BackgroundOvarian carcinosarcoma (OCS), also known as malignant mixed Müllerian tumor, is a rare and highly aggressive subtype of epithelial ovarian cancer, accounting for less than 4% of all cases. It typically presents at advanced stages and is associated with dismal outcomes, with a five-year survival rate below 30%. Despite improvements in cytoreductive surgery and systemic therapies, long-term survival in stage IV disease remains exceedingly uncommon.Case presentationWe report two exceptional cases of stage IVB Müllerian carcinosarcoma occurring in BRCA wild-type postmenopausal women who achieved prolonged complete remission exceeding five years after multimodal management. The first patient, aged 61, presented with bilateral adnexal masses and a solitary pulmonary metastasis. She underwent primary cytoreductive surgery including hysterectomy, bilateral adnexectomy, lymphadenectomy, appendicectomy, and omentectomy, followed by six cycles of platinum-taxane chemotherapy. Residual pulmonary disease was later removed via video-assisted thoracoscopic lobectomy, confirming metastatic OCS. Post-recurrence, she received off-label maintenance with tamoxifen 20 mg daily for five years and remains disease-free at 70 months. The second patient, aged 70, presented with a pelvic mass invading the recto-sigmoid wall and a synchronous hepatic metastasis. She underwent extensive cytoreductive surgery including hysterectomy, en-bloc rectal resection, lymphadenectomy, cholecystectomy, and liver wedge resection, achieving complete macroscopic cytoreduction. Histology confirmed a Müllerian carcinosarcoma with a predominant endometrioid component. Postoperative chemotherapy with carboplatin-paclitaxel was followed by maintenance niraparib 100 mg twice daily for three years. She remains in complete remission at 60 months.DiscussionBoth patients demonstrate durable disease control in the absence of germline or somatic BRCA mutations, suggesting that long-term remission may be achievable even in BRCA-wild-type OCS through optimal surgery and individualized maintenance approaches. Tamoxifen, rarely employed in this setting, may have provided estrogen-receptor-mediated tumor suppression in the first case, while the second case highlights potential activity of PARP inhibition beyond BRCA mutation carriers.ConclusionThese two reports challenge the long-held perception of uniformly poor outcomes in metastatic ovarian carcinosarcoma. Complete cytoreductive surgery combined with tailored systemic and maintenance therapies can achieve sustained remission even in advanced-stage BRCA-wild-type patients. Broader molecular profiling and international collaboration are essential to refine management strategies for this rare and aggressive malignancy.

BACKGROUND:Retrospective analyses of niraparib trials showed that baseline platelets and weight were associated with occurrence of G ≥ 3 thrombocytopenia. A rational adjustment of dose to reduce adverse reactions (RADAR) strategy was never prospectively compared with standard dose. METHODS:NEWTON aimed to evaluate the safety of niraparib RADAR dosing strategy in pts with platinum-sensitive, high-grade serous and endometroid ovarian, fallopian tube, or primary peritoneal cancer, as well as in pts with ovarian cancer and a germline or somatic BRCA mutation, irrespective of histologic subtype. Pts with weight≥ 58 and < 77 kg, or ≥ 77 kg with platelet count < 150,000/μL were randomized to receive niraparib 200 mg (RADAR) or 300 mg (standard). Pts < 58 kg were assigned to 200 mg (RADAR), and pts ≥ 77 kg with baseline platelet count ≥ 150,000/μL were assigned to 300 mg (RADAR). For pts assigned to 200 mg, in the absence of thrombocytopenia, severe neutropenia or anemia within cycle 3, dose escalation to 300 mg was considered at cycle 4. The primary endpoint was G ≥ 3 thrombocytopenia within cycle 3. RESULTS:48 pts were randomized to RADAR or standard dose (300 mg/day) and 34 pts were assigned to RADAR without randomization. A total of 58 pts was included in the entire RADAR cohort. In the randomized part, a lower G≥ 3 thrombocytopenia incidence was observed in the RADAR compared to standard arm (4.2%, vs 41.7%, corresponding to a difference of -37.5%, 72%CI -49.2; -25.8, Z-test p= 0.0044). In the RADAR cohort, 6 pts out of 57 had G≥ 3 thrombocytopenia (10.5%, 70% CI: 5.2-18.6;). Median PFS was 10.3 and 11.7 months in the randomized RADAR and 300 mg arms. The median PFS in the entire RADAR cohort was 10.0 months. CONCLUSIONS:Niraparib RADAR dosing is associated with a lower incidence of severe thrombocytopenia. CLINICALTRIALS:gov number: NCT03891576.

e17547 Background: Sensitive detection of minimal residual disease (MRD) and longitudinal monitoring of treatment response remain critical unmet needs in advanced epithelial ovarian cancer (EOC). ALMA (Agnostic Liquid Biopsy Multi-modal Advancement) is a tumor-agnostic circulating cell-free DNA (cfDNA) platform that integrates multiple orthogonal features—tumor fraction (TF), fragmentomic profile, methylation patterns, and somatic copy number alterations (SCNAs)—to improve MRD detection and disease monitoring. Here, we assessed the clinical feasibility of ALMA in patients with advanced EOC who underwent cytoreductive surgery and were treated with platinum-based chemotherapy plus bevacizumab, with or without olaparib as maintenance therapy within the phase IV IOLANTHE trial (NCT06121401). Methods: Plasma samples were prospectively collected at predefined longitudinal time points. Baseline samples were obtained from all patients prior to any surgical intervention or chemotherapy. A second time point was collected following surgery, either primary debulking (PD) or interval debulking (ID). Additional samples were collected at the end of chemotherapy and at 12 weeks after initiation of maintenance therapy. Whole-genome cfDNA sequencing was performed using a dual strategy: low-pass WGS for TF estimation, fragmentomic profiling, and SCNA detection, and bisulfite-free methylation sequencing (cf-MBD-seq) for genome-wide methylation analysis. To date, the enrollment of IOLANTHE trial has been completed, and 192 patients were included. Results: A total of 55 longitudinal plasma samples were analyzed from 32 patients. Following size-based ctDNA enrichment, TF detection was achieved in 100% of analyzed samples. Mean TF decreased longitudinally from 17.28% at baseline (n=25), to 6.31% after PD or ID surgery (n=19), 5.08% at completion of chemotherapy (n=8), and 3.80% at 12 weeks of maintenance therapy (n=3). Genome-wide methylation profiling identified 2857 differentially methylated regions (adjusted p<0.01), of which 68% were located within CpG islands, predominantly in promoter regions. Conclusions: The ALMA approach proved to be feasible. Analyses of further cases are in progress and the results are expected to be presented at the meeting. Clinical trial information: NCT06121401 .

Niraparib was approved in the EU in 2017 as maintenance treatment for platinum-sensitive, recurrent ovarian cancer, and in 2020 as first-line maintenance after response to platinum-based chemotherapy. Results from a prospective, noninterventional, single-arm, postauthorization safety study characterizing the risk of developing myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) and other second primary malignancies (SPMs) in patients treated with niraparib in routine clinical practice are reported. Adult patients with epithelial ovarian cancer from Germany, Italy, the Netherlands, and Spain who received niraparib maintenance were enrolled. Patients were followed from niraparib initiation (index date) to the earliest of study completion at 5 years’ follow-up, study discontinuation, death, or final database lock (July 11, 2024). Incidence of MDS/AML, and other SPMs were reported, and treatment-emergent adverse events were summarized. Analyses were stratified by niraparib maintenance treatment line. Overall, 745 patients (181 first-line maintenance; 564 recurrent) were enrolled and included in this analysis (median age, 65 years; stage III/IV at diagnosis, 89.5

Background/Objectives: Cancer immunotherapy through the use of PD-1/PD-L1 inhibitors have shown significant promise in endometrial carcinoma (EC), particularly in tumors with microsatellite instability (MSI) or mismatch repair deficiency (dMMR), present in approximately 30% of cases. This review evaluated PD-L1 and PD-1 expression as potential biomarkers for immunotherapy response in EC, focusing on their relationship with MSI status. Methods: A systematic review, adhering to PRISMA guidelines, analyzed studies from MEDLINE and Embase until February 2023 on PD-1/PD-L1 expression in EC stratified by MSI status, including diverse study designs but excluding conference abstracts, with independent screening, data extraction, and additional reference checks to ensure comprehensive coverage. Results: A systematic analysis of 10 studies found that PD-L1 expression was more frequently expressed in MSI tumors (49%) compared to microsatellite-stable tumors (MSS) (33.5%), while PD-1 was expressed in 58% of MSI cases and 48% of MSS cases. Despite these findings, the prognostic value of PD-L1/PD-1 remains uncertain, with conflicting results regarding their association with survival outcomes. PD-L1 expression varied across molecular subtypes, being highest in POLE-mutated tumors (76.56%) and serous carcinomas (73%). Differences in PD-L1 expression between primary and metastatic sites were also noted, complicating its use as a biomarker. Conclusions: The assessment of PD-L1 expression in EC could represent a valuable option for selecting patients who may benefit from immune checkpoint inhibitors (ICI), including those in the MSS cohort, thereby ensuring a more tailored and personalized treatment strategy.

The treatment of Epithelial Ovarian cancer (EOC) could benefit from the addition of bevacizumab (BEV) to standard chemotherapy in selected patients. Gene expression (GE) profiling and the evaluation of immune infiltration are used to define patients’ prognosis. However, their role as prognostic and/or predictive biomarkers for the efficacy of antiangiogenic therapy efficacy remains uncertain. In this study, we combined GE profiling and multiplex immunofluorescence (MIF) analyses on material from patients enrolled in the phase IV MITO16A/MaNGO OV-2 trial, assessing associations between immune infiltrate and patients’ prognosis. Patients were stratified into four molecular subtypes, and CIBERSORTx was applied to infer the cell-type-specific expression pattern of immune populations. MIF evaluated the presence of immune cells in the tumor and stromal compartments. These complementary experimental approaches revealed that immune infiltration is associated with shorter progression-free survival in BEV-treated patients, warranting future investigation to evaluate its use as a viable biomarker for patient stratification. Trial registration: NCT01706120, EudraCT number: 2012-003043-29, Date of registration 24 September 2012.

INTRODUCTION:Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a promising palliative treatment for patients with peritoneal malignancies who are not candidates for curative surgery. This study aimed to assess the efficacy and feasibility of implementing a PIPAC program at a single cancer center. METHODS:An open-label, single-arm, phase II study was conducted, enrolling patients with peritoneal tumors of various origins. Participants received bidirectional chemotherapy (intravenous and PIPAC). The primary endpoint was PIPAC efficacy measured as pathological response, while secondary endpoints included safety and feasibility of the technique, quality of life, and clinical outcomes. RESULTS:From March 2021 to March 2024, 32 patients were screened, and 25 were enrolled, resulting in 58 PIPAC procedures. The complication rate was low, with severe surgical complications occurring in 1.7 % of procedures and CTCAE grade 3 complications in 3.4 %. A major pathological response was observed in 56 % of cases, and seven patients (28.0 %) underwent curative-intent cytoreductive surgery after at least two PIPAC treatments. Both the Peritoneal Cancer Index (PCI) and the Peritoneal Regression Score (PRGS) decreased after repeated PIPAC (p = 0.016 and p = 0.047, respectively). Ascites volume also decreased significantly after the first PIPAC (p = 0.001). The median overall survival (OS) was 9.6 months, with responding patients (PRGS 1-2) showing better clinical outcomes (OS: 21.0 vs. 5.5 months,p < 0.001; PFS: 8.2 vs. 2.4 months,p < 0.001) and quality of life (p = 0.003). CONCLUSION:PIPAC can be safely combined with systemic chemotherapy in patients with peritoneal malignancies, demonstrating efficacy in controlling ascites and achieving major pathological response. Further studies are necessary to determine its potential survival benefits.

Gestational choriocarcinoma (GCC) is a malignant and aggressive tumor composed of neoplastic trophoblasts rarely arising months after a normal gestation or after an hydatidiform mole (HM). Histologically, its main diagnostic features are a trimorphic population of trophoblast cells and an absence of chorionic villi. Recently, extremely rare cases of GCC diagnosed in molar and in placenta specimens have been described and accepted as early forms of GCC. We report two cases of GCC diagnosed in a term placenta and in a complete HM (CHM) and underline the importance of recognizing such a rare early form of GCC.

Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Brain metastasis (BM) is quite an uncommon presentation. However, the likelihood of central nervous system (CNS) metastasization should be considered in the context of disseminated disease. The therapeutic management of BMs is an unmet clinical need, to date. We identified, across different cancer centers, six cases of both BRCA wild-type and BRCA-mutated EOCs spreading to the CNS. They presented either with a single brain lesion or with multiple lesions and most of them had intracranial-only disease. All cases received Poly-ADP ribose polymerase inhibitor (PARPi) maintenance, as per clinical practice, for a long time within a multimodal treatment approach. We also provide an insight into the available body of work regarding the management of this intriguing disease setting, with a glimpse of future therapeutic challenges. Despite the lack of unanimous guidelines, multimodal care pathways should be encouraged for the optimal disease control of this unfortunate patient subset. Albeit not being directly investigated in BM patients, PARPi maintenance is deemed to have a valuable role in this setting. Prospective research, aimed to implement worthwhile strategies in the multimodal patient journey of BMs from EOC, is eagerly awaited.

OBJECTIVE:Recurrent gynecological tumors (e.g., endometrial, and ovarian cancers) are incurable diseases; therefore, new treatment options are urgently needed. The PTEN-AKT-PI3K pathway is frequently altered in these tumors, representing a potential treatment target. Alpelisib is an α-specific PI3K inhibitor approved in PIK3CA-mutated advanced breast cancer. We report outcomes from a large series of patients with PIK3CA-mutated gynecological cancers prospectively treated with alpelisib within a controlled program. METHODS:From April 2021 to December 2022, 36 patients with PIK3CA-mutated advanced gynecological cancers received alpelisib 300 mg orally once daily. Objective response (ORR) and disease control (DCR) rates provided measure of the antitumor activity of alpelisib, the primary objective of the study. RESULTS:Included patients had endometrial (17/36 [47%]), ovarian (10/36 [28%]), or other gynecological cancers (9/36 [25%]). Most patients had received 2-3 prior systemic treatments (endometrial, 47·2%; ovarian, 60%; other, 56%), and presented with visceral metastases at baseline (82%, 70%, and 56%, respectively). Overall, 17 different PIK3CA mutations were found, including 53% in the kinase domain (most commonly H1047R) and 36% in the helical domain (most commonly E545K). Overall, the ORR was 28% and DCR was 61%, with the greatest benefit observed in patients with endometrial cancer (35% and 71%, respectively). CONCLUSION:Alpelisib represents an active treatment option in patients with recurrent gynecological cancers harboring a PIK3CA mutation. These findings support the need of biomarker-driven randomized trials of PI3K inhibitors in gynecological cancers.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by hypophosphatemia, bone mineralization disorders with increased risk of fragility fractures, muscle pain, and progressive weakness. TIO has been associated with increased production of the phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) usually by mesenchymal tumors of soft tissue or bone (Phosphaturic Mesenchymal Tumors—PMTs). In rare cases TIO may be observed in association with other malignancies. We report the case of a 66-year-old woman with an occasional diagnosis of both a PMT and an ovarian cancer during the evaluation of TIO. We also systematically review the literature to discover possible correlations between osteomalacia, FGF23 production, and ovarian cancer. Four studies were eligible for the analysis. Two case reports described an association between TIO development and ovarian cancer, whereas the two case-control studies hypothesized a possible correlation between FGF/FGF receptor axis and cancer development. Although it does not provide conclusive evidence regarding the association between TIO and ovarian cancer, this case report highlights the possibility that in the diagnostic workup of suspected TIO, both FGF23-secreting tumors distinct from PMT and tumors unrelated to the clinical presentation of TIO could be identified. This information is important for guiding successful tumor staging and determining the necessity for surgical intervention and/or eventual adjuvant therapy.

Immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has shown limited efficacy in treating ovarian cancer (OC), possibly due to diverse T cell infiltration patterns in the tumor microenvironment. This review explores how neoadjuvant chemotherapy (NACT) impacts the immune landscape of OC, focusing on tumor-infiltrating lymphocytes (TILs), PD-1/PD-L1 expression, and their clinical implications. A comprehensive literature search across four databases yielded nine relevant studies. These studies evaluated stromal (sTILs) and intra-epithelial (ieTILs) TILs before and after NACT. sTIL responses varied, impacting prognostic outcomes, and ieTILs increased in some patients without clear survival associations. PD-L1 expression after NACT correlated with improved overall survival (OS), and increases in granzyme B+ and PD-1 correlated with longer progression-free survival (PFS). Remarkably, reduced FoxP3+ TILs post-NACT correlated with better prognosis. NACT often increases sTIL/ieTIL and CD8+ subpopulations, but their correlation with improved PFS and OS varies. Upregulation of co-inhibitory molecules, notably PD-L1, suggests an immunosuppressive response to chemotherapy. Ongoing trials exploring neoadjuvant ICIs and chemotherapy offer promise for advancing OC treatment. Standardized measurements assessing TIL density, location, and heterogeneity are crucial for addressing genetic complexity and immunological heterogeneity in OC.