Wetenschappelijk onderzoek in Medisch Spectrum Twente 2010
Inhoudsopgave Inhoudsopgave ........................................................................................................... 2 Voorwoord .................................................................................................................. 3 Overzicht publicaties en de Top 3 .............................................................................. 5 Overzicht aantal publicaties per vakgroep: ................................................................ 6 Promoties in MST in 2010 .......................................................................................... 7 Kindergeneeskunde ............................................................................................... 7 Klinische farmacie ................................................................................................ 15 Longgeneeskunde ................................................................................................ 22 Radiologie ............................................................................................................ 30 Radiotherapie ....................................................................................................... 33 PubMed publicaties per vakgroep ............................................................................ 35 Anesthesiologie .................................................................................................... 35 Cardiologie ........................................................................................................... 37 Gastroenterologie ................................................................................................. 47 Gynaecologie ....................................................................................................... 50 Heelkunde ............................................................................................................ 68 Intensive Care ...................................................................................................... 94 Interne Geneeskunde ........................................................................................... 96 Kaakchirurgie ..................................................................................................... 108 Kindergeneeskunde ........................................................................................... 109 Klinische Chemie................................................................................................ 112 Klinische Farmacie ............................................................................................. 121 Klinische Fysica .................................................................................................. 124 KNO .................................................................................................................... 125 Laboratorium voor Microbiologie ........................................................................ 126 Longziekten ........................................................................................................ 130 Medical School Twente ...................................................................................... 134 Neurologie .......................................................................................................... 145 Nucleaire Geneeskunde ..................................................................................... 162 Orthopedie .......................................................................................................... 163 Pathologie .......................................................................................................... 165 Plastische Chirurgie ........................................................................................... 169 Radiologie .......................................................................................................... 170 Radiotherapie ..................................................................................................... 178 Reumatologie ..................................................................................................... 182 Revalidatiegeneeskunde .................................................................................... 196 Spoedeisende Hulp ............................................................................................ 200 Thoraxchirurgie .................................................................................................. 202
2
Voorwoord Voor u ligt de tweede editie van het jaarlijkse overzicht van het wetenschappelijk overzicht wat door medewerkers van Medisch Spectrum Twente in 2010 is gepubliceerd. Zoals u zult zien is het aantal publicaties dit jaar fors hoger dan vorig jaar. Vermeldenswaard is dat er dit jaar ook 4 artikelen gepubliceerd zijn in the New England Journal of Medicine, 1 in Nature Genetics, 1 in Nature Medicine en 3 in de Lancet, waarvan één als eerste auteur(!), bijna het hoogst haalbare in medisch wetenschappelijk onderzoek! 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 2010 zijn. De zogenaamde “Epub Ahead of Print” artikelen komen in de volgende uitgave. Daarnaast worden ook peer-reviewed artikelen uit Nederlandstalige tijdschriften opgenomen. In 2010 zijn 177 unieke publicaties verschenen in peer-reviewed tijdschriften. Dit is een record want nog nooit publiceerden we er zo veel. In 2007 werden er 89 gepubliceerd, in 2008 74 en in 2009 109. De gemiddelde impact score van alle artikelen is 5,12. Dat is bijna twee punten hoger dan in 2009 en een erg hoog gemiddelde, zeker ook gezien het feit dat 24 publicaties in tijdschriften zijn verschenen die geen impact factor hebben, zoals het Nederlands Tijdschrift voor Geneeskunde. Daarnaast is een aantal tijdschriften nog te nieuw om al een impact factor te hebben verworven. Er waren in 2010 5 promoties in MST. Een van de redenen voor de spectaculaire stijging van de aantallen 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 inmiddels toestemming gegeven om een extra epidemioloog aan te trekken. 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 2010 naast die van 2009 weergegeven.
3
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]
4
Overzicht publicaties en de Top 3 Aantal unieke publicaties Gemiddelde impact factor score
2009: 109 2009: 3,16
2010: 177 2010: 5,12
2009
2010
Top 3: Aantal publicaties: 1
Heelkunde
16
1
Heelkunde
38
2
Cardiologie
14
2
Neurologie
23
2
Reumatologie
14
3
Reumatologie
17
Top 3: Totale impact factor score: 1
Interne Geneeskunde
59,40
1
Heelkunde
213.88
2
Reumatologie
54,18
2
Gynaecologie
140.37
3
Neurologie
41,32
3
Interne Geneeskunde
110.09
10,90
1
Radiotherapie
10.39
Top 3: Gemiddelde impact factor score: 1
Radiotherapie
2
Interne Geneeskunde
4,95
2
Gynaecologie
9.36
3
Gastroenterologie
4,92
3
Interne Geneeskunde
8. 47
Top 3: Aantal publicaties als 1e, 2e of laatste auteur: 1
Cardiologie
12
1
Heelkunde
20
2
Heelkunde
7
2
Cardiologie
12
3
Interne Geneeskunde
5
2
Reumatologie
12
3
Longziekten
5
3
Medical School Twente
5
Top 3: Totale impact factor score als 1e, 2e of laatste auteur: 1
Longziekten
27,84
1
Radiologie
54.23
2
Medical School Twente
20,46
2
Klinische Chemie
44.48
3
Neurologie
16,32
3
Neurologie
43.23
Top 3: Gemiddelde impact factor score als 1e, 2e of laatste auteur: 1
Neurologie
8,16
1
Interne Geneeskunde
2
Longziekten
5,57
2
Klinische Farmacie
6.59
3
Gastroenterologie
4,72
3
Klinische Chemie
5.56
5
17.79
Overzicht aantal publicaties per vakgroep: 2009
2010
1
2
14
14
Gastroenterologie
4
5
Gynaecologie
2
15
16
38
1
2
12
13
Kaakchirurgie
0
1
Kindergeneeskunde
5
4
Klinische Chemie
4
14
Klinische Farmacie
4
3
Anesthesiologie Cardiologie
Heelkunde Intensive Care Interne Geneeskunde
Klinische Fysica
0
1
KNO
0
1
Laboratorium voor Microbiologie
4
6
Longziekten
8
5
12
13
3
0
11
23
Nucleaire Geneeskunde
1
1
Orthopedie
1
2
Pathologie
1
6
Plastische Chirurgie
4
1
Psychiatrie
1
0
Radiologie
2
11
Radiotherapie
2
4
Reumatologie
14
17
Revalidatiegeneeskunde
2
5
Spoedeisende Hulp
0
2
Thoraxchirurgie
4
2
Medical School Twente Neurochirurgie Neurologie
6
Promoties in MST in 2010 Kindergeneeskunde Complex pathways to atopy development Genes and environment 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 28 april 2010 om 14.45 uur door Renske Willemijn Bernadette Bottema geboren op 10 november 1976 te Utrecht
Promotores: Prof. dr. D.S. Postma Prof. dr. C.P. Van Schayck Co-promotor: Dr. M. Kerkhof Dr. G.H. Koppelman Beoordelingscommissie: Prof. dr. W.M. van Aalderen Prof. dr. B.N. Lambrecht Prof. dr. F.D. Martinez
7
Samenvatting Onderzoek naar de genetische achtergrond van allergie en astma richt zich op de samenwerking tussen genen onderling en tussen genen en omgevingsfactoren. Bestudering van de genetische achtergrond toonde aan dat varianten in meerdere genen samen een verhoogd risico kunnen geven op ontwikkeling van astma en allergie via zogenaamde gen-gen interactie. Betrekking van omgevingsfactoren in het genetische onderzoek heeft aangetoond dat omgevingsfactoren -zoals blootstelling aan microbiële bestanddelen- gunstig dan wel ongunstig kunnen zijn, afhankelijk van de genetische achtergrond van een individu. Astma is een ziekte die zich vaak op de kinderleeftijd presenteert, maar sommige mensen ontwikkelen astma pas op latere leeftijd. Allergie en astma komen op jonge leeftijd meer bij jongens voor, maar rond de puberteit slaat dit om naar een hogere prevalentie bij vrouwen. Het is niet goed bekend of en zo ja, welke genen daarbij een rol spelen. In dit proefschrift wordt de invloed onderzocht van genen en hun varianten in combinatie met omgevingsfactoren en de invloed van leeftijd en geslacht op de ontwikkeling van allergie en astma. Inleiding Allergie en astma zijn complexe genetische aandoeningen. Dat betekent dat allergie en astma veroorzaakt worden door een samenwerking van meerdere genen in combinatie met blootstelling aan verschillende omgevingsfactoren. Kennis over de achtergrond van genen en omgevingsfactoren die bijdragen aan de ontwikkeling van allergie en astma is onontbeerlijk voor betere preventie, therapie en genezing van deze aandoeningen. Toenemende kennis over de complexiteit van het menselijke immuunsysteem heeft tot inzicht geleid dat genvarianten niet altijd onafhankelijk van elkaar opereren, maar door andere genen en omgevingsfactoren sterk beïnvloed kunnen worden. Verbetering van laboratoriumtechnieken en de verzameling van klinische gegevens in grote longitudinale cohort studies, maken het nu mogelijk om in prospectieve studies meerdere genen samen met blootstelling aan omgevingsfactoren te bestuderen. Dit geeft een betere benadering van de realiteit dan onderzoek naar alleen de genetische bijdrage, of alleen de bijdrage van de omgevingsfactoren. De bestudering van meerdere genen is belangrijk voor het ontdekken van zogenaamde gen-gen interactie. Bij de bestudering van de invloed van omgevingsfactoren op de wisselwerking tussen genen en daarmee de ontwikkeling van ziekte spreekt men van gen-omgevingsinteractie. Dit proefschrift vertrekt vanuit de laatste ontwikkelingen van het genetisch onderzoek met betrekking tot gen-gen interactie en gen-omgevingsinteractie in de ontwikkeling van astma en allergie. Er wordt een nieuwe methode gebruikt om gengen interactie te bestuderen, genaamd Multifactor Dimensionality Reduction (MDR). Omdat genvarianten meestal niet frequent voorkomen in de bevolking en astma, als voorbeeld, ook maar bij 5% van de bevolking zijn er grote aantallen deelnemers nodig om een relatie tussen genvarianten en ziekte te vinden. Daarom werd geëvalueerd of het mogelijk is om de gegevens uit meerdere cohort studies samen te voegen (Hoofdstuk 4). Dit blijkt mogelijk te zijn onder bepaalde randvoorwaarden. Op basis hiervan konden wij ons onderzoek in samengevoegde cohorten doen. De studies in dit proefschrift zijn gebaseerd op multidisciplinaire nationale en internationale samenwerking. De deelnemers aan de onderzoeken bestaan uit: 188 gezinnen geselecteerd via een patiënt met allergische rhinitis; 407 gezinnen
8
geselecteerd via een patiënt met astma; 118 astmapatiënten en 102 onafhankelijke gezonde controle personen; en ten slotte de Allergenic studie, met 3062 kinderen uit de 3 prospectieve geboortecohorten PIAMA, PREVASC en KOALA. Definities Het woord ‘atopie’ is afkomstig uit de Griekse Oudheid en betekent ‘misplaatst’. De World Allergy Organization definieerde ‘atopie’ als “een persoonlijke en/of familiaire aanleg, meestal tijdens de kinderleeftijd of adolescentie, om gesensibiliseerd te raken en Immunoglobine E (IgE) antilichamen aan te maken naar aanleiding van expositie aan alledaagse allergenen”. De term atopie wordt bij voorkeur gereserveerd voor de mensen die een erfelijke aanleg hebben om gesensibiliseerd te raken voor allergenen(1). De productie van IgE kan een allergische ontstekingsreactie veroorzaken in verschillende organen en leiden tot IgE gemedieerde ziekte zoals allergisch astma, allergische rhinitis (hooikoorts) en atopische dermatitis (eczeem). De term allergie duidt op de buitensporige reactie van het immuunsysteem na expositie aan allergenen en kan zowel door antilichamen als door immuuncellen geïnduceerd worden(1). Allergie is in de meerderheid van de gevallen IgE gemedieerd en de termen atopie en allergie worden frequent door elkaar gebruikt. Allergenen zijn antigenen, vaak eiwitten, afkomstig van bijvoorbeeld (huis)dieren, voeding, insecten, planten en schimmels, die allergie veroorzaken door productie van en reactie met specifieke IgE antilichamen te induceren(1). Onderzoek naar multipele genen en gen-gen interactie De laatste jaren is duidelijk geworden dat de genetische achtergrond van allergie en astma niet door een klein aantal genen verklaard kan worden, zoals dat het geval is bij bijvoorbeeld cystische fibrose. Er is gebleken dat een groot aantal genen dat betrokken is bij een diversiteit aan biologische mechanismen, bijdraagt aan de ontwikkeling van allergische aandoeningen. Theoretisch is het aantal genen dat betrokken is bij een complex genetische ziekte omgekeerd evenredig aan het individuele effect van een gen, dus hoe meer genen betrokken zijn bij astma, hoe kleiner het effect van deze genen zal zijn (Figuur 1). Er zijn meer dan 200 kandidaatgenen voor ziektekenmerken van allergie en astma beschreven in humane associatiestudies en muizenmodellen, slechts een aantal genen zijn echter systematisch bestudeerd en gerepliceerd in twee of meer onafhankelijke populaties(2). Verder werden 9 astma genen gevonden via een andere methode, “positional cloning” (3-10). De eerste genoom brede associatie studies (GWAS), een nieuwe ontwikkeling in de astma genetica waarbij polymorfismen verspreid over het hele genoom gescreend worden voor associatie met ziektekenmerken van astma, hebben recentelijk een aantal nieuwe genen toegevoegd aan de lijst met kandidaatgenen voor allergie en astma, zoals ORMDL3, IL13RA1, CHI3L1, en PDE4D(11-14). De kandidaat-genen welke tot op heden bestudeerd werden geven slechts een beperkt risico op het ontstaan van astma dat tussen de 1.5 en 3 keer hoger is dan in de algemene populatie. Dus de situatie bij astma correspondeert waarschijnlijk met de rechterkant van de curve in figuur 1, met veel genen die een kleine bijdrage leveren. Er zijn duidelijke aanwijzingen dat genen of genproducten elkaar beïnvloeden bij het ontstaan van ziekte. De eerste beschrijving van gen-gen interactie bij astma toonde aan dat twee varianten in de genen interleukine (IL)4
9
receptor alfa(RA) en IL13 samen geassocieerd zij met een sterker verhoogd risico op astma dan de varianten afzonderlijk van elkaar(15). De interleukines IL4 en IL13 zijn cytokines die allergische ontsteking bevorderen door een signaal te geven aan B-lymfocyten. Dat signaal veroorzaakt een verandering in B-lymfocyten, waardoor de lymfocyten IgE gaan produceren, een cruciale gebeurtenis in de ontwikkeling van allergische ziekten. De genen IL4RA en IL13 zijn onderdeel van een groep genen die tot nu toe het beste bestudeerd werd voor zijn rol in de ontwikkeling van astma en allergie: de IL4 / IL13 signaal route. Figuur 1. Hoe meer genen betrokken zijn bij de expressie van een complex genetische ziekte, hoe kleiner hun individuele aandeel aan het ziekteproces is.
De IL4 / IL13 signaal route De genen betrokken bij de IL4 / IL13 signaal route, IL13, IL4, IL4RA, IL13RA en Signal Transducer and Activator of Transcription (STAT)6 vertonen in afzonderlijke studies associatie met de ontwikkeling van astma en / of met de hoogte van serum IgE, een eiwit in het bloed dat bij allergie verhoogd aanwezig is. Er volgden verschillende studies die aanwijzingen voor genetische interactie tussen twee varianten in genen uit deze signaalroute beschreven. Kabesch en medewerkers beschreven de eerste studie naar genetische interactie in de ontwikkeling van astma en allergie waar bij meer dan twee genen betrokken zijn. In een groep van ruim 1100 kinderen werd aangetoond dat combinaties van risicovarianten in de genen IL13, IL4, IL4RA en STAT6 geassocieerd zijn met een sterk verhoogd risico op een verhoogd serum IgE en ontwikkeling van astma. Het risico op een verhoogd serum IgE was 10.8 keer hoger ten opzichte van het maximale individuele effect van een
10
genvariant, het risico op astma was 16.8 keer hoger(16). De studies naar de rol van gen-gen interactie bij de ontwikkeling van astma en allergie geven aanwijzingen dat individuen die in hun genetische materiaal meerdere risicovarianten in verschillende genen hebben, een sterk verhoogd risico lopen op de ontwikkeling van astma. Toekomstige grote cohortonderzoeken gevolgd door functionele studies zullen verder uit moeten wijzen welke combinaties van welke varianten belangrijk zijn en hoe ze elkaar beïnvloeden. In dit proefschrift werd de gen-gen interactie tussen IL13 en IL4RA bevestigd in volwassenen met en zonder astma (Hoofdstuk 3). Genetische variatie in IL13 bleek tevens van belang voor het ontwikkelen van rhinitis, ook als deze mensen geen astma hebben. Dit suggereert dat IL13 astma en rhinitis een in ieder geval gedeeltelijke gezamenlijke pathogenese hebben. De signaalroute van co-stimulatie tussen T-lymfocyten en antigeenproducerende cellen Co-stimulatie kan gezien worden als een soort communicatie tussen verscheidene witte bloedcellen, zoals T-lymfocyten en antigeenproducerende cellen. Deze communicatie vindt plaats via co-stimulatoire receptoren, eiwitten die zich op de celwand bevinden, en kan een cel activeren maar ook deactiveren. In kandidaat-gen studies zijn meerdere co-stimulatoire genen zoals CTLA4 en CD28 van belang gebleken bij de ontwikkeling van allergie en astma. In hoofdstuk 6 wordt de invloed van 24 co-stimulatoire genen bestudeerd op de ontwikkeling van IgE met hulp van de nieuwe methode MDR. Daarbij werden verschillende aanwijzingen voor gen-gen interactie gevonden, zowel eerder beschreven interacties waarbij 2 genen betrokken zijn, als interacties die wel 3 of 4 genen betroffen. Zo werd aangetoond dat gen-gen interactie regelmatig voorkomt als een groep genen bestudeerd wordt die samen een signaalroute vormen. Tevens werd gezien dat het belang van sommige genen alleen duidelijk wordt, als ze in combinatie met andere genen bestudeerd worden. Dit pleit voor verdere ontwikkeling van genetische onderzoeksmethoden waarin multipele genen gezamenlijk bestudeerd worden. De signaalroute van regulatoire T-cellen Het belang van regulatoire T-cellen voor de ontwikkeling van allergie en astma is in de laatste jaren pas duidelijk geworden uit genetisch onderzoek, proefdieronderzoek en humane studies. Deze specifieke T-cellen zijn in staat om een immunologische reactie, zoals een allergische reactie, te onderdrukken. Verkeerde ontwikkeling en / of functie van deze T-cellen kan grote gevolgen hebben. In hoofdstuk 7 worden met hulp van MDR 11 genen uit de signaalroute van de regulatoire T-cellen bestudeerd met betrekking tot de ontwikkeling van IgE, specifiek IgE en astma. Meerdere gengen interacties worden aangetoond. Zo werd gevonden dat de genen FOXP3 en TGFBR2 samen het risico op specifiek IgE voor melk op 1-2 jarige leeftijd, maar ook astma op 6-8 jarige leeftijd beïnvloeden. De gevonden interacties geven aanleiding voor de vorming van nieuwe hypothesen. Associatie van gencombinaties TGFB1, TGFBR2, IL6 en IL6R passen in de nieuwe bevindingen dat allergie ontwikkeling afhankelijk is van een onbalans tussen regulatoire T-cellen en Th 17-cellen, waarvan de functie tot op heden nog niet volledig opgehelderd is. Onderzoek naar omgevingsfactoren en gen-omgevingsinteractie
11
In epidemiologische studies is aangetoond dat naast de sterke invloed van genetische achtergrond, ook omgevingsfactoren zoals (tabaks-)rook, luchtvervuiling, allergeenexpositie, blootstelling aan microbiële producten en infecties een belangrijke invloed hebben op de ontwikkeling van astma en allergie(17;18). Zo werd bijvoorbeeld het voorkomen van astma bestudeerd in eeneiige tweelingen die in een gezamenlijke en in een aparte omgeving opgroeiden. Naast een gemeenschappelijke genetische basis van deze kinderen, bleken ook omgevingsfactoren die verschilden tussen kinderen die apart opgroeiden bij te dragen aan het voorkomen van astma(19). In een andere studie werd aangetoond dat de genetische achtergrond en omgevingsfactoren elkaar ook kunnen beïnvloeden. Kinderen van atopische ouders hadden in deze studie een verhoogd risico op astma bij blootstelling aan tabaksrook, terwijl blootstelling aan tabaksrook het voorkomen van astma niet beïnvloedde bij kinderen van niet atopische ouders(20). Sterke aanwijzing voor het effect van blootstelling aan tabaksrook in interactie met variatie in het genetische materiaal werd ook gevonden in een linkage studie voor astma(21). Op chromosoom 5 werd in 200 Nederlandse families sterke aanwijzing gevonden voor linkage met astma en bronchiale hyperreactiviteit, een karakteristiek kenmerk van astma. Dit verband werd alleen gelegd bij families die blootgesteld waren aan passief roken. Bij bestudering van kandidaat-genen in combinatie met expositie aan tabaksrook (IL13(22), IL4RA(23), β2-adrenerge receptor(24), Glutathion S-Transferase M1(25) en Glutathion S-Transferase T1(26)) worden ook aanwijzingen gevonden dat blootstelling aan rook bij aanwezigheid van varianten in deze genen, de expressie van astma en allergie kan beïnvloeden. Resultaten van deze studies worden voorzichtig geïnterpreteerd en vragen om replicatie alvorens definitieve conclusies te trekken. De associaties zijn steeds gebaseerd op kleine aantallen retrospectieve data en de mogelijkheid bestaat dat vals positieve resultaten optreden bij een grote hoeveelheid statistische toetsen. Gen-omgevingsinteracties in astma en allergie CD14 en LPS Een voorbeeld van gen-omgevingsinteractie in de ontwikkeling van astma en allergie, is de invloed van blootstelling aan lipopolysacchariden (LPS) op de relatie tussen het CD14 genotype en de ontwikkeling van astma en allergie. Dit werd bestudeerd en gerepliceerd in verschillende populaties. LPS is het hoofdbestanddeel van endotoxinen, een product van gram negatieve bacteriën. Bekend is bijvoorbeeld dat het gehalte LPS in stof op boerderijen hoog is. CD14 is onderdeel van het receptorcomplex op monocyten, macrofagen en lymfocyten dat LPS bindt en daarmee de cel stimuleert tot productie van Th 1 cytokines. Aanwezigheid van Th 1 cytokines vermindert de kans op een allergische respons na blootstelling aan allergenen. Tegenstrijdige resultaten van verschillende studies naar de invloed van het CD14 -159 C/T promotor polymorfisme dichtten het C allel in de ene studie een beschermende rol in de ontwikkeling van allergie toe(27;28) terwijl andere studies het bezit van een T allel relateerden aan een verhoogd risico op de ontwikkeling van allergie(29). Het promoter gebied van een gen reguleert de mate van gen-afschrijving. Uit functioneel onderzoek is gebleken dat het hebben van een C allel op plaats -159 in het gen gepaard gaat met afgenomen afschrijving van het gen in vergelijking met het T allel. De tegenstrijdige genetische associatiestudies en de biologische functie van CD14 waren aanleiding tot de bestudering van het CD14159 C/T genotype in interactie met expositie aan LPS. De hypothese was dat LPS
12
expositie in interactie met het CD14 genotype de inflammatoire respons bepaalt en dat het CD14 genotype afhankelijk van de hoogte van LPS expositie, de kans op atopie zou verhogen dan wel verlagen. Verschillende studies leverden bewijs voor deze hypothese(30;31) en beschreven voor mensen met het CD14 -159 TT genotype een verhoogd risico op astma of atopie onder hoge endotoxine expositie en een verlaagd risico op astma of atopie onder lage endotoxine expositie. In de studie van Simpson et al.(32) wordt aangetoond dat de associatie van het CD14 159 CC genotype met de ontwikkeling van sensitisatie afhankelijk is van de hoogte van de expositie aan LPS. Bij toenemende LPS expositie nam bij kinderen met het CC genotype het risico op allergische sensitisatie af. In een omgeving waar de LPS expositie laag is, geeft het C allel dus een verhoogd risico op sensitisatie. Extrapolatie van de resultaten van deze studies suggereert dat afhankelijk van de hoogte van LPS expositie er een tegengesteld effect bestaat op het risico van sensitisatie, afhankelijk van het CD14 genotype (Figuur 2.) CD14 en expositie aan huisdieren en tabaksrook In hoofdstuk 4 werd het gen CD14 onderzocht in relatie met expositie aan huisdieren (kat en hond) en tabaksrook. Er werden gen-omgevingsinteracties aangetoond die in overeenstemming waren met eerdere studies. Verschillende genvarianten in het promotorgebied van CD14 toonden een verlaagd risico op allergische kenmerken, zoals een verhoogd IgE of sensitisatie op de leeftijd 4 en 8 jaar, in kinderen die in het eerste jaar van hun leven blootgesteld werden aan huisdieren, terwijl kinderen met dezelfde genvariant die niet aan huisdieren blootgesteld waren juist een verhoogd risico op allergische kenmerken hadden. De consistentie van de resultaten voor de verschillende cohorten van het Allergenic onderzoek was opmerkelijk en geeft aan dat het hierom een reële bevinding gaat. Een zelfde soort gen-omgevingsinteractie werd gevonden voor de blootstelling aan tabaksrook. De invloed van geslacht en leeftijd in genetisch onderzoek De verschillen in ontwikkeling van astma en allergie tussen jongens en meisjes, mannen en vrouwen worden mogelijk verklaard door de geslachtschromosomen. Mannen hebben een X-chromosoom en een Y-chromosoom, terwijl vrouwen twee X-chromosomen hebben. Daarom werd in hoofdstuk 5 een gen op het Xchromosoom bestudeerd, Forkhead Box-P3 (FOXP3). Er waren inderdaad verschillende resultaten tussen jongens en meisjes. Er zal echter meer onderzoek gedaan moeten worden om dit in een groot aantal mensen te bevestigen en om uit te vinden of het verschil in uitkomsten een gevolg is van technische onderzoeksmethoden, of dat er werkelijk verschillende effecten zijn bij jongens en meisjes. In dit proefschrift werden kinderen en volwassenen van verschillende leeftijden onderzocht. Daarbij werden duidelijke verschillen, maar ook overeenkomsten gezien in resultaten tussen de verschillende leeftijdsgroepen (hoofdstukken 4 t/m 7). Er waren onvoldoende deelnemers die op meerdere leeftijden onderzocht waren en daarom weten we niet zeker waarom de resultaten tussen de leeftijdsgroepen verschillen, komt het verschil inderdaad door de leeftijd, of komt het doordat een andere groep kinderen bestudeerd werd? Onze aanwijzingen dat sommige genen specifiek belangrijk zijn op jonge leeftijd zal bevestigd moeten worden in studies waarin grote groepen kinderen vervolgd
13
worden, of in functionele studies. Nog een aanwijzing voor het belang van leeftijd in genetisch onderzoek is de recente bevinding dat het eerste gepubliceerde gen dat gevonden werd met GWA (ORMDL3) met name van belang is voor ontwikkeling van astma op de kinderleeftijd. Dit onderstreept het belang van verder onderzoek naar dit onderwerp. Figuur 2. Gen-omgevingsinteractie van CD14 -159C/T genotype en expositie aan lipopolysacharide (LPS), gebaseerd op geëxtrapoleerde data van verschillende studies.
Conclusie en vertaling naar de dagelijkse praktijk De significante bijdrage van gen-gen interactie en gen-omgevingsinteractie op de ontwikkeling van astma en allergie is nu in humane studies aangetoond. De huidige opzet van grote longitudinale cohort studies en (internationale) samenwerking tussen verschillende centra maken het bestuderen van meerdere genen in combinatie met meerdere omgevingsblootstellingen mogelijk om met voldoende statistische power de complexe mechanismen die ten grondslag liggen aan astma en allergie te kunnen ontrafelen. Er is nog onvoldoende bekend over astmagenen en vooral over hun samenwerking met elkaar en met omgevingsfactoren om genetische informatie te gebruiken in de klinische setting voor bijvoorbeeld ontwikkeling van genetische testen. De verwachting bestaat dat het onderzoek naar gensystemen in combinatie met de blootstelling aan factoren in de omgeving het in de toekomst mogelijk zal maken kinderen die astma ontwikkelen in een vroeg stadium te identificeren en gerichte preventie en / of vroegtijdige interventies toe te passen.
14
Klinische farmacie Assessment of drug therapy in Parkinson's disease Beoordeling van de behandeling met geneesmiddelen bij de ziekte van Parkinson (met een samenvatting in het Nederlands) 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 op dinsdag 29 juni 2010 des middags te 2.30 uur door Maurits Erwin Leo Arbouw geboren op 24 mei 1974 te ‘s-Gravenhage
Promotoren: Prof.dr. A.C.G. Egberts Prof.dr. H.-J. Guchelaar Prof.dr. C. Neef Co-promotor: Dr. K.L.L. Movig
15
Samenvatting De ziekte van Parkinson Bij de ziekte van Parkinson vindt een afbraakproces (degeneratie) plaats van zenuwcellen in een bepaald gebied in de hersenen: de 'zwarte kernen' (substantia nigra). Door het verdwijnen van zenuwcellen in deze kernen wordt er niet voldoende dopamine aangemaakt. Dopamine is een neurotransmitter, een stof die nodig is om zenuwimpulsen van de ene zenuwcel op de andere over te brengen. Door een tekort aan dopamine gaan de hersenkernen, die betrokken zijn bij het soepel laten verlopen van lichaamsbewegingen, slechter functioneren. De ziekte van Parkinson wordt onder andere gekenmerkt door de volgende bewegingsstoornissen (motorische symptomen): rust tremor (trillen bij rust, eerst aan één hand, arm of been, later aan beide), rigiditeit (stijfheid van de ledematen), bradykinesie (bewegingsarmoede), en posturele instabiliteit (gestoorde, soms voorovergebogen, houding en gestoorde houdingsreflexen). Er wordt nu algemeen aangenomen dat de ziekte van Parkinson een complexe ziekte is met diverse uitingsvormen, waaronder neuropsychiatrische en andere niet-motorische symptomen naast de genoemde motorische symptomen. Naar schatting waren er in 2007 tussen de 33.000 en 61.000 mensen in Nederland die de ziekte van Parkinson hadden. Elk jaar wordt in Nederland bij ongeveer 8.000 mensen de diagnose ziekte van Parkinson gesteld. Leven met de ziekte van Parkinson Patiënten met de ziekte van Parkinson hebben een levensverwachting die maar enkele jaren korter is dan mensen zonder deze ziekte. Echter, de ziekte van Parkinson is een progressieve ziekte. In de meer gevorderde stadia ervaren patiënten zowel motorische als niet-motorische symptomen die zeer lastig te behandelen zijn. Uit een Nederlands onderzoek blijkt dat de ziekte van Parkinson een grote invloed op de kwaliteit van leven heeft: de ziekte van Parkinson (gevorderde stadia) werd als derde gerangschikt na dementie en slokdarmkanker, met een verlies van kwaliteit van leven van 68%. Behandeling van de ziekte van Parkinson De ziekte van Parkinson is niet te genezen en de behandeling is dan ook gericht op het verminderen en verlichten van de klachten en symptomen. De medicamenteuze behandeling van de ziekte van Parkinson bestaat vooral uit levodopa en dopamine agonisten (dopaminerge geneesmiddelen). Deze geneesmiddelen vullen het tekort van dopamine aan of stimuleren de dopamine aangrijpingspunten (receptoren). Naast het beoogde effect kunnen deze geneesmiddelen ook bijwerkingen geven. Een tweetal mogelijke bijwerkingen van dopaminerge geneesmiddelen is in dit proefschrift onderzocht. Variabiliteit van geneesmiddelrespons Het is onbekend waarom sommige patiënten bijwerkingen krijgen en anderen niet, en waarom sommige patiënten veel last hebben van fluctuaties in bewegingssymptomen en anderen minder of niet. Diverse niet-genetische factoren, zoals de ziekteduur of gelijktijdig gebruik van andere geneesmiddelen, zouden hierin een rol kunnen spelen. Ook wordt er aangenomen dat variatie in genen een
16
belangrijke rol speelt in de inter-individuele variabiliteit in de respons op een geneesmiddel. Het betreffen genen die coderen voor enzymen die geneesmiddelen omzetten, voor geneesmiddelenaangrijpingspunten, en voor signaal eiwitten. Farmacogenetica is het onderzoeksgebied dat zich richt op de vraag of, en in welke mate, genetische variatie de respons op geneesmiddelen kan verklaren en voorspellen bij individuele patiënten. Dit proefschrift In dit proefschrift komen diverse aspecten aan de orde die te maken hebben met de behandeling met geneesmiddelen van de ziekte van Parkinson. Het doel van dit proefschrift was om inzicht te krijgen in: - de incidentie (hoe vaak het voorkomt) en determinanten (genetische en nietgenetische) van stoppen van de behandeling met niet-ergoline dopamine agonisten; - het ontstaan van bepaalde complicaties bij patiënten die dopaminerge geneesmiddelen gebruiken; - de resultaten van behandeling van niet-motorische symptomen; - het aandeel van farmacogenetica in het voorspellen en verklaren van variabiliteit van geneesmiddelrespons. Diverse farmaco-epidemiologische principes zijn in dit proefschrift toegepast. In farmaco-epidemiologisch onderzoek staat het bestuderen van effecten en het gebruik van geneesmiddelen in patiëntenpopulaties centraal. Hoofdstuk 1 is een algemene inleiding waar wordt ingegaan op de ziekte van Parkinson en de behandeling ervan. In Hoofdstuk 2 wordt een overzicht gegeven wat de invloed is van genetische variaties op resultaten van behandeling met geneesmiddelen (farmacogenetica). Het is bekend dat er een grote variabiliteit is in respons op de anti-Parkinson geneesmiddelen, zowel ten aanzien van effectiviteit als ten aanzien van toxiciteit/bijwerkingen. Er wordt aangenomen dat genetische variaties in genen belangrijke factoren zijn in de verklaring van deze variabiliteit van geneesmiddelrespons. In de ideale situatie kan kennis over genetische variaties (polymorfismen) helpen om het effect van behandeling met geneesmiddelen te voorspellen. De rol van farmacogenetica in de behandeling van de ziekte van Parkinson is maar beperkt onderzocht. Daarom was het doel om al de beschikbare literatuur in kaart te brengen, en om mogelijk interessante genetische variaties voor de toekomst te beschrijven. Het beperkte aantal onderzoeken bracht een aantal interessante associaties aan het licht, maar sommige resultaten waren helaas tegenstrijdig. Er waren associaties gevonden tussen 1) levodopa-geïnduceerde dyskinesieën (overmatige bewegelijkheid) of motorische fluctuaties en polymorfismen in het dopamine D2 receptor gen; 2) het optreden van hallucinaties en polymorfismen in het dopamine transporter gen, het cholecystokinine gen en het apolipoproteine E gen; en 3) het optreden van slaapaanvallen zonder voortekenen en polymorfismen in het dopamine receptor 2 en dopamine receptor 4 gen. Het is waarschijnlijk dat het aantal geïncludeerde patiënten in veel onderzoeken te klein was om associaties aan
17
te tonen. De conclusie van het literatuuronderzoek was dat aanvullend onderzoek nodig is met grotere patiënten aantallen waarbij variaties in meerdere genen tegelijk moeten worden onderzocht. In Hoofdstuk 3 staan de nieuwere anti-Parkinson geneesmiddelen, de niet-ergoline dopamine agonisten, centraal. Deze geneesmiddelen zijn vanaf 1997 geïntroduceerd en bestaan uit ropinirol, pramipexol en, meer recent, rotigotine. Het is bekend dat geneesmiddelen in onderzoeken slechts gedurende een beperkte tijd worden onderzocht, onder strenge condities en in een homogene, zorgvuldig geselecteerde patiëntengroep. Hierdoor is het moeilijk om resultaten uit dergelijke onderzoeken te vertalen naar de dagelijkse praktijk. Daarom hebben we in Hoofdstuk 3.1 gekeken naar de verschillen tussen patiënten uit de dagelijkse praktijk en patiënten in onderzoeken die een niet-ergoline dopamine agonist gebruikten. We hebben de patiëntenkarakteristieken en het aantal patiënten die de therapie stopten vergeleken. De groep patiënten uit de dagelijkse praktijk omvatte een retrospectief cohort van patiënten van het Medisch Spectrum Twente in Enschede, die voor het eerst ropinirol (45 patiënten) of pramipexol (59 patiënten) gebruikten. Indien er meer dan 180 dagen tussen twee ophaalmomenten bij de apotheek zat, werden deze patiënten geclassificeerd als ‘stoppers’. Het bleek dat binnen drie jaar 51% van de ropinirol gebruikers en 60% van de pramipexol gebruikers waren gestopt. In de literatuur vonden we tien onderzoeken met ropinirol en 12 met pramipexol. De patiëntenkarakteristieken verschilden niet tussen de patiënten in de onderzoeken en de groep uit de dagelijkse praktijk. We concludeerden dat het percentage patiënten die de therapie in de onderzoeken stopten tot één jaar vergelijkbaar was met de dagelijkse praktijk. Het lijkt er op dat voor de langere termijn het percentage stoppers in de dagelijkse praktijk hoger is dan in de onderzoeken. In Hoofdstuk 3.2 hebben we niet-genetische determinanten voor het stoppen met niet-ergoline dopamine agonisten in kaart gebracht. In een deelonderzoek hebben we gekeken naar determinanten in genen die coderen voor de dopamine 2 en dopamine 3 receptor. In het niet-genetische deel hebben we 90 patiënten van het Medisch Spectrum Twente in Enschede geïncludeerd. Het bleek dat het gebruik van het anti-Parkinson geneesmiddel apomorfine geassocieerd was met stoppen van een niet-ergoline dopamine agonist (hazard ratio [HR] 6,26; 95% betrouwbaarheid interval [95%BI] 1,85-21,2). Het aantal gebruikers van apomorfine was echter maar beperkt. Ook levodopa doseringen tussen 500 en 1000 mg waren geassocieerd met stoppen van een niet-ergoline dopamine agonist (HR 2,31; 95%BI 1,08-4,93). In het farmacogenetische deelonderzoek werden 38 patiënten geïncludeerd. Afwezigheid van de 15x CA herhaling in het dopamine receptor 2 gen bleek geassocieerd te zijn met minder stoppen van niet-ergoline dopamine agonist therapie (HR 0,23; 95%BI 0,07-0,81). Een polymorfisme in het dopamine receptor 3 gen liet een niet-significant effect zien, maar het risico op stoppen nam wel per allel toe (allel-dosis effect). Dit ondersteunt het bestaan van een dergelijke relatie. We concludeerden dat onze bevindingen in een grotere groep patiënten dienen te worden onderzocht. In Hoofdstuk 4 hebben we gekeken naar twee mogelijke complicaties door het gebruik van dopaminergica bij patiënten met de ziekte van Parkinson. In Hoofdstuk 4.1 hebben we onderzocht of er een associatie bestaat tussen het gebruik van
18
dopamine agonisten en opname in het ziekenhuis met een ischemische oorzaak (onvoldoende zuurstof door onvoldoende doorbloeding). Er wordt namelijk gesuggereerd dat dopamine agonisten, in het bijzonder de ergoline dopamine agonisten, ischemische complicaties kunnen geven. Het is bekend dat ergotamine, een ergot alkaloïd die bij de behandeling van migraine wordt gebruikt, een verhoogd risico geeft op dergelijke ischemische complicaties. Het bestaan van een associatie is onderzocht door middel van een case-controle onderzoek binnen de PHARMO database. Dit is een Nederlandse onderzoeksdatabank waarin momenteel van meer dan twee miljoen personen (geanonimiseerde) zorggegevens kunnen worden gekoppeld ten behoeve van farmaco-epidemiologisch onderzoek. Alle patiënten met minimaal één voorschrift voor levodopa na het 55ste levensjaar in de periode 1994 tot 2006 zijn geïdentificeerd. Cases waren gedefinieerd als patiënten die na november 1997 waren opgenomen voor een ischemische complicatie (= index datum). Bij iedere case werden maximaal vier controle patiënten gezocht zonder een ischemische complicatie. In het onderzoek werden uiteindelijk 542 case patiënten en 2155 controle patiënten geïncludeerd. Blootstelling aan dopamine agonisten en ook mogelijke verstorende variabelen werden in de periode van één jaar voor de index datum vastgesteld. Het gebruik van dopamine agonisten bleek niet te zijn geassocieerd met een hoger risico op opname in het ziekenhuis voor een ischemische oorzaak (odds ratio [OR] 1.19; 95%BI 0,95-1,49). In Hoofdstuk 4.2 hebben we gekeken naar het effect van dopaminerge geneesmiddelen en gelijktijdig gebruik van psychotrope geneesmiddelen op het risico van heup- of dijbeen fracturen. Dopaminerge geneesmiddelen hebben verscheidene effecten die het valrisico en fractuurrisico kunnen verhogen. Aan de andere kant kunnen dopaminerge geneesmiddelen ook zorgen voor een verlaagd fractuur risico door een betere mobilisatie en door een mogelijke verbetering van de botdichtheid. We hebben een case-controle onderzoek uitgevoerd binnen de PHARMO database met patiëntenregistraties over de periode 1991 tot en met 2002. Cases waren patiënten ouder dan 18 jaar met een eerste heup- of dijbeen fractuur (= index datum). Bij iedere case werden maximaal vier controle patiënten gezocht zonder een fractuur maar die met de cases overeenkwamen wat betreft geboortejaar, geslacht en geografische regio. In het onderzoek werden uiteindelijk 6.763 case patiënten en 26.341 controle patiënten geïncludeerd. Huidig gebruik van dopaminerge geneesmiddelen (1-30 dagen voor de index datum) was in vergelijking met geen gebruik geassocieerd met een verhoogd risico op heup- of dijbeen fracturen (OR 1,76; 95%BI 1,39-3,22), maar dit verhoogde risico verdween wanneer de dopaminerge behandeling meer dan een jaar werd gestopt. Er was geen verschil in fractuur risico tussen de typen dopaminerge geneesmiddelen. Gelijktijdig gebruik van antidepressiva verhoogde het risico op heup- of dijbeen fracturen nog verder (OR 3,5; 95%BI 2,10-5,87), terwijl er geen additioneel verhoogd risico was bij gelijktijdig gebruik met andere psychotrope geneesmiddelen. Het is mogelijk dat de gevonden associatie niet causaal is, maar toe te schrijven is aan verschillen in de ernst van de ziekte van Parkinson. We meenden toch te kunnen concluderen dat een beoordeling op fractuurrisico overwogen moet worden bij oudere gebruikers van dopaminerge geneesmiddelen.
19
In Hoofdstuk 5 hebben we de behandeling van twee niet-motorische symptomen nader belicht. In Hoofdstuk 5.1 hebben we gekeken naar de associatie tussen initieel gebruik van serotonerge antidepressiva en veranderingen in het gebruik van anti-Parkinson geneesmiddelen. Dit is onderzocht in een retrospectief cohort binnen de PHARMO database met patiëntenregistraties over de periode 1994 tot en met 2004. In totaal werden 221 patiënten geïncludeerd die ouder dan 40 jaar waren, en die voor het eerst een antidepressivum kregen en die levodopa gebruikten in periode van minimaal 180 dagen voorafgaand aan het antidepressivum. De patiënten werden gedurende maximaal 180 dagen gevolgd. Het eindpunt was de eerste wijziging in de anti-Parkinson behandeling, gedefinieerd als een toename van de dagelijkse dosering, de start van een nieuwe behandeling, of een wijziging van de doseringsvorm. We classificeerden de antidepressiva op twee manieren: op basis van de geneesmiddelklasse [selectieve serotonine heropnameremmers (SSRIs), tricyclisch antidepressiva (TCAs) en overige antidepressiva] of op basis van de mate van serotonine heropnameremming (hoog, middel, laag). De gecorrigeerde HR op een wijziging in de anti-Parkinson behandeling was 0,7 (95%BI 0,3-1,5) met SSRIs ten opzichte van TCAs. Dit was 0,9 (95%BI 0,4-2,1) met overige antidepressiva ten opzichte van TCAs. De gecorrigeerde HR op een wijziging in de anti-Parkinson behandeling voor middelen met een hoge mate ten opzichte van een lage mate van serotonine heropnameremming was 0,6 (95%BI 0,3-1,4). Dit was 0,7 (95%BI 0,3-1,4) voor middelen met een middel mate ten opzichte van een lage mate van serotonine heropnameremming. Hieruit concludeerden we dat er geen bewijs is om met SSRIs of serotonerge antidepressiva voorzichtiger te zijn ten opzichte van andere antidepressiva. In Hoofdstuk 5.2 hebben we de effectiviteit en veiligheid van behandeling met glycopyrroniumbromide onderzocht in Parkinson patiënten met overmatig speekselverlies. Overmatig speekselverlies treft tot 75% van de Parkinson patiënten. Overmatig speekselverlies wordt vaak behandeld met zogenaamde anticholinergica, maar centrale bijwerkingen, zoals verwardheid, beperken het gebruik. Glycopyrroniumbromide is ook een anticholinergicum, maar het heeft een quaternaire ammonium chemiestructuur, waardoor dit middel de bloedhersenbarrière niet in hoge mate zal kunnen passeren. Dit verkleint de kans op centrale bijwerkingen, hetgeen een voordeel is bij patiënten met de ziekte van Parkinson, waarbij cognitieve problemen veelvuldig voorkomen. We hebben in het Medisch Spectrum Twente in Enschede een vier weken durend, gerandomiseerd, dubbelblind, placebo-gecontroleerd, cross-over onderzoek uitgevoerd bij 23 patiënten met de ziekte van Parkinson. De gebruikte dosering was drie maal daags 1 mg oraal glycopyrroniumbromide. De ernst van het speekselverlies werd vastgesteld met een speekselverlies scoreschaal van 1 (geen speekselverlies) tot 9 (zeer overvloedig speekselverlies). De gemiddelde (standaard deviatie) score verbeterde van 4,6 (1,7) met placebo tot 3,8 (1,6) met glycopyrroniumbromide (p=0,011). Negen patiënten (39,1%) hadden met glycopyrroniumbromide een klinisch relevante verbetering van minstens 30% tegen één patiënt (4,3%) met placebo (p=0,021). Er waren geen significante verschillen in bijwerkingen tussen glycopyrroniumbromide en placebo behandeling. We concludeerden dat drie maal daags 1 mg oraal glycopyrroniumbromide een effectieve en veilige behandeling is van overmatig speekselverlies bij patiënten met de ziekte van Parkinson. In
20
toekomstig onderzoek moet worden overwogen om de effectiviteit en bijwerkingen van hogere doseringen te onderzoeken. In Hoofdstuk 6, de algemene discussie, worden drie onderwerpen in een bredere context bediscussieerd: 1) individualiseren van behandeling met geneesmiddelen; 2) waarde van niet-experimentele versus experimentele onderzoeken; en 3) methodologie. We doen aanbevelingen voor de klinische praktijk en voor toekomstig onderzoek. Concluderend, de ziekte van Parkinson heeft een aanzienlijke invloed op het dagelijkse functioneren. In dit proefschrift hebben we diverse aspecten van de farmacologische behandeling van de ziekte van Parkinson bestudeerd, en hebben we aanbevelingen voor interventies gedaan om de uitkomsten van behandeling met geneesmiddelen te verbeteren.
21
Longgeneeskunde Difficult-to-treat asthma mechanisms and risk factors Proefschrift ter verkrijging van de graad van Doctor aan de Universiteit Leiden, op gezag van de Rector Magnificus Prof. Mr. P.F. van der Heijden, volgens besluit van het College voor Promoties te verdedigen op donderdag 2 september 2010 klokke 15.00 uur door Helena Petronella Agatha Anthonia van Veen geboren te Reeuwijk in 1970
Promotores: Prof. Dr. K.F. Rabe Prof. Dr. E.H. Bel (AMC, Amsterdam) Overige leden Dr. A. ten Brinke (MCL, Leeuwarden) Prof. Dr. G.F. Joos (Universitair Ziekenhuis Gent, Belgiё) Prof. Dr. P.S. Hiemstra Prof. Dr. F.R. Rosendaal Dr. J.K. Sont Prof. Dr. P.J. Sterk (AMC, Amsterdam)
22
Samenvatting Achtergrond Astma is een ziekte van de luchtwegen, gekenmerkt door aanvallen van kortademigheid, hoesten en/of een piepende ademhaling. In de luchtwegen van een patiënt met astma zijn tekenen van chronische ontsteking aanwezig. De spieren van de luchtwegen zijn hyperreactief. Dat wil zeggen dat deze spieren sneller dan bij gezonde mensen en in sterkere mate reageren op prikkels in de omgeving en gaan samentrekken. Dit resulteert in een aanvalsgewijze luchtwegvernauwing die kan optreden als reactie op specifieke (allergische) prikkels in de omgeving (bijvoorbeeld huisstofmijt), maar ook op aspecifieke (niet-allergische) prikkels zoals inspanning, rook of weersomstandigheden. De laatste jaren is steeds duidelijker geworden dat astma zich niet beperkt tot de luchtwegen (bronchiën) maar dat de ontstekingsverschijnselen ook voorkomen in het slijmvlies van de neus en neusbijholtes en in de longblaasjes (alveoli). Astma begint dus eigenlijk bij de neus en reikt tot diep in de longen. De meerderheid van de patiënten met astma (90 to 95%) is goed te behandelen met inhalatiemedicatie bestaande uit ontstekingsremmers (corticosteroïden) en luchtwegverwijders. Echter bij 5 tot 10% van de mensen met astma wordt met deze medicamenten onvoldoende resultaat behaald. Deze groep patiënten hebben een moeilijk behandelbare vorm van astma. Moeilijk behandelbaar astma is een heterogene ziekte, dat wil zeggen dat patiënten onderling veel van elkaar kunnen verschillen. Niet alle mensen met moeilijk behandelbaar astma hebben namelijk dezelfde mate van klachten of dezelfde mate van luchtwegvernauwing. Er kunnen verschillende uitingsvormen van de ziekte, ook wel fenotypes genoemd, worden onderscheiden. Een deel van de patiënten blijft bijvoorbeeld, ondanks behandeling, klachten houden van astma aanvallen, ook wel exacerbaties genoemd. Voor deze aanvallen moeten ze worden behandeld met een hoge dosis corticosteroïden (prednison) en soms zelfs worden opgenomen in het ziekenhuis. Corticosteroïden hebben echter, bij frequent gebruik en hoge dosering, vooral op lange termijn veel bijwerkingen, zoals de ontwikkeling van hoge bloeddruk, staar en botontkalking. Voortdurende klachten van kortademigheid en ziekenhuisopnames kunnen patiënten met moeilijk behandelbaar astma in hun dagelijks functioneren beperken en leiden tot school- of werkverzuim. Een andere groep patiënten die kan worden onderscheiden, zijn patiënten die niet zo zeer last hebben van astma aanvallen, maar waarbij er een blijvende vernauwing is van de luchtwegen (persisterende luchtwegvernauwing). Bij patiënten met dit fenotype is in de loop van de jaren de longfunctie steeds verder achteruit gegaan, waardoor ze snel kortademig zijn en zich minder goed kunnen inspannen. Om patiënten met een ernstige vorm van astma beter te kunnen behandelen is het belangrijk om te begrijpen waarom deze mensen onvoldoende baat hebben bij de gebruikelijke astmamedicatie. Meer kennis over de pathofysiologische mechanismen van moeilijk behandelbaar astma is noodzakelijk om nieuwe, effectievere astma medicijnen te kunnen ontwikkelen. Tot op heden is het echter
23
nog steeds niet goed duidelijk waarom sommige patiënten met astma moeilijk behandelbaar zijn. Een mogelijke verklaring is dat de werking van ontstekingsremmers, zoals corticosteroïden, bij deze patiënten verminderd is. De patiënt is minder gevoelig (resistent) voor deze medicatie en heeft soms een veel hogere dosis nodig. Een andere verklaring is dat bij patiënten met moeilijk behandelbaar astma een ander type ontstekingscellen in de luchtwegen aanwezig is. Bij patiënten met astma zien we meestal een duidelijke ophoping van een specifiek type witte bloedcellen in de luchtwegen, de eosinofiele leukocyten. Deze cellen zijn zeer gevoelig voor corticosteroïden. Bij patiënten met moeilijk behandelbaar astma zien we vaak ook andere ontstekingscellen, zoals neutrofiele granulocyten, die ongevoelig zijn voor corticosteroïden. Een derde verklaring zou kunnen zijn dat juist patiënten met moeilijk behandelbaar astma veel ontstekingsverschijnselen hebben in de neus of diep in de longblaasjes, plaatsen die niet goed bereikt worden met inhalatiemedicatie. Naast genoemde verklaringen zijn er nog veel meer redenen denkbaar waarom een patiënt met astma onvoldoende reageert op de gebruikelijke behandeling. De uitdaging in de klinische praktijk is om eerst bij de individuele patiënt uit te zoeken welke factoren het astma in negatieve zin beïnvloeden, zodat de behandeling vervolgens zo optimaal mogelijk op de patiënt kan worden afgestemd. Dit proefschrift is gericht op het beantwoorden van de volgende onderzoeksvragen: • waarom is een deel van de patiënten met astma moeilijk te behandelen en welke mechanismen liggen hieraan ten grondslag • zijn er factoren die kunnen voorspellen bij welke patiënten met astma een meer dan fysiologische daling van de longfunctie zal plaatsvinden • is het eosinofiele fenotype consistent over een langere tijdsperiode Mechanismen die de ontwikkeling van persisterende luchtwegvernauwing kunnen verklaren. Patiënten met astma zijn tussen de aanvallen door meestal klachtenvrij en hebben een normale longfunctie. Bij patiënten met moeilijk behandelbaar astma treedt echter in ongeveer 50% van de gevallen een persisterende luchtwegvernauwing op. Het is onduidelijk waarom deze persisterende luchtwegvernauwing ontstaat en welke veranderingen in de luchtwegen hiervoor verantwoordelijk zijn. Genetische factoren, blootstelling aan sigarettenrook en chronische ontsteking in de luchtwegen spelen hierbij een belangrijke rol. Hoofdstuk 3: de rol van alpha-1-antitrypsine deficiëntie bij het ontstaan van persisterende luchtwegvernauwing Doel van de studie Alpha-1-antitrypsine is een eiwit dat de long beschermt tegen schadelijke enzymen. Gebrek aan dit eiwit door een genetische afwijking kan leiden tot destructie van de long en resulteren in ernstig longemfyseem. Bij 95 % van de bevolking komt het zogenaamde PiM(M) fenotype van alpha-1-antitrypsine voor waarbij er normale hoeveelheden van het eiwit worden aangemaakt. Andere mogelijke vormen zijn onder andere PiMS, PiMZ, PiSZ en PiZZ. Het PiZZ fenotype is geassocieerd met het optreden van longemfyseem. In dit hoofdstuk werd onderzocht of een
24
genetische deficiëntie in de alpha-1-antitrypsine productie bij patiënten met moeilijk behandelbaar astma geassocieerd is met persisterende luchtwegvernauwing. Onderzoeksmethode Bij 122 patiënten met moeilijk behandelbaar astma werd het alpha-1-antritrypsine (AAT) fenotype bepaald. Patiënten werden ingedeeld in een PiM fenotype (meest voorkomend in de populatie) en het non-PiM fenotype. Tevens werden er longfunctieparameters gemeten: de FEV1 (forced expiratory volume in one second, ook wel eensecondewaarde genoemd) en de VC (vitale capaciteit). Persisterende luchtwegvernauwing werd gedefinieerd als een FEV1 < 75% van de voorspelde waarde of een FEV1/VC ratio <75% van de voorspelde waarde (beide gemeten na bronchusverwijdende medicatie) mits de totale longcapaciteit (TLC) groter was dan 75% van de voorspelde waarde. Resultaten Bij 6 patiënten was er sprake van een non-PiM fenotype (1 PiMF, 3 PiMS, 1 PiMZ en 1 PiSZ). Van de 58 patiënten met persisterende luchtwegvernauwing had slechts 1,7% een non-PiM fenotype vs. 7,8% bij de groep van patiënten zonder persisterende luchtwegvernauwing. Patiënten met een non-PIM fenotype hadden een hogere FEV1/VC ratio dan patiënten met een PiM fenotype. Er was geen associatie tussen het AAT fenotype en de FEV1. Conclusie Alpha-1-antitrypsine deficiëntie lijkt geen belangrijke risicofactor te zijn voor persisterende luchtwegvernauwing bij patiënten met moeilijk behandelbaar astma. Hoewel bevestiging van deze bevindingen nodig is door follow-up studies met meer patiënten lijkt de routine bepaling van het alpha-1-trypsine fenotype bij patiënten met moeilijk behandelbaar astma en persisterende luchtwegvernauwing niet geïndiceerd. Hoofdstuk 4: de relatie tussen alveolair NO en parameters van perifere luchtwegdysfunctie Doel van de studie De rol van de kleine luchtwegen (ook wel perifere luchtwegen genoemd) in astma is nog onvoldoende duidelijk. Ontsteking van de kleine luchtwegen lijkt vooral voor te komen bij patiënten met ernstige vormen van astma. Het is moeilijk om ontsteking en dysfunctie van de kleine luchtwegen op een noninvasieve manier goed te meten. Rond 1990 is echter een nieuwe methode ontwikkeld om stikstofoxide (NO) in de uitademingslucht te meten. Uit onderzoek bleek dat NO in de uitademingslucht een maat is voor de ernst van de ontsteking in de luchtwegen. Door de concentratie NO te meten bij verschillende uitademingssnelheden kan worden afgeleid welk deel van het stikstofoxide uit de kleine luchtwegen (alveolair NO) en welk deel uit de grote luchtwegen (bronchiaal NO) afkomstig is. Met behulp van longfunctieonderzoek kan de (dys)functie van de kleine luchtwegen worden gemeten. De hypothese van deze studie was dat parameters van perifere luchtwegdysfunctie en luchtweginflammatie aan elkaar gerelateerd zijn en dat de ernst van perifere luchtwegafwijkingen toeneemt naarmate de ernst van astma toeneemt.
25
Onderzoeksmethode Bij 17 patiënten met licht tot matig astma en 14 patiënten met ernstig astma werd het alveolaire NO bepaald en vergeleken. Tevens werden parameters van kleine luchtweg dysfunctie gemeten in beide groepen en vergeleken: totale long capaciteit (TLC), residuaal volume (RV), thoracaal gas volume (FRC), helling van de stikstofuitwastest (dN2), closing capacity (CC/TLC) en de afname in FVC (geforceerde vitale capaciteit) tijdens een metacholine provocatietest (ΔFVCpc20). De associatie tussen alveolair NO en bovengenoemde parameters werd onderzocht. Resultaten Bij patiënten met ernstig astma werd een sterke correlatie aangetoond tussen alveolair NO en RV/TLC, FRC, CC/TLC en dN2. Deze correlatie werd niet gevonden bij patiënten met licht tot matig astma. Patiënten met ernstig astma hadden een hoger dN2 en een hoger ΔFVCpc20 dan patiënten met licht tot matig astma. Patiënten met ernstig astma die chronisch orale corticosteroïden (prednison) gebruikten hadden een hoger alveolair NO dan patiënten die alleen inhalatiesteroïden gebruikten en dan patiënten met de lichtere vorm van astma. Conclusie Er is een positieve relatie tussen de ernst van de ontsteking in de perifere luchtwegen (gemeten via alveolair NO) en de mate van dysfunctie van deze luchtwegen bij patiënten met ernstig astma. Patiënten die chronisch orale steroïden gebruiken hebben de meeste afwijkingen in de perifere luchtwegen vergeleken met de andere astma patiënten in deze studie. Dit suggereert dat deze patiënten mogelijk aanvullende ontstekingsremmende medicatie nodig hebben om de afwijkingen in de perifere luchtwegen adequaat te behandelen. Patiënten met moeilijk behandelbaar astma en overgewicht: een apart fenotype? Wetenschappelijk onderzoek heeft een verband laten zien tussen het hebben van obesitas (body mass index (BMI) ≥30) en het vóórkomen van astma. Tevens zijn er aanwijzingen dat het hebben van ernstig overgewicht geassocieerd is met ernstiger astma. Meerdere mechanismen spelen hierbij een rol. Hierbij moet gedacht worden aan genetische factoren die leiden tot zowel astma als overgewicht, mechanische invloed van vetweefsel op de longfunctie, en het vóórkomen van comorbiditeit bij patiënten met astma en overgewicht. Daarnaast is aangetoond dat obesitas leidt tot een lichte vorm van systemische inflammatie ten gevolge van adiponectine en leptine geproduceerd door vetcellen (adipocyten). Deze systemische inflammatie kan mogelijk leiden tot inflammatoire veranderingen in de luchtwegen en resulteren in astma. Hoofdstuk 5: de rol van obesitas bij moeilijk behandelbaar astma Doel van de studie In deze studie werd bij een groep van patiënten met moeilijk behandelbaar astma onderzocht of patiënten met obesitas qua klinisch en inflammatoir profiel verschillen van de patiënten zonder obesitas. Onderzoeksmethode
26
Bij 136 patiënten met moeilijk behandelbaar astma werd de associatie onderzocht tussen obesitas en de volgende parameters: • long functie parameters (FEV1, FRC/TLC (functionele residuale capaciteit/totale longcapaciteit) • inflammatoire markers (% bloed eosinofielen, % sputum eosinofielen en neutrofielen, stikstofoxide in de uitademingslucht (FeNO), C-reactive protein) • bronchiale hyperreactiviteit • comorbiditeit (de aanwezigheid van chronische sinusitis, gastrooesophageale reflux, obstructief slaap apneu syndroom en psychopathologie) onderzocht. Resultaten Patiënten met obesitas (n=29) hadden een hogere FEV1 en een lagere FRC/TLC ten opzichte van niet obese patiënten. Er was een negatieve relatie tussen de BMI en het percentage sputum eosinofielen en tussen de BMI en FeNO. Patiënten met obesitas hadden een hoger risico op gastro-oesophageale reflux en slaap apneu syndroom. Conclusie Patiënten met moeilijk behandelbaar astma en obesitas hebben minder tekenen van luchtweginflammatie dan patiënten zonder obesitas, maar meer comorbiditeit en een afname van de functionele residuale capaciteit. Dit impliceert dat obese patiënten met astma moeilijk behandelbaar kunnen worden door een negatief effect van het overgewicht op de longfunctie, of door de aanwezige comorbiditeit die de astma symptomen verergert. Voorspellers van een versnelde achteruitgang in longfunctie. Eerder onderzoek heeft aangetoond dat patiënten met astma een grotere afname in longfunctie hebben per jaar dan gezonde personen. Een versnelde achteruitgang in longfunctie kan uiteindelijk leiden tot een blijvende luchtwegvernauwing. Door patiënten die een verhoogd risico lopen op het ontwikkelen van blijvende luchtwegvernauwing in een vroege fase te identificeren, kan door aanpassing van de behandeling deze achteruitgang mogelijk worden voorkomen. Biomarkers zijn karakteristieken van biologische processen die meetbaar zijn in het lichaam van de patiënt, zoals bijvoorbeeld in het bloed of in het sputum (slijm uit de longen). Biomarkers worden in de geneeskunde al gebruikt bij de diagnostiek van sommige ziekten, of bijvoorbeeld om het beloop of prognose van een ziekte te voorspellen. De vraag is of bepaalde biomarkers kunnen voorspellen welke patiënten met astma een verhoogd risico hebben op een versnelde achteruitgang in longfunctie. Hoofdstuk 6: voorspellers van de achteruitgang van longfunctie Doel van de studie In deze studie werd onderzocht of bepaalde karakteristieken van de patiënt met astma (zoals leeftijd waarop het astma begon, duur van de ziekte, aanwezigheid van allergie, bronchiale hyperreactiviteit, eosinofielen in bloed en sputum, en
27
stikstofoxide in de uitademingslucht (FeNO) zijn geassocieerd met een versnelde achteruitgang in longfunctie. Onderzoeksmethode Van de 136 patiënten die tussen 1998 en 1999 werden gerekruteerd werd ruim 5 jaar later bij 98 patiënten opnieuw een longfunctie gemeten. De voorspellende waarde van bovengenoemde parameters op de achteruitgang in FEV1 in ml/jaar werd geanalyseerd. Resultaten Van alle parameters die werden onderzocht was alleen FeNO geassocieerd met een versnelde achteruitgang in longfunctie. Patiënten met een hoog FeNO (≥ 20ppb) hadden een bijna twee keer zo grote kans op een versnelde achteruitgang in longfunctie (≥ 25 ml/jaar) dan de overige patiënten. De groep patiënten die bij aanvang van de studie een normale longfunctie had én een hoog FeNO, had het meeste risico op een versnelde achteruitgang in longfunctie (relatief risico 3.1). Conclusie Stikstofoxide in de uitademingslucht is een voorspeller van een versnelde achteruitgang in longfunctie bij patiënten met moeilijk behandelbaar astma, in het bijzonder bij patiënten met een normale longfunctie als uitgangswaarde. Het eosinofiele fenotype: blijvend aanwezig of niet? Tussen patiënten met moeilijk behandelbaar astma bestaan niet alleen onderlinge verschillen in klinische kenmerken, maar er bestaan ook verschillen in het type ontstekingsproces in de luchtwegen. Met betrekking tot dit ontstekingsproces wordt wel onderscheid gemaakt tussen patiënten met en zonder (of een minder uitgesproken) eosinofiele ontsteking in de luchtwegen. Onderzoek heeft aangetoond dat deze eosinofiele ontsteking geassocieerd is met het optreden van ernstige astma aanvallen en de aanwezigheid van persisterende luchtwegvernauwing. Patiënten met moeilijk behandelbaar astma waarbij, ondanks behandeling, een eosinofiele ontsteking in de luchtwegen aantoonbaar is worden beschouwd als een apart fenotype. Het is echter nog onduidelijk of deze eosinofiele ontsteking een permanente karakteristiek is van deze patiënten en hoe deze kan worden verklaard. Antwoord op deze vragen kan ons helpen om in de toekomst een juiste subgroep van patiënten te identificeren die mogelijk baat heeft bij nieuwe anti-inflammatoire therapieën gericht op het tegengaan van deze eosinofiele ontsteking. Hoofdstuk 7: consistentie van het eosinofiele fenotype Doel van de studie Het analyseren van de consistentie van het eosinofiele fenotype in patiënten met moeilijk behandelbaar astma over een periode van 5-6 jaar. Tevens werd onderzocht welke klinische of inflammatoire karakteristieken geassocieerd zijn met permanente eosinofiele ontsteking. Onderzoeksmethode Van 44 patiënten met moeilijk behandelbaar astma werd het sputum onderzocht op twee tijdstippen (tussenperiode van 5-6 jaar) om de consistentie van eosinofiele
28
ontsteking te kunnen bepalen. De associatie tussen permanente eosinofiele ontsteking en klinische kenmerken (leeftijd waarop het astma begon, duur van astma, aanwezigheid van allergie, aantal exacerbaties, FEV1, bronchiale hyperreactiviteit, ontsteking van de neusbijholten (sinussen)) en parameters van luchtwegontsteking (eosinofielen in het bloed, FeNO) werd onderzocht. Resultaten Bij 70% van de patiënten met eosinofiele ontsteking was dit een consistent fenomeen over de tijd. Bij 96% van de patiënten die geen eosinofilie hadden bleef dit ook zo. Ernstige ontsteking van de neusbijholten was de enige onafhankelijke factor die geassocieerd was met permanente eosinofiele ontsteking. Conclusie De aanwezigheid van eosinofiele ontsteking ondanks behandeling met corticosteroïden is een persisterend kenmerk bij patiënten met moeilijk behandelbaar astma. Ernstige ontsteking van de neusbijholten is geassocieerd met persisterende eosinofiele inflammatie van de luchtwegen. Tenslotte Onderzoek leidt zoals alle wetenschappers weten altijd tot meer vragen dan antwoorden. Een aantal van deze vragen zullen wellicht in de nabije of verre toekomst kunnen worden opgelost: • welk mechanisme ligt ten grondslag aan de versnelde achteruitgang van de longfunctie en de ontwikkeling van persisterende luchtwegvernauwing bij een deel van de patiënten met astma? • is behandeling met klein moleculaire steroïden meer effectief dan conventionele steroïden bij patiënten met tekenen van ontsteking van de kleine luchtwegen? • wat is de oorzaak van een hoog FeNO bij patiënten met moeilijk behandelbaar astma en is het zinvol en mogelijk om deze waarden te verlagen? • hoe kunnen we FeNO metingen effectief gebruiken bij de behandeling van patiënten met astma? • kan fenotypering van astma ons helpen om de behandeling van patiënten met moeilijk behandelbaar astma te verbeteren?
29
Radiologie NB: promotie Cum Laude
Treatment of osteoporotic vertebral compression fractures Behandeling van osteoporotische wervelfracturen (met een samenvatting in het Nederlands) 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 op vrijdag 12 november 2010 des middags te 2.30 uur door Caroline A. H. Klazen geboren op 7 april 1977 te Berkel-Enschot
Promotoren: Prof. dr. W.P.Th.M. Mali Prof. dr. J. de Vries Co-promotoren: Dr. P.N.M. Lohle Dr. H.J.J. Verhaar
30
Samenvatting In Hoofdstuk 1 wordt een algemene inleiding gegeven. In Hoofdstuk 2 hebben we prospectief het natuurlijk beloop van pijn veroorzaakt door een conservatief behandelde, acute wervelfractuur in kaart gebracht. Daarbij hebben we onderzocht welke conservatieve behandeling in Nederland wordt gegeven. De fractuur genezing ( en dus pijn afname) van een acute osteoporotische wervelfractuur vond voornamelijk plaats gedurende de eerste 6 maanden. Het hoge percentage (31%) patiënten dat chronisch pijn ontwikkelt na alleen conservatieve therapie rechtvaardigt de overweging van minimaal invasieve technieken voor de bestrijding van pijn. Conservatieve therapie bestaat in Nederland voornamelijk uit pijnmedicatie and fysiotherapie en wordt voorgeschreven door de huisarts. In Hoofdstuk 3 zijn de studie opzet en eindpunten van de VERTOS II studie beschreven. VERTOS II is een open-label gerandomiseerde gecontroleerde trial waarin percutane vertebroplastiek (PV) wordt vergeleken met optimale conservatieve therapie. In Hoofdstuk 4 zijn de belangrijkste uitkomsten van de VERTOS II studie geanalyseerd en beschreven. Onze resultaten laten zien dat patiënten met ernstige persisterende pijn door een acute wervelfractuur (gemiddeld 5,6 weken na start pijn) een snellere en betere pijnafname hebben na PV dan na conservatieve therapie. Zelfs een 1 jaar nadien hadden patiënten met PV nog minder pijn dan met conservatieve therapie. Na PV gebruikten patiënten ook een lagere klasse pijnmedicatie dan na conservatieve therapie, of helemaal geen pijnmedicatie meer. Met conservatieve therapie nam de pijn niet alleen langzamer, maar ook in mindere mate af. Bijna een kwart van de patiënten met conservatieve therapie ontwikkelde zelfs chronische rugpijn, waarschijnlijk op basis van onvolledige consolidatie van de wervelfractuur. Ook verbetering in kwaliteit van leven en functie was significant beter en sneller na PV dan na conservatieve therapie. De additionele kosten van PV komen overeen met de kosten van de procedure. De kosten per gewonnen pijnvrije dag bedragen €20. De kosteneffectiviteit ratio voor PV vergeleken met conservatieve therapie bedroeg €22.685 per gewonnen jaar rekening houdend met de kwaliteit van leven. De kosteneffectiviteit ratio suggereert dat PV kosteneffectief is voor patiënten met een osteoporotische wervelfractuur van gemiddeld 5,6 weken oud. In Hoofdstuk 5 beschrijven we dat de incidentie van nieuwe wervelfracturen in patiënten met een acute osteoporotische wervelfractuur gedurende 1 jaar follow-up gelijk is na PV vergeleken met conservatieve therapie. De enige risicofactor voor het ontstaan van een nieuwe wervelfractuur was het aantal wervelfracturen op baseline, als een maat voor de ernst van de osteoporose. PV beschermt zelfs tegen verdere inzakking van de behandelde wervels en draagt daarmee bij aan het behoud van houding en longfunctie. In Hoofdstuk 6 hebben we met CT de incidentie van cement embolieën in de longen geanalyseerd in een groot deel van de patiënten uit de VERTOS II studie.
31
Kleine, asymptomatische cement embolieën zagen we op CT in ongeveer een kwart van de patiënten na PV. Cement lekkage in de vena azygos was de enige risicofactor. De cement embolieën bleken inert en gaven geen ontstekingsreactie is het omliggende longweefsel op vervolg CT. Het standaard vervaardigen van een vervolg thorax foto of CT na PV is dan ook niet nodig. In Hoofdstuk 7 hebben we de incidentie, anatomische locatie en klinische impact van perivertebrale cementlekkage op de korte en lange termijn in een grote groep patiënten geëvalueerd. Cementlekkage na PV buiten het wervellichaam werd frequent gedetecteerd op CT. De meeste cementlekkages waren in de aangrenzende tussenwervelschijven of segmentale venen en alle patiënten bleven asymptomatisch. Injectie van meer cement vergrootte het risico op lekkage. Latere cementmigratie werd niet gezien. Een standaard CT-scan van de behandelde wervel hoeft niet vervaardigd te worden. In Hoofdstuk 8 wordt pijnbestrijding tijdens de PV procedure besproken. Locale verdoving is niet voor alle patiënten afdoende. De subjectieve pijnbeleving ervaren door de patiënt gedurende de procedure wordt veelal onderschat door de uitvoerend radioloog. In Hoofdstuk 9 worden de resultaten van de VERTOS II studie geïnterpreteerd en de implicaties ervan bediscussieerd.
32
Radiotherapie Prognostic Factors In Breast-Conserving Therapy A Prospective Population-Based Cohort Study 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 donderdag 30 september 2010 om 15.00 uur door Jan Jacobus Jobsen geboren op 4 september 1952 te Goes
Promotoren: Prof. dr. J.A.M. van der Palen Prof. dr. H. Struikmans Deskundige: Dr. S. Siesling Leden: Prof. Dr. E.F.M. Van Limbergen Prof. Dr. D.J. Richel Prof. Dr. E.R. Seydel Prof. Dr. L. Terstappen Dr. M.B.E. Menke-Pluijmers
33
Samenvatting A large cohort study on breast cancer was started that included patients treated with breast-conserving therapy, from the early start of this treatment in the Twente – Achterhoek region, till today, with more than 3700 breast-conserving treatments. Recruitment is still continuing. In chapter 2, on family history, we were able to show that a positive family history with regard to first degree relatives does not result in a worse outcome; on the contrary we demonstrated a trend to a better outcome. In chapter 3 we could establish a young age as a risk factor for local control in breast cancer in accordance with the literature. We also looked at the incidence and outcome for patients with bilateral synchronous breast cancer. We demonstrated that bilateral breast cancer has a poor outcome compared with unilateral breast cancer, in particular in relation to distant metastasis (chapter 4). Boost irradiation in breast-conserving therapy has been an important issue since many years. Not only with regard to the question of the necessity of the boost, but also with regard to the accuracy of delivering the boost to the tumour area. The latest has become more interesting after the introduction of the CT-localisation. We published one of the few papers on external boost volume in breast-conserving therapy (chapter 5) from before the era of the CT-localisation. Most studies describe the impact of boost volume in brachytherapy. We showed no relation of the boost volume to local control despite the fact that probably the accuracy of the boost area was questionable. Timing in breast cancer has become an important item due to the extended treatment with surgery, radiotherapy and systemic therapy. Most studies published focus on local control. We demonstrated in chapter six no effect on local control with the start of radiotherapy till twelve weeks after surgery. Surprisingly we also found that a longer time interval leads to favourable results with respect to distant metastasis and survival (chapter 6). One of the items what intrigued us was margin status. We published three papers on this item (chapters 7, 8, and 9). The main contribution to the already existing literature was that we could show a statistical interaction between age and margin status. In our first paper in 2003 (chapter 7) we demonstrated that the value of positive margins for invasive carcinoma was limited to young women. Our second paper in 2007 (chapter 8) on a larger cohort and with long-term follow-up did not only confirm the findings in the first paper, but also showed that the effect of a positive margin was not limited to local control only, but also to distant metastasis and survival. We also demonstrated that a positive margin for ductal carcinoma in situ was a risk factor for local control in women over 40-years. In our last paper (chapter 9) on margin status we restricted ourselves to lobular carcinoma, and demonstrated the same effect of positive margins for invasive carcinoma as with ductal carcinoma, only this time the turning point was not 40-years but 50-years. This means that in clinical practice analysis of the importance of margin status should always be done according to age category. This thesis is not the end of all publications concerning breast cancer from this cohort. In the near future we will publish more data on timing, family history in relation to BRCA-1/2, and prognostic factors as the mitotic activity index.
34
PubMed publicaties per vakgroep Anesthesiologie 1. Microvascular hemodynamics in human hypothermic circulatory arrest and selective antegrade cerebral perfusion Elbers PW1,2, Ozdemir A2,3, Heijmen RH4, Heeren J5, van Iterson M2, van Dongen EP2, Ince C1 1 Department of Translational Physiology, AMC, Amsterdam; 2 Department of Anesthesia, Intensive Care and Pain Management, 4 Department of Cardiothoracic Surgery, 5 Department of Perfusion, St Antonius Ziekenhuis, Nieuwegein 3 Department of Anesthesiology, Medisch spectrum Twente, Enschede Objective: The behavior of the human microcirculation in the setting of cardiac arrest is largely unknown. Animal experiments have consistently revealed that global hemodynamics do not necessarily reflect microvascular perfusion. In addition, the time it takes for capillary blood flow to stop after the heart arrests is debated. Estimations range from 50 seconds to 5 mins, but data in humans are lacking. Aortic arch surgery frequently necessitates deep hypothermic circulatory arrest and subsequent selective antegrade cerebral perfusion. To elucidate microvascular behavior surrounding cessation of human circulation, we used sublingual microvascular imaging in this setting. Design: Prospective, observational study. Setting: Operating room of a large tertiary referral center for cardiac surgery. Patients: Seven patients undergoing elective aortic arch repair. Interventions: We used sidestream dark field imaging to study the sublingual microcirculation immediately before circulatory arrest, during circulatory arrest, and immediately after selective antegrade cerebral perfusion. Measurements and Main Results: Results are reported as mean (sd) unless indicated otherwise. Before circulatory arrest, perfused vessel density was 6.41 (1.18) for small (<20 µm) and 1.57 (0.88) mm-1 for large (>20 µm) microvessels. Microvascular flow index was a median of 3.0 (interquartile range 3.0–3.0) for both vessel sizes. After circulatory arrest, there was no equilibration of arterial and venous blood pressure before onset of selective antegrade cerebral perfusion after 59 (17) secs (range, 40–80 secs). Flow in small microvessels came to a complete stop after 45 (9) secs (range, 34–57 secs) after transition to circulatory arrest. However, flow in larger microvessels did not completely stop before selective antegrade cerebral perfusion started. Selective antegrade cerebral perfusion restored microvascular flow, reaching precirculatory arrest levels after 45 (27) secs (range, 20–85 secs). Conclusions: In a controlled surgical setting, circulatory arrest in humans induces a complete sublingual small microvessel shutdown within 1 min. However, flow in larger microvessels persists. Selective antegrade cerebral perfusion was able to restore microvascular flow to precirculatory arrest levels within a similar timeframe. Gepubliceerd: Critical Care Medicine 2010;38(7):1548-1553 Impact factor: 6.373
35
2. Withdrawing intra-aortic balloon pump support paradoxically improves microvascular flow Munsterman LD1,2, Elbers PW1,2, Ozdemir A2,3, van Dongen EP2, van Iterson M2, Ince C1 1 Department of Translational Physiology, AMC, University of Amsterdam, Amsterdam 2 Department of Anesthesiology, Intensive Care and Pain Medicine, St. Antonius Hospital, Nieuwegein 3 Department of Anesthesiology, Medisch Spectrum Twente, Enschede Introduction: The Intra-Aortic Balloon Pump (IABP) is frequently used to mechanically support the heart. There is evidence that IABP improves microvascular flow during cardiogenic shock but its influence on the human microcirculation in patients deemed ready for discontinuing IABP support has not yet been studied. Therefore we used sidestream dark field imaging (SDF) to test our hypothesis that human microcirculation remains unaltered with or without IABP support in patients clinically ready for discontinuation of mechanical support. Methods: We studied 15 ICU patients on IABP therapy. Measurements were performed after the clinical decision was made to remove the balloon catheter. We recorded global hemodynamic parameters and performed venous oximetry during maximal IABP support (1:1) and ten minutes after temporarily stopping the IABP therapy. At both time points, we also recorded video clips of the sublingual microcirculation. From these we determined indices of microvascular perfusion including perfused vessel density (PVD) and microvascular flow index (MFI). Results: Ceasing IABP support lowered mean arterial pressure (74 +/- 8 mmHg to 71 +/- 10; P=0.048) and increased diastolic pressure (43 +/- 10 to 53 +/- 9 mmHg; P=0.0002). However, at the level of the microcirculation we found an increase of PVD of small vessels <20[micro]m (5.47+/-1.76 to 6.63+/-1.90; p=0.0039). PVD for vessels >20[micro]m and MFI for both small and large vessels were unaltered. During the procedure global oxygenation parameters (ScvO2/SvO2) remained unchanged. Conclusions: In patients deemed ready for discontinuing IABP support according to current practice, SDF imaging showed an increase of microcirculatory flow of small vessels after ceasing IABP therapy. This observation may indicate that IABP impairs microvascular perfusion in recovered patients, although this warrants confirmation. Gepubliceerd: Crit Care. 2010;14(4):R161 Impact factor: 4.931
Totale impact factor: 11.304 Gemiddelde impact factor: 5.652 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 6.373 Gemiddelde impact factor: 6.373
36
Cardiologie 1. Giant pseudoaneurysm after aortic root replacement van de Wetering ML1, Wagenaar LJ2, Bouma BJ1, Koolbergen DR1 1 Department of Cardiology, AMC, Amsterdam 2 Department of Cardiology, Medisch Spectrum Twente, Enschede Gepubliceerd: Neth Heart J. 2010;18(7-8):381 Impact factor: 1.392
2. TWENTE Study: The Real-World Endeavor Resolute Versus Xience V DrugEluting Stent Study in Twente: study design, rationale and objectives Basalus MW1, Tandjung K1, van Houwelingen KG1, Stoel MG1, de Man FH1, Louwerenburg JW1, Saïd SA2, Linssen GC3, Kleijne MA4, van der Palen5, Huisman J1, Verhorst PM1, von Birgelen C6 1 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede 2 Department of Cardiology, Hospital Group Twente, Hengelo 3 Department of Cardiology, Hospital Group Twente, Almelo 4 Department of Cardiology, Streekziekenhuis Koningin Beatrix, Winterswijk 5 Department of Epidemiology, Medisch Spectrum Twente, Enschede and Department of Research Methodology, Measurement & Data Analysis, University of Twente, Enschede 6 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, and MIRA, Institute for Biomedical Technology & Technical Medicine, University of Twente, Enschede Background. New-generation drug-eluting stents (DES) may solve several problems encountered with first-generation DES, but there is a lack of prospective head-to-head comparisons between new-generation DES. In addition, the outcome of regulatory trials may not perfectly reflect the outcome in 'real world' patients. Objectives. To compare the efficacy and safety of two new-generation DES in a 'real world' patient population. Methods. A prospective, randomised, single-blinded clinical trial to evaluate clinical outcome after Endeavor Resolute vs. Xience V stent implantation. The primary endpoint is target vessel failure at one-year follow-up. In addition, the study comprises a two-year and an open-label five-year follow-up Gepubliceerd: Neth Heart J. 2010;18(7-8):360-4 Impact factor: 1.392
3. Thrombus aspiration in a series of patients with stable or unstable angina pectoris and lesion-site thrombus formation Hermens JA, van Houwelingen GK, de Man FH, Louwerenburg HW, von Birgelen C Department of Cardiologie, Medisch Spectrum Twente, Enschede
37
Background. In acute myocardial infarction, thrombus aspiration prior to percutaneous coronary interventions (PCI) is often beneficial, but this approach has never been studied in patients without acute myocardial infarction. The aim of this retrospective study is to shed light on that topic based on our initial experience with manual thrombus aspiration in patients with stable or unstable angina pectoris and angiographic evidence of lesion-site thrombus. Methods. We assessed the feasibility (thrombus aspiration without predilatation) of this approach; in addition, we determined angiographic coronary flow and myocardial blush grade. Results. During 33 months in which a total of 4725 PCI were performed in our centre, manual thrombus aspiration was attempted in 14 patients with stable or unstable angina pectoris with angiographic evidence of thrombus. In nine of these 14 patients, the aspiration catheter could be advanced into the lesion without predilatation; in eight patients visible thrombus was obtained. The corrected TIMI frame count improved during the entire interventional procedure (21.1±11.2 vs. 12.8±5.9 frames; p=0.015). Myocardial blush grade, which overall improved during PCI (p<0.001), tended to show greater improvement in patients in whom thrombus aspiration could be achieved (1.6±0.9 vs. 0.7±0.5; p=0.06). Conclusions. Preliminary evidence suggests that manual thrombus aspiration may occasionally be considered in selected patients without acute myocardial infarction but with angiographic evidence of lesion-site thrombus. Nevertheless, prospective studies are required to clearly define the role of this approach in clinical practice. Gepubliceerd: Neth Heart J. 2010;18(9):423-9 Impact factor: 1.392
4. Impact of analyzing less image frames per segment for radiofrequency-based volumetric intravascular ultrasound measurements in mild-to-moderate coronary atherosclerosis Huisman J1, Hartmann M1, Mattern ES1, Mintz GS2, Basalus MW1, van Houwelingen GK1, Verhorst PM1, von Birgelen C1 1 Department of Cardiology, Thorax Center Twente, Medisch Spectrum Twente, Enschede 2 Cardiovascular Research Foundation, New York, USA Volumetric radiofrequency-based intravascular ultrasound (RF-IVUS) data of coronary segments are increasingly used as endpoints in serial trials of novel antiatherosclerotic therapies. In a relatively time-consuming process, vessel and lumen contours are defined; these contours are first automatically detected, then visually checked, and finally (in most cases) manually edited to generate reliable volumetric data of vessel geometry and plaque composition. Reduction in number of crosssectional images for volumetric analysis could save analysis time but may also increase measurement variability of volumetric data. To assess whether a 50% reduction in number of frames per segment (every second frame) alters the reproducibility of volumetric measurements, we performed repeated RF-IVUS analyses of 15 coronary segments with mild-to-moderate atherosclerosis (20.2 +/-
38
0.2 mm-long segments with 46 +/- 13% plaque burden). Volumes were calculated based on a total of 731 image frames. Reducing the number of cross-sectional image frames for volumetric measurements saved analysis time (38 +/- 9 vs. 68 +/17 min/segment; P < 0.0001) and resulted for only a few parameters in (borderline) significant but mild differences versus measurements based on all frames (fibrous volume, P < 0.05; necrotic-core volume, P = 0.07). Compared to the intra-observer variability, there was a mild increase in measurement variability for most geometrical and compositional volumetric RF-IVUS parameters. In RF-IVUS studies of mild-tomoderate coronary disease, analyzing less image frames saved analysis time, left most volumetric parameters greatly unaffected, and resulted in a no more than mild increase in measurement variability of volumetric data. Gepubliceerd: Int J Cardiovasc Imaging. 2010;26(5):487-497 Impact factor: 2.151
5. Between-Centre Reproducibility of Volumetric Intravascular Ultrasound Radiofrequency-Based Analyses in Mild-to-Moderate Coronary Atherosclerosis: An International Multicentre Study J Huisman1, R Egede2, A Rdzanek3, D Boese4, R Erbel4, J Kochman3, L Okkels Jensen2, J van der Palen5,6, M Hartmann1, GS Mintz7, C von Birgelen1,8 1 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede 2 Department of Cardiology, Odense University Hospital, Odense, Denmark 3 Department of Cardiology, Central University Hospital, Warsaw, Poland 4 Department of Cardiology, Westdeutsches Herzzentrum Essen, Universitätsklinikum Essen-Duisburg, Germany 5 Department of Epidemiology, Medisch Spectrum Twente, Enschede 6 Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede 7 Cardiovascular Research Foundation, New York, USA 8 University of Twente, MIRA-Institute, Enschede Aim: To assess for the first time in a multicentre design the between-centre reproducibility of volumetric virtual histology intravascular ultrasound (VH-IVUS) measurements with a semi-automated, computer-assisted contour detection system in mild-to-moderately diseased coronary segments. Methods and results: Analysts of 4 European IVUS centres performed independent IVUS analyses (in total 7.188 cross-sectional analyses) and obtained volumetric data to evaluate the reproducibility of volumetric VH-IVUS measurements in 36 coronary segments (length 20.0±0.4mm) from patients with stable angina. Geometrical and compositional VH-IVUS measurements were highly correlated for the different comparisons. Overall intraclass correlation for vessel, lumen, plaque volume and plaque burden were 0.98, 0.92 0.95, and 0.86, respectively; for fibrous, fibro-lipidic, necrotic core and calcified volumes overall intraclass correlations were 0.95, 0.93, 0.99, and 1.00, respectively. There were significant but small differences for vessel, lumen, fibrous and calcified volumes, and there was no significant
39
difference for plaque volume. Of the plaque components necrotic core and calcified volume showed on average the highest reproducibility. Conclusions: These findings underline the necessity to centrally analyze IVUS data obtained in multicentre studies addressing mild-to-moderately diseased coronary arteries. In addition, pooling VH-IVUS data from different studies, analyzed at different centres, may be problematical. Gepubliceerd: EuroIntervention 2010;5(8):925-931 Impact factor: 0
6. ECG Quantification of Myocardial Scar Does Not Differ between Primary and Secondary Prevention ICD Recipients with Ischemic Heart Disease Kraaier K1, van Dessel PF1, van der Palen J2,3, Wilde AA4, Scholten MF1 1 Department of Cardiology, Medisch Spectrum Twente, Enschede 2 Department of Epidemiology, Medisch Spectrum Twente, Enschede 3 Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede 4 Department of Cardiology, Academic Medical Centre, Amsterdam Background: Myocardial scar is an anatomic substrate for potentially lethal arrhythmias. Recent study showed that higher QRS-estimated scar size using the Selvester QRS score was associated with increased arrhythmogenesis during electrophysiologic testing. Therefore, QRS scoring might play a potential role in risk stratification before implantable cardioverter defibrillator (ICD) implantation. In this study, we tested the hypothesis that QRS scores among ICD recipients for secondary prevention are higher than QRS scores in primary prevention patients. Methods and Results: From the hospital database, 100 consecutive patients with ischemic heart disease and prior ICD implantation were selected. Twelve-lead electrocardiograms (ECGs) had been obtained before implantation. ECGs were scored following the 32-points Selvester QRS scoring system and corrected for underlying conduction defects and/or hypertrophy. Ninety-three ECGs were suitable for scoring; seven ECGs were rejected because of noise, missing leads, excessive ventricular extrasystoles, or ventricular pacing. No statistically significant difference in QRS score was found between the primary [6.90 (standard deviation [SD] 3.94), n = 63] and secondary prevention group [6.17 (SD 4.50) (P = 0.260), n = 30]. Left ventricular ejection fraction (LVEF) was significantly higher in the secondary prevention group [31% (SD 13.5) vs 24% (SD 11.7) (P = 0.015)]. When patients with LVEF >/=35% were excluded, QRS scores were still comparable, namely 7.02 (SD 4.04) in the primary prevention group (n = 52) and 6.28 (SD 4.24) in the secondary (P = 0.510) (n = 18). Conclusion: We found no significant difference in QRS score between the ischemic primary and secondary prevention groups. Therefore, a role of the Selvester QRS score as a risk stratifier remains unlikely. Gepubliceerd: Pacing Clin Electrophysiol. 2010;33(2):192-197 Impact factor: 1.578
40
7. Artifactual measurement of low serum HDL-cholesterol due to paraproteinemia van Gorselen EO1, Diekman T2, Hessels J3, Verhorst PM1, von Birgelen C1,4 1 Department of Cardiology, Medisch Spectrum Twente, Enschede 2 Department of Internal Medicine, Deventer Ziekenhuis, Deventer 3 Department of Clinical Chemistry, Deventer Ziekenhuis, Deventer 4 MIRA-Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede Gepubliceerd: Clin Res Cardiol. 2010;99(9):599-602 Impact factor: 2.958
8. Is size really all that matters? Remarks on size and necrotic core content of atherosclerotic plaques C von Birgelen1, 2 , J Huisman1, M Hartmann1 1 Thoraxcentrum Twente, Department of Cardiology, Medisch Spectrum Twente, Enschede 2 MIRA, Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede Gepubliceerd als Editorial Comment: Int J Cardiovasc Imaging. 2010;26(2):173-176 Impact factor: 2.151
9. On the loss of the phosphorylcholine-based DES coating on the abluminal surface of endeavor stents von Birgelen C1,2, Basalus MW1 1 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede 2 MIRA, Institute for Biomedical Technology & Technical Medicine, University of Twente, Enschede Gepubliceerd: Catheter.Cardiovasc.Interv 2010;76:158-159 Impact factor: 2.363
10. Early versus late ST-segment resolution and clinical outcomes after percutaneous coronary intervention for acute myocardial infarction HB van der Zwaan,1 MG Stoel,2 JW Roos-Hesselink,1 G Veen,3 E Boersma,4 C von Birgelen2,5 1 Department of Cardiology, Thoraxcenter, Erasmus MC, Rotterdam 2 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede 3 Department of Cardiology, VU UMC, Amsterdam 4 Department of Epidemiology and Statistics, Erasmus University, Rotterdam 5 Institute of Biomedical Technology, University of Twente, Enschede
41
Background. Absence of complete ST-segment resolution (STR) after percutaneous coronary intervention (PCI) for ST-segment-elevation myocardial infarction (STEMI) is a determinant of mortality. Traditionally, STR is determined on the coronary care unit (CCU) 60 to 90 minutes after the initiation of reperfusion therapy. We studied the prognostic value of STR immediately after PCI. Methods. We analysed 223 consecutive patients with STEMI and successful PCI. Continuous ECG data were collected during PCI and at 30 minutes after arrival on the CCU (mean time 81±17 minutes after reflow of the culprit artery). Patients were divided into three groups: patients with complete STR immediately after PCI ('early'), patients with complete and persistent STR at 30 minutes on the CCU, but not immediately after PCI ('late') and patients without STR. One-year follow-up was obtained for death and rehospitalisation for major adverse cardiac events. Cox proportional hazards regression was used to evaluate the association between STR and outcome. Results. Early STR occurred in 115 (52%) and late STR in 43 (19%) patients. Patients with early or late STR had a lower incidence of one-year cardiac death than those without STR (1.9 vs. 9.2%; p=0.02). In contrast, rehospitalisation occurred more frequently in patients with early or late STR (20.3 vs. 6.2%; p=0.009). As compared with patients without STR, early and late STR had a similar prognostic value (hazard ratios [95% confidence interval] for cardiac death 0.40 [0.08-2.03] and 0.25 [0.03-2.08]). Conclusions. We found no (major) change in prognostic value of STR during the 0 to 90 minutes time window after PCI. Gepubliceerd: Neth Heart J. 2010;18(9):416-22 Impact factor: 1.392
11. Micro-computed tomographic assessment following extremely oversized partial postdilatation of drug-eluting stents Basalus MW1, van Houwelingen KG1, Ankone MJ1, Feijen J2, von Birgelen C1,2 1 Thoraxcentrum Twente, Department of Cardiology, Medisch Spectrum Twente, Enschede 2 MIRA, Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede Aims: To assess the spatial geometry of drug-eluting stents (DES) following extremely oversized proximal postdilatation. Interventions of distal left main (LM) disease generally require stenting across the LM bifurcation with inherent vessel tapering along this segment and a high likelihood of stent malapposition, which can be avoided by such postdilations. Methods and results: Sixteen DES (four 3.5 mm-samples of Cypher Select Plus, Taxus Liberty©, Endeavor Resolute, Xience V) were deployed in water; 12 samples were then proximally postdilated with noncompliant 5.0 mm balloons at 18 atm. All samples were examined by micro-computed tomography. Taxus Liberty©, Endeavor Resolute, and Xience V, showed increased cell areas in the transitional region (just distal to postdilated region), while Cypher Select showed its largest cells inside the postdilated region. Overall, the largest maximum cell area was observed in
42
Endeavor Resolute, while Cypher Select showed the smallest (p<0.001, for both). In addition, the size of the very proximal postdilated cells was relatively small in most DES except Xience V. Conclusions: Extremely oversized partial stent postdilatation demonstrated significant between-DES differences in final spatial stent configuration and maximum cell size. These data could be of practical interest with regard to coronary interventions in LM stems with stenting across the LM bifurcation. Gepubliceerd: EuroIntervention. 2010;6(1):141-148 Impact factor: 0
12. Effect of early, pre-hospital initiation of high bolus dose tirofiban in patients with ST-segment elevation myocardial infarction on short- and long-term clinical outcome. JM ten Berg*, AW van 't Hof†, T Dill‡, T Heestermans†, JW van Werkum*, A Mosterd§, #,**, G van Houwelingen||, PC Koopmans¶, PR Stella**, E Boersma††, C Hamm‡, On-TIME 2 Study Group # Julius Centre for Health Sciences and Primary Care, Utrecht † Department of Cardiology, Isala Klinieken, Zwolle †† Thorax Center Rotterdam, Rotterdam ‡ Kerckhoff-Klinik GmbH, Bad Nauheim, Germany * Department of Cardiology, St Antonius Hospital, Nieuwegein ** UMC Utrecht, Utrecht || Department of Cardiology, Medisch Spectrum Twente, Enschede § Department of Cardiology, Meander Medical Center, Amersfoort Objectives: The purpose of this trial was to study the effect of a high bolus dose (HBD) of tirofiban on clinical outcome in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI). Background: The On-TIME 2 (Ongoing Tirofiban In Myocardial infarction Evaluation 2) placebo-controlled, double-blind, randomized trial showed that early administration of HBD tirofiban in the ambulance improves ST-segment resolution in patients with STEMI undergoing primary percutaneous coronary intervention. The effect of early tirofiban treatment on clinical outcome is unclear. Methods: The On-TIME 2 trial consisted of 2 phases: an open-label phase, followed by a double-blind, placebo-controlled phase. STEMI patients were randomized to either HBD tirofiban or no tirofiban (phase 1) or placebo (phase 2) in addition to aspirin, heparin, and high-dose clopidogrel. The protocol pre-specified a pooled analysis of the 2 study phases to assess the incidence of major adverse cardiac events at the 30-day follow-up and on total mortality at the 1-year follow-up. Results: During a 3-year period, 1,398 patients were randomized, 414 in phase 1 and 984 in phase 2. Major adverse cardiac events at 30 days were significantly reduced (5.8% vs. 8.6%, p = 0.043). There was a strong trend toward a decrease in mortality (2.2% vs. 4.1%, p = 0.051) in patients who were randomized to tirofiban pre-treatment, which was maintained during the 1-year follow-up (3.7% vs. 5.8%, p = 0.08). No clinically relevant difference in bleeding was observed.
43
Conclusions: Early, pre-hospital initiation of HBD tirofiban, in addition to high-dose clopidogrel, improves the clinical outcome after primary percutaneous coronary intervention in patients with STEMI. Gepubliceerd: J Am Coll Cardiol 2010;55(22):2446-55 Impact factor: 12.640
13. The golden hour of prehospital reperfusion with triple antiplatelet therapy: a subanalysis from the Ongoing Tirofiban in Myocardial Evaluation 2 (On-TIME 2) trial early initiation of triple antiplatelet therapy T Heestermansa, AW van 't Hofb, JM ten Bergc, JW van Werkumc, E Boersmad, A Mosterde, f, g, PR Stellah, AB van Zoelenc, AT Gosselinkb, W Kochmani, T Dillj, PC Koopmansk, G van Houwelingenl, F Zijlstram, C Hammj 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, Erasmus MC, Rotterdam e Department of Cardiology, Meander Medisch Centrum, Amersfoort f Department of Cardiology, UMCUtrecht, Utrecht g Julius Centre for Health Sciences and Primary Care, UMC Utrecht, Utrecht h Department of Cardiology, Universitair Medisch Centrum, Utrecht i Department of Cardiology, Swissmed Centrum, Zdrowia S.A., Poland j Department of Cardiology, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany k Department of Medical Statistics, Diagram BV, Zwolle l Department of Cardiology, Medisch Spectrum Twente, Enschede m Department of Cardiology, UMC, Groningen Background: It is known that the efficacy of thrombolytic therapy in ST-segment elevation myocardial infarction (STEMI) is highly time dependent with the best efficacy when given within the so-called golden hour. This analysis from the OnTIME 2 trial evaluated the efficacy of triple antiplatelet therapy on initial patency and ST-segment resolution (STR) in relation to time from symptom onset to first medical contact. Methods: The On-TIME 2 trial included 1,398 consecutive STEMI patients referred for primary percutaneous coronary intervention (PCI). Patients were randomized to dual (500 mg aspirin and 600 mg clopidogrel) or triple antiplatelet (500 mg aspirin, 600 mg clopidogrel, and tirofiban 25 mug/kg bolus and 0.15 mug/kg per minute maintenance infusion for 18 hours) pretreatment in the ambulance. Primary outcome of this sub-analysis was initial patency of the infarct-related vessel and STR before PCI according to time from symptom onset to first medical contact in quartiles. In addition, the incidence of aborted myocardial infarction, defined as the absence of a rise in creatinine kinase, was assessed. Results: Initial patency, STR before PCI, and the incidence of aborted myocardial infarction gradually increased with shorter time from symptom onset to first medical contact. Initial Thrombolysis in Myocardial Infarction flow was present in 21.2% in the total population and 26.2%, 21.5%, 18.1%, and 18.8% in the time quartiles, respectively (P for trend=.01). The incidence of complete STR pre-angiography was
44
16.6% in the total population and 23.4%, 18.2%, 14.7%, and 9.9% in the 4 quartiles, respectively (P for trend<.001). This was largely driven by the effect of triple antiplatelet therapy, which further improved initial patency and STR and led to a significantly higher incidence of aborted myocardial infarction (13.2% vs 8.7%, P=.011), especially in the patients with short duration of symptoms. Conclusion: Antiplatelet pretreatment before primary PCI, including a glycoprotein IIb/IIIa blocker, seems to be most effective when given shortly after symptom onset. Further studies should be performed to test this hypothesis. Gepubliceerd: Am Heart J. 2010 Dec;160(6):1079-84 Impact factor: 4.357
14. Three-dimensional CT overlay in comparison to CartoMerge for pulmonary vein antrum isolation Stevenhagen J1,4, van der Voort PH1, Dekker LR1, Bullens RW2, van den Bosch H3, Meijer A1 1 Department of Cardiology, Catharina Hospital, Eindhoven 2 Philips Health Care, Best 3 Department of Radiology, Catharina Hospital, Eindhoven 4 Department of Cardiology, Medisch Spectrum Twente, Enschede Introduction: Three-dimensional (3D) navigation systems are widely used for pulmonary vein antrum isolation (PVAI). To circumvent left atrial (LA) mapping, 3D CT reconstructions of the LA can be superimposed directly (CT overlay) on the fluoroscopy image to guide ablation catheters and to mark ablation sites. Methods and results: Sixty-eight patients (pts) with symptomatic AF refractory to medical therapy were randomly assigned to CT overlay (group 1, n = 38) or CartoMerge (group 2, n = 30). In group 1 registration of the CT image was performed with contrast injections in 2 orthogonal projections. In group 2, visualization of all pulmonary vein (PV) ostia was done by PV angiography, followed by merging of the CT image and the Carto shell. We compared procedural success, procedure time, fluoroscopy time and radiation burden, measured as dose area product (DAP). Baseline characteristics were comparable in both groups. Procedural success, defined as disappearance of PV potentials in all PVs, was achieved in 37/38 (97%) of group 1 patients and 27/30 (90%) patients in group 2 (P = NS). Total procedure time was significantly shorter in group 1 compared to group 2 (129 +/- 34 vs 181 +/- 30 min, P < 0.0001). Although fluoroscopy time tended to be longer in the CT overlay group (47 +/- 16 vs 40 +/- 13 min, P = 0.06), proper use of diaphragmation resulted in comparable radiation values for both groups (DAP 53 +/27 vs 56 +/- 35 Gy cm(2), P = 0.76). Conclusions: CT overlay for PV isolation is feasible and may, in comparison to conventional LA navigation systems, shorten procedural time without increases in radiation burden. Gepubliceerd: J Cardiovasc Electrophysiol 2010 Jun 1;21(6):634-9 Impact factor: 3.703
45
Totale impact factor: 37.469 Gemiddelde impact factor: 2.676 Aantal artikelen 1e, 2e of laatste auteur: 12 Totale impact factor: 20.472 Gemiddelde impact factor: 1.706
46
Gastroenterologie 1. Fatigue and health-related quality of life in inflammatory bowel disease: Results from a population-based study in the Netherlands: The IBD-South Limburg cohort MJ Romberg-Camps1, Y Bol2, PC Dagnelie3, MA Hesselink-van de Kruijs1, AD Kester4, LG Engels5, C van Deursen6, WHA Hameeteman1, M Pierik1, F Wolters7, MG Russel8, RW Stockbrügger1 1 Department of Gastroenterology and Hepatology, Maastricht UMC, Maastricht 2 Department of Medical Psychology and Psychiatry, Orbis Medical Centre, Sittard 3 Department of Epidemiology, Maastricht University, Maastricht 4 Department of Methodology and Statistics, Maastricht University, Maastricht 5 Department of Gastroenterology, Maasland Hospital, Sittard 6 Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht 7 Department of Gastroenterology and Hepatology, University Hospital Maastricht, Maastricht 8 Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede Background: The importance of fatigue in chronic disease has been increasingly recognized; however, little is known about fatigue in inflammatory bowel disease (IBD). The aim of the present study was to investigate the prevalence and severity of fatigue and the impact on health-related quality of life (HRQoL) in patients included in a population-based IBD cohort in the Netherlands. Methods: IBD patients, diagnosed between January 1st, 1991, and January 1st, 2003, were followed up for a median of 7.1 years. They completed a questionnaire, which included a disease activity score, the Multidimensional Fatigue Inventory (MFI-20), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the Short Form health survey (SF-36). Hemoglobin levels were recorded. Results: Data were available in 304 Crohn's disease (CD), 368 ulcerative colitis (UC), and 35 indeterminate colitis (IC) patients. During quiescent disease, the prevalence of fatigue was nearly 40%. MFI-20 and HRQoL scores were significantly worse in IBD patients having active disease. In a multivariate analysis, disease activity was positively related with the level of fatigue in both CD and UC. In UC, anemia influenced the general fatigue score independently of disease activity. Disease activity as well as fatigue were independently associated with an impaired IBDQ. Conclusions: In IBD, even in remission, fatigue is an important feature. Both in CD and in UC, fatigue determined HRQoL independently of disease activity or anemia. This implies that in IBD patients physicians need to be aware of fatigue in order to better understand its impact and to improve the HRQoL. Gepubliceerd: Inflamm Bowel Dis. 2010;16(12):2137-47 Impact factor: 4.643
2. Invited commentary
47
Geelkerken RH1, Kolkman JJ2, Huisman AB3 Department of 1Surgery, 2Gastroenterology, 3Radiology, Medisch Spectrum Twente, Enschede Gepubliceerd: J Vasc Surg 2010;51(1):147 Impact factor: 3.517
3. Open or percutaneous revascularization for chronic splanchnic syndrome Van Petersen AS1, Kolkman JJ2, Beuk RJ1, Huisman AB3, Doelman CJ4, Geelkerken RH1 Department of 1surgery, 2Gastroenterology, 3Radiology, 4Clinical Chemistry, Medisch Spectrum Twente, Enschede Background: Treatment of chronic splanchnic syndrome remains controversial. In the past 10 years, endovascular repair (ER) has replaced open repair (OR) to some extent. This evidence summary reviews the available evidence for ER or OR of chronic splanchnic syndrome. Methods: A systematic literature search of MEDLINE database was performed to identify all studies that evaluated treatment of chronic splanchnic syndrome between 1988 and 2009. Results: The best available evidence consists of prospectively accumulated but retrospectively analyzed data with a high risk for confounding. Only a few of these studies incorporated functional tests to assess splanchnic ischemia before or after treatment. ER has the advantage of low short-term morbidity but the disadvantage of decreased long-term primary patency compared with OR. ER and OR have similar rates of secondary patency, although the reintervention rate after ER is higher. Conclusion: ER appears to be preferential in the treatment of elderly patients and in patients with comorbidity, severe cachexia, or hostile abdomen. Long-term results after OR are excellent. OR can still be proposed as the preferred option for relatively young and fit patients. Gepubliceerd: J Vasc Surg. 2010;51(5):1309-1316 Impact factor: 3.517
4. "Re: Management of median arcuate ligament syndrome: a new paradigm" van Petersen A, Meerwaldt R, Beuk R, Kolkman J, Geelkerken R Gepubliceerd: Ann Vasc Surg. 2010;24(5):699-700 Impact factor: 1.169
5. Appropriateness of early management of newly diagnosed Crohn's disease in a European population-based cohort Juillerat P1, Pittet V, Mottet C, Felley C, Gonvers JJ, Vader JP, Burnand B, Froehlich F, Wolters FL, Stockbrügger RW, Michetti P; EC-IBD Group. Includes Russel MG*1
48
Department of Gastroenterology & Hepatology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland * Department of Gastroenterology, Medisch Spectrum Twente, Enschede Objective: The European Panel on the Appropriateness of Crohn's disease Therapy (EPACT) has developed appropriateness criteria. We have applied these criteria retrospectively to the population-based inception cohort of Crohn's disease (CD) patients of the European Collaborative Study Group on Inflammatory Bowel Disease (EC-IBD). Material and methods: A total of 426 diagnosed CD patients from 13 European centers were enrolled at the time of diagnosis (first flare, naive patients). We used the EPACT definitions to identify 247 patients with active luminal CD. We then assessed the appropriateness of the initial drug prescription according to the EPACT criteria. Results: Among the cohort patients 163 suffered from mild-to-moderate CD and 84 from severe CD. Among the mild-to-moderate disease group, 96 patients (59%) received an appropriate treatment, whereas for 66 patients (40%) the treatment was uncertain and in one case (1%) inappropriate. Among the severe disease group, 86% were treated medically and 14% required surgery. 59 (70%) were appropriately treated, whereas for one patient (1%) the procedure was considered uncertain and for 24 patients (29%) inappropriate. Conclusion: Initial treatment was appropriate in the majority of cases for noncomplicated luminal CD. Inappropriate or uncertain treatment was given in a significant minority of patients, with an increased potential risk of adverse events. Gepubliceerd: Scand J Gastroenterol. 2010;45(12):1449-56 Impact factor: 2.084
Totale impact factor: 14.930 Gemiddelde impact factor: 2.986 Aantal artikelen 1e, 2e of laatste auteur: 2 Totale impact factor: 7.034 Gemiddelde impact factor: 3.517
49
Gynaecologie 1. Hysterectomy, endometrial destruction, and levonorgestrel releasing intrauterine system (Mirena) for heavy menstrual bleeding: systematic review and meta-analysis of data from individual patients Middleton LJ 1, Champaneria R1, Daniels JP 1, Bhattacharya S2, Cooper KG3, Hilken NH 1, O’Donovan P4,5, Gannon M6, Gray R1, Khan KS 7, Abbott J8, Barrington J9, Bongers MY10, Brun JL11, Busfield R12, Clark TJ13, Cooper J14, Cooper KG15, Corson SL16, Dickersin K17, Dwyer N18, Gannon M19, Hawe J20, Hurskainen R21, Meyer WR22, O'Connor H23, Pinion S24, Sambrook AM25, Tam WH26, van Zon-Rabelink IA27, Zupi E28 1 Birmingham Clinical Trials Unit, University of Birmingham, UK; 2Section of Applied Clinical Sciences, Division of Applied Health Sciences, School of Medicine and Dentistry, University of Aberdeen, Aberdeen Maternity Hospital, Aberdeen, UK; 3 Department of Obstetrics and Gynaecology, Aberdeen Royal Infirmary, Aberdeen, UK; 4Bradford Royal Infirmary, Bradford, UK; 5University of Bradford, Bradford, UK; 6 Department of Obstetrics and Gynaecology, Midland Regional Hospital, Mullingar, Co Westmeath, Ireland; 7Academic Department of Obstetrics and Gynaecology, Division of Reproductive and Child Health, University of Birmingham, Birmingham Women’s Hospital, Birmingham, UK; 8 University of New South Wales, Sydney, Australia; 9 Torbay Hospital, South Devon, UK; 10 Maxima Medical Centre, Veldhoven; 11 Hopital Universitarie Pellegrin, Bordeaux, France; 12 Auckland Obstetric Centre, New Zealand; 13 Birmingham Women’s Hospital, Birmingham, UK; 14 Microsulis Medical, Hampshire; 15 Aberdeen Royal Infirmary, Aberdeen, UK; 16 Boston Scientific Corporation, Marlborough, USA; 17 John Hopkins Bloomberg School of Public Health, USA; 18 Weston General Hospital, Weston Super Mare, UK; 19 Midland Regional Hospital, Mullingar, Ireland; 20 Countess of Chester Hospital, Chester, UK; 21 University of Helsinki, Finland; 22 Johnson and Johnson, New Jersey, USA; 23 Coombe Women’s Hospital, Dublin, Ireland; 24 Aberdeen Royal Infirmary, Aberdeen, UK; 25 Aberdeen Royal Infirmary, Aberdeen, UK; 26 Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China; 27 Medical Spectrum Twente, Enschede; 28 Tor Vergata University, Rome, Italy Objective: To evaluate the relative effectiveness of hysterectomy, endometrial destruction (both "first generation" hysteroscopic and "second generation" nonhysteroscopic techniques), and the levonorgestrel releasing intrauterine system (Mirena) in the treatment of heavy menstrual bleeding. Design: Meta-analysis of data from individual patients, with direct and indirect comparisons made on the primary outcome measure of patients' dissatisfaction. Data sources: Data were sought from the 30 randomised controlled trials identified after a comprehensive search of the Cochrane Library, Medline, Embase, and CINAHL databases, reference lists, and contact with experts. Raw data were available from 2814 women randomised into 17 trials (seven trials including 1359 women for first v second generation endometrial destruction; six trials including 1042 women for hysterectomy v first generation endometrial destruction; one trial including 236 women for hysterectomy v Mirena; three trials including 177 women for second generation endometrial destruction v Mirena). Eligibility criteria for
50
selecting studies Randomised controlled trials comparing hysterectomy, first and second generation endometrial destruction, and Mirena for women with heavy menstrual bleeding unresponsive to other medical treatment. Results: At around 12 months, more women were dissatisfied with outcome with first generation hysteroscopic techniques than with hysterectomy (13% v 5%; odds ratio 2.46, 95% confidence interval 1.54 to 3.9, P<0.001), but hospital stay (weighted mean difference 3.0 days, 2.9 to 3.1 days, P<0.001) and time to resumption of normal activities (5.2 days, 4.7 to 5.7 days, P<0.001) were longer for hysterectomy. Unsatisfactory outcomes were comparable with first and second generation techniques (odds ratio 1.2, 0.9 to 1.6, P=0.2), although second generation techniques were quicker (weighted mean difference 14.5 minutes, 13.7 to 15.3 minutes, P<0.001) and women recovered sooner (0.48 days, 0.20 to 0.75 days, P<0.001), with fewer procedural complications. Indirect comparison suggested more unsatisfactory outcomes with second generation techniques than with hysterectomy (11% v 5%; odds ratio 2.3, 1.3 to 4.2, P=0.006). Similar estimates were seen when Mirena was indirectly compared with hysterectomy (17% v 5%; odds ratio 2.2, 0.9 to 5.3, P=0.07), although this comparison lacked power because of the limited amount of data available for analysis. Conclusions: More women are dissatisfied after endometrial destruction than after hysterectomy. Dissatisfaction rates are low after all treatments, and hysterectomy is associated with increased length of stay in hospital and a longer recovery period. Definitive evidence on effectiveness of Mirena compared with more invasive procedures is lacking. Gepubliceerd: BMJ. 2010;341:c3929 Impact factor: 13.660
2. Spontaneous hemoperitoneum and fetal demise in a nulliparous woman requiring hysterectomy with fetus in situ OM Brouckaert, E Oostenveld, H Quartero Department of Obstetrics and Gynecology, Medisch Spectrum Twente, Enschede Spontaneous hemoperitoneum in pregnancy (SHiP) is a rare entity reported to occur in the second half of pregnancy, in labor, or in the early postpartum period [1]. Dramatic maternal and fetal/neonatal mortality rates (0%–49.3% and 31%–36%, respectively) have been reported [1]. The cause of SHiP is unknown. Several reports suggest endometriosis as a risk factor [1,2]. The main presenting symptomis subacute or acute abdominal pain. Diagnosis is established most often at laparotomy [1]. Management of SHiP is dependent upon the case. In several cases reporting preterm SHiP, successful hemostasis was achieved using clips or coagulation, resulting in subsequent delivery at term [1,3]. In other cases, term and preterm cesarean delivery was performed—in one case followed by hysterectomy owing to uncontrollable maternal bleeding of varicose veins on the posterior uterine surface [1,2]. Yet in other cases, delivery was induced after diagnosis of fetal death or severe intrauterine asphyxia was established [1]. A 33-year-old nulliparous woman was admitted to the emergency room with acute abdominal pain at 17 weeks of pregnancy (based on date of last menstrual period).
51
There was no vaginal blood loss and no history of abdominal trauma. Her personal history revealed severe endometriosis (r-AFS stage IV). Treatmentwith triptorelin (Decapeptyl; Ferring BV ), a gonadotropin-releasing hormone analogue, had been initiated several months before in vitro fertilization (IVF) was started. The patient conceived after IVF and embryo transfer. Her antenatal course had been complicated by hydronephrosis that required hospitalization and she received double J-stents at 15 weeks+ 5 days of pregnancy and was discharged at 16 weeks+3 days. Clinical findings were consistent with acute abdomen. Vital parameters were normal. Abdominal ultrasound revealed an intact pregnancy and free peritoneal fluid. Hemoglobin was 6.1 mmol/L; hematocrit 0.30; and leukocytosis 16.1×109 /L. After developing sudden hypotensive shock, laparoscopy was performed and revealed 2600 mL of clots and free blood. A ruptured cyst at the right ovary, fixed in the pouch of Douglas, appeared to be the primary site of bleeding. Partial right ovariectomy was performed and hemostasis was achieved. A second episode of hypotensive shock occurred in the recovery room. Ultrasound was repeated and showed fetal demise and new abdominal free fluid. Second-look surgery by laparotomy was performed and revealed another 3500 mL of free blood. Again, the primary site of bleeding appeared to be situated at the right ovary. After successful right adnexectomy, other sites of bleeding appeared in the pouch of Douglas as well as in the right broad ligament, with a major bleeding site at the level of the uterine artery. Several attempts to achieve hemostasis were unsuccessful. A hysterectomy with the fetus in situ was performed, keeping in mind that even if hemostasis could be achieved, subsequent delivery of the dead fetus would not be without risk. After completing supracervical hysterectomy, other bleeding sites were discovered in areas suggestive of endometriotic lesions. Hemostasis was achieved using bipolar coagulation and sutures. After both surgeries, blood loss was estimated at 14 600 mL. During surgery, 20 units of blood, 2 units of donor platelets, and 10 units of fresh frozen plasma were required. After 1 day spent on the intensive care unit the patient had recovered well physically and she was discharged after another 11 days. The histopathological report described lesions at the parametrial bleeding site suggestive of endometriosis (decidualization). This case of SHiP in the first half of pregnancy reminds clinicians of this rare condition and the therapeutic options that may be required. References [1] Brosens IA, Fusi L, Brosens JJ. Endometriosis is a risk factor for spontaneous hemoperitoneum during pregnancy. Fertil Steril 2009;92(4):1243–5. [2] Passos F, Calhaz-Jorge C, Graca LM. Endometriosis is a possible risk factor for spontaneous hemoperitoneum in the third trimester of pregnancy. Fertil Steril 2008;89(1):251–2. [3] Roger N, Chitrit Y, Souhaid A, Rezig K, Saint-Leger S. Intraperitoneal hemorrhage from rupture of uterine varicose vein during pregnancy: case report and review of the literature [in French]. J Gynecol Obstet Biol Reprod (Paris) 2005;34(5):497–500. Gepubliceerd: Int. J. Gynecol Obstet 2010;110(3):273 Impact factor: 1.408
52
3. Outcomes after internal versus external tocodynamometry for monitoring labor Bakker JJ1, Verhoeven CJ2, Janssen PF3,4, van Lith JM5,6, van Oudgaarden ED6, Bloemenkamp KW7, Papatsonis DN8, Mol BW1,2, van der Post JA1 1 Department of Obstetrics and Gynecology, AMC, Amsterdam; 2 Máxima Medical Center, Veldhoven; 3 VU MC, Amsterdam; 4 Medisch spectrum Twente, Enschede; 5 Onze Lieve Vrouwe Gasthuis, Amsterdam; 6 Slotervaart Hospital, Amsterdam; 7 Leiden UMC, Leiden; 8 Amphia Hospital Breda, Breda Background: It has been hypothesized that internal tocodynamometry, as compared with external monitoring, may provide a more accurate assessment of contractions and thus improve the ability to adjust the dose of oxytocin effectively, resulting in fewer operative deliveries and less fetal distress. However, few data are available to test this hypothesis. Methods: We performed a randomized, controlled trial in six hospitals in The Netherlands to compare internal tocodynamometry with external monitoring of uterine activity in women for whom induced or augmented labor was required. The primary outcome was the rate of operative deliveries, including both cesarean sections and instrumented vaginal deliveries. Secondary outcomes included the use of antibiotics during labor, time from randomization to delivery, and adverse neonatal outcomes (defined as any of the following: an Apgar score at 5 minutes of less than 7, umbilical-artery pH of less than 7.05, and neonatal hospital stay of longer than 48 hours). Results: We randomly assigned 1456 women to either internal tocodynamometry (734) or external monitoring (722). The operative-delivery rate was 31.3% in the internal-tocodynamometry group and 29.6% in the external-monitoring group (relative risk with internal monitoring, 1.1; 95% confidence interval [CI], 0.91 to 1.2). Secondary outcomes did not differ significantly between the two groups. The rate of adverse neonatal outcomes was 14.3% with internal monitoring and 15.0% with external monitoring (relative risk, 0.95; 95% CI, 0.74 to 1.2). No serious adverse events associated with use of the intrauterine pressure catheter were reported. Conclusions: Internal tocodynamometry during induced or augmented labor, as compared with external monitoring, did not significantly reduce the rate of operative deliveries or of adverse neonatal outcomes. Gepubliceerd: N Engl J Med. 2010;362(4):306-13 Impact factor: 47.050
4. Aspirin plus Heparin or Aspirin Alone in Women with Recurrent Miscarriage Kaandorp SP1, Goddijn M2, van der Post JA1, Hutten BA3, Verhoeve HR5, Hamulyák K6, Mol BW7, Folkeringa N8, Nahuis M9, Papatsonis DN10, Büller HR4, van der Veen F2, Middeldorp S11 From the Department of 1Obstetrics and Gynecology, 2the Center for Reproductive Medicine, 3the Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, and 4the Department of Vascular Medicine, AMC, University of Amsterdam, Amsterdam; 5Onze Lieve Vrouwe Gasthuis, Amsterdam; 6University Hospital Maastricht, Maastricht University, Maastricht; 7Máxima Medical Center, Veldhoven; 8UMC Groningen, University of Groningen, Groningen; 9Medisch
53
Spectrum Twente Hospital Group, Enschede; 10Amphia Hospital, Breda; and Leiden UMC, University of Leiden, Leiden
11
Background: Aspirin and low-molecular-weight heparin are prescribed for women with unexplained recurrent miscarriage, with the goal of improving the rate of live births, but limited data from randomized, controlled trials are available to support the use of these drugs. Methods: In this randomized trial, we enrolled 364 women between the ages of 18 and 42 years who had a history of unexplained recurrent miscarriage and were attempting to conceive or were less than 6 weeks pregnant. We then randomly assigned them to receive daily 80 mg of aspirin plus open-label subcutaneous nadroparin (at a dose of 2850 IU, starting as soon as a viable pregnancy was demonstrated), 80 mg of aspirin alone, or placebo. The primary outcome measure was the live-birth rate. Secondary outcomes included rates of miscarriage, obstetrical complications, and maternal and fetal adverse events. Results: Live-birth rates did not differ significantly among the three study groups. The proportions of women who gave birth to a live infant were 54.5% in the group receiving aspirin plus nadroparin (combination-therapy group), 50.8% in the aspirinonly group, and 57.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, -2.6 percentage points; 95% confidence interval [CI], -15.0 to 9.9; aspirin only vs. placebo, -6.2 percentage points; 95% CI, -18.8 to 6.4). Among 299 women who became pregnant, the live-birth rates were 69.1% in the combination-therapy group, 61.6% in the aspirin-only group, and 67.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, 2.1 percentage points; 95% CI, -10.8 to 15.0; aspirin alone vs. placebo -5.4 percentage points; 95% CI, -18.6 to 7.8). An increased tendency to bruise and swelling or itching at the injection site occurred significantly more frequently in the combination-therapy group than in the other two study groups. Conclusions: Neither aspirin combined with nadroparin nor aspirin alone improved the live-birth rate, as compared with placebo, among women with unexplained recurrent miscarriage. Gepubliceerd: N Engl J Med. 2010;362(17):1586-1596 Impact factor: 47.050
5. The LIFESTYLE study: costs and effects of a structured lifestyle program in overweight and obese subfertile women to reduce the need for fertility treatment and improve reproductive outcome. A randomised controlled trial MA Mutsaerts¹, H Groen2 , NCW ter Bogt3, JHT Bolster¹, JA Land¹, WJE Bemelmans4, WKH Kuchenbecker5, PGA Hompes6, NS Macklon7, RP Stolk2, F van der Veen8, JWM Maas9, NF Klijn10, EM Kaaijk11, GJE Oosterhuis12, PXJM Bouckaert13, JM Schierbeek14, YM van Kasteren15, AW Nap16, FJ Broekmans7, EA Brinkhuis17, CAM Koks18, JM Burggraaff19, AS Blankhart20, DAM Perquin21, MH Gerards22, RJAB Mulder23, ETCM Gondrie24, BWJ Mol25, A Hoek¹ 1 Department of Obstetrics and Gynaecology, 2 Epidemiology, and 3 Department of General Practice, UMC Groningen, University; of Groningen, Groningen; 4 Centre for Prevention and Health Services Research, National Institute for Public; Health and
54
the Environment, Bilthoven; Department of Obstetrics and Gynaecology 5 Isala Clinics, Zwolle, 6 VU MC, Amsterdam, 7 Utrecht MC University, University of Utrecht, 8 AMC, University of, Amsterdam, Amsterdam, 9 Maastricht University Medical, Center, University of Maastricht, Maastricht, 10 LUMC, University of Leiden, Leiden, 11 Onze Lieve Vrouwe Gasthuis, Amsterdam, 12 Medical Spectrum Twente, Enschede, 13 Atrium Medical Center, Heerlen, 14 Deventer Hospital, Deventer, 15 Medical Center Alkmaar, Alkmaar, 16 Rijnstate Hospital, Arnhem, 17 Meander Medical Center, Amersfoort, 18 Maxima Medical Center, Veldhoven, 19 Leveste Hospital, Emmen, 20 Antonius Hospital, Nieuwegein, 21 Medical Center Leeuwarden, Leeuwarden, 22 Martini Hospital, Groningen, 23 Laurentius Hospital, Roermond, 24 Orbis Medical Center, Sittard, 25 AMC, University of Amsterdam, Amsterdam Background: In the Netherlands, 30% of subfertile women are overweight or obese, and at present there is no agreement on fertility care for them. Data from observational and small intervention studies suggest that reduction of weight will increase the chances of conception, decrease pregnancy complications and improve perinatal outcome, but this has not been confirmed in randomised controlled trials. This study will assess the cost and effects of a six-months structured lifestyle program aiming at weight reduction followed by conventional fertility care (intervention group) as compared to conventional fertility care only (control group) in overweight and obese subfertile women. We hypothesize that the intervention will decrease the need for fertility treatment, diminish overweight-related pregnancy complications, and will improve perinatal outcome. Methods: Multicenter randomised controlled trial in subfertile women (age 18-39 year) with a body mass index between 29 and 40 kg/m;2. Exclusion criteria are azoospermia, use of donor semen, severe endometriosis, premature ovarian failure, endocrinopathies or pre-existent hypertensive disorders. In the intervention group the aim is a weight loss of at least 5% to10% in a six-month period, to be achieved by the combination of a diet, increase of physical activity and behavioural modification. After six months, in case no conception has been achieved, these patients will start fertility treatment according to the Dutch fertility guidelines. In the control group treatment will be started according to Dutch fertility guidelines, independently of the patient's weight. Outcome measures and analysis: The primary outcome measure is a healthy singleton born after at least 37 weeks of gestation after vaginal delivery. Secondary outcome parameters including pregnancy outcome and complications, percentage of women needing fertility treatment, clinical and ongoing pregnancy rates, body weight, quality of life and costs. Data will be analysed according to the intention to treat principle, and cost-effectiveness analysis will be performed to compare the costs and health effects in the intervention and control group. Discussion: The trial will provide evidence for costs and effects of a lifestyle intervention aiming at weight reduction in overweight and obese subfertile women and will offer guidance to clinicians for the treatment of these patients. Gepubliceerd: BMC Womens Health. 2010;10(1):22 Impact factor: 0
55
6. Restless Genital Syndrome Before and After Clitoridectomy for Spontaneous Orgasms: A Case Report Waldinger MD1,2, Venema PL3, van Gils AP4, Schutter EM5, Schweitzer DH6 1 Department of Psychiatry and Neurosexology, HagaHospital Leyenburg, The Hague 2 Department of Psychopharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute for Neurosciences, Utrecht University, Utrecht 3 Outpatient Department of Continence, HagaHospital Leyenburg, The Hague 4 Department of Radiology and Nuclear Medicine, HagaHospital Leyenburg, The Hague 5 Department of Obstetrics and Gynaecology, Medisch Spectrum Twente, Enschede 6 Department of Internal Medicine and Endocrinology, Reinier de Graaf Groep of Hospitals, Delft-Voorburg Introduction. Females despairing of restless genital syndrome (ReGS) may request clitoridectomy for treatment of unwanted genital sensations. Aim. The aim of this study was to report persistence of ReGS despite clitoridectomy. Methods. Following a clitoridectomy for spontaneous orgasms, a 77-year-old woman was referred to our clinic for persistent unwanted genital sensations and feelings of imminent orgasm. An in-depth interview, routine and hormonal investigations, electroencephalography (EEG) and magnetic resonance imaging (MRI) of the brain and pelvis were performed. The localizations of genital sensations were investigated by manual examination of the ramus inferior of the pubic bone (RIPB) and by sensory testing of the skin of the genital area with a cotton swab. Main Outcome Measures. The main outcome measures included sensitivity of dorsal nerve of the clitoris in RIPB and MRI-pelvis. Results. Genital dysesthesias, paresthesias, intolerance (allodynia) for tight clothes, aggravation of symptoms during sitting, restless legs, and overactive bladder were diagnosed. Laboratory assessments, and EEG and MRI of the brain were in agreement with aging, but all results were within the normal range. MRI of the pelvis disclosed varices of the uterus and of the left ovarian vein, and a visible scar in the region of the clitoris. Sensory testing of the genital area showed various points of static mechanical hyperesthesia at the left dermatome of the pudendal nerve. Manual examination of the RIPB also elicited the genital sensations at the left side of the vagina at about the 3 o'clock position. Conclusions. This patient fulfilled all clinical criteria of ReGS that is believed to be caused by neuropathy of the left pudendal nerve. Clitoridectomy abolished spontaneous orgasms for a great part but not completely, and it did not diminish the typical dysesthesias, paresthesias, and feelings of imminent orgasms that typically belong to ReGS. Clitoridectomy is no optional treatment of ReGS. There is a need for publications of ReGS in general medical journals. Gepubliceerd: J Sex Med. 2010;7:1029-1034 Impact factor: 4.884
7. The number of metastatic sites for stage IIIA endometrial carcinoma, endometrioid cell type, is a strong negative prognostic factor
56
Jobsen JJ1, Ten Cate LN2, Lybeert ML3, van der Steen-Banasik EM4, Scholten A5, van der Palen J6,11, Slot A7, Kroese MC8, Schutter EM9, Siesling S10 1 Department of Radiation Oncology, Medisch Spectrum Twente, Enschede 2 Laboratorium Pathologie Oost Nederland, Enschede 3 Department of Radiation Oncology, Catharina Hospital, Eindhoven 4 Arnhem Radiotherapeutic Institute, Arnhem 5 Department of Clinical Oncology, Leiden UMC, Leiden 6 Department of Research Methodology, Measurement, and Data Analysis, Faculty of Behavioral Science, University of Twente 7 Radiotherapy Institute Friesland, Leeuwarden 8 Radiotherapy Institute Steden en Omstreken, Deventer 9 Departments of Obstetrics and Gynaecology, Medisch Spectrum Twente, Enschede 10 Comprehensive Cancer Centre North East, Enschede/Groningen 11 Clinical Epidemiology, Medisch Spectrum Twente, Enschede The aim of this study was to look at the impact of the number of sites with tumour involvement on outcome for patients with stage IIIA endometrioid-type endometrial carcinoma. Patients and methods: 141 patients stage IIIA were included. A central histopathological review was performed. Patients staged solely on the presence of a positive peritoneal washing were excluded. Follow-up ranged from 2 to 217 months with a median of 43 months. Endpoints of the study were locoregional recurrence rates, distant metastasis-free survival (DMFS), disease-free survival (DFS) and disease-specific survival (DSS). Results: In multivariate analyses the number of involved sites showed to be the only independent significant variable for DMFS, DFS, and DSS with a Hazard Ratio of 2.1, 2.2, and 2.2, respectively. The DSS was significantly related to the number of involved sites, with a 5-year DSS of 70.4% for one site, 42.8% for two sites, and 43.9% for three sites, respectively (p=0.001). Conclusion: The number of involved sites outside the corpus uterine for stage IIIA seems to be a strong negative prognostic factor for stage IIIA endometrial carcinoma. Gepubliceerd: Gynecol Oncol. 2010;117:32-36 Impact factor: 3.733
8. Primary retroperitoneal mucinous cystadenocarcinoma: a case report and review of the literature I. Dierickxa, e,f, G. Jacomenb, V. Schelfhoutb, P. Moermand, P. Corveleyna, T. Spiessensc, F. Amante, P. Berteloota, e Departments of aObstetrics and Gynecology, bPathology and cSurgery, Sint Maarten Ziekenhuis Campus Rooienberg, Duffel, and Departments of dPathology and e Obstetrics and Gynecology, Katholieke Universiteit Leuven, Leuven, Belgium f Department of Obstetrics and Gynecology, Medisch Spectrum Twente, Enschede
57
A 50-year-old female complained of a painless abdominal distension. Histopathologic examination after cystectomy showed a primary poorly differentiated retroperitoneal mucinous cystadenocarcinoma with a sarcoma-like mural nodule. The patient subsequently underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy, appendectomy, omentectomy and lymphadenectomy. Adjuvant chemotherapy consisted of 6 times carboplatin (AUC 7) in monotherapy (every 4 weeks). Based on 49 cases of primary retroperitoneal mucinous cystadenocarcinoma, we discuss the histogenesis and we define the appropriate treatment. Gepubliceerd: Gynecol Obstet Invest. 2010;70(3):186-91 Impact factor: 1.045
9. Recurrent incarceration and/or sacculation of the gravid uterus: a review Dierickx I1,5, Mesens T1, Van Holsbeke C1, Meylaerts L2, Voets W3, Gyselaers W1,4 1 Department of Obstetrics and Gynecology and 2Department of Medical Imaging, Ziekenhuis Oost Limburg, Genk, Belgium; 3Department of Obstetrics and Gynecology, Salvator-St.-Ursula Ziekenhuis, Hasselt, Belgium; 4Department of Physiology, Hasselt University, Diepenbeek, Belgium 5 Department of Obstetrics and Gynecology, Medisch Spectrum Twente, Enschede Retroverted uterine incarceration with sacculation of the anterior wall is reported to occur approximately in 1/3000 pregnancies. A literature search identified only one case report of incarceration of an anteflexed gravid uterus and six reported cases of recurrent incarceration and/or sacculation. We present a case of an incarceration of an anteflexed uterus in the first pregnancy, followed by a retroflexed incarceration in the second pregnancy. From this, a review is presented on recurrent uterine incarceration and/or sacculation. Gepubliceerd: J Matern Fetal Neonatal Med. 2010 Aug;23(8):776-80 Impact factor: 1.362
10. Blood-borne angiogenic factors and sustained multiple implantation: a comparison of singleton and twin pregnancies Groeneveld E1, Lambers MJ1, Hoozemans DA1,2, Schats R1, Hompes PG1, Lambalk CB1 1 Department of Obstetrics, Gynaecology and Reproductive Medicine, VU MC, Amsterdam 2 Department of Obstetrics and Gynecology, Medisch Spectrum Twente, Enschede This study aimed to compare longitudinal serum concentrations of angiogenic implantation factors between ongoing singleton and twin pregnancies after doubleembryo transfer and to investigate whether these are involved in sustained double implantation. Sixteen patients with an ongoing singleton and nine patients with an ongoing twin pregnancy after double-embryo transfer were included in this prospective observational study. Main outcome measures were concentrations of
58
vascular endothelial growth factor-A (VEGF-A), inhibin A, glycodelin A, insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), insulin-like growth factor binding protein-1 (IGFBP-1) and insulin-like growth factor binding protein-3 (IGFBP3) at baseline, during the IVF treatment and in early pregnancy. It appeared that VEGF-A concentrations prior to any treatment and at early implantation as well as body mass index (BMI) were higher in women who conceived a twin pregnancy (P = 0.04). Soon after implantation, inhibin A concentrations were higher in twin pregnancies (P=0.02). Secretion profiles of glycodelin A and members of the IGF family did not differ between singleton and twin pregnancies. VEGF-A appears to play a role in sustained double implantation. Furthermore a high BMI is associated with ongoing double implantation. Future studies should investigate the predictive value of VEGF-A for having an ongoing singleton or twin pregnancy. Gepubliceerd: Reprod Biomed Online. 2010 Jun;20(6):822-30 Impact factor: 2.380
11. Hysterectomy or a minimal invasive alternative? A systematic review on quality of life and satisfaction Brölmann HA1, Bijdevaate AJ2, Vonk Noordegraaf A4, Janssen PF2,3, Huirne JA1 1 Department of Gynecology, VU UMC, Amsterdam 2 Department of Obstetrics and Gynecology, VU University center, Amsterdam 3 Department of Obstetrics and Gynecology, Medisch Spectrum Twente, Enschede 4 Department of Obstetrics and Gynecology, AMC, Amsterdam Nowadays, an increasing number of minimal invasive treatment alternatives to hysterectomy may be offered to the patient. In determining the appropriate treatment option, the patient has a distinct dilemma if a minimal invasive treatment with lesser effect than hysterectomy should be chosen or if a hysterectomy should be chosen which is a major surgery and requires longer recovery than the minimal invasive alternative. Quality-of-life (QoL) questionnaires that take subjective health perception into account are currently used to assess the treatment effects. The objective of this literature study is to determine and discuss the role of QoL as an outcome in randomized controlled trials (RCT) or systematic reviews of RCTs that study the treatment effect of hysterectomy compared to that of minimal invasive alternatives. A systematic literature search was performed in the PubMed database and in the Cochrane database to find randomized trials and systematic reviews of randomized trials, comparing hysterectomy with minimal invasive or conservative treatment options with sufficient follow-up using satisfaction, health status, and quality of life as outcomes. The results were based on nine randomized trials and two systematic reviews. The differences are mostly in favor of hysterectomy. In two out of four studied treatment alternatives, the satisfaction or health status is different in favor of hysterectomy while the QoL is equivalent. After 2 years of follow-up, differences between both groups have disappeared, possibly because of the crossover effect. Possible reasons for the lesser response of QoL compared to satisfaction or health status are discussed. The fundamental question if patients have a better quality of life at all times if they choose for a minimal invasive alternative of hysterectomy remains unresolved. Information, individualization, and
59
freedom of choice before surgery probably best serve the sense of well being and quality of life thereafter. Gepubliceerd: Gynecol Surg. 2010;7(3):205-210 Impact factor: 0
12. Review of the safety, efficacy, costs and patient acceptability of recombinant follicle-stimulating hormone for injection in assisting ovulation induction in infertile women M Nahuis1,2,3, F van der Veen1, J Oosterhuis2, BW Mol1, P Hompes3, M van Wely1 1 Center for Reproductive Medicine, Department of Obstetrics and Gynaecology, AMC, University of Amsterdam, Amsterdam 2 Department of Obstetrics and Gynaecology, Medisch Spectrum Twente, Enschede 3 Department of Obstetrics and Gynaecology, VU Medical Center, Amsterdam Anovulation is a common cause of female subfertility. Treatment of anovulation is aimed at induction of ovulation. In women with clomiphene-citrate resistant WHO group II anovulation, one of the treatment options is ovulation induction with exogenous follicle-stimulating hormone (FSH or follitropin). FSH is derived from urine or is produced as recombinant FSH. Two forms of recombinant FSH are available - follitropin alpha and follitropin beta. To evaluate the efficacy, safety, costs and acceptability of recombinant FSH, we performed a review to compare recombinant FSH with urinary-derived FSH products. Follitropin alpha, beta and urinary FSH products appeared to be equally effective in terms of pregnancy rates. Patient safety was also found to be comparable, as the incidence of side effects including multiple pregnancies was similar for all FSH products. In practice follitropin alpha and beta may be more convenient to use due to the ease of selfadministration, but they are also more expensive than the urinary products. Gepubliceerd: Int J Womens Health 2010;1:205-11 Impact factor: 0
13. Qualitative Assessment of the Progesterone Receptor and HER2 Improves the Nottingham Prognostic Index Up to 5 Years After Breast Cancer Diagnosis V Van Belle, B Van Calster, O Brouckaert*, I Van den Bempt, S Pintens, V Harvey, P Murray, B Naume, G Wiedswang, R Paridaens, P Moerman, F Amant, K Leunen, A Smeets, M Drijkoningen, H Wildiers, MR Christiaens, I Vergote, S Van Huffel, P Neven From the Katholieke Universiteit Leuven; Multidisciplinary Breast Centre, University Hospitals Leuven, Leuven; Virga Jesse Hospital, Hasselt, Belgium; Auckland Breast Cancer Registry, Greenlane Clinical Centre; Regional Cancer Centre, Auckland City Hospital, Auckland, New Zealand; Ullevål University; and Norwegian Radium Hospital, Oslo, Norway * Department of Obstetrics and Gynecology, Medisch Spectrum Twente, Enschede
60
Purpose To investigate whether the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) can improve the Nottingham Prognostic Index (NPI) in the classification of patients with primary operable breast cancer for disease-free survival (DFS). Patients and Methods The analysis is based on 1,927 patients with breast cancer treated between 2000 and 2005 at the University Hospitals, Leuven. We compared performances of NPI with and without ER, PR and/or HER2. Validation was done on two external data sets containing 862 and 2,805 patients from Oslo (Norway) and Auckland (New Zealand), respectively. Results In the Leuven cohort, median follow-up was 66 months, and 13.7% of patients experienced a breast cancer–related event. Positive staining for ER, PR, and HER2 was detected, respectively, in 86.9%, 75.5%, and 11.9% of patients. Based on multivariate Cox regression modeling, the improved NPI (iNPI) was derived as NPI − PR positivity + HER2 positivity. Validation results showed a risk group reclassification of 20% to 30% of patients when using iNPI with its optimal risk boundaries versus NPI, in a majority of patients to more appropriate risk groups. An additional 10% of patients were classified into the extreme risk groups, where clinical actions are less ambiguous. Survival curves of reclassified patients resembled more closely those for patients in the same iNPI group than those for patients in the same NPI group. Conclusion The addition of PR and HER2 to NPI increases its 5-year prognostic accuracy. The iNPI can be considered as a clinically useful tool for stratification of patients with breast cancer receiving standard of care. Gepubliceerd: J Clin Oncol 2010;28(27):4129-34 Impact factor: 17.793
14. Manchester fothergill: Fac lege artis, cut it off or cut it out? Everhardt E Afdeling Gynaecologie en Obstetrie, Medisch Spectrum Twente, Enschede Prolapschirurgie anno 2010 is meer uitdagend dan ooit. De belangrijkste reden hiervoor is de langere levensduur van een toenemend kritische patiëntenpopulatie. Dit betekent soms lastige afwegingen voor de behandelend urogynaecoloog, die een keuze moet maken tussen primair altijd lichaamseigen weefsel gebruiken dan wel meshmateriaal, tussen de meest solide oplossing met lange operatieduur en herstelperiode of een eenvoudiger ingreep met meer recidiefrisico, tussen of-of respectievelijk en-en correctie van suspensie en support, et cetera. De introductie van de trans vaginal mesh (TVM) leek velen een goede oplossing voor het herstel van de suspensie bij ontbreken van de natuurlijke suspensoren (ligamenta sacro-uterina /cardinalia), maar ook uitermate geschikt als versteviging van vaginavoor- en achter- wand. De aanvankelijke voorzichtigheid om dit alleen toe te passen bij patiënten met een recidief en bij voorkeur in trialverband werd al ras verlaten, in ieder geval in ons land. Inmiddels wordt de TVM in bijna ieder ziekenhuis door de gynaecologen met UG-aandachtsgebied uitgevoerd, daartoe gestimuleerd door de industrie en blijven de complicaties van TVM-chirurgie onderbelicht doordat de introductiesnelheid van nieuwe meshes groter is dan de
61
publicatiesnelheid van artikelen over meshcomplicaties. Zelfs eerste procedures worden op deze manier verricht in klinieken van alle signatuur. En ieder mesh brengt weer een eigen leercurve met zich mee.1 De verwachting dat het steeds maar verwijden van de meshmazen en dunner maken van het materiaal de kans op meshkrimp belangrijk reduceert, is tot nu toe illusoir gebleken. Bij een substantieel deel van de patiënten zal daarom vroeger of later een meshgerelateerde complicatie optreden omdat meshkrimp een chronisch gebeuren is en levenslange oestrogeenmedicatie inmiddels onacceptabel is geworden. Wat doen de beroepsgroep en de industrie als er claims gaan komen? Want patiënten zullen het ons niet in dank afnemen als het ongemak van de prolaps wordt vervangen door pijn, niet alleen bij coïtus, mictie en defecatie, maar soms zelfs spontane pijn. Opmerkelijk is dat ook in het verleden natuurlijk suspensiemateriaal niet altijd op de juiste waarde is geschat, terwijl een hysterectomie sec natuurlijk geen prolapsoperatie is. En dat, toen dit inzicht en de waarde ervan doordrongen, de optimale suspensoren aanvankelijk niet als zodanig werden herkend: immers begin jaren tachtig van de vorige eeuw werden de ligamenta rotunda nog in veel klinieken in de vaginatop gehecht bij het verwijderen van de uterus. Het was McCall die voor het eerst de ligamenta sacro-uterina waardeerde en beschreef hoe tijdens een vaginale hysterectomie een enterokèle verholpen kon worden door deze ligamenten via plicatie in te korten en deze tegen de fornix posterior te hechten. Hiermee werd niet alleen de breukpoort gesloten, maar ook fixatie van de vaginatop boven de levatorplaat gerealiseerd als ‘nuttig bijproduct’, wat door Nichols werd uitgebouwd tot het bekende suspensie-supportconcept.2,3 Wanneer deze natuurlijke suspensoren niet meer beschikbaar zijn, zoals het geval is na een eerdere hysterectomie, moet men wel naar kunstmaterialen uitwijken. Zo werd de sacrocolpopexie ontwikkeld, met gunstig resultaat.4 De risico’s en zwaarte van de laparotomie leidden tot de minder belastende laparoscopische variant en ook tot vaginale alternatieven, zoals de posterior IVS. 5,6 Deze drie ingrepen respecteerden alle het Nichols concept en herstelden de ‘sacraal gerichte as’ van het middelste compartiment. De reden waarom verder gezocht werd naar alternatieven had van doen met het risico van prolapsrecidief en dan met name van de zwakste plek van de vrouwelijk genitalia, de vaginavoorwand. De sacrospinale fixatie, die ook de sacraal gerichte vector respecteert, bleek hiervoor geen oplossing. Integendeel zelfs, omdat deze ingreep via eenzijdige fixatie aan het rechter ligament juist een overcorrectie van vaginavoorwand bewerkstelligt, waardoor dit meest kwetsbare compartiment nog meer neigt tot recidiefvorming. De variant waarbij de uterus behouden wordt (sacrospinale hysteropexie) heeft dit bezwaar niet kunnen wegnemen.7,8 In de zoektocht naar de meest ideale operatie leek het zinvol om niet alleen vooruit, maar ook terug te kijken naar voormalige prolapsoperaties en deze opnieuw kritisch op hun bruikbaarheid te bezien. Daarbij kwam de Manchester-Fothergill naar voren als een ingreep die indertijd al een goede reputatie had en voor herwaardering in
62
aanmerking zou kunnen komen.9,10 Verdere verbetering zou ook in dit tijdsgewricht perspectief kunnen bieden in die gevallen waarin er geen medische noodzaak bestaat voor een hysterectomie. Deze operatie was aan het begin van de 20e eeuw door Donald in Manchester ontwikkeld als volwaardige prolapsoperatie inclusief cervixamputatie en plastieken. Fothergill verbeterde deze ingreep door reving van de parametria; dit resulteerde in een solide correctie van de prolaps van het middelste compartiment, met behoud van de uterus. Bestudering van zijn artikel leerde dat hij met ‘parametria’ in feite de ligamenta cardinalia bedoelde. De Nederlandse variant, die verder de ‘gemodificeerde Manchester’ zal worden genoemd, introduceerde het extraperitoneaal reven van de ligamenta sacrouterina. Naast de voordelen van de oorspronkelijke ingreep, die al voldeed aan de criteria van relatief eenvoudig (vaginaal, met behoud uterus, zonder openen peritoneum) met weinig complicaties, effectueert de modificatie tevens de sacraal gerichte vector door optimaal gebruik te maken van de gecondenseerde ligamenta sacro-uterina. Door het in anteflexie brengen van het corpus uteri wordt bovendien bewerkstelligd dat intra-abdominale drukverhoging primair wordt opgevangen door de uterus, die als een stootkussen fungeert (figuur 1). Hierdoor zou, in ieder geval in theorie, het risico op een cystokèle lager moet zijn. Een eerste followupstudie lijkt dit te bevestigen.11 Dat maakt de gemodificeerde Manchester een interessante ingreep om in een prospectief onderzoek uit te zetten tegen de sacrospinale hysteropexie en/of VUE-McCall. De gemodificeerde Manchester is aanvankelijk in Den Bosch ontwikkeld, maar in het UMC St Radboud onder leiding van Julien Dony uitgebouwd tot een eenvoudige, veilige en solide prolapsoperatie, die inmiddels in verschillende klinieken in het palet is opgenomen en die nu rijp is om grotere bekendheid te krijgen. Het is een ingreep die aan alle gestelde eisen voldoet: simpel, veilig, vaginaal, weinig complicaties en goede (langetermijn) resultaten. Het percentage voorwandrecidieven is bijna de helft van wat na andere ingrepen wordt gezien en het zijn tevreden patiënten die deze ingreep in > 90% van de gevallen aan een vriendin zouden aanbevelen.11 Nieuw aan de gemodificeerde Manchester zijn de volgende stappen van de ingreep: 1. hydrodissectie;
63
2. circulair e manche tprepara tie (voor ruime expositi e van ligament a cardinali a en sacro-uterina); 3. extraperitoneale reving van de ligamenta sacro-uterina met fixatie van de achterste fornix hiertegen (extraperitoneale mccall-hechting). Hydrodissectie met fysiologisch zout maakt het prepareren van de vaginale manchet eenvoudiger door verruiming van het dissectievlak als gevolg van hydratie. Een alternatief is het gebruik van een lokaal anestheticum met adrenaline dat als voordeel heeft dat door vasoconstrictie ook het bloedverlies wordt gereduceerd (figuur 2). Na de circulaire incisie van de cervix volgt de manchetpreparatie over een afstand van ongeveer vier centimeter (figuur 3). Om te bewerkstelligen dat zo veel mogelijk perivesicale fascie op de blaas blijft zitten, verdient scherp prepareren tegen de vagina-achterzijde de voorkeur. Vervolgens wordt het septum vesicocervicale doorgenomen en de blaas stomp afgeschoven, net als bij een vaginale hysterectomie (figuur 4). Dit is noodzakelijk om de ureteren naar craniaal te verplaatsen, om de volgende stap veilig te kunnen uitvoeren. Deze derde stap is cruciaal in de gemodificeerde manchesterprocedure, namelijk het extraperitoneaal reven van de ligamenta sacrouterina aan de dorsale zijde van de cervix (figuur 5 en 6). Drie tot vier reefhechtingen realiseren voldoende duplicatie en verkorting van de ligamenten, doordat na knopen in plaats van een omgekeerde V-vorm een omgekeerde Y wordt gerealiseerd met suspensie richting sacrum als gevolg. De voorlaatste hechting wordt door de fornix posterior gestoken, als een extraperitoneale mccall-hechting. Daarna volgen de andere stappen zoals eerder beschreven bij de oorspronkelijke Manchester-Fothergill waarbij het reven van de ligamenta cardinalia (figuur 7), de cervixamputatie en vaginawandplastieken de belangrijkste zijn. Deze gemodificeerde manchesteroperatie is geschikt voor die vrouwen met een prolaps van het middelste compartiment POPQ- stadium tot en
64
met 2 (figuur 8) en in geval van een substantiële elongatio colli ook zelfs stadium 3. Een relatieve contra-indicatie is een verhoogd risico op maligniteit van het endometrium (HNPCCsyndroom, IDDM, hoge BMI). Negatieve effecten van de operatie kunnen zijn het optreden van bloedinganomalieën (indien de cervixamputatie te hoog is ingezet bij vrouwen in de fertiele fase; dysmenorroe (door ontstaan van een stenotisch ostium) en de novo dyspareunie (door obliteratie van de fornix posterior, zoals ook het geval kan zijn bij een oorspronkelijke mccall). Uit onze follow-upstudie blijkt dat deze problemen relatief weinig voorkomen.11 De conclusie moet zijn dat deze modificatie een revival van de Manchester-Fothergill betekent, waardoor de gemodificeerde manchesteroperatie een waardevolle aanwinst is en een meer prominente plaats verdient in het huidige operatiepalet. 1. Caquant F, Collinet P, Debodinance P, et al. Safety of Trans Vaginal Mesh procedure: retrospective study of 684 patients. Obstet Gynaecol Res 2008;34:44956. 2. McCall ML. Posterior culdeplasty: surgical correction of enterocele during vaginal preliminary report. Obstet Gynecol 1957;10:595-602. 3. Nichols DH, Randall CL. Vaginal surgery. 3th ed. Baltimore: Williams & Wilkins, 1989. 4. Rust JA, Botte JM, Howlett RJ. Prolapse of the vaginal vault: improved techniques for management of the abdominal approach or vaginal approach. Am J Obstet Gynecol 1976;125:768-76. 5. Papa Petros PE. Vault prolapse I: Dynamic supports of the vagina. Int Urogynecol J Pelvic Floor Dysfunct 2001;12:292-5. 6. Papa Petros PE. Vault prolapse II: Restoration of dynamic vaginal supports by infracoccygeal sacropexy, an axial day-case vaginal procedure. Int Urogynecol J Pelvic Floor Dysfunct 2001;12:296-303. 7. Richter K. Die operatieve Behandlung des prolabierten Scheidengrundes nach Uterusextirpation. Geburtshilfe Frauenheilkunde 1967;27:941-54. 8. Dietz V. Preservation of the uterus in vaginal prolapse surgery: the sacrospinous hysteropexy (dissertatie). Enschede: Gildeprint drukkerijen, 2008. 9. Fothergill WE. On the operative treatment of displacements of the pelvic viscera. Tr Edinburgh Obstet Soc 1908;33:129-45. 10. Shaw WF. The treatment of prolapsus uteri, with special reference to the Manchester operation of colporrhaphy. Am J Obstet Gynecol 1933;26:667-86.
65
11. West N te, Zon IAA van, Everhardt E. Uterine preservation in treating pelvic organ prolapse: the Modified Manchester-Fothergill procedure: a follow-up study. San Francisco: ICS congress abstract 729, 2009. Gepubliceerd: NTOG 2010;123:243-6 Impact factor: 0
15. Dermoidcyste Kelderman S, Schutter EM Afdeling gynaecologie, Medisch Spectrum Twente, Enschede Een 22-jarige vrouw presenteert zich op onze polikliniek gynaecologie met sinds enkele maanden pijn linksonder in de buik. Bij onderzoek wordt een cysteuze afwijking gepalpeerd met een diameter van ongeveer 10 cm. Echoscopisch wordt een cysteuze afwijking van 85 x 65 millimeter met echoarme inhoud gezien in het linkerovarium. Het rechterovarium heeft een normaal aspect. Er is geen vocht aanwezig in het cavum douglasi. Tumormarkers CA125, alfa-1-foetoproteïne en bèta-HCG zijn normaal. Een röntgenfoto toont verdichtingen in het kleine bekken die sprekend lijken op tanden (zie foto).
Er volgt een laparoscopische cystectomie uit het linkerovarium. Macroscopisch onderzoek toont haren, talg, enkele losse tanden en kiezen en een bothard weefselstuk. Microscopische analyse toont weefselfragmenten opgebouwd uit collageenrijk bindweefsel en plaatselijk vetweefsel. In het stroma worden haarrestanten en een rondkernig ontstekingsinfiltraat met meerkernige reuscellen gezien, tevens is er plaatselijk necrose. De diagnose dermoïdcyste wordt gesteld.
66
De dermoïdcyste of het mature teratoom valt onder de kiemceltumoren en is met 20 tot 25 procent de meest voorkomende soort onder de ovariële neoplasmata. De volgroeide variant is vrijwel altijd benigne van aard, terwijl onvolgroeide teratomen kunnen leiden tot maligne transformatie, waarmee de kans van ingroei en uitzaaiing naar andere delen van het lichaam groter wordt. In 10 tot 17 procent van de gevallen komen deze tumoren bilateraal voor. Volgroeide dermoïdcysten bevatten spierweefsel, darm- en longweefsel, gebitselementen, haren en zenuwweefsel. Ze ontstaan mogelijk door een falende meiose II of uit een premeiotische cel waarvan de meiose I heeft gefaald. De meeste patiënten zijn asymptomatisch en klachten zijn afhankelijk van de grootte en/of torsiemomenten. Dermoïdcysten kunnen laparoscopisch of laparotomisch verwijderd worden. Daarbij moet ‘spill’ worden voorkomen, omdat de sebaceuze inhoud van de cyste het peritoneum kan prikkelen. Patiënte is nog eenmaal op de poli geweest. Zij is zonder klachten uit onze controle ontslagen. Gepubliceerd: Medisch Contact 2010; Vol 65; 45: 2394 Impact factor: 0
Totale impact factor: 140.365 Gemiddelde impact factor: 9.358 Aantal artikelen 1e, 2e of laatste auteur: 6 Totale impact factor: 4.175 Gemiddelde impact factor: 0.696
67
Heelkunde 1. Fissurectomy combined with botulinum toxin A injection for medically resistant chronic anal fissures Witte ME, Klaase JM, Koop R Department of Surgery, Medisch Spectrum Twente, Enschede Chemical sphincterotomy, the use of pharmacological agents to reduce anal sphincter resting pressure, has become more and more popular in the treatment of chronic anal fissures (CAFs). It offers the possibility to avoid a lateral internal sphincterotomy and its associated risk of incontinence. In our hospital, patients with a chronic anal fissure are consecutively treated with isosorbide dinitrate 1% ointment, applied 6 times a day for 8 weeks, followed by diltiazem 2% ointment, applied 2 times a day for 8 weeks and Botulin Toxin A injections (Dysport(R)) in the internal anal sphincter. In a previous study (1), we describe high healing rates with this regime. Twenty-one patients (10 males, median age 48 years) with persistent symptoms of chronic anal fissures after following the above mentioned treatment, were enrolled in this study evaluating the effect of the combination of fissurectomy with Botulinum Toxin A (80 U of Dysport(R)) under regional anesthesia in day care. After 12 weeks 19/21 CAFs (90%) had healed. Median follow-up was 16 (9-30) months. No recurrences were seen. Conclusion: Fissurectomy in combination with Botulinum Toxin A injections in the internal anal sphincter is an effective treatment for medically resistant CAFs. Gepubliceerd: Colorectal Dis. 2010;12(7):e163-9 Impact factor: 2.410
2. A step-up approach or open necrosectomy for necrotizing pancreatitis van Santvoort HC1, Besselink MG1, Bakker OJ1, Hofker HS2, Boermeester MA3, De Jong CH4, van Goor H5, Schaapherder AF7, van Eijck CH8, Bollen TL9, van Ramshorst B9, Nieuwenhuijs VB2, Timmer R9, Laméris JS3, Kruyt PM10, Manusama ER11, van der Harst E12, van der Schelling GP13, Karsten T14, Hesselink EJ15, van Laarhoven CJ5, Rosman C6, Bosscha K16, de Wit RJ17, Houdijk AP18, van Leeuwen MS1, Buskens E1,2, Gooszen HG1; Dutch Pancreatitis Study Group From 1 the UMC, Utrecht; 2 UMC, Groningen; 3 AMC, Amsterdam; 4 Maastricht UMC, Maastricht; 5 Radboud University Nijmegen MC, Nijmegen 6 Canisius–Wilhelmina Hospital, Nijmegen; 7 Leiden UMC, Leiden; 8 Erasmus MC, Rotterdam; 9 St. Antonius Hospital, Nieuwegein; 10 Gelderse Vallei Hospital, Ede; 11 Leeuwarden Medical Center, Leeuwarden; 12 Maasstad Hospital, Rotterdam; 13 Amphia Hospital, Breda; 14 Reinier de Graaf Hospital, Delft; 15 Gelre Hospital, Apeldoorn; 16 Jeroen Bosch Hospital, Den Bosch; 17 Medical Spectrum Twente, Enschede; 18 Medical Center Alkmaar, Alkmaar Background: Necrotizing pancreatitis with infected necrotic tissue is associated with a high rate of complications and death. Standard treatment is open necrosectomy. The outcome may be improved by a minimally invasive step-up approach.
68
Methods: In this multicenter study, we randomly assigned 88 patients with necrotizing pancreatitis and suspected or confirmed infected necrotic tissue to undergo primary open necrosectomy or a step-up approach to treatment. The stepup approach consisted of percutaneous drainage followed, if necessary, by minimally invasive retroperitoneal necrosectomy. The primary end point was a composite of major complications (new-onset multiple-organ failure or multiple systemic complications, perforation of a visceral organ or enterocutaneous fistula, or bleeding) or death. Results: The primary end point occurred in 31 of 45 patients (69%) assigned to open necrosectomy and in 17 of 43 patients (40%) assigned to the step-up approach (risk ratio with the step-up approach, 0.57; 95% confidence interval, 0.38 to 0.87; P=0.006). Of the patients assigned to the step-up approach, 35% were treated with percutaneous drainage only. New-onset multiple-organ failure occurred less often in patients assigned to the step-up approach than in those assigned to open necrosectomy (12% vs. 40%, P=0.002). The rate of death did not differ significantly between groups (19% vs. 16%, P=0.70). Patients assigned to the stepup approach had a lower rate of incisional hernias (7% vs. 24%, P=0.03) and newonset diabetes (16% vs. 38%, P=0.02). Conclusions: A minimally invasive step-up approach, as compared with open necrosectomy, reduced the rate of the composite end point of major complications or death among patients with necrotizing pancreatitis and infected necrotic tissue. Gepubliceerd: N Engl J Med. 2010;362(16):1491-1502 Impact factor: 47.050
3. Association of the TGF-beta receptor genes with abdominal aortic aneurysm AF Baas1, J Medic2, R van 't Slot2, CG de Kovel2, A Zhernakova2, RH Geelkerken3, SE Kranendonk4, SM van Sterkenburg5, DE Grobbee1, AP Boll6, C Wijmenga2,7, JD Blankensteijn8,9, YM Ruigrok10 1 Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht 2 Department of Biomedical Genetics, Complex Genetics Section, UMC Utrecht, Utrecht 3 Department of Surgery, Medical Spectrum Twente, Enschede 4 Department of Surgery, TweeSteden Hospital Tilburg, Dr. Deelenlaan 5, Tilburg 5 Division of Vascular Surgery, Department of Surgery, Alysis Zorggroep, Location Rijnstate, Arnhem 6 Department of Surgery, Canisius Wilhelmina Hospital Nijmegen, Nijmegen 7 Department of Genetics, UMC Groningen, Groningen 8 Department of Vascular Surgery, Radboud UMC Nijmegen, Nijmegen 9 Division of Vascular Surgery, VU MC, University of Amsterdam, Amsterdam 10 Department of Neurology, Rudolf Magnus Institute of Neuroscience, UMC Utrecht, Utrecht Abdominal aortic aneurysm (AAA) is a multifactorial condition. The transforming growth factor beta (TGF-beta) pathway regulates vascular remodeling and mutations in its receptor genes, TGFBR1 and TGFBR2, cause syndromes with thoracic aortic aneurysm (TAA). The TGF-beta pathway may be involved in aneurysm development
69
in general. We performed an association study by analyzing all the common genetic variants in TGFBR1 and TGFBR2 using tag single nucleotide polymorphisms (SNPs) in a Dutch AAA case-control population in a two-stage genotyping approach. In stage 1, analyzing 376 cases and 648 controls, three of the four TGFBR1 SNPs and nine of the 28 TGFBR2 SNPs had a P<0.07. Genotyping of these SNPs in an independent cohort of 360 cases and 376 controls in stage 2 confirmed association (P<0.05) for the same allele of one SNP in TGFBR1 and two SNPs in TGFBR2. Joint analysis of the 736 cases and 1024 controls showed statistically significant associations of these SNPs, which sustained after proper correction for multiple testing (TGFBR1 rs1626340 OR 1.32 95% CI 1.11-1.56 P=0.001 and TGFBR2 rs1036095 OR 1.32 95% CI 1.12-1.54 P=0.001 and rs4522809 OR 1.28 95% CI 1.12-1.46 P=0.0004). We conclude that genetic variations in TGFBR1 and TGFBR2 associate with AAA in the Dutch population. This suggests that AAA may develop partly by similar defects as TAA, which in the future may provide novel therapeutic options. Gepubliceerd: Eur J Hum Genet. 2010;18(2):240-4 Impact factor: 3.564
4. Invited commentary Geelkerken RH1, Kolkman JJ2, Huisman AB3 Department of 1Surgery, 2Gastroenterology, 3Radiology, Medisch Spectrum Twente, Enschede Gepubliceerd: J Vasc Surg 2010;51(1):147 Impact factor: 3.517
5. Preoperative Biliary Drainage for Cancer of the Head of the Pancreas NA van der Gaag1, EAJ Rauws2, CHJ van Eijck5, MJ Bruno6, E van der Harst7, FJGM Kubben8, JJGM Gerritsen9, JW Greve10, MF Gerhards11, IHJT de Hingh12, JH Klinkenbijl13, CY Nio3, SMM de Castro1, ORC Busch1, TM van Gulik1, PMM Bossuyt4, DJ Gouma1 1 Departments of Surgery, 2 Gastroenterology, 3 Radiology, and 4 Clinical Epidemiology and Biostatistics, AMC, Amsterdam; 5 Departments of Surgery and 6 Gastroenterology, Erasmus MC, Rotterdam; 7 Departments of Surgery and 8 Gastroenterology, Maasstad Hospital, Rotterdam; 9 Department of Surgery, Medical Spectrum Twente, Enschede; 10 Department of Surgery, University Hospital Maastricht, Maastricht; 11 Department of Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam; 12 Department of Surgery, Catharina Hospital, Eindhoven; 13 Department of Surgery, Rijnstaete Hospital, Arnhem Background The benefits of preoperative biliary drainage, which was introduced to improve the postoperative outcome in patients with obstructive jaundice caused by a tumor of the pancreatic head, are unclear. Methods In this multicenter, randomized trial, we compared preoperative biliary drainage with surgery alone for patients with cancer of the pancreatic head. Patients
70
with obstructive jaundice and a bilirubin level of 40 to 250 µmol per liter (2.3 to 14.6 mg per deciliter) were randomly assigned to undergo either preoperative biliary drainage for 4 to 6 weeks, followed by surgery, or surgery alone within 1 week after diagnosis. Preoperative biliary drainage was attempted primarily with the placement of an endoprosthesis by means of endoscopic retrograde cholangiopancreatography. The primary outcome was the rate of serious complications within 120 days after randomization. Results We enrolled 202 patients; 96 were assigned to undergo early surgery and 106 to undergo preoperative biliary drainage; 6 patients were excluded from the analysis. The rates of serious complications were 39% (37 patients) in the earlysurgery group and 74% (75 patients) in the biliary-drainage group (relative risk in the early-surgery group, 0.54; 95% confidence interval [CI], 0.41 to 0.71; P<0.001). Preoperative biliary drainage was successful in 96 patients (94%) after one or more attempts, with complications in 47 patients (46%). Surgery-related complications occurred in 35 patients (37%) in the early-surgery group and in 48 patients (47%) in the biliary-drainage group (relative risk, 0.79; 95% CI, 0.57 to 1.11; P=0.14). Mortality and the length of hospital stay did not differ significantly between the two groups. Conclusions Routine preoperative biliary drainage in patients undergoing surgery for cancer of the pancreatic head increases the rate of complications. Gepubliceerd: N Engl J Med 2010;362:129-137 Impact factor: 47.050
6. Preoperatieve galwegdrainage voor pancreaskoptumoren: meer complicaties NA van der Gaag1, EAJ Rauws2, CHJ van Eijck5, MJ Bruno6, E van der Harst7, FJGM Kubben8, JJGM Gerritsen9, JW Greve10, MF Gerhards11, IHJT de Hingh12, JH Klinkenbijl13, CY Nio3, SMM de Castro1, ORC Busch1, TM van Gulik1, PMM Bossuyt4, DJ Gouma1 1 Departments of Surgery, 2 Gastroenterology, 3 Radiology, and 4 Clinical Epidemiology and Biostatistics, AMC, Amsterdam; 5 Departments of Surgery and 6 Gastroenterology, Erasmus MC, Rotterdam; 7 Departments of Surgery and 8 Gastroenterology, Maasstad Hospital, Rotterdam; 9 Department of Surgery, Medical Spectrum Twente, Enschede; 10 Department of Surgery, University Hospital Maastricht, Maastricht; 11 Department of Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam; 12 Department of Surgery, Catharina Hospital, Eindhoven; 13 Department of Surgery, Rijnstaete Hospital, Arnhem Doel. Nagaan of bij patiënten met obstructie-icterus door een tumor in de pancreaskop preoperatieve galwegdrainage gevolgd door chirurgische resectie minder complicaties geeft dan chirurgische resectie alleen. Opzet. Multicentrische, gerandomiseerde, klinische trial. Trialnummer: ISRCTN31939699. Methode. Patiënten met obstructie-icterus door een tumor in de pancreaskop en een serumwaarde van totaal bilirubine van 40-250 µmol/l, werden gerandomiseerd voor chirurgie zonder preoperatieve galwegdrainage binnen één week na diagnose, of 4-6 weken galwegdrainage gevolgd door chirurgie. Galwegdrainage werd primair
71
verricht door stentplaatsing via endoscopische retrograde cholangiopancreatografie. Primaire uitkomstmaat was het optreden van ernstige complicaties gerelateerd aan drainage of chirurgie binnen 120 dagen na randomisatie. De analyses volgden een ‘intention-to-treat’-benadering. Resultaten. 202 patiënten werden opgenomen in de studie, 96 werden toegewezen aan directe chirurgie en 106 aan galwegdrainage gevolgd door chirurgie. 6 patiënten werden voor de analyse geëxcludeerd. Significant minder patiënten in de directechirurgiegroep kregen complicaties: 37 (39%) tegen 75 (74%) in de drainagegroep (relatief risico (RR): 0,54; 95%-BI: 0,41-0,71; p < 0,001). In de drainagegroep was galwegdrainage succesvol bij 96 patiënten (94%) na één of meerdere pogingen, complicaties traden op bij 47 patiënten (46%). Complicaties gerelateerd aan chirurgie traden op bij 35 patiënten (37%) in de directe-operatiegroep tegen 47 (47%) in de drainagegroep (RR: 0,79; 95%-BI: 0,57-1,11; p < 0,14). Sterfte en opnameduur waren niet significant verschillend tussen beide groepen. Conclusie. Bij patiënten die een operatie dienen te ondergaan vanwege een tumor in de pancreaskop verhoogt het routinematig verrichten van preoperatieve galwegdrainage het aantal complicaties, terwijl het aantal complicaties door de resectie niet afneemt. Gepubliceerd: Ned Tijdschr Geneeskd. 2010;154(29):A1883 Impact factor: 0
7. Therapeutic Delay and Survival After Surgery for Cancer of the Pancreatic Head With or Without Preoperative Biliary Drainage Eshuis WJ*; van der Gaag NA*; Rauws EA†; van Eijck CH‡; Bruno MJ§; Kuipers EJ§; Coene PP¶; Kubben FJ **; Gerritsen JJ ††; Greve JW ‡‡; Gerhards MF§§; de Hingh IH¶¶; Klinkenbijl JH***; Nio CY†††; de Castro SM*; Busch OR*; van Gulik TM*; Bossuyt PM‡‡‡; Gouma DJ* * Department of Surgery, AMC, Amsterdam; †Department of Gastroenterology, AMC, Amsterdam; ‡Department of Surgery, Erasmus MC, Rotterdam; §Department of Gastroenterology, Erasmus MC, Rotterdam; ¶Department of Surgery, Maasstad Hospital, Rotterdam; **Department of Gastroenterology, Maasstad Hospital, Rotterdam; ††Department of Surgery, Medical Spectrum Twente, Enschede; ‡‡ Department of Surgery, University Hospital Maastricht, Maastricht, now Department of Surgery, Atrium MC, Heerlen; §§Department of Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam; ¶¶Department of Surgery, Catharina Hospital, Eindhoven; ***Department of Surgery, Rijnstaete Hospital, Arnhem, now Department of Surgery, AMC, Amsterdam; †††Department of Radiology, AMC, Amsterdam; ‡‡‡ Department of Clinical Epidemiology and Biostatistics, AMC, Amsterdam Objective: To evaluate the relation between delay in surgery because of preoperative biliary drainage (PBD) and survival in patients scheduled for surgery for pancreatic head cancer. Background: Patients with obstructive jaundice due to pancreatic head cancer can undergo PBD. The associated delay of surgery can lead to more advanced cancer stages at surgical exploration, affecting resection rate and survival.
72
Methods: We conducted a multicenter, randomized controlled clinical trial to compare PBD with early surgery (ES) for pancreatic head cancer for complications. We obtained Kaplan-Meier estimates of overall survival for patients with pathologyproven malignancy and compared survival functions of ES and PBD groups using log-rank test statistics. Multivariable Cox regression analyses were performed to evaluate the prognostic role of time to surgery for overall survival. Results: Mean times from randomization to surgery were 1.2 (0.9-1.5) and 5.1 (4.85.5) weeks in the ES and PBD groups, respectively (P < 0.001). In the ES group, 60 (67%) of 89 patients underwent resection, versus 53 (58%) of 91 patients in the PBD group (P = 0.20). Median survival after randomization was 12.2 (9.1-15.4) months in the ES group versus 12.7 (8.9-16.6) months in the PBD group (P = 0.91). A longer time to surgery was significantly associated with slightly lower mortality rate after surgery (hazard ratio = 0.90, 95% CI, 0.83-0.97), when taking into account resection, bilirubin, complications, pancreatic adenocarcinoma, tumor-positive lymph nodes, and microscopically residual disease. Conclusions: In patients with pancreatic head cancer, the delay in surgery associated with PBD does not impair or benefit survival rate. Gepubliceerd: Ann Surg. 2010;252(5):840-849 Impact factor: 7.900
8. Preoperative Staging with Chest CT in Patients with Colorectal Carcinoma: Not as a Routine Procedure Grossmann I1, Avenarius JK2, Mastboom WJ1, Klaase JM1 Departments of 1 Surgery and 2Radiology, Medisch Spectrum Twente, Enschede Background: Preoperative staging of patients with colorectal carcinoma (CRC) has the potential benefit of altering treatment options when metastases are present. The clinical value of chest computed tomography (CT) in staging remains unclear. Materials and methods: All patients who undergo colorectal surgery in our hospital are prospectively registered, including patient, treatment, and histopathological characteristics; outcome; and follow-up. Since January 2007, routine preoperative staging CT of chest and abdomen for patients with CRC has been performed as part of our regional guidelines. In this observational cohort study, an analysis on outcome was done after inclusion of 200 consecutive patients. Results: Synchronous metastases were present in 60 patients (30%). Staging chest CT revealed pulmonary metastases in 6 patients, with 1 false positive finding. In 50 patients indeterminate lesions were seen on chest CT (25%). These were diagnosed during follow-up as true metastases (n = 8), bronchus carcinoma (n = 2), benign lesions (n = 25), and remaining unknown (n = 15). Ultimately, synchronous pulmonary metastases were diagnosed in 13 patients (7%), in 6 patients confined to the lung (3%). In none of the patients the treatment plan for the primary tumor was changed based on the staging chest CT. Conclusion: The low incidence of pulmonary metastases and minimal consequences for the treatment plan limits the clinical value of routine staging chest CT before operation. It has several disadvantages such as costs, radiation exposure, and prolonged uncertainty because of the frequent finding of
73
indeterminate lesions. Based on this study, a routine staging chest CT in CRC patients is not advocated. Gepubliceerd: Ann Surg Oncol. 2010;17(8):2045-2050 Impact factor: 4.130
9. In Reply: The Importance of Preoperative Staging with Chest CT Scan in Patients with Colorectal Cancer Grossmann I1, Avenarius JK2, Mastboom WJ1, Klaase JM1 Departments of 1 Surgery and 2Radiology, Medisch Spectrum Twente, Enschede Gepubliceerd: Ann Surg Oncol. 2010; DOI 10.1245/s10434-010-1307-6 Impact factor: 4.130
10. Surgical gastrojejunostomy or endoscopic stent placement for the palliation of malignant gastric outlet obstruction (SUSTENT study): a multicenter randomized trial Jeurnink SMa, Steyerberg EWb, van Hooft JEe, van Eijck CHc, Schwartz MPf, Vleggaar FPg, Kuipers EJa,d, Siersema PDa,g; Dutch SUSTENT Study Group* Includes Klaase JM a Departments of Gastroenterology and Hepatology, b Public Health, c Surgery, and d Internal Medicine, Erasmus MC-UMC Rotterdam, Rotterdam e Department of Gastroenterology and Hepatology, AMC Amsterdam, Amsterdam f Department of Gastroenterology and Hepatology, Meander Medical Center Amersfoort, Amersfoort g Department of Gastroenterology and Hepatology (F.P.V., P.D.S.), UMC Utrecht, Utrecht * Department of Surgery, Medisch Spectrum Twente, Enschede Background. Both gastrojejunostomy (GJJ) and stent placement are commonly used palliative treatments of obstructive symptoms caused by malignant gastric outlet obstruction (GOO). Objective. Compare GJJ and stent placement. Design. Multicenter, randomized trial. Setting. Twenty-one centers in The Netherlands. Patients. Patients with GOO. Interventions. GJJ and stent placement. Main Outcome Measurements. Outcomes were medical effects, quality of life, and costs. Analysis was by intent to treat. Results. Eighteen patients were randomized to GJJ and 21 to stent placement. Food intake improved more rapidly after stent placement than after GJJ (GOO Scoring System score ≥2: median 5 vs 8 days, respectively; P < .01) but long-term relief was better after GJJ, with more patients living more days with a GOO Scoring System score of 2 or more than after stent placement (72 vs 50 days, respectively; P = .05). More major complications (stent: 6 in 4 patients vs GJJ: 0; P = .02), recurrent obstructive symptoms (stent: 8 in 5 patients vs GJJ: 1 in 1 patient; P = .02), and reinterventions (stent: 10 in 7 patients vs GJJ: 2 in 2 patients; P < .01) were
74
observed after stent placement compared with GJJ. When stent obstruction was not regarded as a major complication, no differences in complications were found (P = .4). There were also no differences in median survival (stent: 56 days vs GJJ: 78 days) and quality of life. Mean total costs of GJJ were higher compared with stent placement ($16,535 vs $11,720, respectively; P = .049 [comparing medians]). Because of the small study population, only initial hospital costs would have been statistically significant if the Bonferroni correction for multiple testing had been applied. Limitations. Relatively small patient population. Conclusions. Despite slow initial symptom improvement, GJJ was associated with better long-term results and is therefore the treatment of choice in patients with a life expectancy of 2 months or longer. Because stent placement was associated with better short-term outcomes, this treatment is preferable for patients expected to live less than 2 months. Gepubliceerd: Gastrointest Endosc. 2010;71(3):490-9 Impact factor: 6.713
11. DIRECT trial: Diverticulitis Recurrences or Continuing Symptoms; Operative versus Conservative Treatment. A Multicenter Randomised Clinical Trial van de Wall BJ1, Draaisma WA1, Consten EC1, van der Graaf Y2, Otten MH3, de Wit AG2, van Stel HF2, Gerhards MF4, Wiezer RM5, Cense HA6, Stockmann HB7, Leijtens JW8, Zimmerman DD9, Belgers E10, van Wagensveld BA11, Sonneveld ED12, Prins HA13, Coene PP14, Karsten TM15, Klaase JM16, Statius Muller MG17, Crolla RM18, Broeders IA1, and the Dutch Diverticular Disease Collaborative Study Group 1 Department of Surgery, Meander Medical Center Amersfoort, Amersfoort. 2 Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht 3 Department of Gastroenterology, Meander Medical Center Amersfoort, Amersfoort. 4 Department of Surgery, Onze Lieve Vrouwe Gasthuis Amsterdam, Amsterdam; 5 Sint Antonius Hospital Nieuwegein, Nieuwegein; 6 Rode Kruis Hospital Beverwijk, Beverwijk; 7 Kennemer Gasthuis Haarlem, Haarlem; 8 Laurentius Hospital Roermond, Roermond; 9 Diakonessenhuis Utrecht, Utrecht; 10 Atrium Medical Center Heerlen, Heerlen; 11 Lucas Andreas Hospital Amsterdam, Amsterdam; 12 Westfriesgasthuis Hoorn, Hoorn; 13 Jeroen Bosch Hospital ‘s-Hertogenbosch, ‘sHertogenbosch; 14 Maasstad Hospital Rotterdam, Rotterdam; 15 Reinier de Graaf Hospital Voorburg, Voorburg; 16 Medisch Spectrum Twente, Enschede; 17 MC Zuiderzee Hospital Lelystad, Lelystad; 18 Amphia Hospital Oosterhout, Oosterhout Background: Persisting abdominal complaints are common after an episode of diverticulitis treated conservatively. Furthermore, some patients develop frequent recurrences. These two groups of patients suffer greatly from their disease, as shown by impaired health related quality of life and increased costs due to multiple specialist consultations, pain medication and productivity losses. Both conservative and operative management of patients with persisting abdominal complaints after an episode of diverticulitis and/or frequently recurring diverticulitis are applied. However, direct comparison by a randomised controlled trial is necessary to determine which is superior in relieving symptoms, optimising health related quality
75
of life, minimising costs and preventing diverticulitis recurrences against acceptable morbidity and mortality associated with surgery or the occurrence of a complicated recurrence after conservative management. We, therefore, constructed a randomised clinical trial comparing these two treatment strategies. Methods: The DIRECT trial is a multicenter randomised clinical trial. Patients (18-75 years) presenting themselves with persisting abdominal complaints after an episode of diverticulitis and/or three or more recurrences within 2 years will be included and randomised. Patients randomised for conservative treatment are treated according to the current daily practice (antibiotics, analgetics and/or expectant management). Patients randomised for elective resection will undergo an elective resection of the affected colon segment. Preferably, a laparoscopic approach is used. The primary outcome is health related quality of life measured by the Gastro-intestinal Quality of Life Index, Short-Form 36, EQ-5D and a visual analogue scale for pain quantification. Secondary endpoints are morbidity, mortality and total costs. The total follow-up will be three years. Discussion: Considering the high incidence and the multicenter design of this study, it may be assumed that the number of patients needed for this study (n= 214), may be gathered within one and a half year. Depending on the expertise and available equipment, we prefer to perform a laparoscopic resection on patients randomised for elective surgery. Should this be impossible, an open technique may be used as this also reflects the current situation. Gepubliceerd: BMC Surg. 2010;10(1):25 Impact factor: 0
12. 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 1 Department of Traumatology, Medisch Spectrum Twente, Enschede 2 BAAT Medical Engineering, Hengelo Introduction: 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. Patients and methods: Internal fixation with the DLBP was performed in 25 consecutive patients with an intracapsular hip fracture within 24 h from admission. Failure of fixation, due to non-union, avascular necrosis, implant failure or secondary displacement of the fracture, was the primary outcome measurer. Functional outcome was assessed by the Harris Hip Score.
76
Results: Following internal fixation of intracapsular hip fractures with the DLBP, a failure rate of 2 out of 25 patients and excellent functional results were seen after a follow-up of more than 2 years. Conclusion: The initial clinical results of the DLBP are promising and justify the start of a randomised controlled trial. Gepubliceerd: Arch Orthop Trauma Surg. 2010;DOI: 10.1007/s00402-010-1195-z Impact factor: 1.117
13. Long-Term Results of the Cut-Closed-Reconnected Roux Loop for Enterogastric Reflux Kummer EW, Gerritsen JJ, Klaase JM Department of Surgery, Medisch Spectrum Twente, Enschede Background: The aim of this study was to present the long-term results of the cutclosed-reconnected (CCR)-Roux procedure for reflux gastritis. Methods: A retrospective analysis was performed on 14 patients with proven reflux gastritis and/or esophagitis who were treated at our institution with a CCR-Roux procedure between 1992 and 1997. Results: The closure of the afferent loop in the CCR-Roux procedure is effective and permanent. The CCR-Roux patients did not need a rest gastrectomy. No signs of Roux stasis syndrome were seen. There was a consistent weight gain at 2 and 5 years of follow-up. These results permit a comparison with those of the Roux-Y procedure and other alternative procedures as well. Conclusion: In the long run, the CCR-Roux procedure is effective in the treatment of reflux gastritis. Gepubliceerd: Dig Surg. 2010;27(3):205-211 Impact factor: 1.372
14. Regarding "Serum carboxymethyllysine concentrations are reduced in diabetic men with abdominal aortic aneurysms: Health In Men Study" Meerwaldt R1, Zeebregts CJ2 1 Department of Surgery, Medical Spectrum Twente, Enschede 2 Department of Surgery, Division of Vascular Surgery, UMC Groningen, Groningen Gepubliceerd: J Vasc Surg. 2010;52(2):535-6 Impact factor: 3.517
15. Accuracy of FDG-PET-CT in the Diagnostic Work-up of Vascular Prosthetic Graft Infection Bruggink JL1, Glaudemans AW2, Saleem BR1, Meerwaldt R3, Alkefaji H4, Prins TR4, Slart RH2, Zeebregts CJ1 1 Department of Surgery, Division of Vascular Surgery, UMC Groningen, Groningen
77
2
Department of Nuclear Medicine and Molecular Imaging, UMC Groningen, Groningen 3 Department of Surgery, Medisch Spectrum Twente, Enschede 4 Department of Radiology, UMC Groningen, Groningen Objectives: To investigate the diagnostic accuracy of fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) compared with computed tomography (CT) scanning and added value of fused FDG-PET-CT in diagnosing vascular prosthetic graft infection. Design: Prospective cohort study with retrospective analysis. Materials: Twenty five patients with clinically suspected vascular prosthetic infection underwent CT and FDG-PET scanning. Methods: Two nuclear medicine physicians assessed the FDG-PET scans; all CT scans were assessed by two radiologists. Fused FDG-PET/CT were judged by the radiologist and the nuclear medicine physician. The concordance between CT and FDG-PET and the inter-observer agreement between the different readers were investigated. Results: Fifteen patients had a proven infection by culture. Single FDG-PET had the best results (sensitivity 93%, specificity 70%, positive predictive value 82% and negative predictive value 88%). For CT, these values were 56%, 57%, 60% and 58%, respectively. Fused CT and FDG-PET imaging also showed high sensitivity and specificity rates and high positive and negative values. Inter-observer agreement for FDG-PET analysis was excellent (kappa = 1.00) and moderate for CT and fused FDG-PET-CT analysis (0.63 and 0.66, respectively). Conclusion: FDG-PET scanning showed a better diagnostic accuracy than CT for the detection of vascular prosthetic infection. This study suggests that FDG-PET provides a useful tool in the work-up for diagnosis of vascular prosthetic graft infection. Copyright © 2010 European Society for Vascular Surgery. Gepubliceerd: Eur J Vasc Endovasc Surg. 2010;40(3):348-54 Impact factor: 2.919
16. Surgical strategy in patients with secondary and tertiary hyperparathyroidism. A bi-institutional series Blomme RA1, Blomme AM1, Rinkes IH1, Meerwaldt R2, van der Wal MB1, Valk GD1, Vriens MR1 1 Department of Surgery, UMC Utrecht, Utrecht 2 Department of Surgery, Medisch Spectrum Twente, Enschede Background: Although total parathyroidectomy with forearm autotransplantation is a widely accepted treatment for patients with secondary/tertiary hyperparathyroidism (HPT) some debate persists about the optimal surgical strategy. In particular, the question what to do when less than four parathyroid glands can be found during surgery has yet to be resolved. The aim of this retrospective study was to review the outcome of total parathyroidectomy with autotransplantation and to assess the proper procedure (to autotransplant or not) when finding less than 4 glands after extensive surgical exploration.
78
Methods: Between 1995 and 2005, parathyroidectomy was performed in 74 patients in two affiliated centers. In this case-control study both clinical and biochemical outcomes of a total or subtotal parathyroidectomy were compared. The parathyroid hormone (PTH), serum calcium concentration, phosphate and alkaline phosphatase levels were monitored preoperatively, 1 and 12 months postoperatively. Results: Sixty five patients underwent a total parathyroidectomy and nine patients underwent a subtotal parathyroidectomy. Persistent HPT was seen in nine patients (12%). Recurrent HPT was seen in eight patients (11%). There were no significant differences between the group with > or = 4 glands excised and the group with three glands excised regarding serum PTH levels after 12 months and the number of patients with a hypo- or hyperparathyroidism (persistent or recurrent). Procedure related morbidity was minimal. Conclusions: Total parathyroidectomy with forearm autotransplantation is safe and effective for patients with secondary/tertiary hyperparathyroidism. In case of not finding a fourth gland after extensive surgical exploration, our general advice is to proceed as planned with the autotransplantation. Gepubliceerd: Acta Chir Belg. 2010;110(1):35-9 Impact factor: 0.424
17. Conservative treatment of vascular prosthetic graft infection is associated with high mortality Saleem BR1, Meerwaldt R2, Tielliu IF1, Verhoeven EL1, van den Dungen JJ1, Zeebregts CJ1 1 Department of Surgery, Division of Vascular Surgery, UMC Groningen, Groningen 2 Department of Surgery, Medisch Spectrum Twente, Enschede Background: The aim of this study was to identify patient-related and/or diseaserelated factors that influence outcomes in patients with vascular prosthetic graft infections. Methods: Through the hospital patient administration system, between January 1997 and December 2007, a total of 44 patients were diagnosed with central prosthetic graft infections. Univariate and multivariate analyses were performed to define factors predictive of mortality. Results: Thirty-three men and 11 women (mean age, 71 years) were included. There was considerable comorbidity. Coagulase-negative Staphylococcus and S aureus were isolated in almost 50% of the patients. The mean follow-up duration was 5 years, during which 20 patients (46%) died. The main causes of death were related to vascular disease. Conservative treatment with antibiotics was the only variable with significant predictive value on multivariate analysis (hazard ratio, 3.62; 95% confidence interval, 1.17-11.24; P = .02). Conclusions: Conservative treatment of prosthetic graft infections was associated with high mortality; therefore, it should be limited to a specific group. Patients who are not capable of undergoing open repair may benefit from conservative management. Otherwise, aggressive open treatment seems indicated. Gepubliceerd: Am J Surg. 2010;200(1):47-52
79
Impact factor: 2.363
18. Spectroscopy to improve identification of vulnerable plaques in cardiovascular disease JL Bruggink1, R Meerwaldt2, GM van Dam1, JD Lefrandt3, RH Slart4, RA Tio5, AJ Smit3, CJ Zeebregts1 1 Department of Surgery, Division of Vascular Surgery, UMC Groningen, Groningen 2 Department of Surgery, Medisch Spectrum Twente, Enschede 3 Department of Internal Medicine, UMC Groningen, Groningen 4 Department of Nuclear Medicine and Molecular Imaging, UMC Groningen, Groningen 5 Department of Cardiology, UMC Groningen, Groningen Many apparent healthy persons die from cardiovascular disease, despite major advances in prevention and treatment of cardiovascular disease. Traditional cardiovascular risk factors are able to predict cardiovascular events in the long run, but fail to assess current disease activity or nearby cardiovascular events. There is a clear relation between the occurrence of cardiovascular events and the presence of so-called vulnerable plaques. These vulnerable plaques are characterized by active inflammation, a thin cap and a large lipid pool. Spectroscopy is an optical imaging technique which depicts the interaction between light and tissues, and thereby shows the biochemical composition of tissues. In recent years, impressive advances have been made in spectroscopy technology and intravascular spectroscopy is able to assess the composition of plaques of interest and thereby to identify and actually quantify plaque vulnerability. This review summarizes the current evidence for spectroscopy as a measure of plaque vulnerability and discusses the potential role of intravascular spectroscopic imaging techniques. Gepubliceerd: Int J Cardiovasc Imaging. 2010;26(1):111-9 Impact factor: 2.151
19. PET/SPECT imaging: from carotid vulnerability to brain viability R Meerwaldta, RH Slartc, GM van Damb, GJ Luijckxd, RA Tioe, CJ Zeebregtsb a Department of Surgery, Medisch Spectrum Twente, Enschede b Department of Surgery, UMC Groningen, Groningen c Department of Nuclear Medicine & Molecular Imaging, UMC Groningen, Groningen d Department of Neurology, UMC Groningen, Groningen e Department of Cardiology, UMC Groningen, Groningen Background: Current key issues in ischemic stroke are related to carotid plaque vulnerability, brain viability, and timing of intervention. The treatment of ischemic stroke has evolved into urgent active interventions, as 'time is brain'. Functional imaging such as positron emission tomography (PET)/single photon emission computed tomography (SPECT) could improve selection of patients with a vulnerable plaque and evaluation of brain viability in ischemic stroke.
80
Objective: To describe the current applications of PET and SPECT as a diagnostic tool in relation to ischemic stroke. Methods: A literature search using PubMed identified articles. Manual crossreferencing was also performed. Results: Several papers, all observational studies, identified PET/SPECT to be used as a tool to monitor systemic atheroma modifying treatment and to select highrisk patients for surgery regardless of the degree of luminal stenosis in carotid lesions. Furthermore, PET/SPECT is able to quantify the penumbra region during ischemic stroke and in this way may identify those patients who may benefit from timely intervention. Discussion: Functional imaging modalities such as PET/SPECT may become important tools for risk-assessment and evaluation of treatment strategies in carotid plaque vulnerability and brain viability. Prospective clinical studies are needed to evaluate the diagnostic accuracy of PET/SPECT. Gepubliceerd: Eur J Radiol. 2010;74(1):104-9 Impact factor: 2.645
20. Is time to closure a factor in the occurrence of infection in traumatic wounds? A prospective cohort study in a Dutch level 1 trauma centre van den Baar MT1, van der Palen J2, Vroon MI1, Bertelink P1, Hendrix R3 1 Department of Surgery, Medisch Spectrum Twente, Enschede 2 Medical School Twente, Medisch Spectrum Twente, Enschede 3 Laboratory of Microbiology Oost Nederland, Enschede Background The dogma that traumatic wounds should not be sutured after 6 h is based on an animal experiment by P L Friedrich in 1898. There is no adequately powered prospective study on this cut-off of 6 h to confirm or disprove the dogma. The aim of this study was to provide evidence against the dogma that wounds should be sutured within 6 h after trauma. Method 425 patients were included in a prospective cohort study. Patients' wounds were closed, independent of time after trauma. All patients were seen after 7-10 days for removal of stitches and wound control on infection. Results Of the 425 patients, 17 were lost to follow-up. Of the remaining 408 patients, 45 had wounds older than 6 h after trauma. At follow-up 372 patients (91%) had no infection and 36 patients had redness of the suture sites or worse. 11 patients (2.7%) had general redness or pus. Of those with a wound older than 6 h, three of 45 (6.7%) wounds were infected, versus 30 of 363 (9.1%) in wounds younger than 6 h (p=0.59). Conclusion In everyday practice wounds are sutured regardless of elapsed time. Here an attempt was made to present the evidence for this daily routine, contrary to Friedrich's Dogma. Gepubliceerd: Emerg Med J 2010;27:540-543 Impact factor: 1.477
81
21. The Ladies trial: laparoscopic peritoneal lavage or resection for purulent peritonitis and Hartmann's procedure or resection with primary anastomosis for purulent or faecal peritonitis in perforated diverticulitis Swank HA, Vermeulen J, Lange JF, Mulder IM, van der Hoeven JA, Stassen LP, Crolla RM, Sosef MN, Nienhuijs SW, Bosker RJ, Boom MJ, Kruyt PM, Swank DJ, Steup WH, de Graaf EJ, Weidema WF, Pierik RE, Prins HA, Stockmann HB, Tollenaar RA, van Wagensveld BA, Coene PP, Slooter GD, Consten EC, van Duyn EB*, Gerhards MF, Hoofwijk AG, Karsten TM, Neijenhuis PA, Blanken-Peeters CF, Cense HA, Mannaerts GH, Bruin SC, Eijsbouts QA, Wiezer MJ, Hazebroek EJ, van Geloven AA, Maring JK, d'Hoore A, Kartheuser A, Remue C, van Grevenstein WM, Konsten JL, van der Peet DL, Govaert MJ, Engel AF, Reitsma JB, Bemelman WA, 3d TD * Department of Surgery, Medisch Spectrum Twente, Enschede Background: Recently, excellent results are reported on laparoscopic lavage in patients with purulent perforated diverticulitis as an alternative for sigmoidectomy and ostomy. The objective of this study is to determine whether LaparOscopic LAvage and drainage is a safe and effective treatment for patients with purulent peritonitis (LOLA-arm) and to determine the optimal resectional strategy in patients with a purulent or faecal peritonitis (DIVA-arm: perforated DIVerticulitis with or without Anastomosis). Design In this multicentre randomised trial all patients with perforated diverticulitis are included. Upon laparoscopy, patients with purulent peritonitis are treated with laparoscopic lavage and drainage, Hartmann's procedure or sigmoidectomy with primary anastomosis in a ratio of 2:1:1 (LOLA-arm). Patients with faecal peritonitis will be randomised 1:1 between Hartmann's procedure and resection with primary anastomosis (DIVA-arm). The primary combined endpoint of the LOLA-arm is major morbidity and mortality. A sample size of 132:66:66 patients will be able to detect a difference in the primary endpoint from 25% in resectional groups compared to 10% in the laparoscopic lavage group (two sided alpha = 5%, power = 90%). Endpoint of the DIVA-arm is stoma free survival one year after initial surgery. In this arm 212 patients are needed to significantly demonstrate a difference of 30% (log rank test two sided alpha = 5% and power = 90%) in favour of the patients with resection with primary anastomosis. Secondary endpoints for both arms are the number of days alive and outside the hospital, health related quality of life, health care utilisation and associated costs. Discussion The Ladies trial is a nationwide multicentre randomised trial on perforated diverticulitis that will provide evidence on the merits of laparoscopic lavage and drainage for purulent generalised peritonitis and on the optimal resectional strategy for both purulent and faecal generalised peritonitis. Gepubliceerd: BMC Surg. 2010;10(1):29 Impact factor: 0
22. Open or percutaneous revascularization for chronic splanchnic syndrome Van Petersen AS1, Kolkman JJ2, Beuk RJ1, Huisman AB3, Doelman CJ4, Geelkerken RH1
82
Department of 1surgery, 2Gastroenterology, 3Radiology, 4Clinical Chemistry, Medisch Spectrum Twente, Enschede Background: Treatment of chronic splanchnic syndrome remains controversial. In the past 10 years, endovascular repair (ER) has replaced open repair (OR) to some extent. This evidence summary reviews the available evidence for ER or OR of chronic splanchnic syndrome. Methods: A systematic literature search of MEDLINE database was performed to identify all studies that evaluated treatment of chronic splanchnic syndrome between 1988 and 2009. Results: The best available evidence consists of prospectively accumulated but retrospectively analyzed data with a high risk for confounding. Only a few of these studies incorporated functional tests to assess splanchnic ischemia before or after treatment. ER has the advantage of low short-term morbidity but the disadvantage of decreased long-term primary patency compared with OR. ER and OR have similar rates of secondary patency, although the reintervention rate after ER is higher. Conclusion: ER appears to be preferential in the treatment of elderly patients and in patients with comorbidity, severe cachexia, or hostile abdomen. Long-term results after OR are excellent. OR can still be proposed as the preferred option for relatively young and fit patients. Gepubliceerd: J Vasc Surg. 2010;51(5):1309-1316 Impact factor: 3.517
23. "Re: Management of median arcuate ligament syndrome: a new paradigm" van Petersen A, Meerwaldt R, Beuk R, Kolkman J, Geelkerken R Gepubliceerd: Ann Vasc Surg. 2010;24(5):699-700 Impact factor: 1.169
24. Predictors for the Selection of Patients for Abdominal CT After Blunt Trauma: A Proposal for a Diagnostic Algorithm Deunk J1, Brink M2, Dekker HM2, Kool DR2, Blickman JG2, van Vugt AB3, Edwards MJ4 From the Departments of 1Surgery and Trauma, 2Radiology, and 4Emergency Medicine, Radboud University Nijmegen MC, Nijmegen 3 Department of Surgery, Medisch spectrum Twente, Enschede Objective: To select parameters that can predict which patients should receive abdominal computed tomography (CT) after high-energy blunt trauma. Summary background data: Abdominal CT accurately detects injuries of the abdomen, pelvis, and lumbar spine, but has important disadvantages. More evidence for an appropriate patient selection for CT is required. Methods: A prospective observational study was performed on consecutive adult high-energy blunt trauma patients. All patients received primary and secondary surveys according to the advanced trauma life support, sonography (focused
83
assessment with sonography for trauma [FAST]), conventional radiography (CR) of the chest, pelvis, and spine and routine abdominal CT. Parameters from prehospital information, physical examination, laboratory investigations, FAST, and CR were prospectively recorded for all patients. Independent predictors for the presence of >/=1 injuries on abdominal CT were determined using a multivariate logistic regression analysis. Results: A total of 1040 patients were included, 309 had injuries on abdominal CT. Nine parameters were independent predictors for injuries on CT: abnormal CR of the pelvis (odds ratio [OR], 46.8), lumbar spine (OR, 16.2), and chest (OR, 2.37), abnormal FAST (OR, 26.7), abnormalities in physical examination of the abdomen/pelvis (OR, 2.41) or lumbar spine (OR 2.53), base excess <-3 (OR, 2.39), systolic blood pressure <90 mm Hg (OR, 3.81), and long bone fractures (OR, 1.61). The prediction model based on these predictors resulted in a R of 0.60, a sensitivity of 97%, and a specificity of 33%. A diagnostic algorithm was subsequently proposed, which could reduce CT usage with 22% as compared with a routine use. Conclusions: Based on parameters from physical examination, laboratory, FAST, and CR, we created a prediction model with a high sensitivity to select patients for abdominal CT after blunt trauma. A diagnostic algorithm was proposed. Gepubliceerd: Ann Surg. 2010;251(3):512-20 Impact factor: 7.900
25. The clinical outcome of occult pulmonary contusion on multidetector-row computed tomography in blunt trauma patients Deunk J1, Poels TC2, Brink M3, Dekker HM3, Kool DR3, Blickman JG4, van Vugt AB5, Edwards MJ1 From the Departments of 1Surgery, 2Accidents and Emergency Medicine, and 3 Radiology, Radboud University, Nijmegen MC, Nijmegen 4 Department of Imaging Sciences, University of Rochester Medical Center, Rochester, New York 5 Department of Surgery, Medical Spectrum Twente, Enschede Background: Multidetector-row computed tomography (MDCT) is a more sensitive modality as compared with conventional radiography (CR) in detecting pulmonary injuries. MDCT often detects pulmonary contusion that is not visualized by CR, defined as occult pulmonary contusion (OPC). The aim of this study was to investigate whether OPC on MDCT has implications for the outcome in blunt trauma patients. Methods: We used prospectively collected data from 1,040 adult high-energy blunt trauma patients who were primarily presented at our emergency department and who underwent CR and MDCT of the chest. All patients with pulmonary contusion were identified and divided into two groups: The "CR/computed tomography (CT) group" consisted of patients with pulmonary contusion visible on both CR and MDCT. The "CT-only" group consisted of patients with OPC, visible exclusively on MDCT. The control group consisted of blunt trauma patients without pulmonary contusion. These groups were compared with respect to difference in mortality and other outcome measures. In addition, a multivariate analysis was performed.
84
Results: Two hundred fifty-five patients suffered pulmonary contusion: The CT-only group consisted of 157 and the CR/CT group of 98 patients. The CT-only group did not differ from the control group with respect to mortality rate and other outcome measures. However, compared with the CR/CT group, mortality rate was significantly lower (8% versus 16%, p = 0.039) and most other outcome measures were significantly better in the CT-only group. Conclusion: OPC on MDCT is not associated with a worse outcome as compared with patients without pulmonary contusion. OPC has a better outcome as compared with pulmonary contusion visible on both CR and MDCT. Gepubliceerd: J Trauma. 2010;68(2):387-94 Impact factor: 2.626
26. Criteria for the selective use of chest computed tomography in blunt trauma patients Brink M, Deunk J, Dekker HM, Edwards MJ, Kool DR, van Vugt AB*, van Kuijk C, Blickman JG Department of Radiology, Radboud University Nijmegen MC, Nijmegen * Department of Surgery, Medisch Spectrum Twente, Enschede Purpose: The purpose of this study was to derive parameters that predict which high-energy blunt trauma patients should undergo computed tomography (CT) for detection of chest injury. Methods: This observational study prospectively included consecutive patients (>/=16 years old) who underwent multidetector CT of the chest after a high-energy mechanism of blunt trauma in one trauma centre. Results: We included 1,047 patients (median age, 37; 70% male), of whom 508 had chest injuries identified by CT. Using logistic regression, we identified nine predictors of chest injury presence on CT (age >/=55 years, abnormal chest physical examination, altered sensorium, abnormal thoracic spine physical examination, abnormal chest conventional radiography (CR), abnormal thoracic spine CR, abnormal pelvic CR or abdominal ultrasound, base excess <-3 mmol/l and haemoglobin <6 mmol/l). Of 855 patients with >/=1 positive predictors, 484 had injury on CT (95% of all 508 patients with injury). Of all 192 patients with no positive predictor, 24 (13%) had chest injury, of whom 4 (2%) had injuries that were considered clinically relevant. Conclusion: Omission of CT in patients without any positive predictor could reduce imaging frequency by 18%, while most clinically relevant chest injuries remain adequately detected. Gepubliceerd: Eur Radiol. 2010;20(4):818-28 Impact factor: 2.645
27. Outcome prediction in mild traumatic brain injury: age and clinical variables are stronger predictors than CT abnormalities
85
Jacobs B, Beems T, Stulemeijer M, van Vugt AB*, van der Vliet TM, Borm GF, Vos PE Department of Neurology, Radboud University Nijmegen MC, Nijmegen * Department of Surgery, Medisch Spectrum Twente, Enschede Mild traumatic brain injury (MTBI) is a frequent, heterogeneous neurological disorder, covering a wide range of possible clinical outcomes. For optimal treatment, accurate prediction of outcome is desirable. This study aimed both to identify the demographic, clinical and CT characteristics associated with unfavorable outcome at six months after MTBI, and to design a prediction model for application in daily practice. All consecutive MTBI patients (GCS score: 13-15) admitted to our hospital, aged above 16, were included during an eight year period as part of the prospective Radboud University Brain Injury Cohort Study (RUBICS). Outcome was assessed six months post-trauma using the extended Glasgow Outcome Scale (GOSE), dichotomized in unfavorable (GOSE 1-6) and favorable (GOSE 7-8) outcome. The predictive value of several variables was determined using multivariate binary logistic regression analysis. We included 2784 MTBI patients and found CT abnormalities in 20.7% of the 1999 patients that underwent a head CT. Age, extracranial injuries and day-of-injury alcohol intoxication proved to be the strongest outcome predictors. The presence of facial fractures and the number of hemorrhagic contusions emerged as CT predictors. Furthermore, we showed that the predictive value of a prediction rule based on a modified ISS, alcohol intoxication and age was as good as one that also included CT characteristics. It was better than a rule based on CT characteristics alone. We conclude that, although valuable for the identification of the individual MTBI patient at risk for deterioration and eventual neurosurgical intervention, CT characteristics are imperfect predictors of outcome after MTBI. Gepubliceerd: J Neurotrauma 2010;27(4):655-68 Impact factor: 4.252
28. Effect of a new pelvic stabilizer (T-POD®) on reduction of pelvic volume and haemodynamic stability in unstable pelvic fractures Tan EC1, van Stigt SF1, van Vugt AB2 1 Department of Surgery-Division of Trauma Surgery, Radboud University Nijmegen MC, Nijmegen 2 Department of Surgery, Medisch Spectrum Twente, Enschede Background: Pelvic fractures, often the result of high energy blunt trauma, are associated with severe morbidity and mortality. A new pelvic stabilizer (T-POD((R))) provides secure and effective simultaneous circumferential compression of the pelvis. Methods: In this study we describe 15 patients with a prehospital untreated unstable pelvic fracture with signs of hypovolaemic shock with the T-POD((R)). Before and 2min after applying the T-POD((R)), heart rate and blood pressure were measured. An X-ray before and directly after applying the T-POD((R)) was made to measure the effect on reduction in symphyseal diastasis.
86
Results: Application of the T-POD((R)) reduced the symphyseal diastasis with 60% (p=0.01). The mean arterial pressure (MAP) increased significant from 65.3 to 81.2mm Hg (p=0.03) and the heart rate declined from 107 beats per minute to 94 (p=0.02). Out of ten patients in whom the circulatory response before and after the T-POD((R)) was recorded, seven were good responders, one had a transient response and two responded poor. Conclusion: In the acute setting, the T-POD((R)) device has a clear compressive effect on the pelvic volume in unstable pelvic fractures. The T-POD((R)) is therefore an effective and easy to use device in (temporarily) stabilizing the pelvic ring in haemodynamically unstable patients. Gepubliceerd: Injury 2010;41(12):1239-1243 Impact factor: 2.383
29. First aid and basic life support: a questionnaire survey of medical schools in the Netherlands Tan EC1, Hekkert KD1, van Vugt AB1,2, Biert J1 1 Department of Surgery-Division of Trauma Surgery, Radboud University Nijmegen MC, Nijmegen 2 Department of Surgery, Medisch Spectrum Twente, Enschede Purpose: Adequate education in first aid and basic life support (BLS) should be considered as an essential aspect of the medical curriculum. The objective of this study was to investigate the current medical training in first aid and BLS at all 8 medical schools in the Netherlands. Summary: An evaluation was made, by sending a questionnaire to all medical schools, regarding whether the medical training was performed in accordance with the national Dutch guidelines for medical education. The response was 100%. Seven of the eight medical schools train their students in first aid and BLS during the medical curriculum. An average of only 38% of the clinical pictures and diseases and 69% of the skills were mastered at the level-defined national Dutch guidelines. Conclusion: The medical education in the Netherlands does not meet the required objectives as stated in the national Dutch guidelines concerning first aid and BLS. Gepubliceerd: Teach Learn Med. 2010;22(2):112-5 Impact factor: 0.741
30. Internal fixation of intracapsular hip fractures with a dynamic locking plate: initial experience and results for 83 patients treated with a new implant Roerdink WH1, van Walsum AD2 1 Department of Surgery, Deventer Ziekenhuis, Deventer 2 Department of Surgery, Medisch Spectrum Twente, Enschede Gepubliceerd: Injury 2010;41:1066-1067 Impact factor: 2.383
87
31. Functional treatment versus plaster for simple elbow dislocations (FuncSiE): a randomized trial de Haan J1, den Hartog D2, Tuinebreijer WE2, Iordens GI2, Breederveld RS3, Bronkhorst MW4, Bruijninckx MM5, De Vries MR6, Dwars BJ7, Eygendaal D8, Haverlag R9, Meylaerts SA10, Mulder JW11, Ponsen KJ12, Roerdink WH13, Roukema GR14, Schipper IB15, Schouten MA16, Sintenie JB17, Sivro S18, Van den Brand JG19, Van der Meulen HG20, Van Thiel TP21, Van Vugt AB22, Verleisdonk EJ23, Vroemen JP24, Waleboer M25, Willems WJ26, Polinder S27, Patka P2, van Lieshout EM2, Schep NW2 Department of Surgery-Traumatology, 1Westfriesgasthuis, Hoorn; 2 Erasmus MC, UMC Rotterdam, Rotterdam; 3 Red Cross Hospital, Beverwijk; 4 Bronovo Hospital, The Hague; 5 IJsselland Hospital, Capelle a/d IJssel; 6 Reinier de Graaf Gasthuis, Delft; 7 Slotervaart Hospital, Amsterdam; 9 Onze Lieve Vrouwe Gasthuis, Amsterdam; 10 Medical Center Haaglanden, ‘s Gravenhage; 11 Zaans Medical Center, Zaandam; 12 Academic Medical Center, Amsterdam; 13 Deventer Hospital, Deventer; 14 Maasstad Hospital, Rotterdam; 15 Leiden UMC, Leiden; 16 Hospital Rivierenland, Tiel; 17 Elkerliek Hospital, Helmond; 18 Flevo Hospital, Almere; 19 Medical Center Alkmaar, Alkmaar; 20 Haga Hospital, ‘s Gravenhage; 21 Hospital Queen Beatrix, Winterswijk; 22 Medical Spectrum Twente, Enschede; 23 Diakonessenhuis, Utrecht; 24 Amphia Hospital, Breda; 25 Admiraal de Ruyter Hospital, Goes 8 Department of Orthpaedic Surgery, Amphia Hospital, Breda; 26 Onze Lieve Vrouwe Gasthuis, Amsterdam 27 Department of Public Health, Erasmus MC, UMC Rotterdam, Rotterdam 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. After reduction of a simple dislocation, treatment options include immobilization in a static plaster for different periods of time or so-called functional treatment. Functional treatment is characterized by early active motion within the limits of pain with or without the use of a sling or hinged brace. Theoretically, functional treatment should prevent stiffness without introducing increased joint instability. The primary aim of this randomized controlled trial is to compare early functional treatment versus plaster immobilization following simple dislocations of the elbow. Methods: The design of the study will be a multicenter randomized controlled trial of 100 patients who have sustained a simple elbow dislocation. After reduction of the dislocation, patients are randomized between a pressure bandage for 5-7 days and early functional treatment or a plaster in 90 degrees flexion, neutral position for prosupination for a period of three weeks. In the functional group, treatment is started with early active motion within the limits of pain. Function, pain, and radiographic recovery will be monitored at regular intervals over the subsequent 12 months. The primary outcome measure 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, rate of secondary interventions and complication rates in both groups (secondary dislocation, instability, relaxation), health-related quality of life (Short-
88
Form 36 and EuroQol-5D), radiographic appearance of the elbow joint (degenerative changes and heterotopic ossifications), costs, and cost-effectiveness. Discussion: The successful completion of this trial will provide evidence on the effectiveness of a functional treatment for the management of simple elbow dislocations. Gepubliceerd: BMC Musculoskelet Disord. 2010;11(1):263 Impact factor: 1.880
32. Carotid Endarterectomy: Current Consensus and Controversies Meerwaldt R1, Hermus L2, Reijnen MM2, Zorggroep A2, Zeebregts CJ2 1 Department of Surgery, Medical Spectrum Twente, Enschede 2 Department of Surgery, Division of Vascular Surgery, UMC Groningen, Groningen Stroke is the third most common cause of mortality, and carotid artery stenosis causes 8% to 29% of all ischemic strokes. Best medical treatment forms the basis of carotid stenosis treatment, and carotid endarterectomy (CEA) has an additional beneficial effect in high-grade stenosis. Carotid angioplasty and stenting (CAS) has challenged CEA as a primary carotid intervention. At present, CEA remains the gold standard, but in the future, CAS techniques will evolve and might become beneficial for subgroups of patients with carotid stenosis. This chapter briefly describes the history of carotid interventions and current consensus and controversies in CEA. In the last two years, several meta-analyses were published on a variety of aspects of best medical treatment, CEA, and CAS. It is still a matter of debate as to whether asymptomatic patients with carotid stenosis should undergo a carotid intervention. Especially because medical treatment has dramatically evolved since the early carotid trials. On the other hand, it is clear that carotid interventions in symptomatic patients with a high-grade stenosis should be performed as early as possible after the initial neurological event in order to achieve optimal stroke risk reduction. In CEA, the use of patching is advocated above primary closure, while the role of selective patching is still unclear. No differences in stroke and mortality rates are observed for routine versus selective shunting, for conventional versus eversion CEA, or for local versus general anesthesia. It is anticipated that in the future, there will be several interesting developments in carotid interventions such as plaque morphology analysis, acute interventions during stroke in progress, and further evolvement of CAS techniques. Gepubliceerd: Surg Technol Int. 2010;20:283-291 Impact factor: 0
33. Using a web application to improve satisfaction among patients undergoing surgery RH Koop1, JM Klaase1, J van der Palen2,3, PAM Kommers4, AJ Sanders4, J Jonker4 1 Department of Surgery, Medisch Spectrum Twente, Enschede 2 Medical School Twente, Medisch Spectrum Twente, Enschede
89
3
Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede 4 University of Twente The study explores whether patient satisfaction is increased when a web application is used to inform patients about a surgical intervention. A randomised single centre study was conducted. The study population consisted of 32 patients that underwent an elective colon resection for colon cancer (15 in the experimental and 17 in the control group; patient characteristics were equally divided between both groups). The study group got the information with the web application from the nurse practitioner at least 10 days before surgery; the control group was given the standard oral information by the nurse practitioner. Satisfaction level was measured with a validated patient satisfaction questionnaire directly after giving the information and two weeks after the surgical intervention. The results indicate that patients are more satisfied when information is given by means of a web application. Given that expectations regarding hospital admission are more realistic when information is given in the optimal manner, this has consequences for the use of multimedia information techniques in healthcare in the near future. Gepubliceerd: J Management & Marketing in Healthcare 2010;3(4):264–271 Impact factor: 0
34. Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm Gretarsdottir S, Baas AF, Thorleifsson G, Holm H, den Heijer M, de Vries JP, Kranendonk SE, Zeebregts CJ, van Sterkenburg SM, Geelkerken RH*, van Rij AM, Williams MJ, Boll AP, Kostic JP, Jonasdottir A, Jonasdottir A, Walters GB, Masson G, Sulem P, Saemundsdottir J, Mouy M, Magnusson KP, Tromp G, Elmore JR, Sakalihasan N, Limet R, Defraigne JO, Ferrell RE, Ronkainen A, Ruigrok YM, Wijmenga C, Grobbee DE, Shah SH, Granger CB, Quyyumi AA, Vaccarino V, Patel RS, Zafari AM, Levey AI, Austin H, Girelli D, Pignatti PF, Olivieri O, Martinelli N, Malerba G, Trabetti E, Becker LC, Becker DM, Reilly MP, Rader DJ, Mueller T, Dieplinger B, Haltmayer M, Urbonavicius S, Lindblad B, Gottsäter A, Gaetani E, Pola R, Wells P, Rodger M, Forgie M, Langlois N, Corral J, Vicente V, Fontcuberta J, España F, Grarup N, Jørgensen T, Witte DR, Hansen T, Pedersen O, Aben KK, de Graaf J, Holewijn S, Folkersen L, Franco-Cereceda A, Eriksson P, Collier DA, Stefansson H, Steinthorsdottir V, Rafnar T, Valdimarsson EM, Magnadottir HB, Sveinbjornsdottir S, Olafsson I, Magnusson MK, Palmason R, Haraldsdottir V, Andersen K, Onundarson PT, Thorgeirsson G, Kiemeney LA, Powell JT, Carey DJ, Kuivaniemi H, Lindholt JS, Jones GT, Kong A, Blankensteijn JD, Matthiasson SE, Thorsteinsdottir U, Stefansson K 1 Population Genomics, deCODE Genetics, Reykjavik, Iceland * Department of Surgery, Medisch Spectrum Twente, Enschede We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs
90
and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 × 10−10. In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 × 10−5), peripheral arterial disease (OR = 1.14, P = 3.9 × 10−5) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases— that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival. Gepubliceerd: Nature Genetics 2010;42:692–7 Impact factor: 34.284
35. Patterns of care in Dutch postmenopausal patients with hormone-sensitive early breast cancer participating in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial JG van Nes1, C Seynaeve2, E Maartense3, RM Roumen4, RS de Jong5, LV Beex6, WM Meershoek-Klein Kranenbarg7, H Putter8, JW Nortier9, CJ van de Velde1, and the Cooperating investigators of the Dutch TEAM trial. Includes Mastboom WJ* 1 Department of Surgery, Leiden UMC, Leiden 2 Department of Medical Oncology, Erasmus Medical Centre–Daniel den Hoed Cancer Centre, Rotterdam 3 Department of Internal Medicine, Reinier de Graaf Gasthuis, Delft 4 Department of Surgery, Máxima Medical Centre, Veldhoven 5 Department of Internal Medicine, Martini Hospital, Groningen 6 Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen 7 Datacentre Surgery, Leiden UMC, Leiden 8 Department of Medical Statistics 9 Department of Medical Oncology, Leiden UMC, Leiden Background: The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial investigates the efficacy and safety of adjuvant exemestane alone and in sequence after tamoxifen in postmenopausal women with hormone-sensitive early breast cancer. As there was a nationwide participation in The Netherlands, we studied the variations in patterns of care in the Comprehensive Cancer Centre Regions (CCCRs) and compliance with national guidelines. Methods: Clinicopathological characteristics, carried out local treatment strategies and adjuvant chemotherapy data were collected. Results: From 2001 to January 2006, 2754 Dutch patients were randomised to the study. Mean age of patients was 65 years (standard deviation 9). Tumours were ≤2 cm in 46% (within CCCRs 39%–50%), node-negative disease varied from 25% to 45%, and PgR status was determined in 75%–100% of patients. Mastectomy was carried out in 55% (45%–70%), sentinel lymph node procedure in 68% (42%–79%) and axillary lymph node dissections in 77% (67%–83%) of patients, all different between CCCRs (PԜ<Ԝ0.0001). Adjuvant chemotherapy was given in 15%–70% of eligible patients (PԜ<Ԝ0.001).
91
Discussion: In spite of national guidelines, breast cancer treatment on specific issues widely varied between the various Dutch regions. These data provide valuable information for breast cancer organisations indicating (lack of) guideline adherence and areas for breast cancer care improvement. Gepubliceerd: Ann Oncol. 2010;21(5):974-82 Impact factor: 5.647
36. Duodenal Lipoma as a Rare Cause of Upper Gastrointestinal Bleeding HM Ouwerkerka, MH Rabera, G Frelingb, JM Klaasea a Department of Surgery, Medisch Spectrum Twente, Enschede b Department of Pathology, Medisch Spectrum Twente, Enschede A 52-year-old female was referred because of melaena. After initial work-up, including gastroduodenoscopy, endosonography and CT scan, a duodenotomy was performed. Definite diagnosis was a duodenal lipoma based on histological findings. Lipomas of the gastrointestinal tract are rare. Only 4% occur in the duodenum. The peak incidence is around the 5th and 7th decade of life, with a slight female preponderance. Gastrointestinal lipomas are usually asymptomatic, but can present with mild to severe gastrointestinal bleeding, intussusceptions, abdominal pain, constipation and diarrhea. Clinical, endoscopical, surgical, and radiological features are described in this case of duodenal lipoma. Gepubliceerd: Gastroenterology Research 2010;3(6):290-292 Impact factor: 0
37. Gastric Schwannoma Presenting as an Incidentaloma on CT-Scan and MRI MH Rabera, CM Ziedses des Plantesb, R Vinkc, JM Klaasea a Department of Surgery, Medisch Spectrum Twente, Enschede b Department of Radiology, Medisch Spectrum Twente, Enschede c Laboratorium Pathologie Oost Nederland, Enschede A 67 year old female was referred because of an incidentaloma on CT-scan and MRI which showed a 5.0 cm large mass in the wall of the distal stomach. After an initial work-up which suggested a gastrointestinal stromal tumor (GIST), a partial gastrectomy with a Billroth II gastrojejunostomy was performed. The histological diagnosis was a schwannoma. Gastric schwannomas are rare tumors which comprise 0.2% of all gastric tumors and 4% of all benign gastric neoplasms with a peak of incidence in the 4th and 5th decade of life. Gastric schwannomas are usually asymptomatic, but can present with ulceration and/or gastrointestinal bleeding. Clinical, endoscopical, surgical, radiological and histological features of this case are described and the relevant literature is reviewed. Gepubliceerd: Gastroenterology Research 2010;3(6):276-280 Impact factor: 0
92
38. De effectiviteit van beugelbehandeling (orthonyxie) versus chirurgie bij de ingegroeide teennagel S Kruijff1, RJ van Det1, RH Geelkerken1, CM van den Berg2, J van der Palen3,4, CL Gerritsma-Bleeker5 1 Afdeling Heelkunde, Medisch Spectrum Twente, Enschede 2 Podotherapeut, Medisch Spectrum Twente, Enschede 3 Afdeling Epidemiologie, Medisch Spectrum Twente, Enschede 4 Afdeling Onderzoeksmethodologie, meetmethoden en data analyse, Faculteit Gedragswetenschappen, Universiteit Twente, Enschede 5 Afdeling orthopedie, Martini ziekenhuis, Groningen Doel: Bepalen welke therapie, Segmentiele Phenolisatie (SP), Partiële Matrix Excisie (PME) of Beugelbehandeling (orthonyxie), het meest eff ectief is voor de behandeling van de ingegroeide teennagel van de hallux. Studie-opzet: Er werd een analyse verricht over een tweetal eerder uitgevoerde geblindeerde prospectieve gerandomiseerde klinische trials (RCT) met ieder een follow-up van 12 maanden. Beide studies werden eerder verricht in ons centrum en hadden een identieke methodologische opzet. In het eerste onderzoek (SP; n=29, PME1; n=34), werd segmentiele phenolisatie met partiële matrix excisie vergeleken en in het tweede onderzoek (Orthonyxie; n=51, PME 2; n=58) werd de beugelbehandeling met partiële matrix vergeleken. Voor de analyse werden in totaal de data van 163 patiënten met 172 ingegroeide teennagels samengevoegd. Het primaire eindpunt was recidief na 12 maanden. Secundaire eindpunten waren postoperatieve morbiditeit en tijd tot volledig herstel. Resultaten: Na 12 maanden werden 6 recidieven in de segmentiele phenolisatie groep (20.7%), 7 in de eerste partiële matrix excisie groep (20.6%), 4 in de tweede partiële matrix excisie groep (6.9%) en 8 (15.7%) in de beugelbehandelings groep vastgesteld (p=0.16). Postoperatieve morbiditeit (roodheid, pus, bloeding), tijd tot volledig herstel, dragen van schoenen en het uitvoeren van ADL en hobby’s, postoperatieve symptomen en patiënt tevredenheid scoorden signifi cant aanzienlijk beter bij de behandeling met een nagelbeugel ten opzichte van partiële matrix excisie en segmentiele phenolisatie. Conclusie: Segmentiele phenolisatie, partiële matrix excisie en een beugelbehandeling zijn even eff ectief in de behandeling van unguis incarnatus van de hallux. Echter, de beugelbehandeling toont met name op vroege termijn aanzienlijk betere resultaten daar waar het de postoperatieve morbiditeit, tijd tot volledig herstel, postoperatieve symptomen en patiënt tevredenheid betreft. Gepubliceerd: Nederlands Tijdschrift voor Heelkunde 2010;19(5):183-190 Impact factor: 0
Totale impact factor: 213.876 Gemiddelde impact factor: 5.628 Aantal artikelen 1e, 2e of laatste auteur: 20 Totale impact factor: 38.281 Gemiddelde impact factor: 1.914
93
Intensive Care 1. Lung Transplantation from Nonheparinized Category III Non-Heart-Beating Donors. A Single-Centre Report Erasmus ME1, Verschuuren EA2, Nijkamp DM3, Vermeijden JW4, van der Bij W1 Department of 1 Cardiothoracic Surgery, 2 Pulmonary Diseases and Lung Transplantation, and 3 Surgery, Division of Organ Donation, University of Groningen, Groningen 4 Department of Intensive Care, Medisch Spectrum Twente, Enschede Background: Despite the increasing use of extended lung donors, the shortage of lung donors remains. Usage of non-heart-beating (NHB) lung donors contributes to fight this shortage. We describe our experience in 21 consecutive adult lung transplantations using nonheparinized category III NHB donors and standard flush preservation. Methods: From January 2005 to December 2008, we collected donor and recipient data of all NHB category III lung transplantations performed in our center. For comparison, we also collected the data of all heart-beating (HB) lung transplantations in the same period. We focused on data describing the donor, the donor procedure, the recipient's primary graft dysfunction, survival, rejection episodes, and the lung graft function. Results: Twenty-one NHB and 77 HB lung transplantations were performed. Circulation arrest occurred after 14 (4-62) min and warm ischemia time was 30 (1944) min. Occurrence of primary graft dysfunction, acute rejection episodes, development of bronchiolitis obliterans syndrome was equal to the HB cohort as was the 2 years survival of 95% in the NHB group compared with 86% in the HB group. Lung graft function during the first 2 years tended to be better preserved in the NHB group. Conclusion: Category III NHB lung donation is a good alternative in addition to HB lung donation. Using nonheparinized category III NHB donors and standard anteand retrograde, flush perfusion resulted in good lung graft function and survival. NHB donation offers a great opportunity to reduce the burden of donor lung shortage. Gepubliceerd: Transplantation. 2010;89(4):452-7 Impact factor: 3.498
2. Greater cardiac response of colloid than saline fluid loading in septic and nonseptic critically ill patients with clinical hypovolaemia Trof RJ1, Sukul SP2, Twisk JW3, Girbes AR2, Groeneveld AB2,4 1 Department of Intensive Care, Medical Spectrum Twente, Enschede 2 Department of Intensive Care, VU UMC, Amsterdam 3 Department of Clinical Epidemiology and Biostatistics, VU Medical Center, Amsterdam 4 Institute for Cardiovascular Research, VU Medical Center, Amsterdam
94
Background and objective: The haemodynamics of crystalloid and colloid fluid loading may depend on underlying disease, i.e. sepsis versus non-sepsis. Design and setting: A single-centre, single-blinded, randomized clinical trial was carried out on 24 critically ill sepsis and 24 non-sepsis patients with clinical hypovolaemia, assigned to loading with normal saline, gelatin 4%, hydroxyethyl starch 6% or albumin 5% in a 90-min (delta) central venous pressure (CVP)-guided fluid loading protocol. Transpulmonary thermodilution was done each 30 min, yielding, among others, global end-diastolic volume and cardiac indices (GEDVI, CI). Results: Sepsis patients had hyperdynamic hypotension in spite of myocardial depression and dilatation, and greater inotropic/vasopressor requirements than nonsepsis patients. Independent of underlying disease, CVP and GEDVI increased more after colloid than saline loading (P < 0.018), so that CI increased by about 2% after saline and 12% after colloid loading (P = 0.029). The increase in preloadrecruitable stroke work was also greater with colloids and did not differ among conditions. Conclusion: Fluid loading with colloids results in a greater linear increase in cardiac filling, output and stroke work than does saline loading, in both septic and non-septic clinical hypovolaemia, in spite of myocardial depression and presumably increased vasopermeability potentially decreasing the effects of colloid fluid loading in the former. Gepubliceerd: Intensive Care Med. 2010;36(4):697-701 Impact factor: 5.168
Totale impact factor: 8.666 Gemiddelde impact factor: 4.333 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 5.168 Gemiddelde impact factor: 5.168
95
Interne Geneeskunde 1. Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per microL in Europe and North America: a pooled cohort observational study Study Group on Death Rates at High CD4 Count in Antiretroviral Naive Patients* Lodwick RK1, Sabin CA, Porter K, Ledergerber B, van Sighem A, Cozzi-Lepri A, Khaykin P, Mocroft A, Jacobson L, De Wit S, Obel N, Castagna A, Wasmuth JC, Gill J, Klein MB, Gange S, Riera M, Mussini C, Gutiérrez F, Touloumi G, Carrieri P, Guest JL, Brockmeyer NH, Phillips AN 1 HIV Epidemiology and Biostatistics Group, Research Department of Infection and Population Health, UCL Medical School, Royal Free Campus, London, UK * Includes: ten Napel CH, Department of Internal Medicine, Medisch Spectrum Twente, Enschede Background: Whether people living with HIV who have not received antiretroviral therapy (ART) and have high CD4 cell counts have higher mortality than the general population is unknown. We aimed to examine this by analysis of pooled data from industrialised countries. Methods: We merged data on demographics, CD4 cell counts, viral-load measurements, hepatitis C co-infection status, smoking status, date of death, and whether death was AIDS-related or not from 23 European and North American cohorts. We calculated standardised mortality ratios (SMRs) standardised by age, sex, and year, stratifying by risk group. Data were included for patients aged 20-59 years who had at least one CD4 count greater than 350 cells per microL while ART naive. All pre-ART CD4 counts greater than 350 cells per microL from January, 1990, to December, 2004, were included. We investigated mortality for four risk groups--men who have sex with men, heterosexual people, injecting drug users, and those at other or unknown risk. The association between CD4 cell count and death rate was investigated by use of Poisson regression methods. Findings: Data were analysed for 40,830 patients contributing 80,682 person-years of follow-up. Of 419 deaths, 401 were used in the SMR analysis: 100 men who have sex with men (SMR 1.30, 95% CI 1.06-1.58); 68 heterosexual people (2.94, 2.283.73); 203 injecting drug users (9.37, 8.13-10.75); and 30 in the other or unknown risk category (4.57, 3.09-6.53). Compared with CD4 counts of 350-499 cells per microL, death rate was lower in patients with counts of 500-699 cells per microL (adjusted rate ratio 0.77, 95% CI 0.61-0.95) and counts of 700 cells per microL (0.66, 0.52-0.85). Interpretation: In HIV-infected ART-naive patients with high CD4 cell counts, death rates were raised compared with the general population. In men who have sex with men this was modest, suggesting that a substantial proportion of the increased risk in other groups is due to confounding by other factors. Even though the increased risk is small, new studies of potential benefits of ART in this group are merited. Gepubliceerd: Lancet. 2010;376(9738):340-5 Impact factor: 30.758
96
2. Heavy chain myosin 9-related disease MYH9 -RD: Neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder A Savoia 1, 2, D De Rocco 1, 2, E Panza 3, 2, V Bozzi 4, 2, R Scandellari 5, 2, G Loffredo 6, 2 , A Mumford 7, PG Heller 8, P Noris 4, 2, MR De Groot 9, M Giani 10, 2, P Freddi 11, 2, F Scognamiglio 12, 2, S Riondino 13, 2, N Pujol-Moix 14, F Fabris 5, 2, M Seri 3, 2, CL Balduini 4, 2, A Pecci 4, 2 1 Medical Genetics, Department of Reproductive and Developmental Sciences, Institute for Maternal and Child Health – IRCCS Burlo Garofolo, University of Trieste, Trieste, Italy; 2 Italian Registry for MYH9-Related Disease, Pavia, Italy; 3 Department of Internal Medicine, Cardioangiology and Hepatology, University of Bologna, Bologna, Italy; 4 Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy; 5 Department of Medical Sciences, University of Padova, Padova, Italy; 6 Department of Oncology, Azienda „Santobono-Pausilipon“, Pausilipon Hospital, Napoli, Italy; 7 Bristol Heart Institute, University of Bristol, Bristol, UK; 8 Instituto de Investigaciones Medicas IDIM, “A. Lanari”, University of Buenos Aires, Buenos Aires, Argentina; 9 Department of Internal Medicine, Medical Spectrum Twente, Enschede; 10 Pediatric Nephrology Unit, IRCCS OspedaleMaggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy; 11 Nephrology Unit, Ospedali Riuniti, Ancona, Italy; 12 Hematology Unit, “San Bortolo” Hospital, Vicenza, Italy; 13 Department of Laboratory Medicine & Advanced Technologies, IRCCS San Raffaele Pisana, Rome, Italy; 14 Autonomous University of Barcelona & Platelet Pathology Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain MYH9 -related disease MYH9 -RD is an autosomal dominant thrombocytopenia with giant platelets variably associated with young-adult onset of progressive sensorineural hearing loss, presenile cataract, and renal damage. MYH9 -RD is caused by mutations of MYH9 , the gene encoding for non-muscle heavy-chain myosin-9. Wild-type and mutant myosin-9 aggregate as cytoplasmic inclusions in patients’ leukocytes, the identification of which by immunofluorescence has been proposed as a suitable tool for the diagnosis of MYH9 -RD. Since the predictive value of this assay, in terms of sensitivity and specificity, is unknown, we investigated 118 consecutive unrelated patients with a clinical presentation strongly consistent with MYH9 -RD. All patients prospectively underwent both the immunofluorescence assay for myosin-9 aggregate detection and molecular genetic analysis of the MYH9 gene. Myosin-9 aggregates were identified in 82 patients, 80 of which 98% had also a MYH9 mutation. In the remaining 36 patients neither myosin-9 aggregates nor MYH9 mutations were found. Sensitivity and specificity of the immunofluorescence assay was evaluated to be 100% and 95%, respectively. Except for the presence of aggregates, we did not find any other significant difference between patients with or without aggregates, demonstrating that the myosin-9 inclusions in neutrophils are a pathognomonic sign of the disease. However, the identification of the specific MYH9 mutation is still of importance for prognostic aspects of MYH9 –RD. Gepubliceerd: Thromb Haemost. 2010;103(4):826-32 Impact factor: 4.451
97
3. Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase III study B Löwenberg1, J Beck2, C Graux3, W van Putten4, HC Schouten5, LF Verdonck6, A Ferrant7, P Sonneveld1, M Jongen-Lavrencic1, M von Lilienfeld-Toal8, BJ Biemond9, E Vellenga10, D Breems11, H de Muijnck12, MR Schaafsma13, G Verhoef14, H Döhner15, A Gratwohl16, Th Pabst17, GJ Ossenkoppele18, J Maertens14 1 Erasmus UMC, Rotterdam; 2 Department Internal Medicine III, University-Hospital, Mainz, Germany; 3 Hopital Mont Godinne, Yvoir, Belgium; 4 HOVON Data Center and Dept of Trials and Statistics, Erasmus UMC, Rotterdam; 5 UMC, Maastricht; 6 UMC, Utrecht; 7 Hopital St Luc, Bruxelles, Belgium; 8 University Hospital, Bonn, Germany; 9 Amsterdam UMC, Amsterdam; 10 UMC, Groningen; 11 Hospital Stuivenberg, Antwerp, Belgium; 12 Hospital Heilig Hart, Roeselaere, Belgium; 13 Medisch Spectrum Twente, Enschede; 14 University Hospital Gasthuisberg, Leuven, Belgium; 15 Dept of Internal Medicine III, University Ulm, Ulm, Germany; 16 University Hospital, Basel, Switzerland; 17 Inselspital, Bern, Switzerland; 18 VU UMC, Amsterdam In older patients with AML prevention of relapse has remained one of the major therapeutic challenges with more than 75% relapses following complete remission (CR). The anti-CD33 immuno-toxin conjugate gemtuzumab ozogamicin (GO) has shown antileukemic remission induction activity in relapsed AML. Patients with AML or RAEB in first CR attained after intensive induction chemotherapy were randomized between three cycles of GO (6 mg/m(2) q 4-weeks) or no postremission therapy (control) to assess whether GO would improve outcome. The two treatment groups (113 pts GO versus 119 pts control) were comparable as regards age (6078, median 67), performance status and cytogenetics. 110/113 received at least one cycle of GO and 65/113 patients completed the three cycles. Premature discontinuation was mainly due to incomplete hematological recovery or intercurrent relapse. Time towards recovery of platelets 50x10(9)/L and neutrophils 0.5x 10(9)/L after GO was 14 days and 20 days (median). Nonhematological toxicities were overall mild but there was one toxic death due to liver failure. There were no significant differences between both treatment groups as regards relapse probabilities, nonrelapse mortality, overall survival or disease-free survival (17% versus 16% at 5 years). Postremission treatment with GO in AML at older age does not provide benefits regarding any of the clinical endpoints. Gepubliceerd: Blood. 2010;115(13):2586-91 Impact factor: 10.555
4. Analysis of efficacy and prognostic factors of lenalidomide treatment as part of a Dutch compassionate use program. Kneppers E, Lokhorst HM, Eeltink CM, Huls G, Kersten MJ, Koedam J, Minnema MC, van Oers MH, Raymakers RA, Schaafsma MR*, Vellenga E, Wijermans PW, Wittebol S, Sonneveld P, Zweegman S Department of Haematology, UMC, Utrecht * Department of Internal medicine, Medisch Spectrum Twente, Enschede
98
Background and methods: To obtain efficacy and safety data on lenalidomide treatment outside of clinical trials, we analyzed the clinical data of 114 patients with refractory or relapsed multiple myeloma treated with lenalidomide on a compassionate use basis. The recommended treatment consisted of lenalidomide 25 mg given on days 1-21 of a 28-day cycle, in combination with dexamethasone. A median of 3 previous lines of therapy were given, including thalidomide in 91%. Most patients were treated until progression or intolerable toxicity. Results: The median number of cycles was 7 (range, 1-21+ cycles) with a maximum response after a median of 3 cycles (range, 1-10 cycles). The overall response rate was 69%, including complete response in 6%, very good partial response in 19%, and partial response in 44%. The response rate was not influenced by previous thalidomide and/or bortezomib treatment. The median time to progression (TTP) was 9 months and the median overall survival (OS) was 22 months. A significantly longer TTP was observed in patients who previously underwent allogeneic stem cell transplantation (12.5 months vs. 8 months; P = .036). Overall survival was significantly affected by performance status (P < .0001). Lenalidomide toxicity was predominantly hematologic (37%; Common Toxicity Criteria > or = 3) and the incidence of venous thrombotic events was low (5%) using the recommended prophylaxis. Conclusion: This analysis confirms that, outside clinical prospective trials, treatment with lenalidomide is highly effective and feasible in heavily pretreated patients with multiple myeloma. Gepubliceerd: Clin Lymphoma Myeloma Leuk. 2010;10(2):138-43 Impact factor: 2.638
5. Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia W Deenik,1 JJ Janssen,2 B van der Holt,1 GE Verhoef,3 WM Smit,4 MJ Kersten,5 SM Daenen,6 LF Verdonck,7 A Ferrant,8 AV Schattenberg,9 P Sonneveld,1 M van Marwijk Kooy,7 S Wittebol,10 R Willemze,11 PW Wijermans,12 HB Beverloo,1 B Löwenberg,1 PJ Valk,1 GJ Ossenkoppele,2 JJ Cornelissen1 1 Erasmus UMC, Rotterdam; 2 VU Medical Center, Amsterdam; 3 University Hospital Gasthuisberg, Leuven, Belgium; 4 Medical Spectrum Twente, Enschede; 5 Academic Medical Center, Amsterdam; 6 UMC Groningen, Groningen; 7 Isala Clinic, Sophia, Zwolle; 8 University Hospital St-Luc, Brussels, Belgium; 9 UMC Nijmegen, Nijmegen; 10 Meander Medical Center, Amersfoort; 11 Leiden UMC, Leiden; 12 Haga Hospital, The Hague Background. In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study. Design and Methods. Having reported feasibility previously, we hereby report the efficacy of escalated imatinib (200 mg, 400 mg, 600 mg or 800 mg) in combination with two cycles of intravenous cytarabine (200 mg/m2 or 1000 mg/m2 days 1 to 7) in 162 patients with chronic myeloid leukemia.
99
Results. With a median follow-up of 55 months, the 5-year cumulative incidences of complete cytogenetic response, major molecular response, and complete molecular response were 89%, 71%, and 53%, respectively. A higher Sokal risk score was inversely associated with complete cytogenetic response (hazard ratio of 0.63; 95% confidence interval, 0.50–0.79, P<0.001). A higher dose of imatinib and a higher dose of cytarabine were associated with increased complete molecular response with hazard ratios of 1.60 (95% confidence interval, 0.96–2.68, P=0.07) and 1.66 (95% confidence interval, 1.02–2.72, P=0.04), respectively. Progression-free survival and overall survival rates at 5 years were 92% and 96%, respectively. Achieving a major molecular response at 1 year was associated with complete absence of progression and a probability of achieving a complete molecular response of 89%. Conclusions. The addition of intravenous cytarabine to imatinib as upfront therapy for patients with chronic myeloid leukemia is associated with a high rate of complete molecular responses. Gepubliceerd: Haematologica. 2010; 95(6): 914–921 Impact factor: 6.416
6. Lapatinib: clinical benefit in patients with HER 2-positive advanced breast cancer JR Kroep1, SC Linn2, E Boven3, HJ Bloemendal4, J Baas1, IAM Mandjes2, J van den Bosch5, WM Smit6, H de Graaf7, CP Schröder8, GJ Vermeulen9, WCJ Hop10, JWR Nortier1 Departments of Medical Oncology, 1Leiden UMC, Leiden, 2Antoni van Leeuwenhoek Hospital – Netherlands Cancer Institute, Amsterdam, 3VU UMC, Amsterdam, 4 Meander Medical Center, Amersfoort, 5Albert Schweitzer Hospital, Dordrecht, 6 Medisch Spectrum Twente, Enschede, 7Leeuwarden Medical Center, Leeuwarden, 8 University Medical Centre Groningen, Groningen; 9 GlaxoSmithKline, Zeist; 10 Department of Biostatistics, Erasmus Medical Center, Rotterdam Background: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor 2 (HER2), has shown activity in combination with capecitabine in patients with HER2-positive advanced breast cancer progressive on standard treatment regimens. We present results on preapproval drug access for this combination in such patients occurring in the general oncology practice in the Netherlands. Methods: Patients with HER2-positive advanced breast cancer progressive on schedules containing anthracyclines, taxanes, and trastuzumab were eligible. Brain metastases were allowed if stable. Lapatinib 1250 mg÷day was given continuously in combination with capecitabine 1000 mg÷m2 twice daily for two weeks in a threeweek cycle. Efficacy was assessed by use of response evaluation criteria in solid tumours version 1.0. Progression-free survival (PFS) and overall survival (OS) were calculated. Results: Eighty-three patients were enrolled from January 2007 until July 2008. The combination was generally well tolerated and the most common drug-related serious adverse events were nausea and÷or vomiting (5%) and diarrhoea (2%). Seventyeight patients were evaluable for response. Clinical benefit (response or stable
100
disease for at least 12 weeks) was observed in 50 patients (64%) of whom 15 had a partial response and 35 stable disease. The median PFS and OS were 17 weeks (95% CI: 13 to 21) and 39 weeks (95% CI: 24 to 54), respectively. For OS, higher Eastern Cooperative Oncology Group (ECOG) status (p=0.016), brain metastases at study entry (p=0.010) and higher number of metastatic sites (p=0.012) were significantly negative predictive factors. Conclusion: In a patient population with heavily pretreated HER2-positive advanced breast cancer lapatinib plus capecitabine was well tolerated and offered clinical benefit. Gepubliceerd: Neth J Med. 2010;68(9):371-6 Impact factor: 1.503
7. Abacavir/Lamivudine/Zidovudine Maintenance After Standard Induction in Antiretroviral Therapy-Naïve Patients: FREE Randomized Trial Interim Results HG Sprenger1; N Langebeek2; PGH Mulder3; CHH Ten Napel4; R Vriesendorp5; AIM Hoepelman6; JC Legrand7; PP Koopmans8; MEE Van Kasteren9; B Bravenboer10; RW Ten Kate11; PHP Groeneveld12; TS van der Werf1; EH Gisolf2; C Richter2 Department of Internal Medicine, 1UMC Groningen, Groningen; 2Rijnstate Hospital, Arnhem; 3Erasmus Medical Center, Rotterdam; 4Medical Spectrum Twente, Enschede; 5Medical Center Haaglanden, The Hague; 6UMC Utrecht, Utrecht; 7 University Hospital Center, Charleroi, Belgium; 8Radboud UMC, Nijmegen; 9 Elisabeth Hospital, Tilburg; 10Catharina 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
101
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: 2.638
8. Experiences and attitudes of Dutch rheumatologists and oncologists with regard to their patients' health-related Internet use van Uden-Kraan CF1, Drossaert CH1, Taal E1, Smit WM2, Seydel ER1, van de Laar MA1,3 1 Institute for Behavioural Research, University of Twente, Enschede 2 Department of Internal Medicine, Medisch Spectrum Twente, Enschede 3 Department of Rheumatology, Medisch Spectrum Twente, Enschede The objective of this study is to explore the experiences and attitudes of rheumatologists and oncologists with regard to their patients' health-related Internet use. In addition, we explored how often physicians referred their patients to healthrelated Internet sites. We sent a questionnaire to all the rheumatologists and oncologists in the Netherlands. The questionnaire included questions concerning demographics, experiences with patients' health-related Internet use, referral behavior, and attitudes to the consequences of patients' health-related Internet use (for patients themselves, the physician-patient relationship and the health care). The response rate was 46% (N = 238). Of these respondents, 134 practiced as a rheumatologist and 104 as an oncologist. Almost all physicians encountered their patients raising information from the Internet during a consultation. They were not, however, confronted with their patients' health-related Internet use on a daily basis. Physicians had a moderately positive attitude towards the consequences of patients' health-related Internet use, the physician-patient relationship and the health care. Oncologists were significantly less positive than rheumatologists about the consequences of health-related Internet use. Most of the physicians had never (32%) or only sometimes (42%) referred a patient to a health-related Internet site. Most physicians (53%) found it difficult to stay up-to-date with reliable Internet sites for patients. Physicians are moderately positive about their patients' health-related Internet use but only seldom refer them to relevant sites. Offering an up-to-date site with accredited websites for patients might help physicians refer their patients Gepubliceerd: Clin Rheumatol 2010: Impact factor: 1.668
9. Higher incidence of relapse in patients with acute myelocytic leukemia infused with higher doses of CD34+ cells from leukapheresis products autografted during the first remission NC Gorin1,2, M Labopin1,2, J Reiffers3, N Milpied3, D Blaise4, F Witz5, T de Witte6, G Meloni7, M Attal8, T Bernal9, V Rocha2,10, Acute Leukemia Working Party of the
102
European Cooperative Group for Blood and Marrow Transplantation. Includes Schaafsma MR* 1 Department of Hematology, Hôpital Saint Antoine, Paris, France; 2 Acute Leukemia Working Party, European Cooperative Group for Blood and Marrow Transplantation, Faculté de Médecine St-Antoine Université Pierre et Marie Curie Paris 6 and Unité Mixte de Recherche (UMR) 893, Paris, France; 3 Centre Hospitalier Universitaire Bordeaux Hôpital Haut-Leveque, Pessac, France; 4 Unité de transplantation et de thérapie cellulaire, Institut Paoli Calmettes, Inserm UMR 599, Marseille, France; 5 Hématologie & Médecine Interne, Hôpital de Brabois, Nancy, France; 6 Department of Haematology, UMC Saint Radboud, Nijmegen; 7 Dipartimento di Biotecnologie Cellulari e Ematologia, University La Sapienza, Rome, Italy; 8 Department of Hematology, Hôpital Purpan Centre Hospitalier Universitaire, Toulouse, France; 9 Clinical Hematology Department, University Hospital of Asturias, Oviedo, Spain; and 10 Department of Hematology and Bone Marrow Transplantation, Hôpital Saint Louis, Paris, France *Department of Internal Medicine, Medisch Spectrum Twente, Enschede The stem cell source for autologous transplantation has shifted from bone marrow to peripheral blood (PB). We previously showed that relapse incidence in patients with acute myelocytic leukemia autografted in first remission (CR1) was greater with PB than bone marrow, and a poorer outcome was associated with a shorter CR1 to PB transplantation interval (≤ 80 days). Leukemic and normal progenitors are CD34(+) and can be concomitantly mobilized; we assessed whether an association exists between the infused CD34(+) cell dose and outcome. The infused CD34(+) cell doses were available for 772 patients autografted more than 80 days after CR1 and were categorized by percentiles. We selected the highest quintile (> 7.16 × 10(6)/kg) as the cutoff point. By multivariate analysis, relapse was more probable in patients who received the highest dose (hazard ratio = 1.48; 95% confidence interval, 1.121.95; P = .005), and leukemia-free survival was worse (hazard ratio = 0.72; 95% confidence interval, 0.55-0.93; P = .01). In conclusion, in patients autografted in first remission, relapse was higher and leukemia-free survival lower for those who received the highest CD34(+) PB doses. Gepubliceerd: Blood. 2010;116(17):3157-62 Impact factor: 10.555
10. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome MA Sanz1, P Montesinos1, C Rayón2, A Holowiecka3, J de la Serna4, G Milone5, E de Lisa6, S Brunet7, V Rubio8, J M. Ribera9, C Rivas10, I Krsnik11, J Bergua12, J González13, J Díaz-Mediavilla14, R Rojas15, F Manso16, G Ossenkoppele17, JD González18, B Lowenberg19, on behalf of the PETHEMA and HOVON Groups. Includes De Groot MR* 1 Hospital Universitario La Fe, Valencia, Spain; 2 Hospital Central de Asturias, Oviedo, Spain; 3 Department of Clinical and Experimental Oncology, Comprehensive Cancer Center, M. Sklodowska-Curie Memorial Institute, Gliwice
103
Branch, Poland; 4 Hospital 12 de Octubre, Madrid, Spain; 5 Fundaleu, Buenos Aires, Argentina; 6 Hospital Maciel, Montevideo, Uruguay; 7 Hospital Sant Pau, Barcelona, Spain; 8 Hospital General, Jerez de la Frontera, Spain; 9 Hospital Tries i Pujol, Badalona, Spain; 10 Hospital General, Alicante, Spain; 11 Hospital Puerta de Hierro, Madrid, Spain; 12 Hospital San Pedro de Alcántara, Cáceres, Spain; 13 Hospital Universitario Virgen del Rocío, Sevilla, Spain; 14 Hospital Clínico San Carlos, Madrid, Spain; 15 Hospital Reina Sofía, Córdoba, Spain; 16 Hospital General, Albacete, Spain; 17 VU UMC, Amsterdam; 18 Hospital Insular, Las Palmas, Spain; and 19 Erasmus UMC, Rotterdam *Department of Internal Medicine, Medisch Spectrum Twente, Enschede A risk-adapted strategy based on all-trans retinoic acid (ATRA) and anthracycline monochemotherapy (PETHEMA LPA99 trial) has demonstrated a high antileukemic efficacy in acute promyelocytic leukemia. We designed a new trial (LPA2005) with the objective of achieving stepwise improvements in outcome. Between July 2005 and April 2009, low- and intermediate-risk patients (leukocytes < 10 x 109/L) received a reduced dose of mitoxantrone for the second consolidation course, whereas high- risk patients younger than 60 years of age received cytarabine combined with ATRA and idarubicin in the first and third consolidation courses. Of 372 patients attaining complete remission after ATRA plus idarubicin (92.5%), 368 proceeded to consolidation therapy. For low- and intermediate-risk patients, duration of neutropenia and thrombocytopenia and hospital stay were significantly reduced without sacrificing antileukemic efficacy, compared with the previous LPA99 trial. For high-risk patients, the 3-year relapse rate was significantly lower in the LPA2005 trial (11%) than in the LPA99 (26%; P = .03). Overall disease-free survival was also better in the LPA2005 trial (P = .04). In conclusion, the lower dose of mitoxantrone resulted in a significant reduction of toxicity and hospital stay while maintaining the antileukemic activity, and the combination of ATRA, idarubicin, and cytarabine for high-risk acute promyelocytic leukemia significantly reduced the relapse rate in this setting. Gepubliceerd: Blood 2010;115(25):5137-46 Impact factor: 10,555
11. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma HM Lokhorst1, B van der Holt2, S Zweegman3, E Vellenga4, S Croockewit5, MH van Oers6, P von dem Borne7, P Wijermans8, R Schaafsma9, O de Weerdt10, S Wittebol11, M Delforge12, H Berenschot13, GM Bos14, KS Jie15, H Sinnige16, M van Marwijk-Kooy17, P Joosten18, MC Minnema1, R van Ammerlaan2, P Sonneveld19, for Dutch-Belgian Hemato-Oncology Group (HOVON) 1 University Medical Center, Utrecht, 2 Erasmus Medical Center-HOVON Data Center, Rotterdam, 3 VU Medical Center, Amsterdam, 4 Universital Medical Center, Groningen, 5 Radboud Hospital, Nijmegen, 6 Amsterdam Medical Center, Amsterdam, 7 Leiden University Medical Center, Leiden, 8 Haga Hospital, Den Haag, 9 Medisch Spectrum Twente, Enschede, 10 Antonius Hospital, Nieuwegein, 11
104
Meander Medical Center, Amersfoort, 12 University of Leuven, Leuven, Belgium; , 13 Albert Schweitzer Hospital, Dordrecht, 14 Academisch Ziekenhuis, Maastricht, 15 Atrium MC, Heerlen, 16 Jeroen Bosch Hospital, Den Bosch, 17 Isala Kliniek, Zwolle, 18 Medisch Centrum, Leeuwardenand , 19 Erasmus Medical Center, Rotterdam The phase 3 trial HOVON-50 was designed to evaluate the effect of thalidomide during induction treatment and as maintenance in patients with multiple myeloma who were transplant candidates. A total of 556 patients was randomly assigned to arm A: 3 cycles of vincristine, adriamycin, and dexamethasone, or to arm B: thalidomide 200 mg orally, days 1 to 28 plus adriamycin and dexamethasone. After induction therapy and stem cell mobilization, patients were to receive high-dose melphalan, 200 mg/m(2), followed by maintenance with alpha-interferon (arm A) or thalidomide 50 mg daily (arm B). Thalidomide significantly improved overall response rate as well as quality of the response before and after high dose melphalan. Best overall response rate on protocol was 88% and 79% (P = .005), at least very good partial remission 66% and 54% (P = .005), and complete remission 31% and 23% (P = .04), respectively, in favor of the thalidomide arm. Thalidomide also significantly improved event-free survival from median 22 months to 34 months (P < .001), and prolonged progression free from median 25 months to 34 months (P < .001). Median survival was longer in the thalidomide arm, 73 versus 60 months; however, this difference was not significant (P = .77). Patients randomized to thalidomide had strongly reduced survival after relapse. Gepubliceerd: Blood. 2010 Feb 11;115(6):1113-20 Impact factor: 10.555
12. Autologous stem cell transplantation in haematological disorders,1980-2002 Beckers MM, Verdonck LF, Cornelissen JJ, Schattenberg AV, Janssen JJ, Willemze R, van Imhoff GW, van der Lelie JH, Wijermans P, Schaafsma R, Baars J, van Marwijk Kooij MR, Biesma DH, van Biezen A, Brand R, Schouten HC In de Nederlandse Stamceltransplantatie Registratie ‘TYPHON’ (thans: Nederlandse Stamceltransplantatie Registratie van het datacentrum van de stichting HematoOncologie voor volwassenen Nederland (HOVON)), werken de volgende centra samen: UMC St Radboud Nijmegen, Academisch Ziekenhuis Maastricht, Leids UMC, Erasmus MC Rotterdam, AMC Amsterdam, VU MC Amsterdam, UMC Groningen, UMC Utrecht, Antoni van Leeuwenhoek Ziekenhuis Amsterdam, Isala Klinieken Zwolle, HagaZiekenhuis Den Haag, Medisch Spectrum Twente Enschede, St. Antonius Ziekenhuis Nieuwegein, Europdonor Leiden en de Stamceldonorbank Europdonor Nijmegen Objective: To describe activities in the field of autologous stem cell transplantation in haematological disorders in the Netherlands in the periods before and after 1993 (at that time blood was introduced as source of stem cells). Design: Descriptive, retrospective cohort study. Method: Data were collected from the Netherlands Stem Cell Transplantation Registry TYPHON. Details of all transplant patients were reported to TYPHON by the individual transplantation centres. In this overview we describe the changes in
105
transplantation-related mortality, relapse rates and survival in the periods 1 January 1980-31 December 1992 and 1 January 1980-31 December 2002. Results: The number of autologous stem cell transplantations increased almost five-fold in the period 1993-2002. Since 1993 the main indications for transplantation were multiple myeloma (MM) and non-Hodgkin lymphoma (NHL), as well as acute myeloid leukaemia (AML), which was the main indication in the period before 1993. In the period before 1993 most relapses were observed in patients with acute lymphoblastic leukaemia (ALL) and MM, which resulted in low survival rates. After 1993 no great differences in relapse or survival rates were observed between the different disorders. The survival rates for patients with ALL improved during the last research period, especially among younger patients (< 45 years). Conclusion: The number of autologous stem cell transplantations has increased considerably since 1993, especially in patients with MM and NHL. Gepubliceerd: Ned Tijdschr Geneeskd. 2010;154:A2025 Impact factor: 0 13. Phase III Study of the Value of Thalidomide Added to Melphalan Plus Prednisone in Elderly Patients With Newly Diagnosed Multiple Myeloma: The HOVON 49 Study Wijermans P, Schaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, Sinnige H, Zweegman S, van Marwijk Kooy M, van der Griend R, Lokhorst H, Sonneveld P From the Haga Hospital, the Hague; MST Twente, Enschede; Stichting HematoOncologie voor Volwassenen Nederland (HOVON) Data Center, Erasmus MC, Rotterdam; Meander Hospital, Amersfoort; Jeroen Bosch Hospital, 's Hertogenbosch; VU MC, Amsterdam; Isala Hospital, Zwolle; Diaconessen Hospital; and UMC Utrecht, Utrecht Purpose For several decades, the treatment of elderly patients with multiple myeloma (MM) has consisted of melphalan and prednisone (MP). The DutchBelgium Hemato-Oncology Cooperative Group (HOVON) investigated the efficacy of thalidomide added to MP (MP-T) in a randomized phase III trial. The objective of this study was to investigate the efficacy, toxicity, and effects on quality of life of MP-T. Patients and Methods A randomized phase III trial compared standard MP with MP-T (thalidomide 200 mg/d) in newly diagnosed patients with multiple myeloma older than age 65 years. Maintenance therapy with thalidomide 50 mg/d was administered to patients after MP-T until relapse. The primary end point was eventfree survival (EFS); response rate, overall survival (OS), and progression-free survival (PFS) were secondary end points. Results An intent-to-treat analysis of 333 evaluable patients showed significantly higher response rates in MP-T–treated patients compared with MP-treated patients a response (≥ partial response: 66% v 45%, respectively; P < .001; and ≥ very good partial response [VGPR]: 27% v 10%, respectively; P < .001). EFS was 13 months with MP-T versus 9 months with MP (P < .001). OS was 40 months with MP-T versus 31 months with MP (P = .05). Conclusion This study demonstrates that thalidomide improves the response rate and VGPR in elderly patients with newly diagnosed MM. MP-T also results in a better EFS, PFS, and OS.
106
Gepubliceerd: J Clin Oncol. 2010;28(19):3160-6 Impact factor: 17.793
Totale impact factor: 110.085 Gemiddelde impact factor: 8.468 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 17.793 Gemiddelde impact factor: 17.793
107
Kaakchirurgie 1. Evaluation of alveolar nerve function after surgical lengthening of the mandible by a bilateral sagittal split osteotomy or distraction osteogenesis Baas EM1, de Lange J1,2, Horsthuis RB1,2,3 1 Department of Oral and Maxillofacial Surgery, Isala Klinieken, Zwolle 2 Department of Oral and Maxillofacial Surgery, AMC/Academic Center for Dentistry (ACTA), University of Amsterdam 3 Department of Oral and Maxillofacial Surgery, Medisch Spectrum Twente, Enschede This study compares the effects of bilateral sagittal split osteotomy (BSSO) and distraction osteogenesis (DO) for lengthening the mandible regarding loss of function of the inferior alveolar nerve (IAN). In a retrospective cohort study design, the function of the IAN was tested with a Weinstein monofilament 3.22, 1 year after the surgical procedure in 65 patients (35 BSSO; 30 DO). This was defined as the upper limit for normal function. Of 130 IAN studied (70 BSSO, 54%; 60 DO, 46%), nerve function was disturbed in 23 (18%). In this group, 14 cases (61%) had undergone BSSO and 9 (39%) DO. One-hundred and seven nerves had no neurosensory IAN changes; of these BSSO had been performed in 56 cases (52%) and DO in 51 cases (48%). After eliminating confounding factors, there was no significant difference in the occurrence of neurosensory changes between the treatment options (DO versus BSSO, odds ratio: 1.254 with 95% CI: 0.366-4.300). In conclusion, there was no difference in IAN function between patients treated with BSSO or DO for lengthening the mandible. Gepubliceerd: Int J Oral Maxillofac Surg. 2010;39(6):529-33 Impact factor: 1.444
Totale impact factor: 1.444 Gemiddelde impact factor: 1.444 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 1.444 Gemiddelde impact factor: 1.444
108
Kindergeneeskunde 1. MB11 BERAphone((R)) hearing screening compared to ALGOportable in a Dutch NICU: A pilot study van den Berg E1,2, Deiman C1, van Straaten HL1 1 Department of pediatrics, medisch Spectrum Twente, Enschede 2 Department of Neonatology, Isala Clinics, Zwolle Objective: Since 2001 all Dutch Neonatal Intensive Care Units use a highly reliable automated auditory brainstem response (AABR) newborn hearing screening device, the (ALGOportable). A more recent AABR newborn hearing screening device, the MB11 BERAphone((R)), does not make use of disposable ear couplers and has a different algorithm, a possible advantage with regard to a faster response acquisition. Use of the MB11 BERAphone((R)) is therefore potentially more cost effective and faster. This study compares test results and suitability of the MB11 BERAphone((R)) to the ALGOportable as reference AABR hearing screening test for newborns during neonatal intensive care admission. Methods: In 54 NICU graduates [median GA 31 2/7 weeks, median BW 1760g] 55 (110 ears) hearing screening test results and total test time were examined with both the MB11 BERAphone((R)) and ALGOportable. Test time was measured from the start of the procedure, including child preparation, until a bilateral result (pass/refer) was obtained. RESUlTS: The median postconceptional age of testing was 34 3/7 weeks (range 3041 6/7). In 3 ears MB11 BERAphone((R)) screening failed due to continuous myogenic activity. In 104/107 ears final results were congruent [87/107 (81%) pass; 17/107 (16%) refer] leaving an incongruity in 3 ears of 2 infants: MB11 BERAphone((R)) "refer" and ALGOportable "pass". Diagnostic investigative audiology confirmed a 35dB unilateral conductive hearing loss in 1 child. At 15 months of age speech and language development in the other child was normal. When using the ALGOportable as reference test, the sensitivity of the MB11 BERAphone((R)) is 100% (17/17), specificity 97% (87/90). The mean MB11 BERAphone((R)) test time was slightly, but not significantly, shorter 11.4min (SD 6.6) than with the ALGOportable 13.9 (p<0.08). Conclusion: The MB11 BERAphone((R)) is a reliable and feasible hearing screening device for use with NICU graduates under NICU circumstances. It is potentially more cost effective than the ALGOportable. Gepubliceerd: Int J Pediatr Otorhinolaryngol. 2010;74(10):1189-92 Impact factor: 1.148
2. Pilot study: The effect of reducing treatment on exercise induced bronchoconstriction Kersten ET, Driessen JM, van Leeuwen JC, Thio BJ Department of Pediatrics, Medisch Spectrum Twente, Enschede Rationale: Asthma therapy should be stepped up or stepped down in response to changes in asthma control. However, there is little evidence available on the optimal
109
timing, sequence, and degree of medication reductions. In this study we analyzed clinically stable asthmatic children who underwent a medication reduction from a combination preparation consisting of an inhaled corticosteroid (ICS) and long acting beta2-agonist (LABA) to monotherapy with the same dose of the ICS. We hypothesized that the extent of exercise-induced bronchoconstriction (EIB) would not increase after the cessation of the LABA. Methods: Nineteen children, aged 8-16 years, with clinically stable asthma, receiving LABA/ICS combination therapy, were analyzed in this open-label pilot study. Children performed an exercise challenge at baseline and 3 weeks after the medication reduction. Best values of spirometric measurements of the forced expiratory volume in 1 sec (FEV(1)) were used for statistical calculations. Results: Maximum percent fall in FEV(1) was significantly lower after 3 weeks of ICS monotherapy (P = 0.03). Eight of 19 children had a >/=15% fall in FEV(1) after exercise at the initial exercise challenge. In this subgroup, maximum percent fall in FEV(1) after the medication reduction was significantly lower (P < 0.01), and in six children it decreased to <15%, indicating they no longer had EIB. Conclusion: In clinically stable asthmatic children on LABA/ICS combination therapy, the cessation of the LABA can reduce and in most cases abolish EIB. Gepubliceerd: Pediatr Pulmonol. 2010;45(9):927-33 Impact factor: 1.816
3. Effect of the “InSurE” procedure on cerebral oxygenation and electrical brain activity of the preterm infant E van den Berg1,3, P M A Lemmers1, M C Toet1, J H G Klaessens2, F van Bel1 1 Department of Neonatology, UMC Utrecht, Wilhelmina Children’s Hospital, Utrecht 2 Department of Medical Technology and Clinical Physics, UMC Utrecht, Wilhelmina Children’s Hospital, Utrecht 3 Department of Pediatrics, Medisch Spectrum Twente, Enschede Background: In preterm infants with respiratory distress syndrome (RDS) nasal continuous positive airway pressure (nCPAP) with the “InSurE” procedure (intubation, surfactant, extubation) is increasingly used. However, its effect on cerebral oxygenation and brain function is not known. Objective: To evaluate the effects of the “InSurE” procedure in infants with RDS on regional cerebral oxygen saturation (rScO2) and relative cerebral fractional tissue oxygen extraction (cFTOE) using near infrared spectroscopy and on electrical brain activity using amplitude-integrated electroencephalography (aEEG). Methods: Sixteen infants with RDS, treated with the “InSurE” procedure, and 16 matched controls with nCPAP, were monitored for mean arterial blood pressure (MABP), arterial oxygen saturation (SaO2), rScO2, cFTOE and aEEG. Ten-minute periods were selected and averaged at 120 and 20 minutes before, during the procedure and at 30 minutes, 1, 2, 6, 12 and 24 h after the start of the “InSurE” procedure. aEEG was analysed by quantitative and qualitative (Burdjalov score) methods. Results: MABP was not different between groups on all time points. rScO2 and cFTOE were comparable between groups, but there was a trend towards lower
110
rScO2 and higher cFTOE 30 minutes after opioid administration in the “InSurE” infants compared with controls (62% (SD 11) vs 68% (SD 10) and 0.30 (SD 0.10 ) vs 0.28 (SD 0.11), respectively). aEEG amplitudes and Burdjalov scores were significantly lower in “InSurE” infants from 30 minutes after opioid administration up to 24 h after the start of the procedure (p<0.05). Conclusion: In the present study, the “InSurE” procedure did not induce perturbation of cerebral oxygen delivery and extraction, whereas electrical brain activity decreased for a prolonged period of time. Gepubliceerd: Arch Dis Child Fetal Neonatal Ed 2010;95:F53-F58 Impact factor: 2.493
4. Het syndroom van Chediak Higashi bij een jong meisje: casuistische mededeling de Mare A1, Jonge Poerink-Stockschläder AB2, Bruin MC3, Slomp J1 1 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede 2 Department of Pediatrics, Medisch Spectrum Twente, Enschede 3 Afdeling Kinderhematologie en –oncologie, UMC Utrecht, Utrecht Een meisje van 14 maanden oud presenteerde zich begin 2008 met een ernstige luchtweginfectie. Bij differentiatieonderzoek van de leukocyten werden grote abnormale granulae gezien. Het voorkomen van dergelijke vergrote granulae is pathognomonisch voor het chédiak-higashisyndroom (CHS), een zeldzame letale ziekte. CHS wordt veroorzaakt door een mutatie in een eiwit dat de morfologie en/of het transport van de granulae reguleert. De ziekte kenmerkt zich door oculocutaan albinisme, een verminderde werking van trombocyten en een verstoorde secretie van neurotransmitters. Het belangrijkste is echter een deficiënte immuunfunctie als gevolg van afwijkende granulae in de leukocyten. Patiënten presenteren zich daarom vaak met recidiverende infecties. Het merendeel krijgt uiteindelijk een lymfoproliferatief syndroom, gekenmerkt door een diffuse infiltratie door lymfocyten en macrofagen in een groot aantal organen, waaraan de meesten van hen komen te overlijden. Hoewel CHS niet te genezen is, kunnen de hematologische en immunologische problemen worden behandeld met een allogene stamceltransplantatie. Dit dient te gebeuren voordat het lymfoproliferatief syndroom optreedt en daarvoor is het belangrijk dat de diagnose in een vroeg stadium wordt gesteld. Hierbij is een belangrijke rol weggelegd voor het laboratorium. Gepubliceerd: Ned Tijdschr Hematol. 2010;7(4):163-8 Impact factor: 0
Totale impact factor: 5.457 Gemiddelde impact factor: 1.364 Aantal artikelen 1e, 2e of laatste auteur: 4 Totale impact factor: 5.457 Gemiddelde impact factor: 1.364
111
Klinische Chemie 1. A Rapid Single-Tube Multiplex Polymerase Chain Reaction Assay for the Seven Most Prevalent alpha-Thalassemia Deletions and alpha alpha alpha (anti 3.7) alphaGlobin Gene Triplication de Mare A, Groeneger AH, Schuurman S, van den Bergh FA, Slomp J Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede Alpha-Globin gene triplications may exacerbate the alpha chain and beta chain imbalance in beta-thalassemia (beta-thal) and may compensate for the effect of alpha-globin gene deletion in alpha-thal. Identification of an alpha-globin gene triplication is, therefore, valuable in predicting the clinical phenotype of the thalassemias. To be able to detect alpha-globin gene triplications, we have modified an existing multiplex polymerase chain reaction (PCR) assay for the seven most prevalent alpha-globin gene deletions by incorporating two triplication-specific primers and concurrently substituting one of the original primers by a newly designed primer. This modified multiplex PCR assay was evaluated by performing the assay on archival DNA samples and on peripheral blood samples from 163 suspected thalassemia cases. It was found to function properly. Our assay thereby represents the first multiplex PCR assay that can detect both the seven most prevalent alpha-globin gene deletions and the alphaalphaalpha(anti 3.7) alphaglobin gene triplication in a single-tube reaction. Gepubliceerd: Hemoglobin. 2010;34(2):184-90 Impact factor: 1.274
2. Role of T cell competition in the induction of cytotoxic T lymphocyte activity during viral vector-based immunization regimens Lambeck AJ1,2, Nijman HW2, Hoogeboom BN1, Regts J1, de Mare A1,3, Wilschut J1, Daemen T1 1 Department of Medical Microbiology, Molecular Virology Section, UMC Groningen, University of Groningen, Groningen 2 Department of Gynaecology, UMC Groningen, University of Groningen, Groningen 3 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede T cell competition between antigen- and vector-specific T cells may determine the outcome of viral vector-based immunization regimens, as we previously proposed. Here, we unravelled the interplay between antigen- and vector-specific immunity, using recombinant Semliki Forest virus (rSFV). Priming of mice with rSFV, encoding LacZ (SFVLacZ), or with empty rSFV strongly suppressed subsequent induction of ovalbumin or Human Papilloma virus (HPV) E6/E7-specific CTL activity by a booster with SFVeOVA or SFVeE6,7, respectively. Yet, priming with irradiated, i.e. replication-defective, SFVLacZ did not affect subsequent CTL induction, indicating that the interfering vector-specific immunity was directed against the viral replicase. However, immune responses against the strongly immunogenic nucleoprotein of influenza virus encoded by SFV were less severely affected by priming with
112
SFVLacZ. Thus the outcome of heterologous prime-boost immunizations appears to depend on the immunogenicity of the respective antigens. Gepubliceerd: Vaccine. 2010;28(26):4275-82 Impact factor: 3.616
3. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming MJ Kwakkenbos1,2, SA Diehl2, E Yasuda1,2, AQ Bakker1,2, CMM van Geelen1,2, MV Lukens3,7, GM van Bleek3, MN Widjojoatmodjo4, WMJM Bogers5, H Mei6, A Radbruch6, FA Scheeren2, H Spits1,2, T Beaumont1,2 1 AIMM Therapeutics, Academic Medical Center, Amsterdam; 2 Department of Cell Biology and Histology, Academic Medical Center, Amsterdam; 3 Department of Pediatrics, The Wilhelmina Children's Hospital, UMC, Utrecht; 4 Netherlands Vaccine Institute, Bilthoven; 5 Department of Virology, Biomedical Primate Research Centre, Rijswijk; 6 German Rheumatism Research Center, Berlin, Germany; 7 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede The B cell lymphoma-6 (Bcl-6) and Bcl-xL proteins are expressed in germinal center B cells and enable them to endure the proliferative and mutagenic environment of the germinal center. By introducing these genes into peripheral blood memory B cells and culturing these cells with two factors produced by follicular helper T cells, CD40 ligand (CD40L) and interleukin-21 (IL-21), we convert them to highly proliferating, cell surface B cell receptor (BCR)-positive, immunoglobulin-secreting B cells with features of germinal center B cells, including expression of activationinduced cytidine deaminase (AID). We generated cloned lines of B cells specific for respiratory syncytial virus and used these cells as a source of antibodies that effectively neutralized this virus in vivo. This method provides a new tool to study B cell biology and signal transduction through antigen-specific B cell receptors and for the rapid generation of high-affinity human monoclonal antibodies. Gepubliceerd: Nat Med. 2010;16(1):123-128 Impact factor: 27.136
4. A Systemic Neutrophil Response Precedes Robust CD8+ T-Cell Activation during Natural Respiratory Syncytial Virus Infection in Infants MV Lukens,1,5 AC van de Pol,1,2 FEJ Coenjaerts,2 NJG Jansen,1 VM Kamp,3 JLL Kimpen,1 JWA Rossen,2,4 LH Ulfman,3 CEA Tacke,1 MC Viveen,2 L Koenderman,3 TFW Wolfs,1 GM van Bleek1 1 Department of Pediatrics, The Wilhelmina Children's Hospital; 2 Department of Medical Microbiology; 3 Department of Respiratory Medicine, UMC, Utrecht; 4 Laboratory of Medical Microbiology and Immunology, St Elisabeth Hospital, Tilburg; 5 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede Severe primary respiratory syncytial virus (RSV) infections are characterized by bronchiolitis accompanied by wheezing. Controversy exists as to whether infants
113
suffer from virus-induced lung pathology or from excessive immune responses. Furthermore, detailed knowledge about the development of primary T-cell responses to viral infections in infants is lacking. We studied the dynamics of innate neutrophil and adaptive T-cell responses in peripheral blood in relation to theviral load and parameters of disease in infants admitted to the intensive care unit with severe RSV infection. Analysis of primary T-cell responses showed substantial CD8+ T-cell activation, which peaked during convalescence. A strong neutrophil response, characterized by mobilization of bone marrow-derived neutrophil precursors, preceded the peak in T-cell activation. The kinetics of this neutrophil response followed the peak of clinical symptoms and the viral load with a 2- to 3-day delay. From the sequence of events, we conclude that CD8+ T-cell responses, initiated during primary RSV infections, are unlikely to contribute to disease when it is most severe. The mobilization of precursor neutrophils might reflect the strong neutrophil influx into the airways, which is a characteristic feature during RSV infections and might be an integral pathogenic process in the disease. Gepubliceerd: Journal of Virology 2010;84(5):2374-2383 Impact factor: 5.150
5. A microfluidic wound healing assay for quantifying endothelial cell migration van der Meer A1, Vermeul K1, Poot AA1, Feijen J1, Vermes I1,2 Polymer Chemistry and Biomaterials Group, Faculty of Science and Technology, University of Twente, Enschede 1 Department of Polymer Chemistry and Biomaterials, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 2 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede Endothelial migration is an important process in the formation of blood vessels and the repair of damaged tissue. To study this process in the laboratory, versatile and reliable migration assays are essential. The purpose of this study was to investigate if the microfluidic version of the conventional wound healing assay is a useful research tool for vascular science. Endothelial cells were seeded in a 500 mum wide microfluidic channel. After overnight incubation, cells had formed a viable and confluent monolayer. Then, a wound was generated in this monolayer by flushing the channel with three parallel fluid streams, of which the middle one contained the protease trypsin. By analyzing the closing of the wound over time, endothelial cell migration could be measured. Although the migration rate was two times lower in the microfluidic assay than in the conventional assay, an identical 1.5 times increase in migration rate was found in both assays when vascular endothelial growth factor (VEGF165) was added. In the microfluidic wound healing assay, a stable gradient of VEGF165 could be generated at the wound edge. This led to a 2 times increase in migration rate compared to the untreated control. Finally, when a shear stress of 1.3 Pa was applied to the wound, the migration rate increased 1.8 times. In conclusion, the microfluidic assay is a solid alternative for the conventional wound healing assay when measuring endothelial cell migration. Moreover, it offers unique advantages, such as gradient generation and application of shear stress. Key words: endothelial cell, migration, microfluidics, wound healing assay.
114
Gepubliceerd: Am J Physiol Heart Circ Physiol. 2010;298:H719-H725 Impact factor: 3.712
6. Apoptosis- and necrosis-induced changes in light attenuation measured by optical coherence tomography van der Meer FJ, Faber DJ, Aalders MC, Poot AA, Vermes I*, van Leeuwen TG Department of Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam, Amsterdam * Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede Optical coherence tomography (OCT) was used to determine optical properties of pelleted human fibroblasts in which necrosis or apoptosis had been induced. We analysed the OCT data, including both the scattering properties of the medium and the axial point spread function of the OCT system. The optical attenuation coefficient in necrotic cells decreased from 2.2 +/- 0.3 mm(-1) to 1.3 +/- 0.6 mm(-1), whereas, in the apoptotic cells, an increase to 6.4 +/- 1.7 mm(-1) was observed. The results from cultured cells, as presented in this study, indicate the ability of OCT to detect and differentiate between viable, apoptotic, and necrotic cells, based on their attenuation coefficient. This functional supplement to high-resolution OCT imaging can be of great clinical benefit, enabling on-line monitoring of tissues, e.g. for feedback in cancer treatment. Gepubliceerd: Lasers Med Sci. 2010;25:259-267 Impact factor: 2.574
7. Flexible and elastic porous poly(trimethylene carbonate) structures for use in vascular tissue engineering Song Y1, Kamphuis MM1, Zhang Z1, Sterk LM1, Vermes I1,2, Poot AA1, 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 Biocompatible and elastic porous tubular structures based on poly(1,3-trimethylene carbonate), PTMC, were developed as scaffolds for tissue engineering of smalldiameter blood vessels. High-molecular-weight PTMC (M(n)=4.37x10(5)) was crosslinked by gamma-irradiation in an inert nitrogen atmosphere. The resulting networks (50-70% gel content) were elastic and creep resistant. The PTMC materials were highly biocompatible as determined by cell adhesion and proliferation studies using various relevant cell types (human umbilical vein endothelial cells (HUVECs), smooth muscle cells (SMCs) and mesenchymal stem cells (MSCs)). Dimensionally stable tubular scaffolds with an interconnected pore network were prepared by particulate leaching. Different cross-linked porous PTMC specimens with average pore sizes ranging between 55 and 116mum, and porosities ranging from 59% to
115
83% were prepared. These scaffolds were highly compliant and flexible, with high elongations at break. Furthermore, their resistance to creep was excellent and under cyclic loading conditions (20 deformation cycles to 30% elongation) no permanent deformation occurred. Seeding of SMCs into the wall of the tubular structures was done by carefully perfusing cell suspensions with syringes from the lumen through the wall. The cells were then cultured for 7days. Upon proliferation of the SMCs, the formed blood vessel constructs had excellent mechanical properties. Their radial tensile strengths had increased from 0.23 to 0.78MPa, which is close to those of natural blood vessels. Gepubliceerd: Acta Biomater. 2010;6(4):1269-77 Impact factor: 3.975
8. On-chip determination of spermatozoa concentration using electrical impedance measurements Segerink LI1, Sprenkels AJ1, Ter Braak PM1, Vermes I1,2, van den Berg A1 1 BIOS - the Lab-on-a-Chip group, MESA+ Institute of Nanotechnology, University of Twente, Enschede 2 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede In this article we describe the development of a microfluidic chip to determine the concentration of spermatozoa in semen, which is a main quality parameter for the fertility of a man. A microfluidic glass-glass chip is used, consisting of a microchannel with a planar electrode pair that allows the detection of spermatozoa passing the electrodes using electrical impedance measurements. Cells other than spermatozoa in semen also cause a change in impedance when passing the electrodes, interfering with the spermatozoa count. We demonstrate that the change in electrical impedance is related to the size of cells passing the electrodes, allowing to distinguish between spermatozoa and HL-60 cells suspended in washing medium. In the same way we are able to distinguish between polystyrene beads and spermatozoa. Thus, by adding a known concentration of polystyrene beads to a boar semen sample, the spermatozoa concentrations of seven mixtures are measured and show a good correlation with the actual concentration (R(2)-value = 0.97). To our knowledge this is the first time that the concentration of spermatozoa has been determined on chip using electrical impedance measurements without a need to know the actual flow speed. The proposed method to determine the concentration can be easily applied to other cells. The described on-chip determination of the spermatozoa concentration is a first step towards a microfluidic system for a complete quality analysis of semen. Gepubliceerd: Lab Chip. 2010;10(8):1018-24 Impact factor: 6.342
9. Analyzing shear stress-induced alignment of actin filaments in endothelial cells with a microfluidic assay van der Meer AD1, Poot AA1, Feijen J1, Vermes I1,2
116
1
Polymer Chemistry and Biomaterials, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 2 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede The physiology of vascular endothelial cells is strongly affected by fluid shear stress on their surface. In this study, a microfluidic assay was employed to analyze the alignment of actin filaments in endothelial cells in response to shear stress. When cells were cultured in microfluidic channels and subjected to shear stress, the alignment of filaments in the channel direction was significantly higher than in static cultures. By adding inhibitory drugs, the roles of several signaling proteins in the process of alignment were determined. Thus, it is shown how microfluidic technology can be employed to provide a mechanistic insight into cell physiology. Gepubliceerd: Biomicrofluidics. 2010;4(1):11103 Impact factor: 2.895
10. Effective seeding of smooth muscle cells into tubular poly(trimethylene carbonate) scaffolds for vascular tissue engineering Y Song1, JWH Wennink1, MMJ Kamphuis1,2, 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 poly(trimethylene carbonate) (PTMC) scaffolds for vascular tissue engineering, with an inner diameter of 3 mm and a wall thickness of 1 mm, were prepared by means of dip-coating and subsequent leaching of NaCl particles. The scaffolds, with an average pore size of 110 mum and a porosity of 85%, showed a smooth muscle cell (SMC) seeding efficiency of only 10%. To increase the efficiency of cell seeding, these scaffolds were coated with a microporous PTMC outer layer with a thickness of 0.1-0.4 mm, an average pore size of 28 mum, and a porosity of 65%. Coating of the scaffolds with the microporous outer layer did not influence the inner pore structure or the mechanical properties of the scaffolds to a significant extent. The intrinsic permeability of the scaffolds decreased from 60 x 10(-10) m(2) to approximately 5 x 10(-10) m(2) after coating with the microporous outer layer. The latter value is still relatively high indicating that these scaffolds may facilitate sufficient diffusion of nutrients and waste products during cell culturing. The efficiency of SMC seeding determined after 24 h cell adhesion in the scaffolds increased from less than 10% to 43% after coating with the microporous outer layer. The cells were homogeneously distributed in the scaffolds and cell numbers increased 60% during culturing for 7 days under stationary conditions. It is concluded that coating of porous tubular PTMC scaffolds with a microporous PTMC outer layer facilitates effective cell seeding in these scaffolds.
117
Gepubliceerd: J Biomed Mater Res A. 2010;95(2):440-6 Impact factor: 2.816
11. Flow cytometric analysis of the uptake of low-density lipoprotein by endothelial cells in microfluidic channels van der Meer AD1, Vermeul K1, Poot AA1, Feijen J1, Vermes I1,2 1 Department of Polymer Chemistry and Biomaterials, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 2 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede Acceptance of microfluidic technology in everyday laboratory practice by biologists is still low. One of the reasons for this is that the technology combines poorly with standard cell biological and biochemical analysis tools. Flow cytometry is an example of a conventional analytical tool that is considered to be incompatible with microfluidic technology and its inherent small sample sizes. In this study, it is shown that properly designed microfluidic devices contain cell populations that are large enough to be analyzed by flow cytometry. To illustrate this, the uptake of fluorescent human low-density lipoprotein (LDL) by human endothelial cells that were cultured in a microfluidic channel was analyzed. It was found that the uptake of LDL by the cells increased linearly over time. Moreover, the uptake decreased when cells were pretreated with fluid shear stress inside the microfluidic devices. This study shows that microfluidic technology can be combined with conventional flow cytometry, while retaining the advantages of working with microfluidics such as low reagent use and dynamic cell culture conditions. This approach of combining microfluidic technology with conventional laboratory tools may contribute to greater acceptance of microfluidic devices in biological research. Gepubliceerd: Cytometry A. 2010;77(10):971-5 Impact factor: 3.032
12. Open or percutaneous revascularization for chronic splanchnic syndrome Van Petersen AS1, Kolkman JJ2, Beuk RJ1, Huisman AB3, Doelman CJ4, Geelkerken RH1 Department of 1surgery, 2Gastroenterology, 3Radiology, 4Clinical Chemistry, Medisch Spectrum Twente, Enschede Background: Treatment of chronic splanchnic syndrome remains controversial. In the past 10 years, endovascular repair (ER) has replaced open repair (OR) to some extent. This evidence summary reviews the available evidence for ER or OR of chronic splanchnic syndrome. Methods: A systematic literature search of MEDLINE database was performed to identify all studies that evaluated treatment of chronic splanchnic syndrome between 1988 and 2009. Results: The best available evidence consists of prospectively accumulated but retrospectively analyzed data with a high risk for confounding. Only a few of these studies incorporated functional tests to assess splanchnic ischemia before or after
118
treatment. ER has the advantage of low short-term morbidity but the disadvantage of decreased long-term primary patency compared with OR. ER and OR have similar rates of secondary patency, although the reintervention rate after ER is higher. Conclusion: ER appears to be preferential in the treatment of elderly patients and in patients with comorbidity, severe cachexia, or hostile abdomen. Long-term results after OR are excellent. OR can still be proposed as the preferred option for relatively young and fit patients. Gepubliceerd: J Vasc Surg. 2010;51(5):1309-1316 Impact factor: 3.517
13. Shear stress induces a transient and VEGFR-2-dependent decrease in the motion of injected particles in endothelial cells van der Meer AD1, Li Y1, Duits MH1, Poot AA1, Feijen J1, Vermes I1,2 1 Department of Polymer Chemistry and Biomaterials, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 2 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede Vascular endothelial cells form the inner lining of all blood vessels and play a central role in vessel physiology and disease. Endothelial cells are highly responsive to the mechanical stimulus of fluid shear stress that is exerted by blood flowing over their surface. In this study, the immediate micromechanical response of endothelial cells to physiological shear stress was characterized by tracking of ballistically injected, sub-micron, fluorescent particles. It was found that the mean squared displacement (MSD) of the particles decreases by a factor 1.5 within 10 min after the onset of shear stress. This decrease in particle motion is transient, since the MSD returns to control values within 15-30 min after the onset of shear. The immediate micromechanical stiffening is dependent on activation of the vascular endothelial growth factor receptor (VEGFR)-2, because inhibition of the receptor abrogates the micromechanical response. This work shows that the cytoskeleton is actively involved in the acute, functional response of endothelial cells to shear stress. Gepubliceerd: Biorheology. 2010;47(3):179-192 Impact factor: 1.279
14. Het syndroom van Chediak Higashi bij een jong meisje: een casuistische mededeling de Mare A1, Jonge Poerink-Stockschläder AB2, Bruin MC3, Slomp J1 1 Department of Clinical Chemistry, Medisch Spectrum Twente, Enschede 2 Department of Pediatrics, Medisch Spectrum Twente, Enschede 3 Afdeling Kinderhematologie en –oncologie, UMC Utrecht, Utrecht Een meisje van 14 maanden oud presenteerde zich begin 2008 met een ernstige luchtweginfectie. Bij differentiatieonderzoek van de leukocyten werden grote abnormale granulae gezien. Het voorkomen van dergelijke vergrote granulae is pathognomonisch voor het chédiak-higashisyndroom (CHS), een zeldzame letale
119
ziekte. CHS wordt veroorzaakt door een mutatie in een eiwit dat de morfologie en/of het transport van de granulae reguleert. De ziekte kenmerkt zich door oculocutaan albinisme, een verminderde werking van trombocyten en een verstoorde secretie van neurotransmitters. Het belangrijkste is echter een deficiënte immuunfunctie als gevolg van afwijkende granulae in de leukocyten. Patiënten presenteren zich daarom vaak met recidiverende infecties. Het merendeel krijgt uiteindelijk een lymfoproliferatief syndroom, gekenmerkt door een diffuse infiltratie door lymfocyten en macrofagen in een groot aantal organen, waaraan de meesten van hen komen te overlijden. Hoewel CHS niet te genezen is, kunnen de hematologische en immunologische problemen worden behandeld met een allogene stamceltransplantatie. Dit dient te gebeuren voordat het lymfoproliferatief syndroom optreedt en daarvoor is het belangrijk dat de diagnose in een vroeg stadium wordt gesteld. Hierbij is een belangrijke rol weggelegd voor het laboratorium. Gepubliceerd: Ned Tijdschr Hematol. 2010;7(4):163-8 Impact factor: 0
Totale impact factor: 67.318 Gemiddelde impact factor: 4.808 Aantal artikelen 1e, 2e of laatste auteur: 8 Totale impact factor: 44.478 Gemiddelde impact factor: 5.560
120
Klinische Farmacie 1. Dopaminergic drugs and the risk of hip or femur fracture: a population-based case-control study ME Arbouw1,2,3, KL Movig3, TP van Staa1, 4, AC Egberts1, 2, PC Souverein1, F de Vries1,4 1 Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Universiteit Utrecht, Utrecht 2 Department of Clinical Pharmacy, UMC Utrecht, 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. Introduction: Dopaminergic drugs, often used in the treatment of Parkinson's disease, have several pharmacological effects that may increase or decrease the risk of falling and fractures. Thus, the effect of dopaminergic medication on the risk of hip/femur fractures is not clear. The objective of the study was to examine the effect of dopaminergic medication and concomitant use of psychotropics on the risk of hip/femur fractures taking into account the timing of dopaminergic drug use. Methods: A population-based case-control study in the PHARMO database was conducted for the period 1991 to 2002. Cases were patients aged 18 years and older with a first hip or femur fracture and matched to four control patients by year of birth, sex and geographical region. Results: The study population included 6,763 cases and 26,341 controls. Current use of dopaminergic drugs (1-30 days before the index date) was associated with an increased risk of hip/femur fractures compared to never use (OR(adj) 1.76, 95% CIԜ=Ԝ1.39-2.22), but this excess risk rapidly dropped to baseline levels when treatment had been discontinued >1 year ago. Concomitant use of antidepressants among current dopaminergic drug users further increased the risk of hip/femur fractures (OR(adj) 3.51, 95% CIԜ=Ԝ2.10-5.87) while there was no additional risk with concomitant use of other psychotropics. Conclusions: Although the observed association between dopaminergic drugs and fracture risk may not be entirely causal, due to absence of information on the (severity of the) underlying disease, fracture risk assessment may be warranted in elderly users of dopaminergic drugs. Gepubliceerd: Osteoporos Int. 2010;DOI 10.1007/s00198-010-1455-3 Impact factor: 4.997
2. Glycopyrrolate for sialorrhea in Parkinson disease: a randomized, double-blind, crossover trial
121
Arbouw ME1, 3,4, Movig KL1, Koopmann M1, Poels PJ2, Guchelaar HJ5, Egberts TC3,4, Neef C6, van Vugt JP2 1 Department of Clinical Pharmacy and 2 Neurology, Medisch Spectrum Twente, Enschede 3 Department of Clinical Pharmacy, UMC Utrecht 4 Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University 5 Department of Clinical Pharmacy and Toxicology, Leiden UMC 6 Department of Clinical Pharmacy and Toxicology, Maastricht UMC Background: Sialorrhea affects approximately 75% of patients with Parkinson disease (PD). Sialorrhea is often treated with anticholinergics, but central side effects limit their usefulness. Glycopyrrolate (glycopyrronium bromide) is an anticholinergic drug with a quaternary ammonium structure not able to cross the blood-brain barrier in considerable amounts. Therefore, glycopyrrolate exhibits minimal central side effects, which may be an advantage in patients with PD, of whom a significant portion already experience cognitive deficits. Objective: To determine the efficacy and safety of glycopyrrolate in the treatment of sialorrhea in patients with PD. Methods: We conducted a 4-week, randomized, double-blind, placebo-controlled, crossover trial with oral glycopyrrolate 1 mg 3 times daily in 23 patients with PD. The severity of the sialorrhea was scored on a daily basis by the patients or a caregiver with a sialorrhea scoring scale ranging from 1 (no sialorrhea) to 9 (profuse sialorrhea). Results: The mean (SD) sialorrhea score improved from 4.6 (1.7) with placebo to 3.8 (1.6) with glycopyrrolate (p = 0.011). Nine patients (39.1%) with glycopyrrolate had a clinically relevant improvement of at least 30% vs 1 patient (4.3%) with placebo (p = 0.021). There were no significant differences in adverse events between glycopyrrolate and placebo treatment. Conclusions: Oral glycopyrrolate 1 mg 3 times daily is an effective and safe therapy for sialorrhea in Parkinson disease. Classification of evidence: This study provides Class I evidence that glycopyrrolate 1 mg 3 times daily is more effective than placebo in reducing sialorrhea in patients with Parkinson disease during a 4-week study. Gepubliceerd: Neurology. 2010;74(15):1203-7 Impact factor: 8.172
3. Effect of apomorphine on cognitive performance and sensorimotor gating in humans Schellekens AF, Grootens KP, Neef C, Movig KL*, Buitelaar JK, Ellenbroek B, Verkes RJ Department of Psychiatry, Radboud Medical Centre Nijmegen, Nijmegen * Department of Clinical Pharmacy, Medisch spectrum Twente, Enschede Introduction: Dysfunction of brain dopamine systems is involved in various neuropsychiatric disorders. Challenge studies with dopamine receptor agonists have
122
been performed to assess dopamine receptor functioning, classically using the release of growth hormone (GH) from the hindbrain as primary outcome measure. The objective of the current study was to assess dopamine receptor functioning at the forebrain level. Methods: Fifteen healthy male volunteers received apomorphine sublingually (2 mg), subcutaneously (0.005 mg/kg), and placebo in a balanced, double-blind, crossover design. Outcome measures were plasma GH levels, performance on an AX continuous performance test, and prepulse inhibition of the acoustic startle. The relation between central outcome measures and apomorphine levels observed in plasma and calculated in the brain was modeled using a two-compartmental pharmacokinetic-pharmacodynamic analysis. \ Results: After administration of apomorphine, plasma GH increased and performance on the AX continuous performance test deteriorated, particularly in participants with low baseline performance. Apomorphine disrupted prepulse inhibition (PPI) on high-intensity (85 dB) prepulse trials and improved PPI on low intensity (75 dB) prepulse trials, particularly in participants with low baseline PPI. High cognitive performance at baseline was associated with reduced baseline sensorimotor gating. Neurophysiological measures correlated best with calculated brain apomorphine levels after subcutaneous administration. Conclusion: The apomorphine challenge test appears a useful tool to assess dopamine receptor functioning at the forebrain level. Modulation of the effect of apomorphine by baseline performance levels may be explained by an inverted Ushape relation between prefrontal dopamine functioning and cognitive performance, and mesolimbic dopamine functioning and sensorimotor gating. Future apomorphine challenge tests preferentially use multiple outcome measures, after subcutaneous administration of apomorphine. Gepubliceerd: Psychopharmacology 2010; 207(4):559-69 Impact factor: 4.103
Totale impact factor: 17.272 Gemiddelde impact factor: 5.757 Aantal artikelen 1e, 2e of laatste auteur: 2 Totale impact factor: 13.169 Gemiddelde impact factor: 6.585
123
Klinische Fysica 1. Equipment-related incidents in the operating room: an analysis of occurrence, underlying causes and consequences for the clinical process Wubben I1, van Manen JG1, van den Akker BJ1, Vaartjes SR2, van Harten WH1 1 University of Twente, School of Management and Governance, Department of Health Technology and Services Research, Enschede 2 Department of Clinical Physics, Medisch Spectrum Twente, Enschede Background Equipment-related incidents in the operating room (OR) can affect quality of care. In this study, the authors determined the occurrence and effects on the care process in a large teaching hospital. Methods During a 4-week period, OR nurses reported equipment-related incidents during surgery procedures in both locations of the hospital. The incidents were reported using a separate form for each incident. A structured analysis (PRISMA) was used to analyse incidents that resulted in serious delays (>15 min). Results Forms were returned for 911 out of 1580 surgeries (57.7%). In total, 148 incidents were registered, relating to a total of 29 h and 45 min of extra work. In addition, 12 h and 9 min of operational delay was registered. Most incidents involved instruments (46%) or medical devices (28%). 68% occurred during surgery and 32% during the preparation phase. No direct physical harm was reported, although indirect harm, like longer anaesthesia, did occur and can be defined as an adverse event. 10% of the incidents led to a delay of over 15 min. For these incidents, 'management decisions' (eg, inventory capacity, planning procedure) was the most encountered root cause. Only six out of the 148 incidents found corresponded with the blame-free reporting database. Conclusions Equipment-related incidents occurred frequently in the involved hospital sites (up to 15.9%) and resulted in some extra work and additional minutes of delay per event. Management decisions have considerable influence on the occurrence of equipment-related incidents. There was serious under-reporting of incidents. Gepubliceerd: Qual Saf Health Care. 2010;19(6):1-7 Impact factor: 2.803
Totale impact factor: 2.803 Gemiddelde impact factor: 2.803 Aantal artikelen 1e, 2e of laatste auteur: 0 Totale impact factor: 0 Gemiddelde impact factor: 0
124
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 UMC, 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 UMC, Maastricht 4 Department of Otorhinolaryngology, Head and Neck Surgery, UMC Maastricht, Maastricht 5 Department of Otorhinolaryngology, Head and Neck Surgery, UMC 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. 2010;doi:10.1111/j.1365-2753.2010.01422.x Impact factor: 1.487
Totale impact factor: 1.487 Gemiddelde impact factor: 1.487 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 1.487 Gemiddelde impact factor: 1.487
125
Laboratorium voor Microbiologie 1. Is time to closure a factor in the occurrence of infection in traumatic wounds? A prospective cohort study in a Dutch level 1 trauma centre van den Baar MT1, van der Palen J2, Vroon MI1, Bertelink P1, Hendrix R3 1 Department of Surgery, Medisch Spectrum Twente, Enschede 2 Medical School Twente, Medisch Spectrum Twente, Enschede 3 Laboratory of Microbiology Oost Nederland, Enschede Background The dogma that traumatic wounds should not be sutured after 6 h is based on an animal experiment by P L Friedrich in 1898. There is no adequately powered prospective study on this cut-off of 6 h to confirm or disprove the dogma. The aim of this study was to provide evidence against the dogma that wounds should be sutured within 6 h after trauma. Method 425 patients were included in a prospective cohort study. Patients' wounds were closed, independent of time after trauma. All patients were seen after 7-10 days for removal of stitches and wound control on infection. Results Of the 425 patients, 17 were lost to follow-up. Of the remaining 408 patients, 45 had wounds older than 6 h after trauma. At follow-up 372 patients (91%) had no infection and 36 patients had redness of the suture sites or worse. 11 patients (2.7%) had general redness or pus. Of those with a wound older than 6 h, three of 45 (6.7%) wounds were infected, versus 30 of 363 (9.1%) in wounds younger than 6 h (p=0.59). Conclusion In everyday practice wounds are sutured regardless of elapsed time. Here an attempt was made to present the evidence for this daily routine, contrary to Friedrich's Dogma. Gepubliceerd: Emerg Med J 2010;27:540-543 Impact factor: 1.477
2. How nurses seek and evaluate clinical practice guidelines on the Internet Verhoeven F1, Steehouder MF1, Hendrix MG1,2, van Gemert-Pijnen JE1 1 Psychology and Communication of Health and Risk University of Twente, Enschede 2 Laboratory of Microbiology Oost Nederland, Enschede Aim: This paper is a report of a study conducted to assess nurses' informationseeking strategies and problems encountered when seeking clinical guidelines on the Internet, and to investigate the criteria they apply when evaluating the guidelines and the websites communicating the guidelines. Background: As nurses are increasingly taking on clinical responsibilities, they should be able to use the Internet to access up-to-date clinical guidelines. Currently, nurses' information-seeking skills remain rather limited. Method: In 2008, a convenience sample of 20 nurses solved scenario-based tasks using the Internet to seek clinical guidelines regarding methicillin-resistant Staphylococcus aureus while thinking aloud.
126
Results: General background information and universal precautions were successfully identified by participants, in contrast to more specific precautions. Nurses' information-seeking skills appeared rather basic, as they employed a limited number of search terms and consulted a limited number of websites. Ineffective searches were mainly caused by a mismatch between the guidelines and nurses' tacit knowledge. Perceived practical relevance and information completeness were the most frequently applied quality criteria. Accuracy and disclosures, which are emphasized in existing e-health literature, were considered less important. As long as information matched nurses' practical and experiential wisdom, they were satisfied. Conclusion: Nurses appeared to rely predominantly on tacit knowledge during the search process and while evaluating the retrieved guidelines. This is dangerous because nurses' reliance on inaccurate information might result in inadequate behaviour. It is therefore essential to expand nurses' current information base by tailoring both navigation structure and the guideline communication to dovetail with nurses' tacit knowledge. Gepubliceerd: J Adv Nurs.2010:66:114-27 Impact factor: 1.518
3. Micro-evolution of Mycobacterium tuberculosis in a tuberculosis patient Al-Hajoj SA1, Akkerman O2, Parwati I3, Al-Gamdi S4, Rahim Z5, van Soolingen D6, van Ingen J6, Supply P7, van der Zanden AG8 1 Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 2 Department of Pulmonology, Medisch Spectrum Twente, Enschede 3 Department of Clinical Pathology, Dr. Hasan Sadikin Hospital, Padjadjaran University, Bandung, Indonesia; 4 Molecular Diagnostic Unit, Hera General Hospital, Makkah, Saudi Arabia 5 International Centre for Diarrhoeal Disease Research, Bangladesh, 6 National Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment, Bilthoven 7 Center for Infection and Immunity of Lille, Institut Pasteur de Lille, and Genoscreen, Lille, France 8 Laboratory for Medical Microbiology and Public Health, Enschede Five Mycobacterium tuberculosis isolates were obtained from three body sites from a Dutch patient. The isolates displayed a single genotype by 24-locus MIRU-VNTR typing (except of a single locus not amplified from one isolate), but were differentiated by small variations in IS6110 fingerprints, spoligotypes, 6 hypervariable MIRU-VNTR loci and/or DiversiLab(R) profiles, revealing patterns of micro-evolution in a clonal infection. Gepubliceerd: J Clin Microbiol. 2010;48(10):3813-6 Impact factor: 4.162
127
4. 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. 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. 2010;DOI: 10.1111/j.1752-699X.2010.00234.x Impact factor: 0.597
5. Legionella pneumophila pneumonia in a pregnant woman treated with anti-TNF-α antibodies for Crohn's disease: A case report Epping G1, van der Valk PD1, Hendrix R2 1 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 2 Laboratory of Microbiology Oost Nederland, Enschede Anti-TNF-α antibodies are widely used. The indications for their usage are still increasing. With their emerging use, their infectious complications are seen more often. We describe the first case of a pneumonia with Legionella pneumophila in a
128
pregnant women with Crohn's disease, during treatment with anti-TNF-α antibodies. She was treated with erythromycin and made a full recovery. Gepubliceerd: J Crohns Colitis. 2010 Dec;4(6):687-689 Impact factor: 1.729
6. Capaciteitsonderzoek onder medisch-microbiologische analisten RH Hendrix1, GA Kampinga2, JA Kaan3 1 Laboratory of Microbiology Oost Nederland, Enschede 2 Laboratorium Medische Microbiologie, UMC Groningen, Groningen 3 Laboratorium Medische Microbiologie en Immunologie, Diakonessenhuis, Utrecht In maart 2009 is vanuit de Commissie Laboratoriumonderwijs een enquête gehouden onder de medisch-microbiologische laboratoria in Nederland om na te gaan hoe de behoefte is aan analytisch personeel. Het doel was een indruk te krijgen van de formatie en het aantal vacatures om daarmee over een regionale en landelijke raming te beschikken: is of dreigt er een tekort aan analytisch personeel, mogelijk als gevolg van demografische maar ook technologische veranderingen. Ondanks de niet volledige respons op de enquête is de voorlopige conclusie dat het aantal moeilijk te vervullen vacatures vergeleken met eerdergehouden vergelijkbare enquêtes niet zorgwekkend is, maar dat alertheid voor dit onderwerp gezien de ontwikkelingen in het vakgebied, aangewezen is. Gepubliceerd: Ned Tijdschr Med Microbiol 2010;18(2):8-11 Impact factor: 0
Totale impact factor: 9.483 Gemiddelde impact factor: 1.581 Aantal artikelen 1e, 2e of laatste auteur: 4 Totale impact factor: 7.368 Gemiddelde impact factor: 1.842
129
Longziekten 1. Micro-evolution of Mycobacterium tuberculosis in a tuberculosis patient Al-Hajoj SA1, Akkerman O2, Parwati I3, Al-Gamdi S4, Rahim Z5, van Soolingen D6, van Ingen J6, Supply P7, van der Zanden AG8 1 Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; 2 Department of Pulmonology, Medisch Spectrum Twente, Enschede 3 Department of Clinical Pathology, Dr. Hasan Sadikin Hospital, Padjadjaran University, Bandung, Indonesia; 4 Molecular Diagnostic Unit, Hera General Hospital, Makkah, Saudi Arabia 5 International Centre for Diarrhoeal Disease Research, Bangladesh, 6 National Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment, Bilthoven 7 Center for Infection and Immunity of Lille, Institut Pasteur de Lille, and Genoscreen, Lille, France 8 Laboratory for Medical Microbiology and Public Health, Enschede Five Mycobacterium tuberculosis isolates were obtained from three body sites from a Dutch patient. The isolates displayed a single genotype by 24-locus MIRU-VNTR typing (except of a single locus not amplified from one isolate), but were differentiated by small variations in IS6110 fingerprints, spoligotypes, 6 hypervariable MIRU-VNTR loci and/or DiversiLab(R) profiles, revealing patterns of micro-evolution in a clonal infection. Gepubliceerd: J Clin Microbiol. 2010;48(10):3813-6 Impact factor: 4.162
2. 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.
130
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. 2010;DOI: 10.1111/j.1752-699X.2010.00234.x Impact factor: 0.597
3. Aspiration pneumonitis after fire-eating: fire-eater's lung Harding FM1, Hiddinga BI1, Eijsvogel MM1, van Baarlen J2, Oosterhof-Berktas R3 1 department of Pulmonary Medicine, Medisch spectrum Twente, Enschede 2 Laboratorium voor Pathologie Oost-Nederland, Enschede 3 Department of Radiology, Medisch spectrum Twente, Enschede On the emergency department we saw two men aged 19 and 26 with symptoms of lipoid pneumonitis (fire-eater's lung) following aspiration of petroleum during fireeating. They were both admitted to hospital and treated with amoxicillin and clavulanic acid. Both patients were clinically recovered within a few days. Following aspiration of petroleum there is often a period of latency from 8-24 hours before the symptoms occur; it is recommended that patients should be admitted for observation. Known symptoms are coughing, shortness of breath, thoracic pain, fever, tachypnoea and sometimes haemoptysis. Apart from chest radiographs and laboratory values, taking into account the specific history, unless complications are expected additional diagnostic tests are often considered unnecessary. Treatment is symptomatic: administration of oxygen, pain relief, bronchodilation and potentially antibiotics if a bacterial superinfection is suspected. Clinical recovery is usually quick. Temporary restrictive disorders of lung function and reduced diffusion capacity have been described. Recovery of lung function and radiological recovery are seen within weeks to months. Mortality is less than 1%. Gepubliceerd: Ned Tijdschr Geneeskd. 2010;154(45):A2358 Impact factor: 0
131
4. Legionella pneumophila pneumonia in a pregnant woman treated with anti-TNF-α antibodies for Crohn's disease: A case report Epping G1, van der Valk PD1, Hendrix R2 1 Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede 2 Laboratory of Microbiology Oost Nederland, Enschede Anti-TNF-α antibodies are widely used. The indications for their usage are still increasing. With their emerging use, their infectious complications are seen more often. We describe the first case of a pneumonia with Legionella pneumophila in a pregnant women with Crohn's disease, during treatment with anti-TNF-α antibodies. She was treated with erythromycin and made a full recovery. Gepubliceerd: J Crohns Colitis. 2010 Dec;4(6):687-689 Impact factor: 1.729
5. Management of obstructive sleep apnea in Europe Fietze I, Penzel T, Alonderis A, Barbe F, Bonsignore MR, Calverly P, De Backer W, Diefenbach K, Donic V, Eijsvogel MM, Franklin KA, Gislason T, Grote L, Hedner J, Jennum P, Lavie L, Lavie P, Levy P, Lombardi C, Mallin W, Marrone O, Montserrat JM, Papathanasiou ES, Parati G, Plywaczewski R, Pretl M, Riha RL, Rodenstein D, Saaresranta T, Schulz R, Sliwinski P, Steiropoulos P, Svaza J, Tomori Z, Tonnesen P, Varoneckas G, Verbraecken J, Vesely J, Vitols A, Zielinski J, McNicholas WT, 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
132
helpful for implementing these findings into health-service research in order to standardize management in a cost effective perspective. Gepubliceerd: Sleep Med. 2010;12(2):190-197 Impact factor: 3.699
Totale impact factor: 10.187 Gemiddelde impact factor: 2.037 Aantal artikelen 1e, 2e of laatste auteur: 4 Totale impact factor: 6.488 Gemiddelde impact factor: 1.622
133
Medical School Twente 1. Mesh-fixation method and pain and quality of life after laparoscopic ventral or incisional hernia repair: a randomized trial of three fixation techniques Wassenaar E 1,2, Schoenmaeckers E 1, Raymakers J 1, van der Palen J 3, Rakic S 1 1 Center for Video-endoscopic Surgery, Department of Surgery, University of Washington, Seattle, WA, USA 2 Department of Surgery, Twenteborg Ziekehhuis, Almelo 3 Medical School Twente, Medisch Spectrum Twente, Enschede Background: Persistent, activity-limiting pain after laparoscopic ventral or incisional hernia repair (LVIHR) appears to be related to fixation of the implanted mesh. A randomized study comparing commonly used fixation techniques with respect to postoperative pain and quality of life has not previously been reported. Methods: A total of 199 patients undergoing non-urgent LVIHR in our unit between August 2005 and July 2008 were randomly assigned to one of three mesh-fixation groups: absorbable sutures (AS) with tacks; double crown (DC), which involved two circles of tacks and no sutures; and nonabsorbable sutures (NS) with tacks. All operations were performed by one of two experienced surgeons, who used a standardized technique and the same type of mesh and mesh-fixation materials. The severity of the patients' pain was assessed preoperatively and at 2 weeks, 6 weeks and 3 months postoperatively by using a visual analogue scale (VAS). Quality of life (QoL) was evaluated by administering a standard health survey before and 3 months after surgery. Results in the three groups were compared. Results: The AS, DC, and NS mesh-fixation groups had similar patient demographic, hernia and operative characteristics. There were no significant differences among the groups in VAS scores at any assessment time or in the change in VAS score from preoperative to postoperative evaluations. The QoL survey data showed a significant difference among groups for only two of the eight health areas analyzed. Conclusion: In this trial, the three mesh-fixation methods were associated with similar postoperative pain and QoL findings. These results suggest that none of the techniques can be considered to have a pain-reduction advantage over the others. Development of new methods for securing the mesh may be required to decrease the rate or severity of pain after LVIHR. Gepubliceerd: Surg Endosc. 2010;24(6):1296-1302 Impact factor: 3.307
2. TWENTE Study: The Real-World Endeavor Resolute Versus Xience V DrugEluting Stent Study in Twente: study design, rationale and objectives Basalus MW1, Tandjung K1, van Houwelingen KG1, Stoel MG1, de Man FH1, Louwerenburg JW1, Saïd SA2, Linssen GC3, Kleijne MA4, van der Palen5, Huisman J1, Verhorst PM1, von Birgelen C6 1 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede
134
2
Department of Cardiology, Hospital Group Twente, Hengelo Department of Cardiology, Hospital Group Twente, Almelo 4 Department of Cardiology, Streekziekenhuis Koningin Beatrix, Winterswijk 5 Department of Epidemiology, Medisch Spectrum Twente, Enschede and Department of Research Methodology, Measurement & Data Analysis, University of Twente, Enschede 6 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, and MIRA, Institute for Biomedical Technology & Technical Medicine, University of Twente, Enschede 3
Background. New-generation drug-eluting stents (DES) may solve several problems encountered with first-generation DES, but there is a lack of prospective head-to-head comparisons between new-generation DES. In addition, the outcome of regulatory trials may not perfectly reflect the outcome in 'real world' patients. Objectives. To compare the efficacy and safety of two new-generation DES in a 'real world' patient population. Methods. A prospective, randomised, single-blinded clinical trial to evaluate clinical outcome after Endeavor Resolute vs. Xience V stent implantation. The primary endpoint is target vessel failure at one-year follow-up. In addition, the study comprises a two-year and an open-label five-year follow-up Gepubliceerd: Neth Heart J. 2010;18(7-8):360-4 Impact factor: 1.392
3. Between-Centre Reproducibility of Volumetric Intravascular Ultrasound Radiofrequency-Based Analyses in Mild-to-Moderate Coronary Atherosclerosis: An International Multicentre Study J Huisman1, R Egede2, A Rdzanek3, D Boese4, R Erbel4, J Kochman3, L Okkels Jensen2, J van der Palen5,6, M Hartmann1, GS Mintz7, C von Birgelen1,8 1 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede 2 Department of Cardiology, Odense University Hospital, Odense, Denmark 3 Department of Cardiology, Central University Hospital, Warsaw, Poland 4 Department of Cardiology, Westdeutsches Herzzentrum Essen, Universitätsklinikum Essen-Duisburg, Germany 5 Department of Epidemiology, Medisch Spectrum Twente, Enschede 6 Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede 7 Cardiovascular Research Foundation, New York, USA 8 University of Twente, MIRA-Institute, Enschede Aim: To assess for the first time in a multicentre design the between-centre reproducibility of volumetric virtual histology intravascular ultrasound (VH-IVUS) measurements with a semi-automated, computer-assisted contour detection system in mild-to-moderately diseased coronary segments. Methods and results: Analysts of 4 European IVUS centres performed independent IVUS analyses (in total 7.188 cross-sectional analyses) and obtained
135
volumetric data to evaluate the reproducibility of volumetric VH-IVUS measurements in 36 coronary segments (length 20.0±0.4mm) from patients with stable angina. Geometrical and compositional VH-IVUS measurements were highly correlated for the different comparisons. Overall intraclass correlation for vessel, lumen, plaque volume and plaque burden were 0.98, 0.92 0.95, and 0.86, respectively; for fibrous, fibro-lipidic, necrotic core and calcified volumes overall intraclass correlations were 0.95, 0.93, 0.99, and 1.00, respectively. There were significant but small differences for vessel, lumen, fibrous and calcified volumes, and there was no significant difference for plaque volume. Of the plaque components necrotic core and calcified volume showed on average the highest reproducibility. Conclusions: These findings underline the necessity to centrally analyze IVUS data obtained in multicentre studies addressing mild-to-moderately diseased coronary arteries. In addition, pooling VH-IVUS data from different studies, analyzed at different centres, may be problematical. Gepubliceerd: EuroIntervention 2010;5(8):925-931 Impact factor: 0
4. ECG Quantification of Myocardial Scar Does Not Differ between Primary and Secondary Prevention ICD Recipients with Ischemic Heart Disease Kraaier K1, van Dessel PF1, van der Palen J2,3, Wilde AA4, Scholten MF1 1 Department of Cardiology, Medisch Spectrum Twente, Enschede 2 Department of Epidemiology, Medisch Spectrum Twente, Enschede 3 Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede 4 Department of Cardiology, Academic Medical Centre, Amsterdam Background: Myocardial scar is an anatomic substrate for potentially lethal arrhythmias. Recent study showed that higher QRS-estimated scar size using the Selvester QRS score was associated with increased arrhythmogenesis during electrophysiologic testing. Therefore, QRS scoring might play a potential role in risk stratification before implantable cardioverter defibrillator (ICD) implantation. In this study, we tested the hypothesis that QRS scores among ICD recipients for secondary prevention are higher than QRS scores in primary prevention patients. Methods and Results: From the hospital database, 100 consecutive patients with ischemic heart disease and prior ICD implantation were selected. Twelve-lead electrocardiograms (ECGs) had been obtained before implantation. ECGs were scored following the 32-points Selvester QRS scoring system and corrected for underlying conduction defects and/or hypertrophy. Ninety-three ECGs were suitable for scoring; seven ECGs were rejected because of noise, missing leads, excessive ventricular extrasystoles, or ventricular pacing. No statistically significant difference in QRS score was found between the primary [6.90 (standard deviation [SD] 3.94), n = 63] and secondary prevention group [6.17 (SD 4.50) (P = 0.260), n = 30]. Left ventricular ejection fraction (LVEF) was significantly higher in the secondary prevention group [31% (SD 13.5) vs 24% (SD 11.7) (P = 0.015)]. When patients with LVEF >/=35% were excluded, QRS scores were still comparable, namely 7.02 (SD
136
4.04) in the primary prevention group (n = 52) and 6.28 (SD 4.24) in the secondary (P = 0.510) (n = 18). Conclusion: We found no significant difference in QRS score between the ischemic primary and secondary prevention groups. Therefore, a role of the Selvester QRS score as a risk stratifier remains unlikely. Gepubliceerd: Pacing Clin Electrophysiol. 2010;33(2):192-197 Impact factor: 1.578
5. Is time to closure a factor in the occurrence of infection in traumatic wounds? A prospective cohort study in a Dutch level 1 trauma centre van den Baar MT1, van der Palen J2, Vroon MI1, Bertelink P1, Hendrix R3 1 Department of Surgery, Medisch Spectrum Twente, Enschede 2 Medical School Twente, Medisch Spectrum Twente, Enschede 3 Laboratory of Microbiology Oost Nederland, Enschede Background The dogma that traumatic wounds should not be sutured after 6 h is based on an animal experiment by P L Friedrich in 1898. There is no adequately powered prospective study on this cut-off of 6 h to confirm or disprove the dogma. The aim of this study was to provide evidence against the dogma that wounds should be sutured within 6 h after trauma. Method 425 patients were included in a prospective cohort study. Patients' wounds were closed, independent of time after trauma. All patients were seen after 7-10 days for removal of stitches and wound control on infection. Results Of the 425 patients, 17 were lost to follow-up. Of the remaining 408 patients, 45 had wounds older than 6 h after trauma. At follow-up 372 patients (91%) had no infection and 36 patients had redness of the suture sites or worse. 11 patients (2.7%) had general redness or pus. Of those with a wound older than 6 h, three of 45 (6.7%) wounds were infected, versus 30 of 363 (9.1%) in wounds younger than 6 h (p=0.59). Conclusion In everyday practice wounds are sutured regardless of elapsed time. Here an attempt was made to present the evidence for this daily routine, contrary to Friedrich's Dogma. Gepubliceerd: Emerg Med J 2010;27:540-543 Impact factor: 1.477
6. Chronotypes and subjective sleep parameters in epilepsy patients: a large questionnaire study Hofstra WA1,2, Gordijn MC1, van Hemert-van der Poel JC1, van der Palen J3, De Weerd AW1 1 Department of Clinical Neurophysiology and Sleep Centre SEIN Zwolle, Zwolle 2 Department of Neurology, Medisch Spectrum Twente, Enschede 3 Medical School Twente, Medisch Spectrum Twente, Enschede
137
Accumulating evidence suggests epilepsy and seizures may influence circadian rhythms and that circadian rhythms may influence epilepsy. It is also conceivable that seizure timing influences the timing of daily activities, sleeping, and wakefulness (i.e., chronotype). Only one group has studied the distribution of chronotypes of epileptics, showing significant differences between the diurnal activity patterns in two groups of patients with different epilepsy syndromes. The authors performed a questionnaire-based study of 200 epilepsy patients to compare the distribution of chronotypes and subjective sleep parameters of sleep duration and time of midsleep on free days to the distribution in the general population (n = 4042). Within this large group of epilepsy patients, we also compared the chronotypes of subsamples with well-defined epilepsy syndromes, i.e., temporal lobe epilepsy [TLE; n = 46], frontal lobe epilepsy [FLE; n = 30], and juvenile myoclonic epilepsy [JME; n = 38]. In addition, 27 patients who had had surgery for TLE were compared with those with TLE who had not had surgery. Both the Morningness-Eveningness Questionnaire and Munich Chronotype Questionnaire were used to determine chronotypes and subjective sleep parameters. Significant differences in morningness/eveningness distribution, timing of mid-sleep (corrected for sleep duration), and total sleep time on free days were found between epileptics and healthy controls. Those with epilepsy were more morning oriented, had earlier mid-sleep on free days, and longer sleep duration on free days (p < .001). However, distributions of chronotypes and sleep parameters between the groups of people with TLE, FLE, and JME did not differ. Persons who had surgery for TLE had similar morningness-eveningness parameters and similar sleep durations compared to those without surgery, but midsleep on free days was earlier in operated patients (p = .039). In conclusion, this is the first large study focusing on chronotypes in people with epilepsy. We show that the distribution of chronotypes and subjective sleep parameters of epileptics, in general, is different from that of healthy controls. Nevertheless, no differences are observed between patients with specified epilepsy syndromes, although they exhibit seizures with different diurnal patterns. Our results suggest that epilepsy, itself, rather than seizure timing, has a significant influence on chronotype behavior and subjective sleep parameters. Gepubliceerd: Chronobiol Int. 2010;27(6):1271-86 Impact factor: 3.987
7. Evaluation of the finger wrinkling test: a pilot study van Barneveld S1,3, van der Palen J2,5, van Putten MJ1,4 1 Department of Clinical Neurophysiology, Medisch Spectrum Twente, Enschede 2 Department of Epidemiology, Medisch Spectrum Twente, Enschede 3 Department of Medicine, University of Groningen, Groningen 4 MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 5 Department of Research Methodology, Measurement and Data Analysis, Faculty of Behavioral Sciences, University of Twente, Enschede Purpose: Tilt table testing mainly evaluates the systemic cardiovascular part of the autonomic nervous system, while it is assumed that the finger wrinkling test assesses the peripheral part of the autonomic nervous system. In this study we
138
explored whether the finger wrinkling test could be a useful test for autonomic dysfunction and whether the clinical evaluation of wrinkling can be improved by digital analysis of photographs. Methods: As much as 20 healthy subjects and 15 patients underwent tilt table testing and finger wrinkling testing. During the finger wrinkling test the right hand was immersed in water at 40 degrees C. The degree of wrinkling was assessed with a 5-point clinical scale at baseline, 5, 15 and 30 min of immersion. Photographs were taken at the same intervals. Several features were evaluated using digital analysis: length and gradient of automatically detected wrinkle and mean, maximum, minimum, variance and derivative of grey value of pixels. Results: Clinical scoring of wrinkling allowed differentiation between healthy subjects and patients with a normal and an abnormal response to tilt table testing. Relevant features obtained with digital analysis were mean grey value and the gradient of automatically detected wrinkle. McNemar's test showed no difference in test results between the tilt table test and the finger wrinkling test with a kappa of 0.68. Conclusion: The finger wrinkling test can be used as a screening test before tilt table testing. Visual evaluation of wrinkling is still superior to digital analysis of photographs. Gepubliceerd: Clin Auton Res. 2010; 20(4):249-53 Impact factor: 1.278
8. The impact of margin status in breast-conserving therapy for lobular carcinoma is age related JJ Jobsen a, S Riemersma b, J van der Palen c, F Ong a, A Jonkman a, H Struikmans d a
Department of Radiation Oncology, Medisch Spectrum Twente, Enschede Laboratorium Pathologie Oost Nederland, Enschede c Department of Research Methodology, Measurement, and Data Analysis, Faculty of Behavioral Science, University of Twente d Department of Radiation Oncology, Leiden University Medical Centre, Leiden b
Purpose: The aim is to look at the impact of margin status and outcome of invasive lobular carcinoma (ILC) treated with breast-conserving therapy (BCT). Methods: This manuscript describes an analysis on 330 BCT in 318 patients with ILC. Results: The 12-year local relapse free survival (LRFS) is 89%. In multivariate analysis, positive margin status, age>50 years, contra lateral breast cancer, and adjuvant systemic therapy were significant predictors of local relapse free survival. In a separate analysis limited to a positive margin for invasive carcinoma or carcinoma in situ, only a positive margin for invasive carcinoma was a significant predictor of local relapse free survival. This was limited to women
139
factors were also relevant for distant metastasis-free survival (DMFS) and diseasefree survival (DFS). Conclusions: Positive margins for invasive carcinoma seem to be a strong predictor for local recurrence in particular for women
9. The number of metastatic sites for stage IIIA endometrial carcinoma, endometrioid cell type, is a strong negative prognostic factor Jobsen JJ1, Ten Cate LN2, Lybeert ML3, van der Steen-Banasik EM4, Scholten A5, van der Palen J6,11, Slot A7, Kroese MC8, Schutter EM9, Siesling S10 1 Department of Radiation Oncology, Medisch Spectrum Twente, Enschede 2 Laboratorium Pathologie Oost Nederland, Enschede 3 Department of Radiation Oncology, Catharina Hospital, Eindhoven 4 Arnhem Radiotherapeutic Institute, Arnhem 5 Department of Clinical Oncology, Leiden UMC, Leiden 6 Department of Research Methodology, Measurement, and Data Analysis, Faculty of Behavioral Science, University of Twente 7 Radiotherapy Institute Friesland, Leeuwarden 8 Radiotherapy Institute Steden en Omstreken, Deventer 9 Departments of Obstetrics and Gynaecology, Medisch Spectrum Twente, Enschede 10 Comprehensive Cancer Centre North East, Enschede/Groningen 11 Clinical Epidemiology, Medisch Spectrum Twente, Enschede The aim of this study was to look at the impact of the number of sites with tumour involvement on outcome for patients with stage IIIA endometrioid-type endometrial carcinoma. Patients and methods: 141 patients stage IIIA were included. A central histopathological review was performed. Patients staged solely on the presence of a positive peritoneal washing were excluded. Follow-up ranged from 2 to 217 months with a median of 43 months. Endpoints of the study were locoregional recurrence rates, distant metastasis-free survival (DMFS), disease-free survival (DFS) and disease-specific survival (DSS). Results: In multivariate analyses the number of involved sites showed to be the only independent significant variable for DMFS, DFS, and DSS with a Hazard Ratio of 2.1, 2.2, and 2.2, respectively. The DSS was significantly related to the number of involved sites, with a 5-year DSS of 70.4% for one site, 42.8% for two sites, and 43.9% for three sites, respectively (p=0.001). Conclusion: The number of involved sites outside the corpus uterine for stage IIIA seems to be a strong negative prognostic factor for stage IIIA endometrial carcinoma. Gepubliceerd: Gynecol Oncol. 2010;117:32-36
140
Impact factor: 3.733
10. Arm Crank Ergometer is Reliable and Valid for Measuring Aerobic Capacity During Submaximal Exercise Bulthuis Y1, Drossaers-Bakker W2, Oosterveld F3, van der Palen J4, van de Laar M1,2 1 University of Twente, Institute for Behavioral Research, Department of Psychology & Communication of Health & Risk, Enschede 2 Department of Rheumatology and Clinical Immunology, Medisch Spectrum Twente, Enschede 3 Saxion University of Professional Education, Department of Health, Welfare and Technology, Enschede 4 Department of Epidemiology, Medisch Spectrum Twente, Enschede Measuring physical fitness becomes more important. Yet most instruments depend upon the function of the lower extremities. Hence, we investigated whether an adapted submaximal arm crank test on an ergometer for the upper body is reliable to use, and if the submaximal test for the arm crank ergometer is valid compared to the test on the bicycle ergometer. Different types of reliability measures of the adapted submaximal test on an arm crank ergometer were assessed in healthy volunteers, such as test-retest, interobserver, interergometer, and between arm crank and bicycle ergometer. A crossover design was used. The measurements were proportionally distributed over 30 volunteers. Based on the intraclass correlation coefficient (ICC) and the magnitude of within-person differences, we revealed a good reliability of the submaximal test. For the test-retest reliability, the ICC was 0.76, the interobserver reliability was 0.82, and the interergometer reliability 0.63. In addition, the criterion validity was also tested by comparing the calculated &OV0312;o2max during the submaximal test on the arm crank ergometer and on the bicycle ergometer. Between &OV0312;o2max on the arm crank and bicycle ergometer, an ICC of 0.64 was found. The results of the submaximal test on the arm crank ergometer are reliable and valid as compared with those on the bicycle crank ergometer. We showed that the submaximal test on the arm crank ergometer is suitable for measuring physical fitness in healthy people. We expect that disabled people can use this submaximal test on the arm crank ergometer for measuring their physical fitness, also. Gepubliceerd: J Strength Cond Res. 2010;24(10):2809-15 Impact factor: 1.457
11. 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
141
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. 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. 2010;DOI: 10.1111/j.1752-699X.2010.00234.x Impact factor: 0.597
12 Using a web application to improve satisfaction among patients undergoing surgery RH Koop1, JM Klaase1, J van der Palen2,3, PAM Kommers4, AJ Sanders4, J Jonker4 1 Department of Surgery, 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 University of Twente The study explores whether patient satisfaction is increased when a web application is used to inform patients about a surgical intervention. A randomised single centre study was conducted. The study population consisted of 32 patients that underwent an elective colon resection for colon cancer (15 in the experimental and 17 in the control group; patient characteristics were equally divided between both groups). The study group got the information with the web application from the nurse practitioner at least 10 days before surgery; the control group was given the standard oral information by the nurse practitioner. Satisfaction level was measured with a validated patient satisfaction questionnaire directly after giving the information
142
and two weeks after the surgical intervention. The results indicate that patients are more satisfied when information is given by means of a web application. Given that expectations regarding hospital admission are more realistic when information is given in the optimal manner, this has consequences for the use of multimedia information techniques in healthcare in the near future. Gepubliceerd: J Management & Marketing in Healthcare 2010;3(4):264–271 Impact factor: 0
13. De effectiviteit van beugelbehandeling (orthonyxie) versus chirurgie bij de ingegroeide teennagel S Kruijff1, RJ van Det1, RH Geelkerken1, CM van den Berg2, J van der Palen3,4, CL Gerritsma-Bleeker5 1 Afdeling Heelkunde, Medisch Spectrum Twente, Enschede 2 Podotherapeut, Medisch Spectrum Twente, Enschede 3 Afdeling Epidemiologie, Medisch Spectrum Twente, Enschede 4 Afdeling Onderzoeksmethodologie, meetmethoden en data analyse, Faculteit Gedragswetenschappen, Universiteit Twente, Enschede 5 Afdeling orthopedie, Martini ziekenhuis, Groningen Doel: Bepalen welke therapie, Segmentiele Phenolisatie (SP), Partiële Matrix Excisie (PME) of Beugelbehandeling (orthonyxie), het meest eff ectief is voor de behandeling van de ingegroeide teennagel van de hallux. Studie-opzet: Er werd een analyse verricht over een tweetal eerder uitgevoerde geblindeerde prospectieve gerandomiseerde klinische trials (RCT) met ieder een follow-up van 12 maanden. Beide studies werden eerder verricht in ons centrum en hadden een identieke methodologische opzet. In het eerste onderzoek (SP; n=29, PME1; n=34), werd segmentiele phenolisatie met partiële matrix excisie vergeleken en in het tweede onderzoek (Orthonyxie; n=51, PME 2; n=58) werd de beugelbehandeling met partiële matrix vergeleken. Voor de analyse werden in totaal de data van 163 patiënten met 172 ingegroeide teennagels samengevoegd. Het primaire eindpunt was recidief na 12 maanden. Secundaire eindpunten waren postoperatieve morbiditeit en tijd tot volledig herstel. Resultaten: Na 12 maanden werden 6 recidieven in de segmentiele phenolisatie groep (20.7%), 7 in de eerste partiële matrix excisie groep (20.6%), 4 in de tweede partiële matrix excisie groep (6.9%) en 8 (15.7%) in de beugelbehandelings groep vastgesteld (p=0.16). Postoperatieve morbiditeit (roodheid, pus, bloeding), tijd tot volledig herstel, dragen van schoenen en het uitvoeren van ADL en hobby’s, postoperatieve symptomen en patiënt tevredenheid scoorden signifi cant aanzienlijk beter bij de behandeling met een nagelbeugel ten opzichte van partiële matrix excisie en segmentiele phenolisatie. Conclusie: Segmentiele phenolisatie, partiële matrix excisie en een beugelbehandeling zijn even eff ectief in de behandeling van unguis incarnatus van de hallux. Echter, de beugelbehandeling toont met name op vroege termijn aanzienlijk betere resultaten daar waar het de postoperatieve morbiditeit, tijd tot volledig herstel, postoperatieve symptomen en patiënt tevredenheid betreft.
143
Gepubliceerd: Nederlands Tijdschrift voor Heelkunde 2010;19(5):183-190 Impact factor: 0
Totale impact factor: 21.297 Gemiddelde impact factor: 1.638 Aantal artikelen 1e, 2e of laatste auteur: 3 Totale impact factor: 3.352 Gemiddelde impact factor: 1.117
144
Neurologie 1. Vagus nerve stimulation for epilepsy activates the vocal folds maximally at therapeutic levels Ardesch JJ, Sikken JR, Veltink PH, van der Aa HE, Hageman G, Buschman HP Department of Neurology, Medisch Spectrum Twente, 7513 ER Enschede Purpose: Vagus nerve stimulation (VNS) for medically refractory epilepsy can give hoarseness due to stimulation of the recurrent laryngeal nerve. For a group of VNStherapy users this side-effect interferes severely with their daily activities. Our goal was to investigate the severity of intra-operative VNS-related vocal fold contraction at different pulse widths and current output parameters. We investigated electromyographic and morphometric alterations on the vocal folds during VNS. Methods: Vocal fold EMG experiments were conducted intra-operatively during the implantation of a VNS system. During surgery the VNS pulse generator was programmed to stimulate at different pulse durations. At each pulse width the EMGthreshold current was determined by electrical stimulation of the vagus nerve with increasing stimulation currents. Laryngostroboscopic examination was performed after surgery to analyze the effects of spontaneous stimulation on the larynx. Results: The vocal fold EMG and morphodynamic changes in the larynx have been analyzed in eight patients. In all patients left vocal fold EMG-threshold was between 0.25 and 0.50mA. Pulse duration had little influence on the EMG-threshold level. Vocal fold EMG saturation levels were reached between 0.75 and 1.00mA. Video stroboscopic monitoring showed that stimulation induced an adductory spasm of either the ipsilateral vocal fold or the vestibular fold, and was present remarkably irrespective of the presence of hoarseness. Conclusions: VNS causes pronounced effects on the vocal folds even at low stimulation amplitudes. At therapeutic levels even at the lowest stimulation pulse durations, the vocal fold contract, however, this does not necessarily give hoarseness. Gepubliceerd: Epilepsy Res. 2010;89:227-31 Impact factor: 2.479
2. Late Effects From Radiation Therapy: The Hits Just Keep on Coming Aleman BM1, De Bruin ML2, Dorresteijn LD3, Krol AD4, Van 't Veer MB5, Boogerd W6, Van Leeuwen FE2 1 Department of Radiotherapy and 2Department of Epidemiology Cancer Institute, Amsterdam; 3Department of Neurology, Medisch Spectrum Twente, Enschede; 4 Department of Radiotherapy, Leiden UMC, Leiden; 5Department of Hematology, Erasmus MC, Daniel den Hoed Cancer Center, Rotterdam; 6Department of Neurooncology Cancer Institute, Amsterdam Gepubliceerd: J Natl Cancer Inst. 2010;102(8):576-8 Impact factor: 14.069
145
3. Outcome of Carotid Artery Stenting for Radiation-Induced Stenosis LDA Dorresteijn1,2, OJM Vogels3, FE de Leeuw1, JA Vos4, MH Christiaans5, RGA Ackerstaff3, AC Kappelle1 1 Department of Neurology, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen 2 Department of Neurology, Medisch spectrum Twente, Enschede 3 Department of Neurology and Clinical Neurophysiology, St Antonius Hospital, Nieuwegein 4 Department of Radiology, St Antonius Hospital, Nieuwegein 5 Department of Neurology, Diakonessenhuis, Utrecht Purpose: Patients who have been irradiated at the neck have an increased risk of symptomatic stenosis of the carotid artery during follow-up. Carotid angioplasty and stenting (CAS) can be a preferable alternative treatment to carotid endarterectomy, which is associated with increased operative risks in these patients. Methods and materials: We performed a prospective cohort study of 24 previously irradiated patients who underwent CAS for symptomatic carotid stenosis. We assessed periprocedural and nonprocedural events including transient ischemic attack (TIA), nondisabling stroke, disabling stoke, and death. Patency rates were evaluated on duplex ultrasound scans. Restenosis was defined as a stenosis of >50% at the stent location. Results: Periprocedural TIA rate was 8%, and periprocedural stroke (nondisabling) occurred in 4% of patients. After a mean follow-up of 3.3 years (range, 0.3-11.0 years), only one ipsilateral incident event (TIA) had occurred (4%). In 12% of patients, a contralateral incident event was present: one TIA (4%) and two strokes (12%, two disabling strokes). Restenosis was apparent in 17%, 33%, and 42% at 3, 12, and 24 months, respectively, although none of the patients with restenosed vessels became symptomatic. The length of the irradiation to CAS interval proved the only significant risk factor for restenosis. Conclusions: The results of CAS for radiation-induced carotid stenosis are favorable in terms of recurrence of cerebrovascular events at the CAS site. Gepubliceerd: Int J Radiat Oncol Biol Phys. 2010;77(5):1386-90 Impact factor: 4.592
4. Sensitivity and specificity of the 'Awaji' electrodiagnostic criteria for amyotrophic lateral sclerosis: Retrospective comparison of the Awaji and revised El Escorial criteria for ALS. Boekestein WA1, Kleine BU1, Hageman G2, Schelhaas HJ1, Zwarts MJ1 1 Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen 2 Department of Neurology, Medisch Spectrum Twente, Enschede The Awaji Commission recently proposed a modification of the electrodiagnostic criteria for ALS. We assessed whether the Awaji recommendations improve the sensitivity of the early diagnosis of ALS. In a retrospective study we reviewed clinical and neurophysiological data for 213 patients who visited our motor neuron disease
146
outpatient clinic between October 2006 and December 2008. Using the El Escorial criteria, 51 patients were diagnosed with definite or probable ALS, 14 with probable laboratory-supported ALS, and 28 with possible ALS. An alternative diagnosis was present in 120 patients. Applying the Awaji recommendations, 66 patients were diagnosed with either definite or probable ALS, and 27 with possible ALS. Of the 14 patients diagnosed with probable laboratory-supported ALS, eight switched to probable ALS and six to possible ALS using the Awaji recommendations; none of the patients with an ALS mimic was diagnosed with ALS according to the Awaji recommendations. In conclusion, the new criteria for ALS do not result in a loss of specificity and can potentially improve the sensitivity by 16%. However, this diagnostic improvement appears eliminated if patients with probable laboratorysupported ALS - due to UMN signs in one region - should be categorized as possible ALS. Gepubliceerd: Amyotroph Lateral Scler. 2010;11(6):497-501 Impact factor: 2.963
5. Chronotypes and subjective sleep parameters in epilepsy patients: a large questionnaire study Hofstra WA1,2, Gordijn MC1, van Hemert-van der Poel JC1, van der Palen J3, De Weerd AW1 1 Department of Clinical Neurophysiology and Sleep Centre SEIN Zwolle, Zwolle 2 Department of Neurology, Medisch Spectrum Twente, Enschede 3 Medical School Twente, Medisch Spectrum Twente, Enschede Accumulating evidence suggests epilepsy and seizures may influence circadian rhythms and that circadian rhythms may influence epilepsy. It is also conceivable that seizure timing influences the timing of daily activities, sleeping, and wakefulness (i.e., chronotype). Only one group has studied the distribution of chronotypes of epileptics, showing significant differences between the diurnal activity patterns in two groups of patients with different epilepsy syndromes. The authors performed a questionnaire-based study of 200 epilepsy patients to compare the distribution of chronotypes and subjective sleep parameters of sleep duration and time of midsleep on free days to the distribution in the general population (n = 4042). Within this large group of epilepsy patients, we also compared the chronotypes of subsamples with well-defined epilepsy syndromes, i.e., temporal lobe epilepsy [TLE; n = 46], frontal lobe epilepsy [FLE; n = 30], and juvenile myoclonic epilepsy [JME; n = 38]. In addition, 27 patients who had had surgery for TLE were compared with those with TLE who had not had surgery. Both the Morningness-Eveningness Questionnaire and Munich Chronotype Questionnaire were used to determine chronotypes and subjective sleep parameters. Significant differences in morningness/eveningness distribution, timing of mid-sleep (corrected for sleep duration), and total sleep time on free days were found between epileptics and healthy controls. Those with epilepsy were more morning oriented, had earlier mid-sleep on free days, and longer sleep duration on free days (p < .001). However, distributions of chronotypes and sleep parameters between the groups of people with TLE, FLE, and JME did not differ. Persons who had surgery for TLE had similar morningness-eveningness
147
parameters and similar sleep durations compared to those without surgery, but midsleep on free days was earlier in operated patients (p = .039). In conclusion, this is the first large study focusing on chronotypes in people with epilepsy. We show that the distribution of chronotypes and subjective sleep parameters of epileptics, in general, is different from that of healthy controls. Nevertheless, no differences are observed between patients with specified epilepsy syndromes, although they exhibit seizures with different diurnal patterns. Our results suggest that epilepsy, itself, rather than seizure timing, has a significant influence on chronotype behavior and subjective sleep parameters. Gepubliceerd: Chronobiol Int. 2010;27(6):1271-86 Impact factor: 3.987
6. The nature and timing of specific copy number changes in the course of molecular progression in diffuse gliomas; further elucidation of their genetic 'life story' JW Jeuken1, A Sijben1,2,7, FE Bleeker3, SH Boots-Sprenger1, J Rijntjes1, JM Gijtenbeek4, W Mueller5, P Wesseling1,6 1 Department of Pathology, Nijmegen Center for Molecular Life Sciences UMC St Radboud, Nijmegen 2 Department of Neurology, Canisius Wilhelmina Hospital, Nijmegen 3 Neurosurgical Center Amsterdam, Location AMC, Amsterdam 4 Department of Neurology, UMC St Radboud, Nijmegen 5 Department of Neuropathology, German Cancer Research Center, Heidelberg, Germany 6 Department of Pathology, Canisius Wilhelmina Hospital, Nijmegen 7 Department of Neurology, Medisch Spectrum Twente, Enschede Up till now, typing and grading of diffuse gliomas is based on histopathological features. However, more objective tools are needed to improve reliable assessment of their biological behavior. We evaluated 331 diffuse gliomas for copy number changes involving 1p, 19q, CDKN2A, PTEN, and EGFR(vIII) by MLPA. Specifically based on the co-occurrence of these aberrations we build a model for the timing of the different events and their exact nature (hemi- → homozygous loss; low-level gain → (high-copy) amplification) in the course of molecular progression. The mutation status of IDH1 and TP53 was also evaluated and shown to correlate with the level of molecular progression. The relevance of the proposed model was confirmed by analysis of 36 sets of gliomas and their 39 recurrence(s) whereas survival analysis for anaplastic gliomas confirmed the actual prognostic relevance of detecting molecular malignancy. Moreover, based on our results, molecular diagnostic analysis of 1p/19q can be further improved as different aberrations were identified, some of them being indicative for advanced molecular malignancy rather than for favorable tumor behavior. In conclusion, identification of molecular malignancy as proposed will aid in establishing a risk-profile for individual patients and thereby in therapeutic decision making. Gepubliceerd: Brain Pathol. 2010;DOI: 10.1111/j.1750-3639.2010.00447.x Impact factor: 5.903
148
7. A patient with a transient photomyogenic response Bax-de Stegge BM,van Putten MJ Department of Neurology and Clinical Neurophysiology, Medisch Spectrum Twente, Enschede Gepubliceerd: Clin.Neurophysiol. 2010;121:118-20 Impact factor: 3.122
8. Uncommon EEG burst-suppression in severe postanoxic encephalopathy van Putten MJ, van Putten MH Department of neurology and neurophysiology, Medisch Spectrum Twente, Enschede Objective: In patients suffering from severe hypoxia, the EEG may show a burstsuppression pattern, characterized by low-voltage activity and the occurrence of high amplitude burst-like events. We describe the two-timescale burst phenomenology of this postanoxic condition. Methods: We present EEG recordings showing remarkable burst phenomenology in two postanoxic patients and consider potential mechanisms responsible for the generation of the burst-suppression patterns. We quantify the postanoxic condition in terms of the dimension (number of degrees of freedom) of its dynamics by comparing our data with a system of three ordinary differential equations with two timescales subject to varying degrees of noise. Results: EEGs displayed extreme similarity of the bursts, separated by interburst intervals up to more than 300s. This pattern reflects a significant reduction in the number of functional brain states. This post-anoxic condition is found to have dimension 3, consisting of fast dynamics responsible for the bifurcation to bursting behavior, and a long time-scale responsible for burst termination and the interburst intervals. Conclusions: Low-dimensional postanoxic brain states, as manifested by burstsimilarity, appears to indicate an irreversible loss of brain function and consciousness. Significance: Evidence of brain functionality in a persistent low dimensional state due to severe hypoxia is indicative of permanent loss of consciousness with essentially no chance for recovery. Quantitative evidence for such degenerate states is important for clinical decision making. Gepubliceerd: Clin Neurophysiol. 2010;121(8):1213-9 Impact factor: 3.122
9. Evaluation of the finger wrinkling test: a pilot study van Barneveld S1,3, van der Palen J2,5, van Putten MJ1,4 1 Department of Clinical Neurophysiology, Medisch Spectrum Twente, Enschede 2 Department of Epidemiology, Medisch Spectrum Twente, Enschede 3 Department of Medicine, University of Groningen, Groningen
149
4
MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 5 Department of Research Methodology, Measurement and Data Analysis, Faculty of Behavioral Sciences, University of Twente, Enschede Purpose: Tilt table testing mainly evaluates the systemic cardiovascular part of the autonomic nervous system, while it is assumed that the finger wrinkling test assesses the peripheral part of the autonomic nervous system. In this study we explored whether the finger wrinkling test could be a useful test for autonomic dysfunction and whether the clinical evaluation of wrinkling can be improved by digital analysis of photographs. Methods: As much as 20 healthy subjects and 15 patients underwent tilt table testing and finger wrinkling testing. During the finger wrinkling test the right hand was immersed in water at 40 degrees C. The degree of wrinkling was assessed with a 5-point clinical scale at baseline, 5, 15 and 30 min of immersion. Photographs were taken at the same intervals. Several features were evaluated using digital analysis: length and gradient of automatically detected wrinkle and mean, maximum, minimum, variance and derivative of grey value of pixels. Results: Clinical scoring of wrinkling allowed differentiation between healthy subjects and patients with a normal and an abnormal response to tilt table testing. Relevant features obtained with digital analysis were mean grey value and the gradient of automatically detected wrinkle. McNemar's test showed no difference in test results between the tilt table test and the finger wrinkling test with a kappa of 0.68. Conclusion: The finger wrinkling test can be used as a screening test before tilt table testing. Visual evaluation of wrinkling is still superior to digital analysis of photographs. Gepubliceerd: Clin Auton Res. 2010; 20(4):249-53 Impact factor: 1.278
10. Glycopyrrolate for sialorrhea in Parkinson disease: a randomized, double-blind, crossover trial Arbouw ME1, 3,4, Movig KL1, Koopmann M1, Poels PJ2, Guchelaar HJ5, Egberts TC3,4, Neef C6, van Vugt JP2 1 Department of Clinical Pharmacy and 2 Neurology, Medisch Spectrum Twente, Enschede 3 Department of Clinical Pharmacy, UMC Utrecht 4 Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University 5 Department of Clinical Pharmacy and Toxicology, Leiden UMC 6 Department of Clinical Pharmacy and Toxicology, Maastricht UMC Background: Sialorrhea affects approximately 75% of patients with Parkinson disease (PD). Sialorrhea is often treated with anticholinergics, but central side effects limit their usefulness. Glycopyrrolate (glycopyrronium bromide) is an anticholinergic drug with a quaternary ammonium structure not able to cross the blood-brain barrier in considerable amounts. Therefore, glycopyrrolate exhibits
150
minimal central side effects, which may be an advantage in patients with PD, of whom a significant portion already experience cognitive deficits. Objective: To determine the efficacy and safety of glycopyrrolate in the treatment of sialorrhea in patients with PD. Methods: We conducted a 4-week, randomized, double-blind, placebo-controlled, crossover trial with oral glycopyrrolate 1 mg 3 times daily in 23 patients with PD. The severity of the sialorrhea was scored on a daily basis by the patients or a caregiver with a sialorrhea scoring scale ranging from 1 (no sialorrhea) to 9 (profuse sialorrhea). Results: The mean (SD) sialorrhea score improved from 4.6 (1.7) with placebo to 3.8 (1.6) with glycopyrrolate (p = 0.011). Nine patients (39.1%) with glycopyrrolate had a clinically relevant improvement of at least 30% vs 1 patient (4.3%) with placebo (p = 0.021). There were no significant differences in adverse events between glycopyrrolate and placebo treatment. Conclusions: Oral glycopyrrolate 1 mg 3 times daily is an effective and safe therapy for sialorrhea in Parkinson disease. Classification of evidence: This study provides Class I evidence that glycopyrrolate 1 mg 3 times daily is more effective than placebo in reducing sialorrhea in patients with Parkinson disease during a 4-week study. Gepubliceerd: Neurology. 2010;74(15):1203-7 Impact factor: 8.172
11. Comparing Epileptiform Behavior of Mesoscale Detailed Models and Population Models of Neocortex S Visser1,2 , HG Meijer1,2 HC Lee3, W van Drongelen3, MJ van Putten2,4, SA van Gils1,2 From the 1Department of Applied Mathematics and 2MIRA-Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands; 3Department of Pediatrics, The University of Chicago, Chicago, Illinois, U.S.A.; 4 Department of Clinical Neurophysiology, Medical Spectrum Twente, Enschede Two models of the neocortex are developed to study normal and pathologic neuronal activity. One model contains a detailed description of a neocortical microcolumn represented by 656 neurons, including superficial and deep pyramidal cells, four types of inhibitory neurons, and realistic synaptic contacts. Simulations show that neurons of a given type exhibit similar, synchronized behavior in this detailed model. This observation is captured by a population model that describes the activity of large neuronal populations with two differential equations with two delays. Both models appear to have similar sensitivity to variations of total network excitation. Analysis of the population model reveals the presence of multistability, which was also observed in various simulations of the detailed model. Gepubliceerd: J Clin Neurophysiol. 2010;27:471-8 Impact factor: 1.472
151
12. Wnt2 regulates progenitor proliferation in the developing ventral midbrain KM Sousa1,5, JC Villaescusa1, L Cajanek1, JK Ondr2, G Castelo-Branco1,2, W Hofstra1,7, Vitezslav Bryja1,3, C Palmberg4, T Bergman4, B Wainwright6, RA Lang2, E Arenas1,3 1 Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden 2 Developmental Biology Division and Department of Ophthalmology, Children's Hospital Research Foundation, Cincinnati, Ohio, USA 3 Institute of Experimental Biology, Faculty of Science, Masaryk University & Institute of Biophysics AS CR, Brno, Czech Republic 4 Department of Medical Biochemistry and Biophysics, Division of Chemistry I, Karolinska Institute, Stockholm, Sweden, 5 Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA 6 Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Australia 7 Department of Neurology, Medisch Spectrum Twente, Enschede Wnts are secreted, lipidated proteins that regulate multiple aspects of brain development, including dopaminergic neuron development. In this study, we perform the first purification and signaling analysis of Wnt2 and define the function of Wnt2 in ventral midbrain precursor cultures, as well as in Wnt2-null mice in vivo. We found that purified Wnt2 induces the phosphorylation of both Lrp5/6 and Dvl-2/3, and activates beta-catenin in SN4741 dopaminergic cells. Moreover, purified Wnt2 increases progenitor proliferation, and the number of dopaminergic neurons in ventral midbrain precursor cultures. In agreement with these findings, analysis of the ventral midbrain of developing Wnt2-null mice revealed a decrease in progenitor proliferation and neurogenesis that lead to a decrease in the number of postmitotic precursors and dopaminergic neurons. Collectively, our observations identify Wnt2 as a novel regulator of dopaminergic progenitors and dopaminergic neuron development. Gepubliceerd: J Biol Chem 2010 Mar 5;285(10):7246-53 Impact factor: 5.328
13. Observing Huntington’s Disease: the European Huntington’s Disease Network’s REGISTRY M Orth,* OJ Handley,† C Schwenke,‡ SB Dunnett,§ D Craufurd,¶ AK Ho,# E Wild,** SJ Tabrizi,† GB Landwehrmeyer,* and the investigators of the European Huntington's Disease Network ††Includes van Vugt JP * Department of Neurology, University of Ulm, Ulm Germany; †Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; ‡Scossis, Statistics and Consulting, Berlin, Germany; §The Brain Repair Group, Cardiff University, Cardiff, Wales, UK; ¶University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK; #University of Reading, School of Psychology,
152
**
UCL Institute of Neurology, London, UK; Bristol University, UK †† Department of Neurology, Medisch Spectrum Twente, Enschede
Background: Huntington’s disease (HD) is a rare triplet repeat (CAG) disorder. Advanced, multi-centre, multi-national research frameworks are needed to study simultaneously multiple complementary aspects of HD. This includes the natural history of HD, its management and the collection of clinical information and biosamples for research. Methods: We report on cross-sectional data of the first 1766 participants in REGISTRY, the European Huntington’s Disease Network’s (EHDN), multi-lingual, multi-national prospective observational study of HD in Europe. Data collection (demographics, phenotype, genotype, medication, co-morbidities, biosamples) followed a standard protocol. Results: Phenotype, and the HD genotype, of manifest HD participants across different European regions was similar. Motor onset was most common (48%) with a non-motor onset in more than a third of participants. Motor signs increased, and cognitive abilities and functional capacity declined as the disease burden (CAGn35.5) X age) increased. A life-time history of behavioural symptoms was common, but the behavioural score was not related to disease burden. One fifth of participants had severe psychiatric problems, e.g. suicidal ideation and attempts, and/or irritability/aggression, with psychosis being less common. Participants on antidyskinetic medication had a higher motor and lower cognitive score, were older, and more prone to physical trauma. A higher motor and a lower cognitive score predicted more advanced disease. Conclusions: The unparalleled collection of clinical data and biomaterials within the EHDN’s REGISTRY can expedite the search for disease modifiers (genetic and environmental) of age at onset and disease progression that could be harnessed for the development of novel treatments. Gepubliceerd: Version 2. PLoS Curr. 2010 September 30;2: RRN1184 Impact factor: 0
14. Ambulatory Monitoring of Activities and Motor Symptoms in Parkinson¿s Disease Zwartjes D1, Heida T1, van Vugt J2, Geelen J1, Veltink P1 1 Dept. of Electr. Eng., Math. & Comput. Sci., Univ. of Twente, Enschede 2 Department of Neurology, Medisch Spectrum Twente, Enschede Ambulatory monitoring of motor symptoms in Parkinsons disease (PD) can improve our therapeutic strategies, especially in patients with motor fluctuations. Previously published monitors usually assess only one or a few basic aspects of the cardinal motor symptoms in a laboratory setting. We developed a novel ambulatory monitoring system that provides a complete motor assessment by simultaneously analyzing current motor activity of the patient (e.g. sitting, walking) and the severity of many aspects related to tremor, bradykinesia, and hypokinesia. The monitor consists of a set of four inertial sensors. Validity of our monitor was established in seven healthy controls and six PD patients treated with deep brain stimulation (DBS)
153
of the subthalamic nucleus. Patients were tested at three different levels of DBS treatment. Subjects were monitored while performing different tasks, including motor tests of the Unified Parkinsons Disease Rating Scale (UPDRS). Output of the monitor was compared to simultaneously recorded videos. The monitor proved very accurate in discriminating between several motor activities. Monitor output correlated well with blinded UPDRS ratings during different DBS levels. The combined analysis of motor activity and symptom severity by our PD monitor brings true ambulatory monitoring of a wide variety of motor symptoms one step closer.. Gepubliceerd: IEEE Trans Biomed Eng. 2010;57(11):2778-86 Impact factor: 2.154
15. Microvascular determinants of cognitive decline and brain volume change in elderly patients with type 2 diabetes de Bresser Ja,b, Reijmer YDa, van den Berg Ea,d, Breedijk MAc, Kappelle LJa, Viergever MAb, Biessels GJa; Utrecht Diabetic Encephalopathy Study Group* Includes Manschot SM a Department of Neurology, Rudolf Magnus Institute of Neuroscience, UMC Utrecht, Utrecht b Image Sciences Institute, UMC Utrecht, Utrecht c Department of Ophthalmology, UMC Utrecht, Utrecht d Experimental Psychology, Helmholtz Institute, Utrecht University, Utrecht * Department of Neurology, Medisch Spectrum Twente, Enschede Background/aims: The present study examined the relationship between microvascular complications and cognitive decline and the development of structural brain abnormalities over a period of 4 years in patients with type 2 diabetes mellitus (T2DM). Methods: Sixty-eight elderly patients with T2DM had 2 cognitive assessments with a 4-year interval. Two MRI scans, performed at the same time as the cognitive assessments, were available from 55 patients. Changes in cognitive performance over time were expressed as a regression-based index (RBI). Automated volumetric measurements of total brain, lateral ventricles and white matter hyperintensities were performed. The relationship between baseline microvascular complications [diabetic retinopathy, peripheral neuropathy or albuminuria (micro- or macroalbuminuria)] and cognition and brain volumes was examined with linear regression analyses adjusted for age and sex (for cognition also for IQ). Results: At baseline, diabetic retinopathy was present in 18% of patients, peripheral neuropathy in 36%, albuminuria in 15%. Retinopathy or neuropathy were not significantly associated with baseline cognition or brain volumes, or changes in these measures over time. Albuminuria was associated with a lower composite RBI score, indicating accelerated cognitive decline (adjusted mean difference between patients with or without albuminuria: -0.58, 95% CI -0.85 to -0.31, p < 0.001). Conclusion: Albuminuria predicted accelerated cognitive decline in patients with T2DM, but other microvascular complications were unrelated to accelerated cognitive decline or brain MRI abnormalities.
154
Gepubliceerd: Dement Geriatr Cogn Disord. 2010;30(5):381-6 Impact factor: 2.578
16. Cerebral cortical thickness in patients with type 2 diabetes Brundel M a, van den Heuvel M a, de Bresser J a,b, Kappelle LJ a, Biessels GJ a; Utrecht Diabetic Encephalopathy Study Group* Includes Manschot SM c a Department of Neurology, Rudolf Magnus Institute of Neuroscience, UMC Utrecht, Utrecht b Image Sciences Institute, UMC Utrecht, Utrecht * Department of Neurology, Medisch Spectrum Twente, Enschede Objective: Type 2 diabetes mellitus (T2DM) is associated with cortical atrophy on MRI. It is unclear whether this atrophy is global or if there are areas with particular vulnerability. We compared regional cortical atrophy between patients with T2DM and controls and examined determinants of atrophy within the T2DM group. Methods: Cortical surface, volume and thickness were compared between 56 patients with T2DM and 30 controls, both globally and regionally, using the Freesurfer software package. The relationship between atrophy and HbA1c levels, diabetes duration, hypertension, a history of macrovascular disease and cerebral small vessel disease was analyzed within the T2DM group, with linear regression analyses, adjusted for age and gender. Results: Total cortical surface, total cortical volume and mean cortical thickness for both hemispheres were consistently lower in the T2DM group (between group differences: 0.5–4%), but the effects were only significant in the right hemisphere (p<0.05). Post-hoc regional analyses revealed significant differences in the hippocampal region (between group differences cortical thickness and volume: 5– 20.5%) and the middle temporal gyrus (between group differences cortical surface and volume ~8%). Within the T2DM group, smaller cortical thickness of the hippocampal region was associated with cerebral small vessel disease, but no associations between vascular or metabolic determinants and cortical atrophy were found. Conclusion: The effects of T2DM on cortical grey matter are most pronounced in the temporal lobe. This should be considered when atrophy is used as a marker in etiological or therapeutical studies. Gepubliceerd: J Neurol Sci. 2010;299(1-2):126-30 Impact factor: 2.324
17. Progression of cerebral atrophy and white matter hyperintensities in patients with type 2 diabetes J de Bresser,1,2 AM Tiehuis,3 E van den Berg,1 YD Reijmer,1 C Jongen,1,2 LJ Kappelle,1 WP Mali,3 MA Viergever,2 GJ Biessels,1; Utrecht Diabetic Encephalopathy Study Group* Includes Manschot SM 1 Department of Neurology, Rudolf Magnus Institute of Neuroscience, UMC Utrecht, Utrecht 2 Image Sciences Institute, UMC Utrecht, Utrecht
155
3
Department of Radiology, UMC Utrecht, Utrecht * Department of Neurology, Medisch Spectrum Twente, Enschede
Objective: Type 2 diabetes is associated with a moderate degree of cerebral atrophy and a higher white matter hyperintensity (WMH) volume. How these brainimaging abnormalities evolve over time is unknown. The present study aims to quantify cerebral atrophy and WMH progression over 4 years in type 2 diabetes. Research design and methods: A total of 55 patients with type 2 diabetes and 28 age-, sex-, and IQ-matched control participants had two 1.5T magnetic resonance imaging scans with a 4-year interval. Volumetric measurements of total brain, peripheral cerebrospinal fluid (CSF), lateral ventricles, and WMH were performed with k-nearest neighbor–based probabilistic segmentation. All volumes were expressed as percentage of intracranial volume. Linear regression analyses, adjusted for age and sex, were performed to compare brain volumes between the groups and to identify determinants of volumetric change within the type 2 diabetic group. Results: At baseline, patients with type 2 diabetes had a significantly smaller total brain volume and larger peripheral CSF volume than control participants. In both groups, all volumes showed a significant change over time. Patients with type 2 diabetes had a greater increase in lateral ventricular volume than control participants (mean adjusted between-group difference in change over time [95% CI]: 0.11% in 4 years [0.00 to 0.22], P = 0.047). Conclusions: The greater increase in lateral ventricular volume over time in patients with type 2 diabetes compared with control participants shows that type 2 diabetes is associated with a slow increase of cerebral atrophy over the course of years. Gepubliceerd: Diabetes Care. 2010 Jun;33(6):1309-14 Impact factor: 6.718
18. A 4 year follow-up study of cognitive functioning in patients with type 2 diabetes mellitus van den Berg E1, Reijmer YD1, de Bresser J1,2, Kessels RP3,4,5, Kappelle LJ1, Biessels GJ1; Utrecht Diabetic Encephalopathy Study Group* Includes Manschot SM 1 Department of Neurology, Rudolf Magnus Institute of Neuroscience, UMC Utrecht, Utrecht 2 Image Sciences Institute, UMC Utrecht, Utrecht 3 Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen 4 Departments of Medical Psychology and Geriatrics, Radboud University Nijmegen MC, Nijmegen 5 Department of Experimental Psychology, Helmholtz Instituut, Utrecht University, Utrecht * Department of Neurology, Medisch Spectrum Twente, Enschede
156
Aims/hypothesis: Type 2 diabetes mellitus is associated with moderate decrements in cognitive functioning, mainly in verbal memory, informationprocessing speed and executive functions. How this cognitive profile evolves over time is uncertain. The present study aims to provide detailed information on the evolution of cognitive decrements in type 2 diabetes over time. Methods: Sixty-eight patients with type 2 diabetes and 38 controls matched for age, sex and estimated IQ performed an elaborate neuropsychological examination in 2002-2004 and again in 2006-2008, including 11 tasks covering five cognitive domains. Vascular and metabolic determinants were recorded. Data were analysed with repeated measures analysis of variance, including main effects for group, time and the group x time interaction. Results: Patients with type 2 diabetes showed moderate decrements in informationprocessing speed (mean difference in z scores [95% CI] -0.37 [-0.69, -0.05]) and attention and executive functions (-0.25 [-0.49, -0.01]) compared with controls at both the baseline and the 4 year follow-up examination. After 4 years both groups showed a decline in abstract reasoning (-0.16 [-0.30, -0.02]) and attention and executive functioning (-0.29 [-0.40, -0.17]), but there was no evidence for accelerated cognitive decline in the patients with type 2 diabetes as compared with controls (all p > 0.05). Conclusions/interpretation: In non-demented patients with type 2 diabetes, cognitive decrements are moderate in size and cognitive decline over 4 years is largely within the range of what can be viewed in normal ageing. Apparently, diabetes-related cognitive changes develop slowly over a prolonged period of time. Gepubliceerd: Diabetologia 2010 Jan;53(1):58-65 Impact factor: 6.551
19. Autoantibodies against oxidized low-density lipoprotein in cerebral small vessel disease Rouhl RP1,2, van Oostenbrugge RJ1,4, Theunissen RO2, Knottnerus IL1,3, Staals J1, Henskens LH5, Kroon AA4,5, de Leeuw PW4, Lodder J1,4, Tervaert JW2,4, Damoiseaux JG2,5 1 Department of Neurology, Maastricht UMC, Maastricht 2 Department of Internal Medicine, Division of Clinical and Experimental Immunology, Maastricht UMC, Maastricht 3 Department of Neurology, Medisch spectrum Twente, Enschede 4 Cardiovascular Research Institute Maastricht (CARIM), Maastricht UMC, Maastricht 5 Department of Internal Medicine, Division of General Internal Medicine, Maastricht UMC, Maastricht Background and purpose: Oxidized low-density lipoprotein (oxLDL) induces endothelial dysfunction and antibody formation. Because endothelial dysfunction is involved in cerebral small vessel disease (CSVD) (dilated Virchow Robin spaces, lacunar infarcts, and white matter lesions), oxLDL antibodies could play a role in CSVD pathogenesis. Therefore, we studied oxLDL antibodies in patients with high prevalence of CSVD: lacunar stroke patients and essential hypertensive patients.
157
Methods: A total of 158 lacunar stroke patients, 158 hypertensive patients, and 43 healthy controls were included. We determined levels of IgG and IgM against hypochlorite (HOCl) and malondialdehyde (MDA) oxLDL using ELISA (values in optical density). Results: Patients with CSVD had higher levels of IgG-HOCl-oxLDL (0.77 versus 0.70; P<0.01), as well as lower levels of IgM-MDA-oxLDL (0.55 versus 0.65; P<0.05) than patients without such lesions. Higher IgG-HOCl-oxLDL levels were only independently associated with higher numbers of Virchow Robin spaces at the level of the basal ganglia (β=0.218; P<0.001). Conclusions: An autoinflammatory process with lower levels of IgM antibodies and higher levels of IgG antibodies against oxLDL may be involved in CSVD. Gepubliceerd: Stroke. 2010;41:2687-2689 Impact factor: 7.041
20. Endothelial activation in lacunar stroke subtypes Knottnerus IL1,2,3, Govers-Riemslag JW4, Hamulyak K5, Rouhl RP1, Staals J1, Spronk HM4, van Oerle R1,4,van Raak EP1, Lodder J1,3, Ten Cate H3,4, van Oostenbrugge RJ1,3 1 Department of Neurology, Maastricht UMC, Maastricht 2 Department of Neurology, Medisch spectrum Twente, Enschede 3 Cardiovascular Research Institute Maastricht, Maastricht UMC, Maastricht 4 Laboratory for Clinical Thrombosis and Haemostasis, Maastricht UMC, Maastricht 5 Division of Haematology, Department of Internal Medicine (K.H.), Maastricht UMC, Maastricht Background and purpose: Lacunar stroke (LS) can be subtyped according to the absence (isolated lacunar infarct [ILA]) or presence of concomitant white matter lesions (WML) and/or asymptomatic lacunar infarcts. Endothelial activation is thought to play a pivotal role in the subtype with WML and/or asymptomatic lacunar infarcts. The aim of this study was to evaluate whether endothelial activation is associated with WML and/or asymptomatic lacunar infarcts in LS patients. Here, we determined levels of circulating blood markers of endothelial function in LS patients. Methods: In 149 patients, all of whom had brain-MRI, levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), tPA-PAI-1 complex, von Willebrand factor, tissue factor, thrombomodulin, and coagulation factor VIII were determined. Levels of blood markers were related to subtypes of LS and adjusted for age, gender, and vascular risk factors. Results: In subtypes of LS, tPA activity was increased in patients with WML (0.79 IU/mL vs 0.44 IU/mL for ILA; P=0.02) and PAI-1-antigen levels were lowest in patients with WML (27.5 ng/mL vs 44.0 ng/mL for ILA; P=0.02). The association between WML and PAI-1 remained significant after multivariable analysis (OR, 0.99; 95% CI, 0.98-1.00 per ng/mL change of PAI-1; P=0.04). Conclusions: We found further evidence for the hypothesis of endothelial activation in the subtype of LS caused by a diffuse small vessel vasculopathy, as we found higher levels of tPA in patients with concomitant extensive WML than in those with ILA. Second, low levels of PAI-1 were associated with WML. We postulate that
158
differences in activity of components of the fibrinolytic system might contribute to WML development. Gepubliceerd: Stroke.2010;41:1617-1622 Impact factor: 7.041
21. The likelihood of decreasing strokes in atrial fibrillation patients by strict application of guidelines Pisters R1,2, van Oostenbrugge RJ2,3, Knottnerus IL3,6, de Vos CB1,2, Boreas A2,3, Lodder J2,3, Prins MH4, Crijns HJ1,2, Tieleman RG5 1 Department of Cardiology, Maastricht UMC, PO Box 5800, 6202 AZ MaastrichtUMC 2 Cardiovascular Research Institute Maastricht, Maastricht 3 Department of Neurology, Maastricht UMC, Maastricht 4 Department of Clinical Epidemiology, Maastricht UMC, Maastricht 5 Department of Cardiology, Martini Hospital Groningen, Groningen 6 Department of Neurology, Medisch spectrum Twente, Enschede Aims: Despite the known increased stroke risk associated with AF and the benefit of oral anticoagulation (OAC) in high-risk patients, still approximately 20% of all ischaemic strokes are atrial fibrillation (AF) related. We aimed to evaluate the frequency of inappropriate anticoagulation in all patients admitted with AF associated ischaemic stroke and calculate the theoretical number of preventable strokes in case of proper guideline adherence and assess secondary stroke prevention at discharge. Methods and results: In this cross-sectional study, all patients with ischaemic strokes admitted to our hospital during May 2003-August 2006 in whom the diagnosis AF was either known or established during hospital stay were identified. We studied if their admission and discharge antithrombotic therapy was in accordance with the published guidelines. Subsequently, we calculated the number of preventable strokes in case AF patients would have received adequate antithrombotic treatment on admission. On admission, in 51% of the OAC eligible known AF patients the drug was withheld. Improved antithrombotic guideline adherence potentially would have prevented 20 out of the 89 (22%) ischaemic strokes. At discharge at least 10% of the patients were still insufficiently protected against recurrent stroke. Conclusion: Many known AF patients admitted with ischaemic stroke lack adequate antithrombotic treatment on admission. Antithrombotic guideline adherence in these patients has the potential to prevent a substantial number strokes. Secondary stroke prevention at discharge is also suboptimal. Gepubliceerd: Europace.2010;12:779-784 Impact factor: 1.871
159
22. Disappearing hyperdense middle cerebral artery sign is associated with striatocapsular infarcts on follow-up ct in ischemic stroke patients treated with intravenous thrombolysis van Overbeek EC1, Knottnerus IL1,2,3, van Oostenbrugge RJ1,2 1 Department of Neurology, Maastricht UMC, Maastricht 2 Cardiovascular Research Institute Maastricht, Maastricht UMC, Maastricht 3 Department of Neurology, Medisch spectrum Twente, Enschede Background: A striatocapsular infarct (SCI) is a subcortical infarct in the territory of the lenticulostriate arteries, most likely due to transient occlusion of the main stem of the middle cerebral artery (MCA). Presence of the hyperdense middle cerebral artery sign (HMCAS) is a reliable marker of occlusion of the MCA. We hypothesized that SCIs are related to HMCAS at baseline, which subsequently disappears (HMCAS-D) on follow-up CT in stroke patients treated with intravenous rtPA. Methods: Baseline and 24-hour follow-up CTs were evaluated for HMCAS in acute ischemic stroke patients treated with intravenous rtPA and follow-up scans were also reviewed for the presence of isolated cortical (CIn), SCI, cortical and striatocapsular (CI-SCI) or lacunar infarct. We determined the incidence of SCI and the association between SCI and HMCAS on baseline and follow-up CT. Results: Of the 247 patients, 43 had an SCI (17.4%; 95% CI: 13.1-22.5). The presence of HMCAS at baseline was related to the occurrence of infarction with involvement of the striatocapsular region (SCI or CI-SCI) on follow-up CT (OR: 11.6; 95% CI: 5.9-22.8). HMCAS-D on follow-up scans was significantly related to SCI on follow-up CT compared to CI-SCI (OR: 4.9; 95% CI: 3.7-6.1). Conclusions: Occurrence of SCI and CI-SCI is associated with the presence of HMCAS on CT before thrombolysis, whereas HMCAS-D on follow-up CT is strongly related to the occurrence of SCI. Our findings support the causative role of transient occlusion of the MCA main stem in the pathogenesis of SCI. Gepubliceerd: Cerebrovasc Dis.2010;30:285-289 Impact factor: 3.535
23. Metabolic syndrome relates to lacunar stroke without white matter lesions: A study in first-ever lacunar stroke patients Zhang CE1, van Raak EP1, Rouhl RP1, Lodder J1,2, Staals J1, Knottnerus IL1,3, van Oostenbrugge RJ1,2 1 Department of Neurology, Maastricht UMC, and 2 Cardiovascular Research Institute Maastricht (CARIM), University Maastricht, Maastricht 3 Department of Neurology, Medisch spectrum Twente, Enschede Background: Metabolic syndrome (MetS) is a cluster of three or more of the following risk factors: obesity, elevated blood pressure, elevated triglyceride level, elevated glucose level, and low high-density lipoprotein level. Lacunar infarcts (LS) account for 25% of all ischemic strokes and are small, deeply located brain infarcts. Two different subtypes exist, which are distinguished by the presence of concomitant white matter lesions (WML) on brain imaging. We determined the
160
prevalence of MetS in LS and the association between MetS with LS subtypes in a series of first-ever LS patients. Methods: We included 92 patients with a first-ever LS, and 92 patients with a firstever atheroslerotic cortical stroke (CS) matched for age and sex. LS subtypes were defined according to presence of concomitant WML. We defined MetS retrospectively according to previously defined standards. Results: 35.9% of LS patients and 45.7% of CS patients had MetS (OR 0.67; 95% CI 0.37-1.20). MetS was more prevalent in LS without WML than in LS with WML (44.4 and 23.7%, respectively; OR 2.98; 95% CI 1.04-8.47). Similarly, MetS related more to CS compared to LS with WML (OR 2.56; 95% CI 1.03-6.37). Conclusion: MetS relates more strongly to LS without WML and to CS, than to LS with WML. Our results suggest a different underlying mechanism between LS without WML and CS, and lacunar stroke with WML. Gepubliceerd: Cerebrovasc Dis.2010;29:503-507 Impact factor: 3.535
Totale impact factor: 99.835 Gemiddelde impact factor: 4.341 Aantal artikelen 1e, 2e of laatste auteur: 10 Totale impact factor: 43.231 Gemiddelde impact factor: 4.323
161
Nucleaire Geneeskunde 1. Optimizing administered FDG dose for PET imaging Van Dalen JA1,2, Mulder H3, Kamp P2, De Bruin W1, Zuijdwijk MD4, Subramaniam V3 1 Medisch Spectrum Twente, department of NuclearMedicine, Enschede 2 Ziekenhuisgroep Twente, department of Medical Physics, Hengelo 3 University of Twente, Biophysical Engineering, Enschede 4 Ziekenhuisgroep Twente, department of Nuclear Medicine, Hengelo Image quality of FDG-PET usually decreases for obese patients who are dosed using a linear relation between administered dose and patient’s body mass. The aim was to optimize the administered FDG dose providing whole-body FDG-PET images of a more consistent quality, less depending on the patient’s physical characteristics. Whole-body FDG-PET images using a hybrid PET-CT were studied for 51 patients. The Signalto- Noise Ratio (SNR) in the liver was used as a measure for image quality. The dependence of SNR on patient’s body mass was investigated when using a marker dose of 2.3 MBq/kg. A phantom study was performed to obtain a relation between administered dose (Aa) and SNR. Subsequently, different parameters (body mass, BMI, mass per length, lean body mass, fat mass, transverse body cross-section) were investigated and correlated with the image quality, to find the most optimal parameter for calculating the dose to be administered. Using 2.3 MBq/kg, a strong image degradation was found for obese patients (p<0.001). The phantom study showed that SNR was proportional to Aa ½. The patient study resulted in a new dose calculation, described by Anew= η·pδ, where p is the body mass or body mass per body length. In case of body mass, η=1.46·10-3 and δ=2.66. Other parameters such as BMI were suboptimal to use (in general: p<0.02). Using a linear relation between administered FDG dose and patient’s body mass is suboptimal for PET imaging. It is recommended to use a power-law based calculation of dose administration, based on either body mass, or body mass per body length. Gepubliceerd: Tijdschr Nucl Geneesk 2010; 32(1):339-343 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
162
Orthopedie 1. Heterotopic bone formation by nano-apatite containing poly(D,L-lactide) composites D Barbieri1, AJS Renard2, JD de Bruijn1,3, H Yuan1,4 1 Xpand Biotechnology BV, 3723 MB Bilthoven 2 Department of Orthopaedics, Medisch Spectrum Twente, Enschede 3 Department of Materials, Queen Mary University of London, London, UK 4 Tissue Regeneration, University of Twente, 7522 NB Enschede To render polymeric materials osteoinductive, nano-sized calcium phosphate apatite particles (CaP) were introduced into a low molecular weight poly(D,L-lactide). Homogenous composites were made with 10%, 20% and 40% by weight of apatite content while pure polylactide was used as control. Thereafter porous samples (pore size 300-400 mum, 60% porosity) were fabricated and sterilized. In vitro studies showed that calcium ions were released from the composites depending on the apatite content, while surface mineral deposition was observed only on the 40% CaP composites in simulated body fluid (SBF) within 14 days. After 12 weeks of intramuscular implantation in dogs, only the 40% CaP composite implant retained its shape and showed ectopic bone formation within the pores. In conclusion, adding a content of 40% apatite into poly(D,L-lactide) could lead to an osteoinductive material. Future studies will focus on understanding this phenomenon of materialdirected osteoinduction in order to develop a promising bone graft substitute. Gepubliceerd: Eur Cell Mater. 2010;19:252-61 Impact factor: 5.378
2. A link between the accumulation of DNA damage and loss of multipotency of human mesenchymal stromal cells Alves H, Munoz-Najar U, de Wit J, Renard AJ*, Hoeijmakers JH, Sedivy JM, van Blitterswijk C, de Boer J Department of Tissue Regeneration, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede * Department of Orthopedic Surgery, Medisch Spectrum Twente, Enschede Human mesenchymal stromal cells (hMSCs) represent and attractive cell source for clinic applications. Besides being mutipotent, recent clinical trials suggest that they secrete both trophic and immunomodulatory factors, allowing allogenic MSCs to be used in a wider variety of clinical situations. The yield of prospective isolation is however very low, making expansion a required step towards clinical applications. Unfortunately, this leads to a significant decrease in their stemness. To identify the mechanism behind loss of multipotency, hMSCs were expanded until replicative senescence and the concomitant molecular changes were characterized at regular intervals. We observed that, with time of culture, loss of multipotency was associated with both the accumulation of DNA damage and the respective activation of the DNA damage response pathway, suggesting a correlation between both
163
phenomena. Indeed, exposing hMSCs to DNA damage agents led to a significant decrease in the differentiation potential. We also showed that hMSCs are susceptible to accumulate DNA damage upon in vitro expansion, and that although hMSCs maintained an effective nucleotide excision repair activity, there was a progressive accumulation of DNA damage. We propose a model in which DNA damage accumulation contributes to the loss of differentiation potential of hMSCs, which might not only compromise their potential for clinical applications but also contribute to the characteristics of tissue ageing. Gepubliceerd: J Cell Mol Med. 2010:14(12):2729-38 Impact factor: 5.228
Totale impact factor: 10.606 Gemiddelde impact factor: 5.303 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 5.378 Gemiddelde impact factor: 5.378
164
Pathologie 1. The clinical value of lymphatic micrometastases in patients with non-small cell lung cancer Verhagen AF1, Bulten J2, Shirango H2,3, Thunnissen FB4, van der Drift MA5, van der Bruggen W6, Tjan-Heijnen VC7, van Swieten HA1 1 Departments of Cardiothoracic Surgery and 2Pathology, Radboud University Nijmegen Medical Centre, Nijmegen; 3 Department of Pathology, Medisch Spectrum Twente, Enschede; 4 Department of Pathology, Free University Hospital, Amsterdam; 5Departments of Pulmonology and 6 Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen; and 7Division of Medical Oncology, Department of Internal Medicine, Maastricht UMC, Maastricht Introduction: In early stage non-small cell lung cancer (NSCLC), presence of lymphatic micrometastases and isolated tumor cells, primarily detected by immunohistochemistry, is suggested to be a prognostic factor. However, there is no consensus whether immunohistochemistry should be used routinely in lymph node assessment.The goal of our study was to determine whether recurrent disease is associated with the presence of lymphatic micrometastases and/or isolated tumor cells, at the time of the lung resection. Methods: We retrospectively analyzed the prevalence of lymphatic micrometastases and/or isolated tumor cells in two groups of patients, who underwent a curative resection for early stage NSCLC. Group I had a follow-up of 5 years without recurrent disease. Group II consisted of a matched group of patients with recurrent disease. Patients were originally classified as having negative mediastinal lymph nodes.All lymph nodes obtained by mediastinoscopy and thoracotomy were re-examined by serial sectioning and immunohistochemistry. Results: Micrometastases and/or isolated tumor cells were found in one of 16 patients in group I, which was significantly different from six of 16 patients in group II. (Fisher exact test, 4.6; p, 0.04; risk ratio, 2.4).Serial sectioning and immunohistochemistry did not change N-stage for the single patient in group I, in contrast to all six patients in group II. Conclusion: Presence of lymphatic micrometastases and/or isolated tumor cells is associated with distant recurrence in patients with early stage NSCLC. We recommend the routine use of serial sectioning and immunohistochemistry in lymph node assessment to improve the accuracy of staging. Gepubliceerd: J Thorac Oncol. 2010;5(8):1201-5 Impact factor: 4.547
2. Protein profiling in pathology: Analysis and evaluation of 239 frozen tissue biopsies for diagnosis of B-cell lymphomas C Jansen1, T Feuth2, JM Raemaekers3, J Rijntjes1, JW Meijer4, PJ Westenend5, J van Baarlen6, JH van Krieken1, KM Hebeda1, PJ Groenen1 1 Department of Pathology, Radboud University Nijmegen Medical Centre
165
2
Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen 3 Department of Hematology, Radboud University Nijmegen Medical Centre 4 Department of Pathology, Rijnstate Hospital Arnhem 5 Department of Pathology, Laboratory for Pathology Dordrecht 6 Laboratories of Pathology Eastern-Netherlands, Enschede Purpose: We determined the potential value of protein profiling of tissue samples by assessing how precise this approach enables discrimination of B-cell lymphoma from reactive lymph nodes, and how well the profiles can be used for lymphoma classification. Experimental design: Protein lysates from lymph nodes (n=239) from patients with the diagnosis of reactive hyperplasia (n=44), follicular lymphoma (n=63), diffuse large B-cell lymphoma (n=43), mantle cell lymphoma (n=47), and chronic lymphocytic leukemia/small lymphocytic B-cell lymphoma (n=42) were analysed by SELDI-TOF MS. Data analysis was performed by (i) classification and regression tree-based analysis and (ii) binary and polytomous logistic regression analysis. Results: After internal validation by the leave-one-out principle, both the classification and regression tree and logistic regression classification correctly identified the majority of the malignant (87 and 96%, respectively) and benign cases (73 and 75%, respectively). Classification was less successful since approximately one-third of the cases of each group were misclassified according to the histological classification. However, an additional mantle cell lymphoma case that was misclassified as chronic lymphocytic leukemia/small lymphocytic B-cell lymphoma initially was identified based on the protein profile. Conclusions and clinical relevance: SELDI-TOF MS protein profiling allows for reliable identification of the majority of malignant lymphoma cases; however, further validation and testing robustness in a diagnostic setting is needed. Gepubliceerd: Proteomics Clin Appl. 2010 May;4(5):519-527 Impact factor: 1.875
3. Duodenal Lipoma as a Rare Cause of Upper Gastrointestinal Bleeding HM Ouwerkerka, MH Rabera, G Frelingb, JM Klaasea a Department of Surgery, Medisch Spectrum Twente, Enschede b Department of Pathology, Medisch Spectrum Twente, Enschede A 52-year-old female was referred because of melaena. After initial work-up, including gastroduodenoscopy, endosonography and CT scan, a duodenotomy was performed. Definite diagnosis was a duodenal lipoma based on histological findings. Lipomas of the gastrointestinal tract are rare. Only 4% occur in the duodenum. The peak incidence is around the 5th and 7th decade of life, with a slight female preponderance. Gastrointestinal lipomas are usually asymptomatic, but can present with mild to severe gastrointestinal bleeding, intussusceptions, abdominal pain, constipation and diarrhea. Clinical, endoscopical, surgical, and radiological features are described in this case of duodenal lipoma.
166
Gepubliceerd: Gastroenterology Research 2010;3(6):290-292 Impact factor: 0
4. Gastric Schwannoma Presenting as an Incidentaloma on CT-Scan and MRI MH Rabera, CM Ziedses des Plantesb, R Vinkc, JM Klaasea a Department of Surgery, Medisch Spectrum Twente, Enschede b Department of Radiology, Medisch Spectrum Twente, Enschede c Laboratorium Pathologie Oost Nederland, Enschede A 67 year old female was referred because of an incidentaloma on CT-scan and MRI which showed a 5.0 cm large mass in the wall of the distal stomach. After an initial work-up which suggested a gastrointestinal stromal tumor (GIST), a partial gastrectomy with a Billroth II gastrojejunostomy was performed. The histological diagnosis was a schwannoma. Gastric schwannomas are rare tumors which comprise 0.2% of all gastric tumors and 4% of all benign gastric neoplasms with a peak of incidence in the 4th and 5th decade of life. Gastric schwannomas are usually asymptomatic, but can present with ulceration and/or gastrointestinal bleeding. Clinical, endoscopical, surgical, radiological and histological features of this case are described and the relevant literature is reviewed. Gepubliceerd: Gastroenterology Research 2010;3(6):276-280 Impact factor: 0
5. Aspiration pneumonitis after fire-eating: fire-eater's lung Harding FM1, Hiddinga BI1, Eijsvogel MM1, van Baarlen J2, Oosterhof-Berktas R3 1 department of Pulmonary Medicine, Medisch spectrum Twente, Enschede 2 Laboratorium voor Pathologie Oost-Nederland, Enschede 3 Department of Radiology, Medisch spectrum Twente, Enschede On the emergency department we saw two men aged 19 and 26 with symptoms of lipoid pneumonitis (fire-eater's lung) following aspiration of petroleum during fireeating. They were both admitted to hospital and treated with amoxicillin and clavulanic acid. Both patients were clinically recovered within a few days. Following aspiration of petroleum there is often a period of latency from 8-24 hours before the symptoms occur; it is recommended that patients should be admitted for observation. Known symptoms are coughing, shortness of breath, thoracic pain, fever, tachypnoea and sometimes haemoptysis. Apart from chest radiographs and laboratory values, taking into account the specific history, unless complications are expected additional diagnostic tests are often considered unnecessary. Treatment is symptomatic: administration of oxygen, pain relief, bronchodilation and potentially antibiotics if a bacterial superinfection is suspected. Clinical recovery is usually quick. Temporary restrictive disorders of lung function and reduced diffusion capacity have been described. Recovery of lung function and radiological recovery are seen within weeks to months. Mortality is less than 1%. Gepubliceerd: Ned Tijdschr Geneeskd. 2010;154(45):A2358
167
Impact factor: 0
6. The impact of margin status in breast-conserving therapy for lobular carcinoma is age related JJ Jobsen a, S Riemersma b, J van der Palen c, F Ong a, A Jonkman a, H Struikmans d a
Department of Radiation Oncology, Medisch Spectrum Twente, Enschede Laboratorium Pathologie Oost Nederland, Enschede c Department of Research Methodology, Measurement, and Data Analysis, Faculty of Behavioral Science, University of Twente d Department of Radiation Oncology, Leiden University Medical Centre, Leiden b
Purpose: The aim is to look at the impact of margin status and outcome of invasive lobular carcinoma (ILC) treated with breast-conserving therapy (BCT). Methods: This manuscript describes an analysis on 330 BCT in 318 patients with ILC. Results: The 12-year local relapse free survival (LRFS) is 89%. In multivariate analysis, positive margin status, age>50 years, contra lateral breast cancer, and adjuvant systemic therapy were significant predictors of local relapse free survival. In a separate analysis limited to a positive margin for invasive carcinoma or carcinoma in situ, only a positive margin for invasive carcinoma was a significant predictor of local relapse free survival. This was limited to women
Totale impact factor: 8.931 Gemiddelde impact factor: 1.486 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 2.491 Gemiddelde impact factor: 2.491
168
Plastische Chirurgie 1. Extensor pollicis longus tendon rupture with concomitant rupture of the extensor digitorum communis II tendon after distal radius fracture de Boer SW, van Kooten EO*, Ritt MJ Department of Plastic Surgery, Medisch Spectrum Twente, Enschede Gepubliceerd: J Hand Surg Eur Vol. 2010;35(8):679-81 Impact factor: 0.820
Totale impact factor: 0.820 Gemiddelde impact factor: 0.820 Aantal artikelen 1e, 2e of laatste auteur: 1 Totale impact factor: 0.820 Gemiddelde impact factor: 0.820
169
Radiologie 1. Clinical Course of Pain in Acute Osteoporotic Vertebral Compression Fractures CA Klazena,d,,h, HJ Verhaarc, PN Lohlea, LE Lampmanna, JR Juttmannb, MC Schoemakera, KJ van Everdingene, AF Mullerf, WP Malid, J de Vries PhDg a Department of Radiology, St. Elisabeth Hospital, Tilburg b Department of Internal Medicine, St. Elisabeth Hospital, Tilburg c Department of Geriatric Medicine, University Medical Centre, Utrecht d Department of Radiology, University Medical Centre, Utrecht e Department of Radiology, Diakonessenhuis, Utrecht f Department of Internal Medicine, Diakonessenhuis, Utrecht g Department of Medical Psychology, Tilburg University, Tilburg h Department of Radiology, Medisch Spectrum Twente, Enschede Purpose: The authors prospectively determined the natural course of pain in patients with conservatively treated acute osteoporotic vertebral compression fractures (VCF). In addition, the type of conservative therapy that these patients received was assessed. Materials and methods: Patients older than 50 years, referred for spine radiography for acute back pain, were asked to complete a baseline clinical questionnaire. Patients with an acute VCF were followed up at 6 and 23 months with a questionnaire that included a Visual Analog Score (VAS) and type of pain medication and other conservative treatment. Significant pain relief was defined as a decrease in VAS of 50% or more. Results: Forty-nine patients (mean age, 78 years; range, 51-95) with acute VCF were followed up for almost 2 years. Significant pain relief was noted in 22 of 35 patients (63%) at 6 months and in 25 of 36 (69%) at 23 months. In patients with persisting pain at 23 months (mean VAS 6.4), some decrease in VAS was apparent at 6 months but not in the 6-23 months interval. No predictors for significant pain relief could be identified. Patients with significant pain relief used less pain medication and had less physical therapy. Conclusions: In most patients with an acute VCF, pain decreases significantly with conservative therapy, predominantly in the first 6 months. However, almost 2 years after an acute VCF, a third of patients still had severe pain necessitating pain medication and physical therapy in the majority. No predictors for transition from acute to chronic pain could be identified. Gepubliceerd: J Vasc Interv Radiol. 2010;21(9):1405-1409 Impact factor: 1.805
2. Percutaneous Vertebroplasty and Pulmonary Cement Embolism: Results from VERTOS II Venmans A1, Klazen CA1,5, Lohle PN1, van Rooij WJ1, Verhaar HJ3, de Vries J2, Mali WP4 Departments of 1 Radiology and 2 Medical Psychology, St. Elisabeth Hospital, Tilburg; Departments of 3 Geriatric Medicine and 4 Radiology, University Medical
170
Centre Utrecht, Utrecht; 5 Department of Radiology, Medisch Spectrum Twente, Enschede Background and purpose: The reported incidence of PCE during PV varies, depending on the sensitivity of diagnostic tests used. To assess the true incidence of PCE, we performed native chest CT during follow-up in a large proportion of patients from the VERTOS II trial. Materials and methods: VERTOS II is a prospective multicenter randomized controlled trial comparing PV with conservative therapy in 202 patients. After a mean follow-up of 22 months (median, 21 months; range, 6-42 months), 54 of 78 patients (69%) with 80 vertebrae treated with PV underwent native chest CT to detect possible PCE. The presence, location, number, and size of PCE were recorded. In addition, the presence of pulmonary parenchymal changes adjacent to PCE was noted. Possible risk factors for PCE, such as age, sex, number of treated vertebrae, cement volume per vertebra, and presence and location of perivertebral cement leakage, were evaluated. Results: PCE was detected in 14 of 54 patients (26%; 95% CI, 16%-39%). All patients were asymptomatic. Cement emboli were small and randomly distributed in peripheral small vessels. There were no reactive pulmonary changes. Cement leakage in the azygos vein was the only risk factor for the occurrence of PCE (OR, 43; 95% CI, 5-396). Conclusions: Small and clinically silent PCE occurred in a quarter of patients treated with PV. Cement leakage into the azygos vein was the only risk factor. With time, these small cement emboli remained inert, without inflammatory pulmonary response. Standard postprocedural CT or chest radiographs are not necessary. Gepubliceerd: Am J Neuroradiol. 2010;31(8):1451-3 Impact factor: 3.296
3. Percutaneous vertebroplasty and procedural pain Venmans A1, Klazen CA1,2, Lohle PN1, van Rooij WJ1 1 Department of Radiology, St. Elisabeth Ziekenhuis, Tilburg 2 Department of Radiology, Medisch Spectrum Twente, Enschede Background and purpose: No consensus exists regarding pain management during PV. In this study, we evaluated the effectiveness of local infiltration anesthesia as the only pain medication. Materials and methods: From September 2008 to March 2009, 44 consecutive patients (35 women and 9 men; mean age, 74 years) with symptomatic OVCFs were included in the study. Lidocaine was infiltrated to the skin and the periosteum of the pedicle. After PV, patients indicated pain sensation on a VAS. In addition, patients indicated the most painful moment during the procedure: lidocaine infiltration, placing the needles, or cement injection. Finally, patients were asked whether pain medication during the procedure was sufficient. After the procedure the surgeon was asked to judge the expected VAS score of the patient. Results: Mean VAS score was 5.7 (median, 6; range, 1-10). Seventeen of 44 patients (39%) indicated that lidocaine infiltration was insufficient for procedural pain
171
reduction. The mean VAS score of these patients was 7.3 (range, 5-10). Placing the needles was specified as most painful moment in 29 patients (66%), lidocaine infiltration in 11 (25%), and cement injection in 4 (9%). Surgeons' expectations of patients' VAS scores were a mean of 3.3 (median, 3; range, 1-6). Conclusions: For a substantial proportion of patients, local infiltration anesthesia was not sufficient for pain reduction during PV. The severity of pain experienced by the patient is usually not appreciated correctly by the surgeon. Gepubliceerd: Am J Neuroradiol. 2010;31(5):830-1 Impact factor: 3.296
4. Percutaneous Vertebroplasty Is Not a Risk Factor for New Osteoporotic Compression Fractures: Results from VERTOS II Klazen CA1,4, Venmans A1, de Vries J2, van Rooij WJ1, Jansen FH5, Blonk MC6, Lohle PN1, Juttmann JR3, Buskens E7,8, van Everdingen KJ9, Muller A10, Fransen H11, Elgersma OE12, Mali WP13, Verhaar HJ14 From the 1 Departments of Radiology, 2 Medical Psychology, and 3 Internal Medicine, St. Elisabeth Hospital, Tilburg; 4 Department of Radiology, Medisch Spectrum Twente, Enschede; 5 Departments of Radiology and 6 Internal Medicine, Catharina Hospital, Eindhoven; 7 Department of Clinical Epidemiology, Julius Center for Health Sciences and Primary Care, Utrecht; 8 Department of Clinical Epidemiology, University Medical Centre, Groningen; 9 Departments of Radiology and 10 Internal Medicine, Diakonessenhuis Utrecht; 11 Department of Radiology, AZ St. Lucas Hospital, Gent, Belgium; 12 Department of Radiology, Albert Schweitzer Hospital, Dordrecht; 13 Departments of Radiology and 14 Geriatric Medicine, University Medical Centre, Utrecht Background and purpose: PV is increasingly used as treatment for osteoporotic VCFs. However, controversy exists as to whether PV increases the risk for new VCFs during follow-up. The purpose of our research was to assess the incidence of new VCFs in patients with acute VCFs randomized to PV and conservative therapy. Materials and methods: VERTOS II is a prospective multicenter randomized controlled trial comparing PV with conservative therapy in 202 patients. Incidence, distribution, and timing of new VCFs during follow-up were assessed from spine radiographs. In addition, further height loss during follow-up of treated VCFs was measured. Results: After a mean follow-up of 11.4 months (median, 12.0; range, 1-24 months), 18 new VCFs occurred in 15 of 91 patients after PV and 30 new VCFs in 21 of 85 patients after conservative therapy. This difference was not significant (P = .44). There was no higher fracture risk for adjacent-versus-distant vertebrae. Mean time to new VCF was 16.2 months after PV and 17.8 months after conservative treatment (logrank, P = .45). The baseline number of VCFs was the only risk factor for occurrence (OR, 1.43; 95% CI, 1.05-1.95) and number (P = .01) of new VCFs. After conservative therapy, further height loss of treated vertebrae occurred more frequently (35 of 85 versus 11 of 91 patients, P < .001) and was more severe (P < .001) than after PV.
172
Conclusions: Incidence of new VCFs was not different after PV compared with conservative therapy after a mean of 11.4 months' follow-up. The only risk factor for new VCFs was the number of VCFs at baseline. PV contributed to preservation of stature by decreasing both the incidence and severity of further height loss in treated vertebrae. Gepubliceerd: Am J Neuroradiol. 2010;31(8):1447-50 Impact factor: 3.296
5. Vertebroplasty versus conservative treatment in acute osteoporotic vertebral compression fractures (Vertos II): an open-label randomised trial Klazen CA1,16, Lohle PN1, de Vries J2, Jansen FH4, Tielbeek AV4, Blonk MC5, Venmans A1, van Rooij WJ1, Schoemaker MC1, Juttmann JR3, Lo TH6, Verhaar HJ7, van der Graaf Y8, van Everdingen KJ9, Muller AF10, Elgersma OE11, Halkema DR1, Fransen H12, Janssens X13, Buskens E14, Mali WP15 1 Radiology, St Elisabeth Ziekenhuis, Tilburg; 2 Medical Psychology, St Elisabeth Ziekenhuis, Tilburg; 3 Internal Medicine, St Elisabeth Ziekenhuis, Tilburg; 4 Radiology, Catharina-Ziekenhuis, Eindhoven; 5 Internal Medicine, CatharinaZiekenhuis, Eindhoven; 6 Radiology, UMC Utrecht, Utrecht; 7 Geriatric Medicine, UMC Utrecht, Utrecht; 8 Clinical Epidemiology, Julius Centre for Health Sciences and Primary Care, UMC Utrecht, Utrecht; 9 Radiology, Diakonessenhuis Utrecht, Utrecht’10 Internal Medicine, Diakonessenhuis Utrecht, Utrecht; 11 Radiology, Albert Schweitzer Ziekenhuis, Dordrecht; 12 Internal Medicine, Albert Schweitzer Ziekenhuis, Dordrecht; 13 Radiology, AZ St Lucas, Gent, Belgium; 14 Rheumatology, AZ St Lucas, Gent, Belgium; 15 Department of Epidemiology, UMC Groningen, Groningen; 16 Radiology, Medisch Spectrum Twente, Enschede Background: Percutaneous vertebroplasty is increasingly used for treatment of pain in patients with osteoporotic vertebral compression fractures, but the efficacy, costeffectiveness, and safety of the procedure remain uncertain. We aimed to clarify whether vertebroplasty has additional value compared with optimum pain treatment in patients with acute vertebral fractures. Methods: Patients were recruited to this open-label prospective randomised trial from the radiology departments of six hospitals in the Netherlands and Belgium. Patients were aged 50 years or older, had vertebral compression fractures on spine radiograph (minimum 15% height loss; level of fracture at Th5 or lower; bone oedema on MRI), with back pain for 6 weeks or less, and a visual analogue scale (VAS) score of 5 or more. Patients were randomly allocated to percutaneous vertebroplasty or conservative treatment by computer-generated randomisation codes with a block size of six. Masking was not possible for participants, physicians, and outcome assessors. The primary outcome was pain relief at 1 month and 1 year as measured by VAS score. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT00232466. Findings: Between Oct 1, 2005, and June 30, 2008, we identified 431 patients who were eligible for randomisation. 229 (53%) patients had spontaneous pain relief during assessment, and 202 patients with persistent pain were randomly allocated to treatment (101 vertebroplasty, 101 conservative treatment). Vertebroplasty resulted
173
in greater pain relief than did conservative treatment; difference in mean VAS score between baseline and 1 month was -5.2 (95% CI -5.88 to -4.72) after vertebroplasty and -2.7 (-3.22 to -1.98) after conservative treatment, and between baseline and 1 year was -5.7 (-6.22 to -4.98) after vertebroplasty and -3.7 (-4.35 to -3.05) after conservative treatment. The difference between groups in reduction of mean VAS score from baseline was 2.6 (95% CI 1.74-3.37, p<0.0001) at 1 month and 2.0 (1.13-2.80, p<0.0001) at 1 year. No serious complications or adverse events were reported. Interpretation: In a subgroup of patients with acute osteoporotic vertebral compression fractures and persistent pain, percutaneous vertebroplasty is effective and safe. Pain relief after vertebroplasty is immediate, is sustained for at least a year, and is significantly greater than that achieved with conservative treatment, at an acceptable cost. Gepubliceerd: Lancet. 2010;376(9746):1085-92 Impact factor: 30.758
6. Invited commentary Geelkerken RH1, Kolkman JJ2, Huisman AB3 Department of 1Surgery, 2Gastroenterology, 3Radiology, Medisch Spectrum Twente, Enschede Gepubliceerd: J Vasc Surg 2010;51(1):147 Impact factor: 3.517
7. Preoperative Staging with Chest CT in Patients with Colorectal Carcinoma: Not as a Routine Procedure Grossmann I1, Avenarius JK2, Mastboom WJ1, Klaase JM1 Departments of 1 Surgery and 2Radiology, Medisch Spectrum Twente, Enschede Background: Preoperative staging of patients with colorectal carcinoma (CRC) has the potential benefit of altering treatment options when metastases are present. The clinical value of chest computed tomography (CT) in staging remains unclear. Materials and methods: All patients who undergo colorectal surgery in our hospital are prospectively registered, including patient, treatment, and histopathological characteristics; outcome; and follow-up. Since January 2007, routine preoperative staging CT of chest and abdomen for patients with CRC has been performed as part of our regional guidelines. In this observational cohort study, an analysis on outcome was done after inclusion of 200 consecutive patients. Results: Synchronous metastases were present in 60 patients (30%). Staging chest CT revealed pulmonary metastases in 6 patients, with 1 false positive finding. In 50 patients indeterminate lesions were seen on chest CT (25%). These were diagnosed during follow-up as true metastases (n = 8), bronchus carcinoma (n = 2), benign lesions (n = 25), and remaining unknown (n = 15). Ultimately, synchronous pulmonary metastases were diagnosed in 13 patients (7%), in 6 patients confined to
174
the lung (3%). In none of the patients the treatment plan for the primary tumor was changed based on the staging chest CT. Conclusion: The low incidence of pulmonary metastases and minimal consequences for the treatment plan limits the clinical value of routine staging chest CT before operation. It has several disadvantages such as costs, radiation exposure, and prolonged uncertainty because of the frequent finding of indeterminate lesions. Based on this study, a routine staging chest CT in CRC patients is not advocated. Gepubliceerd: Ann Surg Oncol. 2010;17(8):2045-2050 Impact factor: 4.130
8. In Reply: The Importance of Preoperative Staging with Chest CT Scan in Patients with Colorectal Cancer Grossmann I1, Avenarius JK2, Mastboom WJ1, Klaase JM1 Departments of 1 Surgery and 2Radiology, Medisch Spectrum Twente, Enschede Gepubliceerd: Ann Surg Oncol. 2010; DOI 10.1245/s10434-010-1307-6 Impact factor: 4.130
9. Open or percutaneous revascularization for chronic splanchnic syndrome Van Petersen AS1, Kolkman JJ2, Beuk RJ1, Huisman AB3, Doelman CJ4, Geelkerken RH1 Department of 1surgery, 2Gastroenterology, 3Radiology, 4Clinical Chemistry, Medisch Spectrum Twente, Enschede Background: Treatment of chronic splanchnic syndrome remains controversial. In the past 10 years, endovascular repair (ER) has replaced open repair (OR) to some extent. This evidence summary reviews the available evidence for ER or OR of chronic splanchnic syndrome. Methods: A systematic literature search of MEDLINE database was performed to identify all studies that evaluated treatment of chronic splanchnic syndrome between 1988 and 2009. Results: The best available evidence consists of prospectively accumulated but retrospectively analyzed data with a high risk for confounding. Only a few of these studies incorporated functional tests to assess splanchnic ischemia before or after treatment. ER has the advantage of low short-term morbidity but the disadvantage of decreased long-term primary patency compared with OR. ER and OR have similar rates of secondary patency, although the reintervention rate after ER is higher. Conclusion: ER appears to be preferential in the treatment of elderly patients and in patients with comorbidity, severe cachexia, or hostile abdomen. Long-term results after OR are excellent. OR can still be proposed as the preferred option for relatively young and fit patients. Gepubliceerd: J Vasc Surg. 2010;51(5):1309-1316 Impact factor: 3.517
175
10. Aspiration pneumonitis after fire-eating: fire-eater's lung Harding FM1, Hiddinga BI1, Eijsvogel MM1, van Baarlen J2, Oosterhof-Berktas R3 1 department of Pulmonary Medicine, Medisch spectrum Twente, Enschede 2 Laboratorium voor Pathologie Oost-Nederland, Enschede 3 Department of Radiology, Medisch spectrum Twente, Enschede On the emergency department we saw two men aged 19 and 26 with symptoms of lipoid pneumonitis (fire-eater's lung) following aspiration of petroleum during fireeating. They were both admitted to hospital and treated with amoxicillin and clavulanic acid. Both patients were clinically recovered within a few days. Following aspiration of petroleum there is often a period of latency from 8-24 hours before the symptoms occur; it is recommended that patients should be admitted for observation. Known symptoms are coughing, shortness of breath, thoracic pain, fever, tachypnoea and sometimes haemoptysis. Apart from chest radiographs and laboratory values, taking into account the specific history, unless complications are expected additional diagnostic tests are often considered unnecessary. Treatment is symptomatic: administration of oxygen, pain relief, bronchodilation and potentially antibiotics if a bacterial superinfection is suspected. Clinical recovery is usually quick. Temporary restrictive disorders of lung function and reduced diffusion capacity have been described. Recovery of lung function and radiological recovery are seen within weeks to months. Mortality is less than 1%. Gepubliceerd: Ned Tijdschr Geneeskd. 2010;154(45):A2358 Impact factor: 0
11. Gastric Schwannoma Presenting as an Incidentaloma on CT-Scan and MRI MH Rabera, CM Ziedses des Plantesb, R Vinkc, JM Klaasea a Department of Surgery, Medisch Spectrum Twente, Enschede b Department of Radiology, Medisch Spectrum Twente, Enschede c Laboratorium Pathologie Oost Nederland, Enschede A 67 year old female was referred because of an incidentaloma on CT-scan and MRI which showed a 5.0 cm large mass in the wall of the distal stomach. After an initial work-up which suggested a gastrointestinal stromal tumor (GIST), a partial gastrectomy with a Billroth II gastrojejunostomy was performed. The histological diagnosis was a schwannoma. Gastric schwannomas are rare tumors which comprise 0.2% of all gastric tumors and 4% of all benign gastric neoplasms with a peak of incidence in the 4th and 5th decade of life. Gastric schwannomas are usually asymptomatic, but can present with ulceration and/or gastrointestinal bleeding. Clinical, endoscopical, surgical, radiological and histological features of this case are described and the relevant literature is reviewed. Gepubliceerd: Gastroenterology Research 2010;3(6):276-280 Impact factor: 0
176
Totale impact factor: 57.745 Gemiddelde impact factor: 5.250 Aantal artikelen 1e, 2e of laatste auteur: 10 Totale impact factor: 54.228 Gemiddelde impact factor: 5.423
177
Radiotherapie 1. Ipsilateral Irradiation for Oral and Oropharyngeal Carcinoma Treated With Primary Surgery and Postoperative Radiotherapy MR Vergeer3, PA Doornaert3, A Jonkman1, JH Kaanders2, PL van den Ende 4, MA de Jong6, CR Leemans5, BJ Slotman3, JA Langendijk1 1 Department of Radiation Oncology, UMC Groningen, Groningen and Medisch spectrum Twente, Enschede 2 Department of Radiation Oncology, Radboud University Nijmegen Medical Center, Nijmegen 3 Department of Radiation Oncology, VU Medical Center, Amsterdam 4 MAASTRO Clinic, Maastricht 5 Department of Otolaryngology/Head and Neck Surgery, VU Medical Center, Amsterdam 6 Department of Radiation Oncology, Leiden UMC, Leiden Purpose. The purpose was to evaluate the contralateral nodal control (CLNC) in postoperative patients with oral and oropharyngeal cancer treated with ipsilateral irradiation of the neck and primary site. Late radiation-induced morbidity was also evaluated. Methods and Materials. The study included 123 patients with well-lateralized squamous cell carcinomas treated with surgery and unilateral postoperative irradiation. Most patients had tumors of the gingiva (41%) or buccal mucosa (21%). The majority of patients underwent surgery of the ipsilateral neck (n = 102 [83%]). The N classification was N0 in 73 cases (59%), N1 or N2a in 23 (19%), and N2b in 27 cases (22%). Results. Contralateral metastases developed in 7 patients (6%). The 5-year actuarial CLNC was 92%. The number of lymph node metastases was the only significant prognostic factor with regard to CLNC. The 5-year CLNC was 99% in N0 cases, 88% in N1 or N2a cases, and 73% in N2b cases (p = 0.008). Borderline significance (p = 0.06) was found for extranodal spread. Successful salvage could be performed in 71% of patients with contralateral metastases. The prevalence of Grade 2 or higher xerostomia was 2.6% at 5 years. Conclusions. Selected patients with oral or oropharyngeal carcinoma treated with primary surgery and postoperative ipsilateral radiotherapy have a very high CLNC with a high probability of successful salvage in case of contralateral metastases. However, bilateral irradiation should be applied in case of multiple lymph node metastases in the ipsilateral neck, particularly in the presence of extranodal spread. The incidence of radiation-induced morbidity is considerably lower as observed after bilateral irradiation. Gepubliceerd: Int J Radiat Oncol Biol Phys. 2010;78:682-8 Impact factor: 4.592
2. The number of metastatic sites for stage IIIA endometrial carcinoma, endometrioid cell type, is a strong negative prognostic factor
178
Jobsen JJ1, Ten Cate LN2, Lybeert ML3, van der Steen-Banasik EM4, Scholten A5, van der Palen J6,11, Slot A7, Kroese MC8, Schutter EM9, Siesling S10 1 Department of Radiation Oncology, Medisch Spectrum Twente, Enschede 2 Laboratorium Pathologie Oost Nederland, Enschede 3 Department of Radiation Oncology, Catharina Hospital, Eindhoven 4 Arnhem Radiotherapeutic Institute, Arnhem 5 Department of Clinical Oncology, Leiden UMC, Leiden 6 Department of Research Methodology, Measurement, and Data Analysis, Faculty of Behavioral Science, University of Twente 7 Radiotherapy Institute Friesland, Leeuwarden 8 Radiotherapy Institute Steden en Omstreken, Deventer 9 Departments of Obstetrics and Gynaecology, Medisch Spectrum Twente, Enschede 10 Comprehensive Cancer Centre North East, Enschede/Groningen 11 Clinical Epidemiology, Medisch Spectrum Twente, Enschede The aim of this study was to look at the impact of the number of sites with tumour involvement on outcome for patients with stage IIIA endometrioid-type endometrial carcinoma. Patients and methods: 141 patients stage IIIA were included. A central histopathological review was performed. Patients staged solely on the presence of a positive peritoneal washing were excluded. Follow-up ranged from 2 to 217 months with a median of 43 months. Endpoints of the study were locoregional recurrence rates, distant metastasis-free survival (DMFS), disease-free survival (DFS) and disease-specific survival (DSS). Results: In multivariate analyses the number of involved sites showed to be the only independent significant variable for DMFS, DFS, and DSS with a Hazard Ratio of 2.1, 2.2, and 2.2, respectively. The DSS was significantly related to the number of involved sites, with a 5-year DSS of 70.4% for one site, 42.8% for two sites, and 43.9% for three sites, respectively (p=0.001). Conclusion: The number of involved sites outside the corpus uterine for stage IIIA seems to be a strong negative prognostic factor for stage IIIA endometrial carcinoma. Gepubliceerd: Gynecol Oncol. 2010;117:32-36 Impact factor: 3.733
3. The impact of margin status in breast-conserving therapy for lobular carcinoma is age related JJ Jobsen a, S Riemersma b, J van der Palen c, F Ong a, A Jonkman a, H Struikmans d a
Department of Radiation Oncology, Medisch Spectrum Twente, Enschede Laboratorium Pathologie Oost Nederland, Enschede c Department of Research Methodology, Measurement, and Data Analysis, Faculty of Behavioral Science, University of Twente d Department of Radiation Oncology, Leiden University Medical Centre, Leiden b
179
Purpose: The aim is to look at the impact of margin status and outcome of invasive lobular carcinoma (ILC) treated with breast-conserving therapy (BCT). Methods: This manuscript describes an analysis on 330 BCT in 318 patients with ILC. Results: The 12-year local relapse free survival (LRFS) is 89%. In multivariate analysis, positive margin status, age>50 years, contra lateral breast cancer, and adjuvant systemic therapy were significant predictors of local relapse free survival. In a separate analysis limited to a positive margin for invasive carcinoma or carcinoma in situ, only a positive margin for invasive carcinoma was a significant predictor of local relapse free survival. This was limited to women
4. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, noninferiority, randomised trial RA Nout a, VT Smit b, H Putter c, IM Jürgenliemk-Schulz d, JJ Jobsen e, LC Lutgens f, EM van der Steen-Banasik g, JW Mens h, A Slot k, MC Stenfert Kroese l, BN van Bunningen m, AC Ansink j, WL van Putten i, CL Creutzberg a for the PORTEC Study Group a Department of Clinical Oncology, Leiden UMC, Leiden b Department of Pathology, Leiden UMC, Leiden c Department of Medical Statistics, Leiden UMC, Leiden d Department of Radiation Oncology, UMC Utrecht, Utrecht e Department of Radiotherapy, Medisch Spectrum Twente, Enschede f MAASTricht Radiation Oncology Clinic, Maastricht g Arnhem Radiotherapy Institute, Arnhem h Department of Radiation Oncology, ErasmusMC-Daniel den Hoed Cancer Center, Rotterdam i Department of Biostatistics, ErasmusMC-Daniel den Hoed Cancer Center, Rotterdam j Department of Gynecology, ErasmusMC-Daniel den Hoed Cancer Center, Rotterdam k Radiotherapy Institute Friesland, Leeuwarden l Radiotherapy Institute Stedendriehoek en Omstreken, Deventer m Department of Radiotherapy Cancer Institute, Amsterdam
180
Background: After surgery for intermediate-risk endometrial carcinoma, the vagina is the most frequent site of recurrence. This study established whether vaginal brachytherapy (VBT) is as effective as pelvic external beam radiotherapy (EBRT) in prevention of vaginal recurrence, with fewer adverse effects and improved quality of life. Methods: In this open-label, non-inferiority, randomised trial undertaken in 19 Dutch radiation oncology centres, 427 patients with stage I or IIA endometrial carcinoma with features of high-intermediate risk were randomly assigned by a computergenerated, biased coin minimisation procedure to pelvic EBRT (46 Gy in 23 fractions; n=214) or VBT (21 Gy high-dose rate in three fractions, or 30 Gy low-dose rate; n=213). All investigators were masked to the assignment of treatment group. The primary endpoint was vaginal recurrence. The predefined non-inferiority margin was an absolute difference of 6% in vaginal recurrence. Analysis was by intention to treat, with competing risk methods. The study is registered, number ISRCTN16228756. Findings: At median follow-up of 45 months (range 18-78), three vaginal recurrences had been diagnosed after VBT and four after EBRT. Estimated 5-year rates of vaginal recurrence were 1.8% (95% CI 0.6-5.9) for VBT and 1.6% (0.5-4.9) for EBRT (hazard ratio [HR] 0.78, 95% CI 0.17-3.49; p=0.74). 5-year rates of locoregional relapse (vaginal or pelvic recurrence, or both) were 5.1% (2.8-9.6) for VBT and 2.1% (0.8-5.8) for EBRT (HR 2.08, 0.71-6.09; p=0.17). 1.5% (0.5-4.5) versus 0.5% (0.1-3.4) of patients presented with isolated pelvic recurrence (HR 3.10, 0.32-29.9; p=0.30), and rates of distant metastases were similar (8.3% [5.1-13.4] vs 5.7% [3.3-9.9]; HR 1.32, 0.63-2.74; p=0.46). We recorded no differences in overall (84.8% [95% CI 79.3-90.3] vs 79.6% [71.2-88.0]; HR 1.17, 0.69-1.98; p=0.57) or disease-free survival (82.7% [76.9-88.6] vs 78.1% [69.7-86.5]; HR 1.09, 0.66-1.78; p=0.74). Rates of acute grade 1-2 gastrointestinal toxicity were significantly lower in the VBT group than in the EBRT group at completion of radiotherapy (12.6% [27/215] vs 53.8% [112/208]). Interpretation: VBT is effective in ensuring vaginal control, with fewer gastrointestinal toxic effects than with EBRT. VBT should be the adjuvant treatment of choice for patients with endometrial carcinoma of high-intermediate risk. Gepubliceerd: Lancet. 2010;375(9717):816-23 Impact factor: 30.758
Totale impact factor: 41.574 Gemiddelde impact factor: 10.394 Aantal artikelen 1e, 2e of laatste auteur: 2 Totale impact factor: 6.224 Gemiddelde impact factor: 3.112
181
Reumatologie 1. Nonsteroidal anti-inflammatory drugs: adverse effects and their prevention Vonkeman HE, van de Laar MA Department of Rheumatology and Clinical Immunology, Medisch Spectrum Twente and University of Twente, Enschede Objectives: To discuss nonsteroidal anti-inflammatory drugs (NSAIDs), their history, development, mode of action, toxicities, strategies for the prevention of toxicity, and future developments. Methods: Medline search for articles published up to 2007, using the keywords acetylsalicylic acid, aspirin, NSAIDS, cyclo-oxygenase 2, adverse effects, ulcer, and cardiovascular. Results: NSAIDs are 1 of the oldest, most successful drugs known to modern medicine. NSAIDs are effective for alleviating pain, fever, and inflammation by inhibiting prostaglandin synthesis. Aspirin, by its irreversible inhibition of blood platelet function, is also effective in the prevention of cardiovascular disease. Conversely, NSAIDs may also be considered the most fatal drugs for nonfatal diseases. NSAIDs may cause gastrointestinal ulcers, serious cardiovascular events, hypertension, acute renal failure, and worsening of preexisting heart failure. Conclusions: Physicians should always prescribe the lowest effective dose for the shortest possible time and must take into account both the gastrointestinal and the cardiovascular risks of individual patients when prescribing NSAIDs Gepubliceerd: Semin Arthritis Rheum 2010;39:294-312 Impact factor: 4.724
2. Patient-initiated online support groups: motives for initiation, extent of success and success factors van Uden-Kraan CF1, Drossaert CH1,2, Taal E1, Seydel ER1, van de Laar MA1,2 1 Institute of Behavioural Research, University of Twente, Enschede 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede We studied the success and success factors of online support groups (OSGs) for patients, and the motives and goals of people who start such groups. We interviewed 23 webmasters of OSGs for patients with breast cancer, fibromyalgia and arthritis. The majority were women (n = 20) and most were patients (n = 21). Analysis of the interviews revealed that webmasters had altruistic and intrinsic motives for initiating an online support group. They defined success as the fulfilment of the goals they had in mind when they initiated their groups. To be able to make a group successful, decisions about its organization and management need to be coherent with these goals. Most webmasters stressed that promoting the group, keeping it alive and moderating the messages were vital success factors during the evolution stage. Management of the OSGs took up much of the webmasters' time and energy. On average webmasters were occupied with the group for 10-15 hours
182
a week. Our study provides an overview of the pros and cons of differing decisions that have to be made when initiating an OSG. Gepubliceerd: J Telemed Telecare. 2010;16(1):30-4 Impact factor: 0.921
3. New insights into the experience of fatigue among patients with rheumatoid arthritis: a qualitative study Nikolaus S, Bode C, Taal E, van de Laar MA 1 Institute for Behavioral Research, Faculty of Behavioral Sciences, University of Twente, Enschede 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede Objectives: Patients with rheumatoid arthritis (RA) complain about fatigue. Aim of this study was to gain further insight into the experience of fatigue in RA. Methods: Participants were 31 RA outpatients of the Medical Spectrum Twente, with all levels of fatigue. In-depth structured interviews on the patients' experience of fatigue were conducted and analyzed using a bottom-up coding scheme, meaning that answers of patients were summarized and categorized. Results: Patients' mean fatigue severity score was 50 (VAS; theoretical range 0100). Interviews showed inter-individual differences in the experience and impact of fatigue. Different patterns in emotions, consequences and management of fatigue were found. Especially younger women with multiple daily roles seemed to be vulnerable to the negative impact of RA fatigue. Patients also reported positive aspects of fatigue. Moreover, varying forms of fatigue were described. Conclusions: Results point to the existence of differences in fatigue experience according to gender, age, and daily roles. This finding indicates a need for targeting advice and interventions to the individual situation of a patient. Furthermore, the positive aspects patients reported about their fatigue could facilitate an approach that is focused on remaining opportunities and not only on restrictions. Gepubliceerd: Ann Rheum Dis. 2010;69(5):895-897 Impact factor: 8.111
4. Experiences and attitudes of Dutch rheumatologists and oncologists with regard to their patients' health-related Internet use van Uden-Kraan CF1, Drossaert CH1, Taal E1, Smit WM2, Seydel ER1, van de Laar MA1,3 1 Institute for Behavioural Research, University of Twente, Enschede 2 Department of Internal Medicine, Medisch Spectrum Twente, Enschede 3 Department of Rheumatology, Medisch Spectrum Twente, Enschede The objective of this study is to explore the experiences and attitudes of rheumatologists and oncologists with regard to their patients' health-related Internet use. In addition, we explored how often physicians referred their patients to healthrelated Internet sites. We sent a questionnaire to all the rheumatologists and
183
oncologists in the Netherlands. The questionnaire included questions concerning demographics, experiences with patients' health-related Internet use, referral behavior, and attitudes to the consequences of patients' health-related Internet use (for patients themselves, the physician-patient relationship and the health care). The response rate was 46% (N = 238). Of these respondents, 134 practiced as a rheumatologist and 104 as an oncologist. Almost all physicians encountered their patients raising information from the Internet during a consultation. They were not, however, confronted with their patients' health-related Internet use on a daily basis. Physicians had a moderately positive attitude towards the consequences of patients' health-related Internet use, the physician-patient relationship and the health care. Oncologists were significantly less positive than rheumatologists about the consequences of health-related Internet use. Most of the physicians had never (32%) or only sometimes (42%) referred a patient to a health-related Internet site. Most physicians (53%) found it difficult to stay up-to-date with reliable Internet sites for patients. Physicians are moderately positive about their patients' health-related Internet use but only seldom refer them to relevant sites. Offering an up-to-date site with accredited websites for patients might help physicians refer their patients Gepubliceerd: Clin Rheumatol 2010: Impact factor: 1.668
5. The relationship between change in subjective outcome and change in disease: a potential paradox W Kievit1, 2 , J Hendrikx1, PFM Stalmeier2, 3, MA van de Laar4, PL Van Riel1, EM Adang2 1 Department of Rheumatology, Radboud University Nijmegen Medical Centre, PO box 9101, 6500 HB Nijmegen 2 Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Centre, Nijmegen 3 Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen 4 Department of Rheumatology, Medisch Spectrum Twente & University Twente, Enschede Background: Response shift theory suggests that improvements in health lead patients to change their internal standards and re-assess former health states as worse than initially rated when using retrospective ratings via the then-test. The predictions of response shift theory can be illustrated using prospect theory, whereby a change in current health causes a change in reference frame. Therefore, if health deteriorates, the former health state will receive a better rating, whereas if it improves, the former health state will receive a worse rating. Objective: To explore the predictions of response shift and prospect theory by relating subjective change to objective change. Methods: Baseline and 3-month follow-up data from a cohort of rheumatoid arthritis patients (N = 197) starting on TNFalpha-blocking agents were used. Objective disease change was classified according to a disease-specific clinical outcome measure (DAS28). Visual analogue scales (VAS) for general health (GH) and pain
184
were used as self-reported measures. Three months after starting on anti-TNFalpha, patients used the then-test to re-rate their baseline health with regard to general health and pain. Differences between then-test value and baseline values were calculated and tested between improved, non-improved and deteriorated patients by the Student t-test. Results: At 3 months, 51 (25.9%) patients had good improvement in health, 83 (42.1%) had moderate improvement, and 63 (32.0%) had no improvement or deteriorated in health. All patients no matter whether they improved, did not improve, or even became worse rated their health as worse retrospectively. The difference between the then-test rating and the baseline value was similarly sized in all groups. Conclusion: More positive ratings of retrospective health are independent of disease change. This suggests that patients do not necessarily change their standards in line with their disease change, and therefore it is inappropriate to use the then-test to correct for such a change. If a then-test is used to correct for shifts in internal standards, it might lead to the paradoxical result that patients who do not improve or even deteriorate increase significantly on self-reported health and pain. An alternative explanation for differences in retrospective and prospective ratings of health is the implicit theory of change which is more successful in explaining our results than prospect theory. Gepubliceerd: Qual Life Res. 2010;19(7):985-994 Impact factor: 2.376
6. Application of the health assessment questionnaire disability index to various rheumatic diseases van Groen MM1, Ten Klooster PM1, Taal E1, van de Laar MA1,2, Glas CA1 1 Institute for Behavioral Research, Faculty of Behavioral Sciences, University of Twente, Enschede 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede Purpose: To investigate whether the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) can serve as a generic instrument for measuring disability across different rheumatic diseases and to propose a scoring method based on item response theory (IRT) modeling to support this goal. Methods: The HAQ-DI was administered to a cross-sectional sample of patients with confirmed rheumatoid arthritis (n = 619), osteoarthritis (n = 125), or gout (n = 102). The results were analyzed using the generalized partial credit model as an IRT model. Results: It was found that 4 out of 8 item categories of the HAQ-DI displayed substantial differential item functioning (DIF) over the three diseases. Further, it was shown that this DIF could be modeled using an IRT model with disease-specific item parameters, which produces measures that are comparable for the three diseases. Conclusion: Although the HAQ-DI partially functioned differently in the three disease groups, the measurement regarding the disability level of the patients can be made comparable using IRT methods. Gepubliceerd: Qual Life Res. 2010;19(9):1255-63
185
Impact factor: 2.376
7. Survival, comorbidities and joint damage 11 years after the COBRA combination therapy trial in early rheumatoid arthritis. LH van Tuyl1, M Boers1, WF Lems1, RB Landewé2, H Han3, S van der Linden2, M van de Laar4, R Westhovens5, JC van Denderen6, ML Westedt7, AJ Peeters8, P Jacobs9, TW Huizinga10, H van de Brink11, BA Dijkmans1, AE Voskuyl1 Department of Rheumatology 1 VU UMC, Amsterdam; 2 UMC, Maastricht; 3 Medical Center Rijnmond Zuid, Rotterdam; 4 Medisch Spectrum Twente and University Twente, Enschede; 5 University Hospitals, KU, Leuven, Belgium; 6 Jan van Breemen Institute, Amsterdam; 7 Bronovo Hospital, Den Haag; 8 Reinier de Graaf Hospital, Delft; 9 Sint Laurentius Hospital, Roermond; 10 Leiden UMC, Leiden; 11 Medical Center Alkmaar, Alkmaar Background: COBRA (for 'COmbinatie therapie Bij Rheumatoide Artritis') combination therapy is effective for the treatment of rheumatoid arthritis (RA), but long-term safety is unknown. This study evaluates survival, comorbidities and joint damage in the original COBRA trial cohort. Methods: In the COBRA trial, 155 patients with early RA were treated with sulfasalazine (SSZ) monotherapy (SSZ group) or a combination of step-down prednisolone, methotrexate (MTX) and SSZ (COBRA group). The current 11-year follow-up study of the COBRA trial invited all original patients and performed protocollised scrutiny of clinical records, questionnaires, physical examination, laboratory and imaging tests. Results: In all, 152 out of 155 patients yielded at least partial data. After a mean of 11 years follow-up, 18 (12%) patients had died, 6 COBRA patients and 12 SSZ patients, HR 0.57 (95% CI 0.21 to 1.52). Treatment for hypertension was significantly more prevalent in the COBRA group (p=0.02) with similar trends for diabetes and cataract. Conversely, hypercholesterolaemia, cancer and infection showed a trend in favour of COBRA. Other comorbidities such as cardiovascular disease and fractures appeared in similar frequency. Radiographic findings suggest as a minimum sustained benefit for COBRA therapy, that is, difference in joint damage but similar subsequent progression rates after 5 years. Imputation to compensate for selective dropout suggests increasing benefit for COBRA, that is, difference in yearly progression rates similar to that seen in the first 5 years of follow-up. Conclusions: After 11 years, initial COBRA combination therapy resulted in numerically lower mortality and similar prevalence of comorbidity compared with initial SSZ monotherapy. In addition, lower progression of joint damage suggests long-term disease modification. Gepubliceerd: Ann Rheum Dis. 2010;69(5):807-12 Impact factor: 8.111
8. Four different patterns of fatigue in rheumatoid arthritis patients: results of a Qsort study
186
Nikolaus S1, Bode C1, Taal E1, van de Laar MA1,2 1 Institute for Behavioral Research, Faculty of Behavioral Sciences, University of Twente, Enschede 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede Objectives. Many patients with RA complain about fatigue. Whereas qualitative studies have covered the meaning of fatigue for RA patients, it was still unknown whether subgroups of patients could be distinguished. This study aimed to describe different perspectives on the experience of fatigue. Methods. Participants were 30 outpatients with established controlled RA of the Medical Spectrum Twente, with a mean fatigue severity score of 4.67 (visual analogue scale 0-10). They evaluated 57 statements about fatigue according to Qmethodology. Data were analysed with PCQ for Windows (Portland, OR, USA), using centroid factor analysis with varimax rotation (i.e. the participants but not the items of a scale are the variables). Factor scores of statements on the different dimensions were calculated to investigate which items are relevant when describing and distinguishing fatigue experiences. Demographic and clinical patient characteristics were collected to describe each of the dimensions that resulted from centroid factor analysis. Results. After statistical and theoretical considerations, a four-factor structure of the data was obtained. Each factor represented a perspective on the experience of fatigue, shared by a certain group of patients. Physical, psychological and social patient characteristics seemed to be associated with those experiences. The factors were labelled as: 'Little impact of fatigue'; 'Good coping and bad sleep'; 'Search for balance'; and 'High distress'. Conclusions. Results indicated that fatigue experience is a complex phenomenon. Existing questionnaires to measure fatigue do not meet this complexity. Extensive research is warranted and new efforts to develop instruments that take into account all aspects of fatigue are indicated. Gepubliceerd: Rheumatology (Oxford). 2010;49(11):2191-9 Impact factor: 4.236
9. Frequency and effectiveness of dose increase of adalimumab, etanercept, and infliximab in daily clinical practice Blom M1, Kievit W1, Kuper HH2, Jansen TL3, Visser H4, den Broeder AA5, Brus HL6, van de Laar MA2, van Riel PL1 Department of Rheumatology, 1 Radboud University Nijmegen Medical Centre, Nijmegen; 2 Medisch Spectrum Twente, Enschede; 3 Medical Centre Leeuwarden, Leeuwarden; 4 Alysis Care Group, Arnhem; 5 Sint Maartenskliniek, Nijmegen; 6 Twee Steden Hospital, Tilburg Objective: To describe the frequency and effectiveness of dose increase of adalimumab, etanercept, and infliximab in the treatment of rheumatoid arthritis (RA) in daily clinical practice. Methods: All RA patients with a dose increase of tumor necrosis factor (TNF)blocking therapy between January 1997 and January 2008 were selected from a
187
register including data from RA patients starting a first TNF-blocking agent (the Dutch Rheumatoid Arthritis Monitoring registry). The primary outcome was change in Disease Activity Score in 28 joints (DAS28) at 3 months after dose increase. Secondary outcomes were the change in DAS28 at 6 months after dose increase, the European League Against Rheumatism response rates, and the percentages of patients reaching a DAS28 of ≤3.2 at 3 and at 6 months after dose increase. Furthermore, the effectiveness of dose increase was assessed for the different reasons for dose increase: nonresponse, loss of response, and partial response. Results: During the study period, the dose was increased in 44 (12%) of the 368 adalimumab patients, 32 (8%) of the 420 etanercept patients, and 115 (36%) of the 323 infliximab patients. The change in DAS28 at 3 months and 6 months after dose increase was limited and only significant in etanercept patients at 3 months (-0.51; P = 0.035). Disease activity decreased significantly at 3 months from dose increase in the nonresponders and patients with loss of response (-0.66 and -0.99, respectively; both P = 0.001), but not in the partial responders. Conclusion: Although dose increase was applied in all 3 TNF-blocking agents in daily clinical practice, these results suggest that the effectiveness of dose increase is limited. Gepubliceerd: Arthritis Care Res. 2010;62(9):1335-41 Impact factor: 4.152
10. Arm Crank Ergometer is Reliable and Valid for Measuring Aerobic Capacity During Submaximal Exercise Bulthuis Y1, Drossaers-Bakker W2, Oosterveld F3, van der Palen J4, van de Laar M1,2 1 University of Twente, Institute for Behavioral Research, Department of Psychology & Communication of Health & Risk, Enschede 2 Department of Rheumatology and Clinical Immunology, Medisch Spectrum Twente, Enschede 3 Saxion University of Professional Education, Department of Health, Welfare and Technology, Enschede 4 Department of Epidemiology, Medisch Spectrum Twente, Enschede Measuring physical fitness becomes more important. Yet most instruments depend upon the function of the lower extremities. Hence, we investigated whether an adapted submaximal arm crank test on an ergometer for the upper body is reliable to use, and if the submaximal test for the arm crank ergometer is valid compared to the test on the bicycle ergometer. Different types of reliability measures of the adapted submaximal test on an arm crank ergometer were assessed in healthy volunteers, such as test-retest, interobserver, interergometer, and between arm crank and bicycle ergometer. A crossover design was used. The measurements were proportionally distributed over 30 volunteers. Based on the intraclass correlation coefficient (ICC) and the magnitude of within-person differences, we revealed a good reliability of the submaximal test. For the test-retest reliability, the ICC was 0.76, the interobserver reliability was 0.82, and the interergometer reliability 0.63. In addition, the criterion validity was also tested by comparing the calculated &OV0312;o2max during the submaximal test on the arm crank ergometer and on
188
the bicycle ergometer. Between &OV0312;o2max on the arm crank and bicycle ergometer, an ICC of 0.64 was found. The results of the submaximal test on the arm crank ergometer are reliable and valid as compared with those on the bicycle crank ergometer. We showed that the submaximal test on the arm crank ergometer is suitable for measuring physical fitness in healthy people. We expect that disabled people can use this submaximal test on the arm crank ergometer for measuring their physical fitness, also. Gepubliceerd: J Strength Cond Res. 2010;24(10):2809-15 Impact factor: 1.457
11. 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 2 Institute for Behavioral Research, Faculty of Behavioral Sciences, 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 2010;DOI: 10.3109/09638288.2010.509459 Impact factor: 1.555
12. 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
189
1
Department of Rheumatology, Radboud University Nijmegen Medical Centre, 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 Rituximab (RTX) is used for the treatment of lymphomas and rheumatoid arthritis (RA), achieving its benefi cial effect through B cell depletion. 1 2 Recently it has been suggested that the effect of RTX may be inhibited by the concomitant use of statins. 3-5 B cell depletion is achieved through apoptosis of B cells induced by hypercrosslinking of CD20 molecules with RTX. This process depends on the presence and integrity of lipid rafts in the cell membrane. 3 6 7 In vitro, Winiarska et al showed that cholesterol depletion reduces apoptosis by RTX, inhibiting B cell depletion. 3 However, two clinical studies that investigated concomitant statin use in patients with lymphoma reported no diminished effect on patient survival. 8 9 These patients received chemotherapy, cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like, containing several other medications apart from RTX, making it difficult to study the isolated effect of statins on RTX. In RA the question remains whether statins can inhibit the effect of RTX. To our knowledge, this has not been studied to date. The objective of this study was to investigate whether the concomitant use of statins and RTX leads to an inhibited effect of RTX on RA disease activity compared with RTX alone. All patients with RA who started RTX in the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry (N=187) were included in this prospective cohort study; 23 patients were exposed to the combination of statins and RTX. With the first RTX infusion all patients received 50 mg prednisone. The primary outcome was change in disease activity score using 28 joint counts (DAS28) from 0 to 6 months, analysed by analysis of covariance including potential confounders in the model. Power was calculated in advance and exceeded 0.80, α=0.05. The secondary outcome was effective period of the first RTX course which was analysed using Kaplan–Meier plots and Cox proportional hazards regression including confounder correction. The effective period was determined by the length of time between the initial course of RTX and the point where the patient was in need of RTX or another disease-modifying antirheumatic drug because of an increase or an insufficient decrease in disease activity (failure event). Patients exposed to statins (n=23) were older and more frequently male than unexposed patients (n=164). DAS28 scores of both groups were similar at baseline (p=0.999). Other variables did not differ significantly at baseline (table 1). The course of disease activity over time is shown in figure 1A , the common 3-month effects probably induced by the standard prednisone therapy. At 6 months the mean±SD reduction in DAS28 differed between patients exposed to statins and controls (0.5±1.9 vs 0.1±1.3), a difference of borderline significance (p=0.049) when corrected for age, gender, baseline DAS28 and rheumatoid factor positivity. Patients exposed to statins experienced a shorter effective period than those not exposed (median 7 months vs 9 months, p<0.001, figure 1B). Exposed patients were more
190
likely to experience a failure event than non-exposed patients (p=0.002, HR 2.3, 95% CI 1.4 to 3.9) corrected for the same confounders. Some study limitations need to be addressed. A relatively small sample size was included although the power was sufficient and a clinically relevant difference in change in DAS28 0–6 months and effective period of RTX was demonstrated. No randomisation was performed, although this should not be a problem because confounding by indication is unlikely. B cell depletion could not be measured. Keeping in mind these limitations, our findings suggest that statins can inhibit the effect of RTX in RA. More information is required regarding the repeatability of these findings and the magnitude of this effect. Particularly interesting is the influence of different cholesterol levels and statin dosages on B cell depletion rates. Significant interactions of statins with RTX in RA have not previously been shown. A critical review of common practice regarding concomitant use of statins in RTX-treated patients with RA is needed. Table 1 Patient characteristics at baseline Exposed (n=23)
Unexposed (n=164)
p Value 0.007 0.004 0.355 0.999 0.845 0.864 0.387 0.245 1.000 0.062 1.000 0.368 0.129 0.715 0.616 0.170 – 0.342
Mean±SD age (years) 65.6 ± 8.1 58.3 ± 12.4 Women, n (%) 12 (52.2) 130 (79.8) Mean±SD disease duration (years) 13.6 ± 7.8 12.2 ± 6.9 Mean±SD DAS28 5.3 ±1. 5.3 ± 1.2 ESR, median (P25–P75) 126.0 (20.0–46.0) 32.5 (18.0–47.0) SJC, median (P25–P75) 9.0 (4.0–13.0) 9.0 (4.0–12.0) TJC, median (P25–P75) 8.0 (4.0–13.0) 6.0 (3.0–11.0) VAS GH, median (P25–P75) 67.0 (50–80) 63.0 (40.0–75.0) Glucocorticoids (oral), n (%) 13 (56.5) 93 (56.7) Dose (mg), median (P25–P75) 10.0 (5.0–15.0) 10.0 (5.0–10.0) Glucocorticoids (im/ia), n (%) 4 (17.4) 27 (16.5) Dose (mg), median (P25–P75) 120.0 (105.0–120.0) 120.0 (80.0–120.0) Previous DMARDS*, median (P25–P75) 6.0 (4.0–9.0) 5.0 (4.0–7.0) Previous anti-TNF*, median (P25–P75) 3.0 (2.0–4.0) 3.0 (2.0–4.0) Co-therapy with methotrexate†, n (%) 15 (65.2) 98 (79.3) Rheumatoid factor +, n (%) 21 (79.3) 130 (91.3) Mean±SD duration statin use‡ (years) 2.8 ± 3.0 – Patients completing a course of RTX§, n 23 (100%) 164 (100%) (%) *Medication prescribed prior to the start of treatment with RTX. †Concomitant prescription of methotrexate at start of RTX treatment. ‡Duration of statin use at baseline. §A complete course of RTX consists of two infusions 2 weeks apart. DAS28, Disease Activity Score using 28 joint counts; ESR, erythrocyte sedimentation rate; ia, intra-articular injection; im, intramuscular injection; RTX, rituximab; SJC, swollen joint count; TJC, tender joint count; TNF, tumour necrosis factor; VAS GH, visual analogue scale general health.
191
Figure 1 Effect of concomitant statins on (A) course of disease activity (DAS28) over time and (B) cumulative survival curve for rituximab effective period. References 1. Cheson BD, Leonard JP. Monoclonal antibody therapy for B-cell non-Hodgkin’s lymphoma. N Engl J Med 2008;359:613-26 . 2. Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary effi cacy and safety at twenty-four weeks. Arthritis Rheum 2006;54:2793-806 . 3. Winiarska M, Bil J, Wilczek E, et al. Statins impair antitumor effects of rituximab by inducing conformational changes of CD20. PLoS Med 2008;5:e64 . 4. Goldstein MR, Mascitelli L, Pezzetta F. Monoclonal antibody therapy and nonHodgkin’s lymphoma. N Engl J Med 2009;360:192;author reply 193. 5. Rabinowitz I. Interaction between statins and rituximab in non-Hodgkin’s lymphoma. J Clin Oncol 2008;26:5486;author reply 5486. 6. Deans JP, Li H, Polyak MJ. CD20-mediated apoptosis: signalling through lipid rafts. Immunology 2002;107:176-82 . 7. Janas E, Priest R, Wilde JI, et al. Rituxan (anti-CD20 antibody)-induced translocation of CD20 into lipid rafts is crucial for calcium infl ux and apoptosis. Clin Exp Immunol 2005;139:439-46 . 8. Nowakowski GS, Maurer MJ, Habermann TM, et al. Statin use and prognosis in patients with diffuse large B-cell lymphoma and follicular lymphoma in the rituximab era. J Clin Oncol 2010;28:412-17 . 9. Samaras P, Heider H, Haile SR, et al. Concomitant statin use does not impair the clinical outcome of patients with diffuse large B cell lymphoma treated with rituximab-CHOP. Ann Hematol 2010;89:783-7 . Gepubliceerd: Ann Rheum Dis. 2010;doi:10.1136/ard.2010.136093 Impact factor: 8.111
13. Methotrexate bioavailability van Roon EN1, van de Laar MA2
192
1
Department of Pharmacotherapy and Pharmaceutical Care, University of Groningen, Groningen 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede The clinical relevance of the concept of bioavailability rests on two main principles. First, that measurement of the active component at the site of action is generally not possible and, secondly, that a relationship exists between on the one hand efficacy and/or safety and on the other hand concentration of the active compound or its active metabolite(s) in the systemic circulation. Applying these principles to the current knowledge on methotrexate (MTX), it is clear that bioavailability of MTX is an important parameter for optimal dosing. In this manuscript the current knowledge on MTX bioavailability is reviewed. This review reveals that bioavailability of MTX in higher oral doses is decreased, most probably by limitation of absorption from the gastro-intestinal tract. It is suggested that higher doses can be given either by splitting the oral dose or by parenteral administration. Both will result in improved bioavailability as compared with one higher oral dose. However, larger, prospective studies directly comparing the efficacy and safety of the splitted oral dose strategy and the switch to parenteral MTX are needed. Gepubliceerd: Clin Exp Rheumatol. 2010;28(5 Suppl 61):S27-32 Impact factor: 2.396
14. Comparison of measures of functional disability in patients with gout Ten Klooster PM1, Oude Voshaar MA1, Taal E1, van de Laar MA1,2 1 Department of Psychology and Communication of Health and Risk, Institute for Behavioural Research, University of Twente, Enschede 2 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 αԜ≥0.93), strong intercorrelations (rԜ≥Ԝ0.75), 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
193
current instruments cover all aspects of physical functioning relevant to patients with gout. Gepubliceerd: Rheumatology (Oxford). 2010;doi:10.1093/rheumatology/keq387 Impact factor: 4.236
15. Body-self unity and self-esteem in patients with rheumatic diseases Bode C1, van der Heij A1, Taal E1, van de Laar MA1,2 1 Institute for Behavioural Research, University of Twente, Enschede 2 Department of Rheumatology, Medisch Spectrum Twente, Enschede Perceptions and evaluations of the own body are important sources of self-esteem. Having a rheumatic disease challenges maintenance of positive self-esteem due to consequences of the disease such as unfavorable sensations as pain and limited (physical) functioning. We expect that a positive experience of the own body in spite of a rheumatic disease (body-self harmony) will be associated with higher levels of self-esteem and that experiencing the body as unworthy part of the own person or as disabler for own strivings (body-self alienation) will result in lower levels of selfesteem. For this explorative study, the body experience questionnaire (BEQ) measuring body-self unity was developed and piloted. One hundred sixty-eight patients visiting the outpatient rheumatology clinic of the Medisch Spectrum Twente, Enschede, The Netherlands, completed a questionnaire on touchscreen computers to measure body-self unity (BEQ), illness cognitions (illness cognition questionnaire), pain intensity, functional limitations (health assessment questionnaire disability index), self-esteem (Rosenberg Self-Esteem Scale) and demographics. To analyze predictors of self-esteem, hierarchical regression analyses were employed. The BEQ revealed a two-factor structure with good reliability (subscale harmony, four items, Cronbach's α = 0.76; subscale alienation, six items, Cronbach's α = 0.84). The final model of the hierarchical regression analyses showed that self-esteem can be predicted by the illness cognitions helplessness and acceptance, by harmony and most strongly by alienation from the body. R(2) of the final model was 0.50. The relationship between functional limitations and self-esteem was totally mediated by the psychological constructs body-self unity and illness cognitions. This explorative study showed the importance of the unity of body and self for self-esteem in patients with a rheumatic disease. Gepubliceerd: Psychol Health Med. 2010;15(6):672-684 Impact factor: 0
16. Non-Steroidal Anti-Inflammatory Drugs: An Overview of Cardiovascular Risks IL Meek, MA van de Laar, HE Vonkeman Department of Rheumatology and Clinical Immunology, Medisch Spectrum Twente and University of Twente, Enschede While aspirin may offer protection, other non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) can cause serious cardiovascular side effects and complications.
194
This has led to a general "black box" warning for cardiovascular adverse events for NSAIDs. This review explores the different mechanisms underlying the protective effects of aspirin, the NSAID associated renovascular effects causing hypertension, edema and heart failure, the cardiovascular effects causing myocardial infarction and stroke, and the possible deleterious interaction between NSAIDs and aspirin. Gepubliceerd: Pharmaceuticals 2010;3(7):2146-62 Impact factor: 0
17. Risk management of risk management: Combining proton pump inhibitors with low-dose aspirin HE Vonkeman, IL Meek, MA van de Laar Department of Rheumatology and Clinical Immunology, Medisch Spectrum Twente and University of Twente, Enschede Low-dose aspirin is widely used in the primary and secondary prevention of cardiovascular events, but is associated with a range of upper gastrointestinal side effects. In this review, we summarize the rationale for low-dose aspirin therapy, quantify the risk for upper gastrointestinal side effects, identify the risk factors involved, and provide an overview of preventive strategies, thereby focusing on the rationale and clinical utility of combining proton-pump inhibitors with low-dose aspirin. Gepubliceerd: Drug, Healthcare and Patient Safety 2010;2:191-204 Impact factor: 2.612
Totale impact factor: 57.042 Gemiddelde impact factor: 3.355 Aantal artikelen 1e, 2e of laatste auteur: 12 Totale impact factor: 31.916 Gemiddelde impact factor: 2.660
195
Revalidatiegeneeskunde 1. Relationships between coping strategies and lumbar muscle activity in subjects with chronic low back pain van der Hulst M1, Vollenbroek-Hutten M1, Schreurs K1, Rietman J1,2, Hermens H1 1 Roessingh Research & Development, enschede 2 Department of Rehabilitation Medicine, Medisch Spectrum Twente, Enschede Background: Concerning chronic low back pain (CLBP), different cognitivebehavioral models have hypothesized that coping strategies play a role in the chronification of pain by changes in physical activity. Strategies such as avoidance or persistent coping may be related to changes in (lumbar) muscle activity. AIM: Investigate the different coping strategies present in CLBP and whether these are differentially related to lumbar muscle activity during walking. Methods: In a cross sectional study, 63 subjects with CLBP walked on a treadmill at 3.8km/h. Coping strategies were measured with the Dutch version of the Coping Strategies Questionnaire and three factors were identified with principal component analysis. Surface electromyography data of the erector spinae were obtained and smooth rectified electromyography (SRE) values were averaged per periods of swing and double support. The ratio of SRE values (swing/double support) was used as a measure of relaxation. The relation between SRE values and coping strategies was analyzed with random coefficient analysis. Results: Three coping strategies (i.e. "catastrophizing", "distraction" and "persistence and control") could be discerned. "Catastrophizing" was positively related to (natural logarithm) SRE values (beta=0.06, 95% CI=0.01-0.10; R(2)=7.7%). "Distraction" was negatively associated with SRE ratios (beta=-0.03, 95% CI=-0.05 to -0.01; R(2)=7.5%). No relation was found between "persistence and control" and SRE values or ratios. Conclusions: In CLBP, a maladaptive coping strategy like "catastrophizing" is related to increased lumbar muscle activity, and an adaptive strategy like "distraction" to increased lumbar muscle relaxation during walking. Gepubliceerd: Eur J Pain. 2010;14(6):640-7 Impact factor: 3.371
2. Lumbar and abdominal muscle activity during walking in subjects with chronic low back pain: support of the "guarding" hypothesis? van der Hulst M1,2, Vollenbroek-Hutten MM1,3, Rietman JS1,2,3,4, Hermens HJ1,3 1 Roessingh Research and Development, Enschede 2 Rehabilitation Centre het Roessingh, Enschede 3 Faculty of Electrical Engineering, Mathematics and Informatics, University of Twente, Enschede 4 Department of Rehabilitation Medicine, Medisch spectrum Twente, Enschede It has been hypothesized that changes in trunk muscle activity in chronic low back pain (CLBP) reflect an underlying "guarding" mechanism, which will manifest itself
196
as increased superficial abdominal - and lumbar muscle activity. During a functional task like walking, it may be further provoked at higher walking velocities. The purpose of this cross sectional study was to investigate whether subjects with CLBP show increased co-activation of superficial abdominal - and lumbar muscles during walking on a treadmill, when compared to asymptomatic controls. Sixty-three subjects with CLBP and 33 asymptomatic controls walked on a treadmill at different velocities. Surface electromyography data of the erector spinae, rectus abdominis and obliquus abdominis externus muscles were obtained and averaged per stride. Results show that, compared to asymptomatic controls, subjects with CLBP have increased muscle activity of the erector spinae and rectus abdominis, but not of the obliquus abdominis externus. These differences in trunk muscle activity between groups do not increase with higher walking velocities. In conclusion, the observed increased trunk muscle activity in subjects with CLBP during walking supports the guarding hypothesis. Gepubliceerd: J Electromyogr Kinesiol. 2010;20(1):31-8 Impact factor: 1.995
3. Stop using the Ashworth Scale for the assessment of spasticity Fleuren JF1, Voerman GE1, Erren-Wolters CV1, Snoek GJ1, Rietman JS1,2,3,4, Hermens HJ1,3, Nene AV1 1 Roessingh Research and Development, Enschede 2 Rehabilitation Centre het Roessingh, Enschede 3 Faculty of Electrical Engineering, Mathematics and Informatics, University of Twente, Enschede 4 Department of Rehabilitation Medicine, Medisch spectrum Twente, Enschede Aim: Many studies have been performed on the methodological qualities of the (modified) Ashworth Scale but overall these studies seem inconclusive. The aim of this study was to investigate the construct validity and inter-rater reliability of the Ashworth Scale (AS) for the assessment of spasticity in the upper and lower extremities. Method: A cross-sectional study on spasticity in the elbow flexors (part 1) and knee extensors (part 2) was carried out. In both parts AS was assessed while muscle activity and resistance were recorded simultaneously in patients with upper motor neuron syndrome. Each patient was measured by three raters. Results: 30 patients participated, 19 in each part of the study. For elbow flexor muscles, AS was not significantly associated with electromyographic parameters, except for rater 2 (rho = 0.66, p<0.01). A significant moderate association was found with resistance (0.54< or = rho < or =0.61, p<0.05). For knee extensors, AS scores were moderately associated with muscle activity (0.56< or = rho < or =0.66, p<0.05) and also with resistance (0.55< or = rho < or =0.87, p<0.05). The intraclass correlation coefficient for absolute agreement was 0.58 for elbow flexors and 0.63 for knee extensors. In linear mixed model analysis, the factor rater appeared to be highly associated with AS. Conclusion: The validity and reliability of the AS is insufficient to be used as a measure of spasticity.
197
Gepubliceerd: J Neurol Neurosurg Psychiatry. 2010;81(1):46-52 Impact factor: 4.869
4. Back muscle activation patterns in chronic low back pain during walking: a "guarding" hypothesis van der Hulst M1,2, Vollenbroek-Hutten MM1,3, Rietman JS1,2,3,4, Schaake L1, Groothuis-Oudshoorn KG1, Hermens HJ1,3 1 Roessingh Research and Development, Enschede 2 Rehabilitation Centre het Roessingh, Enschede 3 Faculty of Electrical Engineering, Mathematics and Informatics, University of Twente, Enschede 4 Department of Rehabilitation Medicine, Medisch spectrum Twente, Enschede Objectives: To investigate whether patients with chronic low back pain (CLBP) show "guarded" movements during walking. It is hypothesized that guarding will be reflected by increased lumbar muscle activity during all periods of stride and secondary, relatively lesser relaxation during periods of swing compared with double support. Furthermore, it is hypothesized that higher levels of perceived fear and disability are related to increased muscle activity and less relative relaxation. Materials and methods: In a cross-sectional study 63 patients with CLBP and 33 healthy controls walked on a treadmill at 3.8 km/h. Surface electromyography (sEMG) data of the erector spinae were obtained and smoothed rectified sEMG (SRE) values were calculated per period of swing and double support. The ratio of SRE values in swing to double support was used as a measure of relative relaxation (SRE ratio). In addition, the relationship between SRE values, the Roland Morris Disability Questionnaire, and the Tampa Scale for Kinesiophobia was analyzed in patients with CLBP. Results: Mean SRE values were significantly higher in patients with CLBP than in controls both during periods of double support and swing. SRE ratios were not significantly different between groups. Results showed no influence of disability or fear of movement on either SRE values or ratios. Discussion: In patients with CLBP, increased lumbar muscle activity during all periods of stride, with comparable alteration between swing and double support, suggests difficulties with total muscle relaxation. On the basis of this evaluation, it is concluded that patients with CLBP show a guarding mechanism during walking. No relationship is found between perceived fear, disability, and muscle activity. Gepubliceerd: Clin J Pain. 2010;26(1):30-7 Impact factor: 3.005
5. A Longitudinal Comparison of Arm Morbidity in Stage I-II Breast Cancer Patients Treated with Sentinel Lymph Node Biopsy, Sentinel Lymph Node Biopsy Followed by Completion Lymph Node Dissection, or Axillary Lymph Node Dissection Kootstra JJ1,2, Hoekstra-Weebers JE3,4,5, Rietman JS6,7, de Vries J1, Baas PC8, Geertzen JH5, Hoekstra HJ1
198
1
Department of Surgical Oncology, UMC Groningen, University of Groningen, Groningen; 2 Department of Surgery, Isala Klinieken, Zwolle 3 Wenckebach Institute, UMC Groningen, University of Groningen, Groningen; 4 Comprehensive Cancer Center North-East, Groningen; 5 SHARE, Graduate School for Health Research, University of Groningen, Groningen; 6 Roessingh Research and Development, Enschede; 7 Laboratory of Biomedical Engineering, Faculty of Engineering Technology, Twente University, Enschede; 8 Department of Surgery, Martini Hospital, Groningen; 9 Department of Rehabilitation, University Medical Centre Groningen, University of Groningen, Groningen Background: Long-term shoulder and arm function following sentinel lymph node biopsy (SLNB) may surpass that following complete axillary lymph node dissection (CLND) or axillary lymph node dissection (ALND). We objectively examined the morbidity and compared outcomes after SLNB, SLNB + CLND, and ALND in stage I/II breast cancer patients. Materials and methods: Breast cancer patients who had SLNB (n = 51), SLNB + CLND (n = 55), and ALND (n = 65) were physically examined 1 day before surgery (T0), and after 6 (T1), 26 (T2), 52 (T3), and 104 (T4) weeks. Differences in 8 parameters between the affected and unaffected arms were calculated. General linear models were computed to examine time, group, and interaction effects. Results: All outcomes changed significantly, mostly nonlinearly, over time (T0-T4). Between T1 and T4, limitations decreased in abduction (all groups); anteflexion, abduction-exorotation, abduction strength (SLNB + CLND, ALND); flexion strength (SLNB + CLND); and arm volume (SLNB, SLNB + CLND). At T4, limitations in anteflexion (SLNB, ALND), abduction (SLNB + CLND, ALND), exorotation (ALND), abduction-exorotation (all groups), and volume (SLNB + CLND, ALND) increased significantly compared with T0. The SLNB group showed an advantage in anteflexion, abduction, abduction-exorotation, and volume. Groups changed significantly but differently over time in anteflexion, abduction, abduction/exorotation, abduction strength, flexion strength, and volume. Effect sizes varied from 0.19 to 0.00. C Conclusion: Initial declines in range of motion and strength were followed by recovery, although not always to presurgery levels. Range of motion and volume outcomes were better for SLNB than ALND, but not strength. SLNB surpassed SLNB + CLND in 2 of the range of motion variables. The clinical relevance of these results is negligible. Gepubliceerd: Ann Surg Oncol. 2010;17(9):2384-94 Impact factor: 4.130
Totale impact factor: 17.37 Gemiddelde impact factor: 3.474 Aantal artikelen 1e, 2e of laatste auteur: 0 Totale impact factor: 0 Gemiddelde impact factor: 0
199
Spoedeisende Hulp 1. Acute pijn op de Spoedeisende Hulp: beter behandelen Gaakeer MI1, Veugelers R2, Houser CM3, Berben SA4, Bierens JJ5 1 Medisch Spectrum Twente, afd. Spoedeisende Geneeskunde, Enschede 2 Albert Schweitzer Ziekenhuis, afd. Spoedeisende Geneeskunde, Dordrecht 3 AMC /Universiteit van Amsterdam, afd. Spoedeisende Geneeskunde, Amsterdam 4 Universitair Medisch Centrum St Radboud, afd. Spoedeisende Hulp, Nijmegen 5 Maxima Medisch Centrum, afd. Anesthesiologie, 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. 2010;154(2):A2241 Impact factor: 0
2. Pain management in emergency departments: a review of present protocols in The Netherlands Gaakeer MIa, van Lieshout JM b, Bierens JJ c a Department of Emergency Medicine, Medisch Spectrum Twente, Enschede b Department of Emergency Medicine, Oosterschelde Hospital, Goes c Department of Anaesthesiology, VU UMC, Amsterdam This descriptive study presents availability and content of acute pain protocols in emergency departments (EDs) in The Netherlands. Current acute pain protocols were collected and an a priori list of questions was used for analysis. Findings were compared with current international standards. Sixty-six of the 108 EDs responded. Fifty-six percent of the protocols did not address adults and 35% did not address children. Protocols were rather conservative and showed poor multidisciplinary approach. Seventy-three percent required a diagnosis before pain relief. Six percent did not include opioids, 36% did not allow intravenous opioids and only 49% allowed direct administration of opioids in severe pain. Pain measurement was included in 55% and in only 5% a target score was defined. Nonpharmacological approaches were mentioned in 6%. Acute pain protocols are lacking in many EDs. Most protocols did not apply current standards. We exposed an area with space for leadership. Gepubliceerd: Eur J Emerg Med. 2010 Oct;17(5):286-9 Impact factor: 0.733
200
Totale impact factor: 0.733 Gemiddelde impact factor: 0.367 Aantal artikelen 1e, 2e of laatste auteur: 2 Totale impact factor: 0.733 Gemiddelde impact factor: 0.367
201
Thoraxchirurgie 1. Reply Arrigoni SC1, Mecozzi G1, Zijlstra F2, Mariani MA2 1 Department of Thoracic Surgery, Thoraxcentrum Twente, Enschede 2 Department of Thoracic Surgery, Thoraxcentrum UMC Groningen, Groningen Gepubliceerd: Ann Thorac Surg. 2010;90(4):1393-4 Impact factor: 3.644
2. Off pump Y-graft coronary artery bypass in a patient with situs inversus totalis Arrigoni SC1, Oosterhof R2, Mariani MA2 1 Department of Thoracic Surgery, Thoraxcentrum Twente, Enschede 2 Department of Thoracic Surgery, Thoraxcentrum UMC Groningen, Groningen Situs inversus is the mirror image of situs solitus. Situs inversus with dextrocardia is termed 'situs inversus totalis'. Since situs inversus totalis is a rare condition, there are a only a few reports about off-pump coronary artery bypass (OPCAB) in these patients. A 67-year-old man with a diagnosis of situs inversus totalis and threevessel disease, underwent an elective surgical revascularization. The operation consisted of an OPCAB using a total arterial composite Y-graft. The right internal mammary artery (RIMA) and the left radial artery (RA) were harvested as pedicles and they were anastomized as Y-grafts. Three distal anastomoses were performed: the RIMA to the anterior descending artery and the RA sequentially to the obtuse marginal branch and the posterior descending artery. The peculiarity of OPCAB notouch with a composite graft in a patient with situs inversus totalis consisted in the mirroring of the whole surgical set-up and of the surgical strategy. The surgery as well as the postoperative period were uneventful. This case report shows the feasibility of OPCAB 'no-touch' with composite arterial grafting in a patient with situs inversus totalis. Gepubliceerd: Interact Cardiovasc Thorac Surg. 2010;11(6):822-4 Impact factor: 0
Totale impact factor: 3.644 Gemiddelde impact factor: 1.822 Aantal artikelen 1e, 2e of laatste auteur: 2 Totale impact factor: 3.644 Gemiddelde impact factor: 1.822
202
