1
Verslag 2009 - 2014
INLEIDING
Het CGOA is een samenwerkingsverband van alle gynaecoloog-oncologen in Amsterdam, te weten van het AMC, het NKI-AVL en het VUmc. De Raden van Bestuur hebben in 2008 de ambitie uitgesproken om samen te werken op het gebied van de gynaecologische oncologie. Hiertoe is het Centrum voor Oncologische Gynaecologie Amsterdam (CGOA) opgericht, aangestuurd door hoogleraar prof. dr. Gemma Kenter, die leiding geeft aan de (sub)afdelingen oncologische gynaecologie van de drie ziekenhuizen. Zij is van buiten angetrokken en per 1 augustus 2009 gestart. Deze opzet biedt een unieke kans om van afzonderlijke afdelingen één geheel te maken en daarmee een Center of Excellence binnen Nederland en Europa te worden. Door samenwerking kunnen zowel patiëntenzorg, onderwijs, opleiding en wetenschap op hoog niveau worden uitgeoefend en kan het CGOA een belangrijke plaats gaan innemen in dit veld. De groep oncologisch gynaecologen van het CGOA verzorgt de oncologische gynaecologie in drie instituten te weten AMC, NKI-AVL en VUmc en de consultatieve diensten in de gehele IKA regio en een deel van de IKST regio. De patiëntenzorg is gericht op de behandeling van (pre)maligne aandoeningen van de vrouwelijke geslachtsorganen. Dit behoort tot de categorie laag volume en hoog complexe zorg. Er wordt op drie locaties gewerkt. Het team bestaat uit een groep geregistreerde gynaecoloog- oncologen aangevuld met fellows in opleiding tot gynaecoloog-oncoloog, een verpleegkundig specialist, een physician assistent, een screeningsarts voor erfelijke tumoren en een team van verpleegkundigen op de poliklinieken en de verpleegafdelingen. Er wordt nauw samengewerkt met medisch onvcologen, radiotherapeuten, chirurgen en plastisch chirurgen, urologen, radiologen en pathologen. Tevens wordt psycho-sociale ondersteuning rond het ziekteproces geboden door maatschappelijk werkenden. Het CGOA biedt opleiding voor basis- en differentiatie-aios. In dit verslag worden de ontwikkelingen beschreven in de periode 2009-2014 op gebied van patiëntenzorg, wetenschap, onderwijs en opleiding.
2
QUOTES VAN DE CGOA BESTUURDERS VAN HET EERSTE UUR:
Maas Jan Heineman, AMC: Wanneer professionals elkaar vinden in de gezamenlijke ambitie om de best mogelijke zorg voor hun patiënten te realiseren dan staan individuele belangen minder op de voorgrond, dan verdwijnen de grenzen van instituties, en dan draag je bij aan de ontwikkeling van je vak. Dat waren de gedachten die speelden toen we 5 jaar geleden startten met het ontwerp van het CGOA. Inmiddels is het fundament gelegd en vordert de bouw gestaag. Ik heb de hoop en verwachting dat het resultaat van de CGOA-samenwerking een voorbeeld voor veel anderen zal zijn. Hans Schoo, AVL: De samenwerking binnen de oncologische gynaecologie in Amsterdam kent een lange historie. Het vormen van het gynaecologisch-oncologische centrum van AMC, AVL en VUmc – het CGOA – in 2009 bleek een logische vervolgstap. Veel van de oorspronkelijke doelstellingen zijn inmiddels verwezenlijkt. Echte samenwerking is verder tot stand gekomen, met daarbij de patiënt goed in het vizier. Met dezelfde ambitie als vijf jaar geleden – kunnen de uitdagingen voor de toekomst worden aangegaan. Ik wens jullie daar veel succes bij. Hans Brölmann, VUmc: Dat in Amsterdam de krachten van gynaecologisch-oncologische centra moesten worden gebundeld, gelet op complexiteit en frequentie van deze zorg, was ook 5 jaar geleden vanzelfsprekend. De weg naar deze concentratiebeweging kent vele obstakels. Het einde is nog niet in zicht, maar er zijn al goede stappen gezet. Sterkte met het volbrengen van de taak.
PATIENTENZORG
Er is veel aandacht besteed aan het uniformeren van de werkwijze op 3 locaties, en dit wordt door de medewerkers van het CGOA gezien als enorme winst. De richtlijnen voor diagnostiek en behandeling van de meest voorkomende gynaecologische tumoren zijn multidisciplinair opgesteld. Het betreft de richtlijnen endometrium-, cervix-, vulva- en ovariumcarcinoom en uterussarcomen. De meest recente tekst van de richtlijnen is te vinden op de website van het CGOA (www.cgoa.nl). Op alle locaties bestaat een multidisciplinair overleg waar alle nieuwe en recidief patiënten worden besproken. Tevens is veel aandacht besteed aan het invoeren van de sneldiagnostiek met als doel om binnen enkele dagen na het eerste polikliniekbezoek een behandelplan te kunnen overleggen en te bespreken met de patiënt. Vanwege de complexiteit van de zorg binnen de gynaecologische oncologie bestaat conform de wensen van de beroepsgroep, verzekeraars en inspectie- de behoefte om over te gaan tot zoveel mogelijk concentratie van zorg. Sinds 1-1-2012 worden nieuwe patiënten uitsluitend gezien op 2 lokaties: Meibergdreef en Plesmanlaan. De complexe behandelingen vinden ook op die locaties plaats. In het VUmc ligt de nadruk op minimaal invasieve verrichtingen.
3
4 Aantal nieuwe patiënten/tumorsoort: in 5 jaar 30% gegroeid
Aantal nieuwe patienten/tumorsoort: in 5 jaar 30% gegroeid
1200 1000
800 600 400 200 0 vulva vagina cervix endometrium ovarium trofoblast overig totaal
2009 76 14 180 149 245 5 23 692
2010 91 10 186 167 315 10 16 795
2011 102 20 206 180 323 16 24 871
2012 111 12 220 166 403 10 29 951
2013 84 13 173 216 393 5 48 932
2014 129 20 192 222 413 10 41 1027
Behandelingen per jaar per tumorsoort:
900
gast OK deb/stg2
800
robot sta
700
lap stg
600
met LA
proeflap aeu/tlh
500
exen robot RH
400
RH
300
abd trach
200
conus
100
met SN
lieskl dis RV/RLE
0 2009
2010
2011
2012
2013
2014
5
Tabel: behandelingen per jaar per tumorsoort 2009
2010
2011
2012
2013
2014
rad vulvectomie/ruime lokale excisie
61
73
97
93
75
98
met sentinel node
26
26
42
35
36
62
liesklierdissectie
16
20
19
20
19
32
conisatie
12
26
25
16
13
17
abd trachelectomie
0
0
2
6
1
2
open radicale hysterectomie
56
57
69
78
57
48
robot geassisteerde radicale hysterectomie
0
4
0
5
5
7
exenteratie
4
6
2
6
9
5
abd hysterectomie /tlh voor cx of corpus ca
140
130
131
116
106
122
met lymphadenectomie
8
15
26
29
18
21
proeflaparotomie verdenking ovariumcarcinoom 0
0
0
61
82
105
laparoscopische stagering
9
17
28
27
28
17
robot geassisteerde stagering
0
0
0
6
18
13
debulking /stagering ovariumcarcinoom
218
192
204
206
288
254
gastoperatie regio
95
83
77
86
7
5
totaal
645
649
722
790
762
808
Tussen 2009 en 2014 werden 23 patienten met een cervixcarcinoom verwezen naar andere centra voor een vaginale trachelectomie
Rogoa: Verwijzingen hoog complexe zorg Het CGOA vormt samen met ziekenhuizen uit de regio het ROGOA (Regionaal Overleg Gynaecologische Oncologie Amsterdam). Deze regio omvat de oorspronkelijke IKA regio evenals de IKST regio en het St. Jansdal in Harderwijk. In 2010 zijn in samenwerking met het IKNL alle regionale ziekenhuizen bezocht voor het bespreken en bevestigen van de bestaande afspraken. Met alle aangesloten ziekenhuizen worden (twee) wekelijks consultatieve besprekingen gevoerd per video-conferencing. Alle patienten met een cervix- of vulvacarcinoom worden verwezen naar het CGOA. Voor de behandeling van patiënten met een (verdenking op) ovariumcarcinoom en patiënten met een hoog risico endometriumcarcinoom wordt gewerkt volgens afspraken binnen het “ROGOA“. Dit betekent dat over al deze patiënten wordt overlegd met één van de oncologisch gynaecologen uit het centrum over wijze en plaats van behandeling. Operaties op locatie, zg, gastoperaties, vonden tot 1-1-2013 plaats in bijna alle ziekenhuizen die bij het Rogoa zijn aangesloten. Sinds 1-1-2013 worden alle patiënten op verdenking ovariumcarcinoom voor een proeflaparotomie verwezen naar het CGOA.
6 De ziekenhuizen waarvoor het CGOA fungeert als verwijscentrum zijn de volgende:
St. Lucas/Andreas ziekenhuis (Amsterdam) OLVG (Amsterdam) Slotervaart ziekenhuis (Amsterdam) BovenIJ ziekenhuis (Amsterdam) Ziekenhuis Amstelland (Amstelveen) Zaans Medisch Centrum (Zaandam) Waterlandziekenhuis (Purmerend) West Fries Gasthuis (Hoorn) Rode Kruis Ziekenhuis (Beverwijk) Gemini ziekenhuis (Den helder) Medisch centrum Alkmaar (Alkmaar) Ter Gooi ziekenhuizen (Hilversum en Blaricum) Flevoziekenhuis (Almere) IJsselmeer ziekenhuis (Lelystad) Kennemer Gasthuis (Haarlem) Spaarne Ziekenhuis (Hoofddorp) Deventer Ziekenhuis (Deventer) Gelre Ziekenhuizen (Apeldoorn en Zutphen) Sint Jansdal (Harderwijk ) sinds 1-1-2012 De oncologische gynaecologie van het CGOA trekt topreferente zorg aan, gerekend over > 7.5 km komt dat op 91% en >20 km op 67%.
7 Verwijspatronen CGOA 2014
5
0
Informatie per tumorsoort: Voor de meest voorkomende tumorsoorten wordt hier achtereenvolgens weergegeven: aantallen per stadium en behandelresultaten over de afgelopen 5 jaar. Deze gegevens komen voort uit de data van de Nederlandse Kanker Registratie (NKR) en geven de absolute overleving weer. Dat betekent dat de sterfte oorzaak niet altijd bekend was en niet altijd gerelateerd aan de ziekte. Er is soms discrepantie tussen de aantallen afkomstig uit de database van het CGOA (nieuwe patiënten per tumorsoort) en die van de NKR (stadia en resultaten)vanwege de verschillen die worden gehanteerd in registratie tussen de database van het CGOA en die van de NKR.
8 VULVACARCINOOM
Stadium bij diagnose
stadium bij diagnose
80
Aantallen per stadium
70 60 50
onbekend 4
40
3 2
30
1b 1a
20 10 0 2009
2010
2011
2012
2013
Overleving van patiënten met vulvacarcinoom gediagnosticeerd tussen 2005 en 2013, naar FIGO- stadium Overleving van patiënten met vulvacarcinoom gediagnosticeerd tussen 2005 en 2013, naar FIGO- stadium
9 CERVIXCARCINOOM
Stadium bij diagnose
180
stadium bij diagnose
160
Aantallen per stadium
140 rec
120
IV
100
III
80
IIB
60
Ib/IIa
IB2/IIa2 Ia
40 20 0 2009
2010
2011
2012
2013
Figure 1: Overleving van patiënten met baarmoederhalskanker gediagnosticeerd tussen 2005 en 2013, naar FIGOstadium Overleving van patiënten met baarmoederhalskanker gediagnosticeerd tussen 2005 en 2013, naar FIGO- stadium
10 CORPUSCARCINOOM
Stadium bij diagnose
200
Stadium bij diagnose
180
Aantallen per stadium
160 140
overig
120
IV III
100
2
80
Ic
60
Ib Ia
40 20
0 2009
2010
2011
2012
2013
Overleving van patiënten met baarmoederkanker gediagnosticeerd tussen 2005 en 2013, naar FIGO- stadium Overleving van patiënten met baarmoederkanker gediagnosticeerd tussen 2005 en 2013, naar FIGO- stadium
11 OVARIUMCARCINOOM
Stadium verdeling
stadium verdeling
250
Aantallen per stadium
200
150
IV
III II
100
I
50
0 2009
2010
2011
2012
2013
Overleving van patiënten met ovariumcarcinoom gediagnosticeerd tussen 2005 en 2013, naar FIGO-stadium Overleving van patiënten met ovariumcarcinoom gediagnosticeerd tussen 2005 en 2013, naar FIGO-stadium
12 RESEARCH CGOA
In de periode 2009-2014 is veel aandacht besteed aan het combineren van de bestaande researchlijnen en het bijeen brengen van de beste onderzoekers binnen die lijnen en de 3 instituten. Daarbij hoort het samenvoegen van klinische data en opgeslagen biomateriaal voor klinische studies. Er wordt gefocused op 3 onderzoekslijnen, zoals hier onder beschreven:
Translationele research Ia: Immunotherapie, immunosurveillance en screening bij HPV gerelateerde (pre) maligniteiten - Immunotherapie in HPVgerelateerde afwijkingen; Gemma Kenter, John Haanen (NKI), Ton Schumacher (NKI), PiaKvistborg (NKI), KatjaJordanova (VUmc), Willemien van Driel), Marc v. Beurden, Lot Zuur (H&N, NKI), Jan Paul de Boer (H&N, NKI), Joost van de Berg (NKI), Sjoerd van de Burg (LUMC), Hans Nijman (UMCG), Kees Melief (ISA pharmaceuticals) - Immunosurveillance bij HPV infectie, de rol van de drainerende lymfe klieren en het micro-milieu in HPV gerelateerde tumoren. Katja Jordanova (VUmc), Henry Zijlmans, Gemma kenter (CGOA), Tanja de Gruil (VUmc) - HPV bij de screening op cervixcarcinoom; Chris Meijer, Peter Snijders, Hans Berkhof, Renske Scheepmaker, Gemma Kenter
Ib: Biomarkers in gynaecologische maligniteiten Genetische profielen inclusief proteomics ten behoeve van de ontwikkeling van behandeling op maat van patiënten met een ovariumcarcinoom. Marrije Buist, Frederike Dijk, Marc van de Vijver, Hans Aerts, Danielle Meijer, Koen vande Vijver, Gemma Kenter - Detectie van markers bij de ontwikkeling van het vulva carcinoom in patiënten met chronische afwijkingen aan de vulva; Maaike Bleeker, Mark v. Beurden, Renske Steenbergen, Gemma Kenter - Biomarkers in ovarium carcinoom; Christianne Lok, Marrije Buist, Rienk van Nieuwland, Tiny Korse, Gemma Kenter
13 Klinische evaluatie studies, innovatie en kwaliteit van leven - Ovhipec trial; intra-abdominale chemo-hyperthermie tijdens interval debulking in ovarium carcinoom; Willemien van Driel, Gabe Sonke, Harm van Tinteren - Lapovca trial: Laparoscopie in de preoperatieve work-up bij het gevorderd ovarium carcinoom; Marrije Buist, Ben Willem Mol, Gemma Kenter - EORTC 55994: Neo-adjuvante chemotherapie gevolgd door radicale chirurgie versus primare chemoradiatie bij bulky cervix carcinoom; Gemma Kenter, Stefano Greggi, Fabio Landoni. - Prognostische modellen in cervix carcinoom; Petra Biewenga, Marrije Buist, Ko van der Velden, Lukas Stalpers, Gemma Kenter - Prognostische modellen bij het ovariumcarcinoom; Marrije Buist, Mark vd Vijver, Ben Willem Mol, Gemma Kenter, - Kwaliteit van leven na prophylactische chirurgie voor erfelijk ovarium carcinoom; Marc van Beurden, Niel Aaronson (NKI), Tiny Korse (AVL), Gemma Kenter - Late gevolgen van behandeling voor cervix carcinoom; Gemma Kenter, Ko van der Velden, Luc v. Lonkhuizen, JP Roovers (AMC), Moniek ter Kuile (psychosomatiek, LUMC), Marco de Ruiter, (anatomie LUMC), - Optical coherence tomography (OCT) in (pre)maligne vulva lesies.; Marc v. Beurden, Theo Ruers (AVL) - Gynaecologische maligniteiten in relatie tot zwangerschap; Christianne Lok, Leon Massuger (UMCN), Gemma Kenter (CGOA), Frederic Amant (Leuven)
Bovengenoemd onderzoek is gefinancierd met hulp van verschillende onderzoeksgrants: - Sexual complaints in female cancer survivors: Is there a need for treatment? Alpe d’huzes program KWF (terKuijle, Kenter, Stiggelbout). 2010 - ZON MW project (80-82310-97-11056): Towards a cost-effective diagnostic work-up for women with ovarian carcinoma. (Buist en Kenter). 2011 - Vaccination with SLP in HIV pos patients with AIN grade III. (Prins, Kenter, de Vries). ZON MW 2012 - RAID project: a translational project with the use of personalised medicine including chemo-immunotherapy in cervical carcinoma. A European consortium study. Approved may 2012
14 - NKB project: Translating immune characteristics of metastatic tumour cells into therapeutic targets for cervical cancer” (Jordanova, de Gruijl en Kenter). 2013 - Overige bijdragen: CHDR-oio; NKI-oio; divisie 3-VUmc-oio ; EORTC ; Humavac, RIVM; AMC-oio; startgeld divisie E AMC; Eur Cancer Center; Fujirebo; Eur Cancer Center grant; CKTO; Pohl- Boskam; Genticel; ISA-pharmaceuticals; CGOA en private giften
15 Promovendi: G. Fons: Tissue microarray in prognostic studies on vulva cancer. UVA, dec 2009 S. Piersma: Tumour-specific regulatory T-cells in cancer patients. Leiden 4 maart 2010 M. Heusinkveld: Pre-clinical studies on local APC and HPV-specific T cell interactions in human tumors for therapeutic vaccination strategies. Leiden May 2012 M. van den Hende: The role of HPV 16 peptide vaccination on the T cell response in HPV related disorders of the female genital tract. Leiden Mei 2012 H. Zijlmans: The cytokine profile in cervical carcinoma. Leiden febr. 2014 P. Biewenga: Prognostic variables in carcinoma of the cervix. UVA. Gepland 2015 P. de Vos van Steenwijk: The effect of HPV peptide vaccination on the local en systemic immune environment in HPV related disorders of the female genital tract. Leiden Gepland 2015 R. Wessels: Optical coherencetomography (OCT) in (pre)malignant vulva lesions. Enschede Gepland 2015 H. van Meurs: Improving treatment strategies in ovarian cancer: towards more individualized patient care. UVA. Gepland 2015 M. Rutten: Predicting outcome in ovarian cancer treatment. UVA Gepland 2015 W. Wegdam: Proteomics in ovarian carcinoma. UVA Gepland 2015 H. van Meir: Farmacological aspects of chemo-immunotherapy. Leiden Gepland 2016 D. Ferns: The immunological role of draining lymph nodes in cervical carcinoma.VU Gepland 2016 M. Derks: Morbidity or radicality in the treatment for carcinoma of the cervix. UVA. Gepland 2016 R. Luttmer: Stratification of hrHPV-positive women for risk of cervical (pre)malignant lesions’. VU Gepland 2016 S.Samuels: Immunosurveillance and Immunotherapy in carcinoma of the cervix. Gepland 2016 A. Stiekema: Biomarkers in ovarian carcinoma. UVA. Gepland 2016 I. van Luijk: Genomicprofiling in bulkytumours in cervical carcinoma: VU Gepland 2017
16 M. Heeren: Translating immune characteristics of metastatic tumour cells into therapeutic targets for cervical cancer. VU, Gepland 2017 J. v. Baal: Tripple B: Blood-Belly-Barrier in low grade and high grade ovarian cancer. UVA. Gepland 2017 M. de Vree: Risk Factors in Gestational Trophoblastic Disease. VU. Gepland 2017 R. Vermeulen: The impact of RRSO on physical en physiological health among women at increased hereditary or familial risk for ovarian cancer. VU, Gepland 2017 M. v. Zummeren: Improving cervical cancer screening by finding new objective biomarkers. VU, Gepland 2017 N. Polman: Improving cervical cancer screening by using selfsampling and biomarkers. VU, Gepland 2017 Desiree Hooij: Screening for cervical cancer in Curacao.Gepland 2017
17 OPLEIDING EN ONDERWIJS
De opleiding tot gynaecoloog vindt plaats in zowel het cluster AMC als het cluster VUmc. Beide opleidingen volgen de eindtermen en leerdoelen zoals vastgelegd in het specifieke kader besluit en het opleidingsplan. Van de totale opleidingsduur van 6 jaar vindt het eerste en laatste deel (2x 1½ jaar) plaats in niet-universitaire opleidingsklinieken. Deze zijn voor AMC en VUmc gelijk. In beide universitaire klinieken is de gynaecologische oncologie ondergebracht in een stage. Afhankelijk van het aanbod werd deze stage gevolgd in AMC of VUmc. Men kon tevens een differentiatiestage (etalagejaar) volgen in het NKI-AVL, dat sinds mei 2010 een MSRC erkende stageplek heeft van 6 – 12 maanden. Ook AIOS van andere clusters volgden een differentiatie stage in het CGOA en namen daarvoor eigen financiering mee. Op termijn zal de opleiding worden veranderd in een 2-2-2 jaar schema, waarbij de laatste twee jaar van de opleiding binnen een aandachtsgebied wordt gevolgd. (notitie BOEG NVOG). In dat geval kan de oncologische gynaecologie als differentiatie worden gevolgd binnen de afdelingen van het CGOA. Na de opleiding tot gynaecoloog kan binnen het CGOA een fellowship gynaecologische oncologie worden gevolgd. Het CGOA heeft ruimte voor 1 Nederlandse fellow. Naast fellows uit eigen land werden ook stages gevolgd door Indonesische fellows en observers via de zgn Dutch School of gynaecologic Oncology. Stafleden van het CGOA participeerden in het onderwijs voor medisch studenten van AMC en VUmc. Dit betrof colleges in het blok Oncologie van het AMC. Daarnaast namen docenten deel aan het snijzaalpracticum in het AMC en de masterstudie “Oncologie” en “Innovatieve therapien” in het VUmc. Andere activiteiten betroffen het landelijk cursorisch onderwijs voor aios gynaecologie en radiotherapie en de landelijke oncologiecursus van de WOG. Op alle 3 locaties volgden co assistenten een keuze co-schap oncologische gynaecologie en/of wetenschapsstages.
18 Bachelor en master studenten tussen 2009-2014: Anneke Leede (VUmc): The influence of the number of excised lymph nodes on the prognosis of cervical cancer.(v. Mensdorf, Kenter) Paulien Schut (UMCU): The influence of the number of resected lymph nodes on morbidity and survival in patients with cervical carcinoma with lymph nodes metastases treated with surgery and chemoradiotherapy. (Kenter) Suzanne Bleker (UMCG): The predictive value of Examination Under Anesthesia versus Magnetic Resonance Imaging for parametrial infiltration in cervical cancer. (Kenter) Marjolein Kooy (VUmc): Dysplatische lesies in de tuba als voorbode voor het ontstaan van een ovariumcarcinoom. (Piek, Kenter) Anna Stiekema (UMCU): Evaluation of human epididymis protein 4 (HE4) as a new tumormarker for ovarian cancer. (Lok, Kenter) S.Koch (AMC): Primary debulking in ovarian cancer. bachelorthesis: (Rutten/Buist) Kim Fliers (AMC): Ervaringen met gecombineerde IP en IV chemotherapie bij het gevorderd ovariumcarcinoom. (v.d. Velden) Lies Rustenburg (AMC): Progression free and overall survival of patients with advanced stage epithelial ovarian cancer; (Buist, Rutten) Gemma Heijink (UMCG): CT scan evaluation as predictor for the outcome of a debulking laparotomy in ovarian cancer.(v. Driel, Kenter) Paulien Oud (AMC): Morbidity after surgery of cervical cancer: differences in sexual functioning between three types of surgery in The Netherlands. (Kenter). Hannah van Meurs (AMC): Granulosacel tumor of the ovary. (v.d. Velden) Ploni Witteveen (AMC): mictieklachten bij chemo-radiatie patienten met een cervixcarcinoom (Derks, Kenter) Jan Hein Boldingh (UMCG): Predicting survival in epithelial ovarian cancer. (Rutten, Buist) Chu Chu Yu (VU, dept chemistry): Value based health care as tool for cost evaluation. (Kenter, Versluis) Charlotte Koch (AMC) (bachelorthesis). The predictive value of CT in predicting operability of epithelial ovarian cancer, (Buist, Rutten) Minke Freystein (Erasmus): The effect of different cervical cancer treatment modalities on urinary function: a cross-sectional observational study. (Kenter)
19 Francien de Leeuw: (AMC): Women with papillary serour cuterine carcinoma: an evaluation of therapy. (Rijcken) Marijn Poll (AMC): Routine pre-operatief bloedonderzoek bij gynaecologisch oncologische patienten. (v. Lonkhuizen). Lianne v. Soolingen: (AMC): The role of P-glycoprotein exposing extracellular vesicles in multidrug resistance in epithelial ovarian carcinoma. (Lok, Kenter) B. Ransdorp: bachelorthesis (AMC): Cost-effectiveness laparoscopic hysterectomy (Buist) Marijne Heeren: (Master Biomolecular Sciences VUmc); Characterization of immune cell subsets in tumor draining lymph nodes of cervical cancer patients.( Jordanova, Kenter) Roelien van de Vrie (AMC) : CT scan prediction model on residual disease after primary cytoreductive surgery in patients with advanced stage ovarian cancer; ( Buist, Rutten) Quirien Boldingh (UMCG). (Lok) Pamela Jacobs: (Master Biomedical Sciences VUmc). Lymphocytes infiltration and HLA class I expression in penile squamous cells carcinoma in correlation to disease specific survival and clinical outcome. (Jordanova) Eline de Boer: (Bachelor Gezondheid en Leven VUMC). The characterization, distribution and localization of immune cells in tumor-positive and tumor-negative lymph nodes of cervical cancer patients. (Jordanova) Mandy Gruijs: (Bachelor Gezondheid en Leven VUMC). Glycine cleavage system in thyroid carcinoma. (Jordanova) Sabine Kluin: (bachelorthesis AMC). Which tumor immune-escape mechanisms of cervical cancer and correspondent lymph node metastasis do exist? (Jordanova) Nalini Siewnath: (Scriptie Master Biomedical Sciences VUmc). P53 Mutations and associated protein expression in Spindle cell containing vulvar carcinomas, mutation events related to high E6 spliced transcript levels and trends linking histopathology to viral load and survival in Human Papillomavirus type 18 positive cervical cancer patients. (Jordanova) Martine Wessling (AMC): BAF250a expression in endometriosis-associated ovarian cancers and atypical endometriosis: do aromidia mutations cause cancer? Vancouver. (Kenter) Anneloes Eleveld (UMCU): Prediction model ovarian cancer. (Schreuder/Buist/Rutten)
20 ORGANISATIE
Het CGOA is een samenwerkingsverband van 3 partijen. Er is een stuurgroep bestaande uit de afdelingshoofden : Prof. Dr M.J. Heineman, (AMC), H. Schoo, (NKI-AVL) en Prof. Dr H. Brolmann, (VUmc). In 2014 is dit overgenomen door Prof. Dr v.d. Post (AMC), Prof. C.J.M. de Groot (VUmc) en H. Schoo (NKI-AVL). De gynaecologische oncologie maakt deel uit van de afdelingen verloskunde en gynaecologie van het AMC en het VUmc en van de afdeling HOD (heelkundig oncologische disciplines) van het NKI-AVL.
CGOA-BESTUUR HOOGLERAAR
AMC
NK1-AVL
VU-mc
Divisie E
HOD
Divisie 3
•Gyn./oncologie
•Gynaecologie
•Gynaecologie
•Alg gyn
•Heelkunde
-algemeen
•Fertiliteit
•Hals hoofd
-oncologie
•Verloskunde
•Urologie
•Verloskunde
•Plastische
•Fertiliteit
Medewerkers: Hoofd: Gemma Kenter Bea Hiemstra (secretariaat) Locatie AMC Marrije Buist (1.0) Guus Fons (0,8) Marten Schilthuis (1.0)(tot 1-2-2014) Ko van der Velden (1.0) Luc van Lonkhuijzen (0,9) (vanaf 1-2-2013) Fon Kosterman (0,8 research verpleegkundige)
Locatie NKI-AVL Petra Biewenga (0,9) Marc v. Beurden (1,0) Jan Lange (0,7) (tot 1-4-2012) Aagje Bais (1,0) (1-4-2012 tot 1-9-2012) Willemien van Driel (0,8) Henry Zijlmans (0,9) (sinds 1-1-2012) Anoesjka Lechner (0,8) verpl. specialist Monique Brood (0,2) arts familiaire tumoren Luc van Lonkhuizen (0,9)(1-9-2012 tot 1-2-2013)
21 LokatieVUmc Marchien van Baal (1,0) tot 1-9-2010 Hans Trum (0,9) vanaf 1-1-2010 Ming Tjiong (0,8) vanaf 1-9-2011 Christianne Lok 1-5-2010 tot 1-8-2011 Jose Kramer, physician assistant (0,4- 0,8) Monique Brood (0,2) arts familiaire tumoren Fellows Jurgen Piek (1,0; 1-7-2009 tot 1-7-2011) Fleur Rijcken (0,9; 1-2-2010 tot 1-5-2012) Christianne Lok (1,0; 1-8-2011 tot 1-8-2013) Nienke van Trommel (0,8; start 1-9-2013) Hoofden Verpleegafdelingen Daniel de Ron, AMC tot 1-8-2011 Ingeborg Goes, AMC vanaf 1-8-2011 Sietske de Vries, NKI-AVL tot 31-12-2014 Yolanda Brugman, VUmc tot 1-12-2011 Sandra van den Berge,VUmc (1-12-2011 tot 1-5-2013) Wilma Teekens, VUmc vanaf 1-6-2013 Maatschappelijk werk Ria van der Bij ( AMC) tot 4-12-2010, Tjitske Klinge (AMC) vanaf 1-2-2010 Karin Kohlinger (AMC) vanaf 1-12-2013 Postdocs Danielle Meijer(AMC)(1-5-2010 tot 1-5-2013) Pia Kvistborg (NKI) (1-8-2010 tot 1-8-2014) Sylvia von Mensdorff-Pouilly, (VUmc) (tot 1-1-2012) Katja Jordanova (VUmc) (0,8) (vanaf 1-1-2012) Samenwerkende specialisten Medisch oncologen: Anneke Westermann (AMC) Gabe Sonke (AVL) Jacqeline Stouthard (AVL) Carolien Smoorenburg (AVL) Maurice v. der Vorst (VUmc)
Radiotherapeuten Lukas Stalpers (AMC) Rachel Davila Fajardo (AMC) Henrike Westerveld (AMC) Nina Bijker (AMC) Baukelien van Triest (AVL) Monique Bloemers (AVL) Govert Salverda (AVL) Otto Meijer (VUmc) Maartje Piek (VUmc) Radiodiagnostiek Anje Spijkerboor (AMC) Annemarie Bruining (AVL) Jan Hein v. Waesberghe (VUmc) Pathologie Marc van de Vijver (AMC) Maaike Bleeker (AMC en VUmc) Hester van Boven (AVL) Bart v.d. Wiel (AVL) Mijke Bol (AVL) Koen Van de Vijver (AVL) (plastische) Chirurgie Pieter Tanis (AMC) Vick Verwaal (AVL) Frits v. Coevorden (AVL) Arend Aalbers (AVL) Joris Verhage (AVL)
22 BIJZONDERE GEBEURTENISSEN
17-11- 2009: Promotie Guus Fons 01-04-2010: IKA bijeenkomst met presentatie van het CGOA aan de regio 10-09-2010: Oratie Gemma kenter “Menage a Trois” 26- 03-2011: Uitreiking VNVA-Corrie Herman prijs aan Gemma Kenter met symposium “Opera in academia”. 29- 03-2011: Spiegelgesprek met 9 patiënten van alle 3 lokaties en medewerkers van poliklinieken, verpleegafdelingen en de medische staf. 13-10-2011: EORTC–GOG meeting in Amsterdam met symposium “Novelties in gynaecologic Oncology. 26-09-2013: Eerste Nederlandse deelname aan wereldwijde actie Globe-athon 23-01-2013: Afscheid Marten Schilthuis 13-02-2014: Promotie Henry Zijlmans 26-04-2014: Bijeenkomst EU consortium RAID in Amsterdam 27-09-2014: Tweede Nederlandse deelname aan wereldwijde actie Globe athon Dec 2014: Eerste audit gynaecologische oncologie samen met behandelaars uit verwijzend centrum huisarts en betrokkenen vanuit CGOA
23 Dankwoord Velen hebben een bijdrage geleverd aan het tot stand komen van het CGOA en hebben meegewerkt aan dit overzicht. Allereerst de groep gynaecoloog-oncologen van de verschillende huizen die het hebben aangedurfd om de discussie over een gezamenlijk centrum op te starten. De afdelingshoofden Heineman, Brolmann en Schoo, die op bestuurlijk niveau hebben bijgedragen tot de eerste aanzet. Het IKA, dat d.m.v. een financiële bijdrage een eerste onderzoek naar de haalbaarheid heeft mogelijk gemaakt. Begeleiders op verschillend niveau zoals Teresa Mom, Mark van Bergen en Annemarie van Iren. Jeroen Colette en Marlies Jansen-Landheer, die hebben meegewerkt aan het tot stand komen van een business plan. Otto Visser van het IKNL en Harm van Tinteren, statisticus en hoofd van de Tumorregistratie van het AVL hebben bijgedragen aan het tot stand komen van de getallen en overzichten. De verwijzers uit de regio waar wij mee samenwerken en allen die op positieve of kritische wijze hebben meegedacht.
24 Posters onderzoekers CGOA dd. 2014 Onderstaand volgt in alfabetische volgorde een serie posters gemaakt door de promovendi van het CGOA, die in september 2014 werden voorbereid vanwege het 5 jarig bestaan van het CGOA.
Role of the peritoneal elastic lamina in tumor invasion of epithelial ovarian cancer J.O.A.M. van Baal1, K.K. van de Vijver2, W.J. van Driel1, M.J. Buist1, G.G. Kenter1, C.A.R. Lok1 1Department
of Gynecologic Oncology, Center of Gynecologic Oncology Amsterdam, The Netherlands. of Diagnostic Oncology & Molecular Pathology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
2Division
Introduction Epithelial ovarian cancer (EOC) metastasises through the abdominal cavity. Extensive involvement of the peritoneum is often seen in advanced disease. However, tumor growth through the peritoneum and invasion of the abdominal wall is rare. The peritoneum consists of the mesothelium, a basement membrane, underlying connective tissue and a peritoneal elastic lamina (PEL). The presence and function of the PEL in relation to EOC, is not clearly understood. The aim of this study is to determine anatomical components of the peritoneum that inhibit tumor invasion. In this study we attempt to demonstrate the integrity of the PEL in relation to tumor invasion and growth pattern.
Materials & Methods
Results
During cytoreductive surgery, samples of peritoneal depositions from parietal peritoneum of 11 patients with high grade serous EOC were collected. Immunohistochemical staining with hematoxylin and eosin (H&E) and Elastica van Gieson (EVG) was performed. H&E sections were examined by light-microscopy to confirm diagnosis and determine depth of tumor invasion. EVG was carried out to verify presence and integrity of the elastic lamina in relation to tumor infiltration.
All patients showed tumor depositions of high grade serous EOC in their peritoneal samples. In tumor-free areas, the elastic lamina was identified just beneath the mesothelium, and separated from the mesothelium by a thin layer of connective tissue (fig. 1). In the area of tumor depositions, the elastic lamina appears less superficial and connective tissue between mesothelial cells and the elastic lamina has gained more volume. Staining with EVG showed in all samples a well distinguishable PEL encapsulated by dense connective tissue, almost continuous with the surface of the peritoneum. In onethird of the peritoneal samples (4/11), tumor depositions did not grow through the continuous fibre network of the PEL, but demonstrated a more pushing growth pattern (fig. 2). In the other two-third of patients, tumor depositions grew through a destructed or fragmented PEL, demonstrating an infiltrative growth pattern (fig. 3).
A
B
Table 1. Characteristics of included patients. Peritoneum samples of tumor depositions of high grade serous ovarian cancer.
Tumor growth through fragmented PEL***
Fig. 1. Histological features of PEL in identical tissue of healthy peritoneum. A H&E staining, B EVG staining. The PEL is shown by the blue colored line (see arrows). PEL is a thin fiber network, located superficially, parallel to the peritoneal surface.
C
D
Fig. 2. Histological features of PEL invasion in identical tissue in HGSC. C H&E staining shows tumor cells with pushing growth pattern. Tumor cells are demonstrated by arrows. D EVG staining demonstrates a thickened PEL (see arrows). Tumor cells do not grow through the intact PEL.
E
F
Tumor growth not through intact PEL
Number of patients
7
4
Mean age (yr)
63.3
60.0
FIGO stage 3 4
4 (57,1%) 3 (42.9%)
3 (75.0%) 1 (25.0%)
NACT*
6 (85.0%)
2 (50.0%)
Response to NACT** Good Moderate Poor
2 (33.3%) 4 (66.7%) 0
1 (50.0%) 1 (50.0%) 0
Cytoreduction Complete Optimal Incomplete
2 (28.6%) 4 (57.1%) 1 (14.3%)
2 (50.0%) 0 2 (50.0%)
Tumor growth pattern
Infiltrative
Pushing
*Neo-adjuvant chemotherapy **Response to chemotherapy based on radiological findings ***Peritoneal elastic lamina
Conclusion These results suggest a role of the intact PEL in the function of the peritoneum as barrier against tumor depositions. Some patients showed tumor growth through the PEL, possibly reflecting a more aggressive infiltrative tumor behavior.
Fig. 3. Histological features of PEL invasion in identical tissue in HGSC. E H&E staining showing tumor cells with infiltrating growth pattern (see arrows). F EVG staining demonstrates a fragmented PEL with tumor cells growing through the PEL.
A larger study population is required to further investigate the prognostic significance of the integrity of PEL and its correlation with tumor behavior and growth pattern.
25 Morbidity and survival in treatment of cervical cancer M. Derks1, J. van der Velden¹, L. R.C.W. van Lonkhuijzen¹, M.C. de Ruiter², G.G. Kenter3 1 Dept of Gynecology, Academic Medical Center, Amsterdam, the Netherlands 2 Dept of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands 3 Center for Gynecologic Oncology Amsterdam, Amsterdam, the Netherlands
Surgical treatment for cervical cancer: Multicenter retrospective cohort study In the Netherlands various techniques to perform a radical hysterectomy with pelvic lymphadenectomy have been used. The aim of this study is to determine the role of the extent of the radicality of the hysterectomy for cervical cancer with respect to pattern of recurrence and survival, and to identify a group of patients who are eligible for a less radical type of hysterectomy. In progress
Lymphatic drainage pathways from the cervix uteri; implications for radical hysterectomy? We hypothesized that the good survival rates of the Okabayashi technique might be explained by accurate removal of lymphatic pathways in the ventrocaudal parametrium draining the cervix uteri. A developmental series of human fetal pelves was studied in order to reveal the lymphatic drainage pathways of the cervix uteri and their connections with those of the bladder and rectum during different stages of development. Results: Two major pathways drained the cervix uteri: a supra-ureteral pathway, running in the cardinal ligament superior to the ureter, and a dorsal pathway, running in the utero-sacral ligament towards the rectal pillars. No lymph vessels draining the cervix uteri were detected in the VUL. In the paracolpal parametrium lymph vessels draining the upper vagina fused with those from the bladder. The VUL does not contain lymphatics from the cervix uteri. Hence, the favorable survival outcomes of the Okabayashi technique cannot be explained by radical removal of lymphatic pathways in the ventrocaudal parametrium.
Pelvic dysfunctions and quality of life (QoL) after treatment for cervical cancer: A mulicenter observational study
Radical surgery in patients with stage IB2/IIA2 cervical cancer
Given the relatively good prognosis and the young age of cervical cancer survivors (CCS), QoL has become an important aspect of increasing interest in choosing cancer therapies. Comprehension in variables causing morbidity and affecting QoL is important for counseling and tailoring of treatment. In a large cohort of CCS, this study determined the prevalence of urinary- and bowel dysfunction and QoL of women who were treated for cervical cancer by different treatment modalities.
There is an ongoing discussion about the primary treatment in a subgroup of patients with bulky early stage cervical cancer. An important point against primary surgery in bulky cervical cancer is the fact that many stage IB2 patients have unfavorable prognostic factors necessitating the need for adjuvant (chemo) radiotherapy in 30% to 84% of patients, resulting in increased morbidity for these patients. The aim of this study was to assess the results of radical surgery for patients with stage IB2/IIA2 cervical cancer in terms of recurrence patterns and survival.
Results: In total 347 CCS responded. Patients treated with primary or adjuvant radtiotherapy reported significantly more frequency. Dysuria was more reported in the group of primary (chemo)radiotherapy. Patients in the surgery only group reported significantly more obstructive voiding problems. Multivariate analysis showed that the character of complains is mainly defined by type of treatment. Body image and Global Health are negatively influenced by treatment with (adjuvant or primary) radiotherapy.
Results: Five year disease specific survival (DSS) was 84%. Fifty percent of the patients received adjuvant treatment. Histology, differentiation grade, tumor diameter, parametrial involvement, presence of lymph node metastasis and tumor positive surgical margins was associated with DSS.
Validation of prognostic model for survival of patients with early stage cervical cancer. For good management of early stage cervical cancer, knowledge about the prognosis is critical. Biewenga et al. developed a prognostic model for survival in early stage cervical cancer and identified the prognostic weight of clinical and histological factors for disease-specific survival (DSS) in 710 consecutive patients who had surgery for FIGO stage IA2-IIA cervical caner. This study aims to validate this model on a dataset of 1200 patients from two large Dutch academic centers. In progress
26 Indoleamine-2,3-dioxygenase (IDO) metabolic activity is detrimental for cervical cancer patient survival Debbie M. Ferns1, Ido P. Kema2, Marrije R. Buist3, Hans W. Nijman4, Gemma G. Kenter1,3, Ekaterina S. Jordanova1* 1, Centre for Gynaecological Oncology Amsterdam, Location: Free University Medical Centre, The Netherlands. 2, Department of Laboratory Medicine, University Medical Centre Groningen, University, The Netherlands. 3, Centre for Gynaecological Oncology Amsterdam, Location: Academic Medical Centre, The Netherlands. 4, Department of Gynaecological Oncology, University Medical Centre Groningen, The Netherlands.
Introduction
The immuno-modulating enzyme indoleamine-2,3dioxygenase (IDO) provokes immune tolerance through catalysing degradation of the essential amino acid L-tryptophan. Tryptophan is used for protein and indole synthesis and is metabolized along the kynurenine pathway. Kynurenines, which include L-kynurenine, 3-hydroxykynurenine, 3hydroxyanthranilic acid, and quinolinic acid, have been reported to block T-cell proliferation, resulting in growth arrest of alloreactive T-cells and natural killer (NK) cells. In serum, IDO activity can be estimated by the kynurenine-to-tryptophan (Kyn/Trp) ratio, which represents the quotient of the first product of the IDO pathway (kynurenine), divided by the substrate tryptophan. In cancer patients, lower serum concentrations of tryptophan, higher kynurenine concentrations, and a higher Kyn/Trp ratio have been reported by us and others.
Goal In the present study, concentrations of tryptophan, 3-hydroxykynurenine, kynurenine and IDO were measured in pre-treatment serum samples of 251 cervical cancer patients by a mass-spectrometric method (XLC-MS/MS). We are the first to make correlations between serum concentrations, clinicopathological characteristics and patient survival in a large cohort of cervical cancer patients.
Results
Low concentration of tryptophan was associated with tumor size greater than 4cm (p=0.016) and lymph node metastases (p=0.003). Furthermore, a significant positive association was found between high kynurenine concentration and tumor size (p=0.037), advanced stage of disease (FIGO >IIA) (p<0.001), parametrial invasion (p<0.0001) and lymph node metastases (p=0.045). High concentration of 3-hydroxykynurenine was associated with advanced stage of disease (FIGO >IIA) (p=0.009) and lymph node metastases (p=0.012). A high Kyn/Trp ratio (IDO) was related to lymph node metastasis, FIGO stage, tumor size and parametrial invasion (all p<0.001). In addition, high Kyn/Trp ratio (IDO) was associated with poor disease-specific survival (p=0.007).
Backround
Cervical cancer is the fourth most common cancer in women worldwide and is caused by a persistent human papillomavirus (HPV) infection. Although 80% of women will be infected by HPV, the majority are able to clear the infection, indicating a crucial role for the immune system in cervical carcinogenesis and progression. Not surprisingly, various mechanisms are employed by tumor cells to escape from recognition and destruction by the immune system and to modulate the tumor microenvironment allowing tumor development and growth. Here, we investigate numerous immune-escape mechanisms in metastasized cervical cancer patients.
Conclusion
In this study, we showed for the first time that tryptophan degradation along the kynurenine pathway (the presence of active IDO) in pretreatment serum, as measured by the Kyn/Trp ratio, is associated with detrimental clinicopathological parameters and poor survival in a large cohort of cervical cancer patients
Other projects
1. Microenvironment of tumor draining lymph nodes (TDLN) in cervical cancer In both, tumor free and tumor positive lymph nodes of cervical cancer patients, we investigated various T-cell populations, APC subsets and MDSC subsets 2. Soluble MICA and HLA-G in cervical cancer patients We measured sMICA and sHLA-G in pre-treatment sera of a large cohort of cervical cancer patients (n=366) by ELISA and related the amounts of sMICA and sHLA-G with patient characteristics and survival rates 3. HLA class I aberrations in paired cervical adenocarcinoma and squamous cell carcinoma primary tumor and lymph node metastasis We investigate HLA expression in relation to histology (squamous cell carcinoma (SCC) vs. adenocarcinoma (AC)), metastasis, and patient survival in a large cohort of cervical cancer patients (n=136) 4. IDO expression in the primary tumor combined with IDO expression in serum of cervical cancer patients Protocol in progress.
27 Malignant melanoma in pregnancy: Report on 48 cases. J. de Haan1, C.A.R. Lok2, S. Han3, F. Amant3, C.J.M. de Groot1 1. Department of Obstetrics and Gynaecology, VU University Medical Center, Amsterdam, The Netherlands. 2. Department of Gynaecologic Oncology, Center for Gynaecologic Oncology Amsterdam, The Netherlands. 3. Department of Obstetrics and Gynaecology, UZ Leuven, Leuven, Belgium.
Introduction
Summary
Cancer in pregnancy is a rare phenomenon with an incidence of one in 1000 pregnancies. Melanoma is the third most common malignancy in pregnancy (8%), after breast and cervical cancer. Proper diagnostic testing and standard therapeutic interventions are neccesary for a better prognosis. But the co-existence of malignant melanoma and pregnancy is a challenging situation for both caretakers and parents. However, literature on this subject is scarce and only a small number of case series has been published. Aim To describe the diagnostic and staging procedures of melanoma and to evaluate the short time effect of treatment and the subsequent maternal and fetal outcome. 3
3 1
43
Excision Biopsy MRI X-Ray
Fig 1. Diagnostic interventions during pregnancy
Methods
Stage I
n = 6 (12%)
Stage II
n = 4 (8%)
Stage III
n = 10 (21%)
Stage IV
n = 8 (17%)
Unknown
n = 20 (42%)
Diagnostic and therapeutic interventions were performed without causing spontaneous preterm delivery, intrauterine growth restriction or congenital abnormalities.
A total of 48 women where diagnosed with a melanoma in pregnancy. Eleven women had a recurrent disease.
Management of a women with a melanoma during pregnancy should be individualized.
Results A total of 48 women were diagnosed with a malignant melanoma during pregnancy between 1995 and 2014 in five different countries. Recurrent disease was found in 11 women during pregnancy. The mean maternal age at diagnosis was 33 ± 4.6 years and the mean gestational age was 196/7 ± 94/7 weeks. The most common complaint was a changed appearance or bleeding of a naevus (n=23). Diagnostics: All but seven patients underwent an excision of the lesion for diagnostic testing. In four patients a biopsy was conducted, one patient got an x-ray taken, six patients underwent ultrasound for diagnostic reasons and four patients underwent magnetic resonance imaging (MRI) for staging. Treatment characteristics: 29 patients (60%) underwent treatment during pregnancy. The other 19 patients were treated after delivery. In all patients surgical treatment was performed. Three patients received radiotherapy of the head and upper torso and one received chemotherapy during pregnancy. No immunotherapy was given, neither in nor after pregnancy.
This study was designed as a retrospective, multicenter, European wide observational study. Cases were selected from the database of the ‘International Network on 12 Cancer, Infertility and Pregnancy’ (INCIP). 10 Women diagnosed between 1995 and 2014 with a histologically confirmed malignant melanoma during pregnancy were eligible for the present study. Clinical information was collected from the database. Missing data was retrieved by reviewing hospital files.
Malignant melanoma is the third most common malignancy in pregnancy. Since therapy is stage dependent, diagnostic interventions are necessary for a better outcome.
Fig 3. GA at delivery and mode Induced Spontanious No FU
Re-excision
0 3
1
11 29 12
Sentinel node biopsie Lymfe node dissection Radiotherapy Chemotherapy Immunotherapy
Fig 2. Treatment during pregnancy
Conclusion
8
Malignant melanoma is the third most common type of malignancy diagnosed during pregnancy. Symptoms are similar between both pregnant and non-pregnant women.
6 4 2 0 Term
Premature
Deceased
Preliminary Fetal and Maternal outcome: Fig 3 shows GA at delivery and delivery mode. Eleven patients are known to be deceased, one of them died during pregnancy. No congenital abnormalities or growth restriction were reported so far.
Based on short term effects, re-excision, sentinel node biopsy and lymph node dissection seem to be a safe option in pregnancy as well as (adjusted) chemotherapy and radiotherapy with proper shielding. Decisions about both diagnostic and therapeutic interventions should be in a multidisciplinary team on an individual basis.
28 High and Interrelated Rates of CD14+PD-L1+ Antigenpresenting Cells and Regulatory T cells mark the Microenvironment of Metastatic Lymph Nodes from Patients with Cervical Cancer A. M. Heeren1,2, B.D. Koster1, S. Samuels3, D.M. Ferns2, D. Chondronasiou1, G.G. Kenter2,3, E.S. Jordanova2, T.D. de Gruijl1 1Department
of Medical Oncology (VUmc), 2Department of Obstetrics & Gyneacology (VUmc), 3Department of Gyneacology (AvL-NKI)
Background
Introduction A better understanding of the microenvironment of tumordraining lymph nodes (TDLNs) is essential for the development of effective immunotherapeutic strategies against cervical cancer.
In cervical cancer, immunosuppressive cells are recruited, expanded and activated at the site of the primary tumor. Tumor-draining lymph nodes (TDLNs) are the first LNs that are under the influence of tumor-derived factors and in which an immune response can be generated by the activation of naïve T and B cells.
Aim Characterization of immune-cell subsets in tumor-positive (LN+) and tumor-negative (LN-) lymph nodes from patients with cervical cancer
Thus, the state of the TDLN microenvironment is critical in the initial decision between
Material & Methods
activation and suppression of
Cells were scraped from cervical TDLNs removed during a radical hysterectomy with lymphadenectomy or lymph node debulking • Four-color flow cytometry • Immunofluorescence staining
the immune system by the primary tumor. Figure from Swartz (2012), Nature reviews
Results Tcell frequencies
Fig 1. T-cell subsets. (A) Lower percentages of CD4+ T cells and higher percentages of CD8+ T cells, double negative (CD4-CD8+) and double positive (CD4+CD8+) T cells were found in LN+ compared to LN-. (B) Higher frequencies of CD4+ and CD8+ T cells expressing activation markers (HLA-DR and ICOS) and coinhibitory markers (CTLA-4 and PD-1) in LN+ compared to LN-. Error bars represent SEM. * P = 0.01 to 0.05, ** P = 0.001 to 0.01, and *** P < 0.001.
A
B
RegulatoryTcells
AntigenͲpresentingcells
A
B
LNͲ
LN+ Fig 3. Triple immunofluorescence staining of CD14, CD163 and PD-L1 of representative tumor negative (LN-) and positive (LN+) lymph node specimen reveals the presence of elevated numbers of CD14+CD163+ cells expressing PD-L1 in LN+ and low to non-detectable expression levels of PD-L1 on sporadic CD14+CD163+ cells in LN- (400x magnification).
C
Conclusion
D
E R = 0.56 P = 0.01
R = 0.55 P = 0.02
Fig 2. Tregs and APC subsets. Significantly more (A) CD4+ as well as CD8+ (FoxP3+) Tregs and significantly higher percentages of (B) DDCs, LCs, CD14+ APCs, CD14- LNDCs and no significant differences for pDCs were found in LN+ compared to LN-. (C) Median Fluorescence Index (MFI) of co-inhibitory molecule PD-L1 on CD14+ APCs was significantly higher in LN+. (D) Scatter plot showing that increased levels of CD4+ Tregs were accompanied with significantly increased levels of CD14+ APCs and (E) CD14+ APCs expressing PDL1 in TDLNs of cervical cancer patients. Dotted lines indicate the 95% confidence interval of the regression line. Error bars represent SEM. * P = 0.01 to 0.05, ** P = 0.001 to 0.01, and *** P < 0.001.
Despite increased T-cell differentiation and activation, a striking switch to a profound immune suppressive microenvironment in LN+ of cervical cancer patients will enable immune escape. Our data point to the CD14+PDL1+ APC/Treg axis as a particularly attractive and relevant therapeutic target to specifically tackle microenvironmental immune suppression and thus enhance the efficacy of immunotherapy in patients with metastasized cervical cancer.
Heeren et al., 2014. Cancer Immunol. Res.
1
29 The importance of awareness after hysterectomy. Women with intact cervix after hysterectomy should continue cervical cancer screening D.J.Hooi, W.Quint, C.J.M. Meijer, H.M. Pinedo, M. De Koning, H. Berkhof, L. Elstak, G.Kenter 1, Centre for Gynaecological Oncology Amsterdam, Location: Free University Medical Centre, The Netherlands. 2, Department of Human Pathology, Location: Free University Medical Centre, The Netherlands. 3, Centre for HPV research and Population screening, Location: Prevention Centre, Willemstad Curaҫao. 4, DDL Diagnostic Laboratories, Location: Rijswijk, The Netherlands. 5, Analytic Diagnostic Centre ADC, Location: Willemstad Curaҫao.
Introduction
In the Caribbean, cervical cancer ranks at the second place of cancer amongst women. Cervical cancer prevalence is the highest in the group of none responders for screening. In Curaçao, cervical cancer ranks at 4th place however the screening coverage is <40%.. The group of women who underwent a hysterectomy and do not know if they have an intact cervix after the surgery should be taken into account. The WHO wants to solve the cervical cancer problem in the world and therefore it is important that special notice is taken to the information that women receive after subtotal hysterectomy about the importance of still participating in screening programs.
Goal
Fundashon Prevenshon wants to intervene in improvement of screening awareness in women that have their uterus removed. Professionals should also be well informed and should introduce uniform guidelines in their daily practice. At the end all women with an intact cervix after subtotal hysterectomy should be included in the invitation program “CIS” in order to receive regular screening opportunity.
Method
A retrospective analysis was performed at the Pathology department, recruiting all hysterectomies performed from 2003-2013 in Curaçao. This information was ranked according to the type of surgery. After this analysis; we gave an anonymous questionnaire to 207 volunteered women who underwent a hysterectomy. Most of the women who participated with this questionnaire were clients that came to Fundashon Prevenshon for breast cancer screening.
Results
Background
Curaҫao will start with the cervical cancer population screening program in 2015. During a voluntary pilot in 2013 it was remarkable that most women do not know whether they have their cervix intact or not after hysterectomy. Most did not see the importance of participation, because they had their uterus removed. In Curaҫao a total of 4184 hysterectomies were performed between 2003 and 2013. From 2003 to 2013, 122/4,184 women that underwent this surgery still have an intact cervix. When leaving the cervix intact, it’s important that women continue screening for cervical cancer. Research has shown that the most cervical cancer cases is in the none screened population. Most women that underwent a hysterectomy will not respond to an invitation for screening because they do not know if they have their cervix intact.
Conclusion
Amongst the answers to the questionnaire several important patterns came forward that are worth wile noting. The most important conclusion that can be drawn is that the majority of women (68.9%) are not aware of having an intact cervix or not. In case of a subtotal hysterectomy awareness shouldhave higher priority in the follow up of these women, since they are at the same risk of developing cervical cancer as women with an intact uterus.
Other projects
1. Clinical and epidemiological HPV genotype analysis in a population of 253 18 were referred patients with known abnormal cytology 12/18 SPF10 and 8/18 GP5+/6+ positive 235 were volunteers average age 49.9 years HPV prevalence with SPF10 93/ 235 (39.57%) HPV prevalence with GP5+/6+ 43/235 (18.30%) 2. HPV genotyping with SPF10 on CIN 1,2,3 paraffin embedded tissue and cervical cancer paraffin embedded tissue. HPV types Cervical cancer CIN 2+3 CIN 1 HPV 16, 18 58.70% 49.40% 17.50% Other high risks 37.00% 54.40% 62.50% Low risks 4.34% 8.90% 20.00%
Retrospective analyses in hysterectomies data shows 122 women with a hysterectomy and intact cervix. 3. Oropharyngeal vs. vaginal HPV genotyping in sexual workers Two hundred and seven women participated with a Results of oral samples in 76 participants: 8/76 HPV pos, 4/8 hrHPV, 4/8 unidentified, 7/8 Single questionnaire. Hysterectomies in this group were Infection, 1/8 multiple infection. performed between 1971 and 2014. Results of vaginal samples in the same participants: 30/76 HPV pos, 18/30 hrHPV, 5/30 When asked if the woman is aware of removal of the unidentified, 12/30 Single infection, 18/30 Multiple infection. cervix during surgery, 142 women answered: “I do not know” (68.9%). When women were asked when they had their last pap smear the most frequent 4. HPV prevalence in normal cytology, a study in 1000 women stratified in age groups 2565 years old answer was “before having a hysterectomy”(117/207women). Starting in March 2015 Of these 117 women 90 (76.9%) did not know whether or not their cervix was still intact. In 21/49( 42.86%) of 5. Self test response in the population of Curaҫao the woman knew she had an intact cervix but she had Starting in March 2015 not had a pap smear since their surgery.
30 Antigen-specific T cells in human ovarian cancer S. Kelderman1, C. Linnemann1, M. van Zon1, J.H. van den Berg1, L. Bies1, H.J.M.M.A. Zijlmans2, W.J. van Driel2, G.S. Sonke3, G.G. Kenter2, J.B.A.G. Haanen1,3, T.N.M. Schumacher1 1. NKI-AVL, division of Immunology, 2. NKI-AVL, department of Gynecology, 3. NKI-AVL, division of Medical Oncology
Introduction
Background
The presence of intratumoral immune cells and in particular CD8 (cytotoxic) T cells has been associated with favorable prognosis in several malignancies including melanoma, ovarian cancer and colorectal cancer. These observations have in large part inspired the development of adoptive T cell therapy for the treatment of metastasized disease, often using melanoma as a platform. Importantly, thus far, melanoma remains the only disease for which tumor-infiltrating lymphocyte (TIL) therapy has reproducibly shown clinical response rates of up to 50%.
Ovarian cancer is one of many cancers that contains TILs. In addition, the presence of these TILs is positively correlated to clinical outcome (right figure), suggesting that TIL therapy could be beneficial for ovarian cancer patients. More recent data have shown that selection for CD137 (4-1BB) positive TILs resulted in tumor-reactive TIL cultures from ovarian cancer.
Single-cell TCR isolation To achieve our first research aim, we will isolate T cell receptor (TCR) DNA sequences from single-cell T lymphocytes that have infiltrated ovarian cancer lesions. Material collection is ongoing from patients treated at the NKI-AVL. The identified TCR genes will then be expressed in naïve peripheral blood lymphocytes using a retroviral transduction system. Subsequently, cells expressing the exogenous patient-derived TCR will be tested for their ability to recognize autologous tumor cells. TIL therapy Our second research aim has a more clinical focus. Here, we aim to set-up a system similar to melanoma, where patients undergoing surgery for ovarian cancer will be treated (upon disease recurrence) with an autologous T cell product that consists of ex vivo expanded TIL. To assess the feasibility of this approach in ovarian cancer, material will be collected and laboratory-scale expansion of TIL cultures performed. Additionally, assays will be performed to determine whether these TIL cultures are functionally reactive against autologous tumor cells.
Zhang et al. 2003 NEJM
100
Material collection is ongoing and additional samples will be included in the single-cell TCR isolation and reactivity screens. TIL therapy TIL cultures from three independent donors have been established according to standardized protocols (Table. 1). Subsequent reactivity assays showed that all three TIL cultures were able to produce interferon gamma upon coculture with the autologous primary tumor (Figure. 1). Fold expansion Patient 1
780
Patient 2
1690
Patient 3
1190
Table 1. Established TIL cultures from primary ovarian cancer samples were subjected to a Rapid Expansion Protocol (REP) to obtain clinically relevant cell numbers. This protocol is used clinically in several melanoma TIL trials. Fold expansion of these three ovarian cancer samples is similar to melanoma cultures.
50
90 80 30 20 10 0
% CD8+ IFN-γ+ (of total CD8+)
Methods
Results Single-cell TCR isolation A total of 96 single tumor-infiltrating CD8+ T cells have been isolated from one donor out of which 41 TCRs have been identified. A first set of 20 TCR constructs has been ordered and will be tested in the beginning of 2015 for functional reactivity against the autologous primary tumor digest.
% CD8+ IFN-γ+ (of total CD8+)
In our research projects, we aim to address whether 1) the tumor-resident T cell populations in human ovarian cancer are intrinsically tumor-reactive and 2) if this can be exploited clinically.
Combined, these data are highly suggestive for the presence of tumor antigen-specific T cells within ovarian cancer.
Patient 1
40
Patient 2
Patient 3
30 20 10 0
TIL vs Tumor
Background
TIL alone
TIL + Tumor
Figure 1. Three expanded TIL cultures were tested for their ability to produce interferon-‐gamma upon coculture with the autologous primary tumor. All three paLent samples showed marked increase in cytokine producLon relaLve to unsLmulated controls. This was the case for both CD8+ and, to a lesser degree, CD4+ T cells (not shown).
Conclusion We are now able to isolate TCR sequences from T lymphocytes infiltrating human ovarian cancer, which enables us to assess their intrinsic tumor-reactive capacity at the single-cell level. Furthermore, our preclinical data suggest that a substantial fraction of TIL in ovarian cancer is directed towards tumor antigens. Our future efforts will focus on generating T cell products from primary human ovarian cancer and determine whether these can be utilized in clinical studies.
31 Triage of hrHPV DNA-positive women: a comparison of septavalent hrHPV E7 mRNA NASBA testing, HPV16/18 DNA genotyping and cytology R. Luttmer1, J. Berkhof2, M.G. Dijkstra3, F.J. van Kemenade4, P.J.F. Snijders1, D.A.M. Heideman1, C.J.L.M. Meijer1
1Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands; 2 Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands 3 Department of Obstetrics & Gynecology, VU University Medical Center, Amsterdam, the Netherlands; 4 Department of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands
Introduction Women who test positive for high-risk human papillomavirus (hrHPV) DNA require triage testing to identify those with cervical high-grade intraepithelial neoplasia or cancer (≥CIN2). We compared the performance of HPV16/18/31/33/45/52/58 E7 mRNA testing, HPV16/18 DNA genotyping and cytology for detection of ≥CIN2 in hrHPV DNA-positive women.
Methods hrHPV DNA-positive women (18-63 years) were recruited from gynaecology outpatient clinics for a prospective observational cohort study. From all (hrHPV-positive) women (n=348), a cervical scrape and colposcopy-directed biopsies were obtained. We compared the performance of HPV16/18/31/33/45/52/58 E7 mRNA testing, HPV16/18 DNA genotyping and cytology for detection of ≥CIN2 in hrHPV DNA-positive women.
Cervical scrapes were tested for presence of E7 mRNA of HPV16/18/31/33/45/52/58 by nucleic acid sequence-based amplification (NASBA), HPV16/18 DNA genotyping and cytology. Sensitivities and specificities for ≥CIN2 and ≥CIN3 were compared between triage tests using the McNemar’s Chi Square test. For subsequent unbiased comparisons of molecular triage tests with cytology, women who were included in the study because of an abnormal cytology result were excluded.
Table 1: Clinical performance of septavalent E7 mRNA (NASBA) testing, HPV16/18 DNA genotyping and cytology to detect ≥CIN2 or ≥CIN3 in hrHPV DNA-positive women – total study population, n=348
Table 2: Clinical performance of septavalent E7 mRNA (NASBA) testing, HPV16/18 DNA genotyping and cytology to detect ≥CIN2 or ≥CIN3 in hrHPV DNA-positive women – subpopulation of women referred to the gynecologist because of non-cervix-related complaints (not because of an abnormal cytology result in national screening, n=133)
Results Of the 348 recruited women, 62% (215/348) had been referred to the gynaecologist because of an abnormal cytology result, and 38% (133/348) because of other, non-cervix-related, gynecological complaints. The sensitivity of E7 mRNA testing for ≥CIN2 was slightly higher than that of HPV16/18 DNA genotyping (66.9% versus 60.9%; ratio 1.10, 95%CI: 1.0002-1.21) while specificities were
similar (54.8% versus 52.3%; ratio 1.05, 95%CI: 0.93-1.18; Table 1). In the cohort of women not referred on the basis of abnormal cytology the sensitivities of hrHPV E7 mRNA testing and cytology were not significantly different (68.8% versus 75.0%; ratio 0.92, 95%CI; 0.72-1.17), and neither were the specificities (59.4% versus 65.3%; ratio 0.91, 95%CI, 0.75-1.10; Table 2).
Conclusion For detection of ≥CIN2 in hrHPV DNA-positive women, E7 mRNA HPV16/18/31/33/45/52/58 testing performs similar to HPV16/18 DNA genotyping and cytology
32 Evaluation of response to hormone therapy in patients with measurable adult granulosa cell tumors of the ovary H.S. van Meurs 1, J. van der Velden 1, M.R. Buist 1, W.J. van Driel 2, G.G. Kenter 1, L.R.C.W. van Lonkhuijzen 1 1 Department of Gynecology, Center for Gynecologic Oncology Amsterdam, Academic Medical Center, Amsterdam 2 Department of Gynecology, Center for Gynecologic Oncology Amsterdam, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam
Introduction Granulosa cell tumors (GCTs) represent rare ovarian malignancies arising from sex-cordstromal cells. Responses to hormone therapy (HT) of advanced primary disease or recurrences have been published in case reports only. The goal The aim of this study was to determine the objective response rate to HT for patients with an adult GCT of the ovary in a consecutive series of patients.
Methods All patients treated for an adult GCT within the Academic Medical Center (between 1990 and 2013), the Free University (between 1984 and 2013) and the Antoni van Leeuwenhoek Hospital (between 1979 and 2013), together accounting for the Center for Gynecologic Oncology Amsterdam, were identified and their records were screened for HT administration. The main outcome was the objective response rate to HT. Response Complete Partial Stable Progressive
Number of patients n=22 (%) 1 (4.5%) 3 (14%) 14 (64%) 4 (18%)
Table 2. Response to hormone therapy in all patients.
Fig. 1. Progression free survival in months of 22 patients after start of hormone therapy for measurable disease.
Case
Age at diagnosis
Initial stage
Prior treatment
Moment of HT
Reason for HT
Type of HT
1
34
IV
Sx+CT+RT
P
Residue
MPAb
Mode of Duration Dose of HT Response response of HT (M) PFS (M) DSS (M) NA
PR
Clinical
2
2
2
DOD
2
63
IIIC
Sx(3x)+RT+CT
R3
Residue
Tamoxifenc
100 mg t.i.d
SD
RECIST
2
2
18
DOD
3
47
IIIC
Sx(2x)+RT+CT( 2x)
R2
Residue
Tamoxifenc
40 mg q.d.
PD
Marker
5
3
4
Status
DOD
4
34
IA
Sx(4x)+CT
R4
Marker increase
Megestrol Acetateb
160 mg q.d.
CR
Marker
Ongoing
34+
34+
NED
5a
60
IIA
Sx(4x)+RT(2x)
R5
Prim for R5
Tamoxifenc
40 mg q.d.
SD
RECIST
7
7
26+
ICD (withD)
5
60
IIA
Sx(4x)+RT(2x)+ HT
R5
Residue
Megestrol Acetateb
160 mg q.d.
SD
RECIST
19
19+
19+
ICD (withD)
6a
32
IA
Sx(5x)+RT(2x)
R6
Prim for R6
Tamoxifenc
20 mg b.i.d
PD
RECIST
6
32
IA
Sx(5x)+RT(2x)+ HT+CT
R6
Residue
Megestrol Acetateb
NA
SD
RECIST
3
3
27
DOD
7
60
IC
Sx(3x)
R2
Prim for R2
Megestrol Acetateb
160 mg q.d.
PR
Marker
10
5
10
4
15+
44
AWD
DOD
8
44
IIB
Sx
R1
Prim for R1
Megestrol Acetateb
160 mg q.d.
SD
RECIST
Ongoing
7+
7+
AWD
PD
RECIST
9
50
IA
Sx(5x)+RT
R5
Prim for R5
Letrozoled
2,5 mg q.d.
3
3
11+
ICD (withD)
10
68
IIB
Sx(3x)
R3
Prim for R3
Megestrol Acetateb
160 mg q.d.
SD
RECIST
Ongoing
4+
4+
AWD
11
47
IA
Sx(3x)
R3
Prim for R3
Letrozoled
2,5 mg q.d.
SD
RECIST
Ongoing
9
29+
NED
12
38
IC
Sx(6x)+CT(4x)
R6
Residue
Aromatase Inhibitorf
NA
SD
Imaging
3
4
17+
AWD
13
31
IC
R5
Residue
Tamoxifenc
40 mg q.d.
PR
Clinical
5
5
13
DOD
13a
31
IC
R5
Residue
Megestrol Acetateb
160 mg q.d.
PD
Imaging
4
2
8
DOD
13a
31
IC
R5
Residue
Gosereline
NA
PD
Imaging
4
3
4
DOD
Sx(4x)+CT(3x)+ RT Sx(4x)+CT(3x)+ RT+HT Sx(4x)+CT(3x)+ RT+HT(2x)
43
IIIC
Letrozoled
2,5 mg q.d.
SD
Imaging
14
44+
44+
AWD
14a
43
IIIC
Sx(4x)+HT
R4
Residue
Letrozoled
NA
SD
Imaging
7
30+
30+
AWD
15
51
IIB
Sx(2x)+CT
R2
Prim for R2
Tamoxifenc
NA
PD
Imaging
2
2
14
DOD
16
69
IC
Sx(3x)
R3
Prim for R3
Tamoxifenc
1/4 wk sc
PD
RECIST
8
8
11+
AWD
16a
69
IC
Sx(3x)+HT
R3
Residue
Letrozoled
2,5 mg q.d.
PD
Imaging
3
3
3+
AWD
76
SD
14
Sx(4x)
R4
Prim for R4
NA
Sx(2x)+HT
Residue
Letrozoled
2,5 mg q.d.
Marker
13
18
102
18
24
IC
Sx(6x)+CT(3x)+ RT
R5
Residue
Megestrol Acetateb
160 mg q.d.
SD
Imaging
29
33
73+
AWD
19a
44
IC
Sx(2x)+CT
R2
Prim for R2
Anastrozoled
1/4 wk sc
PD
Imaging
5
5
11+
AWD
SD
RECIST
17
19
44
IC
20
52
IIIC
21
38
II
22
44
I
R1
Sx(2x)+CT+HT
R2
Residu
Letrozoled
Ongoing
8+
8+
AWD
Sx(2x)
R2
Prim for R2
Anastrozoled
1 mg q.d.
SD
Imaging
5
12+
12+
AWD
R4
Residue
Gosereline
1/4 wk sc
SD
Imaging
4
53
112
DOD
R3
Residue
Tamoxifenc
10 mg t.i.d.
SD
NA
5
36
36
DOD
Sx(4x)+CT(5x)+ RT Sx(3x)+CT(3x)+ RT
NA
DOD
Table 1. Characteristics and responses of all patients with hormone therapy on measurable disease. aDifferent
hormone therapy leading to less response in the patient described with same case number, bSteroidal progestin, cSelective Estrogen Receptor Modulator (SERM), Inhibitor, eGonadotropin-Releasing Hormone (GnRH) agonist, fType of aromatase inhibitor unknown.
dAromatase
Abbreviations: HT, hormone therapy; PFS, progression free survival; DSS, disease specific survival; M, month(s); Sx, surgery; CT, chemotherapy; RT, radiotherapy; HT, hormone therapy; P, primary disease; R1, first recurrence; R2, second recurrence; R3, third recurrence; R4, fourth recurrence; R5, fifth recurrence; R6, sixth recurrence; Prim, primary treatment; MPA, medroxyprogesterone acetate; sc, subcutaneous; q.d., once a day; b.i.d., two times a day; t.i.d., three times a day; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors; NED, no evidence of disease; AWD, alive with disease; ICD, intercurrent death; withD, with GCT disease; DOD, dead of disease; NA, not available; n/a, not applicable.
Results We identified 127 patients with an adult GCT, of which 81 (64%) had a recurrence. Twenty-five of these patients (20%) were treated with hormones, of these 22 had measurable disease at the start of their treatment. The characteristics of these 22 patients, the type of HT administered and the response to HT on measurable GCT disease are presented in Table 1. Pooled objective response rate to HT was 18% (4/22) (95% Confidence Interval 6-41%). In one patient (4.5%) a complete response and in three (14%) a partial response was described (Table 2). Fourteen patients (64%) had stable disease and in 4 patients (18%) disease was progressive. Median PFS after HT was 10 months (range 2-53) and is shown in Figure 1. Median DSS after HT was 36 months (range 2-112) (Figure 2).
Fig. 2. Disease specific survival in months of 22 patients after start of hormone therapy for measurable disease.
Conclusion Although several case reports described good responses to HT in patients with a GCT, we found only a moderate demonstrable effectiveness in this large consecutive series of patients.
33 p16/Ki-67 dual-stained cytology in HPV-positives with normal cytology M.H. Uijterwaal1, N.J. Polman1, B.I. Witte2, FJ. van Kemenade3, D. Rijkaart1, J. Berkhof2, G.A.M.A. Balfoort-van der Meij4, R. Ridder5, P.J.F. Snijders1, C.J.L.M. Meijer1 1Pathology
and 2Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands, Erasmus University Medical Center, Rotterdam, The Netherlands, 4Saltro Diagnostic Centre, Utrecht, The Netherlands and 5Ventana Medical Systems Inc., Tucson, Arizona, United States of America 3Pathology,
Introduction
Results
• The main drawback of primary human papillomavirus (HPV) based screening is a lower specificity for high-grade CIN lesions compared to cytology. • p16/Ki-67 dual-stained cytology has been suggested as an more objective biomarker for triage of HPV positive women1,2.
• Cross-sectional analysis: p16/Ki-67 dual-stained cytology has a high sensitivity and specificity for the detection of CIN2+ and CIN3+ lesions in HPVpositive women with normal cytology (Table 1). Table 1. Clinical performance of p16/Ki-67 and HPV testing to detect CIN2+ or CIN3+ in HPV positive women with normal cytology.
Aim of study • To evaluate the cross-sectional and longitudinal performance of p16/Ki-67 dual-stained cytology for the triage of HPV-positive women with normal cytology.
Subjects and Methods • Conventional cytology specimens from 847 HPV-positive women with normal cytology derived from the VUSA-Screen study were subjected to p16/Ki-67 dualstained cytology. • Cross-sectional analysis of clinical performance of p16/Ki-67 dual-staining compared with HPV genotyping. • Longitudinal 5-years analysis of triaging HPV-positive women with p16/Ki-67 dualstaining compared to triaging with HPV genotyping. • Outcome: CIN3+ (CIN2+)
• Longitudinal analysis: Cumulative incidence rates for CIN3+ lesions are shown in Figure 2.
Figure 2. Cumulative incidence risk curve for CIN3+ for HPV positive women with normal cytology and different triage tests.
Conclusion • p16/Ki-67 dual-stained cytology, detects >70% of the underlying CIN3+ in HPV+/Pap1 women at baseline and decreases 5-year CIN3+ risk of HPV+/Pap1 women from 6.9% to 3.3%. Figure 1. Cervical epithelial cells dual-stained for p16/Ki-67.
References: 1Petry, Gynecol Oncol 2011; 2Carozzi, Lancet Oncol 2013.
34 Effective immunotherapy in HPV-related cancer: a long road ahead. S. Samuels1, A.M. Heeren2,3, D.M. Ferns3, W.J. van Driel1, H.J. Zijlmans1, C.L. Zuur4, J.P. de Boer4, J.B. Haanen5,, P. Kvistborg6, E.S. Jordanova3, G.G. Kenter7 1 Dept of Gynecology, The Netherlands Cancer Institute, 2 Dept of Medical Oncology, VU University Medical Center, 3 Dept of Obstetrics & Gynecology, VU University Medical Center, 4 Dept of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, 5 Division of Medical Oncology, The Netherlands Cancer Institute, 6 Division of Immunology, The Netherlands Cancer Institute, 7 Dept of Gynecology, Center for Gynecologic Oncology Amsterdam.
Projects 1. Microenvironment of tumor draining lymph nodes (TDLN) in cervical cancer. To investigate the state of the TDLN microenvironment, we analyzed various Tcell populations, APC subsets and MDSC subsets in tumor-free (LN-) and metastatic (LN+) TDLNs of cervical cancer patients. 2. Soluble MICA and HLA-G in cervical cancer patients. To determine whether patient characteristics and survival rates are affected by high levels of sMICA and sHLA-G, we measured sMICA and sHLA-G in pretreatment serum levels of 366 cervical cancer patients by ELISA. 3. Biomarker evaluation in advanced stage cervical cancer by an international working group. Tumor stages IB2-IV. A prospective multicenter European trial with tumor biopsies, and blood collection for molecular analysis at predetermined time points to assess dominant mutations and activation pathways in cervical cancers predictive to standard treatment response. 4. The immunological effects of conventional therapy ((chemo)radiotherapy) for the treatment of head and neck squamous cell carcinoma (HNSCC): an exploratory study. To monitor the systemic effects of radiotherapy (RT) alone or in combination with concurrent chemotherapy (CRT) (cisplatin) on the immune response and T cells over time in patients with HPV+ head and neck squamous cell carcinoma (HNSCC) to determine the optimal timing for future vaccination in HPV+ HNSCC patients. 5. Safety, toxicity and immunogenicity of HPV16 E7 DNA vaccination in HPV16positive vulvar intraepithelial neoplasia grade III: a phase I study. A single center, non-randomized phase I study. Patients with HPV16+ VINIII lesions will be enrolled. Patients will receive a primary vaccination consisting of three intradermal injections followed after four weeks with another three booster injections with a fixed dose of an HPV DNA vaccine. Two dose levels will be tested.
Background
Overall, human papilloma virus (HPV) is responsible for more than 5% of the global cancer burden, the majority of which can be ascribed to cervical cancer, while 0.7% is accounted by cancer of the penis, vulva, vagina, anus and oropharynx. The immune system plays an important role in the development, maintenance and expansion of cancer. Carcinogenesis often leads to an immunosuppressive environment that promotes tumor growth and protects the tumor from immune attack. Many different mechanisms of immunosuppression can impair the host defense against tumors.
6. Regulatory B cells (Bregs) in HPVrelated cancer. To determine if Bregs are expressed in HPVrelated cancers we will perform immunofluorescent staining of formalinfixed, paraffin-embedded cancer tissue sections of the cervix, penis, vulva and oropharynx.
Immunotherapy forms an attractive approach for treating patients with HPVrelated (pre)cancer. However, to date the clinical translation of immunotherapy has resulted in limited success. A better understanding of the microenvironment and its influence on cancer is essential for the development of effective immunotherapeutic strategies against HPV-related cancer. Furthermore, the effect of conventional therapies on the immune response will enable us to answer the important question how a combination treatment with vaccines can be exploited to the best benefit of the patient.
Results
1. There are substantial differences in the frequencies of immune effector cell subsets and cytokine production between LN- and LN+ of cervical cancer patients. We mainly found that high and interrelated rates of PD-L1+CD14+ APCs and regulatory T cells (Tregs) mark the microenvironment of LN+ (see fig.1). 2. sHLA-G does not seem to have prognostic significance in cervical cancer regardless of histological subtype. Interestingly, high level of sMICA is associated with improved disease-free and disease-specific survival in cervical adenocarcinoma, strengthening the idea that these tumors are immunologically different.
Fig. 1. Tregs and APC subsets in TDLNs of cervical cancer patients. A) More Tregs in LN+ than in LN-. B) Higher percentages of APCs in LN+. C) Median fluorescence index of co-stimulatory molecules and coinhibitory molecules on CD14+ APCs. D/E) PD-L1 expression in LN+ and LN-.
Conclusion
3. Inclusion of participants is ongoing. 4. Protocol submitted to MEC. 5. Inclusion of participants is ongoing. 6. Protocol in progress.
There is a long road ahead to effective immunotherapy in HPV-related cancer. Combination therapy, for example DNA vaccines with PD-1/PD-L1 checkpoint inhibition, is the most promising strategy. However, it is not clear which costimulatory molecules are the optimal effectors for the best immune response.
35 Serum Human Epididymal protein 4 (HE4) as biomarker for the differentiation between primary ovarian cancer and ovarian metastases A.Stiekema1, Q.J.A.J Boldingh1, C.A.R. Lok 1, H. Boot2, V. van Noort3, W.J van Driel1, G.G Kenter1, C.M Korse4
1 Department of gynecologic oncology 2 Department of medical oncology 3 Department of Biometrics 4 Department of clinical chemistry
INTRODUCTION About 5-15% of all malignant ovarian tumors are metastases from other primary tumors. The majority originates from the gastrointestinal (GI) tract. It is crucial to differentiate between primary ovarian cancer and ovarian metastases because different treatment is required. The clinical value of HE4 as a serum biomarker in primary ovarian cancer has been established. However, the possible clinical use of HE4 in the differentiation between primary ovarian cancer and ovarian metastases from other malignancies has never been investigated.
AIM
HUMAN EPIDIDYMAL PROTEIN 4 (HE4): what do we already know? • Identified 20 years ago. • WFDC2 gene, chromosome 20. • Expressed in normal tissue of the reproductive and respiratory tract.
Table 2. Median serum values of HE4, CEA and CA-125
• Overexpression in epithelial ovarian cancer. • HE4 has a higher sensitivity and specificity compared to CA-125 in differentiation between benign and malignant ovarian masses; sensitivity 90% and 91% and specificity of 97% and 65% respectively.
Figure 1. Receiver operating curve (ROC) with area under the curve (AUC) of HE4 and ratio of combined markers
Evaluate the value of biomarker HE4 in the preoperative differentiation between primary ovarian cancer and ovarian metastases compared to tumormarkers CA-125, CEA and ratios hereof.
MATERIALS AND METHODS All patients with ovarian metastases from gastro-intestinal or breast origin who received primary treatment in the NKI/AvL between 1994 and 2012 were included. A control group of patients with epithelial ovarian cancer (EOC) was included. Serum HE4, CA125 and measured prior to treatment.
Table 1. Patients’ characteristics
CEA
were
RESULTS A total of 192 patients were included for analysis; 45 with metastatic disease and 147 with EOC. Median serum HE4 value was significantly higher in patients with EOC compared to patients with ovarian metastases from other malignancies; 431 pmol/L versus 68 pmol/L (p<0.001). Multivariable logistic regression analysis of all markers revealed that HE4 and CEA were independent factors in differentiating between EOC and ovarian metastases (p<0.001 and p=0.001) while CA-125 was not (p=0.262). Using a ratio of these markers, the formula, HE42.5/CEA, was developed to enable optimal identification of EOC preoperatively with a specificity of 80% at a set sensitivity of 90%.
CONCLUSION • Serum HE4 is less frequently elevated in metastatic disease compared to epithelial ovarian cancer.
• Using the HE42.5/CEA ratio more patients will be correctly diagnosed.
RECOMMENDATION • Validate HE42.5/CEA ratio in another patient population.
36 Physical and psychological impacts of RRSO in high-risk women R.F.M. Vermeulen1, M. van Beurden1, C.M. Korse2, K.N. Gaarenstroom3, N. Aaronson4, L.R.C.W. van Lonkhuijzen5, D. van der Broek2, G.G. Kenter6 1 Dept of Gynecology, The Netherlands Cancer Institute, 2 Dept of Clinical Laboratory, The Netherlands Cancer Institute, 3 Dept of Obstetrics & Gynecology, Leiden University Medical Center, 4 Dept of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, 5 Dept of Obstetrics & Gynecology, Amsterdam Medical Center, 6 Dept of Gynecology, Center for Gynecologic Oncology Amsterdam.
Projects 1. Review of literature about the physical and psychological impacts of RRSO in high-risk women. To describe the latest insights in quality of life, sexuality, menopausal complaints, osteoporosis, cardiovascular disease and use of hormone replacement therapy after undergoing a risk reducing salpingooophorectomy in pre- and postmenopausal women at hereditary risk for ovarian carcinoma. Gain more perspective of what the future may bring us in preventive strategies. 2. Impact of RRSO versus screening on quality of life among high-risk women. To determine whether patients who choose for definitive surgery have better quality of life and what the role of hormone replacement therapy in these women is. A prospective study of 359 high risk women. 3. Impact of RRSO on pre- and postmenopausal women regarding menopausal complaints, depression, anxiety and sexual health. A prospective multicenter study of 147 premenopausal (n=85) and postmenopausal (n=62) women who underwent RRSO. To determine differences in symptoms between menopausal state at time of the surgery. 4. The hormonal effects of RRSO on menopausal complaints and sexual health in pre- and postmenopausal high risk women. To monitor the systemic effects of RRSO in serum in order to estimate whether they have influence on postmenopausal complaints. Serum obtained from postmenopausal patients before RRSO will be the reference for the premenopausal women after surgery, because this group experienced natural menopause. A prospective study of 147 women. 5. Using a decision aid. To determine if using a digital decision aid gives higher levels of satisfaction and less stress about the difficult decision of removing the ovaries preventively.
Background It is estimated that approximately 515% of all ovarian cancers are due to inherited predisposition. Women at increased hereditary or familial risk for ovarian cancer (OC) are BRCA 1/2 mutation carriers and women from a HBOC family (Hereditary (Breast and) Ovarian Carcinoma (H(B)OC)). In these families was no mutation found. The cumulative lifetime risk for ovarian cancer at the age of 70 years is 39% in case of a BRCA1 mutation, and 16% in case of a BRCA2 mutation, respectively. A woman from a HOC family, younger than 50 years and with a first- and a first-or second-degree relative with ovarian cancer, has a lifetime risk of ovarian cancer over 10%.
6. Lipid profile and cardiovascular risk profile after RRSO in pre- and postmenopausal women. A prospective study where we determine if loss of the ovaries has a substantial effect on the short time risk for cardiovascular diseases and metabolic syndrome. We will analyze the serum of 147 women before and after surgery on lipid profile and markers for metabolic syndrome. 7. The effect of RRSO on bone health in high risk women for ovarian cancer. To investigate if RRSO will lead to early onset of osteoporosis within six months after surgery. Bone markers (β-CTx, s-P1NP and 25-OH Vit D3) will be determined in serum before and after surgery in pre- and postmenopausal patients.
Conclusion
Because of screening limitations more and more high risk women choose to undergo a risk reducing salpingooophorectomy (RRSO) to lower the risk on OC. RRSO is a procedure that involves removal of both ovaries and fallopian tubes. This will reduce the risk of ovarian cancer by 80%-96%. A major adverse event of RRSO in premenopausal women is an immediate onset of menopause with an increase in non-cancer related morbidity, such as endocrine, sexual and cardiovascular symptoms, and osteoporosis. Hormonal replacement therapy (HRT) can be used to decrease some menopausal complaints and osteoporosis. HRT is contraindicated in women with a prior diagnosis of breast cancer.
Results/Aims 1. Preventive salpingectomy alone will become increasingly important in the prevention of ovarian carcinoma in high risk women. 2. Hormone replacement therapy seems to be a good solution for postmenopausal complaints which arise after surgery, in contrast to what is reported in retrospective studies. 3. Analyzing of questionnaires is ongoing. 4. Serum of all patients is obtained, will be analyzed by LC-MS/MS in 2015. 5. Developing decision aid in progress. 6. Serum of all patients is obtained, will be analyzed by LC-MS/MS in 2015. 7. Serum of all patients is obtained, will be analyzed by LC-MS/MS in 2015.
Risk reducing salpingo-oophorectomy is an effective method to lower the risk on ovarian carcinoma in women at risk. Unfortunately there are a lot of side effects related to this surgery, especially in premenopausal women. With this project we aim to get insight in these symptoms and complaints, and propose systematic improvements for these high risk women.
37 Label-free LC-MSe in tissue and serum reveals protein networks underlying differences between benign and malignant serous ovarian tumors Wouter Wegdam1, Carmen A. Argmann2, Gertjan Kramer3, Johannes P. Vissers4, Marrije R. Buist1, Gemma G. Kenter1, Johannes M.F.G. Aerts3, Danielle Meijer1, Perry D. Moerland5
1 Department of Gynecology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. 2 Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States. 3 Clinical Proteomics Group, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. 4 Waters Corporation MS Technologies Center, Manchester, United Kingdom. 5 Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Objective To identify proteins and (molecular/biological) pathways associated with differences between benign and malignant epithelial ovarian tumors.
Materials and Methods
MetaCore network analysis of differentially expressed serum and tissue proteins inferred GCR-alpha and Sp1 as common transcriptional regulators. Indicating their potentially important role as a transcription factor in the carcinogenic process.
Serum of six patients with a serous adenocarcinoma of the ovary was collected before treatment, with a control group consisting of six matched patients with a serous cystadenoma. In addition to the serum, homogeneous regions of cells exhibiting uniform histology were isolated from benign and cancerous tissue by laser microdissection.
Fig. 3. Figure 7. Interactions between overconnected proteins in tumor tissue. A network built in MetaCore using the 5 overconnected proteins, PCBP-1, Alpha-actinin 4, HSP60, 14-3-3 beta/alpha and 14-3-3 zeta/delta as seed nodes yielded a highly interconnected network amongst the seed nodes and implicated a role for androgen receptor signaling.
Fig. 1. Cancer tissue isolated by microdissection
We subsequently employed label-free liquid chromatography tandem mass spectrometry (LC-MSe) to identify proteins in these serum and tissues samples. Analyses of differential expression between samples were performed using Bioconductor packages and in-house scripts in the statistical software package R. Hierarchical clustering and pathway enrichment analyses were performed, as well as network enrichment and interactome analysis using MetaCore.
Results
In total, we identified 20 and 71 proteins that were significantly differentially expressed between benign and malignant serum and tissue samples, respectively. The differentially expressed protein sets in serum and tissue largely differed with only 2 proteins in common, Apolipoprotein A-I and Serotransferrin.
Interactome analysis highlighted 14-3-3 zeta/delta, 14-3-3 beta/alpha, Alpha-actinin 4, HSP60, and PCBP1 as critical proteins in the tumor proteome signature based on their relative overconnectivity. The role of PCBP1 in ovarian cancer was further investigated in an independent ovarian cancer dataset containing 30 tumors of low malignant potential and 60 serous ovarian cancer tumor samples available at Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/; accession no. GSE12172). Compared to low malignant potential tumors, there was a significant increase in PCBP1 gene expression in malignant ovarian tumors.
Conclusion Fig. 2A and B. Proteins in the serum and tumor datasets that are potentially associated with GCR-alpha and SP1 pathways. The proteins marked in blue were found in the serum dataset, those marked in green in both tumor and serum. Unmarked proteins are specific for the tumor signature (except GCR-alpha and SP1). Proteins are ordered according to their position within the cell (extracellular, membrane bound, cytoplasmic or nucleic). Individual proteins are represented as nodes, the different shapes of the nodes represent the functional class of the proteins. The arrowheads indicate the direction of the interaction, the color of the lines between nodes describes activation (green), inhibition (red), and unspecified (black) interactions. The small circles on top of the protein symbols indicate up-regulation (red) or down-regulation (blue).
Our analysis identified proteins with both novel and previously known associations to ovarian cancer biology. Despite the small overlap between differentially expressed protein sets in serum and tissue, APOA1 and Serotransferrin were significantly lower expressed in both serum and cancer tissue samples, suggesting a tissue-derived effect in serum. Pathway and subsequent interactome analysis also highlighted common regulators in serum and tissue samples, suggesting a yet unknown role for PCBP1 in ovarian cancer pathophysiology.
38 CADM1, MAL and miR124-2 methylation analysis in cervical scrapes to detect cervical and endometrial cancer1 Marjolein van Zummeren*1, Lise MA De Strooper*1, Renske DM Steenbergen*1, Maaike CG Bleeker*1, Albertus T Hesselink*1, G Bea A Wisman*2, Peter JF Snijders*1, Daniëlle AM Heideman*1, Chris JLM Meijer*1 *1 Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands *2 Department of Gynaecological Oncology, University Medical Centre Groningen, Groningen, The Netherlands Journal of Clinical Pathology, October 2014
Introduction Gene promoter hypermethylation is recognised as an essential early step in carcinogenesis, indicating important application areas for DNA methylation analysis in early cancer detection. Yet, no large series of cervical scrapes from women with cervical cancer have been evaluated for methylation analysis so far, as these are not merely encountered in large numbers in a screening setting given the rarity of cervical cancer in the screening population. In the current study, we evaluated CADM1, MAL and miR124-2 methylation in a series of cervical scrapes of women with cervical (n=79) or endometrial (n=21) cancer, cervical intraepithelial neoplasia grade 3 (CIN3) (n=16) or CIN2 (n=32), and women without evidence of CIN2 or worse (n=120). Methylation analysis was done by the PreCursor-M assay, a multiplex quantitative methylationspecific PCR. The goal This study was set out to assess the performance of CADM1, MAL and miR124-2 methylation analysis in cervical scrapes for detection of cervical and endometrial cancer.
DNA methylation analysis of cancer-related genes Hypermethylation of CpG islands in the promoter regions of tumour suppressor genes leads to gene silencing and is recognised as an essential step in cancer development1,2.
Methylation of cancer-related genes has been described in a variety of gynaecological carcinomas, including cervical and endometrial cancer1,3,4. It has been shown that methylation-mediated silencing of CADM1(cell adhesion molecule 1), MAL (T-lymphocyte maturation-associated protein) and miR124-2 (micro-RNA124-2) is functionally involved in cervical carcinogenesis and a frequent event detectable in tissue biopsies from CIN3 lesions and cervical carcinoma1,5,6. Methylation levels of CADM1, MAL and miR124-2 genes have shown to be related to the severity and duration of cervical disease and are exceptionally increased in cervical cancer1,6,7.
Results All samples of women with cervical cancer (79/79, 100%), independent of the histotype, and 76% (16/21; 95% CI 58.0% to 94.4%) of women with endometrial cancer scored positive for DNA methylation for at least one of the three genes. In women without cancer, methylation frequencies increased significantly with severity of disease from 19.2% (23/120; 95% CI 12.1% to 26.2%) in women without CIN2 or worse to 7.5% (12/32; 95% CI 20.7% to 54.3%) and 68.8% (11/16; 95% CI 46.0% to 91.5%) in women with CIN2 and CIN3, respectively. Overall methylation positivity and the number of methylated genes increased proportionally to the lesion severity (see figure 1).
Fig. 1. CADM1, MAL and miR124-2 methylation in cervical scrapes in relation to underlying lesion type. The fraction of methylation-positive cases as determined by multiplex qMSP (y-axis) in relation to the lesion type (x-axis) is shown. *p Value comparing CIN2+ (i.e., CIN2, CIN3, cervical cancer) over ‘no evidence CIN2+, HPV+’. CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; qMSP, quantitative methylation-specific PCR.
Conclusion DNA methylation analysis of CADM1, MAL and miR124-2 in cervical scrapes consistently detects cervical cancer and the majority of CIN3 lesions, and has the capacity to broaden its use on cervical scrapes through the detection of a substantial subset of endometrial carcinomas.
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