IgA transcytosis and antigen recognition govern ovarian cancer immunity.

Most ovarian cancers are infiltrated by prognostically relevant activated T cells1-3, yet exhibit low response rates to immune checkpoint inhibitors4. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer5,6, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.

High Financial Hardship among Patients with Advanced Ovarian Cancer.

Ovarian cancer is considered the most fatal and costly gynecologic cancer. Although personalized therapies have improved ovarian cancer prognosis, they have resulted in increased financial toxicity concerns among this population. This study evaluated financial toxicity in patients with advanced ovarian cancer. Using secondary data from a study of barriers to palliative care, financial toxicity (FT) was measured through the Comprehensive Score for Financial Toxicity scale. Univariate and bivariate analyses were used to assess the relationship between selected demographic (i.e., age, race, ethnicity, education, place of birth, insurance type, yearly household income, employment status) and treatment-specific variables (i.e., years since diagnosis, surgery, chemotherapy, radiation, hormonal and targeted therapy) with clinically relevant financial toxicity. Characteristics were compared using Fisher's exact or chi squared tests. A total of 38 participants with advanced ovarian cancer were included in this study; 24% (n = 9) reported clinically significant FT. Income (p = .001), place of birth (p = .048) and employment status (p = .001) were related to FT. Study findings highlight that advanced ovarian cancer patients experience high FT, particularly those with low income, who are not able to work and were born outside the US. Further research using larger datasets and more representative samples is needed to inform intervention development and implementation.

"It doesn't really apply to what I'm going through": a mixed-methods study of barriers to palliative care among patients with advanced ovarian cancer.

PURPOSE: Palliative care aims to provide symptom relief and general support for patients with serious illness. Despite experiencing significant treatment side effects, specialty palliative care is under-utilized by patients with advanced ovarian cancer. We explored barriers to palliative care in this population. METHODS: We conducted a sequential mixed-methods study. Qualitative: we interviewed patients with advanced ovarian cancer (N = 7). Guided by the Social Ecological Model (SEM), interviews assessed intrapersonal, interpersonal, organizational, and policy-level barriers to receipt of specialty palliative care. Interviews were audio-recorded, transcribed, and analyzed with directed content analysis. Quantitative: patients with advanced ovarian cancer (N = 38) completed self-report surveys assessing knowledge about, attitudes towards, and prior experiences with specialty palliative care. Descriptive statistics were used to characterize survey responses. RESULTS: Qualitative analysis identified barriers to specialty palliative care at each SEM level. Intrapersonal factors (e.g., knowledge, attitudes) were most frequently discussed. Other common barriers included insurance coverage and distance/travel time. Survey responses indicated most participants were aware of palliative care (74%) but had mixed attitudes towards palliative care and did not feel they needed for palliative care. No survey respondents had received a physician recommendation for palliative care, and a sizable minority (29%) thought palliative care referral should only take place when patients have no remaining treatment options. CONCLUSION: Among patients with advanced ovarian cancer, barriers to specialty palliative care exist at multiple levels. Our results underscore the potential value of a multilevel intervention to support receipt of palliative care in this population.

Prospective Analyses of Sedentary Behavior in Relation to Risk of Ovarian Cancer.

We examined the association of sedentary behavior with risk of ovarian cancer overall, by tumor subtype, and by participant characteristics in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II). A total of 69,558 NHS participants (1992-2016) and 104,130 NHS II participants (1991-2015) who reported on time spent sitting at home, at work, and while watching television were included in the analysis, which included 884 histologically confirmed ovarian cancer cases. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for ovarian cancer by sitting time (no mutual adjustment for individual sitting types in primary analyses). We examined potential heterogeneity by tumor histological type (type I or II), body mass index (weight (kg)/height (m)2; < 25 or ≥25), and total physical activity (<15 or ≥15 metabolic equivalent of task-hours/week). We observed an increased risk of ovarian cancer for women who sat at work for 10-19 hours/week (HR = 1.25, 95% CI: 1.04, 1.51) and ≥20 hours/week (HR = 1.40, 95% CI: 1.14, 1.71) versus <5 hours/week. This association did not vary by body mass index, physical activity, or histotype (P for heterogeneity ≥ 0.43). No associations were observed for overall sitting, sitting while watching television, or other sitting at home. Longer sitting time at work was associated with elevated risk of ovarian cancer. Further investigations are required to confirm these findings and elucidate underlying mechanisms.

The Intersection of Palliative Care and Genetic Counseling in Cancer Care: A Case Discussion.

Up to 10% of cancers have a strong hereditary component. The diagnosis of a hereditary cancer may alter treatment recommendations for the patient. However, the optimal timing and best practices for integrating genetic counseling and testing into the care of women diagnosed with cancer remains unclear. In this study, we demonstrate the potential benefits of discussing genetic testing and counseling in the context of palliative care through two cases. Incorporating referrals for genetic testing into the palliative care context is important. This provides an opportunity to perform previously missed genetic testing. It is also a chance for the patient to leave a legacy while also potentially allowing for alternate targeted treatment possibilities that may be well tolerated and provide a better quality of life for the patients themselves. The benefits of referral to palliative care by the genetics team includes assisting patients with the management of not only physical but also psychological symptoms as well as conducting advanced care planning in patients and families with hereditary mutations.

Oxidized Regenerated Cellulose Mimicking a Retained Laparotomy Sponge.

Oxidized regenerated cellulose (ORC) is an absorbable hemostat commonly used during gynecologic surgery. We present a case in which ORC was used in a patient undergoing posterior pelvic exenteration with ureteroneocystostomy for excision of a malignant pelvic mass. At the conclusion of these procedures, the laparotomy pad count was reported as incomplete likely due to the large number of laparotomy pads used and changes in nursing staff. Abdominal radiographs were obtained to verify no pads were retained in the abdominal cavity. These identified a poorly defined radiolucency deep in the patient's pelvis, requiring the surgical incision be reopened. Upon reexploration, no evidence of a retained surgical sponge could be identified. However, ORC was identified at the site of the radiolucency in question. Radiographs of this material, once removed, confirmed its radiolucent appearance. This experience clearly demonstrates that oxidized regenerated cellulose can mimic a retained surgical sponge on intraoperative radiographs. Dissemination of this knowledge will hopefully help to avoid radiographic misidentification of ORC in the perioperative window and minimizing the risk of unnecessary surgical interventions in the future.

Stage IIIC endometrial cancer review: Current controversies in adjuvant therapy.

Stage IIIC is the most common stage of locally advanced sub-stage of endometrial cancer, nevertheless, the optimal management for these patients remains controversial. Adjuvant chemotherapy alone more effectively suppressed distant metastases but resulted in a higher rate of pelvic failure, while adjuvant radiation more effectively controlled pelvic recurrences but was associated with more frequent distant metastases. Two recent randomized trials, PORTEC3 and GOG 258, each have attempted to integrate multimodal therapy. However, heterogeneous cohorts analyzed together, including high risk stage I, stage III and stage IV, limit our ability to make conclusions specific to stage IIIC disease. Here, we review clinical evidence pertaining to management and outcomes with stage IIIC uterine carcinoma with brief discussion on evolving approaches. The studies reviewed demonstrate for stage IIIC disease radiation improves local control but does not confer an overall survival benefit and chemotherapy can improve overall survival. The data seem to suggest that aside from the possibility of defining subgroups that may confer an overall survival benefit from combined modality therapy, the future to improving survival lies in the exploration of better therapeutic regimens that will result from tailored biomarker-based therapy.

The association of resistance training with risk of ovarian cancer.

BACKGROUND: Increasing evidence, including multiple putative inflammatory risk factors (e.g., c-reactive protein, and adiposity), supports that inflammation plays an important role in ovarian carcinogenesis. Resistance training (RT) is associated with lower levels of circulating inflammatory markers, independent of physical activity. METHODS: We evaluated the relationship between RT and risk of ovarian cancer accounting for other physical activity (e.g., walking) in two large prospective cohorts, the Nurses' Health Study (NHS) and NHSII. KEY RESULTS: In total, analyses included 42,005 NHS participants (2000-2016) and 67,289 NHSII participants (2001-2017) with RT assessed every 4 years. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of RT with ovarian cancer risk overall and by tumor subtype, adjusting for known and putative ovarian cancer risk factors. We identified a total of 609 cases over 1,748,884 person-years. No association was observed with overall ovarian cancer risk (RT ≥60 vs 0 min/wk, HR = 0.95, 95%CI: 0.74-1.22) or by histotype (comparable HR = 0.86 and 0.98 for type I and II tumors, respectively). Results did not differ by body mass index (Pinteraction = 0.97), or other physical activity (Pinteraction = 0.31). CONCLUSIONS & INFERENCES: We observed no evidence that moderate levels of RT were associated with risk of ovarian cancer. Further investigations are required to confirm these findings.

Major vascular injury during gynecologic cancer surgery.

OBJECTIVE: Vascular injury during major gynecologic cancer surgery is a rare but potentially fatal complication. The purpose of this study was to review our experience with major vascular injury during gynecologic cancer surgery. METHODS: This was a retrospective chart review of women undergoing surgery by our gynecologic oncology department from 7/1/99 to 6/30/20 who had a major vascular injury. We identified women who sustained a vascular injury by a combination of CPT code and medical record searches, fellow case logs and a list maintained for an ongoing quality assurance program. Data were expressed as median and range for continuous variables and as frequency and percentage for categorical variables. Fisher's exact test was used to analyze differences in complication rates between groups. RESULTS: Major vascular injury was identified in 52 patients and procedures. The inferior vena cava was the most common site of injury, 32.7% (17/52), followed by the external iliac vein, 23.1% (12/52). Lymph node dissection was the most common time for a vascular injury to occur 51.9% (27/52). The majority of injuries required suture repair, 80.8% (42/52). Estimated blood loss in cases with vascular injury ranged from 100 mL to massive unquantifiable blood loss in the case of an aortic injury. Patients required a median of 2units of packed red blood cells. Postoperative complications included anemia requiring blood transfusion, 19.6% (9/46) and venous thromboembolism, 19.6% (9/46). CONCLUSIONS: Vascular injury remains a rare but potentially morbid complication of gynecologic oncologic surgery. Prompt recognition and management are imperative in minimizing persistent bleeding and complications.

BTN3A1 governs antitumor responses by coordinating αß and γδ T cells.

Gamma delta (γδ) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of γδ T cells can be elicited by butyrophilin and butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members, yet how they regulate and coordinate αß and γδ T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive αß T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of αß T cell effector activity and BTN2A1-dependent γδ lymphocyte cytotoxicity against BTN3A1+ cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by αß and γδ T cells and may present a treatment strategy for tumors resistant to existing immunotherapies.

Intrauterine cleaning after placental delivery at cesarean section: a randomized controlled trial.

OBJECTIVE: The objective of this study is to evaluate whether omission of intrauterine cleaning increases intraoperative and postoperative complications among women who deliver via cesarean section. METHODS: We randomized 206 women undergoing primary elective cesarean deliveries to intrauterine cleaning or omission of cleaning. Postpartum endomyometritis rates across groups were the primary outcome. We also examined secondary outcomes. To detect a 20% difference in infection rate between the cleaned and the non-cleaned groups (two-tailed [alpha] = 0.05, [beta] = 0.2), 103 women were required per group. Analysis was by intention-to-treat. RESULTS: Two hundred and six were randomized as follows: 103 to intrauterine cleaning and 103 to omission of cleaning after placental delivery. There were no statistically significant differences in the rate of endomyometritis between the two groups (2.0% versus 2.9%, RR =0.60; 95% CI 0.40-1.32). There were no statistically significant differences in postpartum hemorrhage rates (5.8% versus 7.7%, RR 0.75; 95% CI 0.6-1.2), hospital readmission rates (2.9 versus 3.8%, RR 0.75; 95% CI 0.5-1.6), time to return of gastrointestinal function, need for repeat surgery, or quantitated blood loss between the two groups. CONCLUSIONS: Our randomized controlled trial provides evidence suggesting that omission of intrauterine cleaning during cesarean deliveries in women at low risk of infection does not increase intraoperative or postoperative complications.

Ornithine decarboxylase as a therapeutic target for endometrial cancer.

Ornithine Decarboxylase (ODC) a key enzyme in polyamine biosynthesis is often overexpressed in cancers and contributes to polyamine-induced cell proliferation. We noted ubiquitous expression of ODC1 in our published endometrial cancer gene array data and confirmed this in the cancer genome atlas (TCGA) with highest expression in non-endometrioid, high grade, and copy number high cancers, which have the worst clinical outcomes. ODC1 expression was associated with worse overall survival and increased recurrence in three endometrial cancer gene expression datasets. Importantly, we confirmed these findings using quantitative real-time polymerase chain reaction (qRT-PCR) in a validation cohort of 60 endometrial cancers and found that endometrial cancers with elevated ODC1 had significantly shorter recurrence-free intervals (KM log-rank p = 0.0312, Wald test p = 5.59e-05). Difluoromethylornithine (DFMO) a specific inhibitor of ODC significantly reduced cell proliferation, cell viability, and colony formation in cell line models derived from undifferentiated, endometrioid, serous, carcinosarcoma (mixed mesodermal tumor; MMT) and clear cell endometrial cancers. DFMO also significantly reduced human endometrial cancer ACI-98 tumor burden in mice compared to controls (p = 0.0023). ODC-regulated polyamines (putrescine [Put] and/or spermidine [Spd]) known activators of cell proliferation were strongly decreased in response to DFMO, in both tumor tissue ([Put] (p = 0.0006), [Spd] (p<0.0001)) and blood plasma ([Put] (p<0.0001), [Spd] (p = 0.0049)) of treated mice. Our study indicates that some endometrial cancers appear particularly sensitive to DFMO and that the polyamine pathway in endometrial cancers in general and specifically those most likely to suffer adverse clinical outcomes could be targeted for effective treatment, chemoprevention or chemoprevention of recurrence.