Survival Outcomes and Patterns of Recurrence After Adjuvant Vaginal Cuff Brachytherapy and Chemotherapy in Early-Stage Uterine Serous Carcinoma

Background: Uterine serous carcinoma (USC) is a relatively rare histology that portends a poor prognosis. The optimal adjuvant therapy for early-stage USC remains controversial; however, adjuvant vaginal cuff brachytherapy (VB) and chemotherapy is a commonly utilized strategy. Objectives: We sought to characterize predictors of survival endpoints and determine recurrence patterns in women with early-stage USC who received adjuvant VB and chemotherapy. Methods: We queried our prospectively maintained database for patients with 2009 FIGO stages I-II USC who underwent adequate surgical staging at our institution and received adjuvant chemotherapy with carboplatin and paclitaxel along with VB. We excluded women with synchronous malignancies. Overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were assessed by Kaplan-Meier and log-rank tests. Univariate (UVA) and multivariate analyses (MVA) were performed to identify statistically significant predictors of survival endpoints. Variables with P\u3c0.1 on UVA were included in a MVA and any variable with P\u3c0.05 was considered statistically significant. Results: We identified 77 women who met our inclusion criteria who underwent surgical staging between 1991 and 2018. The median follow-up time was 36 months (range 6-125). The median age was 66 years. Of the cohort, 70% were FIGO stage IA, 17% were stage IB, and 13% were stage II. The median number of dissected lymph nodes (LN) was 22. There were 10 women (13%) diagnosed with a recurrence with a median time to recurrence of 12.0 months. The main site of initial recurrence was distant in seven patients (70%) with the remaining recurrences being pelvic/para-aortic. The 5-year RFS for patients who experienced a distant recurrence was 87% (95% Confidence Interval [CI] 0.75-0.94). For the entire cohort, 5-year OS, DSS, and RFS were 83% (95% CI 0.68-0.91), 92% (95% CI 0.78-0.97), and 83% (95% CI 0.71-0.91), respectively. The sole predictor of 5-year OS on UVA was receipt of omentectomy (P=0.09). The predictors of 5-year DSS on UVA were presence of positive peritoneal cytology (P=0.03), number of LN examined (Hazard Ratio [HR] 1.10, 95% CI 1.00-1.21, P=0.05), and number of para-aortic LN examined (HR 1.16 [95% CI 1.01-1.32], P=0.03). The sole independent predictor of DSS was the presence of positive peritoneal cytology (HR 0.03 [95% CI 0.00-0.72], P=0.03). Predictors of five-year RFS on UVA were robotic vs open surgery technique (P=0.06), presence of positive peritoneal cytology (P=0.01), percent myometrial invasion (HR 5.59 [95% CI 0.84-37.46], P=0.08), and presence of lymphovascular space invasion (LVSI) (P=0.05). Conclusions: Five-year survival outcomes were promising in this cohort of women with early-stage USC treated with adjuvant chemotherapy and VB; however, this study shows that the predominant pattern of relapse in this population is distant, suggesting the need to optimize systemic therapy. Possible predictors of worse outcomes include positive peritoneal cytology, deep myometrial invasion, and presence of LVSI. Multi-institutional pooled analyses are warranted to confirm our study results

A patient perspective on applying intermittent fasting in gynecologic cancer

OBJECTIVE: Researchers sought patient feedback on a proposed randomized controlled trial (RCT) in which gynecological cancer patients would modify their diets with intermittent fasting to gain insight into patients\u27 perspectives, receptivity, and potential obstacles. A convenience sample of 47 patients who met the inclusion criteria of the proposed RCT provided their feedback on the feasibility and protocols of the RCT using a multi-method approach consisting of focus groups (n = 8 patients) and surveys (n = 36 patients). RESULTS: Patients were generally receptive to the concept of intermittent fasting, and many expressed an interest in attempting it themselves. Patients agreed that the study design was feasible in terms of study assessments, clinic visits, and biospecimen collection. Feedback on what could facilitate adherence included convenient appointment scheduling times and the availability of the research team to answer questions. Regarding recruitment, patients offered suggestions for study advertisements, with the majority concurring that a medical professional approaching them would increase their likelihood of participation

Metformin prevents aggressive ovarian cancer growth driven by high-energy diet: similarity with calorie restriction.

Caloric restriction (CR) was recently demonstrated by us to restrict ovarian cancer growth in vivo. CR resulted in activation of energy regulating enzymes adenosine monophosphate activated kinase (AMPK) and sirtuin 1 (SIRT1) followed by downstream inhibition of Akt-mTOR. In the present study, we investigated the effects of metformin on ovarian cancer growth in mice fed a high energy diet (HED) and regular diet (RD) and compared them to those seen with CR in an immunocompetent isogeneic mouse model of ovarian cancer. Mice either on RD or HED diet bearing ovarian tumors were treated with 200 mg/kg metformin in drinking water. Metformin treatment in RD and HED mice resulted in a significant reduction in tumor burden in the peritoneum, liver, kidney, spleen and bowel accompanied by decreased levels of growth factors (IGF-1, insulin and leptin), inflammatory cytokines (MCP-1, IL-6) and VEGF in plasma and ascitic fluid, akin to the CR diet mice. Metformin resulted in activation of AMPK and SIRT1 and inhibition of pAkt and pmTOR, similar to CR. Thus metformin can closely mimic CR\u27s tumor suppressing effects by inducing similar metabolic changes, providing further evidence of its potential not only as a therapeutic drug but also as a preventive agent

Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer

BACKGROUND: Nanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-α, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin. METHODS: Ovarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra-peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects. RESULTS: We show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model. CONCLUSION: Thus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy

Divergent Metabolic Effects of Metformin Merge to Enhance Eicosapentaenoic Acid Metabolism and Inhibit Ovarian Cancer In Vivo

Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines. Untargeted metabolomics showed metformin to have differential effects on glycolysis and TCA cycle metabolites, while consistent increased fatty acid oxidation intermediates were observed across the three cell lines. Metabolite set enrichment analysis showed alpha-linolenic/linoleic acid metabolism as being most upregulated. Downstream mediators of the alpha-linolenic/linoleic acid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were abundant in all three cell lines. EPA was more effective in inhibiting SKOV3 and CaOV3 xenografts, which correlated with inhibition of inflammatory markers and indicated a role for EPA-derived specialized pro-resolving mediators such as Resolvin E1. Thus, modulation of the metabolism of omega-3 fatty acids and their anti-inflammatory signaling molecules appears to be one of the common mechanisms of metformin\u27s antitumor activity. The distinct metabolic signature of the tumors may indicate metformin response and aid the preclinical and clinical interpretation of metformin therapy in ovarian and other cancers

Evaluation of a microperforate hymen leading to the incidental diagnosis of a borderline ovarian tumour

Microperforate hymens are rare anatomical variants with an unknown incidence and very few reported cases. Borderline ovarian tumours are similarly uncommon, with an incidence of approximately 0.002%-0.006%. The concurrent presence of a microperforate hymen and a borderline ovarian tumour is therefore exceedingly unique with no documented cases to date. In this report, we review the case of a nulliparous woman in her late 20s who initially presented with an inability to have penetrative intercourse. A subocclusive hymenal variant was noted on examination and further imaging work-up resulted in the incidental discovery of a large ovarian mass subsequently noted to be a borderline ovarian tumour. Herein, we review contemporary approaches to the diagnosis and management of both hymenal variants and borderline ovarian tumours, and discuss fertility-sparing strategies for young women diagnosed with ovarian neoplasms

Folic Acid Tagged Nanoceria As A Novel Therapeutic Agent In Ovarian Cancer

Background: Nanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-α, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin. Methods: Ovarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra-peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects. Results: We show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model. Conclusion: Thus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy

Quantification of recurrence risk based on number of adverse prognostic factors in women with stage I uterine endometrioid carcinoma

OBJECTIVE: The goal was to develop an updated model to predict the risk of recurrence, based on the number of adverse pathologic features in women with International Federation of Gynecology and Obstetrics stage I uterine endometrioid carcinoma, who did not undergo any adjuvant treatment. MATERIAL AND METHODS: Women at a single center who underwent surgical staging without adjuvant therapy between January 1990 and December 2019 were included. Cox proportional hazards model was used to identify independent predictors of relapse free survival (RFS). Prognostic groups were then created based on the number of independent predictors of recurrence that were identified (0, 1, or 2-3 risk factors). Overall survival (OS) and disease specific survival (DSS) were also calculated for each group. RESULTS: In total 1133 women were eligible for inclusion. Median follow-up was 84 months. Independent prognostic factors of recurrence included: age ≥60; grade 2 or 3 differentiation; and presence of lymphovascular space invasion (LVSI). Due to the small number of patients with either 2 or 3 risk factors, these groups were combined into one (group 2/3). Isolated vaginal cuff recurrence was the most common site of recurrence in all study groups (2%, 7%, and 17% for groups 0, 1, and 2/3, respectively). Five-year RFS rates were 96%, 85%, and 57% for groups 0, 1, and 2/3 (p\u3c0.01), respectively. Five-year DSS rates were 99%, 96%, and 85% and 5-year OS rates were 94%, 85%, and 62% (p\u3c0.01), respectively. CONCLUSION: We identified older age, high grade, and presence of LVSI as independent predictors of recurrence for women with stage I uterine endometrioid carcinoma. Using these prognostic factors, recurrence risk can be quantified for individual patients, and these factors can be used in deciding the appropriate adjuvant management course

Matched-pair Analysis for Survival Endpoints Between Women With Early-stage Uterine Carcinosarcoma and Uterine Serous Carcinoma

OBJECTIVE: The objective of this study was to compare survival endpoints between women with uterine carcinosarcoma and those with uterine serous carcinoma utilizing matching analysis. METHODS: Patients with stages I to II who underwent hysterectomy at our institution were included in this analysis. Patients with carcinosarcoma were then matched to patients with serous carcinoma based on stage, and adjuvant management received (observation, radiation treatment alone, chemotherapy alone, or combined modality with radiotherapy and chemotherapy. Recurrence-free survival, disease-specific survival, and overall survival were calculated for the 2 groups. RESULTS: A total of 134 women were included (67 women with carcinosarcoma and 67 with serous carcinoma, matched 1:1). There was no statistically significant difference between the 2 groups regarding 5-year recurrence-free survival (59% vs. 62%), disease-specific survival (66% vs. 67%), or overall survival (53% vs. 57%), respectively. The only independent predictor of shorter recurrence-free survival for the entire cohort was the lack of adjuvant combined modality therapy, while lower uterine segment involvement was the only independent predictor for shorter disease-specific survival. Lack of lymph node dissection and lack of adjuvant combined modality therapy were independent predictors of shorter overall survival. DISCUSSION: When matched based on stage and adjuvant treatment, our study suggests that there is no statistically significant difference in survival endpoints between women with early-stage carcinosarcoma and serous carcinoma. Adjuvant combined modality treatment is an independent predictor of longer recurrence-free survival and overall survival