Clinical parameters 137 pPET+ and pPET-

OBJECTIVE:Approximately 15% to 20% of complete hydatidiform moles progress to post-molar gestational trophoblastic neoplasia. The presence of atypical extra-villous trophoblast foci, described in complete hydatidiform moles, has been associated with an increased risk of developing post-molar gestational trophoblastic neoplasia. The primary objective of this study was to evaluate the predictive value of atypical extra-villous trophoblast foci for treatment response in post-molar gestational trophoblastic neoplasia. Secondary objectives were to assess the clinical impact of these foci on disease characteristics, the International Federation of Gynecology and Obstetrics (FIGO) score, disease stage, and human chorionic gonadotropin (hCG) kinetics. METHODS:A retrospective multi-center study was conducted by the Belgian Gestational Trophoblastic Diseases Registry (French-speaking center) between January 2017 and December 2022. All cases of complete hydatidiform mole were centrally reviewed by expert pathologists specialized in placental pathology from 3 university hospitals. Post-molar gestational trophoblastic neoplasia was diagnosed according to FIGO 2000 criteria. Clinical features were compared according to the presence or absence of atypical trophoblast foci. RESULTS:Among 216 patients diagnosed with complete hydatidiform mole, 56 (26%) developed post-molar gestational trophoblastic neoplasia. Atypical extra-villous trophoblast foci were identified in 38 of 56 (68%) cases. Baseline demographic characteristics, including age, were comparable between the 2 groups. Patients with atypical foci more frequently had FIGO scores ≥6 (p =.044) and pulmonary metastases (18.4% vs 5.6%). All patients requiring multi-agent chemotherapy belonged to the atypical foci group (p =.073). Pre-treatment hCG nadir levels were higher, and hCG slopes steeper in the atypical group (p =.0027 and p =.0052). CONCLUSIONS:Post-molar gestational trophoblastic neoplasia arising from complete hydatidiform moles with atypical extra-villous trophoblast foci is more frequently associated with an unfavorable prognosis and the need for multi-agent chemotherapy than disease arising from moles without atypical foci.

Clinical characteristics of patients included in statistical analyses

TUMOR UNIVARIATE and MULTIVARIATE ANALYSIS

BACKGROUND:The PARP inhibitor olaparib is used for first-line maintenance of patients with BRCA-mutated advanced ovarian cancer. We aimed to evaluate the efficacy and safety of pembrolizumab plus chemotherapy followed by pembrolizumab plus olaparib maintenance with or without bevacizumab as first-line treatment for patients with advanced BRCA1/2 non-mutated epithelial ovarian cancer. METHODS:This randomised, double-blind, active-controlled, placebo-controlled, phase 3 trial was conducted at 224 gynaecological oncology centres in 22 countries. Eligible participants were aged 18 years or older; had histologically confirmed stage III-IV epithelial ovarian, primary peritoneal, or fallopian tube cancer with no BRCA mutation; did not receive previous anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy or an agent directed at another stimulatory or coinhibitory T-cell receptor or a PARP inhibitor; had an Eastern Cooperative Oncology Group performance status score of 0 or 1; and evaluable disease as per Response Evaluation Criteria in Solid Tumors (RECIST). After one lead-in chemotherapy cycle, participants were randomly assigned (1:1:1), using an integrated interactive voice and web response system, to receive pembrolizumab plus chemotherapy followed by pembrolizumab plus olaparib maintenance (pembrolizumab-olaparib group); pembrolizumab plus chemotherapy followed by pembrolizumab plus placebo maintenance (pembrolizumab group); or placebo plus chemotherapy followed by placebo maintenance (control group); and could receive bevacizumab at the investigators discretion. Treatment allocation was stratified by PD-L1 combined positive score (CPS <10 vs ≥10), planned bevacizumab use, and surgery status. Planned treatment was intravenous pembrolizumab 200 mg (or matching placebo) every 3 weeks for 35 cycles, carboplatin plus paclitaxel (or docetaxel) chemotherapy according to local standard of care for five cycles, and maintenance oral olaparib 300 mg (or matching placebo) twice per day until discontinuation or up to 2 years. The primary endpoint was progression-free survival, tested first in the CPS (≥10) population and then in the intention-to-treat (ITT) population using a hierarchical testing strategy. This study is registered with ClinicalTrials.gov, NCT03740165 and is complete. FINDINGS:Between Jan 30, 2019, and Aug 6, 2021, 2547 patients were assessed for eligibility, and 1367 were randomly assigned (ITT population) to receive pembrolizumab-olaparib (n=455), pembrolizumab (n=458), or the control (n=454). All participants were female and the median age was 61 years (IQR 52-68). 1084 (79%) of 1364 participants were White, 233 (17%) were Asian, 27 (2%) were of multiple race, 15 (1%) were Black or African American, and 5 (<1%) were American Indian or Alaska Native. At the first interim analysis (Jan 9, 2023; median follow-up 30·1 months [IQR 23·9-37·0]), pembrolizumab-olaparib significantly improved progression-free survival versus the control in the CPS (≥10; HR 0·63 [95% CI 0·49-0·80]; p<0·0001) and ITT populations (HR 0·68 [0·58-0·81]; p<0·0001). At the final analysis (Aug 26, 2024; median follow-up 49·6 months [IQR 43·4-56·5]), progression-free survival with pembrolizumab-olaparib was maintained (HR 0·66 [95% CI 0·53-0·83] in the CPS [≥10] population and 0·71 [0·61-0·84] in the ITT population). Pembrolizumab alone compared with the control group remained non-significant in the CPS (≥10) population (HR 0·95 [0·77-1·19]; p=0·33); therefore, there was no formal testing of progression-free survival in the ITT population. 297 (66%) of 452 participants in the pembrolizumab-olaparib group, 255 (56%) of 456 in the pembrolizumab group, and 232 (51%) of 454 in the control group had a grade 3 or higher treatment-related adverse event; the most common being neutropenia (102 [23%], 78 [17%], and 89 [20%]), anaemia (100 [22%], 59 [13%], and 48 [11%]), and neutrophil count decreased (66 [15%], 66 [15%], 68 [15%]). Serious treatment-related adverse events were reported in 110 (24%) participants in the pembrolizumab-olaparib group, 96 (21%) in the pembrolizumab group, and 39 (9%) in the control group, with the most common being febrile neutropenia (19 [4%], 16 [4%], and nine [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab-olaparib group (cerebral haemorrhage, cholangitis sclerosing, haemophagocytic lymphohistiocytosis, and colitis), and one (<1%) in the pembrolizumab group (gastrointestinal haemorrhage). INTERPRETATION:Pembrolizumab plus chemotherapy followed by maintenance with pembrolizumab-olaparib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy, suggesting that this regimen might have potential for patients with newly diagnosed BRCA non-mutated stage III-IV epithelial ovarian cancer. FUNDING:Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.

PURPOSE:Treatment of locally advanced cervical cancer (LACC) is guided notably by the European Society of Gynaecological Oncology guidelines; unfortunately, relapse remains frequent despite standard chemoradiotherapy and brachytherapy. We evaluated whether histologic assessment of nonmetastatic para-aortic lymph nodes (PAoLN) provides prognostic value in LACC. EXPERIMENTAL DESIGN:Primary tumor and PAoLNs from 137 patients with nonmetastatic LACC were stratified by pretherapeutic 18F-2'-deoxy-2'-fluorodeoxyglucose PET/CT into pelvic PET-positive (pPET+, n = 72) and pelvic PET-negative (pPET-, n = 65) groups. Immunohistochemistry on whole sections assessed germinal centers, CD4+, CD8+, FOXP3+ cells, neutrophils [CD66b+, neutrophil extracellular traps (NET)], and high-endothelial venules (HEV). Associations with progression-free survival (PFS) were examined via uni- and multivariate analyses after a median follow-up of 55.4 months. RESULTS:The primary tumor profile was not associated with outcome, whereas PAoLN features were strongly predictive. In pPET- patients, higher NETs were associated with shorter PFS [P = 0.015; hazard ratio (HR) = 2.768], whereas an elevated CD4/CD8 ratio improved outcomes (P = 0.047, HR = 0.497). In pPET+ patients, shorter PFS was linked to FOXP3+ (P = 0.04, HR = 1.918) and proliferating FOXP3+ cell (P = 0.018, HR = 1.668) density. Across the full cohort, abundant germinal centers (P = 0.0355, HR = 0.273) and an elevated CD4/CD8 ratio (P = 0.001, HR = 0.490) independently correlated with lower recurrence risk. Internal validation was conducted through a bootstrap resampling method. Combinatorial analyses revealed distinct predictive signatures according to pPET status: higher NETs, fewer germinal centers, and International Federation of Gynaecology and Obstetrics IIA1 to IIIB status predicted relapse in pPET- patients. CONCLUSIONS:Integrating pPET status with PAoLN histologic analyses improves recurrence risk stratification in LACC. PAoLN evaluation may serve as a complementary tool to guide treatment intensification and surveillance strategies.

Comparison of the model performance after inclusion of continuous PET-derived features

Illustrative IHC of studied PAoLN biological parmaeters

Among mammals, our species is the one whose females pay the heaviest price during parturition. Maternal morbidity and mortality remain a major global public health issue.Recent advances in paleoanthropology and evolutionary biology have shed new light on the complexity and dangerousness of childbirth in modern humans, compared with the great apes. This evolutionary conception invites us to understand and represent obstetrical pathology differently.

Cervical cancer remains the fourth most common cancer in women. Recognition of the involvement of viral infection by human papillomavirus (HPV) in the carcinogenesis of lesions has enabled the evolution and adaptation of screening methods. Early detection of pre-invasive lesions and their treatment ultimately led to a reduction in the incidence and mortality of cervical cancer. In Belgium, the transition to primary screening is validated since January 1st, 2025. Let us nevertheless remember the importance of primary prevention through recommended vaccination for girls and boys.