Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer.

OBJECTIVE: To evaluate adverse events (AEs) of combination lenvatinib plus pembrolizumab for the treatment of recurrent endometrial cancer (EC) and to assess outcomes by lenvatinib starting dose. METHODS: We retrospectively reviewed patients with recurrent EC treated with lenvatinib plus pembrolizumab at our institution between 10/1/2019-11/30/2021. Starting dose of lenvatinib was defined as standard (20 mg) or reduced (10 mg/14 mg). AEs were manually extracted through chart review and graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. PFS, overall survival (OS), and duration of response (DOR) were analyzed. RESULTS: Forty-three patients were identified; median age was 67 years (range, 54-85). The most common histologies were serous (35%), endometrioid (23%), and carcinosarcoma (21%). Starting lenvatinib doses were 10 mg (n = 10), 14 mg (n = 10), and 20 mg (n = 23). Median number of cycles received was 8 (range, 1-42). Twenty-four patients (56%) required ≥1 lenvatinib dose reduction; 3 (7%) discontinued lenvatinib, and 1 (2%) discontinued pembrolizumab for intolerance or AE. Thirty-six patients (84%) experienced grade ≥ 3 AEs; hypertension, weight loss, anemia, fatigue, and thrombocytopenia were most common. The standard dose group experienced significantly shorter observed PFS vs the reduced dose group (P = .02). There was no difference in DOR (P = .09) or OS (P = .27) between the groups. CONCLUSION: In clinical practice, AEs associated with combination lenvatinib plus pembrolizumab were common and comparable to Study 309/KEYNOTE-775 findings. AEs were similar regardless of starting lenvatinib dose. Further dose optimization studies of lenvatinib plus pembrolizumab may be indicated in recurrent EC. Clinical trial data remain the gold standard to guide starting lenvatinib dosing.

Laminin 211 inhibits protein kinase A in Schwann cells to modulate neuregulin 1 type III-driven myelination.

Myelin is required for proper nervous system function. Schwann cells in developing nerves depend on extrinsic signals from the axon and from the extracellular matrix to first sort and ensheathe a single axon and then myelinate it. Neuregulin 1 type III (Nrg1III) and laminin α2ß1γ1 (Lm211) are the key axonal and matrix signals, respectively, but how their signaling is integrated and if each molecule controls both axonal sorting and myelination is unclear. Here, we use a series of epistasis experiments to show that Lm211 modulates neuregulin signaling to ensure the correct timing and amount of myelination. Lm211 can inhibit Nrg1III by limiting protein kinase A (PKA) activation, which is required to initiate myelination. We provide evidence that excessive PKA activation amplifies promyelinating signals downstream of neuregulin, including direct activation of the neuregulin receptor ErbB2 and its effector Grb2-Associated Binder-1 (Gab1), thereby elevating the expression of the key transcription factors Oct6 and early growth response protein 2 (Egr2). The inhibitory effect of Lm211 is seen only in fibers of small caliber. These data may explain why hereditary neuropathies associated with decreased laminin function are characterized by focally thick and redundant myelin.

Benefits of multimodal enhanced recovery pathway in patients undergoing kidney transplantation.

BACKGROUND: Use of enhanced recovery after surgery (ERAS) pathways to accelerate functional recovery and reduce length of stay (LOS) has rarely been investigated in kidney transplantation (KTX). MATERIALS AND METHODS: Consecutive adult isolated KTXs between July 2015 and July 2016 (ERAS, n = 139) were compared with a historical cohort between January 2014 and July 2015 (HISTORIC, n = 95). RESULTS: Enhanced recovery after surgery recipients were significantly more likely to receive kidneys that were non-local (56.1% vs 4.2%), higher Kidney Donor Profile Index (36-85, 58.4% vs 45.2%; >85, 15.2% vs 10.7%), cold ischemia time ≥30 h (62.4% vs 4.7%), induced with antithymocyte globulin (97.1% vs 87.4%), and to develop delayed graft function (46.4% vs 25.0%). LOS was shorter by 1 day among ERAS (mean 4.59) compared to HISTORIC patients (mean 5.65) predominantly due to a shift in discharges within 3 days (32.4% vs 4.2%); 30-day readmission to the hospital (27.3% vs 27.4%) or emergency room visit (9.4% vs 7.4%) was similar. There was one 30-day death in the ERAS group and none in the HISTORIC group. Return to bowel function and early meal consumption were significantly associated with ERAS, however, with somewhat higher diarrhea and emesis rates. CONCLUSION: ERAS following KTX correlated with lower LOS without change in readmissions or ER visits despite higher delayed graft function rates.

The impact of the ban on elective surgery in New York City during the coronavirus outbreak on gynecologic oncology patient care.

Introduction: Elective surgical procedures were suspended during the coronavirus disease pandemic (COVID-19) in New York City (NYC) between March 16 and June 15, 2020. This study characterizes the impact of the ban on surgical delays for patients scheduled for surgery during this first wave of the COVID-19 outbreak. Methods: Patients who were scheduled for surgical treatment of malignant or pre-invasive disease by gynecologic oncologists at three NYC hospitals during NYC's ban on elective surgery were included. Outcomes of interest were the percentage of patients experiencing surgical delay and the nature of delays. Kruskal-Wallis, chi-square, and logistic regression tests were performed with significance set at p < 0.05. Results: Of the 145 patients with malignant or pre-invasive diseases scheduled for surgery during the ban on elective surgery, 40% of patients experienced one or more surgical delays, 10% experienced two or more and 1% experienced three surgical delays. Of patients experiencing an initial delay, 77% were hospital-initiated and 11% were due to known or suspected personal COVID-19. Overall, 81% of patients completed their planned treatment, and 93% of patients underwent their initially planned surgery. Among patients for whom adjuvant therapy was recommended, 67% completed their planned treatment, and the most common reasons for not completing treatment were medically indicated followed by concerns regarding COVID-19. Conclusion: During the ban on elective surgery in NYC during the first outbreak of the COVID-19 pandemic, many patients experienced minor surgical delays, but most patients obtained appropriate, timely care with either surgery or alternative treatment.