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Uterine serous papillary carcinoma (UPSC) is an aggressive tumor, often diagnosed as a metastatic disease and characterized by a high recurrence rate and poor prognosis. UPSC represents a distinct subtype of endometrial cancer which is different in clinical and pathological behaviors from endometrioid endometrial carcinoma (EEC) and resembles more to serous ovarian carcinoma. Since tumors of serous papillary of the ovary are hypothesized to stem from cells of the fallopian tube's fimbria, we hypothesized that UPSC may also origin in the fallopian tubes. In our previous study, using a novel method of computerized morphometry of the fimbrial epithelium we have found significant differences between fimbriae of healthy women and serous ovarian cancer patients. In this study we showed the presence of morphologic differences between twenty-four fimbriae from healthy women, and twenty six fimbriae from uterus cancer (13 from UPSC patients and 13 from EEC patients). All fimbriae reported by the pathologist as \"normal\" were subjected to a computerized histomorphometric analysis. Two-step method of computerized histomorphometry, i.e. Fast Fourier transformation (FFT) followed by a co-occurrence matrix analysis and an additional analysis of the nuclear symmetry of the tubal fimbrial epithelium were applied. Using these novel methods, we were able to show differences in the morphometric characteristics of the fimbriae in UPSC patients compared to EEC and healthy patients. It is yet to be determined the clinical significance of this observation.

Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer. In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) using an interactive voice-response system with integrated web response to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy vs non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2–IIB node positive vs stage III–IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1—by investigator or by histopathologic confirmation of suspected disease progression—and overall survival. Primary analysis was conducted in the intention-to-treat population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants. Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab–chemoradiotherapy group and 531 to the placebo–chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3–22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab–chemoradiotherapy group versus 57% in the placebo–chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55–0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab–chemoradiotherapy group and 81% in the placebo–chemoradiotherapy group (information fraction 42·9%). The HR for death was 0·73 (0·49–1·07); these data have not crossed the boundary of statistical significance. Grade 3 or higher adverse event rates were 75% in the pembrolizumab–chemoradiotherapy group and 69% in the placebo–chemoradiotherapy group. Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer. Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD).

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the field of oncology. For many cancer types, treatment paradigms have changed, as immunotherapy is increasingly being integrated into frontline standard-of-care treatments and producing meaningful and prolonged responses. This has inspired an avalanche of clinical trials studying ICIs in all types of malignancies, including gynecological cancers. Ovarian and endometrial cancers are characterized by DNA damage repair defects, either via disruption of the homologous recombination DNA repair mechanism in the former or via defects in the mismatch repair (MMR) pathway in the latter, which lead to a high load of neoantigens in both. Cervical cancer is dependent on the expression of human papillomavirus (HPV) proteins, which induce an immune response. Regardless, clinical trials testing ICIs in gynecological malignancies have initially led to disappointing results. Despite durable responses in some patients, overall response rates have been dismal. Nevertheless, in recent years, with the development of better predictive tumor biomarkers, such as microsatellite instability for endometrial cancer and programmed death ligand 1 for cervical cancer, ICIs have found their way into routine treatments for patients with advanced-stage disease. ICI-based combinations, although adding toxicity, have further improved response rates, and new combinations are currently being tested in clinical trials, as are other immunotherapy modalities, such as adoptive cell transfer and HPV-based vaccines. This review summarizes current clinical evidence supporting the use of immunotherapy in gynecological malignancies and describes studies in progress, with a focus on ICIs and predictive response biomarkers.

ObjectivesThe need for a sensitive and specific biomarker to detect early disease is essential to revolutionize ovarian cancer treatment. In this study we compared between the levels of CA125 in the serum and in the vaginal secretions of women with and without ovarian cancer. We also compared between the levels of CA125, IL2, IL13, and HE4 in the vaginal fluid in 3 groups: healthy women, patients after chemotherapy before surgery (neoadjuvant) and patients before treatment or surgeryMethodsIn this study we analyzed sixty-five women in our Gynecological Oncology Unit. CA-125 levels in the serum were measured using Human CA125/MUC16 ELISA and Luminex. IL-2, IL-13 and HE4 were analyzed using Luminex.ResultsCA-125 levels were significantly higher in vaginal secretions than in the serum of all groups. There was no statistical difference between the neoadjuvant subgroup compared to the healthy group. We therefore, investigated three additional biomarkers; IL-2, IL-13 and HE4, using only vaginal secretions. Of these, IL-2 and IL-13 showed promising results with statistical significance in differentiating between healthy and ovarian cancer patients. HE4 showed decreased levels in patients that received neoadjuvant treatment that were not significant when compared to the healthy groupConclusionsThis study demonstrates the promise of using vaginal secretions for detection of ovarian cancer. Further research is required.

Introduction/BackgroundPembrolizumab has shown efficacy in patients with cervical cancer. The effect of chemoradiotherapy may be enhanced by immunotherapy. ENGOT-cx11/GOG-3047/KEYNOTE-A18 (NCT04221945) assessed efficacy and safety of pembrolizumab + concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC).MethodologyEligible patients with newly diagnosed, previously untreated, high-risk LACC (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA) were randomized 1:1 to receive 5 cycles of pembrolizumab 200 mg or placebo Q3W + CCRT, then 15 cycles of pembrolizumab 400 mg or placebo Q6W. The CCRT regimen included 5 cycles (with optional sixth dose) of cisplatin 40 mg/m2 Q1W + EBRT then brachytherapy. Patients were stratified by planned EBRT type (IMRT/VMAT vs non-IMRT/non-VMAT), stage at screening (stage IB2-IIB vs III-IVA) and planned total radiotherapy dose. Primary endpoints were PFS per RECIST v1.1 by investigator and OS.Results1060 patients were randomized to pembrolizumab+CCRT (n=529) or placebo+CCRT (n=531). At the protocol-specified first interim analysis (January 9, 2023, data cutoff), median follow-up was 17.9 mo (range, 0.9–31.0). Pembrolizumab+CCRT showed a statistically significant improvement in PFS vs placebo+CCRT. 24-mo PFS was 67.8% with pembrolizumab+CCRT vs 57.3% with placebo+CCRT; median PFS was not reached in either group (HR=0.70 [95% CI, 0.55–0.89; P=0.0020]); results were consistent across all prespecified subgroups. With only 103 events (42.9% maturity), the addition of pembrolizumab to CCRT showed a favorable trend in OS (HR=0.73 [95% CI, 0.49–1.07]); these data have not crossed the boundary of statistical significance. Grade ≥3 TRAE incidence was 67.0% in the pembrolizumab+CCRT group and 60.0% in the placebo+CCRT group.ConclusionPembrolizumab+CCRT showed a statistically significant and clinically meaningful improvement in PFS and a favorable trend in OS compared with placebo+CCRT in patients with high-risk locally advanced cervical cancer and had a manageable safety profile. These data suggest pembrolizumab+CCRT can be considered as a new standard of care for this population.DisclosuresDisclosures are provided via the ESGO COI Disclosure forms.

Background: Missed miscarriage (MM) is a common first-trimester complication. Misoprostol alone achieves moderate success, while combination therapy with mifepristone improves outcomes in spontaneous pregnancies. Evidence in assisted reproductive technology (ART) pregnancies is scarce. We evaluated whether combined mifepristone–misoprostol improves outcomes in ART pregnancies compared with misoprostol alone and compared results with spontaneously conceived (SC) pregnancies. Methods: This retrospective matched cohort study was conducted at a single center (2017–2024). ART pregnancies were matched 1:2 with SC pregnancies by maternal age. Patients received misoprostol alone or 200 mg mifepristone followed 48 h later by misoprostol. The primary outcome was treatment success, defined as complete uterine evacuation without repeat misoprostol or surgery. Secondary outcomes included emergency visits, surgical procedures, and ART-related predictors. Subgroup analyses were performed by ART protocol. Results: Among 307 patients (94 ART, 213 SC), combined therapy yielded higher success than misoprostol alone in SC (84% vs. 71%, p = 0.023) and ART pregnancies (95% vs. 80%, p = 0.035). In hormonally supported frozen embryo transfer (HRT-FET) cycles, success was 100% with combined therapy versus 80% with misoprostol alone. Conclusions: Combined mifepristone–misoprostol is more effective than misoprostol alone, with particularly high success in HRT-FET cycles.