Background Diacylglycerol O-acyltransferase 1 (DGAT1) deficiency is a rare autosomal recessive disorder that disrupts intestinal triglyceride metabolism, leading to congenital diarrhea and enteropathy. This study aimed to characterize the phenotypic and genotypic spectrum of DGAT1 deficiency, evaluate the genotype-phenotype correlations, and assess outcomes following nutritional interventions. Methods We retrospectively analyzed 12 pediatric patients with DGAT1 deficiency diagnosed between 2016 and 2025. Clinical data, genetic profiles, management, and outcomes were collected. Whole-exome sequencing with Sanger validation was performed, and pathogenicity was classified according to the American College of Medical Genetics and Genomics criteria. A systematic review identified 58 previously reported patients. Kaplan-Meier survival analysis evaluated survival, and Fisher's exact test assessed associations between specific genetic variants and treatment responses. Results Among 70 patients, 84.3% presented in the neonatal period. The most frequent symptoms were diarrhea (90.0%), vomiting (81.4%), and failure to thrive (84.3%), with hypoalbuminemia observed in 87.1%. Splice-site variants were most prevalent (37.2%) with distinct ethnic distributions. Homozygous variants, especially missense mutations, were associated with more severe manifestations and poorer survival compared with compound heterozygous or splice-site variants (P = 0.0203). All nine deaths occurred in patients under 2 years of age. A fat-restricted diet significantly improved survival, while recurrent infections were linked to poor outcomes (P < 0.0001). Overall, 80.5% of patients achieved sustained clinical improvement with dietary therapy. Furthermore, the specific genetic variant c.629_631del was identified as a predictor of poor dietary response (P = 0.0497). Conclusions DGAT1 deficiency typically presents with early-onset refractory diarrhea and nutritional complications. Early genetic testing and prompt initiation of a fat-restricted diet within the first 2 years of life markedly improve survival and long-term outcomes.
Background While substantial evidence supports a protective effect of aspirin against colorectal polyps and cancer, the evidence for non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAIDs) remains limited. We studied the association between the use of NA-NSAIDs and the detection of colorectal polyps and cancer among screening participants.Methods We selected participants in the Bowel Cancer Screening trial in Norway-a randomized trial comparing once-only sigmoidoscopy and the biennial faecal immunochemical test (FIT). Using multivariable logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the association between NA-NSAID use in the 4 years before the screening invitation and detection of colorectal cancer (CRC), adenomas, advanced adenomas, and advanced serrated polyps. Long-term use was defined as >= 2 years of use.Results Of 64,889 participants (24,159 sigmoidoscopy, 40,730 FIT), 35,867 (55.3%) were NA-NSAID users, 314 (0.5%) had CRC, 6,208 (9.6%) had adenomas, and 659 (1.0%) had advanced serrated polyps. NA-NSAID users had lower odds of CRC (OR 0.80; 95% CI 0.64-1.00), adenomas (OR 0.94; 95% CI 0.89-1.00), and advanced adenomas (OR 0.87; 95% CI 0.80-0.95) than those with no NA-NSAID prescription. For non-selective NA-NSAIDs, the results were similar to those for any NA-NSAIDs (CRC: OR 0.79, 95% CI 0.63-0.99; adenomas: OR 0.93, 95% CI 0.88-0.99; advanced adenomas: OR 0.87, 95% CI 0.79-0.95). COX2-selective NA-NSAIDs were not associated with CRC or adenomas. Among the long-term NA-NSAIDs users, the ORs were 0.59 (95% CI 0.27-1.26) for CRC, 0.65 (95% CI 0.54-0.79) for adenomas, and 0.59 (95% CI 0.44-0.80) for advanced adenomas. No association was observed between any NA-NSAID use and advanced serrated polyps. The results were consistent across trial arms and sexes.Conclusion Our findings suggest that use of NA-NSAIDs, in particular non-selective NA-NSAIDs, might be associated with a reduced risk of adenomas and CRC, but not advanced serrated polyps.
Background Preventing endoscopic postoperative recurrence (ePOR) remains a major challenge in Crohn's disease (CD). This study aimed to identify the clinical and histopathological predictors of CD ePOR. Methods This nationwide, multicenter retrospective cohort study included 389 CD patients from five tertiary Chinese IBD centers, all of whom underwent curative ileocolonic resection between July 2016 and June 2024. The primary endpoint was ePOR at 6-12 months after surgery, defined as a modified Rutgeerts' score of >= i2b. Prediction models were developed based on the result of multivariate analysis of clinical and pathological data. Results The overall ePOR rate was 24.9%. Multivariate analysis showed that prior exposure to biologics [odds ratio (OR) 2.695, 95% confidence interval (CI) 1.605-4.525, P < 0.001] and baseline serum albumin < 35 g/L (OR 2.095, 95% CI 1.160-3.785, P = 0.014) were independent risk factor for ePOR, while preoperative exclusive enteral nutrition (OR 0.338, 95% CI 0.188-0.610, P < 0.001) and early postoperative prophylactic biologic therapy (OR 0.503, 95% CI 0.304-0.832, P = 0.007) were independently associated with a reduced risk of ePOR. Moderate-to-severe lymphoplasmacytic infiltration in the lamina propria (OR 4.924, 95% CI 2.028-11.957, P < 0.001) and lymphangiectasia (OR 4.916, 95% CI 2.395-10.092, P < 0.001) were identified as the significant histopathological predictors at the surgical margins. A prediction model integrating both clinical and pathological variables [area under the receiver operating characteristic curve (AUROC) 0.829] significantly outperformed the clinical-only model (AUROC 0.715, P = 0.001). Conclusions In the era of biologics and perioperative optimization, the 6-12-month ePOR rate among CD patients was 24.9%. A combined clinical-pathological model showed strong predictive performance.
Background Although radiotherapy (RT) remains the standard of care for locally advanced colorectal cancer (CRC), intrinsic and acquired resistance frequently compromise long-term outcomes. Sacituzumab govitecan (SG)-a TROP2-directed antibody-drug conjugate-offers a targeted platform for intracellular SN-38 delivery. The aim of the present preclinical study was to investigate whether SG enhances radiosensitivity in CRC, thereby providing a preclinical rationale for the clinical evaluation of SG-based combination strategies.Methods We evaluated SG-RT synergy across CRC cell lines with differential TROP2 expression (SW480, DLD-1 vs SW620, HCT116). In mechanistic studies, clonogenic assays, flow cytometry, cell counting kit-8, Western blot, and comet assays were utilized to assess cell survival, apoptosis, and DNA damage. TROP2 was knocked down or overexpressed to validate its role in radiosensitization. In vivo efficacy was evaluated by using cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. Immunohistochemistry for cleaved caspase-3 (CASP3), phosphorylated histone H2AX (gamma-H2AX), and Ki-67 were used to assess treatment-induced biological effects.Results In TROP2-high CRC cell lines (SW480, DLD-1), combined SG and RT markedly inhibited proliferation, increased apoptosis, and amplified DNA double-strand breaks, as evidenced by elevated gamma-H2AX expression and comet assay tail moments. Knockdown of TROP2 abrogated this synergy, whereas TROP2 overexpression restored it. In CDX and PDX models, SG combined with RT significantly suppressed tumor growth, increased cleaved CASP3 and gamma-H2AX expression, and reduced Ki-67 without exacerbating systemic weight loss.Conclusion Our findings identify SG as a potent radiosensitizer, providing a strong rationale for integrating SG into neoadjuvant RT regimens for locally advanced CRC.
Background Traditional immunophenotyping based on cell counts has limited value in predicting neoadjuvant treatment outcomes for locally advanced colorectal cancer (LACRC). Because mitochondrial fitness is an essential factor in T-cell function, we hypothesized that the pretreatment metabolic profile of circulating T cells could predict therapeutic response. This study aimed to develop a novel pretreatment assessment system based on peripheral blood immunometabolic parameters. Methods Baseline peripheral blood samples were prospectively collected from 72 patients with LACRC enrolled in the OPTICAL2 phase II clinical trial (NCT05571644), which compared neoadjuvant mFOLFOXIRI plus cadonilimab versus mFOLFOXIRI or mFOLFOX6. Multicolor flow cytometry was used to analyze the immunophenotype and mitochondrial characteristics of circulating T-cell subsets. A composite index, named Tscore, was constructed by using multivariate logistic regression. This model integrated five parameters: the CD4/CD8 ratio, mitochondrial mass of CD4(+) and CD8(+) central memory T cells and those of effector memory T cells. Results Patients achieving pathological complete response showed higher T-cell mitochondrial mass and lower levels of low membrane potential than non-responders. The baseline Tscore predicted pathological complete response (pCR) with an area under the curve (AUC) of 0.976 (95% CI, 0.927-1.000; P < 0.001) in the immunochemotherapy group and 0.861 (95% CI, 0.736-0.986; P < 0.001) in the chemotherapy-alone group. In a small exploratory external validation (n = 25, 3 pCR events; post hoc power = 41.8%), the model yielded an AUC of 0.848. An R-based calculator was developed to estimate individual pCR probabilities for different neoadjuvant regimens. Conclusions Tscore is a noninvasive biomarker for predicting neoadjuvant therapy response in LACRC. These findings highlight the importance of pretreatment T-cell metabolic characteristics and provide a potential tool for individualized response assessment.
