Plasmapheresis for Pembrolizumab-Induced Hepatitis in a Patient with Squamous Cell Carcinoma and Prior Orthotopic Liver Transplantation.

Checkpoint inhibitor therapy with monoclonal antibodies against programmed cell death protein 1 (PD1) has been implemented in the treatment of numerous malignancies. Pembrolizumab is one such medication. While severe toxicities are very rare, mild immune-mediated reactions with a variety of end organ injuries are among the most commonly encountered adverse events attributed to these medications. Acute liver injury manifesting as biochemical abnormalities with or without synthetic dysfunction is one such potential adverse reaction. Rarely, a relatively severe hepatitis can occur. While such severe adverse events are often successfully managed with systemic corticosteroids and drug discontinuation, our patient was refractory to standard management. We present a case of pembrolizumab-induced hepatitis in a patient with squamous cell carcinoma and prior orthotopic liver transplantation. Through a combination of serial plasmapheresis and intravenous immunoglobulin(IVIG) infusion, the patient's hepatitis resolved as evidenced by virtual normalization of his liver indices. This illustrates the effectiveness of a relatively novel treatment strategy for this rare side effect of checkpoint inhibitor antineoplastic therapy.

Safety and Efficacy of Moderate Sedation in Super Obese Patients Undergoing Lower and Upper GI Endoscopy: a Case-Control Study.

PURPOSE: Obesity is a disease of increasing prevalence. There is minimal research on the safety of sedation for general endoscopic procedures among super obese patients (BMI ≥ 50). The aim of our study was to evaluate the safety of moderate sedation and endoscopic procedural outcomes for super obese patients in a case-control study. MATERIALS AND METHODS: We completed an age and sex-matched case-control study comparing 132 super obese patients with 132 non-obese controls. We assessed intra-procedure adverse events, delayed adverse events, doses of sedation medication used, and procedure duration at a tertiary care setting. RESULTS: The mean BMI for the obese cohort was 55.6 compared with 22.5 for the controls (P < 0.001). The mean intra-procedure fentanyl and midazolam dose was higher for the obese patients compared with the controls, fentanyl 180 mcg, midazolam 7.7 mg vs fentanyl 148 mcg, midazolam 6.4 mg, respectively (P < 0.001). There was a significantly higher percentage of brief intra-procedure hypoxia (oxygen blood saturation < 90%) for the obese patients compared with the controls, 5% vs 0% (P = 0.02). There was no difference in delayed adverse events with 2% of the cases and 2% of the controls having delayed adverse events (P = 1.0). Procedure completion rates were 100% for both cases and controls. CONCLUSION: General endoscopic procedures can be safely and effectively performed in super obese patients with moderate sedation. Brief intra-procedure hypoxia more commonly occurs in super obese patients, and higher medication doses are required.

Indications for and outcomes of liver transplantation in patients with alcohol-associated liver disease.

The manufacture and consumption of alcohol are ubiquitous and as old as time. Alcohol use disorder (AUD) is defined as a problematic pattern of alcohol use leading to clinically significant impairment. The physical injuries that result from excessive alcohol consumption are varied including end-organ damage to liver (alcohol-associated liver disease [ALD]), pancreas, brain and heart, and systemic consequences including several forms of cancer. Liver transplantation (LT) remains the treatment of last resort for life-threatening liver disease. LT provides a valuable magnifying glass under which to examine the complex interactions between social drinking, AUD, and ALD. ALD is the second most frequent indication for LT in the US (data of 2015). We review the current data on evaluation of patients with AUD and ALD for liver transplantation; on the significance of abstinence from alcohol in patient selection and pre- and post-LT management. We discuss monitoring for relapse prior to and after LT. Finally, we look at outcomes, first from the perspective of impact on the allograft and then the perspective of maintaining the health of the LT patient with AUD, which includes management of addiction.

γδ T cell subsets play opposing roles in regulating experimental autoimmune encephalomyelitis.

γδ T cells are resident in cerebrospinal fluid and central nervous system (CNS) lesions of multiple sclerosis (MS) patients, but as multifaceted cells exhibiting innate and adaptive characteristics, their function remains unknown. Previous studies in experimental autoimmune encephalomyelitis (EAE) are contradictory and identified these cells as either promoting or suppressing disease pathogenesis. This study examines distinct γδ T cell subsets during EAE and indicates they mediate differential functions in CNS inflammation and demyelination resulting in pathogenesis or protection. We identified two γδ subsets in the CNS, Vγ1(+) and Vγ4(+), with distinct cytokine profiles and tissue specificity. Anti-γδ T cell receptor (TCR) monoclonal antibody (mAb) administration results in activation and downregulation of surface TCR, rendering the cells undetectable, but with opposing effects: anti-Vγ4 treatment exacerbates disease whereas anti-Vγ1 treatment is protective. The Vγ4(+) subset produces multiple pro-inflammatory cytokines including high levels of IL-17, and accounts for 15-20% of the interleukin-17 (IL-17) producing cells in the CNS, but utilize a variant transcriptional program than CD4(+) Th17 cells. In contrast, the Vγ1 subset produces CCR5 ligands, which may promote regulatory T cell differentiation. γδ T cell subsets thus play distinct and opposing roles during EAE, providing an explanation for previous reports and suggesting selective targeting to optimize regulation as a potential therapy for MS.

High-mobility group box 1 protein (HMGB1) neutralization ameliorates experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune, demyelinating disease and as such, the gold standard of treatment is to selectively suppress the pathogenic autoimmune response without compromising the entire arm of the adaptive immune response. One target of this strategy lying upstream of the pathologic adaptive immune response is the local, innate immune signaling that initiates and drives autoimmunity and sterile injury. High-mobility group box 1 protein (HMGB1) is a ubiquitous nuclear protein that when released from necrotic cells, such as damaged oligodendrocytes in MS lesions, drives pro-inflammatory responses. Here we demonstrate that HMGB1 drives neuroinflammatory responses in experimental autoimmune encephalomyelitis (EAE), a murine model for MS, and that inhibition of HMGB1 signaling ameliorates disease. Specifically i.v. injection of an HMGB1 neutralizing antibody in the C57BL/6 model of chronic EAE or SJL/J model of relapsing-remitting EAE ameliorated clinical disease prophylactically or during ongoing disease, blocked T cell infiltration of the central nervous system, and inhibited systemic CD4(+) T cell responses to myelin epitopes. Additionally, lymphocytes from EAE mice restimulated in vitro in the presence of recombinant HMGB1 exhibited increased proliferation and pro-inflammatory cytokine production, an effect that was blocked by anti-HMGB1 antibody. Similarly recombinant HMGB1 promoted proliferation and pro-inflammatory cytokine production of human peripheral blood mononuclear cells stimulated in vitro, and anti-HMGB1 antibody blocked this effect. These findings indicate that HMGB1 contributes to neuroinflammatory responses that drive EAE pathogenesis and that HMGB1 blockade may be a novel means to selectively disrupt the pro-inflammatory loop that drives MS autoimmunity.