Immune Checkpoint Inhibitor-associated Diarrhea and Colitis: A Systematic Review and Meta-analysis of Observational Studies.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed the management of advanced malignancies but are associated with diarrhea and colitis. The objective of our systematic review and meta-analysis was to determine the incidence and outcomes of ICI-associated diarrhea and colitis. Bibliographic databases were searched through August 13, 2019, for observational studies of ICI therapy reporting the incidence and/or treatment of diarrhea or colitis. The primary outcome was ICI-associated diarrhea and colitis. Meta-analyses were performed with random-effects models. Twenty-five studies (N=12,661) were included. All studies had a high risk of bias in at least 1 domain. The overall incidence of diarrhea/colitis was 12.8% [95% confidence interval (CI), 8.8-18.2, I2=96.5]. The incidence was lower in patients treated with anti-programmed cell death 1/programmed death-ligand 1 (4.1%, 95% CI, 2.6-6.5) than in those treated with anti-cytotoxic T-cell lymphocyte-associated antigen 4 (20.1%, 95% CI, 15.9-25.1). The remission of diarrhea and/or colitis was higher in patients treated with corticosteroids plus biologics (88.4%, 95% CI, 79.4-93.8) than in those treated with corticosteroids alone (58.3%, 95% CI, 49.3-66.7, Q=18.7, P<0.001). ICI were permanently discontinued in 48.1% of patients (95% CI, 17.8-79.1). ICI were restarted after temporary interruption in 48.6% of patients (95% CI, 18.2-79.4) of whom 17.0% (95% CI, 6.4-30.0) experienced recurrence. Real-world incidence of ICI-associated diarrhea/colitis exceeds 10%. These events lead to permanent ICI discontinuation in just over 50% of patients, while <20% have recurrence of symptoms if ICI are resumed. Further studies are needed to identify patients who would benefit from early treatment with biologics as well as appropriate patients to resume ICI therapy.

EGG-4 and EGG-5 Link Events of the Oocyte-to-Embryo Transition with Meiotic Progression in C. elegans.

The molecular underpinnings of the oocyte-to-embryo transition are poorly understood. Here we show that two protein tyrosine phosphatase-like (PTPL) family proteins, EGG-4 and EGG-5, are required for key events of the oocyte-to-embryo transition in Caenorhabditis elegans. The predicted EGG-4 and EGG-5 amino acid sequences are 99% identical and their functions are redundant. In embryos lacking EGG-4 and EGG-5, we observe defects in meiosis, polar body formation, the block to polyspermy, F-actin dynamics, and eggshell deposition. During oogenesis, EGG-4 and EGG-5 assemble at the oocyte cortex with the previously identified regulators or effectors of the oocyte-to-embryo transition EGG-3, CHS-1, and MBK-2 [1, 2]. All of these molecules share a complex interdependence with regards to their dynamics and subcellular localization. Shortly after fertilization, EGG-4 and EGG-5 are required to properly coordinate a redistribution of CHS-1 and EGG-3 away from the cortex during meiotic anaphase I. Therefore, EGG-4 and EGG-5 are not only required for critical events of the oocyte-to-embryo transition but also link the dynamics of the regulatory machinery with the advancing cell cycle.