Fallopian Research Articles

Leveraging genomic instability scores (GIS) to investigate BRCA variants of unknown significance (VUS) in ovarian cancer: An analysis of 14,513 patients in the Myriad Collaborative Research Registry (MCRR).

e17549 Background: In ovarian cancer, use of homologous recombination deficiency (HRD) and BRCA mutation ( BRCAm) status is essential in guiding PARP inhibitor (PARPi) therapy, with the greatest survival benefit in patients harboring BRCAm pathogenic variants (PVs). In other indications, PARPi are only approved for patients with BRCAm or homologous recombination repair mutations (HRRm). Genomic instability scores (GIS), an HRD proxy, are also predictive of PARPi benefit in patients without BRCAm or HRRm, suggesting that other DNA alterations without definitive classification, such as BRCA VUS or variants of Special Interpretation (SI), may be contributing to HRD. Here, we evaluated the association of BRCA VUS and SI variants that have complex clinical interpretation with reduced penetrance. Methods: Retrospective analysis was conducted using de-identified genetic testing data from the MCRR. Eligible patients with ovarian, fallopian tube or primary peritoneal cancer were tested with the MyChoice CDx HRD test between 2016 and 2023, with HRD+ defined as GIS≥42 or presence of BRCAm PV. Patient BRCAm and HRRm status were defined using the most clinically significant variant observed in BRCA1/2 and an HRR 13-gene set, respectively. GIS distributions were compared using Kolmogorov-Smirnov tests and decomposed using mixture models. Results: Overall, 31.9% (4,628/14,513) of patients were HRD+ with 9.3% (N=1,344) having BRCAm PVs. An additional 3.7% (N=538) had a BRCA VUS [N=83 uncharacterized large rearrangement (LR), N=455 non-LR]. The distributions of GIS in both non-LR and LR VUS were significantly different from the distributions in BRCAm PVs and BRCA wildtype tumors (ps < 0.001), likely representing a spectrum of pathogenic and benign variants. Mixture models estimated that 28.8% [95% confidence interval (CI) 21.9, 35.8] of non-LR VUS and 55.8% (95% CI 40.0, 70.4) of LR VUS exhibited GIS similar to BRCAm PVs. Of the 15 non-LR VUS observed more than once, two were observed only in tumors with low GIS and are therefore presumed benign. BRCA SI variants (N=6) were observed in 16 patients and had a distribution of GIS significantly different from BRCA wildtype tumors (p < 0.001), but not significantly different from BRCAm tumors (p = 0.1). Two SI variants had high GIS in multiple patients and are therefore presumed pathogenic. One SI variant had low GIS in two patients and is therefore presumed benign. Conclusions: The BRCA VUS GIS distribution spanned across the BRCAm PV and BRCA wildtype GIS distributions, which suggests that BRCA VUS represent a mix of benign variants and PVs. In these patients, GIS is able to correctly classify HRD status. Additional data are needed to further characterize these uncertain BRCA variants and the appropriate therapeutic and preventive strategies required for these patients.

Trends in palliative care utilization among patients with ovarian cancer in the United States.

e24083 Background: Palliative care is a resource that is utilized for patients with serious illnesses to focus on symptom management, quality of life, and goals of care for patients and their families. It can be initiated at any point in illness course with benefit beginning as early as the time of diagnosis. This study's objective is to evaluate trends in inpatient palliative care utilization and associated factors in patients with ovarian cancer. Methods: We performed a retrospective cohort study using the National Inpatient Sample (NIS) from 2010-2020. Patients with ovarian, fallopian tube, and primary peritoneal cancer and palliative care (PC) utilization were identified using ICD-10 codes. Chi square and t tests were used to evaluate differences between patients who received PC versus patients who did not. Multivariate and multinomial logistic regression was utilized to determine factors associated with PC use. Results: A total of 479,169 patients with a diagnosis of ovarian cancer were included, of which 58,970 (12.3%) utilized inpatient PC. Between 2010 and 2020, there was a significant upwards trend in PC usage in patients hospitalized with a diagnosis of ovarian cancer from 6.9% to 18.1%. Median age of patients using PC was 67 compared to 65 among those not using PC (p < 0.001). PC utilization was more prevalent among patients with a diagnosis of depression (8.7% v 6.4%; p < 0.001), Black race (12.4% v 10.3%; p < 0.001), in urban environments (94.0% v 92.2%; p < 0.001), and those at hospitals designated as teaching status (72.4% v 66.8%; p < 0.001). In a multivariate regression analysis, the odds of palliative care utilization were 1.59times higher (p < 0.001) for patients with moderate loss of function compared to patients with minor loss of function. Patients with hospital stays 0-3 days were more likely to utilize palliative care compared to 4-7 days (p < 0.001) Multinomial logistic regression for disposition among patients using palliative care to additional care versus routine care was 1.59 times higher in patients with 8+ days hospital stay compared to 4-7 days. For those with shorter stays of 1-3 days versus 4-7 days patients were 1.65 times more likely to die versus routine care. Conclusions: The use of inpatient PC for patients with ovarian cancer increased over time. Palliative care utilization was associated with older age, Black race, depression, and treatment in urban environments or in teaching hospitals. The utilization of inpatient palliative care was higher in patients with more extreme losses of function. These patients were more likely to have shorter lengths of stay due to a higher disposition of death over routine care. Given these findings, patients receiving palliative care may be sicker and closer to the end of life than those who do not. Although there have been higher rates of inpatient palliative care over time, there is still room for earlier implementation.

Gemcitabine plus cisplatin in recurrent ovarian, fallopian tube, and primary peritoneal cancer.

Gemcitabine plus cisplatin in recurrent ovarian, fallopian tube, and primary peritoneal cancer.

Randomized pilot study assessing the safety and tolerability hyperthermic intraperitoneal chemotherapy (HIPEC) at completion of interval cytoreductive surgery or chemotherapy the day prior to interval cytoreductive surgery for patients with stage III/IV ovarian cancer undergoing neoadjuvant chemotherapy.

TPS5638 Background: A recent randomized phase III trial demonstrated an improvement in recurrence free and overall survival when heated intraperitoneal chemotherapy (HIPEC) was given at the time of interval cytoreductive surgery (iCRS) for advanced ovarian cancer. While there is rationale for HIPEC’s mechanism of effect, it remains unclear whether the observed benefit is because the chemotherapy schedule is not interrupted perioperatively (typically at least 6-8 weeks). We hypothesize that administration of the same agent and similar dose the day before surgery, will not increase toxicity and may improve feasibility for closing the gap between treatment cycles, while also limiting length of surgery and time under anesthesia. The primary objective of this study is to assess the feasibility, safety, and tolerability of IV Cisplatin the day prior to iCRS compared to HIPEC to determine if this is an acceptable alternative. Methods: This is a single institution randomized Pilot Study (NCT05415709). Patients with newly diagnosed stage III or IV epithelial (serous, mucinous, or endometrioid) ovarian, fallopian tube, or peritoneal cancer are eligible if they achieve a partial or complete response to 3-4 cycles of neoadjuvant carboplatin/paclitaxel +/- bevacizumab and are deemed to have disease amenable to a complete or optimal iCRS. Patients are scheduled for iCRS within 3-4 weeks following the third or fourth cycle and randomized 1:1 to IV Cisplatin (75 mg/m2) given the day prior to iCRS or HIPEC with Cisplatin (100 mg/m2) given intraoperatively over 90 min at 40°Celsius at the completion of surgical debulking. 15 patient per arm are planned (N=30); currently 7 patients have completed study interventions. No formal power calculation was required for this feasibility and safety study. Frequency and severity of adverse events (AEs) and tolerability of the regimens will be collected and summarized by descriptive statistics for each group. Patients who are able to receive planned treatment will be summarized as percentage for each treatment group. Accrual is anticipated to complete in June 2025. As an exploratory secondary endpoint, we plan to explore changes to the gut microbiome before and after HIPEC and examine correlative patterns with response and toxicity. Clinical trial information: NCT05415709 .

A real-world, patient-reported outcomes study in patients with platinum-sensitive recurrent ovarian cancer receiving long-term maintenance therapy with niraparib.

e23164 Background: Niraparib has been approved for the maintenance treatment of newly diagnosed advanced and platinum-sensitive recurrent ovarian cancer (PSR OC). The phase 3 PRIMA and NOVA studies showed that maintenance niraparib did not worsen quality of life (QoL) compared with placebo. However, no QoL data have been reported for Asian OC patients treated with niraparib. Here, we report patient-reported outcomes (PROs) for PSR OC patients who received niraparib as maintenance therapy for more than two years in a real-world setting. Methods: This prospective, real-world study included OC patients participating in the Niraparib Patient Assistance Program (PAP) in China (NCT06037213). Eligible patients had histologically confirmed PSR epithelial OC, fallopian tube, or primary peritoneal cancer, had been maintained on niraparib for more than two years without disease progression and were still receiving niraparib within 28 days. PROs were assessed every 4-6 weeks for three times using the EQ-5D-5L questionnaire and the FOSI. In addition, a 6-question niraparib medication questionnaire including starting dose, adaptive dose, dose adjustments and reasons, missed doses, concomitant medications was administered at baseline. Results: The PAP enrolled 3154 PSR OC patients, 1151 had been on niraparib for more than two years and could be followed up. From August 2023 to January 2024, 604 eligible patients were recruited and completed at least one assessment. The median age was 58 years (range, 27-82 years). The median duration of treatment with niraparib was 34.8 months (range, 30.5-46.7 months). Among 445 patients with BRCAm status, 104 were BRCAm (23.4%) and 341 were BRCAwt (76.6%). A total of 491 patients (81.3%) received niraparib 200 mg as a starting dose, while 107 (17.7%) required dose adjustments in clinical practice. Presently, 503 (83.3%) were on 200mg. 523 (86.6%) were compliant with the daily oral dose of niraparib, without missing any doses in the previous 6 months. 193 patients (32.0%) had common chronic disease, and 176 (29.1%) were taking concomitant medications during maintenance. The EQ-5D-5L HUI and VAS scores remained stable across the three assessments. The baseline mean EQ-5D-5L HUI and VAS scores were 0.98 (SD 0.05) and 84.31 (SD 10.50), respectively, and the least squares (LS) mean changes from baseline to the third assessment were -0.004 (SE 0.001) and -0.609 (SE 0.248), respectively. A similar situation was observed for the FOSI score. The baseline mean FOSI score was 31.13 (SD 1.37), and the LS mean change from baseline to the third assessment was -0.359 (SE 0.033). Conclusions: In the real world, patients with PSR OC who underwent long-term maintenance treatment with niraparib exhibited a consistently stable QoL. This finding highlights the significant clinical value of niraparib in maintaining QoL in these populations.

Paired matched normal sequencing to accurately identify somatic clonal hematopoiesis mutations (CHm) in solid tumor tissue and plasma specimens.

3051 Background: Clonal hematopoiesis (CH), characterized by the presence of somatic mutations in blood cells, can be found in cancer-related genes when sequencing tumor tissue or plasma samples. Inability to distinguish somatic, tumor-derived mutations from CHm can lead to inaccurate treatment decisions. In this prospective study, we confirmed potential CHm in solid tumors by sequencing and analysis of paired matched normal (PMN) specimens. Methods: We prospectively enrolled 56 patients diagnosed with advanced cancer, including lung (16), colorectal (13), breast (10), gastric (7), ovarian (2), pancreatic (2), liver (2), cervix (1), uterine (1), fallopian tube (1), and perihilar bile duct (1). Targeted next-generation sequencing using a 523 gene panel was performed on paired formalin-fixed paraffin-embedded (FFPE) and circulating tumor DNA (ctDNA) samples. Additionally, whole exome sequencing was performed on PMN buffy coat samples. Analysis of all three specimens was performed to classify somatic mutations as tumor-derived or CHm. Results: We identified 21 potential CHm within the FFPE and ctDNA samples of 13 patients (23.2% of the cohort) with lung (7), breast (2), liver (2), colorectal (1), and gastric (1) cancers. CHm were further confirmed when present in buffy coat samples. The VAF of CHm in FFPE and ctDNA samples exhibited a wide range, spanning from 0.85% to 38.4%, with 7 of those identified at <2% VAF. For these same aberrations, VAF in buffy coat samples ranged from 1.6% to 48%, with seven mutations exhibiting VAF levels <5%. Four of these CHm were classified as oncogenic or likely oncogenic. Four CHm, including an oncogenic TP53 mutation, were identified in the oldest patient (75 years old, lung cancer), while an oncogenic DNMT3A mutation was detected in the youngest patient (42 years old, breast cancer). Both had a 30-year history of smoking. Conclusions: Our findings identified somatic CHm in a substantial subset (23.2%) of solid tumors, with four identified as oncogenic or likely oncogenic mutations. The broad spectrum of VAFs for CHm suggests that using VAF as a cut-off to exclude likely CHm may be unreliable. The low VAF CHm found in matched normal specimens indicates low-pass sequencing may not detect critical CHm, even in paired analysis. The diverse age range of patients with CHm (42 to 75 years old) suggests that CHm are not restricted to older populations, and that additional factors, such as smoking history, may play a role. These findings underscore the importance of incorporating routine PMN buffy coat sequencing into clinical practice, to identify somatic CHm that can impact personalized cancer treatment strategies.

Cold prevention of alopecia during chemotherapy: Real clinical practice.

e24132 Background: Alopecia is one of the most common visible adverse effects of anticancer drug therapy. The incidence of grade 2 alopecia can be as high as 90% in patients getting anthracyclines or taxanes. Decreased scalp temperature causes vasoconstriction which limits the flow of chemotherapeutic agents into the scalp and reduces the metabolism of hair follicle cells at the time of maximum concentration of cytotoxic agents in plasma. This leads to a decrease in the antimitotic and antimetabolic effects of chemotherapy. ORBIS II scalp cooling device has been successfully implemented in comprehensive oncology centers. However, the results of large-scale studies are still lacking which delays application of this technology in clinical practice. The aim of our study was to evaluate the efficacy and safety of alopecia cold prophylaxis using ORBIS device in a regional referral center in Russia. Methods: Between 22 June 2022 and 13 December 2023 101 patients (100 women and 1 man) were treated using ORBIS II in the Department of Chemotherapy N1, City Clinical Cancer Hospital N1, Moscow. Various combinations of chemotherapeutic agents depending on cancer type were administered. Breast cancer was the most common type (63), followed by ovarian (15), uterine (9), lung (6) and cervical cancer (3). Other primaries were represented by 1 patient each: pancreatic, rectal, gastric, fallopian tube and colon cancer. Totally 431 scalp cooling procedures were performed including 261 (61%) in breast cancer and 78 (18%) in ovarian cancer patients. Outcomes were evaluated using the CTCAE/CTCAE V5.0 toxicity criteria. We evaluated the development of 1 grade alopecia (hair loss of less than 50% and not requiring a wig) as a positive result. On the contrary, a negative result was registered in patients with grade 2 alopecia, namely hair loss of 50% or more and/or requiring a wig. Results: Grade 1 alopecia was experienced by 61% of patients and the other 39% had grade 2 alopecia. Notably, the highest incidence of grade 2 alopecia was observed in patients who received doxorubicin 60 mg/cm2 + cyclophosphamide 600 mg/cm2 once every 21 days (9.9%). Taxane-based regimens had a 21% incidence of grade 2 alopecia, while platinum-containing regimens had a 11% incidence. No serious adverse events occurred during the application of cold prophylaxis. The procedure was well-tolerated by all patients. Conclusions: The use of a cold helmet is an effective method of preventing chemotherapy-induced alopecia. Our analysis yielded a success rate of 61%, which is comparable to the worldwide data range of 50% to 80%.

Neoadjuvant pamiparib in patients with newly diagnosed advanced ovarian cancer: A single-arm, prospective phase II trial.

e17555 Background: PARP inhibitors have been validated for their efficacy as maintenance therapy in newly diagnosed ovarian cancer, but their effectiveness as neoadjuvant therapy remains uncertain. The aim of this study is to explore the efficacy and safety of the combination of pamiparib with neoadjuvant chemotherapy and bevacizumab in patients with newly diagnosed ovarian cancer. Methods: This is a single-arm prospective phase II study that includes patients who meet the following criteria: newly diagnosed ovarian, fallopian tube, or peritoneal cancer with FIGO stages III-IV; histologically confirmed high-grade serous or endometrioid adenocarcinoma and ineligible for satisfactory debulking surgery. The treatment consists of paclitaxel 175mg/m2 on Day 1 and carboplatin AUC 5 on Day 2, every 3 weeks, for a maximum of 6 cycles. Bevacizumab is administered at a dose of 15mg/kg on Day 1, every 3 weeks, with discontinuation 6 weeks prior to surgery. Pamiparib is given at a dose of 40mg twice daily for a maximum of 6 cycles. Patients who tolerate the treatment and are deemed suitable for surgery undergo interval debulking surgery. After surgery, patients will receive consolidation and maintenance therapy based on the investigator's choice. The chemotherapy response score will be determined based on postoperative pathology evaluation. The primary endpoint was the proportion of patients with a Chemotherapy Response Score 3 (CRS 3). The second endpoints were proportion of patients with pathological complete response (pCR), proportion of patients with satisfactory debulking surgery (R0), progression-free survival (PFS) and safety. The trial is ongoing. Results: Between March 2023 and January 2024, thirteen patients with a median age of 60 years (range: 46 - 73), FIGO stage IIIB (1/13, 7.6%), IIIC (6/13, 46.2%) and IVB (6/13 46.2%) were enrolled. Among the 13 patients, 12 had high-grade serous adenocarcinoma, and 1 had endometrioid adenocarcinoma. 2 patients withdrew their informed consent after receiving 1 cycle of neoadjuvant therapy. Ten patients received four cycles of neoadjuvant therapy, while one patient received three cycles. 8 patients received interval debulking surgery and all of them achieved a R0 resection. Postoperative pathological evaluation showed ovarian CRS3 in 5 patients (62.5%), CRS2 in 2 patients (25%), and CRS1 in 1 patient (12.5%). All of these patients did not achieve a pCR. The most common adverse reactions were neutropenia (92.4%), leukopenia(92.4%), thrombocytopenia(77.0%), and anemia (100%), with grade 3-4 incidence rates of 76.1%, 53.7%, 30.7%, and 38.3%, respectively. No treatment-related death were observed. Conclusions: The combination of pamiparib with neoadjuvant chemotherapy and bevacizumab showed promising efficacy and acceptable toxicity in patients with newly diagnosed advanced ovarian cancer. We will report more data in the future. Clinical trial information: ChiCTR2200059119.

Phase II clinical trial of PLX038 in patients with platinum resistant ovarian, primary peritoneal and fallopian tube cancer.

TPS5630 Background: Platinum-resistant ovarian cancer (PROC) portends a poor prognosis and, although treatments are available, response rates are low. Previous studies have demonstrated that DNA topoisomerase I (TOP1) inhibitors exhibit clinical activity in PROC. Irinotecan also has a 15-25% response rate in some studies of platinum-resistant epithelial ovarian cancer but does not have FDA approval for this indication. Additional studies in preclinical models suggest that TOP1 poisons are more active if administered at low doses on prolonged schedules. PLX038 is a long-acting prodrug of the potent TOP1 inhibitor SN-38. In PLX038, SN-38 is covalently conjugated to circulating polyethylene glycol and is slowly released at a constant rate to provide the active agent with a long half-life, a low Cmax and very high exposure – important facets for optimal safety and efficacy of this drug. Further, in preclinical studies the nanoparticle prodrug accumulates and is retained in tumors, where it slowly releases the SN-38. Methods: This single arm, phase 2 clinical trial is open at Mayo Clinic in Rochester, MN. The primary endpoint is overall response rate and secondary endpoints include progression-free survival and assessment of tolerability of PLX038. Correlative goals include i) measurement of TOP1-DNA covalent complexes in tumor biopsies and circulating tumor cells to assess successful target engagement; ii) assessment of homologous recombination status and SLFN11 expression for correlation with tumor response rate; and iii) pharmacokinetics of SN-38 and SN-38G as well as their association with GI toxicity. Assessment of gut microbiota and association with GI toxicity profile are also being investigated. Eligible patients include women with platinum resistant high grade serous ovarian, primary peritoneal, and fallopian tube cancer who have received fewer than two prior chemotherapy regimens in the platinum-resistant setting. All patients must have an ECOG performance status of 0, 1, or 2 and adequate bone marrow, renal, and hepatic function. As of January 31, 2024, 12 of planned 37 patients have enrolled. Clinical trial information: NCT05465941 .

REJOICE-Ovarian01: A phase 2/3 study of raludotatug deruxtecan (R-DXd) in patients with platinum-resistant ovarian cancer (OVC).

TPS5625 Background: Platinum resistance develops in most patients with OVC. Prognosis is poor and therapeutic options are limited, illustrating the significant unmet need in these patients. R-DXd is an antibody–drug conjugate comprising a humanized immunoglobulin G1 antibody targeting cadherin 6 (CDH6), a stable linker selectively cleaved within tumor cells, and a membrane-permeable topoisomerase I inhibitor (DXd) payload. In the first-in-human study of R-DXd (NCT04707248) in patients with advanced/metastatic OVC who had prior systemic therapy, doses of 4.8–8.0 mg/kg showed an objective response rate (ORR) of 46% (95% confidence interval [CI]: 32, 61) and a median duration of response (DOR) of 11.2 months (95% CI: 3.0, not estimable). At doses currently being evaluated for RP2D (or dose optimization), R-DXd exhibited a positive benefit/risk profile, with manageable toxicities for further clinical development. Given these promising data, a Phase 2/3 study in patients with platinum-resistant OVC is underway. Methods: REJOICE-Ovarian01 (NCT06161025; ENGOT-ov77; GOG-3096) is a global, randomized, open-label Phase 2/3 study in patients with platinum-resistant OVC who have not been selected for CDH6 expression. Eligible patients are adults with high-grade serous or endometrioid OVC, primary peritoneal cancer, or fallopian tube cancer with acquired platinum resistance and 1–3 prior systemic lines of therapy (LOT) including prior bevacizumab treatment (unless ineligible) and prior mirvetuximab soravtansine treatment for patients whose tumors are folate receptor alpha-positive (unless ineligible or not available). Patients with primary platinum-refractory disease are not eligible. In the Phase 2 dose-optimization part, approximately 105 patients will be randomized 1:1:1 to receive R-DXd at 4.8, 5.6, or 6.4 mg/kg intravenously every 21 days. In the Phase 3 part, approximately 450 patients will be randomized 1:1 to receive either R-DXd or treatment of physician’s choice (TPC: paclitaxel, pegylated liposomal doxorubicin, gemcitabine, or topotecan). Randomization will be stratified by number of prior LOT (1 vs 2–3) and tumor CDH6 expression (high vs low) in both parts, and additionally by TPC (paclitaxel vs others) in the Phase 3 part. The Phase 2 primary endpoint is ORR by blinded independent central review (BICR). Key secondary endpoints include investigator-assessed ORR and DOR. No hypothesis testing will be performed in the Phase 2 part. The dual primary endpoints in Phase 3 are ORR and progression-free survival (PFS) by BICR; key secondary endpoints are OS and quality of life (QoL). ORR will be analyzed using a Cochran-Mantel-Haenszel test at a 2-sided 1% alpha level, and PFS will be analyzed using a stratified log-rank test at a 2-sided 4% alpha level. OS and one QoL subscale will be tested hierarchically after PFS. Study enrollment is planned to start in February 2024. Clinical trial information: NCT06161025 .

First-in-human phase I trial of the oral first-in-class ubiquitin specific peptidase 1 (USP1) inhibitor KSQ-4279 (KSQi), given as single agent (SA) and in combination with olaparib (OLA) or carboplatin (CARBO) in patients (pts) with advanced solid tumors, enriched for deleterious homologous recombination repair (HRR) mutations.

3005 Background: USP1 is a deubiquitinase that regulates DNA damage response pathways, such as Translesion Synthesis and Fanconi Anemia pathways. KSQi is a potent, selective small molecule inhibitor of USP1 with anti-proliferative activity in tumors with HRR mutations. The combination of KSQi and PARP inhibitors (PARPi) showed strong synergy in Ovarian and TNBC PDX models, supporting this clinical trial. Methods: This is a 2-part study: Part 1 dose escalation using a BOIN design explored safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of KSQi as SA (Arm 1) and in combination with OLA at 200 mg BID (Arm 2) or CARBO at AUC 4 (Arm 3) to determine the MTD and/or recommended dose for expansion (RDE). Part 2 will assess efficacy and safety of the combinations in expansion cohorts. Results: As of Jan 4, 2024, 64 pts (19m/45f; median age 63 y) received KSQi 100 - 1250 mg; Arm 1: 100 mg (3 pts), 150 (3), 200 (4), 300 (6), 450 (5), 650 (9), 900 (7) and 1250 (5); Arm 2: 200 (5), 450 (5) and 900 (5); Arm 3: 200 (3) and 450 (4). Median number of prior therapies was 5, 4 and 3 for Arm 1, 2 and 3, respectively. 29% had prior PARPi in Arm 1, 53% in Arm 2, and 71% in Arm 3. All pts in Arms 2 and 3 had tumors with deleterious HRR mutations. Most common treatment-emergent adverse events (TEAE) were anemia (36%), increased creatinine (33%) as SA, and anemia in combination with OLA (87%) and CARBO (71%). The most common G3+ TEAEs were hyponatremia (12%) as SA and anemia in combination with OLA (73%) and CARBO (29%). DLTs (n = 3) were G3 maculopapular rash at 1250 mg (Arm 1) and G3 WBC decrease at 200 mg, G3 anemia at 450 mg (Arm 2). 30% (19/64) of pts had an interruption in KSQi dosing and 1 (1.6%) discontinued treatment. PK AUC and Cmax increased almost dose-proportionally up to 650 mg. A preliminary review of OLA concentrations following co-administration with KSQi showed no significant impact of OLA at C2D1. Ubiquitinated PCNA induction was observed in paired tumor biopsies from pts receiving KSQi, supporting intra-tumoral USP1 inhibition. A RECIST PR was observed in a fallopian tube cancer pt lasting 7 weeks and SD in 9 pts treated with SA KSQi; best response in combination with OLA was SD in 6 pts and 2 SD with CARBO. Disease control rate at 16 weeks was 28% (Arm 1), 40% (Arm 2) and 29% (Arm 3). Conclusions: KSQi is a first-in-class USP1 inhibitor with an acceptable safety profile as SA and in combination. An MTD was not reached in any Arms. PD results support the mechanism of action of USP1 inhibition. The RDE will be determined in additional back-fill cohorts. Clinical trial information: NCT05240898 .

MiR-4443 Contained Extracellular Vesicles: A Factor for Endometriosis Progression by PI3K/AKT/ACSS2 Cascade in-vitro.

Endometriosis (EM) is an estrogen-dependent benign gynecologic disease affecting approximately 10% of reproductive-age women with a highrecurrence rate, butlacks reliablebiomarkers. No previous studies have investigated the possible use of extracellular vesicle (EV)-associated micro RNAs (miRNAs) from menstrual blood (MB) as candidate diagnostic or prognostic markers of EM. Specimens were obtained from endometriosis and non-endometriosis patients at the International Peace Maternity and Child Health Hospital in Shanghai. Microarray was used to screen differentially expressed miRNAs among peritoneal fluid (PF), fallopian tube fluid (FF), and MB. Dual-luciferase reporter gene assay was carried out to verify the relationship between miR-4443 and ACSS2. Cell proliferation and Transwell invasion assays were performed in vitro after intervention on miR-4443 and ACSS2 in hEM15A human endometrial stromal cells and primary human endometrial stromal cells (hESCs). Spearman correlation analysis, receiver operating characteristic (ROC) curve analysis, and survival analysis were applied to clinical data, including severity of symptoms and relapse of EM among EM patients. EV-associated miR-4443 was abundant in MB of endometriosis patients. ACSS2 knockdown and miR-4443 overexpression promoted cell proliferation and migration via the PI3K/AKT pathway. miR-4443 levels in MB-EVs were positively correlated with the degree of dyspareunia (r=0.64; P<0.0001) and dysmenorrhea (r=0.42; P<0.01) in the endometriosis group. ROC curve analyses showed an area under the curve (AUC) of 0.741 (95% CI 0.624-0.858; P<0.05) for miR-4443 and an AUC of 0.929 (95% CI 0.880-0.978; P<0.05) for the combination of miR-4443 and dysmenorrhea. MB-derived EV-associated miR-4443 might participate in endometriosis development, thus providing a new candidate biomarker for the noninvasive prediction of endometriosis recurrence.

Spontaneous dual ectopic pregnancies in the ipsilateral fallopian tube and ovary: A case report and literature review

AbstractBackgroundConcurrent ectopic pregnancies in differing anatomical locations are a rarity. It is imperative to be able to identify these cases as extrauterine pregnancies require emergent evaluation and treatment.CaseWe describe a case of suspected ruptured ectopic pregnancy in a low‐risk multiparous female found to have ipsilateral ovarian and tubal ectopic pregnancies on laparoscopy and subsequent pathology.ConclusionAlthough the co‐occurrence of these pregnancies presented as a diagnostic challenge, preoperative ultrasound imaging increased our suspicion in conjunction with laparoscopic findings. Thorough examination of the uterus and bilateral adnexa during laparoscopy is essential in identifying pathology and reducing morbidity. Furthermore, sampling or removal of suspicious concomitant lesions may aid in diagnosis. Following beta HCG trends may provide additional information in patients with unclear findings on laparoscopy.

A novel oral microtubule inhibitor utidelone capsule (UTD2): A phase 1 clinical study to assess the tolerability, safety, and efficacy in advanced solid tumors.

e15014 Background: Utidelone is a potential best-in-class novel microtubule stabilizing agent that offers several advantages including improved efficacy and safety, broader anti-cancer spectrum, blood-brain barrier penetrance, and response against multidrug-resistant tumors. Utidelone injection (UTD1) has been approved for advanced breast cancer in China since 2021 (30 mg/m2/d-5day in combination with capecitabine; 35mg/m2/d-5day for monotherapy’s recommended dose). Utidelone is not susceptible to P-glycoprotein, leading to better oral bioavailability and successful development of an oral capsule. This is the first-in-human study of Utidelone Capsule (UTD2) in the United States. Methods: This is an ongoing phase I, open-label, dose escalation study (NCT05681000). Eligible patients are aged ≥18, and have an ECOG PS of 0-1, life expectancy ≥12weeks, adequate organ functions, pathologic confirmed advanced solid tumor refractory to prior standard therapies. Patients are treated with UTD2 monotherapy. The starting dose is 25 mg/m2/d-5day, with planned escalation to 50, 75, 100 mg/m2/d-5day, 70 mg/m2/d-7day and 85 mg/m2/d-7day in a 21-day cycle. The primary objective is to determine DLT and MTD. Secondary objectives include efficacy, pharmacokinetic profile and phase II dose recommendation. Results: As of 22nd January 2024, 10 advanced solid tumor patients were enrolled with median age of 62.5 years (range 52.0-81.0), 5 females and 5 males. All patients had received prior treatment in advanced settings. Dose escalation is ongoing, and 100mg/m2/d-5day cohort is under evaluation. The first 8 patients were evaluated for efficacy with an outcome of 1 CR (ovarian cancer), 5 SD (prostate adenocarcinoma, testicular Sertoli cell tumor, non-small cell lung cancer, pancreatic adenocarcinoma and appendiceal adenocarcinoma) and 2 PD (carcinoma of fallopian tube and adenocarcinoma of sigmoid colon), among whom 5 patients are still on the treatment with durations of 2 to 11 cycles. The ovarian patient with CR was enrolled to the lowest dose cohort, and is still on treatment. She is heavily pre-treated with multiple prior lines including chemotherapies. Regarding safety, most treatment-emergent adverse events (TEAEs) were Grade 1/2, manageable, and included diarrhoea, nausea, alopecia. There were two cases of Grade 3 diarrhea that recovered to Grade 1 through dose reduction or medical support. No grade 4 or 5 adverse events and no treatment discontinuations due to AE were reported. There have been no DLTs and the MTD is not yet reached. Conclusions: This study has demonstrated encouraging anti-tumor activity with good tolerance and manageable safety profile of UTD2 in patients with heavily pre-treated advanced solid tumors. This study is still actively ongoing, and further data will be provided at time of presentation. Clinical trial information: NCT05681000 .

Open-label, phase 2 study of adebrelimab combined with fuzuloparib in the treatment of patients with HRD-positive, recurrent platinum-resistant ovarian cancer.

TPS5634 Background: Adebrelimab, a humanized anti-PD-L1 monoclonal antibody, selectively targets PD-L1 molecules to inhibit the PD-1/PD-L1 pathway, reversing tumor-induced immune tolerance and revitalizing the immune system's capacity to combat tumors. Fuzuloparib, a novel PARP inhibitor, impedes the activity of poly (ADP-ribose) polymerase, halting the DNA repair mechanism for single-stranded breaks, resulting in DNA damage accumulation and consequent cancer cell apoptosis. Emerging evidence strongly supports that PARP inhibitors significantly extend progression-free survival in homologous recombination-deficient (HRD)-positive ovarian cancer. The TOPACIO study demonstrated that the combination of niraparib and pembrolizumab for platinum-resistant ovarian cancer achieved an objective response rate (ORR) of 18%, with durable responses in patients. This underscores the potential of integrating PARP inhibitors with immune checkpoint inhibitors in clinical protocols. For platinum-resistant recurrent ovarian cancer, known for its challenging prognosis, we propose conducting exploratory clinical trials on the combination of adebrelimab and fuzuloparib, aiming to establish robust evidence for future clinical applications. Methods: This open-label, single-arm, Phase 2 study aims to evaluate the anti-tumor activity and safety of adebrelimab in combination with fuzuloparib in approximately 37 patients with HRD-positive, recurrent platinum-resistant epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer (hereinafter referred to as ovarian cancer). The primary endpoint is to determine the objective response rate of the combined treatment regimen, as defined by the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints encompass disease control rate, progression-free survival overall survival, along with the assessment of safety and tolerability. Patients must be aged 18-70 years with an Eastern Cooperative Oncology Group performance status of 0–1 and have recurrent histologically confirmed ovarian cancer with HRD-positive tumor. Patients must have progressed within less than 6 months after the last treatment with platinum-containing chemotherapy. HRD status confirmed by testing BRCA gene, loss of heterozygosity, telomeric allelic imbalance and large-scale transition. Adebrelimab (20 mg/kg) is administered intravenously every 3 weeks and fuzuloparib (100mg) is administered orally twice daily as until the patient experiences disease progression, intolerable toxicity, or other study treatment discontinuation criteria are met. This clinical trial is in progress and 7 patients have been enrolled. Clinical trial information: NCT05753826 .

Histomorphological and Histochemical study of the uterine tubes in the premature female goats

Histomorphological and Histochemical study of the uterine tubes in the premature female goats

A HISTOMORPHOLOGICAL STUDY OF FALLOPIAN TUBES IN A TERTIARY CARE HOSPITAL IN SOUTH INDIA

Introduction: Fallopian tubes are complex structures 1. Fallopian tubes are part of female genital tract named after Italian physician Gabriele Fallopias in 16thcentury 2,16. Fallopian tube lesions are non-neoplastic and neoplastic. Non neoplastic lesions are the major cause of sterility13. Present study was under taken with objectives of study all histomorphological lesions of fallopian tubes in bilateral salphigoophorectomised patients. Material and methods: A total number of 249 specimens of hysterectomy with bilateral salpingectomy. Histosalphingooophorectomy cause were studied in the department of pathology SDM College of medical sciences and Hospital Dharwad over a period of 7 years form July 2012 to June 2019. The clinical data, gross and microscopic findings were studied. Incidence and prevalence were calculated. Results: In our study Hydrosalphinx (20.1%) is the commonest finding, Tubal atypia 14.9%, Tubal metaplasia 14%, acute salphingitis 9.2%, Metastatic lesions 6%, Hematosalphinx 6.8%, fallopian tube showing STIC lesions 3.6%, TuberculousSalphingitis 3.2% Conclusion: Fallopian tube lesions present with different pathological findings. Precursors of malignancy in fallopian tube has to be thoroughly examined.

Hysteroscopic evaluation of endometrial changes and fallopian tubal functions in women using progestin-only contraceptives

The purpose of this prospective study was to investigate whether office hysteroscopy (OH) can be used to assess the mechanisms of action of progestogen-only contraceptives (POCs), diagnose possible local causes of abnormal uterine bleeding (AUB), and support the treatment plan of symptomatic patients using POCs compared with those who do not use hormones. The study included 140 women who were divided into two groups. Group A consisted of 70 women who used POCs, whereas group B consisted of 70 women who did not use hormones. They were successively examined using transvaginal ultrasonography (TVS), OH, and endometrial sampling. The TVS results were consistent with those of OH and histopathology. The changes in endometrial thickness and vasculature, as well as fallopian tube (FT) functions, were significantly more pronounced in POC users than in non-POC users. There was a significant reduction in the peristalsis of the proximal part of the FT, as well as a reduction in the bubble flow test in group A compared with group B. In addition, the combination of peristalsis and the bubble flow test (Darwishscope test) was significantly lower in group A. It was concluded that using OH as a simple diagnostic tool in women with POCs would contribute to a better understanding of the mechanisms of endometrial and FT effects and explain some local endometrial causes of AUB. This ensures that the combination of TVS and OH would limit routine endometrial sampling in POCs users.

RISK FACTORS, CLINICAL PRESENTATION AND TREATMENT MODALITIES OF ECTOPIC PREGNANCY: A CROSS SECTIONAL STUDY AT TERTIARY CARE HOSPITAL

Background: Ectopic pregnancy is a pregnancy anywhere other than uterine cavity. Approximately 1-2% pregnancies are ectopic associated with significant morbidity and mortality. Fallopian tube is the commonest site. Present study deals with the analysis of risk factors, clinical presentation and treatment modalities of ectopic pregnancy. Material and Method: A cross sectional study was carried out on 100 cases which were diagnosed and treated at Department of Obstetrics and Gynaecology, J K Lon Hospital, Government Medical College, Kota (Raj.), India. Parameters studied were age, parity, gestation period (weeks), risk factors, clinical presentation, medical management and surgical intervention. Results: Present study included 100 cases in which 72% belonged to age group of 19-30 years. Maximum cases were recorded between parity 0 and 2. Previous abortion (33%) was the most common risk factor. Most of the patients had ruptured (54%) ectopic pregnancy outcome. Tenderness was a common clinical feature on abdominal examination. Medical management was done for 11 patients of which 9 cases were successfully treated (81.8%). In 64% cases, emergency laparotomy with unilateral salpingectomy was applied as surgical intervention. Conclusion: Diagnosis of ectopic pregnancy is a challenging task by its bizarre clinical picture as it is clinically ranging from asymptomatic case to acute abdomen to hemodynamic shock. It is imperative to take close examination with use of advance diagnostic tools and management. Most of the patients of ectopic pregnancy presented ruptured outcome and period of amenorrhea was significantly associated with it. Early diagnosis and advance management would reduce the morbidity and mortality in ectopic pregnancy.

STUDY OF THE CONCEPT OF UTERUS IN AYURVEDA WITH APPLIED ASPECTS

The Uterus is the child bearing organ in female, situated in the pelvis between the bladder and rectum. The uterus can be divided into an upper part, consisting of the fundus and the greater part of the body and a lower part consisting of the body, and of the cervix. The upper narrow end is called the internal os and the narrow lower end is called the external os. The cavity of the uterus communicates with that of the vagina through the external os. The study aims to evaluate various terminologies related to the uterus and its parts in Ayurveda. Morphological considerations of various terminologies along with applied aspects with references were studied. The present study is designed to analyze the concept of the uterus from Ayurvedic classics and interpreted. Elucidated terminologies were analyzed from structural anatomy, dimensions, location, and applied aspects. Various terminologies are used to represent the Uterus and its parts which can be correlated as follows- Uterus: Yoni, Phalayoni, Garbhasaya , Garbhakosha, Kukshi, Kshetra. Cervix with External Os: Garbhamarga, Garbhachidra. Fallopian tube /Uterine tubes: Raktavahasrota, Artavahasrotamsi, Artavavahasrotas, Artavavahamarga. Blood Supply: Artavavahasrotamsi, Artavvahinyadhamani.