Case Report: A severe case of immunosuppressant-refractory immune checkpoint inhibitor-mediated colitis rescued by tofacitinib.

Immune checkpoint inhibitor therapy for cancer treatment can give rise to a variety of adverse events. Here we report a male patient with metastatic melanoma who experienced life-threatening colitis and duodenitis following treatment with ipilimumab and nivolumab. The patient did not respond to the first three lines of immunosuppressive therapy (corticosteroids, infliximab, and vedolizumab), but recovered well after administration of tofacitinib, a JAK inhibitor. Cellular and transcriptional data on colon and duodenum biopsies shows significant inflammation in the tissue, characterized by a large number of CD8 T cells and high expression of PD-L1. While cellular numbers do decrease during three lines of immunosuppressive therapy, CD8 T cells remain relatively high in the epithelium, along with PD-L1 expression in the involved tissue and expression of colitis-associated genes, indicating an ongoing colitis at that moment. Despite all immunosuppressive treatments, the patient has an ongoing tumor response with no evidence of disease. Tofacitinib might be a good candidate to consider more often for ipilimumab/nivolumab-induced colitis.

Academic medical centres in the Netherlands: muddling through or radical change?

Introduction: Academic medical centres (AMCs) are designed to perform multiple tasks within a single organisation. This institutional complexity gives rise to intricate governance challenges and promotes incrementalism and muddling. Method: In this study, we hypothesised that radical change could provide a solution to the current incrementalism and we explored the conditions under which such changes could or could not be achieved. Results: We conducted unstructured interviews with various high-level stakeholders and identified issues that negatively affected the governance of Dutch AMCs, which include: 1) negative undercurrents and unspoken issues due to conflicts of interests, 2) organisational complexity due to relationships with a university and academic medical specialists, 3) lack of sufficient government direction, 4) competition between AMCs due to perverse systemic incentives, 5) different interests, focus, and organisational culture, 6) concentration of care, which does not always lead to enhanced quality and efficiency as the provision of less complex care is of utmost importance for education and research, 7) the infeasibility of public and regional functions of an AMC, 8) the inefficiency of managing three core tasks within the same organisation and, 9) healthcare market regulation. Discussion: Our hypothesis that radical change offers a solution to the current incrementalism in AMCs could not be adequately explored. Indeed, our exploration of the conditions under which radical change could potentially take place revealed that there are factors currently at play that make a substantive conversation between stakeholders about radical change difficult, if not impossible. The results also show that the government is in a position to take the lead and create conditions that foster mutual trust and common interests among AMCs, as well as between AMCs and other hospitals.

Identification of Fusion Genes and Targets for Genetically Matched Therapies in a Large Cohort of Salivary Gland Cancer Patients.

Introduction: Salivary gland cancer (SGC) is a rare cancer for which systemic treatment options are limited. Therefore, it is important to characterize its genetic landscape in search for actionable aberrations, such as NTRK gene fusions. This research aimed to identify these actionable aberrations by combining NGS-based analysis of RNA (gene fusions) and DNA (single and multiple nucleotide variants, copy number variants, microsatellite instability and tumor mutational burden) in a large cohort of SGC patients. Methods: RNA and DNA were extracted from archival tissue of 121 patients with various SGC subtypes. Gene fusion analysis was performed using a customized RNA-based targeted NGS panel. DNA was sequenced using a targeted NGS panel encompassing 523 cancer-related genes. Cross-validation of NGS-based NTRK fusion detection and pan-TRK immunohistochemistry (IHC) was performed. Results: Fusion transcripts were detected in 50% of the cases and included both known (MYB-NFIB, MYBL1-NFIB, CRTC1-MAML2) and previously unknown fusions (including transcripts involving RET, BRAF or RAD51B). Only one NTRK fusion transcript was detected, in a secretory carcinoma case. Pan-TRK IHC (clone EPR17341) was false positive in 74% of cases. The proportion of patients with targets for genetically matched therapies differed among subtypes (salivary duct carcinoma: 82%, adenoid cystic carcinoma 28%, mucoepidermoid carcinoma 50%, acinic cell carcinoma 33%). Actionable aberrations were most often located in PIK3CA (n = 18, 15%), ERBB2 (n = 15, 12%), HRAS and NOTCH1 (both n = 9, 7%). Conclusions: Actionable genetic aberrations were seen in 53.7% of all SGC cases on the RNA and DNA level, with varying percentages between subtypes.

Drug Discovery and Repurposing Inhibits a Major Gut Pathogen-Derived Oncogenic Toxin.

Objective: The human intestinal microbiome plays an important role in inflammatory bowel disease (IBD) and colorectal cancer (CRC) development. One of the first discovered bacterial mediators involves Bacteroides fragilis toxin (BFT, also named as fragilysin), a metalloprotease encoded by enterotoxigenic Bacteroides fragilis (ETBF) that causes barrier disruption and inflammation of the colon, leads to tumorigenesis in susceptible mice, and is enriched in the mucosa of IBD and CRC patients. Thus, targeted inhibition of BFT may benefit ETBF carrying patients. Design: By applying two complementary in silico drug design techniques, drug repositioning and molecular docking, we predicted potential BFT inhibitory compounds. Top candidates were tested in vitro on the CRC epithelial cell line HT29/c1 for their potential to inhibit key aspects of BFT activity, being epithelial morphology changes, E-cadherin cleavage (a marker for barrier function) and increased IL-8 secretion. Results: The primary bile acid and existing drug chenodeoxycholic acid (CDCA), currently used for treating gallstones, cerebrotendinous xanthomatosis, and constipation, was found to significantly inhibit all evaluated cell responses to BFT exposure. The inhibition of BFT resulted from a direct interaction between CDCA and BFT, as confirmed by an increase in the melting temperature of the BFT protein in the presence of CDCA. Conclusion: Together, our results show the potential of in silico drug discovery to combat harmful human and microbiome-derived proteins and more specifically suggests a potential for retargeting CDCA to inhibit the pro-oncogenic toxin BFT.