Multiple Gastrointestinal Immune-Related Adverse Events From Immune Checkpoint Inhibitor Therapy.

INTRODUCTION: We aimed to describe immune-related adverse events (irAEs) affecting multiple organs of the gastrointestinal system in patients who received immune checkpoint inhibitors. METHODS: Within a 2,843 patient retrospective cohort consisting of patients with cancer treated with immune checkpoint inhibitors, we used the Electronic Medical Record Search Engine, an information retrieval system, to search free text in the medical record to identify patients with multiple gastrointestinal irAEs. RESULTS: Thirteen patients developed multiple gastrointestinal irAEs (0.46%). The most common patterns of multisystem gastrointestinal irAE were colitis + pancreatitis and colitis + enteritis. DISCUSSION: Multisystem gastrointestinal irAEs are rare but warrant further characterization and attention.

Virtual Learning and Assessment in Rheumatology Fellowship Training: Objective Structured Clinical Examination Revisited.

OBJECTIVE: With the onset of the COVID-19 pandemic, an annual multi-institutional face-to-face rheumatology objective structured clinical examination (ROSCE) was transformed into a virtual format. The educational goals of the virtual ROSCE (vROSCE) were to reproduce the educational value of the previous in-person ROSCE, providing a valuable formative assessment of rheumatology training activities encompassing the 6 Accreditation Council for Graduate Medical Education (ACGME) core competencies for fellows-in-training (FITs). This article describes the novel design, feasibility, and stakeholder value of a vROSCE. METHODS: Through an established collaboration of 5 rheumatology fellowship training programs, in February 2021, a vROSCE was created and conducted using a Zoom platform. Station development included learning objectives, FIT instructions, faculty proctor instructions, and a checklist by which to provide structured formative feedback. An anonymous, optional web-based survey was sent to FIT participants to evaluate the experience. RESULTS: Twenty-three rheumatology FITs from 5 institutions successfully rotated through 6 stations in the vROSCE. Immediate feedback was given to each FIT using standardized rubrics structured around ACGME core competencies. A total of 65% of FITs (15 of 23) responded to the survey, and 93% of survey respondents agreed or strongly agreed that the vROSCE was a helpful educational activity and identified individualized opportunities for improvement. CONCLUSION: A vROSCE is an innovative, feasible, valuable, and well-received educational technology tool. The vROSCE enriched rheumatology FITs' education and offered collaborative learning experiences across institutions.

Immune Checkpoint Inhibitor-Related Pneumonitis in Lung Cancer: Real-World Incidence, Risk Factors, and Management Practices Across Six Health Care Centers in North Carolina.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are standard treatments for advanced non-small cell lung cancer and have expanded use in small cell lung cancer. Although generally better tolerated than traditional chemotherapy, immune-related adverse events, such as immune checkpoint inhibitor-related pneumonitis (ICI-P), remain poorly understood toxicities that limit ICI treatment and can result in considerable morbidity. In this retrospective case-control study, we assessed a lung cancer cohort to identify ICI-P risk factors. RESEARCH QUESTION: What are the risk factors, clinical presentations, radiographic findings, and outcomes for ICI-P in a real-world lung cancer cohort? Do chronic pulmonary diseases confer increased risk for ICI-P? STUDY DESIGN AND METHODS: Medical records from lung cancer patients receiving nivolumab, pembrolizumab, or combination ipilimumab and nivolumab at six centers in North Carolina were reviewed (January 2004-July 2017). Patients with ICI-P and control participants were characterized, and logistic regression was used to assess for ICI-P risk factors. RESULTS: Three hundred fifteen lung cancer patients who predominantly received nivolumab (76.5%) or pembrolizumab (22%) were included. The incidence of ICI-P was 9.5%, with a median time to diagnosis of 52.5 days. Most patients with ICI-P had cases of high severity, and eight patients (27%) died with ongoing ICI-P treatment. Development of ICI-P was independently associated with the presence of baseline fibrosis on chest CT scan (adjusted OR [aOR], 6.61; 95% CI, 2.48-17.7), a composite measure of obstructive lung disease (aOR, 2.79; 95% CI, 1.07-7.29), and treatment with pembrolizumab (aOR, 2.57; 95% CI, 1.08-6.11). INTERPRETATION: In this cohort, ICI-P was more common and severe than previously reported and carried an unexpectedly high mortality rate. Risk for ICI-P was shown to be independently associated with several chronic pulmonary diseases, which may account for the higher incidence of ICI-P in patients with lung cancer.

The C terminus of c-Src inhibits breast tumor cell growth by a kinase-independent mechanism.

Overexpression or increased activity of cellular Src (c-Src) is frequently detected in human breast cancer, implicating involvement of c-Src in the etiology of breast carcinomas. Curiously, overexpression of c-Src in tissue culture cells results in a weakly or non-transforming phenotype, indicating that it alone is not sufficient for oncogenesis. However, the protein has been demonstrated to potentiate mitogenic signals from transmembrane receptors. This report investigates the requirement for c-Src in breast cancer as a transducer and integrator of anchorage-dependent and -independent growth signals by utilizing the Src family pharmacological inhibitors, PP1 and PP2, or stable overexpression of the catalytically inactive c-Src mutant (K- c-Src). Both methods of inhibiting endogenous c-Src diminished formation of soft agar colonies and tumors in nude mice. The majority of the dominant-negative activity of K- c-Src was mapped to the Src homology 2 (SH2) domain and C-terminal half of the molecule, but not to the Unique domain, Src homology 3 (SH3) domain, or the N-terminal half of K- c-Src. Further analysis of the C terminus revealed that its ability to inhibit growth localized to the N-terminal lobe (N-lobe) of the catalytic region. These results underscore the requirement for c-Src to maintain the oncogenic phenotype of breast cancer cells and suggest that c-Src may be manipulated to inhibit cell growth by the direct disruption of its catalytic activity or the introduction of either the SH2 domain or the N-lobe of K- c-Src.