Review article: Contemporary management of gastrointestinal, pancreatic and hepatic toxicities of immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective oncologic agents which frequently cause immune-related adverse events (irAEs) which can impact multiple organ systems. Onco-Gastroenterology is a novel and emerging subspecialty within gastroenterology focused on cancer treatment-related complications. Gastroenterologists must be prepared to identify and manage diverse immune-mediated toxicities including enterocolitis, hepatitis, pancreatitis and other ICI-induced toxicities. AIM: To provide a narrative review of the epidemiology, diagnostic evaluation and management of checkpoint inhibitor-induced gastrointestinal and hepatic toxicities. METHODS: We searched Cochrane and PubMed databases for articles published through August 2023. RESULTS: Gastrointestinal and hepatic irAEs include most commonly enterocolitis and hepatitis, but also pancreatitis, oesophagitis, gastritis, motility disorders (gastroparesis) and other rarer toxicities. Guidelines from the National Comprehensive Cancer Network, American Society of Clinical Oncology and European Society for Medical Oncology, in combination with emerging cohort and clinical trial data, offer strategies for management of ICI toxicities. Evaluation of irAEs severity by formal classification and clinical stability, and a thorough workup for alternative etiologies which may clinically mimic irAEs underlie initial management. Treatments include corticosteroids, biologics and other immunosuppressive agents plus supportive care; decisions on dosing, timing and choice of steroid adjuncts and potential for subsequent checkpoint inhibitor dosing are nuanced and toxicity-specific. CONCLUSIONS: Expanding clinical trial and cohort data have clarified the epidemiology and clinical characteristics of gastrointestinal, pancreatic and hepatic toxicities of ICIs. Guidelines, though valuable, remain based principally on retrospective cohort data. Quality prospective, controlled studies may refine algorithms for treatment and potential immunotherapy rechallenge.

Establishment of a high-content imaging assay for tau aggregation in hiPSC-derived neurons differentiated from two protocols to routinely evaluate compounds and genetic perturbations.

Aberrant protein aggregation is a pathological cellular hallmark of many neurodegenerative diseases, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), where the tau protein is aggregating, forming neurofibrillary tangles (NFTs), and propagating from neuron to neuron. These processes have been linked to disease progression and a decline in cognitive function. Various therapeutic approaches aim at the prevention or reduction of tau aggregates in neurons. Human induced pluripotent stem cells (hiPSCs) are a very valuable tool in neuroscience discovery, as they offer access to potentially unlimited amounts of cell types that are affected in disease, including cortical neurons, for in vitro studies. We have generated an in vitro model for tau aggregation that uses hiPSC - derived neurons expressing an aggregation prone, fluorescently tagged version of the human tau protein after lentiviral transduction. Upon addition of tau seeds in the form of recombinant sonicated paired helical filaments (sPHFs), the neurons show robust, disease-like aggregation of the tau protein. The model was developed as a plate-based high content screening assay coupled with an image analysis algorithm to evaluate the impact of small molecules or genetic perturbations on tau. We show that the assay can be used to evaluate small molecules or screen targeted compound libraries. Using siRNA-based gene knockdown, genes of interest can be evaluated, and we could show that a targeted gene library can be screened, by screening nearly 100 deubiquitinating enzymes (DUBs) in that assay. The assay uses an imaging-based readout, a relatively short timeline, quantifies the extent of tau aggregation, and also allows the assessment of cell viability. Furthermore, it can be easily adapted to different hiPSC lines or neuronal subtypes. Taken together, this complex and highly relevant approach can be routinely applied on a weekly basis in the screening funnels of several projects and generates data with a turnaround time of approximately five weeks.

Pancreatitis and Hyperlipasemia in the Setting of Immune Checkpoint Inhibitor Therapy.

BACKGROUND: Immune checkpoint inhibitor-induced pancreatic injury (ICI-PI) ranges from asymptomatic hyperlipasemia to symptomatic acute pancreatitis (AP). The proportion of pancreatic injury while receiving ICIs that is attributable to therapy remains unclear. We evaluated the etiology of hyperlipasemia in patients receiving ICIs, and the clinical characteristics, management, and outcomes of ICI-PI. PATIENTS AND METHODS: We assessed 6,450 consecutive adult patients with cancer who received ICI doses between 2011 and 2019, 364 of whom had at least 1 instance of elevated serum lipase after ICI initiation and were included in our trial. Primary outcomes were the development of ICI-PI and ICI-induced acute pancreatitis (ICI-AP). RESULTS: Pancreatic injury was attributable to ICI use in 105 individuals (29% of those with hyperlipasemia; 1.6% overall). Of 27 patients with ICI-AP, 4 (15%) presented asymptomatically with hyperlipasemia and pancreatic inflammation on imaging. In multivariable regression, the presence of other immune-related adverse events was positively associated with ICI-AP (≥2 events: odds ratio, 5.43; 95% CI, 1.47-26.03). Compared with patients with other ICI-PI, those with ICI-AP more frequently required steroids (74% vs 4%), intravenous fluids (85% vs 10%), hospitalization (89% vs 9%), and permanent cessation of ICIs due to pancreatic injury (70% vs 3%), and less frequently continued therapy uninterrupted (0% vs 40%) (P<.01 for all). Of the 105 patients, 3 (3%) developed exocrine insufficiency and 9 (9%) developed endocrine insufficiency, which were concentrated among those with ICI-AP. CONCLUSIONS: A minority of occurrences of pancreatitis and hyperlipasemia in patients receiving ICIs are due to these therapies, supporting NCCN recommendations to exclude alternative etiologies. Because a notable proportion of patients with ICI-AP were asymptomatic but warranted treatment per current guidelines, abdominal imaging is diagnostically valuable in those with significant hyperlipasemia. Patients with ICI-AP should be monitored for exocrine pancreatic insufficiency. Many with hyperlipasemia who do not meet the criteria for AP can continue therapy uninterrupted.

Prognostic Value of Inflammatory Bowel Disease-associated Biomarkers in Patients With Immune Checkpoint Inhibitor Enterocolitis: A Retrospective Cohort Study.

In the emerging field of immune checkpoint inhibitor enterocolitis, biomarkers to predict disease course are lacking. Select genetic polymorphisms (ATG16L1T300A) and serum amyloid A warrant further study as potential biomarkers associated with severe ICI enterocolitis.

Infliximab for Steroid-Refractory Immune Checkpoint Inhibitor-Induced Acute Pancreatitis.

Acute pancreatitis is an infrequent but clinically significant complication of immune checkpoint inhibitor (ICI) therapy. Guidelines recommend high-dose steroids and withdrawal of ICI in patients with severe ICI-induced pancreatitis. Management of steroid-refractory ICI pancreatitis is unclear. Infliximab is used to treat select extrapancreatic immune-related adverse events, but its role in ICI pancreatitis remains undefined. To our knowledge, we describe the first case of ICI pancreatitis successfully treated with infliximab after inadequate steroid response (recurrent pancreatitis on multiple attempted steroid tapers). Infliximab may be a viable treatment of steroid-refractory ICI pancreatitis. Further study of its potential effectiveness may improve guideline-directed care.

Immune checkpoint inhibitor gastritis is often associated with concomitant enterocolitis, which impacts the clinical course.

BACKGROUND: Gastrointestinal immune-related adverse events are frequently caused by immune checkpoint inhibitors (ICIs) and often require interruption of cancer treatment. Compared with ICI colitis and enteritis, limited information exists about ICI gastritis. This study characterized clinical features and treatment outcomes of ICI gastritis. METHODS: Consecutive cancer patients who received ICIs and underwent endoscopy with gastric biopsies while on ICIs from 2011 to 2021 were retrospectively assessed. Specific histopathologic features identified ICI gastritis. RESULTS: Of 6450 ICI-treated patients, 162 (2.5%) underwent endoscopy with gastric biopsies. ICI gastritis was identified in 54 (33%) biopsied patients; 38 (70%) had concurrent ICI enteritis/colitis and 16 (30%) had isolated ICI gastritis. Dyspepsia (38%) and bloating (25%) were the most frequent symptoms of isolated ICI gastritis. Compared with patients with concomitant enteritis/colitis, patients with isolated gastritis were less likely to have diarrhea (13% vs 68%; p < .001) or abdominal pain (19% vs 47%; p = .07). Patients with isolated ICI gastritis less frequently required glucocorticoids (69% vs 92%; p = .04) and had lower incidence of ICI hold/withdrawal (13% vs 42%; p = .06). There was no association between severity or extent of luminal inflammation and antitumor response (p = .85 and p = .44, respectively). Endoscopically, gastric mucosa appeared normal in 11 (20%) patients with biopsy-proven ICI gastritis. CONCLUSION: ICI gastritis may present alone or more commonly with concurrent enteritis/colitis, which may differentiate its clinical course. Gastric biopsies are required to diagnose a substantial minority of endoscopically normal, clinically significant cases. Most patients with isolated gastritis can continue ICI therapy uninterrupted, but a notable proportion require glucocorticoids. PLAIN LANGUAGE SUMMARY: Immune checkpoint inhibitors are effective anticancer treatments, but can cause inflammatory toxicities, including of the stomach (gastritis), intestine, and colon. Limited information is available on gastritis triggered by these agents. Adult patients with cancer who were treated with immune checkpoint inhibitors and had an upper gastrointestinal endoscopy with biopsies of the stomach were examined. More than two-thirds (70%) of people with checkpoint inhibitor gastritis also had inflammatory changes of the small intestine and/or colon. Compared with patients with isolated checkpoint gastritis, the subgroup with concomitant enteritis/colitis more frequently had abdominal pain, diarrhea, needed steroids, and/or needed to pause or stop antitumor therapy.

Mucor and Malignancy: A Double-Hit Case of Intestinal Ischemia.

Mucormycosis is an invasive fungal infection due to molds in the order Mucorales. These opportunistic pathogens found in soil or decaying organic matter mostly affect immunocompromised hosts. Rhino-orbital-cerebral, pulmonary, gastrointestinal, cutaneous, and disseminated patterns are possible. We describe a case of angioinvasive colonic mucormycosis in a patient with recent diabetic ketoacidosis and undiagnosed colon adenocarcinoma. The diagnosis was made on histopathology after the patient developed intestinal ischemia and underwent hemicolectomy. This case highlights the potentially diverse manifestations of Mucorales infections, typical and atypical risk factors, and the index of suspicion necessary for early diagnosis and outcome optimization.

Pharmacological mTOR-inhibition facilitates clearance of AD-related tau aggregates in the mouse brain.

In this study we aimed to reduce tau pathology, a hallmark of Alzheimer's Disease (AD), by activating mTOR-dependent autophagy in a transgenic mouse model of tauopathy by long-term dosing of animals with mTOR-inhibitors. Rapamycin treatment reduced the burden of hyperphosphorylated and aggregated pathological tau in the cerebral cortex only when applied to young mice, prior to the emergence of pathology. Conversely, PQR530 which exhibits better brain exposure and superior pharmacokinetic properties, reduced tau pathology even when the treatment started after the onset of pathology. Our results show that dosing animals twice per week with PQR530 resulted in intermittent, rather than sustained target engagement. Nevertheless, this pulse-like mTOR inhibition followed by longer intervals of re-activation was sufficient to reduce tau pathology in the cerebral cortex in P301S tau transgenic mice. This suggests that balanced therapeutic dosing of blood-brain-barrier permeable mTOR-inhibitors can result in a disease-modifying effect in AD and at the same time prevents toxic side effects due to prolonged over activation of autophagy.

Obesity and Eligibility for Obesity Treatments Among Adults With Disabilities in the U.S.

INTRODUCTION: Obesity has been associated with disability; yet, the proportion who meet clinical criteria for obesity treatment among adults with disabilities remains poorly defined. Characterization of obesity and treatment eligibility by disability type may prioritize high-need groups. This study assessed the prevalence of obesity and eligibility for antiobesity pharmacotherapy and/or bariatric surgery in adults with disability. METHODS: This cross-sectional weighted analysis of the 2019 National Health Interview Survey, including self-reported health and sociodemographic information, was conducted in 2021. Burden of obesity defined by BMI and odds of meeting consensus criteria for antiobesity pharmacotherapy and/or surgery were calculated by functional disability type: vision, hearing, cognition, communication, mobility, and self-care. RESULTS: From 29,170 community-dwelling adult respondents (59.1% response), the overall prevalence of disability was 10%. The prevalence of obesity among adults with a disability was 40.1% vs 30.5% for U.S. adults overall (p<0.0001). An estimated 17.1% with disability met the criteria for both bariatric surgery and antiobesity pharmacotherapy; another 39.8% were eligible for pharmacotherapy alone (vs 7.9% and 33.2%, respectively, for adults overall; p<0.0001). In fully adjusted models, disability was associated with greater ORs for mild obesity (OR=1.2; 95% CI=1.1, 1.4), moderate‒severe obesity (OR=2.1; 95% CI=1.8, 2.3), and criteria for bariatric surgery (OR=2.4; 95% CI=2.1, 2.7) and pharmacotherapy (OR=1.3; 95% CI=1.2, 1.4). Mobility, self-care, and cognition disabilities were associated with eligibility for bariatric surgery and antiobesity pharmacotherapy. CONCLUSIONS: Individuals with disabilities have higher odds of obesity and eligibility for antiobesity treatments. Comorbidities should be considered, accommodations should be provided, and insurance coverage should be expanded to ensure access to antiobesity treatments for adults with disabilities.

Feeding intolerance in critically ill patients with COVID-19.

BACKGROUND & AIMS: Early reports suggest significant difficulty with enteral feeding in critically ill COVID-19 patients. This study aimed to characterize the prevalence, clinical manifestations, and outcomes of feeding intolerance in critically ill patients with COVID-19. METHODS: We examined 323 adult patients with COVID-19 admitted to the intensive care units (ICUs) of Massachusetts General Hospital between March 11 and June 28, 2020 who received enteral nutrition. Systematic chart review determined prevalence, clinical characteristics, and hospital outcomes (ICU complications, length of stay, and mortality) of feeding intolerance. RESULTS: Feeding intolerance developed in 56% of the patients and most commonly manifested as large gastric residual volumes (83.9%), abdominal distension (67.2%), and vomiting (63.9%). Length of intubation (OR 1.05, 95% CI 1.03-1.08), ≥1 GI symptom on presentation (OR 0.76, 95% CI 0.59-0.97), and severe obesity (OR 0.29, 95% CI 0.13-0.66) were independently associated with development of feeding intolerance. Compared to feed-tolerant patients, patients with incident feeding intolerance were significantly more likely to suffer cardiac, renal, hepatic, and hematologic complications during their hospitalization. Feeding intolerance was similarly associated with poor outcomes including longer ICU stay (median [IQR] 21.5 [14-30] vs. 15 [9-22] days, P < 0.001), overall hospitalization time (median [IQR] 30.5 [19-42] vs. 24 [15-35], P < 0.001) and in-hospital mortality (33.9% vs. 16.1%, P < 0.001). Feeding intolerance was independently associated with an increased risk of death (HR 3.32; 95% CI 1.97-5.6). CONCLUSIONS: Feeding intolerance is a frequently encountered complication in critically ill COVID-19 patients in a large tertiary care experience and is associated with poor outcomes.

Bamlanivimab Efficacy in Older and High-BMI Outpatients With COVID-19 Selected for Treatment in a Lottery-Based Allocation Process.

BACKGROUND: Given the challenges associated with timely delivery of monoclonal antibody (mAb) therapy to outpatients with coronavirus disease 2019 (COVID-19) who are most likely to benefit, it is critical to understand the effectiveness of such therapy outside the context of clinical trials. METHODS: This was a case-control study of 1257 adult outpatients with COVID-19, ≥65 years of age or with body mass index (BMI) ≥35, who were entered into a lottery for mAb therapy. RESULTS: Patients who were called to be offered mAb therapy had a statistically significant 44% reduction in the odds of hospitalization within 30 days of a positive severe acute respiratory syndrome coronavirus 2 test compared with those who were not called (odds ratio [OR], 0.56; 95% CI, 0.36-0.89; P=.01). Patients who actually received bamlanivimab had a statistically significant 68% reduction in the odds of hospitalization compared with those who did not receive bamlanivimab (OR, 0.32; 95% CI, 0.11-0.93; P=.04). CONCLUSIONS: This study supports the effectiveness of bamlanivimab in reducing COVID-19-related hospitalizations in patients ≥65 or with BMI ≥35.

Coverage of obesity and obesity disparities on American Board of Medical Specialties (ABMS) examinations.

Obesity is a widespread disease which adversely impacts all organ systems and disproportionately affects African Americans and other minority groups. Physicians across medical specialties must possess current knowledge of obesity as an important, distinct disease with biological and social causes. Coverage of obesity on board certification examinations, which influence standards in medical knowledge and practice in each specialty, has not previously been examined. The member boards of the American Board of Medical Specialties offer a content outline or "blueprint" detailing material tested. We parsed the 24 available general certification exam blueprints for mentions of obesity and related keywords. We categorized blueprints into three tiers: mention of obesity (Tier 1), mention of related terminology but not obesity (Tier 2), and no mention of obesity or related terminology (Tier 3). We analyzed mentions of obesity and related terms by blueprint word count and procedural versus non-procedural specialties. Six (25.0%) of 24 board exam blueprints mentioned obesity (Tier 1), fifteen (62.5%) mentioned related terminology only (Tier 2), and three (12.5%) mentioned neither obesity nor related terminology (Tier 3). There was no significant difference in obesity-related mentions between procedural and non-procedural specialties (X2, p = .50). None of the blueprints included racial/ethnic disparities related to obesity. Word count was not significantly correlated with mentions of obesity in linear regression (p = .42). The absence of any mention of obesity on most content outlines and of racial/ethnic disparities on all content outlines indicates need for increased coverage of the diagnosis, prevention, and treatment of obesity across all board examinations.

Arrayed CRISPR reveals genetic regulators of tau aggregation, autophagy and mitochondria in Alzheimer's disease model.

Alzheimer's disease (AD) is a common neurodegenerative disease with poor prognosis. New options for drug discovery targets are needed. We developed an imaging based arrayed CRISPR method to interrogate the human genome for modulation of in vitro correlates of AD features, and used this to assess 1525 human genes related to tau aggregation, autophagy and mitochondria. This work revealed (I) a network of tau aggregation modulators including the NF-κB pathway and inflammatory signaling, (II) a correlation between mitochondrial morphology, respiratory function and transcriptomics, (III) machine learning predicted novel roles of genes and pathways in autophagic processes and (IV) individual gene function inferences and interactions among biological processes via multi-feature clustering. These studies provide a platform to interrogate underexplored aspects of AD biology and offer several specific hypotheses for future drug discovery efforts.

COVID-19 Vaccination and Obesity: Optimism and Challenges.

Researchers have speculated that vaccines to prevent coronavirus disease 2019 (COVID-19) may be less effective for individuals with obesity, a major risk factor for mortality and morbidity from COVID-19. Initial results from the Pfizer-BioNTech and Moderna COVID-19 vaccine trials, though limited by inadequate power to compare subgroups and incomplete stratification of high-risk groups, appear to have similar efficacy among individuals with and without obesity. Careful follow-up in placebo-controlled studies is required to generate data on long-term vaccine immunogenicity, particularly in high-risk groups. Subsequent analyses should stratify safety and efficacy results by each class of obesity. Speculation about variable effectiveness of COVID-19 vaccines in obesity likely increases vaccine hesitancy among individuals with obesity, who face not only a higher risk of severe outcomes from COVID-19 but also weight stigma, which reduces health care engagement at baseline. Clinical and public health messaging must be data driven, transparent, and sensitive to these biological and sociological vulnerabilities.

Socioeconomics of Obesity.

PURPOSE OF REVIEW: The purpose of this review is to evaluate and emphasize important findings in the recent literature regarding the socioeconomics of obesity. It is important to evaluate trends of this global epidemic and elucidate its impact on different demographic groups and across socioeconomic strata. RECENT FINDINGS: Obesity rates continue to increase domestically and globally which is associated with a concomitant rise in medical and economic costs. There are disparities in obesity rates based on race/ethnicity, sex, gender and sexual identity, and socioeconomic status, yet these disparities are not explained fully by health behaviors, socioeconomic position, or cumulative stress alone-community and societal environmental factors have a significant role in the obesity epidemic. Socioeconomic factors contribute to obesity on an individual and community level, and any viable approach to sustainably addressing the obesity epidemic must take these factors into account.

A rare case of a chest wall abscess caused by a migrating oesophageal stent. An iatrogenic gastrocutaneous fistula.

We report the case of a 65-year-old male, who presented with septicaemia and a chest wall mass on a background of oesophageal carcinoma. This chest wall mass measured 10 cm by 10 cm, was fluctuant, and was situated on the anterior chest wall. Owing to local erythema and surgical emphysema, necrotising fasciitis was suspected and thus intravenous antibiotic and fluid therapy were instituted. Following a chest radiograph, which confirmed the presence of subcutaneous gas, the patient underwent thoraco-abdomino-pelvic CT, which demonstrated oesophageal stent migration through the gastric fundus to the chest wall, between the 10th and 11th left ribs. Through this migration tract, the chest wall was contaminated with gastric contents, accounting for the mass and sepsis. The patient underwent endoscopic stent removal, and incision and drainage to create a gastrocutaneous fistula. Additionally, a nasojejunal tube and intravenous line were sited for jejunal and total parenteral nutrition, respectively, in order to promote healing of the fistula.