Hemophagocytic lymphohistiocytosis (HLH) covers a wide array of related life-threatening conditions featuring ineffective immunity characterized by an uncontrolled hyperinflammatory response. HLH is often triggered by infection. Familial forms result from genetic defects in natural killer cells and cytotoxic T-cells, typically affecting perforin and intracellular vesicles. HLH is likely under-recognized, which contributes to its high morbidity and mortality. Early recognition is crucial for any reasonable attempt at curative therapy to be made. Current treatment regimens include immunosuppression, immune modulation, chemotherapy, and biological response modification, followed by hematopoietic stem-cell transplant (bone marrow transplant). A number of recent studies have contributed to the understanding of HLH pathophysiology, leading to alternate treatment options; however, much work remains to raise awareness and improve the high morbidity and mortality of these complex conditions.

Purpose: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is a recently identified T-cell coinhibitory receptor. In this study, we aimed to determine the clinical impact of TIGIT in patients with acute myelogenous leukemia (AML) and dissect the role of TIGIT in the pathogenesis of leukemia progression.Experimental Design: TIGIT expression on T cells from peripheral blood collected from patients with AML was examined by flow cytometry. The correlation of TIGIT expression to clinical outcomes, including rate of complete remission and relapse post-allogeneic stem cell transplantation (alloSCT) in AML patients, was analyzed. Phenotypic and functional study (cytokine release, proliferation, killing, and apoptosis) of TIGIT-expressing T cells were performed. Using siRNA to silence TIGIT, we further elucidated the regulatory role of TIGIT in the T-cell immune response by dissecting the effect of TIGIT knockdown on cytokine release and apoptosis of T cells from AML patients.Results: TIGIT expression on CD8 þ T cells is elevated in AML patients and high-TIGIT correlates with primary refractory disease and leukemia relapse post-alloSCT. TIGIT þ CD8 þ T cells display phenotypic features of exhaustion and exhibit functional impairment manifested by low production of cytokines and high susceptibility to apoptosis. Importantly, their functional defects are reversed by TIGIT knockdown. Conclusions: TIGIT contributes to functional T-cell impairment and associates with poor clinical outcome in AML. Our study suggests that blockade of TIGIT to restore T-cell function and antitumor immunity may represent a novel effective leukemia therapeutic.

The SARS-CoV-2 pandemic has highlighted the crucial role of pathologists in the health care system at a time of significant decline in the number of US medical students matching to pathology residency positions. To understand this decline, a national survey of fourth-year US allopathic medical students was conducted to assess experiences, knowledge, and attitudes of pathology and factors that impact specialty choice. Participating in a separate pathology course did not increase the probability of choosing pathology. Experiences significantly associated with choosing pathology included clinical or research opportunities in pathology during the last 2 years of medical school, autopsy observation/participation, and participation in pathology interest groups. Many respondents felt they were not sufficiently exposed to pathology to consider it as a specialty. Those who considered pathology but did not choose it were less likely to report understanding the activities of pathologists and being recruited by pathology faculty and more likely to express a preference for more direct patient contact as compared to those entering pathology. In general, respondents agreed that pathology has a good work–life balance and a satisfying degree of intellectual challenge. On the other hand, respondents generally agreed that information on social media and perception of the pathology job market do not seem to be positive and few agreed that pathology is a highly regarded specialty. We identify steps to address these issues and increase the number of US medical students choosing pathology as a specialty crucial to the future of medicine and public health.

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Professionalism and physician well-being are important topics in academic medicine. Lapses in professional judgment may lead to disciplinary action and put patient’s health at risk. Within medical education, students and trainees are exposed to professionalism in the institution’s formal curriculum and hidden curriculum. Development of professionalism starts early in medical school. Trainees entering graduate medical education already have developed professional behavior. As a learned behavior, development of professional behavior is modifiable. In addition to role modeling by faculty, other modalities are needed. Use of case vignettes based on real-life issues encountered in trainee and faculty behavior can serve as a basis for continued development of professionalism in trainees. Based on the experience of program directors and pathology educators, case vignettes were developed in the domains of service, research, and education and subdivided into the areas of duty, integrity, and respect. General and specific questions pertaining to each case were generated to reinforce model behavior and overcome professionalism issues encountered in the hidden curriculum. To address physician burnout, cases were generated to provide trainees with the skills to deal with burnout and promote well-being.