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Objective To estimate the diagnostic value of tumor and immune related proteins in the discrimination between benign and malignant adnexal masses, and between different subgroups of tumors. Methods In this exploratory diagnostic study, 254 patients with an adnexal mass scheduled for surgery were consecutively enrolled at the University Hospitals Leuven (128 benign, 42 borderline, 22 stage I, 55 stage II-IV, and 7 secondary metastatic tumors). The quantification of 33 serum proteins was done preoperatively, using multiplex high throughput immunoassays (Luminex) and electrochemiluminescence immuno-assay (ECLIA). We calculated univariable areas under the Receiver Operating Characteristic Curves (AUCs). To discriminate malignant from benign tumors, multivariable ridge logistic regression with backward elimination was performed, using bootstrapping to validate the resulting AUCs. Results CA125 had the highest univariable AUC to discriminate malignant from benign tumors (0.85, 95% confidence interval 0.79-0.89). Combining CA125 with CA72.4 and HE4 increased the AUC to 0.87. For benign vs borderline tumors, CA125 had the highest univariable AUC (0.74). For borderline vs stage I malignancy, no proteins were promising. For stage I vs II-IV malignancy, CA125, HE4, CA72.4, CA15.3 and LAP had univariable AUCs ≥0.80. Conclusions The results confirm the dominant role of CA125 for identifying malignancy, and suggest that other markers (HE4, CA72.4, CA15.3 and LAP) may help to distinguish between stage I and stage II-IV malignancies. However, further research is needed, also to investigate the added value over clinical and ultrasound predictors of malignancy, focusing on the differentiation between subtypes of malignancy.

Introduction/Background* SENTIX is a prospective cohort multicentric international study on sentinel lymph node (SLN) biopsy without pelvic lymph node dissection (PLND) in patients with early-stage cervical cancer. SLN frozen section (FS) and pathological ultrastaging were mandatory by the protocol. Samples from SLN were reviewed centrally for pathological assessment quality control. Only sites experienced in SLN biopsy technique could join the trial. Methodology In total, 47 sites from 18 countries participated in the trial. Patients with FIGO 2009 stages T1A1/LVSI+ – T1B1 ( Result(s)* Altogether 733 patients were registered until Sentix enrolment closure in October 2020, 83 patients were excluded (table 1) and 650 patients was analysed. Patients` characteristics are shown in table 1. Bilateral SLN detection rate reached 95%. FS detected macrometastases (MAC) in 44 cases and micrometastasis (MIC) in 4 cases. SLN ultrastaging found additional 9 cases with MAC, 26 with micrometastases (MIC) and all 19 cases with isolated tumor cells (ITC). Sensitivity of FS was 83.0% for the detection of MAC, 57.8% for pN1 status (MAC or MIC) and 47.1% for any type of SLN involvement (MAC, MIC, ITC). Table 2. Conclusion* High bilateral detection rate of 95% was achieved in Sentix sites experienced in the SLN biopsy technique. Intraoperative pathological assessment of SLN failed to detect majority of MIC (86.7%), all cases with ITC and 42.2% with pN1 (MIC or MAC).

Introduction/Background* Pembrolizumab, an anti-PD-1 antibody, has demonstrated activity in patients with previously treated mismatch repair (MMR) deficient (dMMR; 57.1% objective response rate [ORR] as monotherapy and 63.6% ORR as combination therapy with lenvatinib) and MMR proficient (pMMR; 36.2% ORR as combination therapy with lenvatinib) endometrial cancer. ENGOT-en11/GOG-3053/KEYNOTE-B21 (NCT04634877) is a phase 3, randomized, double-blind study of pembrolizumab or placebo in combination with adjuvant chemotherapy with/without radiotherapy in patients with endometrial cancer. Methodology Eligible patients are ≥18 years old with newly diagnosed, high-risk (stage I/II non-endometrioid or with p53 abnormality and any histology, stage III/IVA), previously untreated endometrial cancer following surgery with curative intent with no evidence of disease post-operatively. Approximately 990 patients are randomized to receive pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for 6 cycles plus chemotherapy (carboplatin area under the curve [AUC] 5/6 plus paclitaxel 175 mg/m2 Q3W or carboplatin AUC 2/2.7 plus paclitaxel 60 mg/m2 QW) in stage 1. Patients receive pembrolizumab 400 mg or placebo Q6W for 6 cycles in stage 2. Radiotherapy (external beam radiotherapy [EBRT] and/or brachytherapy) ± radiosensitizing cisplatin 50 mg/m2 (days 1 and 29) may be administered after completion of chemotherapy. Randomization is stratified by MMR status (pMMR vs dMMR) and, within pMMR, by planned radiation therapy (cisplatin-EBRT vs EBRT vs no EBRT), histology (endometrioid vs non-endometrioid), and International Federation of Gynecology and Obstetrics surgical stage (I/II vs III/IVA). Dual primary endpoints are disease-free survival (DFS; per investigator assessment) and overall survival (OS). Secondary endpoints include DFS (per blinded independent central review), DFS (per investigator assessment) and OS by biomarker status (PD-L1 and tumor mutational burden), safety (per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0), and quality of life (per European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-C30] and Endometrial Cancer Module [EORTC QLQ-EN24]). Enrolment began December 2020 and is ongoing at 221 sites in 28 countries. Result(s)* N/A Conclusion* N/A

Introduction/Background* Locally advanced cervical cancer can be treated by concomitant chemoradiation therapy (CCRT) followed by brachytherapy or by neo-adjuvant chemotherapy followed by surgery (NACT-S). Quality of life (QoL) and sexual health (SH) are important to evaluate after treatment considering the young mean age in affected women and relatively long 5-year survival. This study aims to compare differences in QoL and SH among women treated for locally advanced cervical cancer, after CCRT versus NACT-S. Methodology In this academic single centre cross-sectional questionnaire study, we included patients > 18 years with a history of locally advanced cervical cancer, who received either CCRT or NACT-S. QoL and SH were assessed using Dutch questionnaires including the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life core module 30 (QLQ-C30), the cervical cancer module 24 (QLQ-CX24), and sexual health questionnaire (SHQ-22). X2-test and T-test were performed to compare the two groups. Result(s)* We sent the questionnaires to 105 women who were treated at our centre in the period between 01-01-2002 and 31-12-2018. A total of 36 patients (34%; n=12 CCRT; n=24 NACT-S) returned the questionnaire and were included for analysis. Six patients in the NACT-S group also underwent adjuvant CCRT. When comparing the CCRT and NACT-S group, 58% vs. 54% did “not at all” feel limited in their daily activities. QoL on average scored 63% vs. 67% (P= 0.29), in the CCRT and NACTS group respectively. Patients were at least “quite a bit” or “very much” satisfied with their sex life in 25% vs. 54% in the CCRT and NACT-S group, respectively (P= 0.048). A total of 33% vs. 46% did “not at all” communicate with medical professionals about sexual issues in the CCRT and NACT-S group, respectively. Conclusion* QoL did not significantly differ when comparing the CCRT to the NACT-S group. Satisfaction with sexual life was higher in the NACT-S group. QoL and SH should receive more attention in patients with cervical cancer after treatment.

Introduction/Background* The vascular endothelial growth factor (VEGF) plays an import role in emergence and spread of high-grade serous tubo-ovarian carcinoma (HGSTOC). Bevacizumab, a monoclonal antibody targeting VEGFA, has therefore been added to first-line treatment of advanced HGSTOC. We here map the dynamics of different stromal components of the tumour microenvironment under chemotherapy with or without bevacizumab. Methodology We performed single-cell RNA-sequencing on 62,461 cells sampled from 6 HGSTOC patients before and after neo-adjuvant platin-based chemotherapy with or without bevacizumab. We identified 44 stromal cell subclusters on which we applied Mixed-effects modelling of Associations of Single Cells to identify cell populations associated with bevacizumab exposure and pathological response using the chemotherapeutic response score. Result(s)* Our study revealed diverse stromal cell subsets associated with bevacizumab exposure. The addition of bevacizumab to frontline chemotherapy increased the odds of endothelial cell (ECs) prevalence by a 3-fold (OR 2.91, 95%CI:2.36-3.58; p Conclusion* We here provide initial evidence on the mechanisms underlying early response to bevacizumab and frontline chemotherapy in HGSTOC, including tip cell impairment, reduced hypoxia and a decrease in regulatory T cells. However, bevacizumab exposure increased the influx of PDGFC-expressing macrophages capable to bypass VEGFA-dependent angiogenesis.

Introduction/Background* Platinum in combination with paclitaxel (P) and bevacizumab is the standard of care in first-line recurrent/advanced cervical cancer (Tewari, NEJM 2020). Nintedanib is an oral tyrosine kinase inhibitor targeting, among others, vascular endothelial growth factor receptor. Methodology Double-blind phase II randomised study in patients with first-line recurrent or primary advanced (FIGO stage IVB) cervical cancer. Patients received carboplatin AUC 5-6 and paclitaxel 175mg/m2 q 3 weeks with oral nintedanib 200 mg BID/placebo. Stratification factor was primary advanced versus recurrent disease. The primary endpoint was progression-free survival (PFS) at 1,5 years with at least 87 events and α=0.15, β=80%, one sided, in favor of the nintedanib (N) versus control (C) arm. The study (NCT02009579) was performed according to the ENGOT model A. Result(s)* 120 patients (62 N, 58 C) were randomised between March 2014 and October 2018. Median follow-up was 35 months. Baseline characteristics were similar in both groups (total population: squamous cell carcinoma 62%, prior radiotherapy 64%, primary advanced 25%, recurrent 75%). The primary endpoint was met with a PFS at 1.5 years of 15.1% versus 12.8% in favour of the nintedanib arm (p = 0.057). Median overall survival (OS) was 21.7 and 16.4 months for N and C, respectively. Subgroup analysis did not demonstrate a difference in PFS in the primary advanced setting, but in the recurrent setting the 1 year PFS was 22.8% and 14.9% for N and C, respectively. Confirmed RECIST response rate was 48% for N and 39% for C. No new adverse events were noted for N. However N was associated with numerically more serious adverse events for anemia and febrile neutropenia. Discontinuation of chemotherapy was similar in both groups. N was discontinued in 3% versus placebo in 1.6% of the patients. Dose reduction of N was necessary in 53% of the patients. Conclusion* The study met its primary endpoint with a prolonged PFS in the N arm. No new safety signals were observed.

Introduction/Background* Recently 3 Phase III first-line studies, PAOLA-1/ENGOT-ov25 (Ray-Coquard et al. NEJM 2019). PRIMA/ENGOT-ov26/GOG-3012 (Gonzales Martin et al. NEJM 2019) and VELIA/GOG-3005 (Coleman et al. NEJM 2019) have demonstrated that the addition of a PARP inhibitor (PARPi) to platinum-based therapy+/-bevacizumab improved progression-free survival (PFS) in advanced ovarian cancer (AOC) patients. The benefit was greater when the tumor was homologous recombination deficient (HRD) according to Myriad myChoice test, independently of BRCA status. The PAOLA-1 olaparib+bevacizumab maintenance regimen was approved in USA/Europe/Japan for HRD positive patients. The European initiative aims at evaluating various HRD tests on PAOLA-1 tumor samples to identify new reliable and feasible HRD tests Methodology The HRD initiative has 2 components; one based on artificial intelligence with various partners and the other, the European HRD ENGOT initiative (EHEI), is led by academic research laboratories (RL) from ENGOT groups. The HRD test evaluation protocol for the EHEI RL includes 3 phases. The phase 1 (2019/12) brought together European RL. Because non-BRCA Homologous Recombination Repair (HRR) mutations have not been found predictive of PARPi activity in PAOLA-1 (Pujade-Lauraine et al, SGO 2021)) RL tests based on these mutations were not selected for the next phases. Phase 2 evaluated the correlation between RL tests and the Myriad myChoice test on tumor samples from 85 PAOLA-1 BRCA wild type patients using the KAPPA statistics. Phase 3 is the final PFS evaluation on more than 350 additional patient samples. Result(s)* A total of 20 RL from 21 ENGOT groups participated to the EHEI phase 1. Half of them had a test mainly based on an HRR gene panel. Three RL did not pursue for various reasons (capacity, financial or regulatory). The remaining 7 RL from 6 countries (table 1) completed the phase 2 in May 2021 and may proceed to phase 3. Conclusion* The EHEI is a unique collaboration of European academic laboratories involved in gynecologic oncology translational research with the aim of providing a reliable biomarker (HRD) for selecting AOC patients who could benefit most from PARPi+/-bevacizumab in first-line therapy. HRD tests performance will be described after their phase 3 is completed.

BACKGROUND: Incomplete surgical staging of patients with early-stage epithelial ovarian cancer (EOC) has been reported in up to 98% of cases, when based on the International Federation of Obstetrics and Gynecology (FIGO) staging procedure. The aim of the present retrospective study was to clarify the reasons for incomplete staging. METHODS: The PRISMA (Prevention Recovery Information System for Monitoring and Analysis) technique was used to evaluate cases with FIGO I-IIa EOC based on incomplete staging from five gynecologic oncologic center hospitals in the Netherlands in the period 2010-2014. RESULTS: Fifty cases with an incomplete surgical staging of EOC according to national guidelines were included. The most common reasons for incomplete staging were insufficient random biopsies of the peritoneum (n = 34, 68%), and less than ten lymph nodes being resected and/or found at pathology (n = 16, 32%). The most mentioned reason for not performing biopsies was, besides forgetting to do so, believing that after careful inspection and palpation, taking biopsies is irrelevant and/or already are being taken while performing a hysterectomy (peritoneum of cul-de-sac, bladder). The value of contralateral pelvic lymph node dissection in case of a unilateral ovarian malignancy was also doubted, influencing the number of lymph nodes resected. CONCLUSIONS: The most important reasons for incomplete staging in EOC are, besides omitting elements by accident, questioning the importance of obligatory elements of the staging procedure. A structured list of staging steps during surgery and more evidence-based consensus concerning these obligatory elements might increase the number of complete staging procedures in EOC. ispartof: Surgery open science vol:7 pages:6-11 ispartof: location:United States status: published

AIM: To evaluate the diagnostic performance of diffusion-weighted imaging (DWI), with and without fusion images, in addition to regular T2-weighted (T2W) sequences for assessment of parametrial invasion.MATERIALS AND METHODS: This prospective cohort included cervical cancer patients who underwent preoperative magnetic resonance imaging (MRI) with T2W and axial DWI sequences prior to radical hysterectomy. Retrospectively, two radiologists independently and blindly scored the likelihood of parametrial invasion by means of a six-point confidence scale. Parametrial invasion was determined by surgical-pathological results. Performance indices for diagnostic tests and area under the receiver operating characteristic curve (AUC) analyses were performed. P-Values ofRESULTS: Of 65 included patients, parametrial invasion was found in eight patients. A statistically significant increase in diagnostic performance for the assessment of parametrial invasion was found when T2W MRI was fused with DWI (fusion T2W/DWI), especially decreasing false-positive findings: the positive predictive value of parametrial invasion using T2W MRI versus fusion T2W MRI/DWI increased from 29% to 50% for observer 1 and from 23% to 50% for observer 2 (AUC=0.80-0.67 versus 0.94-0.94).CONCLUSIONS: Fusion T2W MRI/DWI shows a significant increase in diagnostic performance for the assessment of parametrial invasion in early-stage cervical carcinoma. (C) 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

PURPOSE: In metastatic breast cancer (MBC) population treated with capecitabine monotherapy, we investigated clinical-pathological features as possible biomarkers for the oncological outcome. METHODS: Retrospective study of consecutive MBC patients treated at University Hospitals Leuven starting capecitabine between 1999 and 2017. The primary endpoint was the durable response (DR), defined as non-progressive disease for > 52 weeks. Other main endpoints were objective response rate (ORR), time to progression (TTP) and overall survival (OS). RESULTS: We included 506 patients; mean age at primary breast cancer diagnosis was 51.2 years; 18.2% had de novo MBC; 98.8% were pre-treated with taxanes and/or anthracycline. DR was reached in 11.6%. Patients with DR, as compared to those without DR, were more likely oestrogen receptor (ER) positive (91.5% vs. 76.8%, p = 0.010) at first diagnosis, had a lower incidence of lymph node (LN) involvement (35.6% vs. 49.9%, p = 0.039) before starting capecitabine, were more likely to present with metastases limited to ≤ 2 involved sites (54.2% vs. 38.5%, p = 0.020) and time from metastasis to start of capecitabine was longer (mean 3.5 vs. 2.7 years, p = 0.020). ORR was 22%. Median TTP and OS were 28 and 58 weeks, respectively. In multivariate analysis (only performed for TTP), ER positivity (hazard ratio (HR) = 0.529, p

OBJECTIVES: To apply the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) to a consecutive series of endometrial cancer (EC) patients diagnosed at a tertiary referral center and assign EC specimens to one of four molecular subgroups using immunohistochemistry (IHC) for p53/mismatch repair protein expression and sequencing for Polymerase Epsilon Exonuclease Domain Mutations (POLE-EDM). Mismatch Repair Deficient (MMR-D) cases were more thoroughly investigated to identify underlying somatic or germline genetic defects. METHODS: Hundred-and eight consecutive endometrial cancer patients, diagnosed between March 2017 and April 2019, were subjected to immunohistochemical and molecular analysis, according to ProMisE. IHC for p53 and the mismatch repair proteins (MLH1, PMS2, MSH6 and PMS2) was performed. All patients were also tested for POLE-EDM by Sanger sequencing. In addition, tumor and corresponding normal tissue of cases with abnormal MMR IHC were tested by PCR for microsatellite instability (MSI) (MSI analysis system, Promega). Hypermethylation of MLH1 promotor was tested with (methylation specific) multiplex ligation dependent probe amplification. MMR-D cases were subjected to germline mutation analysis of the mismatch repair genes, using next generation sequencing on MiSeq (Illumina) with the BRCA Hereditary Cancer MASTR Plus, (Multiplicom/Agilent), RNA mutation analysis and MLPA. RESULTS: FIGO classification was stage IA (n = 54), IB (n = 22) II(n = 8), III(n = 18) and IV(n = 6). Of the 33 patients with MMR-D on IHC (31%), 26 showed MLH1 promotor hypermethylation as the probable cause of MMR-D. The remaining 7 patients without MLH1 promotor hypermethylation were referred for germline analysis of Lynch syndrome. Six patients carried a pathogenic germline mutation in one of the mismatch repair genes: MSH6(n = 3), PMS2(n = 1), MLH1(n = 1) and MSH2 (n = 1). Pathogenic POLE-EDM were identified in 7 (6%) patients. Multiple molecular features (POLE-EDM + MMR-D or POLE-EDM + p53 abnormal) were observed in 4 patients (4%). A high concordance between MMR-D and microsatellite instability was observed in our cohort. In cases of a genetic defect in the MMR genes, we do note a large proportion of cases exhibiting microsatellite instability. On the contrary a hypermutation state, as seen in POLE EDM, does not result in accompanied phenotypic changes in MSI status. CONCLUSION: The ProMisE classification proved to be an efficient and easily implementable system. Future research should elucidate the precise biological and prognostic meaning of the cases with multiple molecular markers. ispartof: GYNECOLOGIC ONCOLOGY vol:157 issue:1 pages:245-251 ispartof: location:United States status: published

Introduction/Background Surgical treatment is mutilating and resection often results in involved margins. As a consequence, local recurrences are frequent after surgery. Methodology Retrospective study of patients with vulvar Paget9s disease treated in our hospital between 1993 and 2018. Results Thirty-one consecutive patients with vulvar Paget9s disease were included, whereof twenty patients were irradiated in the primary or recurrent setting. Radiotherapy on the vulva and perineum was performed at a median dose of 60 Gy in fractions of 2 Gy. The median follow-up after radiotherapy was 75 months. Eight (26%) patients underwent as primary treatment radiotherapy only. Only one (13%) had a recurrence (after four months) and was operated. Fifteen (48%) patients had surgery as only primary treatment; five (33%) of them had a recurrence. Four of these had, after 3 or 4 surgical interventions, radiotherapy for recurrence. Only one of these 4, had a relapse after 85 months. Eight (26%) patients had as primary treatment surgery followed by adjuvant radiotherapy (due to positive margins), one (13%) of these recurred and died of disease. Conclusion Surgery is the most commonly used therapy for vulvar Paget9s disease, even though it is difficult to excise the disease adequately and often multiple surgeries are necessary. According to our experience, radiotherapy is a good adjuvant treatment option in patients with vulvar Paget9s disease with positive resection margins. Moreover, in our experience, primary radiotherapy seemed to be a safe alternative to surgery, that can prevent patients with Paget9s disease of the vulva to undergo mutilating and often repeated surgery. Disclosure Nothing to disclose

Introduction/Background Patients with relapsed ovarian cancer receive multiple lines of chemotherapy, each negatively affecting their health-related quality of life (HRQOL). The CLIO trial randomized patients with platinum-resistant relapsed ovarian cancer (PROC) to treatment with olaparib versus standard chemotherapy (paclitaxel weekly, or pegylated liposomal doxorubicin, or gemcitabine or topotecan). Olaparib showed a favorable response rate compared with chemotherapy (Vanderstichele A et al., ASCO 2019). We aimed to assess HRQOL and quality-adjusted survival measures including Q-TWIST (quality-adjusted time without symptoms and toxicities of treatment) and QAPFS (quality-adjusted progression free survival). Methodology EORTC questionnaires QLQ-C30 and QLQ-OV28 were administered at baseline and every three months until end of treatment. Scoring of HRQOL focused on abdominal/gastrointestinal symptoms. Overall survival was partitioned into three health states to calculate Q-TWIST: time with grade ≥2 nausea, vomiting and fatigue (toxicity), time without toxicities (twist) and relapse. Each health state was adjusted by a utility weight derived from the QLQ-C30 global health status. QAPFS calculation was based on Q-TWIST, but excluded relapse status. Results In CLIO, we randomized 100 PROC patients 2:1 towards olaparib (n=67) and chemotherapy (n=33). Baseline compliance rate of questionnaires was 83% (88% olaparib vs. 73% chemotherapy). There was no significant difference in abdominal/gastrointestinal symptoms between both arms (p=0.4). In the olaparib-arm, significant differences were observed between responders and non-responders (p=0.001). Adverse events (AEs) of grade ≥3 occurred in 60% and 52% of patients in the olaparib and chemotherapy arm respectively (p=0.521). The difference in Q-TWIST was 35.6 days (95%CI: -121.5–27.8) in favour of chemotherapy. The difference in QAPFS was 23.8 days (95% CI: -42.2–63.5) in favour of olaparib. Conclusion In PROC patients, olaparib monotherapy showed similar HRQOL compared to standard chemotherapy. There were no significant differences in abdominal/gastrointestinal symptoms, Q-TWIST and QAPFS between the two treatment arms. Disclosure The presenting author, T. Callewaert, has no conflict of interest.

Introduction/Background Lymphovascular space invasion (LVSI), deep stromal invasion (DSI) and large tumor size have been identified as predictors for intermediate risk for recurrence. Adjuvant radiotherapy (RT) has been advocated in these patients (Sedlis Gynecol Oncol 1999,73:177). However, it is still controversial whether adjuvant radiochemotherapy (RCT) improves overall survival (OS). Methodology All consecutive patients (1997–2017) with cervical cancer FIGO (2009) stage IB1 (≤ 4cm) treated in our department were included. Intermediate risk for recurrence was defined as presence of two of the following factors in patients with negative lymph nodes: LVSI, DSI (>10 mm) and large tumor size (>2cm). Results Two hundred-and-one patients were included into the study, of which 186 patients underwent primary surgery and 15 patients received a fertility sparing treatment (table 1). Mean time of follow-up was 11 years (IQR 6–15). Postoperatively, 24 patients received adjuvant therapy due to presence of positive lymph nodes, positive section margins or vaginal intra-epithelial neoplasia: RCT (n=16), RT (n=7) or chemotherapy (n=1). None of the patients with intermediate risk factors according underwent adjuvant RT/RCT. Disease recurrence was observed in 23 patients (11%). The recurrences were local (n=14), distant (n=2) or both local and distant (n=7). Ten patients died of disease. The 5-year OS was 93% and the 5-year progression-free-survival (PFS) was 89%. Cox proportional hazards models showed that intermediate risk factors did not significantly influence OS or PFS. Conclusion Recurrence rate was rather low (11%), despite the fact that only 12% of the patients with cervix cancer stage IB1 received postoperative radio(chemo)therapy. Intermediate risk factors such as LVSI, DSI (>10 mm) or tumor size >2 cm did not predict recurrence nor survival. Future studies are needed to elucidate whether adjuvant radiotherapy is needed in the current era with better survival than in the nineties when the GOG99 (Sedlis et al.) was performed. Disclosure Nothing to disclose.

Introduction/Background High-grade cervical intraepithelial neoplasia (CIN) is the premalignant condition of cervical cancer. Treatment is usually performed by large loop excision of the transformation zone (LLETZ), but is associated with an increased risk of premature birth in subsequent pregnancies. Topical imiquimod cream may be an alternative treatment modality. This study aims to provide evidence on treatment efficacy and side-effects of topical imiquimod cream compared to standard LLETZ treatment. Methodology A multi-centre, non-randomized controlled trial was performed among women with a histological diagnosis of CIN 2/3. Women who opted for standard treatment, underwent LLETZ treatment. Successful treatment was defined as no need for second LLETZ after 6 months follow-up. Women who opted for imiquimod treatment, administered 6.25 mg imiquimod 5% cream vaginally up to three times per week during 16 weeks. Treatment efficacy was evaluated with colposcopy at 20 weeks follow-up and defined as CIN 1 or less. Results 123 patients were included. 62 women underwent LLETZ treatment, which was successful in 58 women (95%). 37% of women reported severe side-effects (Visual analogue scale [VAS] ≥ 8). 61 women underwent topical imiquimod treatment. Twelve women discontinued treatment due to side effects. Treatment was successful in 27 (59%) of remaining women. Side effects were reported by all women who underwent imiquimod treatment and consisted most frequently of headache and fatigue. 69.0% of women reported severe side-effects (VAS ≥ 8). All reported side-effects can be found in tables 1 and 2. Conclusion Topical imiquimod is a feasible alternative treatment for patients with high-grade CIN, although efficacy is considerably lower than LLETZ treatment. It could be an alternative treatment, especially for women with a future pregnancy desire. Predictive biomarkers are necessary to better select those patients who will benefit from imiquimod treatment. Disclosure The authors declare that they have no competing interests. This study and manuscript preparation were funded by the Academic Hospital of Maastricht (Academic Fund) and MedaPharma. Both funding bodies were not involved in the study design and will not be involved in the collection, analysis, and interpretation of data, in the writing of the manuscript and in the decision to submit the manuscript for publication.

Introduction/Background Rucaparib has clinical activity in patients with recurrent OC with or without homologous recombination (HR) deficiency (HRD; eg, a BRCA mutation or high genomic loss of heterozygosity [LOH]) and is hypothesised to provide clinical benefit following frontline treatment. ATHENA is evaluating rucaparib + nivolumab as maintenance treatment following frontline platinum-based chemotherapy in patients with newly diagnosed, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The rationale for this combination includes: tumours with BRCA mutations express tumour-specific proteins (neoantigens), which attract PD-L1-expressing, tumour-infiltrating lymphocytes; ovarian tumours with HRD have more neoantigens relative to HR-proficient tumours and may respond to immune checkpoint inhibitors; rucaparib combined with anti-PD-1 demonstrated improved antitumour activity in an OC model; it is hypothesised that PARP inhibitor-induced DNA damage may increase neoantigens, regardless of HRD status. Methodology Eligible patients must have completed frontline platinum-doublet chemotherapy and surgery and achieved an investigator-assessed response without disease progression or rising CA-125 at any time during frontline treatment. Cytoreductive surgery (R0 permitted) could have been completed prior to chemotherapy or following neoadjuvant chemotherapy. Patients will be randomised 4:4:1:1 to receive maintenance treatment in Arm A (oral rucaparib 600 mg BID + intravenous nivolumab 480 mg Q4W), Arm B (oral rucaparib + intravenous placebo), Arm C (oral placebo + intravenous nivolumab), or Arm D (oral placebo + intravenous placebo). Stratification factors include centrally determined tumour HRD status (BRCA mutant, non-BRCA mutant/LOH high, non-BRCA mutant/LOH low, or non-BRCA mutant/LOH indeterminate), posttreatment disease status, and timing of surgery. Investigator-assessed progression-free survival (RECIST v1.1; primary endpoint) will be compared between arms. Secondary endpoints include blinded independent central review of progression-free survival, overall survival, objective response rate, and safety. Results Patients (n≈1000) will be enrolled at >270 sites worldwide. Conclusion ATHENA is evaluating rucaparib + nivolumab as frontline maintenance treatment in patients with OC. Disclosure AO: Clovis, AstraZeneca, Genmab/Seattle Genetics, ImmunoGen, PharmaMar, Roche, Tesaro DL: Clovis, AstraZeneca, ImmunoGen, Merck, PharmaMar, Roche, Tesaro DC: AstraZeneca, Genmab, Pfizer, Seattle Genetics, BMS, MSD, Roche RLC: Clovis, AbbVie, AstraZeneca, Esperance, Janssen, Millennium, Merck, OncoMed, Roche/Genentech, Bayer, GamaMabs, Genmab, Gradalis, Pfizer, Tesaro KF: Advanced Oncotherapy, AstraZeneca, Chugai-Roche, Daiichi-Sankyo, Eisai, GSK, ImmunoGen, Kaken-Seiyaku, Lilly, Merck, Ono Pharmaceutical, Pfizer, Shionogi, Taiho, Zeria Pharmaceutical AMO: Clovis, Amgen, Immunovaccine, Verastem, AstraZeneca, WebRx SNW: Clovis, AstraZeneca, Bio Ascend, Genentech, Gynecologic Oncology Group, Medivation/Pfizer, Merck, Ovation, Roche, Takeda, Tesaro, Vermillion, ArQule, Bayer, Cotinga Pharmaceuticals, Novartis DMO’M: Clovis, AstraZeneca, Gynecologic Oncology Group, Janssen, Myriad, Tesaro, Amgen, ImmunoGen, AbbVie, Health Analytics, Ambry, Agenus, Ajinomoto, Array BioPharma, BMS, ERGOMED Clinical Research, Exelixis, Genentech, GSK, INC Research, inVentiv Health Clinical, Ludwig Institute for Cancer Research, Novartis, PRA International, Regeneron, Serono, Stemcentrx, TRACON TJH: Clovis, AstraZeneca, Caris, Johnson & Johnson, Roche, Tesaro RE: Clovis, AstraZeneca, Roche/Genentech, Merck, Pfizer, Tesaro MW: AstraZeneca, MSD, Roche SA, NG: Clovis IAM: Clovis, AstraZeneca, Tesaro BJM: Clovis, AstraZeneca, Janssen/Johnson & Johnson, Myriad, Roche/Genentech, Tesaro, Amgen, Bayer, Biodesix, Cerulean, GSK, Gradalis, ImmunoGen, Insys, Mateon, Merck, NuCana, Perthera, Pfizer, Precision Oncology, Verastem, Vermillion RSK: Clovis, Tesaro, Roche All other authors have nothing to disclose.

Introduction/Background We aimed to describe management, complications and survival of malignant bowel obstruction (MBO) in epithelial tubo-ovarian cancer patients. Our primary objective was overall survival, measured in days. MBO complications and management were considered secondary endpoints. Methodology Retrospective monocentric cohort study at the University Hospitals Leuven, Belgium, between January 1st, 2012 until December 31rd, 2016. All primary epithelial tubo-ovarian cancer patients with MBO were identified. The standard conservative approach of MBO in the University Hospitals Leuven is presented in table 1. Results 452 patient files were searched from which 48 patients were included in this study with a total of 84 MBO episodes, (median 1 per patient; range 1–5). Median time interval between two MBO episodes was 59 days (range 2–626). Median hospitalization time was 11 days (range 0–74) per episode. Median time interval between cancer diagnosis and first MBO episode was 342 days (range 0–1155). Further characteristics are noted in table 2. Two complications were registered bowel perforation and bowel ischemia, each in one episode. Conservative treatment was applied in 73 (87%) episodes, including gastrostomy in 3 (4%) episodes. Operative treatment was necessary in 11 (13%) episodes, including exploratory laparoscopy in 2 (2%) episodes and exploratory laparotomy in 9 (11%) episodes. Only one case of postoperative peritonitis was reported. Total parenteral nutrition (TPN) was administered in 15 (31%) patients only. During the study period 35 patients died within a median time interval of 101 days (range 3–917) since the first MBO (figure 1). There was no significant difference in survival between patient groups regarding TPN use, ascites and obstruction at cancer diagnosis. Conclusion Tubo-ovarian cancer patients with MBO have poor prognosis: 73% of our study population died within a relatively short time interval since the first MBO. The majority of patients with MBO were treated conservatively. Disclosure Nothing to disclose.

Introduction/Background Recent research has distinguished various molecular classifications for endometrial carcinoma (EC). The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMise, Talhouk, BJC 2015,113:299) classification consists of immunohistochemistry (IHC) (p53 and mismatch repair proteins) and PCR sequencing for Polymerase Epsylon-Extracellular-Domain-Mutations (POLE-EDM). Methodology Ninety-three consecutive endometrial cancer patients, diagnosed between March 2017 and November 2018, were subjected to molecular and immunohistochemical analyses, according to ProMise. IHC for p53 and the mismatch repair proteins (MLH1, PMS2, MSH6 and PMS2) was performed. All patients were also tested for POLE-EDM using PCR, followed by Sanger sequencing (exon 9, 11, 13 and 14). In addition to the ProMise testing, all tumors and corresponding normal tissue of patients with mismatch repair deficient staining on IHC, were tested with PCR using the Microsatellite Instability (MSI) kit (MSI analysis system, Promega). Hypermethylation of MLH1 promotor and the presence of the BRAF p.V600E missense mutation was tested with (methylation specific) multiplex ligation dependent probe amplification. Results FIGO classification was stage IA(n=45), IB(n=17)) II(n=8), III(n=17) and IV(n=6). Classification according to histological type is presented in table 1. Of the 28 patients with MMR-D (Mismatch Repair-Deficiency) on IHC, 22(79%) showed hypermethylation as the probable cause of MMR-D. The remaining 6 patients were referred for germline analysis of Lynch syndrome. Five patients carried a pathogenic germline mutation in one of the mismatch repair genes: MSH6(n=3), PMS2(n=1), MLH1(n=1). In one patient no germline mutation was identified, hypothesizing a somatic cause. POLE-EDM was identified in 6 (6%) patients. Double positive status (POLE-EDM+MMR-D or POLE-EDM+p53 abnormal) was observed in 4 patients (4%) (table1). Conclusion The ProMise classification proved to be an efficient and easily implementable system. In the group with MMR-D, hypermethylation was the cause in 79%. POLE-EDM was identified in 6% of the patients, but its role needs to be clarified in non-endometrioid tumors. Disclosure Nothing to disclose.

Introduction/Background Skeletal muscle depletion in women with advanced ovarian cancer has been associated with adverse clinical outcome and survival. To validate earlier results in a homogenous population, we analyzed whether a decrease in skeletal muscle index (SMI) during neo-adjuvant chemotherapy (NACT) is associated with worse outcome in patients with stage III epithelial ovarian cancer, who were included in the OVHIPEC trial. Methodology Within the phase III OVHIPEC trial, 245 patients with stage III ovarian cancer were randomized after three cycles of NACT with carboplatin and paclitaxel to receive interval cytoreductive surgery (CRS) with or without HIPEC. Randomization was performed after at least stable disease after two cycles of NACT, and when complete or optimal CRS was achieved. CT-scans performed at baseline (timepoint 1), and after two cycles of NACT (timepoint 2) were selected. A slide on the third lumbar level was selected from each CT-scan, and the difference in SMI between both scans (ΔSMI) was calculated using SliceOMatic. Overall and recurrence-free survival of patients with a decrease or increase in ΔSMI were performed using Kaplan-Meier estimates and log-rank tests. Results Of the 245 patients randomized in the OVHIPEC trial, SMI and ΔSMI of scans at both timepoints were available for 212 patients (87%). After a median follow-up of 4.7 years, 116 of 212 patients (55%) had died. In survival analysis, 43 of 74 patients (58%) in the group with a decrease in ΔSMI, and 73 of 138 of the patients (53%) in the group with stable/increase in ΔSMI had died. Median overall survival did not differ significantly(p=0.764). Conclusion A decreasing skeletal muscle index during neo-adjuvant chemotherapy was not associated with worse outcome in patients with stage III ovarian cancer, who were treated with complete/optimal interval CRS and six cycles of chemotherapy within the OVHIPEC trial. Disclosure Nothing to disclose.

Introduction/Background Recently published data have renewed the debate on surgical approach (open vs. laparoscopic) in radical hysterectomy and its effect on survival and recurrence. In addition, an estimation of risk factors of surgical complications would be beneficial in the management of these patients. Therefore, we aimed to evaluate possible predictors of short-term surgical complications after radical hysterectomy for early-stage cervical cancer. Methodology Patients diagnosed with cervical cancer FIGO (2009) stage IB1 and IIA1 between January 2015 and December 2017 who underwent radical hysterectomy with pelvic lymphadenectomy in one of the nine specialized centres in the Netherlands, were identified from the Netherlands Cancer Registry. Patients were excluded if primary treatment consisted of simple hysterectomy (i.e. without parametrial dissection) or radical trachelectomy. Complications and type of complications, developing within 30 days after surgery, were registered. Multivariable logistic regression analysis was used to identify predictors for surgical complications. Results Of the 472 patients, 166 (35%) developed surgical complications. Predominant FIGO stage was IB1 (97%), mean age was 45±12 years, mean body mass index was 26±5 kg/m2. Most patients were treated with open surgery (58%). The most frequent complications were urinary retention with catheterisation in 73 patients (15%) and excessive perioperative blood loss >1000 mL (EBL) in 50 patients (11%) (table 1). Open surgery, chronic pulmonary disease, vascular disease and medical centre emerged as independent predictors of the occurrence of complications (table 2). BMI was found as negative predictor for urinary retention. Open surgery and BMI were found to be independent predictors for EBL. Conclusion We conclude that open surgery, chronic pulmonary disease, vascular disease and BMI negatively affect the occurrence of short-term surgical complications. We believe these findings should also be taken into consideration, together with data on survival and recurrence, in the choice of surgical approach. Disclosure None of the authors received financial support for the research and/or authorship of this article. Hans Wenzel - Nothing to disclose; Toon van Gorp - Nothing to disclose; Ruud Bekkers - Nothing to disclose; Cor de Kroon - Nothing to disclose; Luc van Lonkhuijzen - Nothing to disclose; Leon Massuger - Nothing to disclose; Hans Nijman - Grant Dutch Cancer Society; Stock owner SME Vicinivax; Grant Aduro; Ramon Smolders - Nothing to disclose; Nienke van Trommel - Nothing to disclose; Refika Yigit - Nothing to disclose; Ronald Zweemer - Proctor Intuitive Surgical; Roy Kruitwagen - Nothing to disclose; Maaike van der Aa - Nothing to disclose

Introduction/Background The aim of this prospective study was to report perioperative outcomes, disease-free and overall survival of robot-assisted management of patients with endometrial cancer, treated in 5 centers in Belgium. Methodology Patients undergoing surgery between August 2007 and December 2018 (n=615) were prospectively collected. Results Median age was 68 years (range, 31–92), median BMI 28 kg/m2 (range, 17–61). Five-hundred-ninety-nine patients underwent robot-assisted hysterectomy and bilateral salpingo-oophorectomy. In addition, full pelvic lymphadenectomy was performed in 151 (25%), and pelvic sentinel nodes biopsies only in 181 patients (29%). Sixteen patients were referred for robotic node staging after hysterectomy performed elsewhere. Histological types were endometrioid (n=512, 84%), serous (n=43, 7%), clear cell (n=8, 1%), mucinous (n=3, 0.5%), squamous (n=2, 0.3%) and carcinosarcoma (n=20, 3%). FIGO stage was: IA (61%), IB (24%), II (4%), IIIA (2%), IIIB (0,3%), IIIC (8%), IV (1%). Metastatic pelvic nodes were found in 43 (7%), positive para-aortic nodes in 3 (0,4%), pelvic and para-aortic nodal metastases in 7 patients (1,2%). Median number of removed pelvic and para-aortic nodes was 15 (range, 0–64) and 10 (range 1–47), respectively. Median estimated blood loss was 50 mL (range 0– 1000), median skin-to-skin time 150 minutes (range 55–480) and conversion rate 0.8% (n=5). Intra-operative complications occurred in 5% (n=30). At least one postoperative complication occurred in 15% (n=89). Median follow-up was 27 months (range, 1–131). Recurrence occurred in 63 patients (11%) and 38 patients (6%) died of endometrial cancer. The 2- and 5-year recurrence-free survival rates were 89% and 84%, respectively. The 2- and 5-year overall survival rates were 92% and 83%, respectively. Conclusion This study confirms the feasibility and safety of robot-assisted management of endometrial cancer with a low complication, conversion and recurrence rate. Disclosure Nothing to disclose.

BACKGROUND: Advanced stage cervical cancer is primarily treated by radiotherapy. Local tumor control is a prerequisite for cure. Imaging after treatment is controversial. Positron emission tomography (PET) combined with computer tomography (PET-CT) shows great promise for detecting metastases. On the other hand, magnetic resonance imaging (MRI) is superior in depicting anatomical details. The combination of PET-MRI could result in more accurate evaluation of cervical cancer treatment outcome. The aim of this pilot study is to share our initial experience with PET-MRI in the evaluation of treatment response in cervical cancer after radiation treatment. METHODS: Ten patients with cervical carcinoma (FIGO ≥IB2) were prospectively evaluated. Eleven weeks (median; range 8-15 weeks) after radiation therapy, treatment response was evaluated by PET-MRI. The PET, MRI, and combined PET-MRI images were evaluated for the presence of local residual tumor and metastasis. Diagnostic performance was assessed by area under the receiver operator characteristic (ROC) curve for evaluation of local residual tumor. The readers were blinded for outcome data. Local residual disease, metastasis, diagnostic confidence, and change of opinion were scored on a 5-point Likert scale. The reference standard consisted of pathology and/or follow-up according to the clinical guidelines. RESULTS: Three out of ten patients had local residual abnormalities suggestive for tumor residue after radiation treatment. The availability of both PET and MRI resulted in an increase in diagnostic confidence in 80-90% of all patients. Change of opinion was observed in 70% and change of policy in 50%, especially in the group with residual tumor. The diagnostic accuracy increased significantly for the radiologist if PET-MRI was combined (AUC .54 versus .83). CONCLUSIONS: PET-MRI shows promise for evaluation of treatment response after radiation for cervical cancer, especially increasing diagnostic confidence, while potentially increasing diagnostic performance. ispartof: EJNMMI RESEARCH vol:8 issue:1 ispartof: location:Germany status: published

OBJECTIVES: To validate externally the performance of the Assessment of Different NEoplasias in the adneXa (ADNEX) model and compare this model with other frequently used models in the differentiation between benign and malignant adnexal masses. METHODS: In this retrospective diagnostic accuracy study, we assessed data collected prospectively from patients with adnexal pathology who underwent real-time transvaginal or transrectal ultrasound by a single expert ultrasonographer in a tertiary care hospital between July 2011 and July 2015. The presence of a malignancy was determined by subjective assessment and use of four prediction models: the ADNEX model, simple ultrasound-based rules (simple rules), Logistic Regression model 2 (LR2) and the Risk of Malignancy Index (RMI), of which three different variants were assessed. Pathology was the clinical reference standard. RESULTS: In total, 851 consecutive patients underwent ultrasound examination for an adnexal mass. For 326 patients (128 premenopausal and 198 postmenopausal), pathology results were available (211 (64.7%) benign; 115 (35.3%) malignant) and these were included in the analysis. The area under the receiver-operating characteristics curve (AUC) of the ADNEX model for the discrimination between benign and malignant tumors was 0.93 (95% CI, 0.89-0.95). AUCs for the subtypes of malignancy (i.e. borderline, Stage I-IV and metastatic adnexal tumors) ranged between 0.60 and 0.90. Only subjective assessment (AUC, 0.96 (95% CI, 0.93-0.98)) was superior to the ADNEX model (P = 0.01) in differentiating malignant from benign tumors. AUCs for the other models were 0.92 (95% CI, 0.89-0.95) for LR2, 0.85 (95% CI, 0.81-0.89) for RMI-I, 0.82 (95% CI, 0.77-0.86) for RMI-II and 0.84 (95% CI, 0.80-0.88) for RMI-III. At the proposed cut-off of ≥ 10%, the ADNEX model had the highest sensitivity (0.98 (95% CI, 0.93-1.00)) but the lowest specificity (0.62 (95% CI, 0.55-0.68)) compared with the other models. Both subjective assessment (sensitivity, 0.90 (95% CI, 0.83-0.95); specificity 0.91 (95% CI, 0.86-0.94)) and the simple rules model with inconclusive cases classified by subjective assessment (sensitivity, 0.89 (95% CI, 0.81-0.94); specificity, 0.90 (95% CI, 0.85-0.94)) had lower sensitivity, but their sensitivity and specificity were better balanced. CONCLUSIONS: Although the test performance of subjective assessment by an expert remains superior, the ADNEX model can help in the differentiation between benign and malignant ovarian tumors. The advantage of the ADNEX model as a polytomous model remains to be shown. © 2016 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. ispartof: ULTRASOUND IN OBSTETRICS & GYNECOLOGY vol:49 issue:6 pages:784-792 ispartof: location:England status: published

The "TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia" (TOPIC) trial was stopped preliminary, due to lagging inclusions. This study aimed to evaluate the treatment efficacy and clinical applicability of imiquimod 5% cream in high-grade cervical intraepithelial neoplasia (CIN). The lagging inclusions were mainly due to a strong patient preference for either of the two treatment modalities. This prompted us to initiate a new study on the same subject, with a non-randomized, open-label design: the 'TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC)-3' study. Original TOPIC-trial: Medical Ethics Committee approval number METC13231; ClinicalTrials.gov Identifier: NCT02329171, 22 December 2014. TOPIC-3 study: Medical Ethics Committee approval number METC162025; ClinicalTrials.gov Identifier: NCT02917746, 16 September 2016. ispartof: BMC CANCER vol:17 issue:1 ispartof: location:England status: published

Objectives The aim of this systematic review is to determine the incidence of lymph-node metastasis in clinical stage I and II sex cord stromal tumours and germ cell tumours of the ovary. Methods Relevant articles were identified from MEDLINE and EMBASE and supplemented with citations from the reference lists of the primary studies. Eligibility was determined by two authors. Included studies were prospective or retrospective cohort and cross-sectional studies analysing at least ten patients with clinical early-stage non-epithelial ovarian cancer who underwent lymphadenectomy or lymph-node sampling as part of a staging laparotomy. Results For sex cord stromal tumours, five articles including 578 patients were analysed and lymph-node metastasis was not detected in the 86 patients who underwent lymph-node removal. The median number of removed lymph nodes was 13 (range 9–29). For malignant germ cell tumours, three articles were eligible including 2436 patients of whom 946 patients underwent lymph-node resection. The mean number of removed nodes was 10 (range 2–14) with a mean incidence of lymph-node metastasis of 10.9% (range 10.5–11.8%). Conclusions The incidence of lymph-node metastasis in patients with clinical stage I and II sex cord stromal tumours is low, whereas the incidence in patients with clinical stage I–II germ cell tumours is considerable, although limited data are available.

BACKGROUND: For various malignancies, prognostic models have shown to be superior to traditional staging systems in predicting overall survival. The purpose of this study was to validate and compare the performance of three prognostic models for overall survival in patients with advanced-stage epithelial ovarian cancer. METHODS: A multi-institutional epithelial ovarian cancer database was used to identify patients and to evaluate the predictive performance of two nomograms, a prognostic index and FIGO (International Federation of Obstetrics and Gynecology) stage. All patients were treated for advanced-stage epithelial ovarian cancer between January 1996 and January 2009 in 11 hospitals in the eastern part of The Netherlands. RESULTS: In total, 542 patients were found to be eligible. Overall performance did not differ between the three prognostic models and FIGO stage. The discriminative performance for Chi's model was moderately good (c indices 0.65 and 0.68) and for the models of Gerestein and Teramukai reasonable (c indices between 0.60 and 0.62). The c indices of FIGO stage ranged between 0.54 and 0.62. After recalibration, the three models showed almost perfect calibration, whereas calibration of FIGO stage was reasonable. CONCLUSION: The three prediction models showed general applicability and a reasonably well-predictive performance, especially in comparison to FIGO stage. To date, there are no studies available that analyse the impact of these prognostic models on decision-making and patient outcome. Therefore, the usefulness of these models in daily clinical practice remains to be investigated. ispartof: BRITISH JOURNAL OF CANCER vol:110 issue:1 pages:42-48 ispartof: location:England status: published

Objective To determine whether serum human-epididymis protein-4 (HE4) levels or Risk of Ovarian Malignancy Algorithm (ROMA) scores are useful second-stage tests for tumors thought to be difficult to characterize as benign or malignant on the basis of ultrasound findings by experienced examiners, and to investigate whether adding information on serum HE4 levels or ROMA scores to ultrasound findings improves diagnostic performance. Methods This was a prospective cross-sectional diagnostic accuracy study conducted in a tertiary referral center that enrolled consecutive women with a known adnexal mass scheduled for surgery. Experienced level III examiners classified each mass as certainly or probably benign, difficult to classify, or probably or certainly malignant after preoperative ultrasound examination. Serum HE4 and CA 125 levels were measured before surgery. Results The final database comprised 360 women, of whom 216 (60%) had benign and 144 (40%) had malignant disease. Examiners were highly confident in 196 cases (54%), moderately confident in 135 (38%) and completely uncertain about their diagnosis in 29 (8%) cases. With a sensitivity of 67% and specificity of 70%, subjective assessment outperformed HE4 and ROMA in the subgroup of difficult tumors. Both tests had low discriminatory capacity with poor areas under the receiver–operating characteristics curve of 0.536 (95% CI, 0.302–0.771) and 0.565 (95% CI, 0.294–0.836), respectively. A strategy that incorporates sequential testing of serum HE4 or ROMA scores after transvaginal ultrasonography resulted in a deterioration in overall test performance. Conclusion Measurement of serum HE4 or calculating scores using the ROMA as secondary tests does not seem useful for classifying adnexal tumors after subjective assessment with transvaginal ultrasonography. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.

Objective Imaging of the lungs is part of the routine diagnostic workup of patients with endometrial cancer. The present study aimed to determine the incidence of lung metastases in patients with endometrial cancer and to evaluate the clinical relevance of preoperative chest imaging in this population. Methods A retrospective cross-sectional study was performed in four regional and one university hospital in the southeastern part of the Netherlands. A total of 784 patients with epithelial endometrial cancer diagnosed between 2002 and 2010 in five hospitals were included. Patients were followed up for at least 1year. Results Of 784 patients, 541 (69.0%) underwent thoracic imaging and 11 showed findings suspicious for metastases perioperatively or during the 1-year follow-up period. In eight patients, the thoracic metastases were related to their endometrial cancer, resulting in an overall incidence of 1.0% (8/784, 95% CI=0.3–1.7%). These eight patients had high-risk subtypes of endometrial cancer (serous, clear cell or poorly differentiated endometrioid), and the incidence was 4.1% (8/193, 95% CI=1.9–8.3%) for these subtypes. Lung metastases were not detected in any of the patients with low-risk subtypes of endometrial cancer ( n =566) at the time of diagnosis (95% CI=0–0.8%). Conclusions The probability of detecting thoracic metastases during the diagnostic workup of patients with endometrial cancer is low. The present data suggest that thoracic imaging could be omitted from the diagnostic workup of patients with low-risk endometrial cancer.

Objective. Cytoreductive surgery and platinum-based systemic therapy constitute the standard treatment of patients with advanced ovarian cancer. The aim of the present study was to evaluate whether the time interval from surgery to start of chemotherapy has an impact on clinical outcome. Methods. Data of 191 patients with advanced serous (FIGO III-IV) ovarian cancer from the prospective multicenter study OVCAD (OVarian CAncer Diagnosis) were analyzed. All patients underwent primary surgery followed by platinum-based chemotherapy. Results. The 25%, 50%, and 75% quartiles of intervals from surgery to start of chemotherapy were 22, 28, and 38 days, respectively (range, 4-158 days). Preoperative performance status (P 28 days; hazard ratio (HR) 1.73 (95% confidence interval 1.08-2.78), P = 0.022], residual disease [HR 2.95 (95% confidence interval 1.87-4.67), P

Objectives Epithelial ovarian cancer (EOC) is the major cause of death due to gynecological malignancies. The most important prognostic factors are residual tumor mass after surgery and platinum-response. No predictive biomarkers are available to identify patients who will benefit from standard treatment. The aim of our study was to analyze the role of HE4 in predicting surgical and clinical outcome in primary EOC. Methods In the European multicentric project "OVCAD", 275 consecutive patients with primary EOC were enrolled. Patients were eligible if radical cytoreductive surgery was performed and platinum-based chemotherapy was applied. Plasma and ascites samples were collected before or during surgery. The concentrations of HE4 and CA125 was determined using ELISA and Luminex technique, respectively. Results Median age at first diagnosis was 58years (range 18–85years). Most patients presented with advanced stage disease, FIGO III or IV (94.6%), grades II–III (96%) and serous histology (86.2%). In most cases a complete cytoreduction to no residual tumor mass was achieved (68.4%). Higher plasma HE4 levels correlated with poor surgery outcome in terms of macroscopically residual tumor mass (p Conclusions The presented data are showing that the combination of HE4 and CA125 expression in plasma might predict the surgical outcome in EOC and by this may have a prognostic impact on PFS and OS.

Introduction Many national guidelines concerning the management of ovarian cancer currently advocate the risk of malignancy index (RMI) to characterise ovarian pathology. However, other methods, such as subjective assessment, International Ovarian Tumour Analysis (IOTA) simple ultrasound-based rules (simple rules) and IOTA logistic regression model 2 (LR2) seem to be superior to the RMI. Our objective was to compare the diagnostic accuracy of subjective assessment, simple rules, LR2 and RMI for differentiating benign from malignant adnexal masses prior to surgery. Materials and methods MEDLINE, EMBASE and CENTRAL were searched (January 1990–August 2015). Eligibility criteria were prospective diagnostic studies designed to preoperatively predict ovarian cancer in women with an adnexal mass. Results We analysed 47 articles, enrolling 19,674 adnexal tumours; 13,953 (70.9%) benign and 5721 (29.1%) malignant. Subjective assessment by experts performed best with a pooled sensitivity of 0.93 (95% confidence interval [CI] 0.92–0.95) and specificity of 0.89 (95% CI 0.86–0.92). Simple rules (classifying inconclusives as malignant) (sensitivity 0.93 [95% CI 0.91–0.95] and specificity 0.80 [95% CI 0.77–0.82]) and LR2 (sensitivity 0.93 [95% CI 0.89–0.95] and specificity 0.84 [95% CI 0.78–0.89]) outperformed RMI (sensitivity 0.75 [95% CI 0.72–0.79], specificity 0.92 [95% CI 0.88–0.94]). A two-step strategy using simple rules, when inconclusive added by subjective assessment, matched test performance of subjective assessment by expert examiners (sensitivity 0.91 [95% CI 0.89–0.93] and specificity 0.91 [95% CI 0.87–0.94]). Conclusions A two-step strategy of simple rules with subjective assessment for inconclusive tumours yielded best results and matched test performance of expert ultrasound examiners. The LR2 model can be used as an alternative if an expert is not available.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) is the premalignant condition of cervical cancer. Whereas not all high grade CIN lesions progress to cervical cancer, the natural history and risk of progression of individual lesions remain unpredictable. Therefore, high-grade CIN is currently treated by surgical excision: large loop excision of the transformation zone (LLETZ). This procedure has potential complications, such as acute haemorrhage, prolonged bleeding, infection and preterm birth in subsequent pregnancies. These complications could be prevented by development of a non-invasive treatment modality, such as topical imiquimod treatment. The primary study objective is to investigate the efficacy of topical imiquimod 5% cream for the treatment of high-grade CIN and to develop a biomarker profile to predict clinical response to imiquimod treatment. Secondary study objectives are to assess treatment side-effects, disease recurrence and quality of life during and after different treatment modalities. METHODS/DESIGN: The study design is a randomized controlled trial. One hundred forty women with a histological diagnosis of high-grade CIN (CIN 2-3) will be randomized into two arms: imiquimod treatment during 16 weeks (experimental arm) or immediate LLETZ (standard care arm). Treatment efficacy will be evaluated by colposcopy with diagnostic biopsies at 20 weeks for the experimental arm. Successful imiquimod treatment is defined as regression to CIN 1 or less, successful LLETZ treatment is defined as PAP 1 after 6 months. Disease recurrence will be evaluated by cytology at 6, 12 and 24 months after treatment. Side-effects will be evaluated using a standardized report form. Quality of life will be evaluated using validated questionnaires at baseline, 20 weeks and 1 year after treatment. Biomarkers, reflecting both host and viral factors in the pathophysiology of CIN, will be tested at baseline with the aim of developing a predictive biomarker profile for the clinical response to imiquimod treatment. DISCUSSION: Treatment of high-grade CIN lesions with imiquimod in a selected patient population may diminish complications as a result of surgical intervention. More knowledge on treatment efficacy, side effects and long-term recurrence rates after treatment is necessary. TRIAL REGISTRATION: EU Clinical Trials Register EU-CTR2013-001260-34 . Registered 18 March 2013. Medical Ethical Committee approval number: NL44336.068.13 (Medical Ethical Committee Maastricht University Hospital, University of Maastricht). Affiliation: Maastricht University Hospital. Registration number ClinicalTrials.gov: NCT02329171. ispartof: BMC CANCER vol:16 ispartof: location:England status: published

BACKGROUND: Cervical cancer is associated with a high yearly mortality. The presence of persistent disease after radiotherapy is a significant predictor of patient survival. The aim of our study was to assess if tumor volume regression measured with MR imaging at the time of brachytherapy can discriminate between patients who eventually will achieve a complete response to radiotherapy from those who will not. The second objective was to evaluate whether tumor volume regression predicts overall treatment failure. METHODS: MRI was evaluated quantitatively in 35 patients; by means of tumor volumetry on T2-weighted MR images before treatment, at the first BCT application, and at the final BCT. The MR images were independently analyzed by two investigators. As a reference standard histopathologic confirmation of residual tumor and/or clinical exam during follow-up > 1 year were used. Area under the curve were compared, P-values 9.4 cm(3) at final BCT and tumor volume regression 2.8 cm(3) at final BCT was associated with overall treatment failure (p

BACKGROUND: Recently, a Risk of Ovarian Malignancy Algorithm (ROMA) utilising human epididymis secretory protein 4 (HE4) and CA125 successfully classified patients as presenting a high or low risk for epithelial ovarian cancer (EOC). We validated this algorithm in an independent prospective study. METHODS: Women with a pelvic mass, who were scheduled to have surgery, were enrolled in a prospective study. Preoperative serum levels of HE4 and CA125 were measured in 389 patients. The performance of each of the markers, as well as that of ROMA, was analysed. RESULTS: When all malignant tumours were included, ROMA (receiver operator characteristic (ROC)-area under curve (AUC) = 0.898) and HE4 (ROC-AUC) = 0.857) did not perform significantly better than CA125 alone (ROC-AUC = 0.877). Using a cutoff for ROMA of 12.5% for pre-menopausal patients, the test had a sensitivity of 67.5% and a specificity of 87.9%. With a cutoff of 14.4% for post-menopausal patients, the test had a sensitivity of 90.8% and a specificity of 66.3%. For EOC vs benign disease, the ROC-AUC of ROMA increased to 0.913 and for invasive EOC vs benign disease to 0.957. CONCLUSION: This independent validation study demonstrated similar performance indices to those recently published. However, in this study, HE4 and ROMA did not increase the detection of malignant disease compared with CA125 alone. Although the initial reports were promising, measurement of HE4 serum levels does not contribute to the diagnosis of ovarian cancer. British Journal of Cancer (2011) 104, 863-870. doi:10.1038/sj.bjc.6606092 www.bjcancer.com Published online 8 February 2011 (C) 2011 Cancer Research UK

It is clear that primary debulking remains the standard of care within the treatment of advanced ovarian cancer (FIGO stage III and IV). This debulking surgery should be performed by a gynecological oncologist without any residual tumor load, or so-called “optimal debulking.” Over the last decades, interest in the use of neoadjuvant chemotherapy together with an interval debulking has increased. Neoadjuvant therapy can be used for patients who are primarily suboptimally debulked due to an extensive tumor load. In this situation, based on the randomized European Organization for Research and Treatment of Cancer–Gynaecological Cancer Group trial, interval debulking by an experienced surgeon improves survival in some patients who did not undergo optimal primary debulking surgery. Based on the GOG 152 data, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecological oncologist. Neoadjuvant chemotherapy can also be used as an alternative to primary debulking. In retrospective analyses, neoadjuvant chemotherapy followed by interval debulking surgery does not seem to worsen prognosis compared to primary debulking surgery followed by chemotherapy. However, we will have to wait for the results of future randomized trials to know whether neoadjuvant chemotherapy followed by interval debulking surgery is a good alternative to primary debulking surgery in stage IIIc and IV patients. Open laparoscopy is probably the most valuable tool for evaluating the operability primarily or at the time of interval debulking surgery

Contains fulltext : 137479.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Appendectomy is often recommended in patients with mucinous borderline ovarian tumours (mBOTs) based on studies suggesting that metastatic disease from a primary appendiceal tumour can mimic mBOT. The present study assessed the incidence of mucinous neoplasms in the appendix associated with the presence of mBOT. METHODS: A retrospective cohort study was performed in two university hospitals in the Netherlands between 1990 and 2011. All patients with mBOT and/or a mucinous appendiceal tumour were included. RESULTS: Of 127 patients included, 98 had a primary mBOT and 29 had a primary mucinous appendiceal tumour. In patients with a mBOT, the appendix was either removed at prior surgery (4%), resected as part of the staging procedure showing no pathological abnormalities (13%), described as normal and not resected (58%), or not described and not resected (25%). During a median follow-up period of 5 years (range 2-23), two patients developed a recurrence in which the appendix was not involved. In all patients with a primary mucinous tumour of the appendix, the appendix appeared abnormal at the time of surgery. Eight of these patients (28%) were diagnosed with invasive ovarian metastases. A review of the literature including the cases from this study identified 510 mucinous ovarian tumours with borderline features and 214 associated appendectomies, of which 4 (1.9%) contained a primary appendiceal malignancy. CONCLUSIONS: A thorough inspection of the appendix should be performed in patients with a mucinous ovarian tumour with borderline features. An appendectomy should only be performed when the appendix is macroscopically abnormal.

Fulvestrant, a novel estrogen receptor (ER) antagonist with no agonist effects, binds, blocks, and degrades the ER, thereby downregulating cellular ER levels, which in turn leads to reduced expression of the progesterone receptor. Due to this specific working mechanism, fulvestrant is an important addition to the armamentarium of endocrine agents in advanced breast cancer (ABC). Fulvestrant has been shown to be equally effective as the third-generation aromatase inhibitor (AI) anastrozole in postmenopausal patients with hormone-sensitive ABC progressing prior to tamoxifen. In another randomized phase III trial, it was shown that fulvestrant had similar efficacy to tamoxifen in the first-line treatment of postmenopausal women with hormone receptor-positive ABC. When comparing the side effects of fulvestrant with tamoxifen and anastrozole, it was shown that fulvestrant is well tolerated compared with these agents and is associated with a lower incidence of joint disorders. Clinical benefit on fulvestrant treatment after AI therapy has been reported in a substantial number of patients (28-46%). On the other hand, it was also shown that sensitivity to further endocrine therapy is retained following progression on first-line or second-line fulvestrant (57% and 46% clinical benefit, respectively). In conclusion, fulvestrant provides us with an additional endocrine treatment option making it possible to prolong the time that patients with ABC can be treated with endocrine therapy.

Objectives The purpose of this review is to determine the incidence of lymph node metastases in clinical stages I and II ovarian cancer. Methods Relevant articles were identified from MEDLINE and EMBASE, supplemented with citations from reference lists from the primary studies. Eligibility was evaluated by two authors. Included studies were prospective or retrospective cohort studies, which analyzed patients with clinical early stage EOC who underwent a complete pelvic and para-aortic lymphadenectomy as a part of a staging laparotomy. Results Fourteen studies were included in the analysis. The mean incidence of lymph node metastases in clinical stages I–II EOC was 14.2% (range 6.1–29.6%), of which 7.1% only in the para-aortic region, 2.9% only in the pelvic region, and 4.3% both in the para-aortic and pelvic region. Grade 1 tumors had a mean incidence of lymph node metastases of 4.0%, grade 2 tumors 16.5.8% and grade 3 tumors 20.0%. According to histological subtype, the highest incidence of lymph node metastases was found in the serous subtype (23.3%), the lowest in the mucinous subtype (2.6%). In unilateral tumors, pelvic lymph node metastases were found in 9.7% on both sides, 8.3% only at the ipsilateral side, and in 3.5% only at the contralateral side. Conclusions The incidence of lymph node metastases in clinical early stage EOC is considerable. Based on the scarce literature data, omitting a systematic lymphadenectomy can only be considered in grade I mucinous tumors.

Objectives. The aim of this Study was to describe the role of diaphragmatic surgery in achieving optimal debulking in patients with advanced ovarian cancer and the assessment of the relative post-operative complications. Methods. Retrospective review was performed of medical records of 89 patients with epithelial ovarian cancer who underwent diaphragmatic surgery during their primary debulking surgery between September 1993 and December 2007. Four different approaches were performed: Coagulation (group I), stripping (group 2), combination stripping with coagulation (group 3) and diaphragm full thickness resection (group 4). Cytoreductive outcome, morbidity, overall Survival (OS) and disease-free Survival (DFS) were analysed. Results. Eight (8.9%) patients had FIGO stage IIIB, 64 (72%) stage IIIC and 17 (19.1%) stage IV disease. In 20 patients (22%) the diaphragmatic disease was coagulated, in 31 patients (35%) was only stripped, in 31 patients (35%) a combination of these techniques was applied and in 7 (8%) the disease was resected with the adjacent infiltrated part of the diaphragm muscle and the pleura above it. Debulking to no residual tumor was achieved in 90%, 86%. 86% and 100% for groups 1, 2, 3 and 4 respectively. Median DFS was 15,15,17 and overall Survival OS for groups 1, 2, and 3 was 40, 42, and 50 months respectively and was not yet reached for group 4. Minor and major complications were comparable among the groups. Pleural effusion was the most frequent associated complication and chest tube placement (17%) or thoracocentesis (12%) was necessary for the relief of respiratory distress. The perioperative mortality rate was 0%. The majority of cases were treated in the last five years Of our 15-year experience. Conclusions. Diaphragmatic surgery increases the rates of optimal primary debulking surgery and improves Survival with an acceptable and manageable morbidity rate. In patients with thick (>0.3 cm) OF large (>4 cm) lesions stripping the diaphragm or full thickness resection of the diaphragmatic muscle is preferred. (C) 2009 Elsevier Inc. All rights reserved

Sir, We appreciate the data and comments provided by Langmar et al (2011) regarding our recent report ‘HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm' (Van Gorp et al, 2011). In their letter Langmar et al suggest that we did not start this prospective study as a generic pelvic mass diagnostic study. They draw this conclusion by the fact that we started this study in 2005, and yet the studies from Moore et al were only published in 2008 and 2009 (Moore et al, 2008, 2009). However, we must point out that several publications on HE4 were already published between 2003 and 2005 (Hellstrom et al, 2003; Lu et al, 2004; Drapkin et al, 2005; Rosen et al, 2005). Between August 2005 and March 2009, 432 consecutive patients with a pelvic mass, who planned to undergo an operation, were eligible to participate in our study. Five patients withdrew consent during the study. Seventeen patients did not have the serum sample taken, or the volume of the retrieved serum was insufficient to perform the marker assays. Pathology reports were missing in 21 patients because the patients were eventually not operated upon due to poor prognosis or patients' decline, or because there was no biopsy taken and therefore no proven histological diagnosis. The remaining 389 patients participated in this study. In 2008 we were confronted with the results from Moore and colleagues. Since they published a significant difference between the performance of CA125 and CA125+HE4 in a study with only 233 patients, one could expect that we should have been able to show a significantly different result with our 389 patients, which is the largest monocentre cohort study on HE4. In fact, if one uses the AUCs of CA125 (0.836) and the combination of CA125 and HE4 (0.914) from the article of Moore et al, with an alpha level of 0.05 and a beta level of 0.20, one can obtain a required minimum sample size of 86 in each group. With a sample size of 389 patients, we broadly exceeded the required number of samples. The authors also suggest that there was a selection bias, with an increased amount of cancers, postmenopausal patients, mucinous tumours, borderline tumours and metastatic tumours of extra-ovarian origin. Indeed, the bigger proportion of these specific categories is a reflection of a patient population with adnexal masses in a tertiary centre as ours. Recruitment was also largely done in collaboration with our ultrasound department, which is an expert centre in the diagnosis of pelvic masses (Timmerman et al, 2010). Hence, there was a relatively large proportion of stage I and borderline tumours in our study, which are more difficult to differentiate from their benign counterparts compared with stage III or IV ovarian cancers. The fact that we were not able to show a statistical difference between CA125 and ROMA illustrates that the ROMA algorithm does not seem to be of any benefit in this particular setting, which in our opinion is an important finding for many centres. Moreover, in this setting, with more difficult tumours to diagnose, the addition of a good diagnostic tumour marker could have been of great importance, and yet, the addition of HE4 to CA125 does not seem to fulfill these expectations. Langmar et al also claim that the non-significant differences between the AUCs of the different tests cannot exclude a gain in diagnostic accuracy with statistical certainty. This strikes us as a contradictio in terminis. As mentioned in the methods section, we used the non-parametric method as described by DeLong et al (1988) to calculate differences in AUCs. The method of DeLong et al is the most widely used method to perform these comparisons. We do not dispute the calculated differences in AUCs and 95% confidence intervals by Langmar et al, but as the P-level was 0.17 we were not able to reject the null hypothesis, and thus in our setting this means that the results were not statistically different. All comparisons and corresponding P-values are clearly mentioned in our results section and are illustrated in the tables and figures. Finally, Langmar et al question our interpretation of the HE4 threshold. They state that the optimal threshold depends on the characteristics of the population and the consequences of the true and false test outcomes. Again, we fully agree with this last remark. In the diagnosis of ovarian cancer one should try to detect as many of the ovarian cancers as possible, and yet avoid unnecessary surgeries for benign cysts. This implies that sensitivity is very important; however, increasing morbidity, costs, pain and fear by performing midline laparotomies for benign cysts are also unacceptable. Therefore we have looked at the optimal cut-off rather than a cut-off at a fixed sensitivity or specificity. As mentioned in our article, the optimal cut-off corresponds to the point on the ROC curve with the highest accuracy. As we did not use healthy controls, we did not intend to find a cut-off for HE4 that could be used in screening. Moreover, we clearly stated that using a cut-off of 150 , as suggested in the product insert, would result in high specificity (96.5%), but in very low sensitivity (50.3%). Therefore, a cut-off of 150 cannot be used in a diagnostic situation in a population as ours. A cut-off of 70 is more appropriate and very close to our calculated optimal cut-off of 72.2 . In conclusion, we understand that these negative results for this promising HE4 marker and ROMA algorithm are disappointing. We can only conclude that neither HE4 nor the combination of HE4 and CA125 in the ROMA algorithm seems to be an improvement in the diagnosis of ovarian cancer in patients with an adnexal mass as referred to a tertiary centre as ours.

British Journal of Cancer (2011) 104, 221–222. doi:10.1038/sj.bjc.6606000 www.bjcancer.comPublished online 23 November 2010& 2011 Cancer Research UKSir,We read with interest the paper by Polterauer et al (2010) inwhich they evaluated the prognostic value of lymph node density(LND) in patients with lymph node-positive cervical cancer. LNDis defined as the ratio of the number of metastatic lymph nodesto the total number of lymph nodes removed. They showed thatLND410% is associated with an impaired disease-free and overallsurvival. Lymph node involvement and lymph vascular spaceinvolvement have always been noted to be a poor prognostic factorin cancer of the cervix (Pecorelli, 2006), and thus this confirms thefact that the higher the number of lymph nodes involved,the worse the prognosis of the patient becomes. The benefit ofusing LND could be that it also incorporates the extent of surgicalstaging. Indeed, it is probably true that when you perform acomplete lymph node dissection instead of a sampling you havemore chance of finding all involved lymph nodes. However, thereis more to it than positive lymph nodes and surgical skills.Although the authors gave the mean/median number ofremoved lymph nodes and positive lymph nodes for all patients,we were not able to discern this information for the LNDp10% orLND410% group separately. We believe that this information ispivotal in a study that examines the ratio of both parameters. In aratio, both the numerator and denominator have an equal role. Theauthors state that they performed a systemic lymphadenectomy inall patients. This means that the mean/median number of removedlymph nodes cannot be statistically different in both groups. As aconsequence, only the denominator will become important, andthus the number of positive lymph nodes will become theprognostic factor. If for any reason the total number of lymphnodes removed in both groups is different, then one must questionthe reasons why. Did the surgeon stop the operation prematurelybecause during the operation he/she discovered bulky involvedlymph nodes? This would make a complete systemic lymphade-nectomy redundant, as the patient is already known to be lymphnode positive based on these few lymph nodes. This is generallyaccepted as an indication for (chemo-)radiotherapy, and thecombination of a radical surgery and pelvic (chemo-)radiotherapywill increase therapy-related morbidity (Quinn et al, 2006). Maybethe pathologist stopped looking intensively for other lymph nodesbecause he/she already found several positive lymph nodes.Second, with respect to the technique used, they referred to aprevious study in which a laparoscopic pelvic lymph node stagingwas described (Polterauer et al, 2008). In this study, patients wereincluded between 1995 and 2007 and, remarkably, the mediannumber of lymph nodes was 15, being more than 3 lymph nodesless than in the present study. Does this implicate a learning curverelated to the laparoscopic technique used? If yes, once more asurgical bias is introduced.Third, we question the cutoff value and how it was established.The authors mentioned that this was based on preliminary datafrom a study by Ooki et al (2007). We wonder how welloesophageal cancer can be compared with cervical cancer. Bothorgans are located in completely different anatomic regions, with adifferent lymph vessel drainage system and lymph node distribu-tion. Did the authors try different cutoff points or was the 10%cutoff the only value examined? If the authors tried different cutoffpoints, one could argue that the authors should have used anindependent validation set to validate this cutoff point.Fourth, with a median of 18.5 lymph nodes (range 12–27),Polterauer et al demonstrated that they routinely performedcomplete lymph node dissections. As the ratio of the mediannumber of involved lymph nodes (n¼2) to the median number ofremoved lymph nodes (n¼18.5) was 10.8%, removing one or twolymph nodes would more or less determine whether the patientbelonged to the category of patients with LNDp10% or LND410%. This would implicate that the surgeon could influence towhich prognostic group the patient will belong. After all, it sufficesto remove more lymph nodes to shift the patient from theLND410% group to the LNDp10% group. It is contradictory thatthe surgeon has to remove more ‘healthy’ lymph nodes to‘improve’ the prognosis of the patient. With more healthy lymphnodes the denominator will become bigger and thus the LNDsmaller. This strikes us as ironic.In conclusion, as LND is influenced by surgical technique,anatomic circumstances and the quality and accuracy of thepathological analysis, we believe that LND is not an objectiveparameter and should not influence the decision on what kind ofadjuvant treatment should be given to a patient. We believe thatthe number of positive lymph nodes is probably the true predictor,but as the number of patients in each of the different groups (1 vs 2vs 42) was low, the authors were unable to reach significance.Using a ratio solved this problem by creating two arbitrary groupsof patients and by using denominators that enlarged the differencePublished online 23 November 2010 between the numerators.*Correspondence: Dr T Van Gorp; E-mail: toon.van.gorp@mumc.nl