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Simple Summary: Surgery is the cornerstone in the treatment of most gynecological cancers and is associated with significant risks. Gynecological cancer patients are generally elderly, overweight, and have a sedentary lifestyle, which are all factors associated with surgical complications. Prehabilitation entails the optimizing of a patient's condition prior to surgery, and has been introduced with the goal of improving postoperative outcomes and recovery. A prehabilitation program has been implemented at an academic hospital in The Netherlands and comprises a physical exercise intervention, nutritional intervention, psychological intervention, and an intoxication cessation program. In this study, we assessed the feasibility of this program in terms of recruitment, adherence, and safety of implementation into the standard care of gynecological oncology patients. The principal finding was that the implementation of a prehabilitation program for gynecological oncology patients is feasible, with high recruitment and adherence rates. In addition, we did not encounter any major adverse events, suggesting its safety. Prehabilitation is an upcoming strategy to optimize patient's functional capacity, nutritional status, and psychosocial well-being in order to reduce surgical complications and enhance recovery. This study aims to assess the feasibility of implementing a multimodal prehabilitation program into the standard care of gynecological oncology patients at an academic hospital in terms of recruitment, adherence, and safety, which were assessed by the number of patients eligible, recruitment rate, participation rate, and adherence to individual modalities. Data were derived from the F4S PREHAB trial, a single-center stepped-wedge trial implementing a multimodal prehabilitation program among various surgical specialties. All patients undergoing elective surgery as part of treatment for ovarian, uterine, and vulvar cancer at the Radboudumc, an academic hospital in The Netherlands, between May 2022 and September 2023 were considered eligible for the F4S PREHAB trial and, consequently, were included in this cohort study. The multimodal prehabilitation program comprised a physical exercise intervention, nutritional intervention, psychological intervention, and an intoxication cessation program. A total of 152 patients were eligible and approached for participation of which 111 consented to participate, resulting in a recruitment rate of 73%. Participants attended an average of six exercise sessions and adhered to 85% of possible training sessions. Respectively, 93% and 98% of participants adhered to the prescribed daily protein and vitamin suppletion. Ten participants were referred to a psychologist and completed consultations. Out of nine active smokers, two managed to quit smoking. A total of 59% adhered to alcohol cessation advice. No adverse events were reported. This study demonstrates that introducing a multimodal prehabilitation program into the standard care of gynecological oncology patients is feasible in terms of recruitment and adherence, with no serious adverse events. [ABSTRACT FROM AUTHOR]

The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin to interval cytoreductive surgery improves recurrence‐free (RFS) and overall survival (OS) in patients with stage III ovarian cancer. Homologous recombination deficient (HRD) ovarian tumors are usually more platinum sensitive. Since hyperthermia impairs BRCA1/2 protein function, we hypothesized that HRD tumors respond best to treatment with HIPEC. We analyzed the effect of HIPEC in patients in the OVHIPEC trial, stratified by HRD status and BRCAm status. Clinical data and tissue samples were collected from patients included in the randomized, phase III OVHIPEC‐1 trial. DNA copy number variation (CNV) profiles, HRD‐related pathogenic mutations and BRCA1 promotor hypermethylation were determined. CNV‐profiles were categorized as HRD or non‐HRD, based on a previously validated algorithm‐based BRCA1‐like classifier. Hazard ratios (HR) and corresponding 99% confidence intervals (CI) for the effect of RFS and OS of HIPEC in the BRCAm, the HRD/BRCAwt and the non‐HRD group were estimated using Cox proportional hazard models. Tumor DNA was available from 200/245 (82%) patients. Seventeen (9%) tumors carried a pathogenic mutation in BRCA1 and 14 (7%) in BRCA2. Ninety‐one (46%) tumors classified as BRCA1‐like. The effect of HIPEC on RFS and OS was absent in BRCAm tumors (HR 1.25; 99%CI 0.48‐3.29), and most present in HRD/BRCAwt (HR 0.44; 99%CI 0.21‐0.91), and non‐HRD/BRCAwt tumors (HR 0.82; 99%CI 0.48‐1.42), interaction P value: 0.024. Patients with HRD tumors without pathogenic BRCA1/2 mutation appear to benefit most from treatment with HIPEC, while benefit in patients with BRCA1/2 pathogenic mutations and patients without HRD seems less evident. [ABSTRACT FROM AUTHOR]

Simple Summary: Surgery is an important mainstay in the treatment of gynaecological cancers but is associated with operative complications, especially for those with poor physical and mental health. Prehabilitation is a new and upcoming strategy to optimise patients' functional capacity, nutritional status and psychosocial wellbeing in order to reduce complications and enhance recovery. In this review, we assessed the evidence on prehabilitation programmes for patients with gynaecological cancer. The limited evidence shows that prehabilitation may reduce length of hospital stay for ovarian cancer patients, and may result in significant weight loss in patients with endometrial and cervical cancer. Comparative prospective studies are required to determine the effectiveness of prehabilitation on reducing operative complications and improving quality of life, and to further specify the content of such a programme for patients with gynaecological cancer. The literature evaluating the effect of prehabilitation programmes on postoperative outcomes and quality of life of patients with gynaecological cancer undergoing surgery was reviewed. Databases including Pubmed, Medline, EMBASE (Ovid) and PsycINFO were systematically searched to identify studies evaluating the effect of prehabilitation programmes on patients with gynaecological cancer. Both unimodal and multimodal prehabilitation programmes were included encompassing physical exercise and nutritional and psychological support. Primary outcomes were surgical complications and quality of life. Secondary outcomes were anthropometric changes and adherence to the prehabilitation programme. Seven studies fulfilled the inclusion criteria, comprising 580 patients. Included studies were nonrandomised prospective studies (n = 4), retrospective studies (n = 2) and one case report. Unimodal programmes and multimodal programmes were included. In patients with ovarian cancer, multimodal prehabilitation resulted in significantly reduced hospital stay and time to chemotherapy. In patients with endometrial and cervical cancer, prehabilitation was associated with significant weight loss, but had no significant effects on surgical complications or mortality. No adverse events of the programmes were reported. Evidence on the effect of prehabilitation for patients with gynaecological cancer is limited. Future studies are needed to determine the effects on postoperative complications and quality of life. [ABSTRACT FROM AUTHOR]

Introduction Hyperthermic intraperitoneal chemotherapy (HIPEC) improved investigator-assessed recurrence-free survival and overall survival in patients with stage III ovarian cancer in the phase III OVHIPEC-1 trial. We analyzed whether an open-label design affected the results of the trial by central blinded assessment of recurrence-free survival, and tested whether HIPEC specifically targets the peritoneal surface by analyzing the site of disease recurrence. Methods OVHIPEC-1 was an open-label, multicenter, phase III trial that randomized 245 patients after three cycles of neoadjuvant chemotherapy to interval cytoreduction with or without HIPEC using cisplatin (100 mg/m2). Patients received three additional cycles of chemotherapy after surgery. Computed tomography (CT) scans and serum cancer antigen 125 (CA125) measurements were performed during chemotherapy, and during follow-up. Two expert radiologists reviewed all available CT scans. They were blinded for treatment allocation and clinical outcome. Central revision included Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 measurements and peritoneal cancer index scorings at baseline, during treatment, and during follow-up. Time to centrally-revised recurrence was compared between study arms using Cox proportional hazard models. Subdistribution models compared time to peritoneal recurrence between arms, accounting for competing risks. Results CT scans for central revision were available for 231 patients (94%) during neoadjuvant treatment and 212 patients (87%) during follow-up. Centrally-assessed median recurrence-free survival was 9.9 months in the surgery group and 13.2 months in the surgery+HIPEC group (HR for disease recurrence or death 0.72, 95% CI 0.55 to 0.94; p=0.015). The improved recurrence-free survival and overall survival associated with HIPEC were irrespective of response to neoadjuvant chemotherapy and baseline peritoneal cancer index. Cumulative incidence of peritoneal recurrence was lower after surgery+HIPEC, but there was no difference in extraperitoneal recurrences. Conclusion Centrally-assessed recurrence-free survival analysis confirms the benefit of adding HIPEC to interval cytoreductive surgery in patients with stage III ovarian cancer, with fewer peritoneal recurrences. These results rule out radiological bias caused by the open-label nature of the study. [ABSTRACT FROM AUTHOR]

Objective: To evaluate consecutive vaginal radical trachelectomies (VRTs) in early-stage cervical cancer in the 2 main referral centers for fertility-preserving surgery in the Netherlands. Materials and Methods: Oncology, fertility, and obstetrical data were recorded in a regional database of all VRTs without neoadjuvant chemotherapy performed in 2 major referral centers between 2000 and 2015. Results: Most of the patients (91.7%) had stage IB1 disease. In 72.0%, squamous cell carcinoma was the histologic diagnosis; in 24.2%, adenocarcinoma; and in 3.8%, adenosquamous carcinoma. The median follow-up was 51 months. Nine (6.8%) recurrences occurred, 4 resulting in death of disease (death rate, 3.0%). Recurrence rates were 12.5% for adenocarcinoma, 20% for adenosquamous carcinoma, and 4.2% for squamous cell carcinoma (P < 0.01). From 117 women, data about fertility and obstetrical outcome were obtained. Almost 60% of women attempted to conceive after a VRT. Of these women, 40% needed fertility treatment. A total of 47 pregnancies were established, and a total of 37 children were born of which 30 (81.1%) were delivered after 32 weeks of gestational age. Conclusions: Nonsquamous cell histology and high-grade disease are associated with a significantly higher risk of recurrence in the univariate and multivariate analyses. Women with both these histology features should be counseled reticently for VRT. Pregnancies after VRT must be regarded as high-risk pregnancies with a high prematurity rate. [ABSTRACT FROM AUTHOR]

The article presents a study which investigated whether mixed compared with pure uterine papillary serous carcinoma histology impacts clinical outcome and assessed uterine papillary serous carcinoma for its link to the precursor lesion endometrial intraepithelial carcinoma. Patients with pure uterine papillary serous carcinoma had a 2.9-times greater risk for recurrence and a 2.6-times greater risk of death compared with those with mixed uterine papillary serous carcinoma.

The pathogenesis of serous ovarian carcinoma (SOC) is still unknown. Recently, endometrial intraepithelial carcinoma (EIC) was proposed to be the precursor lesion of SOC. This study examines the model of EIC as precursor for SOC.Cases of SOC with a noninvasive or superficially invasive serous lesion, a hyperplastic lesion with/without atypia, or EIC in the endometrium were selected for inclusion in this study. Tissue sections from both ovaries, the fallopian tubes, and the uterus were extensively reviewed by an expert gynecopathologist. For both EIC and SOC, immunostaining for p53, Ki-67, estrogen receptor, and progesterone receptor; TP53 mutation analysis; and in situ ploidy analysis were performed.Nine cases of SOC with concurrent EIC in the endometrium were identified. Immunostaining for p53, Ki-67, estrogen receptor, and progesterone receptor revealed almost identical expression patterns and similar intensities in each pair of EIC and coincident SOC. Identical TP53 mutations were found in SOC and coinciding EIC in 33% of the cases, suggesting a clonal origin. DNA ploidy analysis, as a marker for neoplastic progression, demonstrated an increased number of aneuploid nuclei in SOC compared to their corresponding EIC (P = 0.039). In addition, the mean amount of DNA per nucleus in SOC was higher (ie, more aneuploid) compared to EIC (P = 0.039).This study provides a first indication of EIC as possible precursor lesion for SOC. This finding could have major clinical implications for future ovarian cancer management and underscores EIC as a possible target for early SOC detection and prevention. [ABSTRACT FROM AUTHOR]

Objective: Ovarian cancer is the fifth cause of cancer-related death among women. The benefit of targeted therapy for ovarian cancer patients is limited even if treatment is stratified by molecular signature. There remains a high unmet need for alternative diagnostics that better predict targeted therapy, as current diagnostics are generally inaccurate predictors. Quantitative assessment of functional signal transduction pathway (STP) activity from mRNA measurements of target genes is an alternative approach. Therefore, we aim to identify aberrantly activated STPs in tumour tissue of patients with recurrent ovarian cancer and start phenotype -guided targeted therapy to improve survival without compromising quality of life., Study Design: Patients with recurrent ovarian cancer and either 1) have platinum-resistant disease, 2) refrain from standard therapy or 3) are asymptomatic and not yet eligible for standard therapy will be included in this multi-centre prospective cohort study with multiple stepwise executed treatment arms. Targeted therapy will be available for patients with aberrantly high functional activity of the oestrogen receptor, androgen receptor, phosphoinositide 3-kinase or Hedgehog STP. The primary endpoint of this study is the progression-free survival (PFS) ratio (PFS2/PFS1 ratio) according to RECIST 1.1 determined by the PFS on matched targeted therapy (PFS2) compared to PFS on prior therapy (PFS1). Secondary endpoints include among others best overall response, overall survival, side effects, health-related quality of life and cost-effectiveness., Conclusion: The results of this study will show the clinical applicability of STP activity in selecting recurrent ovarian cancer patients for effective therapies., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jurgen Piek reports equipment, drugs, or supplies was provided by InnoSIGN. Phyllis van der Ploeg reports a relationship with Catharina Research Fund that includes: funding grants. Cynthia Hendrikse reports a relationship with Catharina Research Fund that includes: funding grants. Phyllis van der Ploeg reports a relationship with InnoSIGN that includes: funding grants. Cynthia Hendrikse reports a relationship with InnoSIGN that includes: funding grants., (© 2024 The Authors. Published by Elsevier Ltd.)

Objective: Complication rates after cytoreductive surgery are important quality indicators for hospitals that treat patients with advanced-stage ovarian cancer. Case-mix factors are patient and tumor characteristics that may influence hospital outcomes such as the complication rates. Currently, no case-mix adjustment model exists for complications after cytoreductive surgery; therefore, it is unclear whether hospitals are being compared correctly. This study aims to develop the first case-mix adjustment model for complications after surgery for advanced-stage ovarian cancer, enabling an accurate comparison between hospitals., Methods: This population-based study included all patients undergoing cytoreductive surgery for advanced-stage ovarian cancer registered in the Netherlands in 2017-2019. Case-mix variables were identified and assessed using logistic regressions. The primary outcome was the composite outcome measure 'complicated course'. Patients had a complicated course when at least one of the following criteria were met: (1) any complication combined with a prolonged length of hospital stay; (2) complication requiring reintervention; (3) any complication with a prolonged length of stay in the intensive care unit; or (4) 30-day mortality or in-hospital mortality during admission following surgery. Inter-hospital variation was analyzed using univariable and multivariable logistic regressions and visualized using funnel plots., Results: A total of 1822 patients were included, of which 10.7% (n=195) had a complicated course. Comorbidity and tumor stage had a significant impact on complicated course rates in multivariable logistic regression. Inter-hospital variation was not significant for case-mix factors. Complicated course rates ranged between 2.2% and 29.1%, and case-mix adjusted observed/expected ratios ranged from 0.20 to 2.67 between hospitals. Three hospitals performed outside the confidence intervals for complicated course rates. These hospitals remained outliers after case-mix adjustment., Conclusion: There is variation between hospitals regarding complicated course rates after cytoreductive surgery for ovarian cancer in the Netherlands. While comorbidity and tumor stage significantly affected the complicated course rates, adjusting for case-mix factors did not significantly affect hospital outcomes. The limited impact of case-mix adjustment could be a result of the Dutch centralized healthcare model., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Standard treatment for International Federation of Gynecology and Obstetrics (FIGO) 2018 stage 1B2 cervical cancer (i.e., tumor size between 2 and 4 cm) is a radical hysterectomy (RH) with pelvic lymph node dissection (PLND). We evaluated the oncological and fertility outcomes treatment in patients receiving a fertility-sparing alternative consisting of neoadjuvant chemotherapy (NACT) followed by vaginal radical trachelectomy (VRT)., Methods: Patients with stage 1B2 cervical cancer who wished to preserve fertility were included from September 2009 to September 2018. NACT consisted of 6-week cycles of cisplatin or carboplatin with paclitaxel. If tumor size decreased to 2 cm or smaller, NACT was followed by a robot-assisted PLND and VRT., Results: Eighteen patients were included. Median follow-up time was 49.7 months (range 11.4-110.8). Median tumor size was 32 mm (range 22-40 mm). Complete remission after NACT occurred in seven women. Four women had a poor response on NACT. Three underwent RH with PLND; one received chemoradiation after PLND instead of VRT because of positive lymph nodes. The remaining 14 patients received VRT 3-4 weeks after NACT. Four recurrences occurred: three after NACT and VRT and one after NACT and RH. Median time to recurrence was 20.8 months (range 17.0-105.7). Three recurrences occurred in women with adenocarcinoma with lymph vascular space invasion (LVSI). In four women fertility could not be preserved. To date, four women had six pregnancies, including three live births born at term, two first trimester miscarriages, and one currently ongoing pregnancy., Conclusion: NACT and VRT in women with stage 1B2 cervical cancer showed promising results. In 78% fertility was preserved. However, patients with poor response on NACT and with adenocarcinoma and/or LVSI were possibly at risk for recurrence. Long-term results in relation to fertility and oncological outcome are needed to corroborate these findings., Implications for Practice: Standard treatment for women with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage 1B2 cervical cancer (tumor size 2-4 cm) is a radical hysterectomy and pelvic lymph node dissection (PLND). However, many of these women are young and wish to preserve fertility. Data on fertility-sparing treatment options are sparse, but neoadjuvant chemotherapy followed by a vaginal radical trachelectomy and PLND could be an alternative. Since 2009 we performed an observational cohort study in which 18 women opted for this treatment in our center. In 14 women fertility could be preserved. In four patients the tumor recurred. In four women six pregnancies occurred. After careful selection this treatment could be a good fertility-sparing treatment option., (© 2020 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Women who carry a BRCA mutation have a greatly increased risk for serous ovarian carcinoma and tubal carcinoma. Since preventative ovarian screening is not effective, these women are advised to undergo prophylactic bilateral salpingo-oophorectomy (pBSO) around the age of 40 years. Following pBSO, hormone replacement therapy is advisable up to the age of 45-50 years, with the exception of those women with a history of breast cancer. The advice for women with a familial history of ovarian carcinoma but without the BRCA mutation is less clear. Based on data from the literature, we suggest considering pBSO only in women with at least two first or second degree family members with epithelial ovarian carcinoma. pBSO is not indicated in women from families without a BRCA mutation who have no family members, or just one family member, with epithelial ovarian carcinoma. In these families the lifetime risk for ovarian cancer is considered to be well below 10%.

The need for accurate genotyping of human papillomavirus (HPV) infections is becoming increasingly important, since (i) the oncogenic potential among the high-risk HPV genotypes varies in the pathogenesis of cervical cancer, (ii) monitoring multivalent HPV vaccines is essential to investigate the efficiency of the vaccines, and (iii) genotyping is crucial in epidemiologic studies evaluating HPV infections worldwide. Various genotyping assays have been developed to meet this demand. Comparison of different studies that use various HPV genotyping tests is possible only after a performance assessment of the different assays. In the present study, the SPF(10) LiPA version 1 and the recently launched Roche Linear Array HPV genotyping assays are compared. A total of 573 liquid-based cytology samples were tested for the presence of HPV by a DNA enzyme immunoassay; 210 were found to be positive for HPV DNA and were evaluated using both genotyping assays (163 with normal cytology, 22 with atypical squamous cells of undetermined significance, 20 with mild/moderate dysplasia, and 5 with severe dysplasia). Comparison analysis was limited to the HPV genotype probes common to both assays. Of the 160 samples used for comparison analysis, 129 (80.6%) showed absolute agreement between the assays (concordant), 18 (11.2%) showed correspondence for some but not all genotypes detected on both strips (compatible), and the remaining 13 (8.2%) samples did not show any similarity between the tests (discordant). The overall intertest comparison agreement for all individually detectable genotypes was considered very good (kappa value, 0.79). The genotyping assays were therefore highly comparable and reproducible.

Certain high-risk (HR) human papillomavirus (HPV) types are a necessary cause for the development of cervical disorders. Women with persistent HR HPV infections have an increased risk of developing high-grade cervical lesions, compared with those who have no or low-risk HPV infections. Therefore, implementation of HPV detection into cervical screening programs might identify women at risk of cervical cancer. Several HPV detection methods with different sensitivities and specificities are available. Recently, a new PCR-based technique, the Roche AMPLICOR HPV Test, was developed. This test recognizes a group of 13 HR HPV types simultaneously. This study was undertaken to validate and compare HPV detection in 573 cervical scrape specimens by the AMPLICOR HPV Test and the INNO-LiPA HPV detection/genotyping assay (SPF10-LiPA system version 1). Human beta-globin was not detected in nine specimens, which were therefore excluded from the comparison. Eleven scrape specimens containing HPV type 53 or 66 were also excluded from the comparison because these (probably) HR HPV types cannot be detected by the AMPLICOR HPV Test. The results of HPV detection by the Roche AMPLICOR HPV Test were confirmed by INNO-LiPA HPV detection/genotyping assay in 539/553 cases, showing an absolute agreement of 97.5% with a Cohen's kappa of 0.9327, indicating almost complete similarity of the two tests. Like the INNO-LiPA HPV detection/genotyping assay, the AMPLICOR HPV Test was sensitive, specific, feasible, and easy to handle. The value of the Roche AMPLICOR HPV Test with a broad-spectrum HR HPV detection has to be determined in prospective clinical studies.