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Background: One in three children with Crohn's disease develop perianal fistula complications (PFCs), among the most disturbing and difficult-to-treat disease-related complications. Retrospective evidence suggests PFCs may be preventable.

Objective: We aimed to determine if early antitumour necrosis factor-alpha (anti-TNF⍺) therapy prevents PFC development in a well-characterised prospective cohort of paediatric patients with Crohn's disease who were free from PFC at enrolment.

Design: RISK was a multicentre inception cohort of children newly diagnosed with Crohn's disease. We included all patients who had never experienced PFCs 30 days after study enrolment. We conducted nearest-neighbour propensity score-matched triad analyses. Matching was performed to balance patient characteristics across three mutually exclusive treatment groups based on therapy prior to either PFC development or the end of the observation period.

Results: Among 873 patients without perianal fistula, 447 matched patients were included (149 per treatment group). The presence of non-penetrating perianal lesions (large skin tags, ulcers and/or fissures) was significantly associated with PFC development, with 4-fold greater odds of PFC (OR 4.08, 95% CI (95% CI) 1.70 to 9.78; p=0.0016). Early anti-TNF⍺ therapy was associated with an 82% decrease in the odds of PFC (OR 0.18, 95% CI 0.05 to 0.66; p=0.01). Among those with perianal lesions, anti-TNF⍺ therapy was associated with 94% reduced odds of PFC development (OR 0.055, 95% CI 0.006 to 0.50; p=0.010). No other treatment group was associated with reduced risk of PFC.

Conclusion: Early anti-TNF therapy prevents perianal fistula development, especially among patients at increased risk.

Background: Transmembrane 6 superfamily member 2 (TM6SF2) has a protective role against metabolic dysfunction-associated steatotic liver disease (MASLD).

Objective: We aim to investigate the mechanistic role and therapeutic potential of hepatic TM6SF2 in MASLD-related hepatocellular carcinoma (HCC).

Design: Hepatocyte-specific Tm6sf2 knockout (Tm6sf2 ^∆hep) mice were fed with high-fat/high-cholesterol (HFHC) diet or diethylnitrosamine plus HFHC diet to induce MASLD-HCC. TM6SF2 function was also evaluated in orthotopic MASLD-HCC mice. Human MASLD-HCC specimens were included to evaluate clinical significance.

Results: TM6SF2 was downregulated in tumours compared with adjacent normal tissues from MASLD-HCC patients. Hepatocyte-specific Tm6sf2 knockout exacerbated tumour formation in mice with diet-induced or diet-induced and carcinogen-induced MASLD-HCC. The tumour-promoting effect of Tm6sf2 knockout was verified in orthotopic MASLD-HCC mice, while mice bearing Tm6sf2-overexpressing tumours had opposite phenotypes. We observed the reduction of interferon-gamma (IFN-γ)⁺CD8⁺ T cells in the tumours of Tm6sf2 ^∆hep mice and orthotopic Tm6sf2 knockout mice, while the tumour-suppressive effect of Tm6sf2 was abolished after depleting CD8⁺ T cells. The correlation between TM6SF2 and CD8⁺ T cells was confirmed in human MASLD-HCC tissues, inferring that TM6SF2 could promote antitumour immunity. Mechanistically, TM6SF2 directly bound to IKKβ and inhibited NF-κB signalling pathway to reduce interleukin (IL)-6 secretion, thereby activating cytotoxic CD8⁺ T cells. IL-6 neutralisation abolished the tumour-promoting and immunosuppressive effects of Tm6sf2 knockout in mice. Moreover, introducing Tm6sf2 by adenovirus improved immunotherapy response against MASLD-HCC in mice.

Conclusion: Hepatic TM6SF2 protects against MASLD-HCC and activates cytotoxic CD8⁺ T cells via NF-κB-IL-6 axis. TM6SF2 is a promising strategy for sensitising MASLD-HCC to immunotherapy.

Background: The potency of T cell-mediated responses is a determinant of immunotherapy effectiveness in treating malignancies; however, the clinical efficacy of T-cell therapies has been limited in hepatocellular carcinoma (HCC) owing to the extensive immunosuppressive microenvironment.

Objective: Here, we aimed to investigate the key genes contributing to immune escape in HCC and raise a new therapeutic strategy for remoulding the HCC microenvironment.

Design: The genome-wide in vivo clustered regularly interspaced short palindromic repeats (CRISPR) screen library was conducted to identify the key genes associated with immune tolerance. Single-cell RNA-seq (scRNA-seq), flow cytometry, HCC mouse models, chromatin immunoprecipitation and coimmunoprecipitation were used to explore the function and mechanism of adenylate cyclase 7 (ADCY7) in HCC immune surveillance.

Results: Here, a genome-wide in vivo CRISPR screen identified a novel immune modulator-ADCY7. The transmembrane protein ADCY7 undergoes subcellular translocation via caveolae-mediated endocytosis and then translocates to the nucleus with the help of leucine-rich repeat-containing protein 59 (LRRC59) and karyopherin subunit beta 1 (KPNB1). In the nucleus, it functions as a transcription cofactor of CCAAT/enhancer binding protein alpha (CEBPA) to induce CCL5 transcription, thereby increasing CD8⁺ T cell infiltration to restrain HCC progression. Furthermore, ADCY7 can be secreted as exosomes and enter neighbouring tumour cells to promote CCL5 induction. Exosomes with high ADCY7 levels promote intratumoural infiltration of CD8⁺ T cells and suppress HCC tumour growth.

Conclusion: We delineate the unconventional function and subcellular location of ADCY7, highlighting its pivotal role in T cell-mediated immunity in HCC and its potential as a promising treatment target.

Objective: Sphincter of Oddi disorders (SOD) are contentious conditions in patients whose abdominal pain, idiopathic acute pancreatitis (iAP) might arise from pressurisation at the sphincter of Oddi. The present study aimed to measure the benefit of sphincterotomy for suspected SOD.

Design: Prospective cohort conducted at 14 US centres with 12 months follow-up. Patients undergoing first-time endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy for suspected SOD were eligible: pancreatobiliary-type pain with or without iAP. The primary outcome was defined as the composite of improvement by Patient Global Impression of Change (PGIC), no new or increased opioids and no repeat intervention. Missing data were addressed by hierarchal, multiple imputation scheme.

Results: Of 316 screened, 213 were enrolled with 190 (89.2%) of these having a dilated bile duct, abnormal labs, iAP or some combination. By imputation, an average of 122/213 (57.4% (95% CI 50.4% to 64.4%)) improved; response rate was similar for those with complete follow-up (99/161, 61.5% (54.0% to 69.0%)); of these, 118 (73.3%) improved by PGIC alone. Duct size, elevated labs and patient characteristics were not associated with response. AP occurred in 37/213 (17.4%) at a median of 6 months post ERCP and was more likely in those with a history of AP (30.9% vs 2.9%, p<0.0001).

Conclusion: Nearly 60% of patients undergoing ERCP for suspected SOD improve, although the contribution of a placebo response is unknown. Contrary to prevailing belief, duct size and labs are poor response predictors. AP recurrence was common and like observations from prior non-intervention cohorts, suggesting no benefit of sphincterotomy in mitigating future AP episodes.