Search

Background:Incomplete surgical staging is a negative prognostic factor for patients with borderline ovarian tumours (BOT). However, little is known about the prognostic impact of each individual staging procedure.Methods:Clinical parameters of 950 patients with BOT (confirmed by central reference pathology) treated between 1998 and 2008 at 24 German AGO centres were analysed. In 559 patients with serous BOT and adequate ovarian surgery, further recommended staging procedures (omentectomy, peritoneal biopsies, cytology) were evaluated applying Cox regression models with respect to progression-free survival (PFS).Results:For patients with one missing staging procedure, the hazard ratio (HR) for recurrence was 1.25 (95%-CI 0.66-2.39; P=0.497). This risk increased with each additional procedure skipped reaching statistical significance in case of two (HR 1.95; 95%-CI 1.06-3.58; P=0.031) and three missing steps (HR 2.37; 95%-CI 1.22-4.64; P=0.011). The most crucial procedure was omentectomy which retained a statistically significant impact on PFS in multiple analysis (HR 1.91; 95%-CI 1.15-3.19; P=0.013) adjusting for previously established prognostic factors as FIGO stage, tumour residuals, and fertility preservation.Conclusion:Individual surgical staging procedures contribute to the prognosis for patients with serous BOT. In this analysis, recurrence risk increased with each skipped surgical step. This should be considered when re-staging procedures following incomplete primary surgery are discussed. [ABSTRACT FROM AUTHOR]

Background: This study investigates the health-related quality of life in patients with vulvar lichen sclerosus (LS) and the patient-defined therapeutic benefit of clobetasol. Methods: A survey analysis of 96 women with LS after treatment with clobetasol was performed. Quality of life was assessed with the Skindex-29. The Patient Benefit Index (PBI) was used to determine the therapeutic benefit. Results: The overall response rate was 59.2%. Quality of life was most impaired by somatic symptoms (scale 'Symptoms' score 3.2) and emotional stress (scale 'Emotions' score 3.1), while social interactions (scale 'Functioning' score 1.9) played an inferior role (p < 0.001). Primary therapeutic goals 'to have confidence in the therapy' and 'to be free of itching' were achieved in 73.2 and 69.0% of patients who indicated the goal applied to them. The global PBI score was 3.06. In 93.2% of patients it was >1, indicating a potential benefit from clobetasol. Conclusion: Topical clobetasol is of potential therapeutic benefit for patients with vulvar LS and might therefore improve quality of life. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

BACKGROUND: Recurrent cervical cancer is a life-threatening disease, with limited treatment options available when disease progression occurs after first-line combination therapy. METHODS: We conducted a phase 3, multinational, open-label trial of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer. Patients were randomly assigned, in a 1:1 ratio, to receive tisotumab vedotin mono- therapy (2.0 mg per kilogram of body weight every 3 weeks) or the investigator's choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or peme- trexed). The primary end point was overall survival. RESULTS: A total of 502 patients underwent randomization (253 were assigned to the tisotumab vedotin group and 249 to the chemotherapy group); the groups were similar with respect to demographic and disease characteristics. The median overall survival was significantly longer in the tisotumab vedotin group than in the chemotherapy group (11.5 months [95% confidence interval {CI}, 9.8 to 14.9] vs. 9.5 months [95% CI, 7.9 to 10.7]), results that represented a 30°6 lower risk of death with tisotumab vedotin than with chemotherapy (hazard ratio, 0.70; 95% CI, 0.54 to 0.89; two-sided P=0.004). The median progression-free survival was 4.2 months (95% CI, 4.0 to 4.4) with tisotumab vedotin and 2.9 months (95% CI, 2.6 to 3.1) with chemotherapy (hazard ratio, 0.67; 95% CI, 0.54 to 0.82; two-sided P<0.001). The confirmed objective response rate was 1Z8°6 in the tisotumab vedotin group and 5.2% in the chemotherapy group (odds ratio, 4.0; 95% CI, 2.1 to 7.6; twosided P<0.001). A total of 98.4% of patients in the tisotumab vedotin group and 99.2°6 in the chemotherapy group had at least one adverse event that occurred during the treatment period (defined as the period from day 1 of dose 1 until 30 days after the last dose); grade 3 or greater events occurred in 52.0% and 62.396, respectively. A total of 14.8% of patients stopped tisotumab vedotin treatment because of toxic effects. CONCLUSIONS: In patients with recurrent cervical cancer, second- or third-line treatment with tisotumab vedotin resulted in significantly greater efficacy than chemotherapy. [ABSTRACT FROM AUTHOR]

Objective: There are no data, and thus no consensus, on the optimal duration of poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy for exceptional responders (here defined as progression-free for 5 years or longer) with platinum sensitive recurrent ovarian cancer. The current licence is to continue PARP inhibitors until progression or toxicity; however, international practice varies considerably. The risks of late progression and late-onset myeloid malignancies, defined as occurring beyond 5 years of PARP inhibition, are unknown. This study aims to examine the practice patterns and opinions regarding the management and surveillance protocols of exceptional responders with platinum sensitive recurrent ovarian cancer., Methods: An online international survey of experts from June 2023 to June 2024 was carried out, disseminated at Gynaecologic Cancer Intergroup meetings and by Chairs of Cooperative Groups., Results: 210 responses were received from 26 countries including Australia (27 respondents), Germany (24), the UK (21), the Netherlands (16), France (13), Spain (12), Canada (12), Italy (11), Japan (11), and other countries (63). Most respondents did not have institutional or trials group guidelines regarding duration of PARP inhibitors (154, 73.3%). For the minority with guidelines, recommendations varied: 1 year (2), 2 years (13), 3 years (4), and indefinite treatment (22). Individual practice varied considerably for those without guidelines: most (116, 76.3%) recommended ≥5 years of PARP inhibition, of which 73 (48.0%) recommended indefinite PARP inhibition. Sixty-six respondents (31.4%) reported having patients with late progression and 46 (22.0%) had cases with late-onset myeloid malignancies. Surveillance practices varied widely across all respondents., Conclusions: This international survey highlights the diverse practice variations and disparate views on the optimal duration of maintenance therapy with PARP inhibitors in platinum sensitive recurrent ovarian cancer. The responses suggest a notable risk of late progression and myelodysplastic syndrome/acute myeloid leukemia among exceptional responders which needs confirmation. Detailed individual patient data is required to draw more reliable conclusions; another study is underway addressing this., Competing Interests: Competing interests: The authors have the following relevant disclosures within the last 36 months: AGM: honoraria from AstraZeneca, GlaxoSmithKline, Clovis, Roche, Novocure, MSD, Takeda, Zaylab; travel support from AstraZeneca, GSK and MSD; participation on a Data Safety Monitoring Board or Advisory Board for Alkermes, AstraZeneca, Amgen, Clovis, Eisai, GlaxoSmithKline, Immunogen, GenMab, Kartos, Sutro, Roche, Sotio, Macrogenics, Mersana, MSD, Pharmamar, Novartis, Oncoinvent, Regeneron, HederaDx, Illumina, Tubulis, Daiichi Sakyo, Incyte, Novocure, BionTech and other institutional financial or non-financial interests from GSK and Roche. AL: institutional funding from GSK, MSD, AstraZeneca, Immunogen, Owkin, Oseimmuno, Incyte, Adaptimmune, Eisai, Zentalis; consulting fees from MSD, GSK, AstraZeneca, Zentalis, Apmonia, Daiichi, Owkin, Immunogen, Incite, Genmab (payments for these to institution); honoraria from GSK, MSD, AstraZeneca and Servier; travel support from Oseimmuno, AstraZeneca and GSK; participation on a Data Safety Monitoring Board or Advisory Board for Pfizer; leadership role in GINECO; member of strategic committee in GCIG, ENGOT member and ESMO track chair/faculty. AO: grants from AstraZeneca and Amgen; consulting fees from BMS; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca and GSK, Steering Committee for AstraZeneca and GSK; and Principal Investigator of investigator initiated trials for AstraZeneca and GSK. AT: honoraria from GSK and AstraZeneca; travel support from GSK. CM: funded research: EU, FWF, AstraZeneca, Roche; honoraria/expenses from Roche, Novartis, MSD, Pharmamar, AstraZeneca, GSK and Consulting/Advisory Board for Roche, Novartis, MSD, AstraZeneca, Pfizer, Pharmamar, ImmunoGen, Daiichi Sankyo, Biontech, Novocure, Eisai, GSK, Abbvie, and Seagen. CG: manuscript support, grants, and contracts from AstraZeneca, GlaxoSmithKline, Tesaro, Clovis, MSD, BergenBio, Novartis, Aprea, Artios, Verastem, Roche, and Medannex; consulting fees from AstraZeneca, MSD, GlaxoSmithKline, and Verastem; honoraria for lectures and presentations from AstraZeneca, MSD, GlaxoSmithKline, Tesaro, Clovis, Roche, Nucana, Chugai, Takeda, Cor2Ed, and Peervoice; advisory board attendance from AstraZeneca, MSD, GlaxoSmithKline, Tesaro, Roche, Nucana, Chugai, and Verastem; Committee Member for the Scottish Medicines Consortium. CS: grant and research support from Clovis Oncology, Eisai Inc, Sierra Oncology, Roche, Beigene, AstraZeneca; membership on Advisory boards: AstraZeneca, Clovis Oncology, Roche, Eisai, Sierra Oncology, Takeda, MSD; committee membership on GCIG, IRCI (Chair), ANZGOG (Chair). DT: research funding from the National Medical Research Council (NMRC) Clinician Scientist Award Senior Investigator Grant (CSASI21jun-0003), the Pangestu Family Foundation Gynaecological Cancer Research Fund, and product samples from AstraZeneca, Eisai, and MSD (non-financial interest) for research trials; institutional research grants from AstraZeneca, Bayer, Karyopharm Therapeutics, and Roche; personal fees for advisory board membership from AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Eisai, Genmab, GSK, MSD, PMV Pharma, Daiichi Sankyo and Roche; personal fees as an invited speaker from AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche, and Takeda; travel support from AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche, and Takeda; current non-renumerated role as protocol chair of Asia Pacific Gynecologic Oncology Trials Group (APGOT); previous non-renumerated role as Chair of the Asia Pacific Gynecologic Oncology Trials Group (APGOT); a previous non-renumerated role as the Society President of the Gynecologic Cancer Group Singapore; non-renumerated membership of the Board of Directors of the GCIG, and ownership of stocks/shares of Asian Microbiome Library (AMiLi). FA: participation on Advisory Board for MiMark. IM: consulting fees from AstraZeneca, Bicycle Therapeutics, Clovis Oncology/pharma, Duke Street Bio, Epsila Bio, Roche, Scancell, GSK, Theolytics, Transgene Biotek, and OncoC4; honoraria from GSK; participation on a Data Safety Monitoring Board or Advisory Board for Roche; unpaid trustee of Worldwide Cancer Research (charity). IRC: grants/contracts from AstraZeneca, Clovis, GSK, Mersana, BMS and MSD; honoraria from AstraZeneca, Clovis, GSK, Mersana, BMS and MSD, Roche, Pharmamar, Seagen, Eisai, Novartis; travel support from Roche, GSK, AstraZeneca, Pharmamar, MSD; participation on a Data Safety Monitoring Board or Advisory Board for Clovis, Deciphera, Adaptimmune, Sutro, Immunogen. JL: grants from AstraZeneca, Merck/MSD; consulting fees from AstraZeneca, Clovis Oncology, GSK, Artios Pharma, Merck/MSD, VBL Therapeutics, Bristol Myers Squibb, Nuvation, Immagene, Incyte, Immunogen/Abbvie, Novocure; honoraria from AstraZeneca, MSD/Merck, Clovis Oncology, GSK; participation on a Data Safety Monitoring Board or Advisory Board for Mersana and SutroBio; Editor for ESMO Clinical Practice Guidelines – Gynaecological Cancer until December 2023; Past Vice President ESGO until 2021; Chair of National Ovarian Cancer Audit Committee. EMG-G: honoraria and travel support from AstraZeneca, Amgen, Merck and Eisai; participation on a Data Safety Monitoring Board or Advisory Board for Merck, AstraZeneca and Roche. HY: no relevant disclosures. KM: grants/contracts from PTC Therapeutics, Lilly, Clovis, Genentech, GSK, Verastem (all institutional); royalties or licenses from UptoDate; consulting fees from AstraZeneca, Aravive, Aadi, Blueprint pharma, Clovis, Caris, Duality, Eisai, GSK, Genentech/Roche, Hengrui, Immunogen, Iovance, Janssen, Lilly, Mereo, Mersana, Merck, Myriad, Novartis, Novocure, Pannavance, Onconova, VBL Therapeutics, Verastem, Zentalis; honoraria from AstraZeneca, GSK, Immunogen, PRIME, RTP, Medscape, Great Debates and Updates; travel support from AstraZeneca, BioNTech, GOG P Associate Director. LH: support from Pfizer for meeting registration fees. LW: grants/contracts from Seagen, MSD, Roche, Gilead, German Cancer Aid and AstraZeneca (all institutional); consulting fees from Pfizer, MSD, Roche, Seagen, Eisai, GSK, Myriad and AstraZeneca; honoraria from Pfizer, MSD, Roche, Seagen, Eisai, GSK, Novartis and AstraZeneca; travel support from AstraZeneca; participation on a Data Safety Monitoring Board or Advisory Board for MSD, Roche, Seagen/Pfizer, Eisai, GSK and Myriad; leadership roles in German Vulva Cancer Group and current President of the European College for the Study of Vulval Disease. MF: consulting fees from AstraZeneca, Novartis, GSK, Incyclix; honoraria from AstraZeneca, GSK, MSD and The Limbic; participation on a Data Safety Monitoring Board or Advisory Board for AGITG IDSMB, ENDO-3; institutional research grants from AstraZeneca, Beigene and Novartis. NC: grants from AstraZeneca, PharmaMar and Roche; honoraria from AstraZeneca and Novartis; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Clovis Oncology, Eisai, GSK, ImmunoGen, Mersana, MSD/Merck, Nuvation Bio, Onxerna, Pfizer, PharmaMar, Pieris and Roche, Novocure; membership of the ESMO Guidelines Steering Committee; leadership role as Chair of the Alleanza Control il Tumore Ovarico (ACTO) Scientific Committee. OR: consulting fees from AstraZeneca, MSD, Medison, Neopharm; travel support from AstraZeneca and MSD; honoraria from AstraZeneca. PH: grants from AstraZeneca, Roche, GlaxoSmithKline, Genmab, Immunogen, Seagen, Clovis, Novartis; consulting fees from Miltenyi; honoraria from Amgen, AstraZeneca, GSK, Roche, Immunogen, Sotio, Stryker, Zai Lab, MSD, Clovis, Eisai, Mersana, Exscientia, Daiichi Sankyo, Karyopharm; travel support from AstraZeneca; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Roche, GlaxoSmithKline, Clovis, Immunogen, MSD, Miltenyi, Novartis, Eisai. SCC: meeting/travel support from AstraZeneca, MSD and GSK; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, MSD and GSK. SP: research funding from MSD, Roche, AstraZeneca, GSK, Pfizer and honoraria from MSD, AstraZeneca, GSK, Novartis, Pfizer, Pharmamar and Roche. YCL: institutional research grant from BeiGene; honoraria from AstraZeneca; participation on Advisory Board for AstraZeneca., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Adjuvant radiotherapy to the vulva in vulvar squamous cell carcinoma (VSCC) is frequently performed albeit strong evidence is lacking. This systematic review aims to summarize the current literature on this topic., Methods: 19 retrospective studies were included and analyzed, focusing on the primary outcome of local recurrence., Results: The publications present conflicting results. While the benefit of adjuvant radiotherapy to the groins in case of node-positive VSCC is well established, the indication criteria and effectiveness of adjuvant radiotherapy to the vulva remain unclear. Based on the studies included in this review, the current evidence suggests that adjuvant radiotherapy to the vulva might not significantly reduce the risk of recurrence or only in certain subgroups., Conclusion: Most of the studies do not consider individual risk factors such as HPV status, resection margin, lymph node stage, grading and others. As a result, the comparability and reliability of these findings are limited. This review aims to highlight the need of further research addressing the risk stratification, considering both oncologic risk factors and adverse events., Competing Interests: Declaration of competing interest None, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Differentiated vulvar intraepithelial neoplasia (dVIN) is a high-risk preinvasive vulvar lesion and precursor of human papillomavirus-independent vulvar squamous cell carcinoma (VSCC). Due to its rarity, literature data on its malignant potential are scant. The aim of the study is to assess the risk of developing VSCC in patients surgically treated for dVIN not associated with VSCC (solitary dVIN) and the risk of VSCC recurrence in patients treated for dVIN associated with VSCC (dVIN-VSCC) at first diagnosis., Material and Methods: A historical cohort study was performed in a northern Italy referral center for vulvar neoplasms. All consecutive women surgically treated for histologically confirmed dVIN from 1994 to 2021 were collected. Primary outcome was cancer risk or recurrent cancer risk, secondary outcomes were risk factors associated with VSCC development or recurrence. Kaplan-Meier method and log-rank test were used to estimate cancer risk or recurrent cancer risk differences and uni- and multivariate Cox regression analyses to identify risk factors associated with VSCC development in solitary dVIN and recurrence of dVIN-VSCC., Results: Seventy-six patients with dVIN at preoperative biopsy were included: at excisional specimens 44 were solitary dVIN and 32 were dVIN-VSCC. The absolute risk of VSCC development after solitary dVIN treatment was 43.2% with median time to to VSCC diagnosis of 25.4 months (range 3.5-128.0 months). VSCC recurrence absolute risk in treated dVIN-VSCC patients was 31.3% with median time to VSCC recurrence of 52.9 months (range 6.5-94.8 months). At uni- and multivariate regression analyses, only compliant topical ultrapotent corticosteroid treatment after solitary dVIN excision showed an ability to prevent VSCC development. No protective effect by corticosteroid treatment was shown for VSCC recurrence in dVIN-VSCC patients. Smoking was associated with higher cancer recurrence risk in dVIN-VSCC patients on both uni- and multivariate regression analyses., Conclusions: Patients with dVIN have a high risk of developing both primary and recurring VSCC. Early recognition, long-term follow up, and compliant ultrapotent topical corticosteroid treatment are recommended., (© 2024 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Purpose: In 2018, the first guideline-based quality indicators (QI) for vulvar cancer were implemented in the data-sheets of certified gynaecological cancer centres. The certification process includes guideline-based QIs as a fundamental component. These indicators are specifically designed to evaluate the level of care provided within the centres. This article aims to give an overview of the developing process of guideline based-QIs for women with vulvar cancer and presents the QIs results from the certified gynaecological cancer centres., Methods: The QIs were derived in a standardized multiple step process during the update of the 2015 S2k guideline "Diagnosis, Therapy, and Follow-Up Care of Vulvar Cancer and its Precursors" (registry-number: no. 015/059) and are based on strong recommendations., Results: In total, there are eight guideline-based QIs for vulvar cancer. Four QIs are part of the certification process. In the treatment year 2021, 2.466 cases of vulvar cancer were treated in 177 centres. The target values in the centres for pathology reports on tumour resection and lymphadenectomy as well as sentinel lymph nodes have increased since the beginning of the certification process and have been above 90% over the past three treatment years (2019-2021)., Discussion: QIs based on strong guideline recommendations, play a crucial role in measuring and allowing to quantify essential aspects of patient care. By utilizing QIs, centres are able to identify areas for process optimization and draw informed conclusions. Over the years the quality of treatment of vulvar cancer patients measured by the QIs was improved. The certification system is continuously reviewed to enhance patient care even further by using the outcomes from QIs revaluation., (© 2024. The Author(s).)

Background: The GOG240 trial established bevacizumab with chemotherapy as standard first-line therapy for metastatic or recurrent cervical cancer. In the BEATcc trial (ENGOT-Cx10-GEICO 68-C-JGOG1084-GOG-3030), we aimed to evaluate the addition of an immune checkpoint inhibitor to this standard backbone., Methods: In this investigator-initiated, randomised, open-label, phase 3 trial, patients from 92 sites in Europe, Japan, and the USA with metastatic (stage IVB), persistent, or recurrent cervical cancer that was measurable, previously untreated, and not amenable to curative surgery or radiation were randomly assigned 1:1 to receive standard therapy (cisplatin 50 mg/m 2 or carboplatin area under the curve of 5, paclitaxel 175 mg/m 2 , and bevacizumab 15 mg/kg, all on day 1 of every 3-week cycle) with or without atezolizumab 1200 mg. Treatment was continued until disease progression, unacceptable toxicity, patient withdrawal, or death. Stratification factors were previous concomitant chemoradiation (yes vs no), histology (squamous cell carcinoma vs adenocarcinoma including adenosquamous carcinoma), and platinum backbone (cisplatin vs carboplatin). Dual primary endpoints were investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumours version 1.1 and overall survival analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03556839, and is ongoing., Findings: Between Oct 8, 2018, and Aug 20, 2021, 410 of 519 patients assessed for eligibility were enrolled. Median progression-free survival was 13·7 months (95% CI 12·3-16·6) with atezolizumab and 10·4 months (9·7-11·7) with standard therapy (hazard ratio [HR]=0·62 [95% CI 0·49-0·78]; p<0·0001); at the interim overall survival analysis, median overall survival was 32·1 months (95% CI 25·3-36·8) versus 22·8 months (20·3-28·0), respectively (HR 0·68 [95% CI 0·52-0·88]; p=0·0046). Grade 3 or worse adverse events occurred in 79% of patients in the experimental group and in 75% of patients in the standard group. Grade 1-2 diarrhoea, arthralgia, pyrexia, and rash were increased with atezolizumab., Interpretation: Adding atezolizumab to a standard bevacizumab plus platinum regimen for metastatic, persistent, or recurrent cervical cancer significantly improves progression-free and overall survival and should be considered as a new first-line therapy option., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests AO reports personal fees for participation in the advisory boards of AstraZeneca, Clovis Oncology, Deciphera, Genmab, GSK, Immunogen, Mersana Therapeutics, PharmaMar, MSD de España, Agenus, Sutro, Corcept Therapeutics, EMD Serono, Novocure, Shattuck Labs, iTeos, and Eisai; travel and accommodation support from AstraZeneca, PharmaMar, and Roche; and funding paid to institution from AbbVie Deutschland, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics AB, Clovis Oncology, Eisai, F Hoffmann-La Roche, Regeneron Pharmaceuticals, Immunogen, MSD de España, Takeda, PharmaMar, Tesaro, and Bristol Myers Squibb. LG reports support for attending meetings or travel from Viatris, GSK, and MSD; consulting fees paid to institution for participation in the advisory boards of Clovis, GSK, AstraZeneca, and Seagen; and speaker honoraria paid to institution from AstraZeneca, GSK, and Eisai. JM-G reports personal fees for participation in the advisory boards of AstraZeneca, Clovis, GSK, and PharmaMar; research grants paid to institution from GSK and Roche; and travel and accommodation expenses from GSK−Tesaro, Pfizer, and PharmaMar. GV reports honoraria for speaker engagements from MSD, Pierre Fabre, GSK, and Pfizer; and consulting fees from Reveal Genomics. UDG reports personal consulting fees from Amgen, AstraZeneca, Pfizer, BMS, Clovis Oncology, Dompé Farmaceutici, Merck, MSD, PharmaMar, Astellas, Bayer, Ipsen, Novartis, Eisai, and Janssen; other funding paid to institution from AstraZeneca, Sanofi, and Roche; and support for attending meetings or travel from Pfizer, Ipsen, and AstraZeneca. KL reports personal honoraria from Eisai; participation on data safety monitoring or advisory boards of Eisai, MSD, Nykode, AstraZeneca, and GSK (honoraria paid to institution); and funding paid to institution from GSK. LW reports personal honoraria for participation in the advisory boards of AstraZeneca, Pfizer, GSK, Roche, MSD–Merck, Eisai, and Seagen; personal honoraria for speaker engagements from AstraZeneca, Eisai, GSK, Pfizer, Roche, MSD–Merck, and Seagen; and support for attending meetings or travel from GSK and MSD. NC reports consultancy or advisory roles for AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, Mersana, MSD−Merck, Nuvation Bio, OncXerna, Pfizer, Pieris, and Roche; promotional speaker roles for AstraZeneca, Novartis, Clovis Oncology, MSD−Merck, and GSK; research grants from AstraZeneca, GSK, and Roche; and support for attending meetings or travel from AstraZeneca and GSK. LD reports personal fees for scientific advisory boards from Aadi Bioscience and Regeneron; fees paid to institution for scientific advisory boards from Merck; membership of the British Journal of Obstetrics and Gynaecology Editorial Board; personal royalties for writing expert content for UpToDate, Wiley, and the American Society of Clinical Oncology; personal fees for continuing medical education activities for Advance Medical, CEA Group, and Clinical Care Options; research funding paid to institution for investigator-initiated trials from Merck; clinical trial grants paid to institution from Genentech−Roche, AbbVie (GOG 3005), Acrivon, Advaxis, Aduro BioTech, Alkermes, Blueprint, Constellation, Eisai, GSK–Novartis, Immunogen, Inovio, Iovance, Karyopharm, KSQ Therapeutics, Lycera, Merck, Morab, MorphoTek, Naveris, Nurix, OncoQuest, Pfizer, Syndax, Tesaro, and Zentalis; and fees paid to institution for membership of data and safety monitoring committees for Agenus and Inovio. AL reports personal fees for presentations or educational events from Medscape and PeerVoice; consulting fees paid to institution from Owkin; speaker honoraria paid to institution from MSD, GSK, AstraZeneca, and Eisai; fees paid to institution for participation in the advisory boards of AstraZeneca, MSD, Seagen, GSK, Genmab, Zentalis, and Blueprint; non-remunerated independent data safety monitoring board participation for Clovis and BMS; an educational grant paid to institution from AstraZeneca; and support for attending meetings or travel from OSE Immunotherapeutics. AG-O reports honoraria paid to institution for participation in the advisory board of Novartis; personal honoraria for speaker engagements from AstraZeneca, Pfizer, Novartis, and Lilly; and support for attending meetings or travel from Pfizer and Novartis. MJR reports personal fees for participation in the advisory boards of AstraZeneca, Clovis Oncology, GSK, PharmaMar, MSD de España, Eisai, and Roche; personal fees for speaker engagements from MSD, AstraZeneca, Clovis Oncology, GSK, and PharmaMar; and travel and accommodation from AstraZeneca, PharmaMar, Roche, GSK, and MSD de España. LF-M reports honoraria paid to institution for participation in the advisory boards of GSK; honoraria paid to institution for speaker engagements from GSK, AstraZeneca–MSD, and Eisai; and support for attending meetings or travel from AstraZeneca–MSD and GSK. DL reports personal fees for participation in the advisory boards of AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, MSD, Oncoinvent, PharmaMar, Seagen, and Sutro; personal fees for consultancy roles from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, MSD, Novartis, PharmaMar, and Seagen; clinical trial or research funding to institution from Clovis Oncology, GSK, MSD, and PharmaMar; other financial or non-financial interests from AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, Oncoinvent, PharmaMar, Roche, Seagen, and Sutro; and travel grants from AstraZeneca, Clovis Oncology, and GSK. IR-C reports personal honoraria for participation in the advisory boards of Adaptimmune, Agenus, Amgen, AstraZeneca, BMS, Clovis, Daiichi Sankyo, Deciphera, Eisai, EQRx, GSK, Merck Serono, MacroGenics, Mersana, Novartis, Onxeo, Roche, and Sutro Biopharma; honoraria paid to institution for participation in the advisory boards of MSD (translational research); and funding paid to institution for translational research from BMS. LM reports participation in the advisory board of Roche; and honoraria for speaker engagements from Roche, GSK, Clovis Oncology, AstraZeneca, Pfizer, Novartis, and Lilly. FJ reports honoraria for lectures, expert boards, and educational events from AstraZeneca, Clovis Oncology, GSK, and Seagen; travel and accommodation support from GSK, Eisai, and MSD; and financial support for national academic GINECO trials from GSK and AstraZeneca. JA reports honoraria for speaker bureaus from GSK, Roche, AstraZeneca, MSD, PharmaMar, and Clovis; and advisory boards for GSK, MSD, AstraZeneca, and Clovis. PF reports personal fees for expert testimony from Daiichi; personal fees for invited speaker engagements from GSK and MSD; and support for attending meetings or travel from Lilly, Novartis, and GSK. IR reports personal fees for advisory boards from AstraZeneca, Clovis Oncology, GSK, PharmaMar, Roche, and MSD; and travel and accommodation from AstraZeneca, PharmaMar, Roche, and GSK. CL reports honoraria for advisory board participation from GSK; personal honoraria for speaker engagements from GSK, Clovis Oncology, Eisai, and MSD; and support for attending meetings or travel from MSD and GSK. JAP-F reports honoraria for speaker engagements from AstraZeneca, PharmaMar, Pharma&, Clovis, and GSK; payment for expert testimony from AstraZeneca, GSK, Roche, and PharmaMar; support for attending meetings or travel from Karyopharm, AstraZeneca, Roche, and PharmaMar; grants paid to institution from GSK and PharmaMar; equipment, materials, drugs, medical writing, gifts, or other services paid to institution from GSK; participation on data safety monitoring or advisory boards for Ability Pharma; and has a patent pending in breast cancer. HD reports personal honoraria for advisory board participation from AstraZeneca. LMR reports honoraria for speaker engagements from Genmab−Seagen, Blueprint Oncology, Curio Science, and Physicians Education Resource; honoraria for participation in the advisory boards of AstraZeneca, Clovis Oncology, GOG Foundation, Aadi Biosciences, Seagen, OnTarget Laboratories, Merck, Mersana, Rubius Therapeutics, Myriad Genetics, Genentech−Roche, Eisai, Novocure, and Immunogen; consulting fees from the GOG Foundation; and funding paid to institution from Genentech−Roche, On Target Laboratories, Pfizer, Aivita Biomedical, Tesaro, AstraZeneca, Merck, Akeso Biopharma, and Grupo Español de Investigación en Cáncer ginecologico. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: More than 95% of cervical cancers and their precancerous lesions are caused by human papillomavirus (HPV). Cell-free (cf) HPV DNA detection in blood samples may serve as a monitoring tool for cervical cancer., Methods: In our methodological study, an HPV panel for simultaneous detection of 24 types using mass spectrometry-based analysis was developed for liquid biopsy approaches and tested on HPV positive cell lines, plasmid controls, and cervical high-grade squamous intraepithelial lesions (HSIL) in positive smear samples (n = 52). It was validated in cfDNA blood samples (n = 40) of cervical cancer patients., Results: The HPV panel showed proficient results in cell lines and viral plasmids with a limit of detection of 1 IU (international units)/µL for HPV16/18 and 10GE/µL for HPV11/31/33/39/45/51/52/58/59 and a specificity of 100% for the tested HPV types. In cervical smear samples, HPV DNA was detected with a sensitivity of 98.14%. The overall agreement between the new HPV panel and clinical records was 97.2% (κ = 0.84). In cervical cancer cfDNA, 26/40 (65.0%) tested positive for any HPV type, with most infections due to hrHPV (24/26). HPV positive samples were found in all FIGO stages, with the highest positivity ratio in FIGO III and IV. Even the lowest stage, FIGO I, had 12/23 (52.2%) patients with a positive HPV plasma status., Conclusions: This proof-of-concept paper shows that the described assay produces reliable results for detecting HPV types in a multiplex mass spectrometry-based assay in cervical smear and cfDNA with high specificity and sensitivity in both cohorts. The assay shows potential for liquid biopsy-based applications in monitoring cervical cancer progression., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Prognostic markers in routine clinical management of breast cancer are often assessed using RNA-based multi-gene panels that depend on fluctuating tumor purity. Multiplex fluorescence immunohistochemistry (mfIHC) holds the potential for an improved risk assessment. To enable automated prognosis marker detection (i.e., progesterone receptor [PR], estrogen receptor [ER], androgen receptor [AR], GATA3, TROP2, HER2, PD-L1, Ki67, TOP2A), a framework for automated breast cancer identification was developed and validated involving thirteen different artificial intelligence analysis steps and an algorithm for cell distance analysis using 11+1-marker-BLEACH&STAIN-mfIHC staining in 1404 invasive breast cancers of no special type (NST). The framework for automated breast cancer detection discriminated normal glands from malignant glands with an accuracy of 98.4%. This approach identified that five (PR, ER, AR, GATA3, PD-L1) of nine biomarkers were associated with prolonged overall survival ( p ≤ 0.0095 each) and two of these (PR, AR) were found to be independent risk factors in multivariate analysis ( p ≤ 0.0151 each). The combined assessment of PR-ER-AR-GATA3-PD-L1 as a five-marker prognosis score showed strong prognostic relevance ( p < 0.0001) and was an independent risk factor in multivariate analysis ( p = 0.0034). Automated breast cancer detection in combination with an artificial intelligence-based analysis of mfIHC enables a rapid and reliable analysis of multiple prognostic parameters. The strict limitation of the analysis to malignant cells excludes the impact of fluctuating tumor purity on assay precision.

Purpose: Pazopanib has promising antiangiogenetic activity in solid cancers. The investigator-initiated phase I/II trial evaluated the combination of Topotecan with Pazopanib in platinum-resistant or intermediate-sensitive recurrent ovarian cancer (ROC)., Methods: Patients (≥ 18 years) with first or second recurrence were enrolled in this multicentre open-label trial. Phase I analysed Topotecan 4 mg/m 2 (day 1, 8, 15, ever 28 days) for six cycles to identify the maximum tolerated dose (MTD) of Pazopanib added in a dose-escalating scheme with 400 mg starting dose. The phase II analysed safety and efficacy aspects. For all patients with clinical remission a maintenance with Pazopanib until progression was allowed. This trial is registered with ClinicalTrials.gov, number NCT01600573., Results: Between June 2012 and February 2017, 11 patients were enrolled in the phase I, and 50 patients in the phase II study. The MTD of Pazopanib was determined by 400 mg/daily. Haematological and liver toxicities determined the dose limiting toxicities (DLT) and the most common grade 3-4 adverse events: leucopenia (25%), neutropenia (22%), thrombocytopenia (19%), accumulation of cholestatic (20%) and hepatocellular damage (15%), which often caused dose modifications, but no new life-threatening events. Overall response was 16% and clinical benefit rate 68%. Median progression-free survival (PFS) was 3.5 months (95% CI 2.0-5.0). Due to early progression only 20% of the patients were able to start with maintenance treatment., Conclusion: The combination of pazopanib and weekly topotecan is feasible, resulting in a manageable haematological and liver toxicity, but despite its encouraging response rate, was not associated with a significant survival benefit., (© 2023. The Author(s).)

Objective: The quality assurance program for ovarian cancer (QS-OVAR) evaluates the implementation of treatment standards and impact on survival for International Federation of Gynecology and Obstetrics (FIGO) stage I ovarian cancer., Methods: Patients with a first diagnosis of ovarian cancer, diagnosed in the third quarter of 2004, 2008, 2012, and 2016, were documented. Surgical quality was categorized as optimal (maximum one surgical item missing) versus suboptimal (≥2 surgical items missing). Chemotherapy was defined as optimal according to national guidelines. Treatment quality was classified into four categories: surgery and chemotherapy were optimal, optimal surgery and suboptimal chemotherapy, suboptimal surgery and optimal chemotherapy, and surgery and chemotherapy were suboptimal., Results: In total, 19.9% (n=700) of ovarian cancer patients were diagnosed with FIGO stage I. Median age was 60 years (range 18-96), 47.1% had FIGO stage IA and 47.9% had stage IC, with 37.1% high grade serous histology. Optimal surgical quality increased over time from 19.9% to 54.1%. The optimal surgery population increased from 42.2% to 70.9%. Disease free survival improved significantly in the optimal surgery population (84% after 48 months vs 71% in the suboptimal surgery population). Overall survival increased with 91% after 48 months in the optimal surgery population versus 76% in the suboptimal surgery population. In total, 20.7% of patients were undertreated concerning systemic treatment and 1% overtreated. Optimal chemotherapy standard was administered increasingly over time (71.4-80.8%). Disease free survival and overall survival were prolonged with adjuvant chemotherapy. The optimal surgery/chemotherapy subgroup increased from 37.9% to 54.1% with significantly longer disease free survival and overall survival (overall survival at 48 months: optimal surgery and chemotherapy 93%; suboptimal surgery and chemotherapy 68%)., Conclusion: Although QS-OVAR data showed that the quality of therapy has improved over the years, not all surgical standards were met in nearly 50% of patients. The steady increase in the optimal surgery and chemotherapy collective is an important tool for improvement of prognosis of ovarian cancer patients., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) developed consensus statements on pre-invasive vulvar lesions in order to improve the quality of care for patients with vaginal intraepithelial neoplasia (VaIN). The management of VaIN varies according to the grade of the lesion: VaIN 1 (low grade vaginal squamous intraepithelial lesions (SIL)) can be subjected to follow-up, while VaIN 2-3 (high-grade vaginal SIL) should be treated. Treatment needs individualization according to the patient's characteristics, disease extension and previous therapeutic procedures. Surgical excision is the mainstay of treatment and should be performed if invasion cannot be excluded. Total vaginectomy is used only in highly selected cases of extensive and persistent disease. Carbon dioxide (CO 2 ) laser may be used as both an ablation method and an excisional one. Reported cure rates after laser excision and laser ablation are similar. Topical agents are useful for persistent, multifocal lesions or for patients who cannot undergo surgical treatment. Imiquimod was associated with the lowest recurrence rate, highest human papillomavirus (HPV) clearance, and can be considered the best topical approach. Trichloroacetic acid and 5-fluorouracil are historical options and should be discouraged. For VaIN after hysterectomy for cervical intraepithelial neoplasia (CIN) 3, laser vaporization and topical agents are not the best options, since they cannot reach epithelium buried in the vaginal scar. In these cases surgical options are preferable. Brachytherapy has a high overall success rate but due to late side effects should be reserved for poor surgical candidates, having multifocal disease, and with failed prior treatments. VaIN tends to recur and ensuring patient adherence to close follow-up visits is of the utmost importance. The first evaluation should be performed at 6 months with cytology and an HPV test during 2 years and annually thereafter. The implementation of vaccination against HPV infection is expected to contribute to the prevention of VaIN and thus cancer of the vagina. The effects of treatment can have an impact on quality of life and result in psychological and psychosexual issues which should be addressed. Patients with VaIN need clear and up-to-date information on a range of treatment options including risks and benefits, as well as the need for follow-up and the risk of recurrence., Competing Interests: Competing interests: None declared., (© ESGO, ISSVD, EFC, ECSVD 2023. Re-use permitted under CC BY. Published by BMJ.)

Purpose: To evaluate the safety, immunogenicity and efficacy of a therapeutic DNA vaccine VB10.16, using a unique modular vaccine technology that is based on linking antigens to CCL3L1 targeting module, in women with HPV16-positive high-grade cervical intraepithelial neoplasia (CIN)., Patients and Methods: We conducted a first-in-human, open-label, phase I/IIa clinical trial of VB10.16 in subjects with confirmed HPV16-positive CIN 2/3. The primary endpoint was the proportion of participants with adverse events, including dose-limiting toxicities. Secondary outcome measures included measuring the E6/E7-specific cellular immune response. In the Expansion cohort HPV16 clearance, regression of CIN lesion size and grading were assessed during a 12-month follow-up period., Results: A total of 34 women were enrolled: 16 in two dose cohorts and 18 in the expansion cohort. No serious adverse events or dose-limiting toxicities were observed, and none of the subjects discontinued treatment with VB10.16 due to an adverse event. Mild to moderate injection site reactions were the most commonly reported adverse event (79%). HPV16-specific T-cell responses were observed after vaccination in the majority of the subjects. In the expansion cohort, HPV16 clearance was seen in 8 of 17 evaluable subjects (47%). Reductions in lesion size were seen in 16 subjects (94%) and 10 subjects (59%) had regression to CIN 0/1. Correlation between strong IFNγ T-cell responses and lesion size reduction was statistically significant (P < 0.001)., Conclusions: The novel therapeutic DNA vaccine VB10.16 was well tolerated and showed promising evidence of efficacy and strong HPV16-specific T-cell responses in subjects with high-grade CIN., (©2022 American Association for Cancer Research.)

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) developed consensus statements on pre-invasive vulvar lesions in order to improve the quality of care for patients with vulvar squamous intraepithelial neoplasia, vulvar Paget disease in situ, and melanoma in situ. For differentiated vulvar intraepithelial neoplasia (dVIN), an excisional procedure must always be adopted. For vulvar high-grade squamous intraepithelial lesion (VHSIL), both excisional procedures and ablative ones can be used. The latter can be considered for anatomy and function preservation and must be preceded by several representative biopsies to exclude malignancy. Medical treatment (imiquimod or cidofovir) can be considered for VHSIL. Recent studies favor an approach of using imiquimod in vulvar Paget's disease. Surgery must take into consideration that the extension of the disease is usually wider than what is evident in the skin. A 2 cm margin is usually considered necessary. A wide local excision with 1 cm free surgical margins is recommended for melanoma in situ. Following treatment of pre-invasive vulvar lesions, women should be seen on a regular basis for careful clinical assessment, including biopsy of any suspicious area. Follow-up should be modulated according to the risk of recurrence (type of lesion, patient age and immunological conditions, other associated lower genital tract lesions)., Competing Interests: Competing interests: CC: advisory boards for GSK and MSD, support for clinical research from Roche and TherAguiX; DQ: advisory boards for Mimark; EJ: advisory boards for MSD and Roche Diagnostics, grants for traveling from MSD; JB support for clinical research from Merck (Galilee Medical Center Research Fund), member of speakers’ bureau for MSD Israel. BET, BEE, CS, DH, FB, FP, JZ, LW, MB, MEC, MG, MP, MVB, NG, OR, PVB, VK, XC: no conflict of interest., (© IGCS and ESGO 2022. Re-use permitted under CC BY. Published by BMJ.)

Purpose: Major surgery for ovarian cancer is associated with significant morbidity. Recently, guidelines for perioperative care in gynecologic oncology with a structured "Enhanced Recovery after Surgery (ERAS)" program were presented. Our aim was to evaluate if implementation of ERAS reduces postoperative complications in patients undergoing extensive cytoreductive surgery for ovarian cancer., Methods: 134 patients with ovarian cancer (FIGO I-IV) were included. 47 patients were prospectively studied after implementation of a mandatory ERAS protocol (ERAS group) and compared to 87 patients that were treated before implementation (pre-ERAS group). Primary endpoints of this study were the effects of the ERAS protocol on postoperative complications and length of stay in hospital., Results: Preoperative and surgical data were comparable in both groups. Only the POSSUM score was higher in the ERAS group (11.8% vs. 9.3%, p < 0.001), indicating a higher surgical risk in the ERAS group. Total number of postoperative complications (ERAS: 29.8% vs. pre-ERAS: 52.8%, p = 0.011), and length of hospital stay (ERAS: 11 (6-23) vs pre-ERAS: 13 (6-50) days; p < 0.001) differed significantly. A lower fraction of patients of the ERAS group (87.2%) needed postoperative admission to the ICU compared to the pre-ERAS group (97.7%), p = 0.022). Mortality within the ERAS group was 0% vs. 3.4% (p = 0.552) in the pre-ERAS group., Conclusion: The implementation of a mandatory ERAS protocol was associated with a lower rate of postoperative complications and a reduced length of stay in hospital. If ERAS has influence on long-term outcome needs to be further evaluated., (© 2021. The Author(s).)

Objective: At present, maintenance therapy with the antiangiogenic agent bevacizumab or with PARP-inhibitors represent two options for BRCA-wildtype ovarian cancer patients, after platinum-based first line chemotherapy. The identification of molecular markers to predict patient response to different maintenance therapies remains a major challenge. In the present study we analyzed the predictive potential of vascular endothelial growth factor C (VEGF-C) to identify ovarian cancer patients that might benefit from an antiangiogenic therapy., Methods: 101 patients with primary epithelial ovarian cancer were analyzed for serum levels of VEGF-A,-C and CA-125 by ELISA. Serum levels were compared between patients with low pT-stage (pT1a-pT2c n = 11), healthy individuals (n = 27) and patients with higher pT-stage (> = pT3 n = 90). Adjusted ROC curves and an adjusted logistic regression model were carried out to evaluate the potential impact of VEGF-A and -C, as well as CA-125 serum level concentration on bevacizumab-therapy response, under consideration of covariates such as FIGO, pM, pN and residual tumor after surgery., Results: A patient which has in comparison twice the VEGF-C concentration in serum, has a significant increased chance of response to bevacizumab by a factor of 2.79. Further, only VEGF-C serum levels were significantly higher in the group of patients with lower pT-stage compared to healthy individuals, whereas VEGF-A or CA-125 serum levels could not discriminate between healthy individuals and patients with ovarian cancer at low pT-stages., Conclusion: VEGF-C serum level might serve as as a biomarker to evaluate treatment response under bevacizumab., Competing Interests: The authors have declared that no competing interests exist.

The need for pelvic treatment in patients with node-positive vulvar cancer (VSCC) and the value of pelvic lymphadenectomy (LAE) as a staging procedure to plan adjuvant radiotherapy (RT) is controversial. In this retrospective, multicenter analysis, 306 patients with primary node-positive VSCC treated at 33 gynecologic oncology centers in Germany between 2017 and 2019 were analyzed. All patients received surgical staging of the groins; nodal status was as follows: 23.9% (73/306) pN1a, 23.5% (72/306) pN1b, 20.4% (62/306) pN2a/b, and 31.9% (97/306) pN2c/pN3. A total of 35.6% (109/306) received pelvic LAE; pelvic nodal involvement was observed in 18.5%. None of the patients with nodal status pN1a or pN1b and pelvic LAE showed pelvic nodal involvement. Taking only patients with nodal status ≥pN2a into account, the rate of pelvic involvement was 25%. In total, adjuvant RT was applied in 64.4% (197/306). Only half of the pelvic node-positive (N+) patients received adjuvant RT to the pelvis (50%, 10/20 patients); 41.9% (122/291 patients) experienced recurrent disease or died. In patients with histologically-confirmed pelvic metastases after LAE, distant recurrences were most frequently observed (7/20 recurrences). Conclusions: A relevant risk regarding pelvic nodal involvement was observed from nodal status pN2a and higher. Our data support the omission of pelvic treatment in patients with nodal status pN1a and pN1b.

Background: The impact of adjuvant radiotherapy (RT) to the vulva with regard to prognosis and local recurrence in patients with vulvar squamous cell cancer (VSCC) is poorly described., Patients and Methods: In the AGO-CaRE-1 study 1618 patients with primary VSCC FIGO stage ≥ IB, treated between 1998-2008, were documented. In this retrospective subanalysis, 360 patients were included based on the following criteria: nodal involvement (pN+), known RT treatment and known radiation fields., Results: The majority had pT1b/pT2 tumors (n=299; 83.1%). In 76.7%, R0 resection was achieved. 57/360 (15.8%) N+ patients were treated with adjuvant RT to the groins/pelvis and 146/360 (40.5%) received adjuvant RT to the vulva and groins/pelvis. 157/360 (43.6%) patients did not receive any adjuvant RT. HPV status was available in 162/360 patients (45.0%), 75/162 tumors were HPV+(46.3%), 87/162 (53.7%) HPV-. During a median follow-up of 17.2 months, recurrence at the vulva only occurred in 25.5% of patients without adjuvant RT, in 22.8% of patients with adjuvant RT to groins/pelvis and in 15.8% of patients with adjuvant RT to the vulva and groins/pelvis respectively. The risk reducing effect of local RT was independent of the resection margin status. 50% disease free survival time (50% DFST) indicated a stronger impact of adjuvant RT to the vulva in HPV+ compared to HPV- patients (50% DFST 20.7 months vs. 17.8 months)., Conclusion: Adjuvant RT to the vulva was associated with a lower risk for local recurrence in N+ VSCC independent of the resection margin status. This observation was more pronounced in patients with HPV+ tumors in comparison to HPV- tumors., Competing Interests: Declaration of Competing Interest The AGO CaRE-1 study was supported by medac oncology without restriction in protocol or analysis., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

To date, therapeutic strategies in vulvar squamous cell carcinoma (VSCC) are lacking molecular pathological information and targeted therapy hasn't been approved in the treatment of VSCC, yet. Two etiological pathways are widely accepted: HPV induced vs. HPV independent, associated with chronic skin disease, often harboring TP53 mutations (mut). The aim of this analysis was to analyze the RNA expression patterns for subtype stratification on VSCC samples that can be integrated into the previously performed whole exome sequencing data for the detection of prognostic markers and potential therapeutic targets. We performed multiplex gene expression analysis (NanoString) with 770 genes in 24 prior next generation sequenced samples. An integrative data analysis was performed. Here, 98 genes were differentially expressed in TP53mut vs. HPV+ VSCC, in the TP53mut cohort, where 56 genes were upregulated and 42 were downregulated in comparison to the HPV+ tumors. Aberrant expression was primarily observed in cell cycle regulation, especially in HPV+ disease. Within the TP53mut group, a distinct cluster was identified that was correlated to a significantly worse overall survival ( p = 0.017). The RNA expression profiles showed distinct patterns with regard to the known VSCC subtypes and could potentially enable further subclassification in the TP53mut groups.

Methylation of the BRCA1 promoter is an epigenetic gene expression regulator and is frequently observed in ovarian cancer; however, conversion of methylation status is thought to drive disease recurrence. Therefore, longitudinal monitoring of methylation status by liquid biopsy in cell-free DNA may be a predictive marker. In total, 135 plasma samples were collected from 69 ovarian cancer patients before and during systemic treatment. Our liquid biopsy assay could detect down to a single molecule of methylated DNA in a high background of normal DNA (0.03%) with perfect specificity in control samples. We found that 60% of the cancer patients exhibited BRCA1 promoter hypermethylation at one point, although 24% lost hypermethylation during treatment. Multivariate survival analyses indicate that relapses are independent events and that hypermethylation and methylation conversion are independently correlated to longer relapse-free survival. We present a highly sensitive and specific methylation-specific quantitative PCR-based liquid biopsy assay. BRCA1 promoter hypermethylation is frequently found in ovarian cancer and is often reversed upon recurrence, indicating the selection of therapy-resistant clones and unfavorable clinical outcome., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

We investigated the prognostic role of systemic characteristics for cancer exhaustion and the presence of circulating tumor cells (CTCs) in primary epithelial ovarian cancer (EOC) patients. We included 185 patients in this multicenter study with a median follow-up time of 10.25 years. Albumin, c-reactive protein (CRP) and the kynurenine to tryptophan ratio (Kyn/Trp) as well as the CTC-related marker cyclophilin C (PPIC) were obtained before primary therapy and were correlated to the respective clinical and outcome data. The information provided by albumin and Kyn/Trp was integrated in a combined score for cancer exhaustion (CCES). A high CCES characterized by hypoalbuminemia and a high Kyn/Trp was associated with both decreased overall and progression-free survival, independent from other known prognostic factors in a multivariable analysis. The presence of PPIC-positive CTCs was significantly associated with a high CCES, highlighting that the interplay between the systemic microenvironment and CTCs should be considered in "liquid biopsy" biomarker assessment.

Background: As the population at risk for pelvic nodal involvement remains poorly described, the role of pelvic lymphadenectomy (LAE) in vulvar squamous cell cancer (VSCC) has been a matter of discussion for decades., Methods: In the AGO-CaRE-1 study, 1618 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB or higher primary VSCC treated at 29 centers in Germany between 1998 and 2008 were documented. In this analysis, only patients with pelvic LAE (n = 70) were analyzed with regard to prognosis and correlation between inguinal and pelvic lymph node involvement., Results: The majority of patients had T1b/T2 tumors (n = 47; 67.1%), with a median diameter of 40 mm (2-240 mm); 54/70 patients (77.1%) who received pelvic LAE had positive groin nodes. For 42 of these 54 patients, the number of affected groin nodes had been documented as a median of 3; 14/42 (33.3%) of these patients had histologically confirmed pelvic nodal metastases (median number of affected pelvic nodes 3 [1-12]). In these 14 patients, the median number of affected groin nodes was 7 (1-30), with a groin metastases median maximum diameter of 42.5 mm (12-50). Receiver operating characteristic analysis showed an area under the curve of 0.85, with 83.3% sensitivity and 92.6% specificity for the prediction of pelvic involvement in cases of six or more positive groin nodes. No cases of pelvic nodal involvement without groin metastases were observed. Prognosis in cases of pelvic metastasis was poor, with a median progression-free survival of only 12.5 months., Conclusion: For the majority of node-positive patients with VSCC, pelvic nodal staging appears unnecessary since a relevant risk for pelvic nodal involvement only seems to be present in highly node-positive disease., (© 2021. The Author(s).)

Purpose: Post-treatment follow-up in women with cervical pre-cancers (CIN3) is mandatory due to relapse in up to 10% of patients. Standard follow-up based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. The aim of our prospective, multicenter, observational study was to test the hypothesis that an individualized viral-cellular-junction test (vcj-PCR) combined with cytology has a lower false positive rate for the prediction of recurrence compared to standard co-testing., Methods: Pre-surgical cervical swabs served for the identification of HPV16/18 DNA integration sites by next-generation-sequencing (NGS). Samples taken at 6, 12 and 24 months post-surgery were evaluated by cytology, hrHPV-DNA and the patients' individual HPV-integration sites (vcj-PCR on the basis of NGS)., Results: Integration sites were detected in 48 of 445 patients (10.8%), 39 of them had valid follow-up data. The false positive rate was 18.2% (95% CI 8.6-34.4%) for standard hrHPV/cytology at six months compared to 12.1% (95% CI 4.8-27.3%) for vcj-PCR/cytology, respectively (McNemar p = 0.50). Six patients developed recurrences (1 CIN2, 5 CIN3) during follow-up. Standard co-testing detected all, whereas vcj-PCR/cytology detected only five patients with recurrences. Data of 269 patients without evidence of HPV16/18 integration were subject to post-hoc analyses. Standard co-testing revealed a false positive rate of 15.7% (95% CI 11.7-20.7%) and predicted ten of fourteen recurrences at six months., Conclusions: Although highly specific on its own vcj-PCR could not detect all recurrent CIN2/3. Possible reasons for this unexpected result may be multifocal lesions, intratumoral heterogeneity with respect to HPV integration and/or incident CIN.

Background: There are 2 known pathways for tumorigenesis of vulvar squamous cell carcinoma-a human papillomavirus-dependent pathway characterized by p16 overexpression and a human papillomavirus-independent pathway linked to lichen sclerosus, characterized by TP53 mutation. A correlation of human papillomavirus dependency with a favorable prognosis has been proposed., Objective: The objective of the study was to further understand the role of human papillomavirus and p53 status in vulvar squamous cell carcinoma and characterize its clinical relevance., Study Design: The Arbeitsgemeinschaft Gynaecological Oncology Chemo and Radiotherapy in Epithelial Vulvar Cancer-1 study is a retrospective cohort study of 1618 patients with primary vulvar squamous cell carcinoma Fédération Internationale de Gynécologie et d'Obstétrique stage ≥1B treated at 29 gynecologic cancer centers in Germany between 1998 and 2008. For this translational substudy, formalin-fixed paraffin-embedded tissue was collected. A tissue microarray was constructed (n=652 samples); p16 and p53 expression was determined by immunohistochemistry. Human papillomavirus status and subtype were analyzed by polymerase chain reaction., Results: p16 immunohistochemistry was positive in 166 of 550 tumors (30.2%); p53 staining in 187 of 597 tumors (31.3%). Only tumors with available information regarding p16 and p53 immunohistochemistry and without p53 silent expression pattern were further analyzed (n=411); 3 groups were defined: p53+ (n=163), p16+/p53- (n=132), and p16-/p53- (n=116). Human papillomavirus DNA was detected in 85.6% of p16+/p53- tumors; human papillomavirus-16 was the most common subtype (86.3%). Patients with p16+ tumors were younger (64 vs 72 years for p53+, respectively, 69 years for p16-/p53- tumors; P<.0001) and showed lower rates of lymph-node involvement (28.0% vs 42.3% for p53+, respectively, 30.2% for p16-/p53- tumors; P=.050). Notably, 2-year-disease-free and overall survival rates were significantly different among the groups: disease-free survival, 47.1% (p53+), 60.2% (p16-/p53-), and 63.9% (p16+/p53-) (P<.001); overall survival, 70.4% (p53+), 75.4% (p16-/p53-), and 82.5% (p16+/p53-) (P=.002). In multivariate analysis, the p16+/p53- phenotype showed a consistently improved prognosis compared with the other groups (hazard ratio, 0.66; 95% confidence interval, 0.44-0.99; P=.042)., Conclusion: p16 overexpression is associated with an improved prognosis whereas p53 positivity is linked to an adverse outcome. Our data support the hypothesis of a clinically relevant third subgroup of vulvar squamous cell carcinoma with a p53-/p16- phenotype showing an intermediate prognosis that needs to be further characterized., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: We previously reported the prognostic impact of circulating tumor cells (CTCs) in a multicenter study on minimal residual disease in primary ovarian cancer. With additional follow-up data, we evaluated the combined CTC approach (CTCs combo ), in particular for the patients who had survived more than five years., Material and Methods: Blood samples taken at baseline and six months after adjuvant treatment (follow-up) were assessed by quantitative PCR (qPCR) measuring PPIC transcripts and immunofluorescent staining (IF). A positive result with either IF or qPCR was classified as CTC combo -positive. Further, PPIC was assessed in the primary tumor tissue., Results: The concordance of IF and qPCR was 65% at baseline and 83% after treatment. Results showed that 50.5% of the baseline and 29.5% of the follow-up samples were CTC combo -positive. CTCs combo after treatment were associated with increased mortality after adjusting for FIGO stage (HR 2.574, 95% CI: 1.227-5.398, p = 0.012), a higher risk of recurrence after adjusting for peritoneal carcinosis (HR 4.068, 95% CI: 1.948-8.498, p < 0.001), and increased mortality after five survived years., Discussion: The two-sided analytical approach revealed CTC subpopulations associated with ovarian cancer progression and may illuminate a potential treatment-related shift in molecular phenotypes. That approach can identify patients who have elevated risk of recurrence and death due to ovarian cancer and who may require risk-adapted treatment strategies.