United European Gastroenterology Journal最新文献

Background: Emerging RAS inhibitors show promise in treating KRAS-mutated malignancies, but resistance mechanisms limit their clinical efficacy. Given recent clinical findings associating KRAS mutations with reduced response to neoadjuvant therapy in rectal cancer (RC), we aimed to investigate their impact on treatment outcomes and explore potential therapeutic strategies.

Methods: We conducted a retrospective analysis of 390 rectal cancer patients to evaluate the association of KRAS mutations with disease-free survival (DFS) and response to therapy. We assessed the efficacy of KRAS inhibitors in rectal cancer cell lines, patient-derived organoids (PDOs), and patient-derived cell lines (PDCLs), and explored adaptive resistance mechanisms through transcriptomic profiling and unbiased drug screening experiments.

Results: Mutant KRAS was associated with a reduced DFS and RCs harboring G12C and G12V mutations had less complete pathological responses to neo-adjuvant therapies. KRAS-mutated RC cells demonstrated adaptive resistance to KRAS inhibitors, characterized by transcriptomic restoration of oncogenic pathways, including MYC and E2F, and upregulation of ERBB2/3 expression. Consistently, drug screening identified EGFR family inhibitors as potent combinatorial partners, effectively overcoming KRAS inhibitor tolerance by inducing apoptosis. In patient-derived models, the pan-RAS inhibitor RMC-6236 combined with EGFR inhibitors demonstrated significant synergistic effects and prevented long-term tumor cell outgrowth.

Conclusion: Our findings point to the negative impact of KRAS mutations, particularly G12C and G12V, on RC treatment outcomes. Adaptive resistance by upregulation of ERBB genes limits the efficacy of KRAS inhibitors. Combining these with pan-ERBB inhibitors enhances anti-tumor effects in patient-derived cellular RC models, showing its potential as an alternative to the combination with anti-EGFR antibodies.

Background and objectives: Primary sclerosing cholangitis (PSC) is a chronic liver disease with aberrant immune dysregulation and bile duct fibrosis. It is often associated with inflammatory bowel disease (IBD), especially ulcerative colitis, raising questions about distinct immune activation in these conditions. Therefore, we aimed to systematically review and compare immune activation patterns in patients with PSC and IBD (without PSC), which may provide deeper insights into PSC pathophysiology.

Methods: MEDLINE, Scopus, Cochrane Library, and Embase were searched until July 2024 for relevant studies reporting immune cell profiles, cytokine levels, and gene expression patterns in patients with PSC. Reference articles of patients with IBD were then added to compare the immune profile of patients with PSC (with or without IBD) and patients with IBD-only.

Results: Twenty-three articles studying 638 PSC and 557 non-PSC non-IBD subjects were included. PSC patients showed various degrees of immune activation in the systemic circulation, biliary fluid, and liver tissue, most notably regarding integrin β7+ gut-homing T cells, IL-2, and IL-10 compared to their respective controls. Compared with patients with IBD, patients with PSC had reduced Tregs in the systemic circulation. When comparing tissue-based immune markers, PSC-livers had increased Th17 cells, IL-1β, and TNF-α and reduced levels of B cells, IL-2, and IL-10 than the IBD-mucosa.

Conclusions: Patients with PSC and patients with IBD without PSC can be differentiated by a distinct immune activation pattern with upregulation of Th17 and downregulation of Treg functions in PSC while other immune parameters do not allow a differentiation of these conditions.

Background and aims: Elderly-onset inflammatory bowel disease (IBD) patients (age ≥ 60 at diagnosis) have unique characteristics that require special consideration. Using a real-life registry-based cohort, we compared disease phenotypes and treatment exposures between adult-onset (18 ≤ age < 60 years) and elderly-onset IBD patients.

Methods: Demographics, disease characteristics, and treatment were compared between adult- and elderly-onset IBD patients diagnosed during 2000-2022 with ≥ 12 months follow-up.

Results: Of 3307 adult IBD patients, 290 (9%) were elderly-onset. This group exhibited a higher prevalence of colon-only involvement, with higher rates of ulcerative colitis (UC, 38.3% vs. 31.4%, p = 0.02) and more colonic L2 Crohn's Disease (CD, 21% vs. 12%, p < 0.001) then adult-onset group. Elderly-onset CD also showed less ileocolonic L3 disease (14% vs. 29%, p < 0.001), less penetrating B3 phenotype (7.4% vs. 19%, p < 0.001), and less perianal involvement (10% vs. 20%, p < 0.001). Elderly-onset CD and UC patients received more 5-ASA (36% vs. 17%, p < 0.001 in CD and 75% vs. 63%, p = 0.02 in UC). In contrast, these patients were exposed to considerably less biologics and/or JAK inhibitors (37% vs. 56% for CD and 20% vs. 35% for UC, p < 0.001), with higher 15-year biologic-free survival among elderly-onset IBD. First-line biological choices also substantially differed, with adult-onset receiving more anti-TNFs and elderly-onset receiving more Vedolizumab. We did not observe higher rates of IBD-related surgeries and steroid use between the groups.

Conclusions: Elderly-onset IBD shows higher prevalences of colon-only IBD (UC and L2 CD). Treatment strategies in elderly-onset IBD favor 5-ASA and show reduced biological use, with preferences for Vedolizumab over anti-TNFs.

Background and aim: Direct cholangioscopy and pancreatoscopy have become widely implemented techniques in the diagnostic and therapeutic algorithms of several pancreaticobiliary disorders. This study aimed to generate general and indication-specific European consensus recommendations on cholangioscopy and pancreatoscopy.

Methods: Supported by the available literature, statements were formulated and grouped into the following categories: (1) pre-procedural considerations, (2) general technical aspects, (3) biliopancreatic stones, (4) biliary strictures, and (5) other indications. The evidence level of each statement was determined using the GRADE methodology. Cholangioscopy experts were invited to participate in a modified Delphi process. When 80% consensus was not reached, the statement was modified based on expert feedback and subjected to an additional Delphi round. Statements were rejected if they failed to reach consensus after three Delphi rounds.

Results: Thirty cholangioscopy experts completed the Delphi process. Forty-two (97.6%) generated statements were accepted, of which 39 (92.9%) in the first Delphi round. 12 statements on preprocedural and periprocedural settings, 8 statements on biliopancreatic stones, 13 statements on biliary strictures, and 9 statements on other indications were accepted.

Conclusion: Using a modified Delphi process, we developed general and indication-specific consensus recommendations for cholangioscopy to guide clinical practice.

Background: Remimazolam is a short-acting benzodiazepine with less cardiorespiratory depression compared with propofol. The Oxygen Reserve Index (ORi) reflects oxygenation status in the mild hyperoxic range and can detect subtle respiratory depression induced by sedatives.

Objective: We compared remimazolam and propofol in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) and assessed the ORi to evaluate the impact of these sedatives on oxygen reserve.

Methods: Patients scheduled for ERCP were enrolled and randomly assigned to either the remimazolam or the propofol group. They received 0.1 mg kg^-1 remimazolam or 1.0 mg kg^-1 propofol, with bolus injections of either 2 mg remimazolam or 20 mg propofol added as required, according to the group allocation. The primary outcome was the incidence of oxygen reserve depletion, defined as an ORi reduction to 0.00.

Results: Among the 102 patients, oxygen reserve depletion was more frequent in the propofol group (70.6% vs. 41.2%, odds ratio 0.29, 95% confidence interval 0.13-0.66, p = 0.003). The time from sedative injection to endoscope insertion, length of stay in the recovery room, and overall procedure time were comparable between the groups. Patients in the remimazolam group reported a lower incidence of procedural recall, fewer complaints of inadequate sedation, and higher satisfaction scores than those in the propofol group.

Conclusions: Remimazolam effectively preserved the oxygen reserve compared with propofol, lowering the risk of hypoxia during sedation. Remimazolam was also associated with more favorable recovery profiles for patients undergoing ERCP, making it a safe and preferred sedative for this procedure.

Trail registration: Clinicaltrials.gov: NCT06359834.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, mainly due to its aggressive nature, early metastasis, diagnosis at late stages, and limited response to systemic anticancer therapy. Perineural invasion (PNI), defined as the infiltration of neoplastic cells along nerve fibers and within nerve sheaths, is emerging as a critical determinant of PDAC aggressiveness. This position paper by the TRANSPAN PNI Group on Perineural Invasion synthesizes current evidence on the molecular features and clinical implications of PNI in PDAC, compares its prognostic significance in other malignancies, and describes novel biomarker strategies including potential therapeutic interventions.