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Objectives: Microsatellite instability-high (MSI-H) and deficient DNA mismatch repair (dMMR) status have emerged as actionable biomarkers for advanced endometrial cancer (aEC). The objective of this study was to assess clinical outcomes and treatment patterns among MSI-H/dMMR aEC patients who had disease progression following prior systemic therapy (FPST) in the US., Methods: Endometrial Cancer Health Outcomes (ECHO) was a retrospective, medical chart review study of patients with MSI-H/dMMR aEC who had disease progression between 07/01/2016 and 12/31/2018 FPST and were not candidates for curative surgery. Data on patient demographics, clinical and treatment characteristics, and clinical outcomes were collected. Kaplan-Meier analyses were performed to estimate real-world progression-free survival (rwPFS) and overall survival (OS), stratified by drug class., Results: A total of 124 eligible patients who initiated second-line chemotherapy ± bevacizumab or immunotherapy were included. Mean age was 61.4 years at aEC diagnosis and 86.3% of patients were stage IIIB-IV. Median rwPFS and OS were 4.0 months (95% CI: 2.0-9.0) and 7.0 months (95% CI: 5.0-18.0), respectively, among 21 patients who received chemotherapy ± bevacizumab, and 29.0 months (95% CI: 18.0-NE) and not reached (95% CI: 30.0-NA), respectively, among 103 patients who received immunotherapy. Most patients (n = 92) received pembrolizumab; among these patients, rwPFS and OS were 29.0 months (95% CI: 18.0-NE) and 30 months (95% CI: 30.0-NA), respectively., Conclusions: Real-world evidence suggests that pembrolizumab monotherapy provides considerable clinical benefits and has become the standard of care for MSI-H/dMMR aEC patients FPST who are not candidates for curative surgery in real-world settings., Competing Interests: Declaration of Competing Interest Sneha Kelkar, Shelby Corman & Nifasha Rusibamayila report support from Merck & Co., Inc. during the conduct of the study; and consulting fees from Merck & Co., Inc. Vimalanand Prabhu and Robert Orlowski are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc., Rahway, NJ, USA. Vimalanand Prabhu reports stock from Merck & Co., Inc., Rahway, NJ, USA; and other financial interests from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.. Cynthia Macahilig & Shardul Odak report support from RTI-Health Solutions during the conduct of the study. Robert Orlowski reports support from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA during the conduct of the study; patents with Merck & Co., Inc., Rahway, NJ, USA; and stock from Merck & Co., Inc., Rahway, NJ, USA. Linda Duska reports support from Merck & Co., Inc. during the conduct of the study; grants/contracts from Genentech/Roche, Cerulean/NextGen/(GOG 3008), AbbVie/(GOG 3005), Tesaro, Pfizer, GlaxoSmithKlein/Novartis, Morab, MorphoTek, Merck & Co., Inc., Aduro BioTech, Syndax, Ludwig, LEAP Therapeutics, Eisai, Lycera, Inovio, Advaxis, Mersana, Verastem, Ellipses, Corcept, Plexxicon, Constellation, Arch, Mirasol, and Quest Pharmtech; royalties from Elsevier and JB Learning; consulting fees from MorphoTek, Merck & Co., Inc., Genentech/Roche, Advance Medical, UpToDate, Parexel, State of California and ClearView Health Care; personal fees from expert review; and leadership/board roles in ASCO, National Cancer Institute and British Journal of OB/GYN., (Copyright © 2022 Merck Sharp & Dohme LLC., a subsidiary Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Microsatellite instability (MSI) due to defective DNA mismatch repair has emerged as an actionable biomarker in advanced endometrial cancer (aEC). Currently, there are no treatment patterns and outcomes data in non-MSI-high (non-MSI-H) or mismatch repair proficient (pMMR) aEC patients following prior systemic therapy (FPST). Our goal was to describe real-world data in this population in the US in 2019 and prior years., Methods: Endometrial Cancer Health Outcomes (ECHO) is a retrospective patient chart review study conducted in the US. Patients with non-MSI-H/pMMR aEC and progression between 06/01/2016-06/30/2019 FPST were eligible. Data collected included patient demographics, clinical and treatment characteristics, and clinical outcomes. Kaplan-Meier analyses were performed to estimate time to treatment discontinuation, real-world progression-free survival (rwPFS), and overall survival (OS), separately by treatment category., Results: A total of 165 eligible patients initiated second-line therapy with chemotherapy ± bevacizumab (n = 140) or hormonal therapy (n = 25). Median age was 66.0 years at aEC diagnosis, 70.2% were Stage IIIB-IV, 40.0% had ECOG ≥ 2 at second-line therapy initiation. Median rwPFS was 5.0 months (95% CI: 4.0-6.0) for patients receiving chemotherapy ± bevacizumab and 5.5 months (95% CI: 3.0-29.0) for those receiving hormonal therapy. Median OS was 10.0 months (95% CI: 8.0-13.0) and 9.0 months (95% CI: 6.0-NA) in these groups, respectively., Conclusions: Non-MSI-H/pMMR patients who initiated second-line therapy with chemotherapy ± bevacizumab or hormonal therapy had poor clinical outcomes with a median survival less than 1 year and rwPFS less than 6 months. This was the first study to define the clinical unmet need in patients with non-MSI-H/pMMR aEC with conventional therapy., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Sneha Kelkar, Shelby Corman & Nifasha Rusibamayila are employees of Open Health and report that Open Health received consulting fees/funding support from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA during the conduct of the study; Vimalanand Prabhu is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and reports stock from Merck & Co., Inc.; Jingchuan Zhang reports support from Eisai Inc. during the conduct of the study; meeting/travel support from Eisai Inc.; and other financial interests from Eisai Inc. Cynthia Macahilig & Shardul Odak report support from RTI-Health Solutions during the conduct of the study. Linda Duska reports that University of Virginia School of Medicine, Charlottesville, VA received grants/contracts to support clinical research trials from Genentech/Roche, Cerulean/NextGen/(GOG 3008), AbbVie/(GOG 3005), Tesaro, Pfizer, GlaxoSmithKlein/Novartis, Morab, MorphoTek, Merck & Co., Inc., Aduro BioTech, Syndax, Ludwig, LEAP Therapeutics, Eisai, Lycera, Inovio, Advaxis, Mersana, Verastem, Ellipses, Corcept, Plexxicon, Constellation, Arch, Mirasol, and Quest Pharmtech Dr. Duska has received royalties from Elsevier and JB Learning; consulting fees from MorphoTek, Genentech/Roche, Advance Medical, UpToDate, Parexel, State of California and ClearView Health Care; personal fees from legal expert review; and payment for leadership/board roles in ASCO, National Cancer Institute and British Journal of OB/GYN.]., (© 2022 Merck Sharp & Dohme LLC., a subsidiary Merck & Co., Inc.,, The Author(s).)

The Program to Reduce Maternal Deaths in Tanzania was a 13-year (2006-2019) effort in the Kigoma region that evolved over 3 phases to improve and sustain the availability of, access to, and demand for high-quality maternal and reproductive health care services. The Program intended to bring high-quality care closer to more communities. Cutting across the Program was the routine collection of monitoring and evaluation data. The Program achieved significant reductions in maternal and perinatal mortality, a significant increase in the modern contraceptive prevalence rate, and a significant decline in the unmet need for contraception. By 2017, it was apparent that the Program was on track to meet or surpass many of the targets established by the Government of Tanzania. Over the following 2-plus years, efforts to sustain Program interventions intensified. In April 2019, the Program fully transitioned to Government of Tanzania oversight. Four key lessons were learned during implementation that are relevant to governments, donors, and implementing organizations working to reduce maternal mortality: (1) multistakeholder partnerships are critical; (2) demand creation for services, while critical, must rest on a foundation of well-functioning and high-quality clinical services; (3) it is imperative to not only collect robust monitoring and evaluation data, but to be responsive in real time to what the data reveal; and, (4) it is necessary to develop a deliberate sustainability strategy from the start. The Program in Kigoma demonstrates that decentralizing high-quality maternal and reproductive health services in remote, low-resource settings is both feasible and effective and should be considered in places with similar contexts. By embedding the Program in the existing health system, and through efforts to build local capacity, the improvements seen in Kigoma are likely to be sustained. Follow-up evaluations are planned, providing an opportunity to more directly assess sustainability., (© Prasad et al.)

Background: Our objective was to characterize the incidence, risk factors and clinical features of acute kidney injury (AKI) in patients receiving dabrafenib and trametinib., Methods: We performed a retrospective cohort study examining the kidney outcomes of patients in a large healthcare system who received dabrafenib/trametinib between 2010 and 2019. The primary outcome was AKI, defined as a 1.5-fold increase in serum creatinine from baseline within a 12-month study period. AKI severity and etiology was determined for each case by chart review. Logistic regression was used to evaluate baseline predictors of AKI., Results: A total of 199 patients who received dabrafenib in our healthcare system from 2010 to 2019 were included in the analysis. Forty-two patients (21%) experienced AKI within 12 months; 10 patients (5% of the total cohort, 24% of AKI patients) experienced AKI occurring during a dabrafenib/trametinib-induced febrile syndrome characterized by fever, chills, gastrointestinal symptoms and elevated liver enzymes. Preexisting liver disease was the only significant predictor of AKI in the cohort. One patient had biopsy-proven granulomatous acute interstitial nephritis that resolved with corticosteroids., Conclusions: Oncologists and nephrologists should be aware that AKI is common after dabrafenib/trametinib and a substantial number of cases occur in the setting of treatment-induced pyrexia., (© The Author(s) 2020. Published by Oxford University Press on behalf of the ERA.)

Background: Hyponatremia due to endocrinopathies such as adrenal insufficiency and hypothyroidism has been reported in patients receiving immune checkpoint inhibitors (ICIs). We determined the risk and predictors of hyponatremia and other electrolyte abnormalities in a 'real-world' sample of patients receiving ICIs to treat advanced malignancies., Methods: This was a retrospective observational study of all patients who received ICIs from a single cancer center between 2011 and 2018. Patients were followed for 12 months after initiation of ICIs or until death. Common Terminology for Cancer Adverse Events version 5.0 criteria were used to grade the severity of hyponatremia and other electrolyte abnormalities. The predictors of severe (Grade 3 or 4) hyponatremia were determined using a multivariable logistic regression model. The etiology of Grade 3 or 4 hyponatremia was determined by chart review., Results: A total of 2458 patients were included. Their average age was 64 years [standard deviation (SD) 13], 58% were male and 90% were white. In the first year after starting ICIs, 62% experienced hyponatremia (sodium <134 mEq/L) and 136 (6%) experienced severe hyponatremia (<124 mEq/L). Severe hyponatremia occurred on average 164 days (SD 100) after drug initiation. Only nine cases of severe hyponatremia were due to endocrinopathies (0.3% overall incidence). Risk factors for severe hyponatremia included ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor) use, diuretic use and non-White race. Other severe electrolyte abnormalities were also commonly observed: severe hypokalemia (potassium <3.0 mEq/L) occurred in 6%, severe hyperkalemia (potassium ≥6.1 mEq/L) occurred in 0.6%, severe hypophosphatemia (phosphorus <2 mg/dL) occurred in 17% and severe hypocalcemia (corrected calcium <7.0 mg/dL) occurred in 0.2%., Conclusions: Hyponatremia is common in cancer patients receiving ICIs. However, endocrinopathies are an uncommon cause of severe hyponatremia., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Pivotal trials in inflammatory bowel disease (IBD) demonstrate that earlier use of biologics is associated with greater likelihood of response/remission, but multiple studies have identified that in the real world, biologic treatment is often delayed, thereby limiting optimal effectiveness and increasing likelihood of adverse outcomes. Further assessment of patient, provider, and payor factors that contribute to therapy choice is needed. We assessed utilization of vedolizumab (VDZ) and performed a real-world assessment using administrative datasets. Here, we describe the different treatment patterns and demographics of patients who received VDZ., Methods: We identified VDZ-treated patients (aged ≥18 years) with Crohn's disease (CD) or ulcerative colitis (UC) in the MarketScan commercial and Medicare claims databases from 2017 to 2019 and included those who had continuous enrollment in the same health plan for ≥12 months prior to their initial IBD diagnostic claim, ≥1 VDZ claim after the initial IBD diagnosis, and continuous enrollment for ≥12 months prior to and after their initial UC or CD diagnosis. Patients exposed to VDZ, anti-TNF, or other biologic therapy in the 12-month pre-index period were excluded. We pre-defined 5 treatment pathways: (1) EARLY VDZ - VDZ within 30 days of first IBD diagnostic claim; (2) DELAYED VDZ 1 - immunomodulators and then switch to VDZ; (3) DELAYED VDZ 2 - corticosteroids with immunomodulators prior to VDZ; (4) DELAYED VDZ 3 - 5-ASA with corticosteroids prior to VDZ; or (5) DELAYED VDZ 4 - 5-ASA with corticosteroids and immunomodulators prior to VDZ. Differences in patient baseline characteristics among these treatment pathways were analyzed descriptively., Results: We identified 136,315 patients with UC and 103,591 with CD, from which 1,342 patients with UC (median age 43 years; 51.0% male; 96.4% commercially insured; 86.4% diagnosed in 2017) and 964 with CD (median age 45 years; 43.6% male; 94.6% commercially insured; 88.6% diagnosed in 2017) received VDZ and met criteria. The proportions of patients by treatment pathway were (UC|CD): EARLY VDZ (6.6%|9.6%); DELAYED VDZ 1 (7.5%|19.0%); DELAYED VDZ 2 (14.8%|36.8%); DELAYED VDZ 3 (37.6%|19.0%); DELAYED VDZ 4 (33.4%|15.6%). Among patients with UC, EARLY VDZ vs DELAYED VDZ cohorts had median age of 40 vs 44 years and proportion of men of 46.1% vs 51.4%. Among patients with CD, EARLY VDZ vs DELAYED VDZ had median age of 43 vs 45 years and proportion of men of 39.8%% vs 43.9%. For both indications, no meaningful differences among treatment groups by geographic region, payor type (i.e., commercial vs Medicare), and year of diagnosis were observed., Conclusion: In this administrative real-world dataset, fewer than 10% of patients with IBD were treated with VDZ within 30 days of diagnosis, and these patients were more likely to be younger and women. These findings are distinct from guidelines suggesting VDZ may be used earlier, or due to its safety profile, preferentially in older patients at higher risk for infection. Further analyses of safety and effectiveness outcomes are underway., (Copyright © 2021 by The American College of Gastroenterology.)