Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis.

The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune-related adverse effects including colitis. CPI-induced colitis is hallmarked by expansion of resident mucosal IFNγ cytotoxic CD8+ T cells, but how these arise is unclear. Here, we track CPI-bound T cells in intestinal tissue using multimodal single-cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug-bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI-bound cells were largely CD4+ T cells, including enrichment in CPI-bound peripheral helper, follicular helper, and regulatory T cells. IFNγ CD8+ T cells emerged from both tissue-resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co-localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies.

FIT negative clinic as a safety net for low-risk patients with colorectal cancer: impact on endoscopy and radiology utilisation-a retrospective cohort study.

Background: Faecal immunochemical testing (FIT) is recommended by the National Institute for Health and Care Excellence to triage symptomatic primary care patients who have unexplained symptoms but do not meet the criteria for a suspected lower gastrointestinal cancer pathway. During the COVID-19 pandemic, FIT was used to triage patients referred with urgent 2-week wait (2ww) cancer referrals instead of a direct-to-test strategy. FIT-negative patients were assessed and safety netted in a FIT negative clinic. Methods: We reviewed case notes for 622 patients referred on a 2ww pathway and seen in a FIT negative clinic between June 2020 and April 2021 in a tertiary care hospital. We collected information on demographics, indication for referral, dates for referral, clinic visit, investigations and long-term outcomes. Results: The average age of the patients was 71.5 years with 54% female, and a median follow-up of 2.5 years. Indications for referrals included: anaemia (11%), iron deficiency (24%), weight loss (9%), bleeding per rectum (5%) and change in bowel habits (61%). Of the cases, 28% (95% CI 24% to 31%) had endoscopic (15%, 95% CI 12% to 18%) and/or radiological (20%, 95% CI 17% to 23%) investigations requested after clinic review, and among those investigated, malignancy rate was 1.7%, with rectosigmoid neuroendocrine tumour, oesophageal cancer and lung adenocarcinoma. Conclusion: A FIT negative clinic provides a safety net for patients with unexplained symptoms but low risk of colorectal cancer. These real-world data demonstrate significantly reduced demand on endoscopy and radiology services for FIT-negative patients referred via the 2ww pathway.

Unlocking cancer vaccine potential: What are the key factors?

Cancer is a global health challenge, with changing demographics and lifestyle factors producing an increasing burden worldwide. Screening advancements are enabling earlier diagnoses, but current cancer immunotherapies only induce remission in a small proportion of patients and come at a high cost. Cancer vaccines may offer a solution to these challenges, but they have been mired by poor results in past decades. Greater understanding of tumor biology, coupled with the success of vaccine technologies during the COVID-19 pandemic, has reinvigorated cancer vaccine development. With the first signs of efficacy being reported, cancer vaccines may be beginning to fulfill their potential. Solid tumors, however, present different hurdles than infectious diseases. Combining insights from previous cancer vaccine clinical development and contemporary knowledge of tumor immunology, we ask: who are the 'right' patients, what are the 'right' targets, and which are the 'right' modalities to maximize the chances of cancer vaccine success?

Prognostic non-invasive biomarkers for all-cause mortality in non-alcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) represents a growing public health concern, with patients having higher risk of morbidity and mortality. It has a considerably high prevalence in the general population, estimated 20%-40% in Europe, and is asymptomatic until late in the disease course. It is therefore important to identify and validate tools that predict hard outcomes such as mortality for use in clinical practice in risk-stratifying NAFLD patients. AIM: To evaluate available evidence on the use of non-invasive test(s) as prognostic factors for mortality in NAFLD. METHODS: We performed electronic searches of Medline and EMBASE (Ovid) until 7th January 2021 of studies in NAFLD populations. Prognostic markers included serum biomarkers, non-invasive scoring systems, and non-invasive imaging. The population included all spectrums of disease severity, including NAFLD and non-alcoholic steatohepatitis (NASH). Outcomes included all-cause, and cardiovascular mortality. All non-invasive tests were synthesised in a narrative systematic review. Finally, we conducted a meta-analysis of non-invasive scoring systems for predicting all-cause and cardiovascular mortality, calculating pooled hazard ratios and 95% confidence (STATA 16.1). RESULTS: Database searches identified 2850 studies - 24 were included. 16 studies reported non-invasive scoring systems, 10 studies reported individual biomarkers, and 1 study reported imaging modalities. 4 studies on non-invasive scoring systems (6324 participants) had data available for inclusion in the meta-analysis. The non-invasive scoring system that performed best at predicting all-cause mortality was NAFLD fibrosis score (NFS) [pHR 3.07 (1.62-5.83)], followed by fibrosis-4 index [pHR 3.06 (1.54-6.07)], BARD [pHR 2.87 (1.27-6.46)], and AST to platelet ratio index [pHR 1.90 (1.32-2.73)]. NFS was also prognostic of cardiovascular-related mortality [pHR 3.09 (1.78-5.34)]. CONCLUSION: This study reaffirms that non-invasive scoring systems, especially NFS, are reliable prognostic markers of all-cause mortality and cardiovascular mortality in NAFLD patients. These findings can inform clinical practice in risk stratifying NAFLD patients.

Zanubrutinib-induced liver injury: a case report and literature review.

BACKGROUND: Zanubrutinib is a Bruton's tyrosine kinase inhibitor that has been recently licensed in refractory mantle cell lymphoma and under assessment in phase 3 clinical trials for other B cell malignancies. To date, there are no reported cases of hepatotoxicity secondary to zanubrutinib. We report the first case of severe liver injury due to zanubrutinib. CASE PRESENTATION: A 56-year-old Caucasian male with a history of relapsed lymphoplasmacytic lymphoma was admitted to the hospital with new-onset jaundice, choluria, and pruritus for 10 days. He had been on zanubrutinib as part of a clinical trial for 30 months. His blood profile showed a severe hepatocellular injury with jaundice (alanine transaminase 2474 IU/L and total bilirubin 141 umol/L with mild coagulopathy). He had an extensive work-up including virology, autoimmune, and metabolic profiles in addition to abdominal ultrasound with no alternative explanation found for his liver injury. Zanubrutinib-induced liver injury was suspected, and causality assessment by the updated Roussel Uclaf Causality Assessment Method score showed a probable causal relationship with zanubrutinib. His liver histology was also consistent with drug-induced liver injury. His liver biochemistry improved following cessation of zanubrutinib and normalised after 8 weeks. CONCLUSION: We report the first case of severe liver injury secondary to zanubrutinib after 30 months of treatment. This case raises clinical awareness regarding zanubrutinib-induced liver toxicity and the importance of drug withdrawal in the event of liver injury.

"I Miss My Liver." Nonmedical Sources in the History of Hepatocentrism.

Hepatocentrism was a medical doctrine that considered the liver the center of the whole human being. It originated in ancient populations (Mesopotamic civilization) and persisted in Western countries until the seventeenth century. Hidden references to hepatocentrism may be found in artistic representations and literary works, from the myth of Prometheus in the Greco-Roman world to the crucifixion iconography throughout the Middle Ages. In the mid-1600s, fundamental discoveries irrefutably demonstrated the central role of the heart in human physiology, which laid the foundations for creating cardiocentrism, shifting the life's center from the liver to the heart. The advent of cardiocentrism immediately restricted the importance given to the liver, favoring the heart in the fine arts. Nevertheless, the liver maintained its importance in literature and popular belief as is evidenced by the widely acclaimed literary texts "Snow White" by the Brothers Grimm, "Moby Dick" by Herman Melville, and "Ode to the Liver" by Pablo Neruda. Our aim is to analyze the most significant artistic representations and literary works that contain references to hepatocentrism, evaluating the changing ideas and beliefs regarding the role and function of the liver throughout history. We want to underline the tight relationship between art and medicine; fine art and literature could be a valuable source for understanding the history of hepatology. (Hepatology Communications 2018; 00:000-000).

Regulatory T cell-derived extracellular vesicles modify dendritic cell function.

Regulatory T cells (Treg) are a subpopulation of T cells that maintain tolerance to self and limit other immune responses. They achieve this through different mechanisms including the release of extracellular vesicles (EVs) such as exosomes as shown by us, and others. One of the ways that Treg derived EVs inhibit target cells such as effector T cells is via the transfer of miRNA. Another key target for the immunoregulatory function of Tregs is the dendritic cells (DCs). In this study we demonstrate directly, and for the first time, that miRNAs are transferred from Tregs to DCs via Treg derived EVs. In particular two miRNAs, namely miR-150-5p and miR-142-3p, were increased in DCs following their interaction with Tregs and Treg derived exosomes. One of the consequences for DCs following the acquisition of miRNAs contained in Treg derived EVs was the induction of a tolerogenic phenotype in these cells, with increased IL-10 and decreased IL-6 production being observed following LPS stimulation. Altogether our findings provide data to support the idea that intercellular transfer of miRNAs via EVs may be a novel mechanism by which Tregs regulate DC function and could represent a mechanism to inhibit immune reactions in tissues.