Worldwide, obesity has become a major public health crisis. Overweight and obesity not only increase the risk of cardiovascular disease and type-2 diabetes, but also are now known risk factors for a variety of cancer types. Among all cancers, increasing body mass index is most strongly associated with endometrial cancer incidence and mortality. The molecular mechanisms underlying how adipose tissue and obesity contribute to the pathogenesis of endometrial cancer are becoming better understood and have revealed a number of rational strategies, both behavioral and pharmaceutical, for the prevention of both primary and recurrent disease.

Background The COVID-19 pandemic has led highly developed healthcare systems to the brink of collapse due to the large numbers of patients being admitted into hospitals. One of the potential prognostic indicators in patients with COVID-19 is frailty. The degree of frailty could be used to assist both the triage into intensive care, and decisions regarding treatment limitations. Our study sought to determine the interaction of frailty and age in elderly COVID-19 ICU patients. Methods A prospective multicentre study of COVID-19 patients ≥ 70 years admitted to intensive care in 138 ICUs from 28 countries was conducted. The primary endpoint was 30-day mortality. Frailty was assessed using the clinical frailty scale. Additionally, comorbidities, management strategies and treatment limitations were recorded. Results The study included 1346 patients (28% female) with a median age of 75 years (IQR 72–78, range 70–96), 16.3% were older than 80 years, and 21% of the patients were frail. The overall survival at 30 days was 59% (95% CI 56–62), with 66% (63–69) in fit, 53% (47–61) in vulnerable and 41% (35–47) in frail patients (p < 0.001). In frail patients, there was no difference in 30-day survival between different age categories. Frailty was linked to an increased use of treatment limitations and less use of mechanical ventilation. In a model controlling for age, disease severity, sex, treatment limitations and comorbidities, frailty was independently associated with lower survival. Conclusion Frailty provides relevant prognostic information in elderly COVID-19 patients in addition to age and comorbidities. Trial registration Clinicaltrials.gov: NCT04321265, registered 19 March 2020.

Metformin is an oral biguanide commonly used for the treatment of type II diabetes and has recently been demonstrated to possess anti-proliferative properties that can be exploited for the prevention and treatment of a variety of cancers. The mechanisms underlying this effect have not been fully elucidated. Using both in vitro and in vivo models, we examined the effects of metformin on endometrial tumors with defined aberrations in the PI3K/PTEN/mTOR and MAPK signaling pathways to understand metformin mechanism of action and identify clinically useful predictors of response to this agent. In vitro assays of proliferation, cytotoxicity, and apoptosis were used to quantify the effects of metformin on endometrial cancer cell lines with mutations in the PI3K/PTEN/mTOR and MAPK signaling pathways. The in vivo effects of oral metformin on tumor progression were further examined using xenograft mouse models of endometrial cancer. K-Ras localization was analyzed by confocal microscopy using GFP-labeled oncogenic K-Ras and by immunoblot following subcellular fractionation. Metformin inhibited cell proliferation, induced apoptosis, and decreased tumor growth in preclinical endometrial cancer models, with the greatest response observed in cells harboring activating mutations in K-Ras. Furthermore, metformin displaces constitutively active K-Ras from the cell membrane, causing uncoupling of the MAPK signaling pathway. These studies provide a rationale for clinical trials using metformin in combination with PI3K targeted agents for tumors harboring activating K-Ras mutations, and reveal a novel mechanism of action for metformin.

Purpose: Treatment for patients with recurrent endometrioid endometrial cancer (EEC) are limited as paclitaxel is the only second-line chemotherapy with a response rate >13%. Targeting PIK3/mTOR in combination with hormonal therapy has shown promise. The addition of metformin may enhance this response. We conducted a phase II study evaluating everolimus, letrozole, and metformin in advanced/recurrent EEC.Patients and Methods: A Simon two-stage design was employed. Women with 2 prior chemotherapy regimens for recurrence were eligible. Pretreatment biopsy was required, followed by everolimus 10 mg orally, letrozole 2.5 mg orally, and metformin 500 mg orally twice a day on a 4-week cycle. The primary endpoint was clinical benefit (CB), defined as complete response (CR), partial response (PR), or stable disease (SD) confirmed at 16 weeks. Patients were treated until progression or toxicity.Results: Sixty-two patients were enrolled. Median age was 62 years (40-77) with 401 cycles completed, median of 6 cycles (1-31). Fifty-four patients were evaluable for response with a CB rate of 50% (27/54). Best overall response (OR) was PR 28% (15/54) and SD 22% (12/54). Thirteen patients received >12 cycles. Median follow-up was 17.9 months (2-47). Median progression-free survival was 5.7 [95% confidence interval (CI), 3.0-8.1] and OS was 19.6 months (95% CI, 14.2-26.3). Positive progesterone receptor expression was associated with CB (89.5% vs. 27.3%, P ¼ 0.001).Conclusions: Everolimus, letrozole, and metformin resulted in 50% CB and 28% OR in women with recurrent EEC. Progesterone receptor-positive tumors may have better response; validation studies are needed.See related commentary by Madariaga et al., p. 523