Department of Human Genetics, Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium
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Results from case-control and case-case studies indicate that a positive family history of stroke (FHstroke) is an independent risk factor for lacunar stroke. Different lacunar stroke phenotypes can be distinguished on the basis of the presence of asymptomatic lacunar infarcts (aLACs), ischemic white-matter lesions, or brain microbleeds. The aim of the present study was to determine whether familial aggregation of stroke was different for lacunar stroke phenotypes. Gepubliceerd: Stroke. 2011;42(5):1196-200 Impact factor: 5.756
8. Estimating the magnitude of genetic factors by calculating the genetic relative risk of stroke in first-ever lacunar stroke patients IL Knottnerus1,2,3, M Gielen4,5, J Lodder1,2, RP Rouhl1, J Staals1,2, R Vlietinck6, RJ van Oostenbrugge1,2 1 Department of Neurology, Maastricht UMC, Maastricht; 2 Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC, Maastricht; 3 Department of Neurology, Medisch Spectrum Twente, Enschede; 4 Section of Complex Genetics, Department of Genetics and Cell Biology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht; 5 Unit of Genetic Epidemiology, Department of Public Health, Epidemiology and Biostatistics, University of Birmingham, Birmingham, United Kingdom, 6 Department of Human Genetics, Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium Positive family history of stroke is an independent risk factor for lacunar stroke. However, the magnitude of familial aggregation of a certain disease is better evaluated by the genetic relative risk. This is calculated by dividing the prevalence of specific disease in family members of patients by the prevalence of this disease in the general population. In a cohort of lacunar stroke patients, who were subtyped clinically and radiologically, we determined the genetic relative risk of stroke. Gepubliceerd: PLoS One. 2011;6(6):e21439 Impact factor: 4.411
9. Screening for antecedent Campylobacter jejuni infections and anti-ganglioside antibodies in idiopathic neuralgic amyotrophy van Eijk JJ1, van Alfen N1,2, Tio-Gillen AP3, Maas M4, Herbrink P4, Portier RP5, van Doorn PA6, van Engelen BG2, Jacobs BC3,6 1 Department of Neurology 2 Department of Clinical Neurophysiology, Radboud University Nijmegen MC, Nijmegen 3 Department of Immunology, University Medical Centre Rotterdam, Rotterdam 4 Department of Medical Immunology, Diagnostic Centre SSDZ, Delft 5 Department of Neurology, MS Twente, Enschede 6 Department of Neurology, Erasmus MC Rotterdam, Rotterdam Gepubliceerd: J Peripher Nerv Syst. 2011;16(2):153-6
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10. Quantitative EEG in ischemic stroke: Correlation with functional status after 6months RV Sheorajpanday1,2, G Nagels1,2, AJ Weeren3, MJ van Putten4, PP De Deyn1,2 1 Department of Neurology and Memory Clinic, ZNA Middelheim Hospital, Antwerp, Belgium 2 Laboratory for Neurochemistry and Behaviour, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Belgium 3 Statistics Center (StatUa), University of Antwerp, Belgium 4 Department of Neurology and Clinical Neurophysiology, Medisch Spectrum Twente and MIRA-Institute for Biomedical Technology and Technical Medicine, University of Twente Objective: Stroke is a major cause of adult-onset disability and dependency. We investigated whether EEG parameters are of prognostic value for functional outcome 6months after ischemic stroke. Methods: One-hundred and ten patients presenting with acute ischemic stroke and persistent neurological deficits at EEG recording were incrementally included. Clinical characteristics, volume of ischemia and EEG parameters were correlated with functional outcome assessed with the modified Rankin Scale (mRS) score. Predictive values for disability, dependency and death were calculated using receiver operating characteristic (ROC) curves and logistic regression modeling. Results: The EEG pairwise derived Brain Symmetry Index (pdBSI) and (delta+theta)/(alpha+beta) ratio (DTABR) were significantly correlated with the modified Rankin Scale (mRS) score at month 6 (Spearman ρ=0.46 and ρ=0.47, respectively, p<0.0005 for both). NIHSS (OR 1.15, 95% CI 1.04-1.27, p=0.005) and pdBSI (OR 4.07, 95% CI 1.32-12.58, p=0.015) were independently associated with disability 6months after stroke. Dependency was independently indicated by NIHSS (OR 1.22, 95% CI 1.09-1.37, p<0.0005) and DTABR (OR 2.25, 95% CI 1.16-4.37, p=0.016). Six month mortality was independently indicated by age at stroke onset (OR 1.18, 95% CI 1.05-1.32, p=0.007), NIHSS (OR 1.11, 95% CI 1.03-1.21, p=0.009) and DTABR (OR 2.04, 95% CI 1.08-3.85, p=0.028). Conclusions: EEG in the subacute setting of ischemic stroke may be of prognostic value for disability, dependency and death after 6months. Significance: Early prognostication of functional outcome after stroke is relevant to efficient rehabilitation management to enhance recovery and minimize long-term disability. Gepubliceerd: Clin Neurophysiol. 2011;122(5):874-83 Impact factor: 2.786
11. Automated EEG analysis: Characterizing the posterior dominant rhythm Lodder S1, van Putten MJ1,2 1 Clinical Neurophysiology, MIRA-Institute for Biomedical Technology and Technical Medicine, University of Twente
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Dept of Neurology and Clinical Neurophysiology, Medisch Spectrum Twente, Enschede Automated interpretation of clinical EEG recordings will reduce subjectivity and visual bias from analysis and can reduce the time required for interpretation. As a first step in the design of a fully automated system, a method is presented to characterize the main properties of the posterior dominant rhythm (PDR), in particular its frequency, symmetry and reactivity. The presented method searches for dominant peaks in the EEG spectra during eyes-closed states with a threecomponent curve-fitting technique. From the fitted curve, the frequency and amplitude are estimated. The symmetry and the reactivity are found using the spectral power at the PDR frequencies. In addition, a certainty value is introduced as a measure of confidence for each estimate. The method was evaluated on a test set of 1215 clinical EEG recordings and compared to the PDR frequencies obtained from the visual analysis, as reported in the diagnostic reports. The calculated PDR frequencies were within 1.2Hz of the visual estimates in 92.5% of the cases. Even higher accuracies were reached when estimates with low certainty values were discarded. The presented method quantifies essential features of the PDR with a matched accuracy to visual inspection, making it a feasible contribution to the design of a fully automated interpretation system. Gepubliceerd: J Neurosci Methods. 2011;200(1):86-93 Impact factor: 2.100
12. Neural Dynamics during Anoxia and the "Wave of Death" BJ Zandt1, B ten Haken1, JG van Dijk2, MJ van Putten3,4 1 Neuroimaging at MIRA-Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 2 Department of Neurology, Leiden University Medical Center, Leiden 3 Department of Clinical Neurophysiology, Medisch Spectrum Twente, Enschede 4 Clinical Neurophysiology at MIRA-Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede Recent experiments in rats have shown the occurrence of a high amplitude slow brain wave in the EEG approximately 1 minute after decapitation, with a duration of 5-15 s (van Rijn et al, PLoS One 6, e16514, 2011) that was presumed to signify the death of brain neurons. We present a computational model of a single neuron and its intra- and extracellular ion concentrations, which shows the physiological mechanism for this observation. The wave is caused by membrane potential oscillations, that occur after the cessation of activity of the sodium-potassium pumps has lead to an excess of extracellular potassium. These oscillations can be described by the Hodgkin-Huxley equations for the sodium and potassium channels, and result in a sudden change in mean membrane voltage. In combination with a high-pass filter, this sudden depolarization leads to a wave in the EEG. We discuss that this process is not necessarily irreversible. Gepubliceerd: PLoS One. 2011;6(7):e22127
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13. Time-frequency analysis of single pulse electrical stimulation to assist delineation of epileptogenic cortex van 't Klooster MA1,2, Zijlmans M1, Leijten FS1, Ferrier CH1, van Putten MJ2, Huiskamp GJ1 1 Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience, UMC Utrecht, Utrecht 2 Department of Clinical Neurophysiology at the MIRA Institute for Biomedical Technology and Technical Medicine, Twente University, Enschede Epilepsy surgery depends on reliable pre-surgical markers of epileptogenic tissue. The current gold standard is the seizure onset zone in ictal, i.e. chronic, electrocorticography recordings. Single pulse electrical stimulation can evoke epileptic, spike-like responses in areas of seizure onset also recorded by electrocorticography. Recently, spontaneous pathological high-frequency oscillations (80-520ԜHz) have been observed in the electrocorticogram that are related to epileptic spikes, but seem more specific for epileptogenic cortex. We wanted to see whether a quantitative electroencephalography analysis using time-frequency information including the higher frequency range could be applied to evoked responses by single pulse electrical stimulation, to enhance its specificity and clinical use. Electrocorticography data were recorded at a 2048-Hz sampling rate from 13 patients. Single pulse electrical stimulation (10 stimuli, 1Ԝms, 8 mA, 0.2ԜHz) was performed stimulating pairs of adjacent electrodes. A time-frequency analysis based on Morlet wavelet transformation was performed in a [-1ԜsԜ:Ԝ1Ԝs] time interval around the stimulus and a frequency range of 10-520ԜHz. Significant (PԜ=Ԝ0.05) changes in power spectra averaged for 10 epochs were computed, resulting in event-related spectral perturbation images. In these images, time-frequency analysis of single pulse-evoked responses, in the range of 10-80ԜHz for spikes, 80-250ԜHz for ripples and 250-520ԜHz for fast ripples, were scored by two observers independently. Sensitivity, specificity and predictive value of time-frequency single pulse-evoked responses in the three frequency ranges were compared with seizure onset zone and post-surgical outcome. In all patients, evoked responses included spikes, ripples and fast ripples. For the seizure onset zone, the median sensitivity of timefrequency single pulse-evoked responses decreased from 100% for spikes to 67% for fast ripples and the median specificity increased from 17% for spikes to 79% for fast ripples. A median positive predictive value for the evoked responses in the seizure onset zone of 17% was found for spikes, 26% for ripples and 37% for fast ripples. Five out of seven patients with <50% of fast ripples removed by resection had a poor outcome. A wavelet transform-based time-frequency analysis of single pulse electrical stimulation reveals evoked responses in the frequency range of spikes, ripples and fast ripples. We demonstrate that time-frequency analysis of single pulse electrical stimulation can assist in delineation of the epileptogenic cortex using time-frequency single pulse-evoked fast ripples as a potential new marker. Gepubliceerd: Brain. 2011;134(10):2855-66 Impact factor: 9.230
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14. Toward automated, at-home assessment of mobility among patients with Parkinson disease, using a body-worn accelerometer Weiss A1, Sharifi S2,3, Plotnik M1, van Vugt JP3, Giladi N1,4, Hausdorff JM1,4,5 1 Laboratory for Gait & Neurodynamics, Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel 2 Department of Biomedical Signals and Systems, Technical Medicine, University of Twente, Enschede 3 Department of Neurology, Medisch Spectrum Twente, Enschede 4 Department of Physical Therapy (NG) and Neurology (JMH), Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel 5 Department of Medicine, Harvard Medical School, Boston, MA, USA Objective: . To develop an automated and objective method to assess mobility in Parkinson disease (PD) patients in daily-life settings and to investigate whether accelerometer-derived measures discriminate between PD and healthy controls as they walk and simulate activities of daily living (ADL). Methods: . Healthy older adults (17) and patients with PD (22) wore a triaxial accelerometer on their lower back during short walks (validation study) and during a walk around the medical center to simulate daily activities (ADL simulation). The variability (consistency and rhythmicity) of stepping was assessed. The patients completed the walks before and after taking their anti-Parkinsonian medications. Frequency-based acceleration measures included dominant frequency, amplitude (strength of signal frequency), width (frequency dispersion), and slope (a combination reflecting amplitude and width) of the main frequency of the power spectral density in the 0.5- to 3.0-Hz band. A subset of the Unified ParkinsonDisease Rating Scale provided a clinical measure of gait impairment (UPDRSGait5). A PD patient and control wore the sensors for 3 days at home. Results: . The width was larger, and the amplitude and slope were smaller in the PD patients compared to the controls in the validation study and ADL simulation (P < .02). The width decreased, and the amplitude and slope increased when patients took anti-Parkinsonian medications (P < .007). Significant correlations were observed between acceleration-derived measures and UPDRS-Gait5. The data obtained at home was similar to the clinic data. Conclusions: . Frequency-derived measures are valid and sensitive estimates of stride-to-stride variability that can be used to assess the quality and consistency of walking in patients with PD in real-life settings. Gepubliceerd: Neurorehabil Neural Repair. 2011;25(9):810-8 Impact factor: 3.772
15. Endarterectomy more favourable than stenting in symptomatic significant carotid stenosis: higher risk of ischaemic stroke or death following stenting Meerwaldt R1, Beuk RJ1, Huisman AB2, Manschot S3, Zeebregts CJ4, Geelkerken RH1 1 Afd. Chirurgie,2 Radiologie, 3 Neurologie, Medisch Spectrum Twente, Enschede 4 Afd. Chirurgie, UMC Groningen, Groningen.
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Carotid endarterectomy (CEA) has proven its value in the treatment of patients with recent significant carotid artery stenosis.- Percutaneous transluminal angioplasty with carotid artery stenting ('stenting' in short) is an alternative to CEA.- The results of stenting and CEA in patients with symptomatic significant carotid artery stenosis were evaluated in 9 prospective randomized controlled trials and 11 meta-analyses. Almost all of these trials failed to show superiority of stenting to CEA.- According to the 4 largest and most recent studies in this field the risk of a stroke or death within 30 days after the intervention is considerably higher following stenting than following CEA.- In the long run the results of stenting and CEA seem to be comparable.- CEA remains the gold standard in treatment of significant carotid artery stenosis, in particular in patients older than 70. Gepubliceerd: Ned Tijdschr Geneeskd. 2011;155(5):A2411 Impact factor: 0
16. Sporadische chorea: een praktische aanpak JP van Vugt1, JI Hoff2, W Vandenberghe3, RA Roos4 1 Afdeling Neurologie, Medisch Spectrum Twente, Enschede 2 Afdeling Neurologie, St. Antonius Ziekenhuis, Nieuwegein 3 Afdeling Neurologie, Universitaire Ziekenhuizen Leuven 4 Afdeling Neurologie, Leids Universitair Medisch Centrum Chorea is een lastig symptoom, niet alleen voor de patiënt maar ook voor de neuroloog. De reden hiervoor is dat chorea enerzijds vrij zeldzaam is, maar dat anderzijds de differentiaaldiagnose zeer uitgebreid is. Voor een algemeen werkende neuroloog is de diagnostiek van chorea daardoor geen routine. In dit overzicht geven wij een praktische leidraad voor de diagnostische aanpak van patiënten met sporadische chorea. Voor de diagnostiek bij patiënten met erfelijke chorea wordt verwezen naar het recente overzichtsartikel van Roos en Bijlsma in dit tijdschrift. Gepubliceerd: Tijdschr Neurol Neurochir 2011;112:152-60 Impact factor: 0
17. Behandeling van overmatig speekselverlies bij de ziekte van Parkinson ME Arbouw, M Koopmann, JP van Vugt Afdeling Klinische Farmacie, Deventer Ziekenhuis, Deventer Afdeling Klinische Farmacie, Ziekenhuis Gelderse Vallei, Ede Afdeling Neurologie, Medisch Spectrum Twente, Enschede Correspondentie graag richten aan dhr. dr. J.P.P. van Vugt, Medisch Spectrum Twente, afdeling Neurologie Speekselverlies is een frequent en sociaal invaliderend symptoom van de ziekte van Parkinson dat wordt veroorzaakt door afgenomen slikfrequentie, hypomimiek en een voorovergebogen houding. Bij weinig invaliderend speekselverlies zijn conservatieve maatregelen en adviezen vaak voldoende. Optimaliseren van dopaminerge medicatie kan nuttig zijn bij off-gerelateerd speekselverlies. Bij ernstiger
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speekselverlies is oraal glycopyrroniumbromide effectief en veilig bij de ziekte van Parkinson. Anticholinergica die de bloed-hersenbarrière passeren, dienen vermeden te worden in verband met het risico op centrale bijwerkingen. Injectie van de speekselklieren met botulinetoxine is effectief, waarbij echogeleide injectie effectiever lijkt dan ‘blinde’ injectie. Er is momenteel geen bewijs dat injectie in de glandula submandibularis effectiever is dan injectie in de glandula parotidea. Bij falen van bovenstaande opties kan radiotherapie overwogen worden, of in het uiterste geval operatie. Het doel van dit artikel is een overzicht te geven van de incidentie, de oorzaken en mogelijke behandelingen van overmatig speekselverlies. Er wordt een aanbeveling gedaan voor een behandelvolgorde. Gepubliceerd: Tijdschr Neurol Neurochir 2011;112:218-225 Impact factor: 0
18. Observing Huntington's disease: the European Huntington's Disease Network's REGISTRY Orth M1; European Huntington's Disease Network*, Handley OJ, Schwenke C, Dunnett S, Wild EJ, Tabrizi SJ, Landwehrmeyer GB 1 Department of Neurology, Universitätsklinikum Ulm, Ulm, Germany * Includes JP van Vugt, department of neurology, Medisch Spectrum Twente, Enschede J Neurol Neurosurg Psychiatry. 2011;82(12):1409-12 Impact factor: 4.791
19. Sleep disturbances in people with epilepsy; prevalence, impact and treatment van Golde EG1, Gutter T2, de Weerd AW2 1 Department of neurology, Medisch Spectrum Twente, Enschede 2 Department of Clinical Neurophysiology and Sleep Centre SEIN, Zwolle The interaction between epilepsy and sleep is thoroughly studied and is very complex. This review focuses on prevalence, impact on quality of life and effects of treatment of sleep disorders on the course of epilepsy. Self-reported sleep disturbances in people with epilepsy are about twice as prevalent as in healthy controls. People with epilepsy with sleep disturbances have a significant impairment of quality of life compared to those with no sleep disturbances. In children with epilepsy, sleep problems may lead to detrimental effects on daytime behavior and cognition. Most is known about obstructive sleep apnea syndrome (OSAS). Comorbidity of epilepsy and OSAS is shown to be far higher than expected by chance. Treatment of OSAS significantly improves seizure control in people with epilepsy. More studies on the prevalence of other sleep disorders in people with epilepsy and the effect of treatment are required. Reports on the effect of treatment for other sleep disorders are scarce and not unequivocal. Gepubliceerd: Sleep Med Rev. 2011;15(6):357-68 Impact factor: 6.338
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20. N. Vagusstimulatie bij kinderen: meer dan alleen aanvalsreductie R. Griens, G. Hageman Afdeling Neurologie, Medisch Spectrum Twente, Enschede Gepubliceerd : Epilepsie 2011;9(2);9-11 Impact factor: 0
21. Long-term administration of fluoxetine to improve motor recovery after stroke Berends HI1, IJzerman MJ2, Movig KL3, Van Putten MJ1,4 1 Department of Technical Medicine, University of Twente, Enschede 2 Department of Health Technology & Services Research, University of Twente, Enschede 3 Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede 4 Department of Neurology, Medisch Spectrum Twente, Enschede Evaluation of: Chollet F Tardy J, Albucher JF et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 10(2), 123–130 (2011). In this study, the authors examined the effects of administration of fluoxetine for 90 days on the recovery of motor function in acute stroke patients. They found that motor function in the group receiving fluoxetine improved significantly compared with the control group. Before administration of fluoxetine can be used as a new therapeutic treatment to improve the rehabilitation after stroke, the long-term effects in chronic stroke patients, as well as the physiological effects, have to be studied and compared with the results of other neuropharmacalogical agents. Gepubliceerd: Future Neurology 2011;6:455-457 Impact factor: 0
Totale impact factor: 65.769 Gemiddelde impact factor: 3.132 Aantal artikelen 1e, 2e of laatste auteur: 12 Totale impact factor: 29.753 Gemiddelde impact factor: 2.479
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Orthopedie 1. A cementless elastic monoblock socket in young patients: a ten to 18-year clinical and radiological follow-up Pakvis D1, Biemond L2, van Hellemondt G3, Spruit M3 1 Department of Orthopaedic Surgery, Medisch Spectrum Twente, Enschede 2 Orthopedic Research Laboratory, Radboud UMC, Nijmegen 3 Department of Orthopaedic Surgery, St. MaartensKliniek, Nijmegen The survival of acetabular components depends on several factors: wear, osteolysis and septic or aseptic loosening. Osteolysis seems to be the main cause for concern in cementless arthroplasties. Acetabular osteolysis results from particle debris and segmental unloading of acetabular bone by rigid sockets. We investigated a cementless elastic monoblock socket with regard to acetabular osteolysis and aseptic loosening in a cohort of young patients. We evaluated 158 hip arthroplasties with a minimum follow-up of ten years (ten to 18) and a mean age of 42 years (1850). The overall revision rate at 14 years was 80% with a 98% survival rate for aseptic loosening. The mean polyethylene wear rate was 0.11 mm/year. Progressive acetabular osteolysis was seen in 3% of patients evaluated. In conclusion, we found low pelvic osteolysis rates, acceptable overall wear rates, satisfactory overall survival and excellent survival rates for aseptic loosening of a cementless elastic monoblock socket in patients younger than 50 years. Ongoing tribology developments and knowledge about acetabular bone adaptations behind acetabular implants will further lower wear and osteolysis rates and optimise survival rates of cementless sockets. Gepubliceerd: Int Orthop. 2011;35(10):1445-51 Impact factor: 1.561
2. Is there evidence for a superior method of socket fixation in hip arthroplasty? A systematic review Pakvis D, van Hellemondt G2, de Visser E3, Jacobs W4, Spruit M2 1 Department of Orthopaedic Surgery, Medisch Spectrum Twente, Enschede 2 Department of Orthopaedic Surgery, St. MaartensKliniek, Nijmegen 3 Department of Orthopaedic Surgery, Alysis Zorggroep, Arnhem 4 OrthoResearch Unit, St. Maartens Kliniek Research, Development and Education, Nijmegen Purpose: Total hip arthroplasty has been a very succesful orthopaedic procedure. The optimal fixation method of the acetabular component however, has not yet been defined. Methods: We performed a systematic review using the Medline and Embase databases to find evidence for the superiority of cemented or cementless acetabular components on short- and long-term clinical and radiological parameters. Methodological quality for randomised trials was assessed using the van Tulder
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checklist, and for the non randomised studies we used the Newcastle-Ottawa quality assessment scale. Results: Our search strategy revealed 16 randomised controlled trials (RCT) and 19 non RCT studies in which cemented and cementless acetabular components are compared. A best evidence analysis for complications, wear, osteolysis, migration and clinical scores showed no superiority for either cemented or cementless socket in the RCTs. A best evidence analysis for non RCT studies revealed better osteolysis, migration properties and aseptic loosening survival for cementless sockets; however, wear and overall survival favoured the cemented sockets. Conclusions: We recommend that an orthopaedic surgeon should choose an established cemented or cementless socket for hip replacement based on patient characteristics, knowledge, experience and preference. Gepubliceerd: Int Orthop. 2011;35(8)1109-1118 Impact factor: 1.561
3. Long-term survivorship analysis of the cementless spotorno femoral component in patients less than 50 years of age Biemond JE1, Pakvis DF2,3, van Hellemondt GG4, Buma P1 1 Orthopedic Research Laboratory, Radboud UMC, Nijmegen 2 Department of Orthopedic Surgery, Medisch Spectrum Twente, Enschede 3 Department of Orthopedics, Radboud University Medical Center, Nijmegen 4 Department of Orthopedics, Sint Maartenskliniek, Nijmegen The long-term survival of the cementless Spotorno (CLS) femoral component (Zimmer Inc, Warsaw, USA) was evaluated in a consecutive series of 85 patients (100 hips) less than 50 years of age. The mean follow-up was 12.3 years. Two patients (3 hips) were lost to follow-up, and 3 (4 hips) died. The survival rate of the CLS stem was 96.9% (confidence interval [CI], 93.6%-100%) after 13 years based on revision of the stem for any reason. The survival of the stem with revision for aseptic loosening as the end point was 97.9% (CI, 95.1%-100%) at 13 years. The mean Harris hip score at time of follow-up was 94. The long-term survival of the CLS stem is excellent in patients less than 50 years of age. Gepubliceerd: J Arthroplasty. 2011;26(3):386-90 Impact factor: 2.207
Totale impact factor: 5.329 Gemiddelde impact factor: 1.776 Aantal artikelen 1e, 2e of laatste auteur: 3 Totale impact factor: 5.329 Gemiddelde impact factor: 1.776
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Pathologie 1. A second case of Gerstmann-Sträussler-Scheinker disease linked to the G131V mutation in the prion protein gene in a Dutch patient Jansen C1,6, Parchi P2, Capellari S, Strammiello R2, Dopper EG3, van Swieten JC3, Kamphorst W4, Rozemuller AJ1,4,5 1 Dutch Surveillance Centre for Prion Diseases, UMC Utrecht, Utrecht 2 Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna, Italy 3 Department of Neurology, Erasmus UMC, Rotterdam 4 Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam 5 Department of Pathology, VU UMC, Amsterdam 6 Department of Pathology, Medisch Spectrum Twente, Enschede A rare case of Gerstmann-Sträussler-Scheinker disease in a 36-year-old Dutch man is reported. The clinical phenotype was characterized by slowly progressive cognitive decline, later followed by ataxia and parkinsonism. Neuropathologic findings consisted of numerous amyloid plaques in the cerebellum, which showed positive staining for the abnormal prion protein (PrP(Sc)). In addition, there were tau accumulations around numerous amyloid deposits in the cerebral cortex, striatum, hippocampal formation, and midbrain. There was no spongiform degeneration. Western blot analysis showed the co-occurrence of 2 distinct abnormal prion protein species comprising an unglycosylated, protease-resistant fragment of approximately 8 kd, which was found to be truncated at both N- and C-terminal ends by epitope mapping, and a detergent-insoluble but protease-sensitive form of full-length PrP(Sc). Sequence analysis disclosed a mutation at codon 131 of the prion protein gene (PRNP), resulting in a valine-for-glycine substitution (G131V). The patient was heterozygous at the polymorphic codon 129 and carried the mutation on the methionine allele. To our knowledge, this is the second family worldwide in which this mutation has been identified. Gerstmann-Sträussler-Scheinker disease should be considered in patients with a clinical diagnosis of familial frontotemporal dementia. Gepubliceerd: J Neuropathol Exp Neurol. 2011;70(8):698-702 Impact factor: 4.190
2. Degeneration and atherosclerosis inducing increased deposition of type IIA secretory phospholipase A2, C-reactive protein and complement in aortic valves cause neutrophilic granulocyte influx Kupreishvili K1, Baidoshvili A2, ter Weeme M, Huybregts MA, Krijnen PA, Van Hinsbergh VW, Stooker W, Eijsman L, Niessen HW 1 Department of Pathology, VU MC, Amsterdam 2 Department of Pathology, Medisch Spectrum Twente, Enschede Background and aim of the study: Recent studies have indicated that atherosclerosis-like changes are involved in the pathogenesis of aortic valve stenosis. Increased blood and valve tissue levels of C-reactive protein (CRP) have
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been reported in patients with aortic valve disease, although the different pathological conditions involved were not analyzed. The study aim was to monitor the deposition of CRP, its activator sPLA2-IIA and its effector complement, and the subsequent influx of neutrophilic granulocytes in degenerative and atherosclerotic aortic valves. Methods: Human tricuspid aortic valves (n = 57) obtained at autopsy included five control valves, 36 aortic valves with atherosclerotic changes, and 16 with degenerative changes. All valves were analyzed immunohistochemically for the presence of sPLA2-IIA, CRP, C3d and MPO (to detect neutrophilic granulocytes), and subsequently quantified using computer-assisted morphometry. Results: In aortic valves with degeneration, the areas of sPLA2-IIA, CRP and complement deposition were all significantly increased compared to control valves. These mediators were even more extensively deposited in atherosclerotically changed aortic valves. The increased deposition of these mediators coincided with a significant increase of neutrophilic granulocytes in atherosclerotic and degenerated aortic valves, compared to control valves. Conclusion: The study results indicate that sPLA2-IIA, CRP, and C3d are significantly more activated in atherosclerotic aortic valves compared to degeneratively changed aortic valves. A significant increase was also identified in neutrophilic granulocytes in non-infectious, diseased valves (atherosclerosis and degeneration). Gepubliceerd: J Heart Valve Dis. 2011;20(1):29-36 Impact factor: 0.927
3. Human papillomavirus infection in women with and without cervical cancer in Tbilisi, Georgia Alibegashvili T1, Clifford GM2, Vaccarella S2, Baidoshvili A3,4, Gogiashvili L1, Tsagareli Z1, Kureli I1, Snijders PJ3, Heideman DA3, van Kemenade FJ3, Meijer CJ3, Kordzaia D1, Franceschi S2 1 Alexandre Natishvili Institute of Morphology, Tbilisi, Georgia 2 International Agency for Research on Cancer, Lyon, France 3 Department of Pathology, VU MC Amsterdam 4 Department of Pathology, Medisch Spectrum Twente, Enschede Background: No accurate estimates of cervical cancer incidence or mortality currently exist in Georgia. Nor are there any data on the population-based prevalence of high-risk (HR) human papillomavirus (HPV) infection, which, in the absence of good-quality screening, is known to correlate with cervical cancer incidence. Methods: We obtained cervical cell specimens from 1309 women aged 18-59 years from the general population of Tbilisi, and also from 91 locally diagnosed invasive cervical cancers (ICC). DNA of 44 HPV types was tested for using a GP5+/6+-based PCR assay. Results: In the general population (of whom 2% reported a previous Pap smear) HPV prevalence was 13.5% (95% CI: 11.6-15.9), being highest in women aged 2534 years (18.7%) and falling to between 8.6% and 9.5% for all age groups above 34
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years. HR HPV prevalence was 8.6% overall, being 6.8% and 38.9% among women with normal and abnormal cytology, respectively. HPV45 (1.6%) was the most common type in women with normal cytology, whereas HPV16 predominated among women with cervical abnormalities (including 7 of 10 histologically confirmed cervical intraepithelial neoplasia 2/3) and among ICC (57.6%). The next most common types in ICC in Georgia were HPV45 and 18 (13.2 and 11.0%, respectively). Conclusions: We report a relatively high burden of HPV infection in Tbilisi, Georgia. Improving cervical cancer prevention, through screening and/or HPV vaccination, is an important public health issue in Georgia, where 70% of ICC are theoretically preventable by HPV16/18 vaccines. Gepubliceerd: Cancer Epidemiol. 2011;35(5):465-70 Impact factor: 1.182
4. A novel seven-octapeptide repeat insertion in the prion protein gene (PRNP) in a Dutch pedigree with Gerstmann–Sträussler–Scheinker disease phenotype: comparison with similar cases from the literature C Jansen1,10,11, W Voet2, MW Head3, P Parchi4, H Yull3, A Verrips2, P Wesseling5, J Meulstee6, F Baas7, WA van Gool8, JW Ironside3, AJ Rozemuller1,9 1 Dutch Surveillance Centre for Prion Diseases, UMC Utrecht, Utrecht 2 Department of Neurology, Canisius-Wilhelmina Hospital, Nijmegen 3 National Creutzfeldt-Jakob Disease Surveillance Unit, University of Edinburgh, Edinburgh, UK 4 Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna, Italy 5 Department of Pathology, Radboud University Nijmegen MC, Nijmegen 6 Department of Clinical Neurophysiology, Canisius-Wilhelmina Hospital, Nijmegen 7 Department of Neurogenetics, AMC Amsterdam 8 Department of Neurology, AMC Amsterdam 9 Netherlands Brain Bank and Department of Pathology, VU UMC, Amsterdam 10 Department of Pathology, Dutch Surveillance Centre for Prion Diseases, UMC Utrecht, Utrecht 11 Department of Pathology, Medisch spectrum Twente, Enschede Human prion diseases can be sporadic, inherited or acquired by infection and show considerable phenotypic heterogeneity. We describe the clinical, histopathological and pathological prion protein (PrP(Sc)) characteristics of a Dutch family with a novel 7-octapeptide repeat insertion (7-OPRI) in PRNP, the gene encoding the prion protein (PrP). Clinical features were available in four, neuropathological features in three and biochemical characteristics in two members of this family. The clinical phenotype was characterized by slowly progressive cognitive decline, personality change, lethargy, depression with anxiety and panic attacks, apraxia and a hypokinetic-rigid syndrome. Neuropathological findings consisted of numerous multiand unicentric amyloid plaques throughout the cerebrum and cerebellum with varying degrees of spongiform degeneration. Genetic and molecular studies were performed in two male family members. One of them was homozygous for valine and the other heterozygous for methionine and valine at codon 129 of PRNP. Sequence analysis identified a novel 168 bp insertion [R2-R2-R2-R2-R3g-R2-R2] in
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the octapeptide repeat region of PRNP. Both patients carried the mutation on the allele with valine at codon 129. Western blot analysis showed type 1 PrP(Sc) in both patients and detected a smaller ~8 kDa PrP(Sc) fragment in the cerebellum in one patient. The features of this Dutch kindred define an unusual neuropathological phenotype and a novel PRNP haplotype among the previously documented 7-OPRI mutations, further expanding the spectrum of genotype-phenotype correlations in inherited prion diseases. Gepubliceerd: Acta Neuropathol. 2011;121(1):59-68 Impact factor: 7.695
5. The first case of fatal familial insomnia (FFI) in the Netherlands: a patient from Egyptian descent with concurrent four repeat tau deposits C Jansen1,7, P Parchi6, B Jelles2, AA Gouw3, G Beunders4, RM van Spaendonk4, JM van de Kamp4, AW Lemstra3, S Capellari6, AJ Rozemuller1,5 1 Dutch Surveillance Center for Prion Diseases, UMC Utrecht, Utrecht 2 Department of Neurology, Gelre Ziekenhuizen, Zutphen 3 Departments of Neurology, 4 Clinical Genetics, 5 Pathology, VU UMC, Amsterdam 6 Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna, Italy 7 Department of Pathology, Medisch spectrum Twente, Enschede Gepubliceerd: Neuropathol Appl Neurobiol. 2011;37(5):549-53 Impact factor: 3.625
6. Acute left ventricular failure in a patient with hydroxychloroquine-induced cardiomyopathy Hartmann M1, Meek IL2, van Houwelingen GK1, Lambregts HP1, Toes GJ3, van der Wal AC4, von Birgelen C1,5 1 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede 3 Department of Pathology, Medisch Spectrum Twente, Enschede 4 Department of Pathology, AMC, University Amsterdam, Amsterdam 5 University of Twente, MIRA Institute for Biomedical Technology and Technical Medicine, Enschede We present the case of a 75-year-old woman with a medical history of rheumatoid arthritis treated with hydroxychloroquine, who was admitted with acute left-sided heart failure due to a hydroxychloroquine-induced cardiomyopathy as supported by endomyocardial biopsy. Gepubliceerd: Neth Heart J. 2011;19(11):482-5 Impact factor: 1.447
7. Toxic alveolitis after inhalation of a water repellent 171
Epping G1, Van Baarlen J2, Van Der Valk PD1 1 Department of Respiratory Medicine, Medisch Spectrum Twente, Enschede 2 Department of Pathology, Medisch Spectrum Twente, Enschede Inhalation of fluorocarbon polymers can cause pulmonary toxicity. Although multiple cases of lung injury have been reported, cellular characterization of the associated alveolitis occurring acutely after inhalation is limited. We report the case of a previously healthy woman who presented at our Emergency Department with an acute pneumonitis following inhalation of a fluorocarbon polymer-based rain-proofing spray. Bronchoalveolar lavage (BAL) performed shortly after the presentation showed an elevated total cell count, with a high proportion of neutrophils (58%) and eosinophils (9%). In addition, a lipid stain (Oil-Red-O-stain) showed a high level of lipid laden macrophages, a marker that could reflect a direct toxic effect of the spray on alveolar cells. The patient made a full recovery after four days of in-hospital observation with supportive care. Gepubliceerd: Int J Occup Med Environ Health. 2011;24(4):409-13 Impact factor: 1.000
8. Necrotizing sarcoid granulomatosis: A case report and review of progresses in this disease G Epping1, CA Schwengle1, RP Aliredjo2, M Wagenaar1 1 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 2 Department of Pathology, Medisch Spectrum Twente, Enschede We present the case of a young male who visited the emergency room with progressive dyspnea and left sided chest pain. A chest X-ray was performed which showed a pattern of diffuse nodular and reticular opacities. The diagnosis of Necrotizing Sarcoid Granulomatosis (NSG) was made by histopathological examination of a lung biopsy specimen and by excluding other causes of granulomatous disease. He was treated with corticosteroids. Because of persistent extrapulmonary (ocular) involvement a maintenance dose of prednisone was needed. Necrotizing Sarcoid Granulomatosis is a granulomatous disease with necrosis and vasculitis of unknown cause. The resemblance between NSG and (nodular) sarcoidosis is strong, but subtle differences exist. The prognosis is good and therapy is usually not necessary. However in some cases there is a need for therapy with corticosteroids, depending on the involved organs and/or the degree of impairment. Gepubliceerd: Health 2011;3(8):534-536 Impact factor: 0
9. Predictors for Neoplastic Progression in Patients With Barrett's Esophagus: A Prospective Cohort Study M Sikkema1,22, CW Looman2, EW Steyerberg2, M Kerkhof1, F Kastelein1, H van Dekken3, AJ van Vuuren1, WA Bode4, H van der Valk5, RJ Ouwendijk6, R Giard7,
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W Lesterhuis8, R Heinhuis9, EC Klinkenberg10, GA Meijer11, F ter Borg12, JW Arends13, JJ Kolkman14, J van Baarlen15, RA de Vries16, AH Mulder17, AJ van Tilburg18, GJ Offerhaus19, FJ ten Kate19, JG Kusters1, EJ Kuipers1,20, PD Siersema1,21 1 Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam 2 Department of Public Health, Erasmus MC, Rotterdam 3 Department of Pathology, Erasmus MC, Rotterdam 4 Department of Gastroenterology, IJsselland Hospital, Capelle a/d IJssel 5 Pathology Laboratory, PATHAN, Rotterdam 6 Department of Gastroenterology, Ikazia Hospital, Rotterdam 7 Department of Pathology, Maasstad Hospital, Rotterdam 8 Department of Gastroenterology, Albert Schweitzer Hospital, Dordrecht 9 Department of Pathology, Albert Schweitzer Hospital, Dordrecht 10 Department of Gastroenterology and Hepatology, VU Medical Center, Amsterdam 11 Department of Pathology, VU MC, Amsterdam 12 Department of Gastroenterology, Deventer Hospital, Deventer 13 Department of Pathology, Deventer Hospital, Deventer 14 Department of Gastroenterology, Medisch Spectrum Twente, Enschede 15 Laboratorium Pathologie Oost Nederland, Enschede 16 Department of Gastroenterology, Rijnstate Hospital, Arnhem 17 Department of Pathology, Rijnstate Hospital, Arnhem 18 Department of Gastroenterology, Sint Franciscus Gasthuis, Rotterdam 19 Department of Pathology, UMC Utrecht, Utrecht 20 Internal Medicine, Erasmus MC, Rotterdam 21 Department of Gastroenterology, UMC Utrecht, Utrecht 22 Department of Gastroenterology and Hepatology, UMC Utrecht, Utrecht Objectives: Patients with Barrett's esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors. Methods: We included 713 patients with BE (≥2Ԝcm) with no dysplasia (ND) or lowgrade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance. Results: After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of ≥10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3-7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01-1.2), esophagitis (RR 3.5; 95% CI 1.3-9.5), and LGD (RR 9.7; 95% CI 4.4-21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied
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between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (<1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18-40%). Conclusions: In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE. Gepubliceerd: Am J Gastroenterol. 2011;106:1231-8 Impact factor: 6.882
Totale impact factor: 26.948 Gemiddelde impact factor: 2.994 Aantal artikelen 1e, 2e of laatste auteur: 5 Totale impact factor: 17.437 Gemiddelde impact factor: 3.487
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Plastische Chirurgie 1. Use of remodeled femoral head allograft for tarsal reconstruction in the treatment of müller-weiss disease Tan A, Smulders YC, Zöphel OT Department of Plastic, Reconstructive, and Hand Surgery, Medisch Spectrum Twente, Enschede Müller-Weiss disease (MWD), spontaneous avascular necrosis of the navicular in adults, is rare. Without treatment, it can result in permanent disability. Operative treatment is often required. MWD was suspected in a 51-year-old woman with spontaneous pain in her right foot. The radiologic tests showed a comma shaped deformed navicular and severe talonavicular necrosis and sclerosis. After excision of the necrotic navicular, a 5 × 5 × 3-cm defect appeared. A femoral head bone allograft was remodeled to fit this defect precisely. Autologous cancellous bone was also used. The allograft interposition arthrodesis was stabilized with a low contact plate. The histopathologic results showed avascular osteonecrosis, supporting the diagnosis of MWD. After 12 weeks of non-weight-bearing plaster cast immobilization, the radiographs showed consolidation and no osteolysis. At 6 months after surgery, she was fully weight-bearing. The low contact plate was removed, because it impeded exercise. After 10 months, she was walking pain free. At 14 months after surgery, her radiographs still showed good consolidation, with no sign of osteolysis. The use of a bone allograft to cover a tarsal defect could be a safe and effective operative treatment of MWD that has not yet been reported in English-language studies. This treatment also results in minimal donor site morbidity. Gepubliceerd: J Foot Ankle Surg. 2011;50(6):721-6 Impact factor: 0.760
Totale impact factor: 0.760 Gemiddelde impact factor: 0.760 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 0.760 Gemiddelde impact factor: 0.760
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Radiologie 1. A randomised sham controlled trial of vertebroplasty for painful acute osteoporotic vertebral fractures (VERTOS IV) C Firanescu1, PNM Lohle1, J de Vries3,6, CA Klazen4, JR Juttmann2, W Clark5, WJ van Rooij1, On behalf of the VERTOS IV study group 1 Department of Radiology, St. Elisabeth Ziekenhuis, Tilburg 2 Department of Internal Medicine, St. Elisabeth Ziekenhuis, Tilburg 3 Department of Medical Psychology, St. Elisabeth Ziekenhuis, Tilburg 4 Department of Radiology, Medisch Spectrum Twente, Enschede 5 Department of Radiology, St. George Private Hospital, 1 South Street, Kogarah NSW 2217, Australia 6 Department of Medical Psychology, Tilburg University, Tilburg BACKGROUND: The standard care in patients with a painful osteoporotic vertebral compression fracture (VCF) is conservative therapy. Percutaneous vertebroplasty (PV), a minimally invasive technique, is a new treatment option. Recent randomized controlled trials (RCT) provide conflicting results: two sham-controlled studies showed no benefit of PV while an unmasked but controlled RCT (VERTOS II) found effective pain relief at acceptable costs. The objective of this study is to compare pain relief after PV with a sham intervention in selected patients with an acute osteoporotic VCF using the same strict inclusion criteria as in VERTOS II. Secondary outcome measures are back pain related disability and quality of life. METHODS: The VERTOS IV study is a prospective, multicenter RCT with pain relief as primary endpoint. Patients with a painful osteoporotic VCF with bone edema on MR imaging, local back pain for 6 weeks or less, osteopenia and aged 50 years or older, after obtaining informed consent, are included and randomized for PV or a sham intervention. In total 180 patients will be enrolled. Follow-up is at regular intervals during a 1-year period with a standard Visual Analogue Scale (VAS) score for pain and pain medication. Necessary additional therapies and complications are recorded. DISCUSSION: The VERTOS IV study is a methodologically sound RCT designed to assess pain relief after PV compared to a sham intervention in patients with an acute osteoporotic VCF selected on strict inclusion criteria. Gepubliceerd: Trials. 2011;12(1):93 Impact factor: 2.080
2. Postprocedural CT for perivertebral cement leakage in percutaneous vertebroplasty is not necessary-results from VERTOS II A Venmans1, CA Klazen1,4, WJ van Rooij1, J de Vries2, WP Mali3 PN Lohle1 1 Department of Radiology, St. Elisabeth Ziekenhuis Tilburg, Hilvarenbeekseweg 60, 5022 GC Tilburg 2 Department of Medical Psychology, St. Elisabeth Ziekenhuis Tilburg, Tilburg 3 Department of Radiology, University Medical Centre Utrecht, Utrecht 4 Department of Radiology, Medisch Spectrum Twente, Enschede
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Introduction: During percutaneous vertebroplasty (PV), perivertebral cement leakage frequently occurs. There is some concern that cement deposits may migrate towards the lungs via the veins during follow-up. We used baseline and follow-up computed tomography (CT) to assess the incidence and extend of late cement migration in a large consecutive patient cohort. Methods: VERTOS II is a prospective multicenter randomized controlled trial comparing PV with conservative therapy for osteoporotic vertebral compression fractures (OVCFs). Patients assigned to PV had baseline postprocedural CT scans of the treated vertebral bodies. After a mean follow-up of 22 months, 54 of 78 patients (69%) had follow-up CT. CT scans were analyzed and compared for perivertebral venous, discal, and soft tissue leakage. Results: Perivertebral cement leakage occurred in 64 of 80 treated vertebrae (80%; 95% CI, 70% to 87%). All patients remained asymptomatic. Perivertebral venous leakage was present in 56 vertebrae (88%), mostly in the anterior external venous plexus (46 of 56, 82%). Discal leakage occurred in 22 of 64 vertebrae (34%) and soft tissue leakage in two of 64 (4%). Mean injected cement volume in vertebrae with leakage was higher (4.5 versus 3.7 cm(3), p = 0.04). Follow-up CT scan showed unchanged perivertebral cement leakages without late cement migration. Conclusion: Perivertebral cement leaks during PV for OVCFs occurred frequently in the VERTOS II trial. Cement leakage occurred more frequently with higher injected volumes. However, all patients remained asymptomatic, and late cement migration during follow-up did not occur. Standard postprocedural CT of the treated vertebral body in PV is not necessary. Gepubliceerd: Neuroradiology 2011;53(1):19-22 Impact factor: 2.870
3. Magnetic Resonance Imaging of the Rheumatic Foot According to the RAMRIS System Is Reliable Baan H1, Bezooijen R2, Avenarius JK2, Dubbeldam R3, Drossaers-Bakker WK4,5, van de Laar MA4,5 1 Department of Rheumatology, Ziekenhuis Groep Twente, Almelo and Hengelo 2 Department of Radiology, Medisch Spectrum Twente, Enschede 3 Roessingh Research and Development, Enschede 4 The Arthritis Centre Twente, University Twente, Enschede 5 Department of Rheumatology, Medisch Spectrum Twente, Enschede Objective: In rheumatology, magnetic resonance imaging (MRI) is predominantly applied in the assessment and outcome measurement of rheumatoid arthritis (RA) in hands and wrists, leading to the development of the RAMRIS (RA-MRI-Scoring) system. It was initiated by the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT). The RAMRIS system has not been applied widely in the measurement of feet. We investigated the interreader and intrareader agreement of the RAMRIS scoring system in the assessment of feet in RA. Methods: Twenty-nine patients with RA who had radiological damage and/or arthritis underwent MRI. Two experienced readers independently read both
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complete sets. One reader read 6 random sets after the initial session, in order to assess the intrareader agreement. For evaluation of the intrareader and interreader reliability, quadratic-weighted κ scores were calculated per joint and lesion. Results: For the forefeet, interreader scores were excellent, ranging from 0.77 (bone edema) to 0.95 (bone erosion). Hindfoot interreader agreement scores were highest for erosion (0.90) and synovitis global score (0.88), but edema and synovial thickness agreement were also acceptable (0.83 and 0.86). Intrareader scores were on the whole slightly lower, but excellent. Conclusion: Reliability (interreader and intrareader agreement) in the assessment of the rheumatoid foot according to the RAMRIS method is excellent. Gepubliceerd: J Rheumatol. 2011;38(6):1003-8 Impact factor: 3.551
4. The strengths and limitations of routine staging before treatment with abdominal CT in colorectal cancer I Grossmann1,2, JM Klaase2, JK Avenarius3, IH de Hingh4, WJ Mastboom2, T Wiggers1 1 Department of surgery, University Medical Center Groningen, Groningen 2 Department of surgery, Medical Spectrum Twente, Enschede 3 Department of radiology, Medical Spectrum Twente, Enschede 4 Department of Surgery, Catharina Hospital, Eindhoven Background: Advanced colorectal cancer (CRC), either locally advanced (LA), metastasized (mCRC) or both, is present in a relevant proportion of patients. The chances on curation of advanced CRC are continuously improving with modern multi-modality treatment options. Less invasive procedures in incurable CRC may improve short term outcomes and the quality of life. Both situations motivate adequate staging before treatment in CRC. This prospective observational study evaluates the outcomes after the introduction of routine staging with abdominal CT before treatment. Methods: In a prospective observational study of 612 consecutive patients (20072009), the ability of abdominal CT to find liver metastases (LM), peritoneal carcinomatosis (PC) and T4 stage in colon cancer (LACC) was analyzed. Results: Advanced CRC was present in 58% of patients, mCRC in 31%. The ability to find LM was excellent (99%), cT4 stage CC good (86%) and PC poor (33%). In the group of surgical patients with emergency presentations, the incidences of both mCRC (51%) and LACC (69%) were higher than in the elective group (20% and 26% respectively). Staging tended to be omitted more often in the emergency group (35% versus 12% in elective surgery). Conclusion: The strengths of staging with abdominal CT are to find LM and LACC, however it fails in diagnosing PC. On grounds of the incidence of advanced CRC, staging is warranted as well in patients with emergency presentations. Gepubliceerd: BMC Cancer. 2011 Oct 7;11(1):433 Impact factor: 3.153
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5. Imaging tumor vascularization for detection and diagnosis of breast cancer M Heijblom1,2; JM Klaase2; FM van den Engh4; TG van Leeuwen1,3; W Steenbergen1; S Manohar1 1 Biomedical Photonic Imaging Group, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 2 Department of Surgery, Center for Breast Care, Medisch Spectrum Twente, Enschede 3 Biomedical Engineering and Physics, AMC, University of Amsterdam, Amsterdam 4 Department of Radiology, Medisch Spectrum Twente, Enschede Breast cancer is one of the major causes of morbidity and mortality in western women. Current screening and diagnostic imaging modalities, like x-ray mammography and ultrasonography, focus on morphological changes of breast tissue. However, these techniques still miss some cancers and often falsely detect cancer. The sensitivity and specificity for detecting the disease can probably be improved by focusing on the consequences of tumor angiogenesis: the increased microvessel density with altered vascular characteristics. In this review, various techniques for imaging breast tumor vasculature are discussed. Dynamic contrast enhanced magnetic resonance imaging is the most-used imaging modality in this field. It has a proven high sensitivity, but a low specificity and cannot be applied in all women. Moreover, it has problems with detecting ductal carcinoma in situ (DCIS). On the contrary, contrast enhanced digital mammography can detect DCIS, but requires the use of ionizing radiation. Contrast enhanced ultrasound provides realtime information about true intravascular blood volume and flow. However, this technique still has difficulties with discriminating benign from malignant tissue. Moreover, these three imaging modalities all require the injection of contrast agents. Two relatively new techniques that do not use external contrast agents are diffuse optical imaging and photoacoustic imaging. Both visualize the increased concentration of hemoglobin in malignant tissue and thereby provide a high intrinsic contrast. Gepubliceerd: Technol Cancer Res Treat. 2011;10(6):607-23 Impact factor: 1.814
6. Endarterectomy more favourable than stenting in symptomatic significant carotid stenosis: higher risk of ischaemic stroke or death following stenting Meerwaldt R1, Beuk RJ1, Huisman AB2, Manschot S3, Zeebregts CJ4, Geelkerken RH1 1 Afd. Chirurgie,2 Radiologie, 3 Neurologie, Medisch Spectrum Twente, Enschede 4 Afd. Chirurgie, UMC Groningen, Groningen. Carotid endarterectomy (CEA) has proven its value in the treatment of patients with recent significant carotid artery stenosis.- Percutaneous transluminal angioplasty with carotid artery stenting ('stenting' in short) is an alternative to CEA.- The results of stenting and CEA in patients with symptomatic significant carotid artery stenosis were evaluated in 9 prospective randomized controlled trials and 11 meta-analyses.
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Almost all of these trials failed to show superiority of stenting to CEA.- According to the 4 largest and most recent studies in this field the risk of a stroke or death within 30 days after the intervention is considerably higher following stenting than following CEA.- In the long run the results of stenting and CEA seem to be comparable.- CEA remains the gold standard in treatment of significant carotid artery stenosis, in particular in patients older than 70. Gepubliceerd: Ned Tijdschr Geneeskd. 2011;155(5):A2411 Impact factor: 0
Totale impact factor: 13.468 Gemiddelde impact factor: 2.245 Aantal artikelen 1e, 2e of laatste auteur: 2 Totale impact factor: 6.421 Gemiddelde impact factor: 3.211
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Radiotherapie 1. Outcome of Endometrial Cancer Stage IIIA with Adnexa or Serosal Involvement Only Jobsen JJ1, Naudin Ten Cate L2, Lybeert ML3, Scholten A4, van der Steen-Banasik EM5, van der Palen J6,7, Stenfert Kroese MC8, Slot A9, Schutter EM10, Siesling S11 1 Department of Radiation Oncology, Medisch Spectrum Twente, Enschede 2 Laboratorium Pathologie Oost Nederland, Enschede 3 Department of Radiation Oncology, Catharina Hospital, Eindhoven 4 Department of Clinical Oncology, Leiden University Medical Center, Leiden 5 Arnhem Radiotherapeutic Institute, Arnhem 6 Department of Research Methodology, Measurement, and Data Analysis, Faculty of Behavioral Science, University of Twente, Enschede 7 Department of Clinical Epidemiology, Medisch Spectrum Twente, Enschede 8 Radiotherapy Institute Steden en Omstreken, Deventer 9 Radiotherapy Institute Friesland, Leeuwarden 10 Department of Obstetrics and Gynaecology, Medisch Spectrum Twente, Enschede 11 Comprehensive Cancer Centre North East, Enschede/Groningen Objective. The aim of this study is to look at possible differences in outcome between serosa and adnexal involvement stage IIIA endometrial carcinoma. Methods. 67 patients with stage IIIA endometrial carcinoma were included, 46 with adnexal involvement and 21 with serosa. A central histopathological review was performed. Results. The 7-year locoregional failure rate was (LRFR) 2.2% for adnexal involvement and 16.0% for involvement of the serosa (P = .0522). The 7-year distant metastasis-free survival was 72.7% for adnexal involvement and 58.7% for serosa (P = .3994). The 7-year disease-specific survival (DSS) was 71.8% for patients with adnexal involvement and 75.4% for patients with serosa. Conclusion. Endometrial carcinoma stage IIIA with involvement of the adnexa or serosa showed to have a comparable disease-specific survival. Locoregional control was worse for serosa involvement compared to adnexa. Gepubliceerd: Obstet Gynecol Int.;2011:962518 Impact factor: 4.392
2. Long-Term Outcome and Quality of Life of Patients With Endometrial Carcinoma Treated With or Without Pelvic Radiotherapy in the Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) Trial Nout RA, van de Poll-Franse LV, Lybeert ML, Wárlám-Rodenhuis CC, Jobsen JJ*, Mens JW, Lutgens LC, Pras B, van Putten WL, Creutzberg CL From the Leiden UMC, Leiden; Comprehensive Cancer Centre South; Catharina Hospital, Eindhoven; Center of Research on Psychology in Somatic Diseases, Tilburg University, Tilburg; UMC Utrecht, Utrecht; * Department of Radiotherapy, Medisch Spectrum Twente, Enschede; Erasmus Medical Center-Daniel den Hoed
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Cancer Center, Rotterdam; MAASTtricht Radiation Oncology Clinic, Maastricht; and UMC Groningen, Groningen Purpose: To determine the long-term outcome and health-related quality of life (HRQL) of patients with endometrial carcinoma (EC) treated with or without pelvic radiotherapy in the Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) trial. Patients and methods: Between 1990 and 1997, 714 patients with stage IC grade 1 to 2 or IB grade 2 to 3 EC were randomly allocated to pelvic external-beam radiotherapy (EBRT) or no additional treatment (NAT). HRQL was evaluated with the Short Form 36-Item (SF-36) questionnaire; subscales from the European Organisation for Research and Treatment of Cancer (EORTC) PR25 module for bowel and bladder symptoms and the OV28 and CX24 modules for sexual symptoms; and demographic questions. Analysis was by intention-to-treat. Results: Median follow-up was 13.3 years. The 15-year actuarial locoregional recurrence rates were 5.8% for EBRT versus 15.5% for NAT (P < .001), and 15-year overall survival was 52% versus 60% (P = .14). Of the 351 patients confirmed to be alive with correct address, 246 (70%) returned the questionnaire. Patients treated with EBRT reported significant (P < .01) and clinically relevant higher rates of urinary incontinence, diarrhea, and fecal leakage leading to more limitations in daily activities. Increased symptoms were reflected by the frequent use of incontinence materials after EBRT (day and night use, 42.9% v 15.2% for NAT; P < .001). Patients treated with EBRT reported lower scores on the SF-36 scales "physical functioning" (P = .004) and "role-physical" (P = .003). Conclusion: EBRT for endometrial cancer is associated with long-term urinary and bowel symptoms and lower physical and role-physical functioning, even 15 years after treatment. Despite its efficacy in reducing locoregional recurrence, EBRT should be avoided in patients with low- and intermediate-risk EC. Gepubliceerd: J Clin Oncol. 2011;29(13):1692-700 Impact factor: 18.970
3. A population-based study on the utilisation rate of primary radiotherapy for prostate cancer in 4 regions in the Netherlands, 1997-2008 Poortmans PM1, Aarts MJ2, Jobsen JJ3, Koning CC4, Lybeert ML5, Struikmans H6, Vulto JC1, Louwman WJ2, Coebergh JW2,7, Koldewijn EL8 1 Department of Radiation Oncology, Institute Verbeeten, Tilburg 2 Department of Research, Comprehensive Cancer Centre South, Eindhoven 3 Department of Radiation Oncology, Medisch Spectrum Twente, Enschede 4 Department of Radiation Oncology, University of Amsterdam, Amsterdam 5 Department of Radiation Oncology, Catharina Hospital, Eindhoven 6 Radiotherapy Centre West, Medical Centre Haaglanden, The Hague 7 Department of Public Health, Erasmus MC Rotterdam 8 Department of Urology, Catharina Hospital, Eindhoven Aim: The purpose was to study variations in utilisation rates of external beam radiotherapy (EBRT) and brachytherapy (BT) for prostate cancer patients.
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Materials and methods: We calculated the proportion and number of EBRT and BT given or planned within 6months of diagnosis in 4 Dutch regions, according to stage and age in a population-based setting including 47,259 prostate cancer patients diagnosed from 1997 until 2008. Results: During this study period, the overall utilisation rate of EBRT remained stable at around 25%, while the rate of BT for non-metastasized patients increased from 1% (95% CI:0-1%) to 12% (11-13%) in 2006 and slightly decreased towards 10% (9-11%) in 2008. From 2001 on, the overall utilisation rate of EBRT decreased significantly in one region (p<0.05). In this region, a sharp rise in the utilisation rate of BT for non-metastatic patients was noted to 17% (14-20%) in 2008 after a peak of 24% (21-27%) in 2006. For localised disease, BT was used more often at the expense of EBRT while for locally advanced disease the utilisation rate of EBRT increased. In the multivariate analysis, regional differences in the utilisation rate of EBRT persisted with odds ratios ranging from 0.7 to 0.9 compared to the reference region. Moreover, low rates of EBRT were associated with high BT rates. The regional differences could not be explained by differences in risk profiles. Conclusions: The utilisation rate of EBRT remained stable with limited variation between regions while BT was used increasingly with clear regional differences. To cope with this and in view of the increasing incidence of prostate cancer, adequate resources have to be planned for the optimal care of these patients. Gepubliceerd: Radiother Oncol. 2011;99(2):207-13 Impact factor: 4.337
4. An increased utilisation rate and better compliance to guidelines for primary radiotherapy for breast cancer from 1997 till 2008: A population-based study in The Netherlands H Struikmansa, MJ Aartsb, JJ Jobsenc, CC Koningd, JW Merkuse, ML Lybeertf, J Immerzeelg, PM Poortmansh, L Veerbeeki, MW Louwmanb, JW Coeberghb, j a Radiotherapy Centre West, Medical Centre Haaglanden, The Hague b Department of Research, Comprehensive Cancer Centre South, Eindhoven c Department of Radiation Oncology, Medisch Spectrum Twente, Enschede d Department of Radiation Oncology, University of Amsterdam, Amsterda e Department of Surgery, Haga Hospital, The Hague f Department of Radiation Oncology, Catharina Hospital, Eindhoven g Radiation Oncology Institute Stedendriehoek en Omstreken, Deventer h Department of Radiation Oncology, Institute Verbeeten, Tilburg i Department of Research, Comprehensive Cancer Centre West, Leiden j Department of Public Health, Erasmus MC Rotterdam Only scarce data are available on the utilisation rate of primary radiotherapy (RT) for patients with breast cancer. In this study, we compared the use of primary RT for patients with stages I-III breast cancer in 4 of the 9 Dutch Comprehensive Cancer Centres, focussing specifically on time trends as well as age effects. From the population-based cancer registries, we selected all females diagnosed with breast cancer between 1997 and 2008 (N=65,966, about 50% of all Dutch breast cancer patients in this period). We observed an overall increase in the use of primary RT for
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breast cancer patients ranging from 55-61% in 1997 to 58-68% in 2008. This can be explained by a higher rate of breast-conserving surgery (BCS), which was followed by RT in 87-99% of cases, and a reduced rate of total mastectomy (TM) which was followed by RT in 26-47% of cases. Increasing age was associated with a reduced use of RT, especially for those above 75. Finally, we observed a decrease in time of observed regional variances in the use of RT after BCS as well as after TM (for stage III disease). These findings can be attributed to the development and implementation of the Dutch nationwide guidelines for treatment of breast cancer. Gepubliceerd: Radiother Oncol. 2011;100:320-5 Impact factor: 4.337
5. Fifteen-Year Radiotherapy Outcomes of the Randomized PORTEC-1 Trial for Endometrial Carcinoma CL Creutzberg*, RA Nout*, ML Lybeert†, CC Wárlám-Rodenhuis‡, JJ Jobsen§, JW Mens¶, LC Lutgens**, E Pras††, LV van de Poll-Franse‡‡, WL van Putten||, PORTEC study group * Department of Clinical Oncology, Leiden UMC, Leiden † Department of Radiotherapy, Catharina Hospital Eindhoven, Eindhoven ‡ Department of Radiation Oncology, UMC, Utrecht § Department of Radiotherapy, Medisch Spectrum Twente, Enschede ¶ Department of Radiation Oncology, ErasmusMC-Daniel den Hoed Cancer Center, Rotterdam ** MAASTRO clinic, Maastricht †† Department of Radiotherapy, UMC Groningen, Groningen ‡‡ Comprehensive Cancer Centre South, Eindhoven and Center of Research on Psychology in Somatic Diseases, Tilburg University || Department of Biostatistics, ErasmusMC-Daniel den Hoed Cancer Center, Rotterdam Purpose: To evaluate the very long-term results of the randomized Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial for patients with Stage I endometrial carcinoma (EC), focusing on the role of prognostic factors for treatment selection and the long-term risk of second cancers. Patients and methods: The PORTEC trial (1990-1997) included 714 patients with Stage IC Grade 1-2 or Stage IB Grade 2-3 EC. After surgery, patients were randomly allocated to external-beam pelvic radiotherapy (EBRT) or no additional treatment (NAT). Analysis was by intention to treat. Results: 426 patients were alive at the date of analysis. The median follow-up time was 13.3 years. The 15-year actuarial locoregional recurrence (LRR) rates were 6% for EBRT vs. 15.5% for NAT (p < 0.0001). The 15-year overall survival was 52% vs. 60% (p = 0.14), and the failure-free survival was 50% vs. 54% (p = 0.94). For patients with high-intermediate risk criteria, the 15-year overall survival was 41% vs. 48% (p = 0.51), and the 15-year EC-related death was 14% vs. 13%. Most LRR in the NAT group were vaginal recurrences (11.0% of 15.5%). The 15-year rates of distant metastases were 9% vs. 7% (p = 0.25). Second primary cancers had been diagnosed over 15 years in 19% of all patients, 22% vs. 16% for EBRT vs. NAT (p =
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0.10), with observed vs. expected ratios of 1.6 (EBRT) and 1.2 (NAT) compared with a matched population (p = NS). Multivariate analysis confirmed the prognostic significance of Grade 3 for LRR (hazard ratio [HR] 3.4, p = 0.0003) and for EC death (HR 7.3, p < 0.0001), of age >60 (HR 3.9, p = 0.002 for LRR and 2.7, p = 0.01 for EC death) and myometrial invasion >50% (HR 1.9, p = 0.03 and HR 1.9, p = 0.02). Conclusions: The 15-year outcomes of PORTEC-1 confirm the relevance of HIR criteria for treatment selection, and a trend for long-term risk of second cancers. EBRT should be avoided in patients with low- and intermediate-risk EC. Gepubliceerd: Int J Radiat Oncol Biol Phys. 2011;81(4):e631-8 Impact factor: 4.503
Totale impact factor: 36.539 Gemiddelde impact factor: 7.308 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 4.392 Gemiddelde impact factor: 4.392
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Reumatologie 1. Implementation of a treat to target strategy in very early rheumatoid arthritis: Results of the DREAM remission induction cohort M Vermeer1,2, HH Kuper2, M Hoekstra3, CJ Haagsma4, MD Posthumus5, HL Brus6, PL van Riel7, MA van de Laar1,2 1 Institute for Behavioral Research, University of Twente, Enschede 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede 3 Department of Rheumatology, Isala Klinieken, Zwolle 4 Department of Rheumatology, Ziekenhuisgroep Twente, Almelo 5 Department of Rheumatology and Clinical Immunology, UMC Groningen, Groningen 6 Department of Rheumatology, TweeSteden Ziekenhuis, Tilburg 7 Department of Rheumatology, Radboud University Nijmegen MC, Nijmegen Objective: Clinical remission is the ultimate therapeutic goal in rheumatoid arthritis (RA). Although clinical trials have proven this to be a realistic goal, the concept of targeting at remission has not been implemented yet. The objective was to develop, implement and evaluate a treat to target strategy aiming at remission in very early RA in daily clinical practice. Methods: 534 patients with a clinical diagnosis of very early RA were included in the DREAM remission induction cohort. Treatment adjustments were based on the DAS28, aiming at a DAS28 < 2.6 (methotrexate, followed by addition of sulfasalazine, exchange of sulfasalazine by biologics in case of persistent disease activity). Primary outcome was the disease activity after six and twelve months of follow-up: i.e. according to the DAS28, EULAR response criteria, and modified ACR remission criteria. Secondary outcomes were time to first DAS28 remission and radiological outcome. Results: Six and twelve months follow-up data were available in 491 and 389 patients, respectively. At six months, 47.0% of patients achieved DAS28 remission, 57.6% had a good EULAR response, and 32.0% satisfied the ACR remission criteria. At twelve months, 58.1% of patients achieved DAS28 remission, 67.9% had a good EULAR response, and 46.4% achieved ACR remission. Median (IQR) time to first remission was 25.3 (13.0-52.0) weeks. The majority of patients did not have clinically relevant radiological progression after one year. Conclusions: The successful implementation of this treat to target strategy aiming at remission demonstrated that remission is a realistic goal in daily clinical practice. Gepubliceerd: Arthritis Rheum. 2011;63(10):2865-72 Impact factor: 8.435
2. Skin autofluorescence, as marker of accumulation of advanced glycation endproducts and of cumulative metabolic stress, is not increased in patients with systemic sclerosis Hettema ME1,5, Bootsma H1, Graaff R2, de Vries R3, Kallenberg CG1, Smit AJ4
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1
Division of Rheumatology and Clinical Immunology, Department of Internal Medicine, UMC Groningen, University of Groningen, Groningen 2 Department of Biomedical Engineering, UMC Groningen, University of Groningen, Groningen 3 Division of Endocrinology, Department of Internal Medicine, UMC Groningen, University of Groningen, Groningen 4 Division of Vascular Medicine, Department of Internal Medicine, UMC Groningen, University of Groningen, Groningen 5 Department of Rheumatology, Medisch Spectrum Twente, Enschede Objective. To investigate whether advanced glycation endproducts (AGEs) in the skin are increased in patients with systemic sclerosis (SSc) and are related to the presence of disease-related and traditional cardiovascular risk factors. Methods. Skin autofluorescence, as a measure for the accumulation of AGEs, was assessed by measuring UV-A light excitation-emission matrices (AF-EEMS) in 41 SSc patients and 41 age- and sex-matched controls. Traditional cardiovascular risk factors and disease-related risk factors were recorded. Results. Skin AF-EEMS did not differ between SSc patients and controls (1.68 ± 0.58Ԝa.u. versus 1.63 ± 0.41Ԝa.u., P = 0.684). Skin AF-EEMS in SSc patients was associated with levels of CRP (r = 0.44, P = 0.004), Medsger's severity scale (r = 0.45, P = 0.006), and use of agents intervening in the renin-angiotensin system (r = 0.33, P = 0.027). When analysing SSc patients and controls together, in multivariate analysis, only age and use of agents intervening in the renin-angiotensin system were independently associated with AF-EEMS. Conclusion. These data demonstrate that skin AGEs are not increased in SSc patients. Gepubliceerd: Int J Rheumatol. 2011 (2011), Article ID 417813 Impact factor: 0
3. Validating the 28-Tender Joint Count Using Item Response Theory Siemons L1, Ten Klooster PM1, Taal E1, Kuper IH1,2, van Riel PL3, van de Laar MA1,2, Glas CA4 1 Arthritis Center Twente, Department of Psychology, Health and Technology; University of Twente 2 Department of Rheumatology, Medisch Spectrum Twente; Enschede 3 Department of Rheumatology, UMC St. Radboud, Nijmegen 4 Department of Research Methodology, Measurement and Data Analysis, University of Twente Objective: To examine the construct validity of the 28-tender joint count (TJC-28) using item response theory (IRT)-based methods. Methods: A total of 457 patients with early stage rheumatoid arthritis (RA) were included. Internal construct validity of the TJC-28 was evaluated by determining whether the TJC-28 fit a 2-measure logistic IRT model. As well, we tested whether the discrimination and difficulty parameters of the joints properly reflected the known left-right symmetry of joint involvement. External validity was evaluated by
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correlations with other established measures of disease activity, including pain, disability, general health, erythrocyte sedimentation rate (ESR), and the 28-swollen joint count. Results: The TJC-28 showed a good fit with the 2-parameter logistic model, with no relevant differential item functioning across sex, age, and time and with excellent reliability. The 28 joints covered a reasonable range of disease activity, even though they were mainly targeted at patients with moderate or high disease activity levels. The joint parameters reflected the left-right symmetry of joint involvement for all pairs of joints except one. All disease activity measures, except ESR, were significantly correlated with the TJC-28. Most correlations were of the expected magnitude. Conclusion: The TJC-28 showed good internal and acceptable external construct validity for patients with early-stage RA. The IRT analyses did point to some potential limitations of the instrument, a major problem being its limited measurement range. Future research should examine whether instrument modifications might lead to a more robust assessment of disease activity in patients with RA Gepubliceerd: J Rheumatol. 2011;38(12):2557-64 Impact factor: 3.551
4. Long-term effectiveness and safety of TNF-blocking agents in daily clinical practice: results from the Dutch Rheumatoid Arthritis Monitoring register Kievit W1, Fransen J1, Adang EM2, den Broeder AA3, Bernelot Moens HJ4, Visser H5, van de Laar MA6, van Riel PL1 1 Department of Rheumatic Diseases, 2 Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Centre, 3 Rheumatology, Sint Maartenskliniek, Nijmegen, 4 Rheumatology, Ziekenhuis Groep Twente, Hengelo, 5 Rheumatology, Rijnstate Hospital, Arnhem 6 Arthritis Centre Twente, Medisch Spectrum Twente and University Twente, Enschede Objectives. Experience with anti-TNF agents for a decade can be used to research the safety and effectiveness of anti-TNF agents in the long term. The objective of this article is to describe drug survival, disease activity, daily functioning, quality of life and adverse events of TNF-blocking agents in daily clinical practice after 5 years of follow-up. Methods. Data from the Dutch Rheumatoid Arthritis Monitoring (DREAM) register of 1560 RA patients were used for analyses (5-year follow-up, nԜ=Ԝ174). Drug survival and time to first serious infection or malignancy were analysed by Kaplan-Meier analysis. Several outcome measures at several follow-up moments were analysed per intention to treat and per protocol. Results. The 5-year drug survival of the first anti-TNF was 45%, and 60% for total use of TNF-blocking agents. Baseline 28-joint DAS (DAS-28) was 5.1 (s.d. 1.3). After 5 years, the mean DAS-28 was 3.2 (s.d. 1.3) in all patients who had started with TNF-blocking agents and 2.9 (s.d. 1.1) in patients who were still on TNFblocking agents. In the latter group, the HAQ score was 0.88 (s.d. 0.7) and the EuroQol five dimensions (EQ-5D) utility score was 0.7 (s.d. 0.2). Incidence rates of
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serious infections and malignancies were 2.9 and 0.6 per 100 patient-years, respectively. Conclusion. Five-year follow-up of RA patients treated with TNF-blocking agents showed a 60% drug survival accompanied by sustained low disease activity, normalized function and quality of life similar to that in the general population. The benefit to risk ratio for long-term TNF-blocking therapy remains favourable. Gepubliceerd: Rheumatology (Oxford). 2011;50(1):196-203 Impact factor: 4.171
5. Efficacy of serology driven "test and treat strategy" for eradication of H. pylori in patients with rheumatic disease in the Netherlands de Leest HT1, Steen KS1, Lems WF1, van de Laar MA4, Huisman AM5, Kadir SW6, Houben HH7, Kostense PJ3, Kuipers EJ8, Dijkmans BA1, Debets-Ossenkopp YJ2 1 Departments of Rheumatology, VU UMC, Amsterdam, 2 Department of Clinical Microbiology and Infection Control, VU UMC Amsterdam 3 Department of Clinical Epidemiology and Biostatistics, VU UMC Amsterdam 4 Department of Rheumatology and Clinical Immunology, Medisch Spectrum Twente Hospital and University of Twente, Enschede 5 Department of Rheumatology, UMC Utrecht, Utrecht 6 Department of Rheumatology, Rijnstate Hospital, Arnhem 7 Department of Rheumatology, Atrium Medical Center, Heerlen 8 Department of Gastroenterology and Hepatology, Erasmus MC UMC, Rotterdam The treatment of choice of H. pylori infections is a 7-day triple-therapy with a proton pump inhibitor (PPI) plus amoxicillin and either clarithromycin or metronidazole, depending on local antibiotic resistance rates. The data on efficacy of eradication therapy in a group of rheumatology patients on long-term NSAID therapy are reported here. This study was part of a nationwide, multicenter RCT that took place in 2000-2002 in the Netherlands. Patients who tested positive for H. pylori IgG antibodies were included and randomly assigned to either eradication PPI-triple therapy or placebo. After completion, follow-up at 3 months was done by endoscopy and biopsies were sent for culture and histology. In the eradication group 13% (20/152, 95% CI 9-20%) and in the placebo group 79% (123/155, 95% CI 72-85%) of the patients were H. pylori positive by histology or culture. H. pylori was successfully eradicated in 91% of the patients who were fully compliant to therapy, compared to 50% of those who were not (difference of 41%; 95% CI 18-63%). Resistance percentages found in isolates of the placebo group were: 4% to clarithromycin, 19% to metronidazole, 1% to amoxicillin and 2% to tetracycline. Gepubliceerd: Eur J Clin Microbiol Infect Dis. 2011;30(7):903-8 Impact factor: 2.631
6. Foot and ankle joint kinematics in rheumatoid arthritis cannot only be explained by alteration in walking speed
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R Dubbeldama, AV Nenea, JH Buurkea, CG Groothuis-Oudshoorna, H Baanbc, KW Drossaers-Bakkercd, MA van de Laarcd, H Hermensae a Roessingh Research and Development, Enschede b Department of Rheumatology, Ziekenhuis Groep Twente, Almelo c Faculty of Behavioural Sciences, University of Twente, Enschede d Department of Rheumatology, Medisch Spectrum Twente, Enschede e Biomedical Signals and Systems, University of Twente, Faculty of Electrical Engineering, Mathematics and Computer Science, Enschede Rheumatoid arthritis (RA) manifests itself in the foot and ankle of RA patients. The foot and ankle joint kinematics of these patients differ from that of healthy subjects. However, the factors that lead to these differences are not yet fully understood. The aim of this study was to analyse the effect of walking speed and the disease process on foot and ankle joint kinematics of RA subjects. Gait recordings of 23 RA and 14 age-matched healthy subjects were performed and their foot and ankle joint kinematics were analysed during the stance phase of the gait cycle. Stance phase characteristics of the group of RA subjects and of the group of healthy subjects were compared. The healthy subjects walked at 100% (Vc), 75% (V75) and 50% (V50) of their comfortable walking speed. In a multi-level linear model significant differences between the two groups due to the factors walking speed and the disease process were analysed. The ankle dorsi-flexion, medial arch and hallux abduction motion at single-stance and toe-off were only influenced by the walking speed. The hallux maximum flexion at toe-off and the midfoot supination at single-stance were influenced by both the walking speed and the disease process. The hindfoot eversion motion at single-stance was only influenced by the disease process. In conclusion, the reduction of walking speed of RA subjects compared to healthy subjects does not explain all of the observed foot and ankle kinematics differences. Gepubliceerd: Gait Posture. 2011;33(3):390-5 Impact factor: 2.313
7. Magnetic Resonance Imaging of the Rheumatic Foot According to the RAMRIS System Is Reliable Baan H1, Bezooijen R2, Avenarius JK2, Dubbeldam R3, Drossaers-Bakker WK4,5, van de Laar MA4,5 1 Department of Rheumatology, Ziekenhuis Groep Twente, Almelo and Hengelo 2 Department of Radiology, Medisch Spectrum Twente, Enschede 3 Roessingh Research and Development, Enschede 4 The Arthritis Centre Twente, University Twente, Enschede 5 Department of Rheumatology, Medisch Spectrum Twente, Enschede Objective: In rheumatology, magnetic resonance imaging (MRI) is predominantly applied in the assessment and outcome measurement of rheumatoid arthritis (RA) in hands and wrists, leading to the development of the RAMRIS (RA-MRI-Scoring) system. It was initiated by the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT). The RAMRIS system has not been applied widely in the
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measurement of feet. We investigated the interreader and intrareader agreement of the RAMRIS scoring system in the assessment of feet in RA. Methods: Twenty-nine patients with RA who had radiological damage and/or arthritis underwent MRI. Two experienced readers independently read both complete sets. One reader read 6 random sets after the initial session, in order to assess the intrareader agreement. For evaluation of the intrareader and interreader reliability, quadratic-weighted κ scores were calculated per joint and lesion. Results: For the forefeet, interreader scores were excellent, ranging from 0.77 (bone edema) to 0.95 (bone erosion). Hindfoot interreader agreement scores were highest for erosion (0.90) and synovitis global score (0.88), but edema and synovial thickness agreement were also acceptable (0.83 and 0.86). Intrareader scores were on the whole slightly lower, but excellent. Conclusion: Reliability (interreader and intrareader agreement) in the assessment of the rheumatoid foot according to the RAMRIS method is excellent. Gepubliceerd: J Rheumatol. 2011;38(6):1003-8 Impact factor: 3.551
8. Treatment strategies aiming at remission in early rheumatoid arthritis patients: starting with methotrexate monotherapy is cost-effective Schipper LG1, Kievit W1, den Broeder AA2, van de Laar MA3, Adang EM4, Fransen J1, van Riel PL1 1 Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen 2 Department of Rheumatology, Sint Maartenskliniek Nijmegen, Nijmegen 3 Department of Rheumatology, Medisch Spectrum Twente and University Twente, Enschede 4 Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen Objective. To perform a modelling study on the cost-effectiveness of three outcome-directed strategies in early RA patients: Strategy 1: starting MTX monotherapy, followed by the addition of LEF, followed by MTX with addition of antiTNF; Strategy 2: start with MTX and LEF combination followed by MTX with antiTNF; and Strategy 3: immediate start with MTX and anti-TNF. Methods. A validated Markov model was used to evaluate the cost-effectiveness of the three strategies. Effectiveness of the strategies was determined using daily practice data from two cohorts and used as input parameter in the model. Patients treated according to the strategies were matched for baseline 28-joint DAS (DAS28). Using Monte Carlo simulation, expected costs, quality-adjusted life-years (QALYs) and incremental cost per QALY gained for a 5-year time horizon were calculated following both a health-care and a societal perspective. Results. The percentage of patients in remission and number of QALYs were comparable between the three strategies. Starting with a combination (MTX plus LEF or anti-TNF) was more costly than starting with MTX alone. This resulted in an unfavourable incremental cost-effectiveness ratio for starting on anti-TNF vs initially
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MTX: health-care perspective of €138Ԝ028 and from a societal perspective of €136Ԝ150 per QALY gained over 5 years. Conclusion. In this modelling study, starting with MTX or anti-TNF has comparable effectiveness. However, initial anti-TNF was far more expensive than starting with MTX monotherapy. Therefore, based on this study, a treatment strategy starting with MTX monotherapy is favoured over a strategy with MTX and anti-TNF right away in early RA patients. Gepubliceerd: Rheumatology (Oxford). 2011;50(7):1320-30 Impact factor: 4.171
9. The potential risk of infections during (prolonged) rituximab therapy in rheumatoid arthritis Brinkman IH1, van de Laar MA2, Jansen TL3, van Roon EN4,5 1 Department of Clinical Pharmacy & Pharmacology, Medical Centre Leeuwarden, Leeuwarden 2 Department of Rheumatology, Medical Spectrum Twente, Enschede 3 Department of Rheumatology, UMC Nijmegen, Nijmegen 4 Department of Clinical Pharmacy, University Groningen, Groningen 5 Hospital pharmacy, Medical centre Leeuwarden, Leeuwarden Introduction: Biologicals are a fast expanding group of new drugs and rituximab (RTX) is one of them. Long-term efficacy and safety constantly need addressing as little is known about these factors. In rheumatoid arthritis, RTX it is used for active disease that is not responding to other therapies. Since RTX acts by depleting Bcells, concerns regarding the long-term safety of this drug have been raised. Areas covered: This review covers 10 manuscripts on RTX safety in rheumatoid arthritis published between January 2004 and July 2010. Expert opinion: In present literature RTX appears to be safe for up to five courses. In this review, important drawbacks of current research are discussed. Longer follow-up time is needed to make relevant conclusions on RTX safety with regard to infectious complications. Prolonged RTX therapy causes subsequent B-cell depletion. Eventually, plasma cells disappear, causing hypogammaglobulinemias and subsequent problems in immunity. The formation of new plasma cells is halted due to a lack of B-cells. Attention needs to be focused on the status of immunoglobulins and the role this plays in the occurrence of infections. Until a complete, long-term safety profile of RTX is available, it cannot be considered safe with regard to the incidence of infectious complications. Gepubliceerd: Expert Opin Drug Saf. 2011;10(5):715-726 Impact factor: 2.645
10. Comparison of measures of functional disability in patients with gout Ten Klooster PM1, Oude Voshaar MA1, Taal E1, van de Laar MA1,2 1 Institute for Behavioural Research, Faculty of Behavioural Sciences, University of Twente
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Department of Rheumatology, Medisch Spectrum Twente, Enschede
Objective: To compare the measurement properties of the HAQ disability index (HAQ-DI), HAQ-II and short form 36 physical functioning scale (PF-10) in patients with gout. Methods: A cross-sectional sample of 97 patients with gout completed all three measures. Reliability was assessed by examining the internal consistency of the scales. Validity was assessed by testing for expected intercorrelations and associations with other aspects of health status and the ability to discriminate between patients with different levels of general health. Additionally, distributional properties were examined. Results: All three measures demonstrated high reliability (Cronbach's alpha >/= 0.93), strong intercorrelations (r >/= 0.75), and the expected pattern of external correlations. The HAQ-DI and HAQ-II performed somewhat better in discriminating between patients. However, both demonstrated ceiling effects of 34.0 and 25.8%, respectively, compared with only 7.2% of the patients scoring no disability on the PF-10. Conclusions: The HAQ-DI, HAQ-II and PF-10 demonstrated similar and adequate reliability and validity for measuring functional disability in patients with gout. The large ceiling effects of both HAQ versions, however, may point to limited content validity and responsiveness to change. Further research should examine whether current instruments cover all aspects of physical functioning relevant to patients with gout. Gepubliceerd: Rheumatology (Oxford). 2011;50(4):709-13 Impact factor: 4.171
11. Statins inhibit the antirheumatic effects of rituximab in rheumatoid arthritis: results from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry Arts EE1, Jansen TL2, Den Broeder A3, Vonkeman HE4, Dutmer E5, Van de Laar MA4, Van Riel PL1, Fransen J1 1 Department of Rheumatology, Radboud University Nijmegen MC, Nijmegen 2 Department of Rheumatology, Medical Centre Leeuwarden, Leeuwarden 3 Department of Rheumatology, Maartenskliniek 4 Department of Rheumatology, Medisch Spectrum Twente and University of Twente, Enschede 5 Department of Rheumatology, Gelderse Vallei Hospital, Ede Gepubliceerd: Ann Rheum Dis. 2011;70(5):877-8 Impact factor: 9.082
12. Patient preferences for a hospital-based rheumatology Interactive Health Communication Application and factors associated with these preferences van der Vaart R1, Drossaert CH1, Taal E1, van de Laar MA1,2 1 IBR Research Institute for Social Sciences and Technology, Department of Psychology, Health & Technology, University of Twente, enschede
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Department of Rheumatology, Medisch Spectrum Twente, Enschede.
Objectives. To examine current disease-related Internet use and intentions to use various online support services on a hospital-based Interactive Health Communication Application (IHCA) of patients with rheumatic diseases. Furthermore, to examine which variables are associated with the intentions to use different services. Methods. Questionnaires were sent to a random sample of 484 patients of a large hospital's rheumatology clinic: response was 47% (nԜ=Ԝ227). Questions included socio-demographics, health characteristics, health literacy, patients' current diseaserelated Internet use and their intentions to use eight different support services: (i) information about disease and treatment; (ii) information about care and support; (iii) peer communication; (iv) e-consultation; (v) autonomous symptom monitoring; (vi) symptom monitoring with telemonitoring; (vii) self-management support; and (viii) access to their electronic medical records. Results. Although most patients with Internet access had used it in relation to their disease (82%), Internet use was mainly limited to searching information. Many patients (45-68%), however, intended to use seven out of eight possible online services if offered on a hospital-based rheumatology IHCA. An exception was peer communication; only 11% intended to use this service. Of all the services, access to the electronic medical record was mostly preferred, followed by information provision. Demographics, health characteristics and health literacy did not show clear significant relationships with the reported intentions. Conclusion. Results show that patients with rheumatic diseases are interested in online support from the hospital and that they intend to use an IHCA, if it is available. Clear associating variables with reported intentions to use the different services were not found. Gepubliceerd: Rheumatology (Oxford). 2011;50(9):1618-1626 Impact factor: 4.171
13. We should not forget the foot: relations between signs and symptoms, damage, and function in rheumatoid arthritis H Baan1, W Drossaers-Bakker2,3, R Dubbeldam4, MA van de Laar2,3 1 Department of Rheumatology, Ziekenhuis Groep Twente, Almelo & Hengelo 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede 3 Institute for Behavioral Research, University of Twente, Enschede 4 Roessingh Research and Development, Enschede We studied rheumatoid arthritis (RA) patients with foot complaints to address the associations between clinical signs and symptoms, radiographic changes, and function in connection with disease duration. Secondly, we describe the contribution of several foot segments to the clinical presentation and function. In 30 RA patients with complaints of their feet, attributed to either signs of arthritis and/or radiographic damage, we compared radiographic, ultrasound, clinical, and functional parameters of the feet and ankle. Pain and swelling of the ankle were correlated weakly but statistically significantly with limitation and disability (0.273 to 0.293) as measured on
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the 5-Foot Function Index (FFI). The clinical signs of the forefoot joints did not influence any of the functional outcome measures. Radiographic scores for both forefeet (SvdH) and hindfeet (Larsen) were correlated with the total Health Assessment Questionnaire Disability Index (HAQ DI) and the 5-FFI limitation subscale. Pain and disease duration, more than radiographic damage, influence the total HAQ DI significantly. With the progression of time, structural damage and function of the rheumatic foot worsen in RA patients. Pain and swelling of the ankle contribute more to disability than radiographic damage of the foot and ankle. Gepubliceerd: Clin Rheumatol 2011;30(11):1475-9 Impact factor: 1.687
14. Ultrasound findings in rheumatoid wrist arthritis highly correlate with function Baan H1,2, Hoekstra M3, Veehof M2, van de Laar M2,4 1 Department of rheumatology, Ziekenhuis Groep Twente, Almelo & Hengelo 2 Department of rheumatology, University of Twente, Enschede 3 Department of rheumatology, Isala Klinieken, Zwolle 4 Department of rheumatology, Medisch Spectrum Twente, Enschede Purpose: The wrist is almost invariably affected in rheumatoid arthritis (RA) and inflammation of the wrist can lead to impaired function and eventually to severe destruction. Classical signs of inflammation, pain, swelling and heat may often be observed in clinical examination of wrist arthritis and in ultrasound (US) investigation. We described the relation between clinical and ultrasound parameters of wrist arthritis and secondly their relation to function. Patients and methods: In 33 RA patients with wrist arthritis, clinical and US parameters were measured. Function was evaluated with the SODA-S (Sequential Occupational Dexterity Assessment-Short) and the DASH-DLV (Disabilities of the Arm, Shoulder and Hand-Dutch Language Version). Correlation coefficients were calculated and factor analysis was performed to describe the relation between the aforementioned measures. Results: Correlation coefficients between clinical and ultrasound parameters of RA wrist inflammation in this study were fair to moderate. We found a good correlation between ultrasound and observed function. Conclusion: The classical signs of inflammation (pain, swelling, redness, heat and impaired function) seem to reflect different aspects of arthritis. Ultrasound correlates well with function, thus can give paramount information on wrist function, and might therefore be a valuable complementary tool in measuring wrist arthritis in RA. Gepubliceerd: Disabil Rehabil. 2011;33(9):729-33 Impact factor: 1.489
15. Effectiveness of a Third Tumor Necrosis Factor-{alpha}-blocking Agent Compared with Rituximab After Failure of 2 TNF-blocking Agents in Rheumatoid Arthritis
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Blom M1, Kievit W1, Donders AR6, den Broeder AA2, Straten VH2, Kuper I3, Visser H4, Jansen TL1, Brus HL5, Branten AJ4, van de Laar MA3, van Riel PL1 1 Department of Rheumatology, Radboud University Nijmegen MC, Nijmegen; 2 Department of Rheumatology, Sint Maartenskliniek, Nijmegen; 3 Department of Rheumatology, Medisch Spectrum Twente, Enschede; 4 Department of Rheumatology, Rijnstate Hospital, Arnhem; 5 Department of Rheumatology, Twee Steden Hospital, Tilburg; 6 Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen MC, Nijmegen Objective: To compare the effectiveness of a third tumor necrosis factor-α (TNF-α)blocking agent with rituximab after failure of 2 TNF-blocking agents in patients with rheumatoid arthritis (RA) in daily clinical practice. Methods: Patients receiving a third TNF-blocking agent or rituximab after failure of 2 TNF-blocking agents were selected from a Dutch biologic registry. The primary outcome was the results from the Disease Activity Score of 28 joints (DAS28) over the first 12 months after start of the third biologic using mixed-model analyses. Secondary outcomes included the course of the Health Assessment Questionnaire (HAQ) and the separate components of the DAS28 over the first 12 months and the change from baseline in DAS28 and HAQ at 3 and 6 months. Results: The overall course of the DAS28 over the first 12 months was significantly better for rituximab (p = 0.0044), as also observed for the HAQ, although the latter results were not statistically significant (p = 0.0537). The erythrocyte sedimentation rates, C-reactive protein, and swollen joint counts showed a better course for rituximab (p = 0.0008, p = 0.0287, p = 0.0547, respectively), but not the tender joint counts or visual analog scale for general health. DAS28 decreased significantly in both groups at 3 and 6 months (p ≤ 0.024), but the change in HAQ was significant for rituximab only at 3 months (p = 0.009). Conclusion: During the first 12 months of therapy, a larger improvement in disease activity and a trend toward a larger decrease in functional disability was observed in patients receiving rituximab. Switching to a biologic with another mechanism of action might be more effective after failure of 2 TNF-blocking agents in RA. Gepubliceerd: J Rheumatol. 2011;38(11):2355-61 Impact factor: 3.551
16. Patient Perspective Workshop: Moving Towards OMERACT Guidelines for Choosing or Developing Instruments to Measure Patient-Reported Outcomes Kirwan JR1, Fries JF2, Hewlett SE3, Osborne RH4, Newman S5, Ciciriello S6, van de Laar MA7, Dures E8, Minnock P9, Heiberg T10, Sanderson TC3, Flurey CA3, Leong AL11, Montie P12, Richards P1 1 University of Bristol, Academic Rheumatology Unit, Bristol Royal Infirmary 2 Stanford University School of Medicine 3 University of the West of England, Academic Rheumatology Unit, Bristol Royal Infirmary 4 Deakin University, Public Health Innovation 5 University of London, Centre for Behavioural and Social Sciences in Medicine
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Centre for Rheumatic Diseases, The University of Melbourne, Department of Medicine, Royal Melbourne Hospital 7 Arthritis Centre Twente, University Twente and Medisch Spectrum Twente, Enschede 8 University of the West of England, Academic Rheumatology Unit, Bristol Royal Infirmary 9 Rheumatology and Rehabilitation, Our Lady’s Hospice 10 Oslo University Hospital, Lovisenberg Diakonal College 11 Healthy Motivation and Bone and Joint Decade, Santa Barbara 12 Consumer Advisory Board, Arthritis Research Centre The workshop Choosing or Developing Instruments held at the Outcome Measures in Rheumatology (OMERACT) 10 meeting was designed to help participants think about the underlying methods of instrument development. Conference pre-reading material and 3 brief introductory presentations elaborated the issues, and participants broke into discussion groups before reconvening to share insights, engage in a more general discussion of the issues, and vote on recommendations. Tradeoffs between using current imperfect measures and the long and complex process of developing new instruments were considered, together with the need for rigor in patient-reported outcome (PRO) instrument development. The main considerations for PRO instrument development were listed and a research agenda for action produced. As part of the agenda for action, it is recommended that researchers and patient partners work together to tackle these issues, and that OMERACT bring forward proposals for acceptable instrument development protocols that would meet an enhanced "Truth" statement in the OMERACT Filter. Gepubliceerd: J Rheumatol. 2011;38(8):1711-5. Impact factor: 3.551
17. Domains selection for patient-reported outcomes: current activities and options for future methods Tugwell PS1, Petersson IF2, Boers M3, Gossec L4, Kirwan JR5, Rader T6, Sanderson TC7, van de Laar MA8, Ueffing E9, Witter JP10 1 Faculty of Medicine and Institute of Population Health, University of Ottawa 2 Orthopaedics and Rheumatology, Department of Clinical Sciences, Lund University 3 Department of Epidemiology and Biostatistics, VU MC 4 Rheumatology B Department, René Descartes University, Cochin Hospital (AP-HP) 5 Academic Rheumatology Unit, Bristol Royal Infirmary 6 Cochrane Musculoskeletal Group, University of Ottawa 7 Faculty of Life Sciences, University of the West of England 8 Arthritis Centre Twente, Department of Psychology and Communication of Health and Risk, University of Twente, Enschede 9 Campbell and Cochrane Equity Methods Group,University of Ottawa 10 Rheumatic Diseases Clinical Program, Division of Skin and Rheumatic Diseases, NIAMS, NIH, DHHS
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Introduction. Over the years, Outcome Measures in Rheumatology Clinical Trials (OMERACT) has worked toward consensus on core sets for outcome measurement in specific rheumatologic diseases. OMERACT core sets refer to the minimum number of domains and instruments essential to address the desired outcomes in trials. "Domains" are the attributes of an activity or function. This article discusses the need for an open process for selecting domains, existing frameworks for choosing domains, and the importance of describing the methods for selecting domains. Methods: We reviewed the domains selection process of 3 OMERACT groups working on patient-reported outcomes (PRO). We categorized these methods in a hierarchy of comprehensiveness and examined the extent to which they address related issues. Results: There was agreement that a gold standard for domain selection would include 3 important aspects: following a framework, remaining true to the clinical question, and including the clinically relevant outcomes for both benefits and harms. Discussion. OMERACT participants agreed that a guide for the options for developing domains that meet the OMERACT Filter would be useful. More discussion and explanation is needed to outline outcomes related to the patient perspective that are not covered by the current version of the International Classification of Functioning, Disability and Health (ICF) and to explain the usefulness of the population/intervention/comparison/outcome (PICO) structure in domain selection. Future OMERACT work includes addressing these issues and developing a framework based on the ICF to support comprehensive outcome measurements. Gepubliceerd: J Rheumatol. 2011;38(8):1702-10 Impact factor: 3.551
18. Quality of Life: Measuring fatigue in rheumatoid arthritis Nikolaus S1, van de Laar MA1,2 1 Institute for Behavioural Research, Faculty of Behavioural Sciences, University of Twente 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede Gepubliceerd: Nat Rev Rheumatol. 2011;7(10):562-4 Impact factor: 6.448
19. A computer Time Trade-Off: a feasible and reliable alternative for the interview Time Trade-Off in rheumatoid arthritis Buitinga L1, Braakman-Jansen LM1, Taal E1, van de Laar MA1,2 1 Arthritis Center Twente, Department of Psychology, Health and Technology, University of Twente 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede Objectives: The Time Trade-Off (TTO) is an instrument used for valuing healthrelated quality of life. This study evaluated the test-retest reliability of a computer
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TTO in rheumatoid arthritis (RA), and compared the computer with the interview TTO regarding feasibility and agreement. Methods: In study 1 using a cross-over design, thirty patients completed both TTOs. In study 2, twenty-nine other patients completed the computer TTO twice to examine test-retest reliability. Feasibility was measured by assessing actual and perceived time duration and general experience of the patient. Agreement between utility scores of both TTOs was measured by Bland-Altman analysis. Results: Both TTOs were feasible. The computer TTO showed high test-retest reliability (ICC = 0.88). Bland-Altman analysis showed a small mean difference (0.06, SD = 0.14, effect size=0.30) between both TTOs. Limits of agreement were wide (-0.22 to 0.34). Differences between interview and computer TTO utilities did not vary over the range of scores. Conclusions: The computer TTO was feasible and reliable, but did not provide similar results as the interview TTO. However, no systematic biases in the differences were found over the range of scores. Gepubliceerd: Clin Exp Rheumatol. 2011;29(5):783-9 Impact factor: 2.358
20. A discrete event modelling framework for simulation of long-term outcomes of sequential treatment strategies for ankylosing spondylitis A Tran-Duy1, A Boonen2, MA van de Laar3, AC Franke4, JL Severens5 1 Department of Health Services Research, Maastricht University and Caphri Research Institute, Maastricht 2 Department of Internal Medicine, Division of Rheumatology, Maastricht UMC and Caphri Research Institute, Maastricht 3 Department of Rheumatology and Clinical Immunology, medisch Spectrum Twente, Enschede 4 Department of Plant Production Systems, Wageningen University, Wageningen 5 Institute of Health Policy and Management, Erasmus University Rotterdam, Rotterdam Objective To develop a modelling framework which can simulate long-term quality of life, societal costs and cost-effectiveness as affected by sequential drug treatment strategies for ankylosing spondylitis (AS). Methods Discrete event simulation paradigm was selected for model development. Drug efficacy was modelled as changes in disease activity (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)) and functional status (Bath Ankylosing Spondylitis Functional Index (BASFI)), which were linked to costs and health utility using statistical models fitted based on an observational AS cohort. Published clinical data were used to estimate drug efficacy and time to events. Two strategies were compared: (1) five available non-steroidal anti-inflammatory drugs (strategy 1) and (2) same as strategy 1 plus two tumour necrosis factor α inhibitors (strategy 2). 13 000 patients were followed up individually until death. For probability sensitivity analysis, Monte Carlo simulations were performed with 1000 sets of parameters sampled from the appropriate probability distributions.
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Results The models successfully generated valid data on treatments, BASDAI, BASFI, utility, quality-adjusted life years (QALYs) and costs at time points with intervals of 1–3 months during the simulation length of 70 years. Incremental cost per QALY gained in strategy 2 compared with strategy 1 was €35 186. At a willingness-to-pay threshold of €80 000, it was 99.9% certain that strategy 2 was cost-effective. Conclusions The modelling framework provides great flexibility to implement complex algorithms representing treatment selection, disease progression and changes in costs and utilities over time of patients with AS. Results obtained from the simulation are plausible. Gebpubliceerd: Ann Rheum Dis 2011;70(12):2111-8 Impact factor: 9.082
21. Measurement properties of physical function scales validated for use in patients with rheumatoid arthritis: A systematic review of the literature Oude Voshaar MA1, Ten Klooster PM1, Taal E1, van de Laar MA1,2 1 Arthritis Center Twente, University of Twente, Department of Psychology, Health and Technology, Enschede 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede Background: The aim of this study was to systematically review the content validity and measurement properties of all physical function (PF) scales which are currently validated for use with patients with rheumatoid arthritis (RA) Methods: Systematic literature searches were performed in the Scopus and PubMed databases to identify articles on the development or psychometric evaluation of PF scales for patients with RA. The content validity of included scales was evaluated by linking their items to the International Classification of Functioning Disability and Health (ICF). Furthermore, available evidence of the reliability, validity, responsiveness, and interpretability of the included scales was rated according to published quality criteria. Results: The search identified 26 questionnaires with PF scales. Ten questionnaires were rated to have adequate content validity. Construct validity, internal consistency, test-retest reliability and responsiveness was rated favourably for respectively 15, 11, 5, and 6 of the investigated scales. Information about the absolute measurement error and minimal important change scores were rarely reported. Conclusion: Based on this literature review, the disease-specific HAQ and the generic SF-36 can currently be most confidently recommended to measure PF in RA for most research purposes. The HAQ, however, was frequently associated with considerable ceiling effects while the SF-36 has limited content coverage. Alternative scales that might be better suited for specific research purposes are identified along with future directions for research. Gepubliceerd: Health Qual Life Outcomes. 2011;9(1):99 Impact factor: 1.860
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22. Does the eHealth Literacy Scale (eHEALS) Measure What it Intends to Measure? Validation of a Dutch Version of the eHEALS in Two Adult Populations van der Vaart R1, van Deursen AJ1, Drossaert CH1, Taal E1, van Dijk JA1, van de Laar MA1,2 1 Department of Psychology, Health and Technology, University of Twente, Enschede 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede Background: The Internet increases the availability of health information, which consequently expands the amount of skills that health care consumers must have to obtain and evaluate health information. Norman and Skinner in 2006 developed an 8-item self-report eHealth literacy scale to measure these skills: the eHealth Literacy Scale (eHEALS). This instrument has been available only in English and there are no data on its validity. Objectives: The objective of our study was to assess the internal consistency and the construct and predictive validity of a Dutch translation of the eHEALS in two populations. Methods: We examined the translated scale in a sample of patients with rheumatic diseases (n = 189; study 1) and in a stratified sample of the Dutch population (n = 88; study 2). We determined Cronbach alpha coefficients and analyzed the principal components. Convergent validity was determined by studying correlations with age, education, and current (health-related) Internet use. Furthermore, in study 2 we assessed the predictive validity of the instrument by comparing scores on the eHEALS with an actual performance test. Results: The internal consistency of the scale was sufficient: alpha = .93 in study 1 and alpha = .92 in study 2. In both studies the 8 items loaded on 1 single component (respectively 67% and 63% of variance). Correlations between eHEALS and age and education were not found. Significant, though weak, correlations were found between the eHEALS and quantity of Internet use (r = .24, P = .001 and r = .24, P = .02, respectively). Contrary to expectations, correlations between the eHEALS and successfully completed tasks on a performance test were weak and nonsignificant: r = .18 (P = .09). The t tests showed no significant differences in scores on the eHEALS between participants who scored below and above median scores of the performance test. Conclusions: The eHEALS was assessed as unidimensional in a principal component analysis and the internal consistency of the scale was high, which makes the reliability adequate. However, findings suggest that the validity of the eHEALS instrument requires further study, since the relationship with Internet use was weak and expected relationships with age, education, and actual performance were not significant. Further research to develop a self-report instrument with high correlations with people's actual eHealth literacy skills is warranted. Gepubliceerd: J Med Internet Res. 2011;13(4):e86 Impact factor: 4.981
23. Multidisciplinaire richtlijn ‘Verantwoord gebruik van biologicals’
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Bijlsma JW1, Hagemeijer JW2, Bijl M3, Jansen TL4, van de Laar MA5, Landewé RB6, Nurmohamed MT7 1 Afdeling Reumatologie & Klinische Immunologie, UMC Utrecht, Utrecht 2 Orde van Medisch Specialisten, afd. Ondersteuning Professionele Kwaliteit, Utrecht 3 Afdeling Reumatologie, UMC Groningen, Groningen 4 Afdeling Reumatologie, UMC Nijmegen St Radboud, Nijmegen 5 Afdeling Reumatologie, Medisch Spectrum Twente, Enschede 6 Afdeling Reumatologie, Academisch Ziekenhuis Maastricht, Maastricht 7 Afdeling Reumatologie, Jan van Breemen Instituut | Reade, Amsterdam A multidisciplinary working group has developed a practice guideline containing various recommendations on the responsible and efficient use of biologicals.- These biologicals include both soluble immune-receptor proteins and monoclonal antibodies that are aimed at immune mediators, receptors or cells. They are produced by biotechnology.- Biologicals are used to treat patients with immunemediated inflammatory disorders (IMIDs) such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis, juvenile idiopathic arthritis (JIA), psoriasis, ulcerative colitis, Crohn's disease, uveitis and sarcoidosis.- This article summarises the most important recommendations contained in the practice guideline. The practice guideline is intended for members of the medical profession in addition to patients, who are considering, or are already, using biologicals. Gepubliceerd: Ned Tijdschr Geneeskd. 2011;155(30-31):A3114 Impact factor: 0
24. Determinants of Engagement in Face-to-Face and Online Patient Support Groups CF Van Uden-Kraan1, CH Drossaert2, E Taal2, WM Smit3, HJ Bernelot Moens4, MA Van de Laar2,5 1 Department of Otolaryngology / Head and Neck Surgery, VU MC, Amsterdam 2 Institute for Behavioral Research, Department of Psychology, Health, Technology, University of Twente, Enschede 3 Department of Internal Medicine, Medisch Spectrum Twente, Enschede 4 Department of Rheumalotogy, Ziekenhuisgroep Twente, Hengelo 5 Department of Rheumatology, Medisch Spectrum Twente, Enschede Background: Although peer-to-peer contact might empower patients in various ways, studies show that only a few patients actually engage in support groups. Objective: The objective of our study was to explore factors that facilitate or impede engagement in face-to-face and online peer support, using the theory of planned behavior (TPB). Methods: A questionnaire was completed by 679 patients being treated for arthritis, breast cancer, or fibromyalgia at two Dutch regional hospitals. Results: Our results showed that only a minority of the patients engaged in organized forms of peer support. In total 10% (65/679) of the respondents had engaged in face-to-face meetings for patients in the past year. Only 4% (30/679) of
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the respondents had contact with peers via the Internet in the past year. Patients were more positive about face-to-face peer support than about online peer support (P < .001). In accordance with the TPB, having a more positive attitude (P < .01) and feeling more supported by people in the social environment (P < .001) increased the intention to participate in both kinds of peer support. In addition, perceived behavioral control (P = .01) influenced the intention to participate in online peer support. Nevertheless, the intention to engage in face-to-face and online peer support was only modestly predicted by the TPB variables (R(2) = .33 for face-toface contact and R(2) = .26 for online contact). Conclusion: Although Health 2.0 Internet technology has significantly increased opportunities for having contact with fellow patients, only a minority seem to be interested in organized forms of peer contact (either online or face-to-face). Patients seem somewhat more positive about face-to-face contact than about online contact. Gepubliceerd: J Med Internet Res. 2011;13(4):e106 Impact factor: 4.663
25. Acute left ventricular failure in a patient with hydroxychloroquine-induced cardiomyopathy Hartmann M1, Meek IL2, van Houwelingen GK1, Lambregts HP1, Toes GJ3, van der Wal AC4, von Birgelen C1,5 1 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede 3 Department of Pathology, Medisch Spectrum Twente, Enschede 4 Department of Pathology, AMC, University Amsterdam, Amsterdam 5 University of Twente, MIRA Institute for Biomedical Technology and Technical Medicine, Enschede We present the case of a 75-year-old woman with a medical history of rheumatoid arthritis treated with hydroxychloroquine, who was admitted with acute left-sided heart failure due to a hydroxychloroquine-induced cardiomyopathy as supported by endomyocardial biopsy. Gepubliceerd: Neth Heart J. 2011;19(11):482-5 Impact factor: 1.447
Totale impact factor: 93.560 Gemiddelde impact factor: 3.742 Aantal artikelen 1e, 2e of laatste auteur: 15 Totale impact factor: 47.906 Gemiddelde impact factor: 3.194
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Revalidatiegeneeskunde 1. Differences in the Relationship Between Psychosocial Distress and Self-Reported Disability in Patients with Chronic Low Back Pain in Six Pain Rehabilitation Centers in the Netherlands Preuper HR *,†; Boonstra AM ‡; Wever D §; Heuts PH ¶; Dekker JH **; Smeets RJ ††; Brouwer S †,‡‡; Geertzen JH *,†; Reneman MF *,† * Center for Rehabilitation, UMC Groningen, University of Groningen, Groningen † Graduate School for Health Research SHARE, UMC Groningen, University of Groningen, Groningen ‡ Center for Rehabilitation, ‘Revalidatie Friesland', Beetsterzwaag § Center for Rehabilitation, ‘het Roessingh', and Department of Rehabilitation Medicine, Medisch Spectrum Twente, Enschede ¶ Center for Rehabilitation, ‘Leijpark', Tilburg ** Center for Rehabilitation, ‘Heliomare', Wijk aan Zee †† Department of Rehabilitation Medicine, Caphri, Maastricht, University and Rehabilitation Foundation Limburg, Hoensbroek ‡‡ Department of Health Sciences, UMC Groningen, University of Groningen, Groningen Study design: A cross sectional multicenter study in six outpatient Rehabilitation Centers (RCs) in the Netherlands. Objective: This study aims to confirm or refute the finding that a strong relationship exists between psychosocial distress and self-reported disability in patients with nonspecific chronic low back pain (CLBP) by analyzing this relationship in patients with CLBP admitted for treatment in six RCs. Summary of background data: A strong relationship between psychosocial distress and self-reported disability in patients with CLBP is suggested. However, in former research weak relationships were found in two of the RCs participating in this study. Methods: Total study sample consisted of 293 patients (30-66 per RC) with CLBP, admitted for outpatient multidisciplinary rehabilitation in one of the six participating RCs. Psychosocial distress was measured with the Symptom Checklist-90-Revised (SCL-90-R), self-reported disability with the Roland Morris Disability Questionnaire (RMDQ). Pearson correlation coefficients between psychosocial distress and selfreported disability were calculated. Multivariate regression analysis was performed to analyze the relationship between SCL-90-R and VAS pain (independent variables) and RMDQ (dependent variable) for the total group and for each RC separately. A multivariate regression analysis was performed to analyze the relationship between all baseline characteristics and RMDQ in the total group. Results: Correlation coefficient between the SCL-90-R and RMDQ was r = 0.38 for the total sample, indicating a significant (P < 0.05), but weak relationship. For the six individual RCs, correlation coefficients ranged between r = 0.22 and 0.67 (three of the six correlation coefficients were significant). The explained variance (r) of the regression models (SCL-90 and pain intensity as predictors of RMDQ) was 29% for the total sample, and varied between the RCs from 17% to 52%. Results of the multivariate regression analysis of all baseline characteristics of the total group
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revealed that the model explained 36% of the total variance observed in RMDQ score. Overall, the contributions of psychosocial distress to the models were smaller and more variable compared with pain intensity. Conclusion: The overall relationship between psychosocial distress and self reported disability was weak, and differences between RCs were considerable. This indicates that the relationship between psychosocial distress and disability in patients with CLBP is not uniform. Gepubliceerd: Spine 2011;36(12):969-76 Impact factor: 2.510
2. Circle drawing as evaluative movement task in stroke rehabilitation: an explorative study Krabben T1, Molier BI1, Houwink A1, Rietman JS1,2, Buurke JH1, Prange GB1 1 Roessingh Research & Development, Enschede 2 Department of Rehabilitative Medicine, Medisch Spectrum Twente, Enschede The majority of stroke survivors have to cope with deficits in arm function, which is often measured with subjective clinical scales. The objective of this study is to examine whether circle drawing metrics are suitable objective outcome measures for measuring upper extremity function of stroke survivors. Gepubliceerd: J Neuroeng Rehabil. 2011;8:15 Impact factor: 2.638
3. Adaptation Strategies of the Lower Extremities of Patients With a Transtibial or Transfemoral Amputation During Level Walking: A Systematic Review Prinsen EC1,2, Nederhand MJ1,3, Rietman JS1,3,4,5 1 Roessingh Research and Development, Enschede 2 School of Clinical Health Sciences, Master of Physiotherapy Science, Utrecht University, Utrecht 3 Rehabilitation Center Het Roessingh, Enschede 4 Faculty of Engineering Technology, Laboratory of Biomechanical Engineering, University of Twente, Enschede 5 Department of Rehabilitative Medicine, Medisch Spectrum Twente, Enschede Objective: To describe adaptation strategies in terms of joint power or work in the amputated and intact leg of patients with a transtibial (TT) or transfemoral (TF) amputation. Data sources: MEDLINE, CINAHL, Physiotherapy Evidence Database, Embase, and the Cochrane Register of Controlled Trials were searched. Studies were collected up to November 1, 2010. Reference lists were additionally scrutinized. Study selection: Studies were included when they presented joint power or work and compared (1) the amputated and intact legs, (2) the amputated leg and a referent leg, or (3) the intact leg and a referent leg. Eligibility was independently assessed by 2 reviewers. A total of 13 articles were identified.
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Data extraction: Data extraction was performed using standardized forms of the Cochrane Collaboration. Methodologic quality was independently assessed using the Downs and Black instrument by 2 reviewers. The possibility of data pooling was examined. Significant differences found in studies that could not be pooled are also presented. Data synthesis: Significant results (P<.05). For work TT, for the concentric work total stance phase knee, the amputated was less than the intact/referent side, and the referent was less than the intact side. For the eccentric knee extensor (K1) phase, the amputated was less than the intact side, and the intact was greater than the referent side. For the concentric knee extensor (K2) phase, the amputated/referent was less than the intact side. For the concentric work total stance phase hip, the amputated/intact was greater than the referent side. For the concentric hip extensor (H1) phase, the amputated/intact was greater than the referent side. For power TT, for the peak power generation stance phase knee, the amputated was less than the referent side. For peak power generation swing phase knee, the amputated was less than the referent side. For the eccentric knee flexor (K4) phase, the amputated was less than the intact side. For the eccentric hip flexor (H2) phase, the amputated was greater than the intact side. For work TF, for the concentric plantar flexor (A2) phase, the referent was less than the intact side. For the H1 phase, the referent was less than the intact side. For the H2 phase, the amputated was greater than the intact/referent side, and the referent was greater than the intact side. For power TF, for the K2 phase, the referent was less than the intact side. Sensitivity analysis did not alter the conclusions. Conclusions: Adaptations were seen in the amputated and intact legs. TT and TF use remarkably similar adaptation strategies at the level of the hip to compensate for the loss of plantar flexion power and facilitate forward progression. At the knee level, adaptations differed between TT and TF. Gepubliceerd: Arch Phys Med Rehabil. 2011;92(8):1311-1325 Impact factor: 2.254
4. Myoelectric forearm prostheses: state of the art from a user-centered perspective. Peerdeman B1,2, Boere D2,3,4, Witteveen H2,5, Huis in’t Veld R2,3, Hermens H2,3,5, Stramigioli S1,2, Rietman H2,3,4, Veltink P2,5, Misra S2,3,4 1 Control Engineering, University of Twente, Enschede 2 MIRA-Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 3 Roessingh Research and Development, Enschede 4 Biomechanical Engineering, University of Twente, Enschede 5 Biomedical Signals and Systems, University of Twente, Enschede User acceptance of myoelectric forearm prostheses is currently low. Awkward control, lack of feedback, and difficult training are cited as primary reasons. Recently, researchers have focused on exploiting the new possibilities offered by advancements in prosthetic technology. Alternatively, researchers could focus on prosthesis acceptance by developing functional requirements based on activities users are likely to perform. In this article, we describe the process of determining
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such requirements and then the application of these requirements to evaluating the state of the art in myoelectric forearm prosthesis research. As part of a needs assessment, a workshop was organized involving clinicians (representing end users), academics, and engineers. The resulting needs included an increased number of functions, lower reaction and execution times, and intuitiveness of both control and feedback systems. Reviewing the state of the art of research in the main prosthetic subsystems (electromyographic [EMG] sensing, control, and feedback) showed that modern research prototypes only partly fulfill the requirements. We found that focus should be on validating EMG-sensing results with patients, improving simultaneous control of wrist movements and grasps, deriving optimal parameters for force and position feedback, and taking into account the psychophysical aspects of feedback, such as intensity perception and spatial acuity. Gepubliceerd: J Rehabil Res Dev. 2011;48(6):719-37 Impact factor: 1.708
Totale impact factor: 9.110 Gemiddelde impact factor: 2.278 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 2.254 Gemiddelde impact factor: 2.254
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Spoedeisende Hulp 1. Acute pain at the emergency department: better treatment required Gaakeer MI1, Veugelers R2, Houser CM3, Berben SA4, Bierens JJ5 1 Afdeling Spoedeisende Geneeskunde, Medisch Spectrum Twente, Enschede 2 Afdeling Spoedeisende Geneeskunde, Albert Schweitzer Ziekenhuis, Dordrecht 3 Afdeling Spoedeisende Geneeskunde, AMC Amsterdam, Amsterdam 4 Afdeling Spoedeisende Geneeskunde, UMC St Radboud, Nijmegen 5 Afdeling Spoedeisende Geneeskunde, Maxima Medisch Centrum, Veldhoven Acute pain is common among patients at the emergency department and is still not being treated adequately.- Repeated measurement and documentation of pain is essential for adequate pain treatment.- The patient determines how much analgesia is needed.- Pharmacological pain relief should not be delayed during the diagnostic process, not even in cases of abdominal pain.- Opioids play a central role in the treatment of acute pain. Opiophobia is not justified.- Adequate pain relief started at the emergency department must be continued throughout both hospital admission and discharge to home. Gepubliceerd: Ned Tijdschr Geneeskd. 2011;155(2):A2241 Impact factor: 0
Totale impact factor: 0 Gemiddelde impact factor: 0 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 0 Gemiddelde impact factor: 0
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Tandheelkunde 1. In Vitro Oral Biofilm Formation on Triclosan-Coated Sutures in the Absence and Presence of Additional Antiplaque Treatment Venema S1,2, Abbas F1, van de Belt-Gritter B3, van der Mei HC3, Busscher HJ3, van Hoogmoed CG3 1 Academic Centre for Oral Health, Department of Periodontology, UMC Groningen and University of Groningen, Groningen 2 Department of Dentistry, Medisch Spectrum Twente, Enschede 3 Department of Biomedical Engineering, UMC Groningen and University of Groningen, Groningen Purpose: This study evaluated the in vitro plaque inhibitory effect of triclosan-coated polyglactin 910 sutures in the absence and presence of an additional antiplaque agent commonly used after oral surgery. Materials and methods: Triclosan-coated sutures were incubated for 4 hours in freshly collected human saliva and, when appropriate, subsequently treated with an antiplaque rinse containing chlorhexidine-cetyl pyridinium as active components. Sutures without a triclosan-coating served as a control. Results: Triclosan-coated sutures harbored similar amounts of plaque as did uncoated sutures. Exposure to the antiplaque rinse caused significant decreases in viable organisms for uncoated and triclosan-coated sutures. However, after application of the antiplaque rinse, more micro-organisms were found on triclosancoated than on uncoated sutures. Conclusion: Sutures coated with triclosan do not provide a sufficient antimicrobial effect to prevent in vitro colonization by oral bacteria, whereas use in combination with a chlorhexidine-cetyl pyridinium-containing antiplaque rinse appears to be counterproductive. Gepubliceerd: J Oral Maxillofac Surg. 2011;69(4):980-5 Impact factor: 1.500
Totale impact factor: 1.500 Gemiddelde impact factor: 1.500 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 1.500 Gemiddelde impact factor: 1.500
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Thoraxchirurgie 1. Risk factors of delirium after cardiac surgery A systematic review Koster S1, Hensens AG1, Schuurmans MJ2,3, van der Palen J4,5 1 Department of Cardio Thoracic Surgery, Medisch Spectrum Twente, Enschede 2 University of Professional Education Utrecht, Department of Healthcare, Utrecht 3 University Medical Center Utrecht, Nursing Science, Utrecht 4 Department of Epidemiology, Medisch Spectrum Twente, Enschede 5 Department of Research Methodology, Measurement and Data Analysis, Faculty of Behavioral Sciences, University of Twente, Enschede Background: Delirium or acute confusion is a temporary mental disorder that occurs frequently among hospitalized elderly patients, but also in younger patients a delirium can develop. Patients who undergo cardiac surgery have an increased risk of developing delirium that is associated with many negative consequences. Therefore, prevention of delirium is essential. Despite the high incidence of delirium, a paucity of data on risk factors for delirium exists. AIM: The aim of this study was to summarize the available information concerning these risk factors. Methods: A literature research was performed using the PubMed, Cinahl, and Cochrane Library databases and was limited to the last 10 years. Results: Our review revealed 27 risk factors; 12 predisposing and 15 precipitating factors for delirium after cardiac surgery. The most established predisposing risk factors were atrial fibrillation, cognitive impairment, depression, history of stroke, older age, and peripheral vascular disease. The most established precipitating risk factor was a red blood cell transfusion. An abnormal albumin level was reported as the most established precipitating risk factor among blood values tested. A low cardiac output and the use of an Intra Aortic Balloon Pump or inotropic medication seem to be the most relevant risk factors associated with a postoperative delirium. Conclusion: A multifactorial risk model should be applied to identify patients at an increased risk of developing delirium following elective cardiac surgery. In these patients, if possible, preventative interventions can be taken and early recognition of delirium can be realized. This could potentially decrease the incidence of delirium and negative consequences caused by a postoperative delirium. Gepubliceerd: Eur J Cardiovasc Nurs. 2011;10:197–204 Impact factor: 1.348
2. PulseCath(R) as a right ventricular assist device Arrigoni SC1, Kuijpers M2, Mecozzi G1, Mariani MA2 1 Department of Thoracic Surgery, Thoraxcenter, Medisch Spectrum Twente, Enschede 2 Department of Thoracic Surgery, Thoraxcenter, UMC Groningen, Groningen The PulseCath® is a pulsatile pump that offers a circulatory support up to 3 l/min. The PulseCath® is indicated for patients who require a higher degree of support than that offered by the intra-aortic balloon pump. We describe the first two cases of
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the use of the PulseCath® as a temporary support for the right ventricle after insertion through the pulmonary artery trunk. Two patients developed an acute right ventricular failure with severe hemodynamic instability after cardiac surgery. The PulseCath® was chosen to assist the right ventricle. An immediate improvement of hemodynamic parameters was observed in both cases. In the first patient an irreversible metabolic unbalance, already present prior to PulseCath® insertion, led to multi-organ failure and eventually to death. In the second case the early utilization of PulseCath® led to a complete recovery of the right ventricle and the patient was discharged in good clinical condition. Besides the technical feasibility, this report would suggest that a correct timing is the key to success for the PulseCath® as a right ventricular assist device. Gepubliceerd: Interact Cardiovasc Thorac Surg. 2011;12(6):891-4 Impact factor: 0.943
3. Rare prosthesis failure after aortic valve replacement with a Freedom Solo Giordano V1, Hermens JA2, Wajon EM2, Grandjean JG1 1 Department of Cardio-Thoracic Surgery, Thoraxcentrum Twente, Enschede 2 Department of Cardiology, Thoraxcentrum Twente, Enschede We report an unusual case of a 78-year-old man readmitted to our Cardiac Surgery Division due to a severe regurgitation of the stentless bioprosthesis Freedom Solo implanted, strictly following the manufacturer's recommendations, approximately six months before for aortic stenosis of native valve. Although different possible etiologies may be determined for the subacute aortic regurgitation of a bioprosthesis, a partial adhesion of a leaflet to the aortic wall represents an exceptional event. The device was explanted, a new different bioprosthesis model was implanted and the patient recovered uneventfully. But no evidence of aortic or leaflet vegetations suggesting for abscess was found, neither atheromatous or calcified plaques, nor signs of inflammation of the aortic wall were detected. In the end, it is believed that the cause of the cuspal adhesion to the aortic sinus was primary tissue failure. Gepubliceerd: Interact Cardiovasc Thorac Surg. 2011;12(2):273-5 Impact factor: 0.943
4. Endoscopic vein harvesting: just a promised land? Mariani MA1, Arrigoni SC1, Grandjean JG2 1 Thoraxcentrum, UMC Groningen, Groningen 2 Thoraxcentrum, Medisch Spectrum Twente, Enschede Gepubliceerd: Innovations (Phila). 2011;6(4):207-8 Impact factor: 0
5. Obstructive intramyocardial haematoma after percutaneous coronary intervention 211
Slootweg AP1, Louwerenburg JW1, Mecozzi G2, Wagenaar LJ1, Verhorst PM1 1 Department of Cardiology, Medisch Spectrum Twente, Enschede 2 Department of Cardiothoracic Surgery, Medisch Spectrum Twente, Enschede Gepubliceerd: Neth Heart J. 2011;DOI 10.1007/s12471-011-0163-8 Impact factor: 1.447
Totale impact factor: 4.681 Gemiddelde impact factor: 0.936 Aantal artikelen 1e, 2e of laatste auteur: 4 Totale impact factor: 3.234 Gemiddelde impact factor: 0.809
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