High-dose ascorbate exerts anti-tumor activities and improves inhibitory effect of carboplatin through the pro-oxidant function pathway in uterine serous carcinoma cell lines.

OBJECTIVE: Uterine serous carcinoma is a highly aggressive non-endometrioid subtype of endometrial cancer with poor survival rates overall, creating a strong need for new therapeutic strategies to improve outcomes. High-dose ascorbate (vitamin C) has been shown to inhibit cell proliferation and tumor growth in multiple preclinical models and has shown promising anti-tumor activity in combination with chemotherapy, with a favorable safety profile. We aimed to study the anti-tumor effects of ascorbate and its synergistic effect with carboplatin on uterine serous carcinoma cells. METHODS: Cell proliferation was evaluated by MTT and colony formation assays in ARK1, ARK2 and SPEC2 cells. Cellular stress, antioxidant ability, cleaved caspase 3 activity and adhesion were measured by ELISA assays. Cell cycle was detected by Cellometer. Invasion was measured using a wound healing assay. Changes in protein expression were determined by Western immunoblotting. RESULTS: High-dose ascorbate significantly inhibited cell proliferation, caused cell cycle arrest, induced cellular stress, and apoptosis, increased DNA damage, and suppressed cell invasion in ARK1 and SPEC2 cells. Treatment of both cells with 1 mM N-acetylcysteine reversed ascorbate-induced apoptosis and inhibition of cell proliferation. The combination of ascorbate and carboplatin produced significant synergistic effects in inhibiting cell proliferation and invasion, inducing cellular stress, causing DNA damage, and enhancing cleaved caspase 3 levels compared to each compound alone in both cells. CONCLUSIONS: Ascorbate has potent antitumor activity and acts synergistically with carboplatin through its pro-oxidant effects. Clinical trials of ascorbate combined with carboplatin as adjuvant treatment of uterine serous carcinoma are worth exploring.

Clinicopathologic Evaluation of CTNNB1 Mutations in High-Intermediate Risk Endometrial Endometrioid Carcinoma.

CTNNB1 mutations convey increased risk of recurrence in low-risk endometrial endometrioid carcinoma (EEC). Results from previous high-intermediate risk (HIR) cohorts are mixed. The aims of this study were to correlate CTNNB1 mutational status with clinical outcomes and to evaluate the relationship between CTNNB1 mutations and the 4 prognostic subgroups defined by The Cancer Genome Atlas in HIR EEC. CTNNB1 mutational status was determined by Sanger sequencing of exon 3 of the CTNNB1 gene. Mismatch repair, POLE , p53, and L1 cell-adhesion molecule (L1CAM) status were also evaluated. Descriptive statistics and survival analyses were performed. Eighty-eight cases of HIR EEC were identified, of which 22 (25%) were CTNNB1 mutant ( CTNNB1 -mut) and 66 (75%) were wild-type ( CTNNB1 -WT). Median follow-up was 60 mo. Recurrence occurred in 13/88 (15%) patients. Recurrence rates were not significantly different between patients with CTNNB1- mut and CTNNB1- WT tumors (14% vs. 15%, P =0.86). Recurrence-free survival and overall survival were not significantly different (recurrence-free survival hazard ratio: 0.97, 95% confidence interval: 0.27-3.52, P =0.96; overall survival hazard ratio: 0.23, 95% confidence interval: 0.03-1.71, P =0.15). Mismatch repair deficiency was more prevalent in CTNNB1 -WT compared with CTNNB1 -mut tumors (46% vs. 14%, P =0.01); prevalence of POLE mutations and aberrant p53 were not significantly different. In contrast to patients with low-risk EEC, no differences in recurrence or survival were found in patients with HIR EEC with CTNNB1- mut compared with CTNNB1 -WT tumors.

Patterns of palliative care referral in platinum resistant ovarian cancer demonstrate reactive rather than proactive approach.

Objective: To evaluate patterns of palliative care (PC) integration in patients with platinum resistant ovarian cancer. Methods: Single institution retrospective study of patients with ovarian, tubal, or peritoneal high-grade carcinoma treated 2011-2020. Platinum resistance was identified by chemotherapy regimen or provider definition. Data was extracted evaluating treatment regimens, time to progression, PC and hospice referrals, and survival. Descriptive statistics and survival analyses were performed. Results: We identified 258 patients with platinum resistant ovarian cancer. Median survival from diagnosis of platinum resistance was 15 months (range 0-161). Most (71 %) patients were referred to PC, with 43 % of referrals within 3 months of death. Fourteen percent of patients were referred directly to hospice without PC involvement. Of 46 patients living with platinum resistant disease, 93 % meet criteria for early PC referral, but less than half have seen PC. Median time from platinum resistance to PC referral was 9 months (range 0-157) and from PC referral to death was 3 months (range 0-110). Median time from platinum resistance to hospice referral was 7 months (range 1-57) and from hospice referral to death was < 1 month (range 0-12). Conclusion: While rates of PC referral in our cohort are high compared with other single institution cohorts, timing of PC referral suggests referral patterns that are reactive to clinical decline rather than proactive as per national recommendations. A significant percentage of patients are directly referred to hospice for end-of-life care, reflecting missed opportunity for concurrent PC and oncology care earlier in the disease course. Diagnosis of platinum resistance should serve as a stimulus for PC involvement.

Impact of blinding interviewers to written applications on ranking of Gynecologic Oncology fellowship applicants from groups underrepresented in medicine.

Biases in application review may limit access of applicants who are underrepresented in medicine (URM) to graduate medical training opportunities. We aimed to evaluate the association between blinding interviewers to written applications and final ranking of all applicants and URM applicants for Gynecologic Oncology fellowship. During 2020 virtual Gynecologic Oncology fellowship interviews, we blinded one group of interviewers to written applications, including self-reported URM status. Interviewers visually interacted with the applicants but did not review their application. Interviewers submitted independent rank lists. We compared pooled rankings of blinded and non-blinded interviewers for all applicants and for URM applicants using appropriate bivariate statistics. We received 94 applications for two positions through the National Resident Matching Program, of which 18 (19%) self-identified as URM. We invited 40 applicants to interview and interviewed 30 applicants over six sessions. Ten interviewees (33%) self-identified as URM. Of 12 or 13 faculty interviewers during each interview session, 3 or 4 were blinded to the written application. There was no statistically significant difference in rank order when comparing blinded to non-blinded interviewers overall. However, blinded interviewers ranked URM applicants higher than non-blinded interviewers (p = 0.04). Blinding of written application metrics may allow for higher ranking of URM individuals.

Case report of a paraganglioma arising from a mature cystic teratoma of the ovary.

Paragangliomas are rare neuroendocrine neoplasms derived from sympathetic or parasympathetic paraganglia and have the ability to secrete catecholamines. We present the case of a 37-year-old asymptomatic female who underwent right ovarian cystectomy for a mature cystic teratoma and was found to have an intra-tumoral paraganglioma. More research is needed to determine metastatic potential as well as the likelihood of recurrence of these unique neoplasms.

Mismatch repair deficiency identifies patients with high-intermediate-risk (HIR) endometrioid endometrial cancer at the highest risk of recurrence: A prognostic biomarker.

BACKGROUND: The objective of this study was to assess the correlation between mismatch repair (MMR) status, disease recurrence patterns, and recurrence-free survival (RFS) in patients with high-intermediate-risk (HIR) endometrioid endometrial cancer (EEC). METHODS: A single-institution chart review for consecutive patients who were diagnosed with ECC between 2007 and 2016 was undertaken. Tumor MMR status was determined for all patients based on reported findings for mutL homolog 1 (MLH1), postmeiotic segregation (PMS2), mutS homolog 2 (MSH2), and MSH6 immunohistochemistry; and defective MMR (dMMR) status was defined as the lack of expression of at least 1 of these proteins. Patients were classified with HIR EEC according to criteria used for Gynecologic Oncology Group study 249. The factors associated with recurrence were assessed by logistic regression. RFS and associated factors were assessed by Kaplan-Meier survival analysis and Cox proportional-hazards models. RESULTS: In total, 197 patients who had HIR EEC (64 with dMMR and 133 with intact MMR [iMMR]) were identified, of whom 32 (16.2%) developed recurrent disease. The median follow-up was 54 months. The recurrence rate for women who had dMMR was 28% compared with 10.5% for those who had iMMR (P = .002), independent of the type of adjuvant therapy they received. The increase in distant recurrences among patients who had dMMR was even more pronounced (14.1% vs 3%; P = .003). The estimated 5-year RFS was 66% for women who had dMMR compared with 89% for those who had iMMR (P = .001). Excluding isolated vaginal recurrences, the difference in 5-year RFS was 73.5% versus 95%, respectively (P = .0004). CONCLUSIONS: Patients who had HIR EEC with dMMR had increased rates of recurrence and decreased RFS compared with those who had HIR EEC with iMMR, despite the receipt of similar adjuvant treatment. The current findings highlight the need for alternative treatment options and the importance of MMR status as a biomarker for patients with HIR EEC.

Creation and initial assessment of a second-trimester uterine model.

INTRODUCTION: Training for obstetrics and gynecology residents in second-trimester dilation and evacuation (D&E) procedures is extremely limited despite the Accreditation Council for Graduate Medical Education mandating all residents to receive abortion training. Simulation-based training improves surgical competence, but no second-trimester uterine models exist. The purposes of this study were to create a realistic, low-cost model and to assess the prototype. METHODS: A uterine model was created with 6 silicone cervixes of varying texture and dilations that are interchangeable. The uterus is neoprene and opens to allow for objects to be placed within it for extraction. At a national meeting, experienced D&E surgeons assessed the prototype by using the model and then completing a questionnaire. RESULTS: Twenty-one expert surgeons completed the questionnaires. Participants rated the prototype as "useful" or "very useful" for teaching extraction skills and for training in general. Subjects agreed this represented a clinical scenario they were likely to encounter and the model allowed for practicing the necessary steps for performing D&Es. The model cost approximately $35 to fabricate. CONCLUSIONS: Expert surgeons believe that this model accurately and realistically replicates a second-trimester uterus and cervix. This prototype may be used in simulation environments to train obstetrics and gynecology residents.