BACKGROUND: Hepatocellular carcinoma (HCC) represents a major health burden, historically treated with tyrosine kinase inhibitors (TKIs). The advent of immune checkpoint inhibitors (ICIs) has reshaped treatments, with pi...BACKGROUND: Hepatocellular carcinoma (HCC) represents a major health burden, historically treated with tyrosine kinase inhibitors (TKIs). The advent of immune checkpoint inhibitors (ICIs) has reshaped treatments, with pivotal trials (IMbrave150 and HIMALAYA) establishing ICI-based combinations as first-line therapy. Traditional statistical metrics may not fully capture the robustness of trial outcomes. The Survival-Inferred Fragility Index (SIFI) quantifies trial stability as the minimum number of additional survival events required to lose statistical significance. METHODS: We systematically searched PubMed, Embase, Scopus for phase III randomized controlled trials comparing ICIs and TKIs in HCC published up to 31 May 2025. Trials reporting statistically significant time-to-event outcomes were included. Individual survival data were reconstructed from Kaplan-Meier curves using validated methods, SIFI was calculated using specific R algorithms. RESULTS: Six trials (4570 patients) were included for primary analysis (IMbrave150, COSMIC-312, ORIENT-32, CARES-310, HIMALAYA; CheckMate 9DW analyzed separately for its heterogeneous control arm). Median SIFI was 10 (range 5-18) for overall survival, 8 (range 6-19) for progression-free survival. SIFI corresponded to <1% of enrolled patients in most trials. Asian- trials (ORIENT-32, CARES-310) showed higher stability (SIFI 16-20) compared to global trials. CONCLUSIONS: SIFI analysis revealed heterogeneous stability across pivotal HCC trials. Incorporating fragility metrics with conventional statistics may improve interpretation and support balanced interpretation of trial outcomes.
BACKGROUND: Fluorescence Confocal laser microscopy (FCM) with Vivascope in EUS-fine needle biopsy (FNB) samples of pancreatic solid lesion has shown good concordance with final histological evaluation.To assess the accur...BACKGROUND: Fluorescence Confocal laser microscopy (FCM) with Vivascope in EUS-fine needle biopsy (FNB) samples of pancreatic solid lesion has shown good concordance with final histological evaluation.To assess the accuracy of Vivascope in predicting the diagnosis of EUS-guided pancreatic solid lesions samples.To assess the agreement between Vivascope and final histological diagnosis and the possible association between type and size of needles and the histological diagnosis obtainment. METHODS: Multicentre prospective study involving 3 European referral Endoscopy Units. Consecutive patients undergoing EUS-guided sampling of pancreatic solid masses were enrolled. The same samples were assessed by Vivascope and conventional pathology and classified as "Inadequate" or "Adequate" (Benign; Suspicious; Malignant). RESULTS: From April to August 2023 80 patients enrolled. In 78.5% FNB needle was used and in 66.3% it was a 22G needle.The FCM diagnosis with Vivascope was confirmed in 94.8% patients after conventional pathology.The use of FNB needle was not associated with higher rate of diagnostic samples at Vivascope evaluation (88.8% vs 100%, p=0.33), neither were the needle size (19 G 100% vs 22 G 88.7% vs 25 G 96.2 p=0.52) or the sampling technique (93.9% vs 78.5% p=0.09). Vivascope sensitivity was 97.33% (95% CI 90.7-99.7%), Specificity was 80.0% (95% CI 28.4-99.5%) and Accuracy 96.3% (95% CI 89-99.2%).There was moderate concordance between FCM diagnosis with Vivascope and the final histological diagnosis (kappa Cohen's coefficient 0.58). CONCLUSIONS: Our study supports the reliability of FCM with Vivascope for both sample adequacy and diagnosis.It may prevent possible diagnostic delays and allowing centralization of microscopic assessment thanks to its digital nature.
BACKGROUND: Pre-treatment screening for dihydropyrimidine dehydrogenase (DPD) deficiency based on plasma uracil concentration ([U]) is mandatory in France before fluoropyrimidine (FP) administration. However, dose-adjust...BACKGROUND: Pre-treatment screening for dihydropyrimidine dehydrogenase (DPD) deficiency based on plasma uracil concentration ([U]) is mandatory in France before fluoropyrimidine (FP) administration. However, dose-adjustment strategies according to [U] in case of partial DPD deficiency remain empirical, heterogeneous across centers and lacking clear recommendations. METHODS: This national, multicenter, open-label phase II trial will enroll approximately 400 patients schedule to receive FP-based chemotherapy combined with oxaliplatin, with or without targeted therapy. Patients will be stratified by pre-treatment [U] into one control arm (non-DPD-deficient, [U] <16 ng/mL) receiving a full standard FP starting dose, and four DPD-deficient cohorts ([16-20[, [20-50[, [50-100[, and [100-150[ ng/mL) receiving prespecified starting dose. The primary endpoint is FP-induced grade ≥3 hematological and gastrointestinal toxicity during the first two treatment cycles, compared between DPD-deficient cohorts vs control arm within a Bayesian framework. Interim analyses with sequential toxicity monitoring are planned to allow protocol adaptation if safety concerns arise. Secondary endpoints include overall toxicity profiles, dose adaptations, survival outcomes, pharmacokinetic analyses, and correlations between [U] levels and DPYD genotypes. CONCLUSIONS: This trial addresses a major gap between mandatory preemptive DPD phenotyping and actionable FP dosing recommendations, to generate prospective evidence supporting safer and harmonized FP use in routine clinical practice. TRIAL REGISTRATION: FUDOSE is registered at Clinicaltrials.gov (NCT06475352).
BACKGROUND: Microscopic colitis (MC) is presumably mediated by immune dysregulation, with drug exposure being a substantial risk factor. This study aims to identify contemporary MC-drug associations. METHODS: A pharmacov...BACKGROUND: Microscopic colitis (MC) is presumably mediated by immune dysregulation, with drug exposure being a substantial risk factor. This study aims to identify contemporary MC-drug associations. METHODS: A pharmacovigilance study of the FDA adverse event reporting system (FAERS) between July 2014 and June 2024. Disproportionate reporting of MC was assessed using reporting odds ratios (RORs), adjusted for age, sex, and concomitant medications. RESULTS: Of 12,109,491 safety reports, 2648 cases of MC were identified and associated with 55 different medications. Several biologic immunosuppressants showed increased MC reporting, including tocilizumab (ROR = 4.93 [95% CI 3.85-6.31]), interleukin-17 inhibitors (ROR = 3.14 [2.47-3.98]), anti-CD20 agents (ROR = 3.03 [2.46-3.74]), and abatacept (ROR = 2.00 [1.44-2.78]). Synthetic immunosuppressants, particularly leflunomide (ROR = 9.89 [7.30-13.39]), methotrexate (ROR = 2.42 [1.63-3.58]), and mycophenolate (ROR = 2.31 [1.41-3.78]), were also implicated. Immune checkpoint inhibitors showed disproportionate MC reporting (ROR = 3.03 [2.49-3.69]), with the strongest associations for ipilimumab and the ipilimumab-nivolumab combination. Traditional MC-related agents (PPIs, SSRIs, NSAIDs) were corroborated. Additional non-immunomodulatory classes (SNRIs, ARBs, ACE inhibitors, statins, and dopaminergic therapies) also emerged. Concomitant exposure to multiple agents increased MC reporting. CONCLUSIONS: This comprehensive pharmacovigilance study mapped drug-MC associations, suggesting potential novel safety signals while corroborating previously reported agents. Immunomodulatory drugs emerged as substantial risk factors. These findings provide practical insights for clinicians managing patients with MC.
BACKGROUND: Identifying significant liver fibrosis (≥F2) is critical for initiating antiviral therapy in chronic hepatitis B (CHB). Chitinase-3-like protein 1 (CHI3L1) is a promising fibrosis biomarker, but its staging v...BACKGROUND: Identifying significant liver fibrosis (≥F2) is critical for initiating antiviral therapy in chronic hepatitis B (CHB). Chitinase-3-like protein 1 (CHI3L1) is a promising fibrosis biomarker, but its staging value remains unclear. We evaluated CHI3L1 (chemiluminescent immunoassay, CLIA) alone and with machine learning (ML) for differentiating mild (F0-F1) from significant (F2-F4) fibrosis. METHODS: We included 347 participants (303 primary, 44 external validation), most CHB patients with biopsy-confirmed METAVIR staging. Serum markers were measured, and 5 ML models were developed. RESULTS: CHI3L1 levels increased progressively with fibrosis severity and discriminated significant fibrosis (≥F2), with AUC 0.84 (95% CI 0.772-0.908) in the overall CHB cohort and 0.839 (95% CI 0.755-0.924) in CHB patients with normal ALT, outperforming conventional biomarkers. Incorporating CHI3L1 into ML further improved diagnostic performance; the Decision Tree model achieved optimal accuracy AUCs of 0.923 [95% CI 0.891-0.976] and 0.895 [95% CI 0.831-0.960], respectively. SHapley Additive exPlanations (SHAP) analysis identified CHI3L1 as the most influential feature (62.2%) in this model. The model performed consistently in the external validation cohort. CONCLUSIONS: CHI3L1 is a strong noninvasive biomarker for identifying clinically significant fibrosis in CHB. Integration with ML enhances fibrosis staging accuracy, supporting timely antiviral therapy.
BACKGROUND: Some patients with Crohn's disease (CD) lose response to Ustekinumab (UST) standard therapy. Currently, there is limited evidence on efficacy of repeated intravenous (IV) weight-based UST maintenance in refra...BACKGROUND: Some patients with Crohn's disease (CD) lose response to Ustekinumab (UST) standard therapy. Currently, there is limited evidence on efficacy of repeated intravenous (IV) weight-based UST maintenance in refractory CD . Here, we investigated the efficacy and safety of the optimization therapy in such patients. METHODS: In this retrospective study, 134 CD patients who had lost their response to UST were enrolled. Clinical response and remission were assessed at weeks 21 and 42 using the Harvey-Bradshaw Index, while secondary outcomes included biochemical and endoscopic measures. Safety was monitored throughout the study. RESULTS: At week 21, the clinical response and remission rates were 76.9% and 43.3%, respectively. These rates improved to 88.6% and 73.2% by week 42. Among the 75 patients who underwent endoscopic evaluation, 52.0% achieved endoscopic remission, and 76.0% demonstrated a response. Furthermore, the majority of patients (91.8%, 123/134) remained on the optimization regimen throughout week 42, and no significant adverse events were reported. CONCLUSION: Repeated IV weight-based UST maintenance has shown significant and sustained clinical, biochemical, and endoscopic improvements in most patients who have lost their response to standard UST therapy. This optimized regimen offers a promising therapeutic strategy for individuals who would otherwise need to switch to other biologics or dual-targeted therapies.
Catanzaro E, Peviani M, Bonaiuto E
… +10 more, Pezzato F, Benatti M, Cavaliere C, Perin N, Russo FP, Gambato M, Burra P, Floreani A, Motta R, Cazzagon N
BACKGROUND AND AIMS: Fibrates may improve cholestasis and pruritus in Primary Sclerosing Cholangitis (PSC), but long-term data is limited. This study assessed the safety and biochemical, radiological, and clinical effect...BACKGROUND AND AIMS: Fibrates may improve cholestasis and pruritus in Primary Sclerosing Cholangitis (PSC), but long-term data is limited. This study assessed the safety and biochemical, radiological, and clinical effects of fibrates in PSC. METHOD: We retrospectively analysed PSC patients on stable UDCA therapy who received add-on fibrates between 2017 and 2025. Clinical, biochemical, radiological, and elastography data were collected to assess treatment response, safety, and disease progression. RESULTS: Of 37 PSC patients initiating fibrates, 34 were included, 21% with cirrhosis. Fenofibrate was used in 88% for a median of 34 months. Significant reductions in ALP, GGT, and ALT were observed at 6 months and sustained over follow-up. The proportion of patients with ALP < 1.5 × ULN increased from 22% to 45% at 6 months. The Amsterdam-Oxford score (AOM) decreased significantly at 6 and 12 months (p = 0.02). Responders had lower baseline bilirubin, transaminases, AOM, and Mayo Risk score (p < 0.05). Pruritus improved while fatigue, cholangitis frequence, and liver stiffness remain unchanged. MRI follow-up showed worsening of ANALI score due to bile duct dilatation, with stable DiStrict score. Adverse events occurred in 15%, leading to discontinuation in 4 patients. CONCLUSION: Fibrates appear to be a safe and potentially effective option in PSC, especially in early-stage disease, pending confirmation from prospective trials.
BACKGROUND: Some patients with eosinophilic esophagitis (EoE) remain symptomatic despite histological remission. In absence of strictures at endoscopy, empirical dilation has been suggested, however no data on usefulness...BACKGROUND: Some patients with eosinophilic esophagitis (EoE) remain symptomatic despite histological remission. In absence of strictures at endoscopy, empirical dilation has been suggested, however no data on usefulness are available. AIMS: To investigate effectiveness of empirical dilation. METHODS: Retrospective analysis of all EoE patients who achieved histological remission at our Institution between July 2018 and February 2024. Patients with persistent dysphagia and/or bolus impaction underwent dilation irrespective of stricture at endoscopy. Follow-up of ≥6 months was required. RESULTS: Forty-six patients (median age 42 years, 25 men) were included. Thirty-seven had no stricture and 9 had a stricture (i.e., S1 or R3 according to EREFS score). In the former group, 23/37 patients became asymptomatic whereas 14 were still symptomatic and underwent empirical dilation, clinically effective in 13 of them. A second dilation was needed in 2, after 25 and 31 months. In the latter group all patients underwent dilation and achieved clinical remission. All 45 patients remained in clinico-histological remission during a 14(8-46) months follow-up, with no change in medical treatment and a final I-SEE score of 1(0-1). CONCLUSIONS: Empirical esophageal dilation is highly effective when dysphagia/bolus impaction persists despite histological remission and should be considered before escalating treatment.
Histologic evaluation of colonic biopsies in patients with chronic diarrhea or long-standing colitis is frequently performed in the setting of incomplete clinical, endoscopic, or laboratory information. In this context,...Histologic evaluation of colonic biopsies in patients with chronic diarrhea or long-standing colitis is frequently performed in the setting of incomplete clinical, endoscopic, or laboratory information. In this context, overlapping morphologic features across different etiologies often lead to nonspecific or misleading diagnoses, such as "chronic colitis," with potential implications for patient management. To improve diagnostic clarity and clinicopathologic communication, the Italian Group of Digestive Disease Pathology (GIPAD) developed a structured, pattern-based histologic approach for the interpretation and reporting of adult colitis with chronic architectural damage, based on multidisciplinary discussion and critical appraisal of the literature. Distinct histologic patterns are described and correlated with relevant differential diagnoses. Major patterns of colitis with chronic architectural damage are identified, and for each pattern, key morphologic features and principal differential diagnoses-including inflammatory bowel disease and other conditions such as drug-related injury, ischemia, infection, diversion colitis, and immune-mediated disorders-are discussed. A pattern-based histologic approach provides a practical framework for reporting colitis with chronic architectural damage. This strategy narrows differential diagnoses, avoids nonspecific terminology, and supports clinical decision-making, while preserving the primacy of integrated clinicopathologic diagnosis when sufficient information is available.
Tougeron D, Rivera F, Kanonnikoff TF
… +13 more, Le Malicot K, Guarssifi M, Fares N, Soularue E, Dos Santos M, Wagner M, Taieb J, Aparicio T, Laurent-Puig P, Hacker UT, Fernández Montes A, Al-Batran SE, Lordick F
BACKGROUND: Prognosis of metastatic oesogastric adenocarcinoma (mOGC) beyond second‑line therapy remains poor. Trifluridine/tipiracil monotherapy is recommended in later lines but provides limited survival benefits. Anti...BACKGROUND: Prognosis of metastatic oesogastric adenocarcinoma (mOGC) beyond second‑line therapy remains poor. Trifluridine/tipiracil monotherapy is recommended in later lines but provides limited survival benefits. Anti‑angiogenic drugs have demonstrated significant efficacy in mOGC. Fruquintinib is a selective VEGFR‑1, ‑2 and ‑3 inhibitor with demonstrated activity in refractory colorectal adenocarcinoma. This design paper reports the rationale and design of the academic ENGIC 06 - PRODIGE 114 - FFCD 2401 - FRUQUITAS trial within the European network in gastro-intestinal oncology intergroup (ENGIC). METHODS: ENGIC 06 - PRODIGE 114 - FFCD 2401 - FRUQUITAS is an international, multicentre, open‑label, randomized phase III trial comparing trifluridine/tipiracil plus fruquintinib versus trifluridine/tipiracil alone in patients with metastatic oesophageal, gastro-oesophageal junction or gastric adenocarcinoma previously treated with two or three treatment lines. Patients are randomized 1:1 and stratified by treatment line, time from metastatic diagnosis to randomization, WHO performance status and prior anti‑angiogenic exposure. The primary endpoint is overall survival. Secondary endpoints include progression‑free survival, time to progression, objective response rate, disease control rate, safety, quality of life and translational biomarker analyses. PERSPECTIVES: ENGIC 06 - PRODIGE 114 - FFCD 2401 - FRUQUITAS is designed to determine whether VEGFR inhibition with fruquintinib plus trifluridine/tipiracil can meaningfully improve survival outcomes in pre-treated mOGC. TRIAL REGISTRATION: EU CT number 2025‑522395‑92‑00.
BACKGROUND AND AIM: This study assessed post-intervention body mass index (BMI) changes and associated risk factors in chronic pancreatitis (CP) patients undergoing minimally invasive treatment for pancreatic stones. MET...BACKGROUND AND AIM: This study assessed post-intervention body mass index (BMI) changes and associated risk factors in chronic pancreatitis (CP) patients undergoing minimally invasive treatment for pancreatic stones. METHODS: This retrospective-prospective cohort study enrolled adult CP patients with painful pancreatic stones (>5 mm) who underwent combined pancreatic extracorporeal shock wave lithotripsy (P-ESWL) followed by endoscopic retrograde cholangiopancreatography between March 2011 and June 2018. Patients were prospectively followed until March 2024. BMI was assessed pre-intervention and at final follow-up. Logistic regression identified independent predictors of post-procedural BMI changes. RESULTS: Among 1978 patients undergoing P-ESWL, 1562 (79.0 %) with ≥ 1-year follow-up were analyzed. Baseline BMI distribution showed 65.1 % (n = 1017) normal weight (18.5-24.0 kg/m²), 16.9 % (n = 264) overweight/obese (≥24.0 kg/m²), and 18.0 % (n = 281) underweight (<18.5 kg/m²). Post-procedural complication rates were similar across BMI subgroups. During follow-up, 66.8 % (n = 1044) maintained normal BMI, while 33.2 % (n = 518) experienced post-treatment BMI outside the normal range-12.0 % became underweight and 21.2 % overweight/obese. Five independent predictors of post-treatment BMI outside the normal range were identified: baseline BMI status, frequent acute pancreatitis attacks (>1/year), prior severe acute pancreatitis, multiple stones, and CP-related treatment during follow-up. CONCLUSIONS: Minimally invasive pancreatic stone treatment causes significant BMI changes with identifiable predictors. Integrating metabolic risk stratification into CP management algorithms could optimize long-term outcomes.
In patients presenting with intestinal symptoms who undergo colonoscopy with mucosal sampling, the pathologist plays a central role in identifying the underlying etiology in order to guide appropriate clinical management...In patients presenting with intestinal symptoms who undergo colonoscopy with mucosal sampling, the pathologist plays a central role in identifying the underlying etiology in order to guide appropriate clinical management. However, common intestinal symptoms such as diarrhea are shared by a broad spectrum of conditions, including infectious diseases, functional disorders (e.g., irritable bowel syndrome), inflammatory bowel disease (IBD), drug-induced injury, and metabolic disorders (e.g., diabetes mellitus). Although serological biomarkers may support the diagnostic workup, they are frequently insufficient to establish a definitive diagnosis. Moreover, endoscopic examination may fail to detect significant mucosal abnormalities even when histology reveals disease-specific patterns, as occurs in lymphocytic and collagenous colitis (i.e., microscopic colitis). In this complex diagnostic landscape, histomorphological evaluation represents a crucial element, allowing integration of microscopic findings with clinical and endoscopic data to reach an accurate interpretation. In recent years, accumulating evidence has demonstrated that similar histological patterns of intestinal injury-such as IBD-like architectural and inflammatory changes or eosinophil-rich infiltrates-may be associated with different underlying etiologies. This overlap is particularly relevant in patients treated with novel oncologic therapies, including tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and emerging treatments such as chimeric antigen receptor T-cell (CAR-T) therapy. In addition, in daily practice, pathology request forms often lack essential clinical, endoscopic, and laboratory information, further increasing the risk of diagnostic misinterpretation and inappropriate disease attribution. To address these challenges, the Italian Group of Digestive Disease Pathology (GIPAD) proposes a pattern-based histological approach for reporting mucosal damage in patients with colitis. In this first paper, we focus on non-chronic patterns of mucosal injury and discuss their principal differential diagnoses, with the aim of supporting standardized reporting and improving clinicopathological correlation.
Grancher A, Landi M, Ballhausen A
… +17 more, Vidal Tocino R, Alig A, Taravella A, Le Malicot K, Soularue E, Gallois C, Guarssifi M, Pelkowski M, Beltran M, Kochen L, Delliponti L, Taïeb J, Sastre J, Modest DP, Cremolini C, Mazard T, Tougeron D
INTRODUCTION: 5-fluorouracil (5-FU) ± targeted therapy is a standard of care in frail/elderly patients with an unresectable colorectal adenocarcinoma (CRC) in first-line setting. Panitumumab plus sotorasib combination (K...INTRODUCTION: 5-fluorouracil (5-FU) ± targeted therapy is a standard of care in frail/elderly patients with an unresectable colorectal adenocarcinoma (CRC) in first-line setting. Panitumumab plus sotorasib combination (KRAS G12C inhibitor) are promising in advanced line in KRAS G12C-mutated CRC. Here we assess the safety and efficacy of 5-FU combination with panitumumab and sotorasib as first-line treatment in frail/elderly patients with unresectable KRAS G12C-mutated CRC. METHODS: In this ENGIC 01 - PRODIGE 107 - FFCD 2306 - COLOSOTO multicenter, open-label, prospective single-arm phase II trial, the main inclusion criteria are adult patients with unresectable locally advanced or metastatic KRAS G12C-mutated CRC, unfit for a doublet/triplet chemotherapy. All patients will receive 5-FU plus panitumumab and sotorasib in 2-week-cycles until progression or intolerance. The primary endpoint is 8-months progression-free survival (PFS). The secondary endpoints include median PFS, disease control rate, time to progression, overall survival, best objective response rate, duration of response, safety profile, quality of life and geriatric assessment. A 70% 8-months PFS is expected (H <50%), and 37 patients will need to be included. PERSPECTIVES: Treatment with 5-FU plus panitumumab and sotorasib could be a promising alternative to 5-FU ± targeted therapy in first-line setting in frail/elderly patients with unresectable KRAS G12C-mutated CRC.