INTRODUCTION:Colonic diverticulosis is the most common structural abnormality of the colon in developed countries, with an increasing global prevalence. Approximately 20-25% of affected individuals develop symptoms, collectively referred to as diverticular disease. Given its wide clinical spectrum, evolving pathophysiological insights and growing disease burden, updated guidance is essential. METHODS:This International Consensus, developed by 32 experts from 14 countries through a structured Delphi process based on the PICO framework and GRADE methodology, provides evidence-based recommendations across five domains: epidemiology and pathogenesis; clinical features; diagnosis; medical therapy; and surgical management. RESULTS:Key statements define diverticulosis as the presence of diverticula without symptoms and diverticular disease as diverticula associated with symptoms or complications. High dietary fibre intake is protective whereas smoking, obesity and the use of non-steroidal anti-inflammatory drugs, corticosteroids, opioids or immunotherapy increase risk. Imaging is essential in suspected acute diverticulitis: ultrasound may be appropriate in experienced hands, while CT remains preferred for complicated cases. Diverticulosis itself requires no treatment. In symptomatic uncomplicated diverticular disease, dietary fibre, selected probiotics, mesalazine and rifaximin may help relieve symptoms. Routine antibiotic use is not recommended for acute uncomplicated diverticulitis, and elective surgery should be individualised, prioritising quality of life considerations over episode count. CONCLUSIONS:These Consensus statements aim to standardise and optimise the diagnosis, management and prevention of diverticular disease across diverse healthcare systems, while highlighting research priorities such as microbiome characterisation, genetic risk profiling and long-term outcomes of selective antimicrobial and surgical strategies.

BACKGROUND & AIMS:Evidence on optimal bismuth and antibiotic dosing is limited. We aimed to analyze the effectiveness of bismuth-containing quadruple regimens according to drug dosage. METHODS:This was an analysis of an international, prospective, non-interventional registry on the management of Helicobacter pylori infection by European gastroenterologists (European Registry on Helicobacter pylori Management [Hp-EuReg]). Patients receiving empirical bismuth-containing quadruple therapies in any treatment line and registered from 2013 to 2024 were included. Effectiveness was assessed using a modified intention-to-treat (mITT) analysis. RESULTS:A total of 10,767 first-line records were analyzed. The clarithromycin-amoxicillin-bismuth (CAB) scheme was >90% effective with standard doses of amoxicillin and clarithromycin (2000 mg/d and 1000 mg/d), regardless of bismuth dose. The bismuth-metronidazole-tetracycline (BMTc) regimen achieved >90% effectiveness with tetracycline ≥1500 mg/d, metronidazole 1500 mg/d, and bismuth ≥480 mg/d. The amoxicillin-metronidazole-bismuth (AMB) regimen reported ≈90% mITT with amoxicillin 2000 mg/d, metronidazole ≥1000 mg/d, and bismuth 480 mg/d. The clarithromycin-metronidazole-bismuth (CMB) showed ≥90% mITT with metronidazole ≥800 mg/d, without improvement from increasing bismuth dose. In the amoxicillin-levofloxacin-bismuth (ALB) regimen, mITT was >90%, with no benefit from increasing levofloxacin >500 mg/d. A total of 2952 second- to sixth-line treatments were analyzed, all showing mITT <90% (ALB, 83%; BMTc, 79%; CAB, 88%; MDB, 63%; AMB, 88%), with no significant differences with different bismuth doses. CONCLUSIONS:Increasing antibiotic or bismuth doses above the standard did not improve effectiveness of H pylori treatment. Adherence, treatment length, and proton pump inhibitor co-therapy may be more impactful than escalation of antibiotics/bismuth doses. CLINICALTRIALS:gov, Number: NCT02328131.

BACKGROUND:Colorectal cancer (CRC) screening is effective and cost-effective in average-risk individuals. The COLONPREV study recently showed that individuals invited to a faecal immunochemical test (FIT) were more likely to participate in screening than those invited to colonoscopy, and that FIT-based screening was non-inferior to colonoscopy with respect to CRC-related mortality and CRC incidence. OBJECTIVE:To assess whether the outcomes of colonoscopy- and FIT-based screening differ according to sex and age in the invited population. METHODS:Presumptively healthy men and women aged 50-69 years were randomised to either a one-time screening colonoscopy or biennial FIT. In this analysis, we report participation and crossover rates, CRC-related mortality, CRC incidence, all-cause mortality, and diagnostic yield for both screening strategies, stratified by sex and by age group (50-59 and 60-69 years). RESULTS:The eligible population consisted of 26,332 individuals assigned to colonoscopy and 26,719 assigned to FIT. As expected, participation and crossover rates were higher in women than in men and in older individuals compared with younger individuals. Participation was also consistently higher in those invited to FIT screening than in those assigned to colonoscopy across both sexes and age groups. The observed reductions in CRC-related mortality and CRC incidence, which were consistent across both screening strategies, were independent of sex or age. However, CRC-related mortality, all-cause mortality, and CRC incidence remained higher in men and older participants than in women and younger participants. Colonoscopy screening showed a higher diagnostic yield of premalignant precursor lesions across all demographic subgroups. CONCLUSION:Participation and reductions in CRC-related mortality and incidence were consistent across sex and age groups for both FIT- and colonoscopy-based screening strategies. The higher baseline risk observed in men could not be fully mitigated by screening. TRIAL REGISTRATION:ClinicalTrials.gov: NCT00906997.

Background Pancreatic cancer continues to be one of the most challenging malignancies to diagnose and treat, and it is often detected at an advanced stage owing to asymptomatic early phases and limitations in current diagnostic tools, highlighting the need for improved diagnostic methodologies. Methods We aimed to evaluate the potential for integrating information from thermal liquid biopsy (TLB) thermograms with clinical biomarkers to improve the diagnosis and prognosis of pancreatic cancer. Serum samples from 381 Danish patients with pancreatic cancer and 325 patients referred with non-organ specific signs and symptoms of cancer, but without confirmed cancer after clinical and computed tomography evaluation, were analyzed. TLB thermograms provided information on the partial excess heat capacity of the serum as a function of temperature. Three classification models were constructed using machine learning algorithms based on variable selection with penalization, applying cross-validation and resampling techniques: iClin Model (age, Eastern Cooperative Oncology Group Performance Status, carbohydrate antigen 19.9, and C-reactive protein), iTLB Model (discordant pairs of temperatures from thermograms), and iTLB + iClin Model (discordant pairs of temperatures and clinical data). Results The iClin Model achieved high diagnostic performance, with a validation area under the curve (AUC) of 0.95 ± 0.01 for differentiating symptomatic controls from patients with pancreatic ductal adenocarcinoma (PDAC), but showed no significant association with overall survival (OS). The iTLB Model showed limited diagnostic performance, with a validation AUC of 0.59 ± 0.03, but was associated with OS in patients with PDAC. The combined iTLB + iClin Model preserved high diagnostic performance, with a validation AUC of 0.95 ± 0.02, sensitivity of 96.20%, specificity of 91.20%, positive predictive value of 90.48%, and negative predictive value of 96.59%. For early-stage PDAC, the iTLB + iClin Model achieved an AUC of 0.93 (95% CI: 0.89–0.98), compared with 0.96 (95% CI: 0.95–0.98) for stages III–IV. Conclusion This study demonstrates the potential of combining specific clinical biomarker information with advanced techniques such as TLB, to improve the accuracy of pancreatic cancer diagnosis and prognosis.

INTRODUCTION:Acid-related gastrointestinal diseases, particularly gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD), remain major global health burdens despite decades of proton pump inhibitor (PPI)-based therapy. Persistent symptoms, nocturnal acid breakthrough, refractory disease, antibiotic resistance in Helicobacter pylori infection, and interindividual pharmacogenomic variability continue to limit current management strategies. AREAS COVERED:This review summarizes therapeutic advances in acid-related diseases, focusing on articles published between 2020 and 2025 and on potassium-competitive acid blockers (P-CABs), mucosal protective agents, adjunctive pharmacotherapies, endoscopic anti-reflux interventions, and precision medicine studies. Literature from randomized controlled trials, meta-analyses, international guidelines, and observational studies was reviewed to evaluate the efficacy, safety, and clinical positioning of emerging therapies in GERD, PUD, and H. pylori eradication. The search was conducted in PubMed. EXPERT OPINION:P-CABs, particularly vonoprazan, represent the most important advance in acid suppression in recent decades, offering faster, more potent, and more predictable acid inhibition than PPIs. Precision approaches integrating GERD phenotyping, pharmacogenomics, and antibiotic susceptibility testing are shifting management toward individualized care. However, long-term safety data, cost-effectiveness analyses, and robust comparative trials remain limited. Future progress will likely depend on combining phenotype-directed pharmacologic, endoscopic, and microbiome-informed strategies supported by artificial intelligence-driven diagnostics and treatment selection.

BACKGROUND:Pragmatic colorectal cancer (CRC) screening trials compare colonoscopy with faecal immunochemical testing (FIT), but differences in adherence complicate interpretation of comparative outcomes. OBJECTIVE:To compare 10-year risks of CRC mortality, CRC incidence and all-cause mortality under one-time colonoscopy versus sustained FIT strategies in the COLONPREV Trial. DESIGN:We conducted a post hoc per-protocol analysis of 17 270 screening initiators aged 50-69 years in eight Spanish regions, using inverse probability weighting to adjust for observed confounding and informative protocol deviations. RESULTS:Weighted 10-year risks were similar for CRC incidence (0.80% FIT vs 0.86% colonoscopy; risk difference (RD) 0.06%, 95% CI -0.25% to 0.37%) and all-cause mortality (4.02% vs 4.09%; RD 0.07%, 95% CI -0.76% to 0.84%). CRC mortality was lower with colonoscopy (0.072% FIT vs 0.042% colonoscopy; RD -0.03%, 95% CI -0.12% to 0.06%), but estimates were imprecise. CONCLUSION:Sustained colonoscopy and FIT showed similar 10-year outcomes overall, highlighting the importance of adherence pathways in pragmatic screening trials. TRIAL REGISTRATION NUMBER:ClinicalTrials.gov: NCT00906997.

BACKGROUND:The risk of colorectal cancer (CRC) after serrated polyp resection remains unclear, and current surveillance recommendations rely on limited evidence. We evaluated CRC incidence in individuals with advanced serrated lesions (ASL) detected at baseline colonoscopy and compared risk according to the most advanced lesion identified. METHODS:Participants undergoing colonoscopy within the COLONPREV trial (n = 8989) were included in this post hoc analysis. Individuals were classified according to the most advanced baseline lesion: no lesion, non-advanced adenoma, advanced adenoma, or ASL. The primary outcome was incident CRC. Cumulative incidence and hazard ratios (HR) were estimated using Cox proportional hazard models. RESULTS:At baseline colonoscopy, serrated polyps were detected in 19.8% of participants, including ASL in 2.5%. Over a mean follow-up of 9.5 years, 44 CRC cases were diagnosed (cumulative incidence 0.49%; incidence rate 0.52 per 1000 person-years). The 10-year cumulative incidence was 0.27% in individuals without baseline lesions (n = 5496), 0.57% in those with non-advanced adenomas (n = 2091), 1.23% in advanced adenomas (n = 1218), and 1.09% in ASL (n = 184). In multivariable analysis, CRC risk was increased for non-advanced adenomas (HR 3.25, 95% CI 1.48-7.16), advanced adenomas (HR 9.77, 95% CI 4.24-22.50), and ASL (HR 6.37, 95% CI 1.42-28.54). Surveillance colonoscopy was associated with lower CRC incidence (HR 0.46, 95% CI 0.22-0.95 for one colonoscopy; HR 0.09, 95% CI 0.02-0.40 for ≥ 2 colonoscopies). CONCLUSION:In this screening cohort, ASL were associated with increased CRC risk in the range of advanced adenomas. These findings provide risk estimates relevant to post-polypectomy management. TRIAL REGISTRATION NUMBER:NCT00906997.

Early detection of colorectal cancer is essential to improving survival, where yet current diagnostic tools show limited performance. This study aimed to enhance diagnostic accuracy by integrating clinical variables with thermogram profiles obtained through serum-based thermal liquid biopsy and analyzed using machine learning models. We evaluated 328 patients with colorectal cancer and 355 symptomatic individuals with non-organ-specific cancer signs but negative diagnostic evaluations, to reproduce clinically relevant decision settings. The combined model showed improved classification performance compared with the use of clinical variables alone, particularly in patients with early-stage disease. In addition, proteomic analysis of samples stratified bythermogram patterns identified proteins associated with survival, including fibrinogen-like protein 1, supporting the biological relevance of these thermodynamic profiles. Together, these findings indicate that integrating serum thermogram information with routine clinical data can modestly strengthen diagnostic assessment and help identify biologically meaningful patient subgroups, offering a promising non-invasive colorectal cancer evaluation.

BACKGROUND:Colonoscopy and the faecal immunochemical test are accepted strategies for colorectal cancer screening in the average-risk population (ie, people aged ≥50 years without personal or family history of colorectal cancer). In this trial, we aimed to compare whether invitation to screening with faecal immunochemical test was non-inferior to colonoscopy in a screening programme. METHODS:COLONPREV was a pragmatic, randomised, controlled, non-inferiority trial done at 15 tertiary hospitals across eight regions of Spain. Eligible participants were presumptively healthy and aged between 50 years and 69 years without a personal history of colorectal cancer, adenoma or inflammatory bowel disease, family history of hereditary or familial colorectal cancer (ie, two or more first-degree relatives with colorectal cancer or one diagnosed before age 60 years), severe comorbidities, or previous colectomy. Participants were randomly assigned (1:1) to one-time colonoscopy or biennial faecal immunochemical test before invitation to screening. The primary endpoint was colorectal cancer mortality at 10 years, assessed in the intention-to-screen population. An absolute difference of less than 0·16 percentage points was required to show non-inferiority. This trial was registered with ClinicalTrials.gov, NCT00906997. FINDINGS:Between June 1, 2009, and Dec 31, 2021, 57 404 individuals were randomly assigned to receive an invitation for colonoscopy (n=28 708) or the faecal immunochemical test (n=28 696). The intention-to-screen population consisted of 26 332 individuals in the colonoscopy group and 26 719 in the faecal immunochemical test group. In the intention-to-screen population, participation in any form of screening was 31·8% in the colonoscopy group and 39·9% in the faecal immunochemical test group (risk ratio [RR] 0·79 [95% CI 0·77 to 0·82]). Faecal immunochemical testing was non-inferior to colonoscopy with regard to the risk of colorectal cancer mortality at 10 years: the risk was 0·22% (55 deaths) in the colonoscopy group and 0·24% (60 deaths) in the faecal immunochemical test group (risk difference -0·02 [95% CI -0·10 to 0·06; RR 0·92 [95% CI 0·64 to 1·32]; pnon-inferiority=0·0005). INTERPRETATION:Participation in screening was higher among individuals invited to faecal immunochemical test screening than colonoscopy screening. On the basis of participation observed in this study, a faecal immunochemical test-based programme was non-inferior to a colonoscopy-based programme for colorectal cancer-related mortality. FUNDING:Fundación Científica de la Asociación Española contra el Cáncer and Instituto de Salud Carlos III.

PPARD knockdown modifies the expression ratio between MYC and PGC1A

Etomoxir or stromal signals alter different metabolic parameters in PDAC cells

EMT induction by etomoxir and MCM in bulk transcriptomics

Induction of EMT-like phenotype and metabolic switch in PDAC cells upon starvation. A, Representative images illustrating morphologic changes for PDAC-354 cells in response to treatment for 72 hours with the complex I inhibitor metformin (3 mmol/L), the β-oxidation inhibitor etomoxir (20 μmol/L), the complex II inhibitor malonate (5 mmol/L), the pyruvate carrier inhibitor UK5099 (100 μmol/L), or tumor-like conditions [low pH (HCl 50 μmol/L) + low glucose (1 mmol/L) + 3%O2]. Scale bar, 50 μm. B, Expression of EMT-associated genes (ZEB1, SNAI1, SNAI2, LOXL2, and VIM) was determined by RT-qPCR after cells were treated for 48 hours as indicated in A or with MCM. Pooled data for PDAC-185, A6L, 215, 253, and 354 (n ≥ 4 for each cell type). Data are normalized to HPRT1. Eto, etomoxier; Mal, malonate; Met, metformin. C, PDAC-215, 253, and 354 cells were treated with MCM or 20 μmol/L etomoxir for 48 hours and seeded in modified Boyden invasion chambers containing 20% FBS in the lower compartment. The number of invasive cells was analyzed after 16 hours (n = 7–11). D, GFP+-Luciferase+-PDAC-354 cells were treated with control, MCM, or 20 μmol/L etomoxir for 48 hours and then injected intrasplenically to assess their metastatic capacity (n = 9 mice/group). Representative photographs of liver metastasis (top) and subsequent hematoxylin and eosin staining (bottom). Scale bar, 200 μm. E, Representative OCR profile for PDAC-253 cells treated for 48 hours as indicated (mitochondrial stress test). O, ATP synthase inhibitor oligomycin; F, mitochondrial OXPHOS uncoupler FCCP [carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone]; A+R, complex III inhibitor antimycin A + electron transport change inhibitor rotenone. F, Maximal and ATP-linked respiration (resp) in non-CSC vs. CSC cells. Bars represent pooled data from PDAC-215, 253, and 354, showing individual data points corresponding to each PDX (n = 5–7). G, Representative extracellular acidification rate (ECAR) profile for PDAC-253 cells treated for 48 hours as indicated (glycolysis test). G, glucose; O, ATP synthase inhibitor oligomycin; 2DG, glycolysis inhibitor 2-deoxy-glucose. H, Glycolysis, glycolytic capacity, and glycolytic reserve in adherent (non-CSC) vs. sphere-derived cells (CSC). Bars represent pooled data from PDAC-215, 253, and 354, showing individual data points corresponding to each PDX (n = 4–5). All data are represented as the mean ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001. See also Supplementary Figs. S1–S3.

PPARD expression is linked to metabolic switch and EMT in patients with PDAC. A, Expression levels of PPARD in PDAC tumors (T) vs. surrounding normal tissue (N) included in the TCGA and GTEx projects. B, Patients were dichotomized for PPARD expression [higher (n = 58) and lower (n = 81) expression compared with the mean; RNA-seq V2 RSEM values]. Kaplan–Meier curves for disease-free survival are shown. Dotted lines denote the confidence intervals. Survival, 19.48 vs. 13.53 months. C and D, A TMA with 108 cases was stained by IHQ using an anti–PPARδ antibody. Representative images depicting different signal intensities (weak vs. strong) and localizations (nuclear vs. cytoplasmatic) are shown in C. Magnification, ×400. Scale bar, 50 μm. Arrows, stained cancer cells. D, Signal intensity was scored by Allred immunoreactive score, and patients were dichotomized into low (n = 34; scores 0–6) vs. high (n = 59; scores 7–8) PPARδ expression groups. Kaplan–Meier curves for overall survival are shown. Dotted lines denote the confidence intervals. Survival, 17.5 vs. 11 months. E, Correlation between PPARD tumor expression levels family members and an EMT-associated signature composed of SNAI1, SNAI2, and ZEB1. F, Gene sets enriched in the transcriptional profile of tumors belonging to the top PPARD high-expression group compared with the bottom low-expression group in the TCGA data series (PAAD, pancreatic adenocarcinoma). Shown are the normalized enrichment score (NES) values for each pathway using the Hallmark gene sets, meeting the significance criteria: nominal P value of < 0.05, FDR < 25%. G, Enrichment plot for TNFα, EMT, glycolysis, and hypoxia hallmarks in PPARD-high vs. -low samples shown in F, indicating values of normalized enrichment score and FDR q values. H, Representative images of costaining of PPARδ (nuclear and cytoplasmatic, red) and HIF1α (nuclear brown) by IHQ in several patients shown in C and D. Magnification, ×400. Scale bar, 50 μm. Arrows, costained cancer cells. See also Supplementary Fig. S6.