Search Results (1,054)

Background: Cholinesterase inhibitors (ChEIs) are commonly prescribed for the treatment of Alzheimer’s disease (AD) and achieve long-term benefits for cognition and survival in real-world settings. However, the discontinuation rate is high due to their side effects, with gastrointestinal (GI) symptoms hampering long-term prescriptions. The risk of side effects associated with rivastigmine was previously shown to be lower with transdermal delivery than with oral capsules; however, this has yet to be examined in detail for donepezil, the most widely used ChEI. The daily application of a donepezil transdermal patch was officially approved in Japan in 2023. The incidence of side effects was lower with the donepezil transdermal patch than with oral donepezil in healthy volunteers, but has not yet been assessed in clinical settings. Results: We herein report three AD patients in two different memory clinics who developed GI symptoms with oral ChEIs that were attenuated by switching to the donepezil transdermal patch. Conclusions: The donepezil transdermal patch may improve tolerability and adherence in patients who develop gastrointestinal adverse effects with oral donepezil. Full article

Background: The introduction of tyrosine kinase inhibitors has revolutionised the treatment of gastrointestinal stromal tumours (GISTs), yet the role of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in peritoneal GISTosis remains controversial. Methods: A retrospective analysis was conducted on patients with peritoneal GISTosis who underwent CRS plus HIPEC in an 18-year period. We analysed the clinicopathological characteristics and evaluated the perioperative and long-term outcomes based on the extent of disease (peritoneal cancer index, PCI), the resection (completeness of cytoreduction score) and the IM-administration. The survival factors were also analysed and the Kaplan–Meier estimator to model and estimate overall (OS) and progression-free survival (PFS). The median follow-up period was 72 months (range, 12–146). Results: A total of 25 patients (M:F = 15:10) with a median age of 57 years (range, 32–69) underwent CRS with HIPEC for peritoneal GIST metastases, detected either synchronously (n = 11) or metachronously (n = 14). The media PCI score was 9 (range, 4–20) and complete cytoreduction was achieved in 80%. Grade III complications were observed in two patients, whereas there was no postoperative mortality. Neoadjuvant imatinib-mesylate (IM) therapy was administered in 60% of patients who detected with metachronous metastases (n = 8/14), whereas adjuvant IM therapy was administered in 19 of 25 patients. Median OS was 62 months (95% CI = 22.8–101.2). Median OS and DFS for patients with PCI scores ≤ 10 were significantly longer compared to those with PCI scores > 10 (p = 0.009 and p = 0.024, respectively). Patients with CC scores of 0–1 had a significantly longer OS compared to those with CC scores of 2 (p = 0.005) and 3 (p = 0.002) and longer PFS compared to those with CC scores of 3 (p = 0.005). The need for imatinib did not significantly impact OS (p = 0.240) or PFS (p = 0.243). Conclusions: CRS combined with HIPEC shows promising results in peritoneal GISTosis, especially in patients with lower PCI and CC scores. Until larger studies validate its safety and efficacy, it should be primarily performed in expert hands in specialised peritoneal surface oncology centres. Full article

Background/Objectives: Endoscopic submucosal dissection (ESD) is a state-of-the-art en bloc resection for early gastro-intestinal cancers and precursors developed and validated in Japan. Western expertise with this complex technique remains limited. Tutored training might be optimal for patients and ESD learning. We established ESD tutoring courses led by experienced Japanese experts to provide (i) optimal long-term curative outcomes and low complication rates for patients and (ii) hands-on training on difficult lesions for European endoscopists under direct expert supervision. Methods: Prospective data from 2011 to 2015 (follow-up to 12/2024) were analyzed. A total of 118 neoplasms (50% HGIEN and cancer) in 101 patients (median age 68 [37–91] years; 38% with significant comorbidities) were treated with expert or tutored ESD. Japanese experts performed 28 ESDs, while 22 trained beginners conducted 90 supervised procedures on difficult lesions during 5 live and 20 tutoring events (1–4 days each). Results: Analysis of the complete data showed curative and en bloc resection rates of 88% and 95%, respectively, with no recurrence after R0 resections during a median follow-up of 9.8 [1.5–14.9] years. Long-term survival remained recurrence-free after endoscopic resection of 3 recurrent adenomas (at R1/Rx) and curative surgery/2nd ESD for 5 non-curative ESDs. Adverse events occurred in 9.3% without emergency surgery or 30-day mortality. Comparing expert-only vs. tutored ESD procedures, beginners correctly applied curative ESD indications in 94% of 118 neoplasms. Experts resected larger lesions (22 cm²) at a rate of 9.3 cm²/h in 121 min. Tutored beginners achieved a 75% [25–100] self-completion rate on 33% smaller lesions in 112 min. Conclusions: ESD tutoring courses led by Japanese experts ensure excellent patient outcomes and standardized procedural training. This model may foster professional ESD performance across European referral centers. Full article

Background: Serum C–C motif chemokine ligand 18 (seCCL18) in systemic sclerosis (SSc) has been primarily associated with progressive interstitial lung disease (SSc-ILD) and mortality. However, its relationship with non-pulmonary organ involvement, disease activity, and long-term outcome has not been comprehensively evaluated. We therefore examined the clinical relevance of seCCL18 in a single-center SSc cohort. Methods: A total of 151 patients with SSc (83 diffuse cutaneous (dcSSc), 68 limited cutaneous SSc (lcSSc); median (IQR) disease duration: 9 (4;16) years) and 47 age- and sex-matched healthy controls (HCs) were enrolled. Serum CCL18 concentrations were measured by enzyme-linked immunosorbent assay. Elevated seCCL18 was defined as >130 ng/mL (mean + 2 SD of the healthy control group). Organ involvement and disease activity (EUSTAR Activity Index, EUSTAR-AI) were assessed at baseline, while survival was analysed longitudinally. Results: Patients with SSc had significantly higher seCCL18 levels than HCs (mean ± SD: 99.9 ± 43.2 vs. 75.0 ± 27.5 ng/mL, p < 0.01). Elevated seCCL18 was associated with SSc-ILD (81.1% vs. 60.5%, p = 0.022), reduced forced vital capacity (FVC < 70%: 16.2% vs. 3.5%, p = 0.006), and reduced diffusing capacity for carbon monoxide (DLCO < 70%: 80.6% vs. 54.4%, p = 0.005). Higher seCCL18 levels were observed in patients with myocardial disease (104.8 ± 41.8 vs. 83.8 ± 44.2 ng/mL, p = 0.008), left ventricular diastolic dysfunction (107.1 ± 40.5 vs. 84.5 ± 45.0 ng/mL, p < 0.001), and oesophageal involvement (110.7 ± 38.3 vs. 93.3 ± 43.1 ng/mL, p = 0.009). SeCCL18 levels above the cut-off were more frequently associated with tendon friction rubs (51.4% vs. 27.4%, p = 0.007), active disease (EUSTAR-AI ≥ 2.5: 73% vs. 44%, p = 0.002), and elevated inflammatory markers (CRP > 5 mg/L: 51.4% vs. 19.3%, p < 0.001; ESR > 28 mm/h: 37.8% vs. 18.4%, p = 0.015). During a median follow-up of 87 months, 22 patients (15%) died. Elevated baseline seCCL18 predicted poorer survival in univariate analysis (log-rank p = 0.013) and remained an independent predictor of mortality in multivariable Cox regression (HR 1.789; 95% CI 1.133–2.824; p = 0.013), together with declining DLCO and reduced six-minute walk test performance. Conclusions: Elevated seCCL18 may identify patients with systemic sclerosis who exhibit a more severe multisystem phenotype, including cardiopulmonary, gastrointestinal, and musculoskeletal involvement, increased inflammatory activity, and reduced long-term survival. These findings suggest that seCCL18 may have some clinical utility as a prognostic biomarker reflecting widespread disease involvement beyond the lungs, even in patients with long-standing disease; however, the lack of an established cut-off value requires further validation in prospective, multicentre studies. Full article

Infantile-onset lysosomal acid lipase deficiency (LAL-D) (Wolman disease, historically) is a rare inherited, rapidly progressive disorder caused by pathogenic variants in the LIPA gene, which encodes the enzyme LAL. LAL is essential for the metabolism of cholesteryl esters and triglycerides. LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system. Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation. If untreated, rapidly progressive LAL-D typically leads to death within the first year of life. Treatment takes the two-pronged approach of sebelipase alfa, a human lysosomal acid lipase enzyme replacement therapy (ERT) that improves lipid metabolism, combined with nutritional management. Dietary substrate (lipid) reduction, known as substrate reduction therapy, is essential for optimal management in LAL-D. Following a nutritional plan and managing gastrointestinal disturbances together reduce systemic inflammation and improve growth, gut function, liver health, quality of life, and survival in patients with infantile-onset LAL-D. A multidisciplinary specialized team is necessary to manage the highly complex, multisystemic conditions in these patients. Nutritional management of LAL-D has evolved with increasing experience with the clinical management of ERT-treated infantile-onset LAL-D. A review of guidance for best practice nutritional management is needed. This narrative review aims to provide updated recommendations and guidance for the optimal nutritional management of infantile-onset LAL-D. Full article

Background: Site-specific long-term outcomes, including neurofibromatosis type 1 (NF1), Ki-67 prognostic value, and very late recurrences of small bowel gastrointestinal stromal tumors (GISTs), remain inadequately defined. Methods: This retrospective cohort study investigated the clinical characteristics, diagnostic challenges, and long-term outcomes of patients with small bowel GISTs. This retrospective, single-center study (2008–2024) analyzed 27 consecutive patients (average age: 62.2 years) with jejunal/ileal GISTs. Clinicopathologic features, diagnostic yield of balloon-assisted enteroscopy (BAE), treatments, and outcomes were evaluated during a 10.2-year median follow-up period. Recurrence-free survival (RFS) and overall survival (OS) were estimated by Kaplan–Meier with log-rank testing. Ki-67 was assessed using MIB-1; a prespecified 5% cut-off was chosen based on prior evidence. Results: Tumor (mean size, 62.4 mm) sites included the jejunum (74.1%) and ileum (25.9%). NF1 was present in 3/27 (11.1%) patients, all with multiple jejunal tumors. Among the 14 patients who underwent BAE, biopsy was attempted in six and yielded a histological diagnosis in one (16.7%). Six patients had recurrence; two died from disease >10 years postoperatively. Five-year OS and RFS were 91.3% and 68.7%, respectively. Adverse RFS was associated with ileal location (p = 0.03), size ≥ 10 cm (p < 0.001), mitoses > 5/50 high-power fields (p = 0.002), and Ki-67 ≥ 5% (p < 0.001). One patient labeled low risk by conventional models had recurrence with Ki-67 = 10%. Another classified as low risk by conventional models experienced recurrence >10 years after surgery, with a Ki-67 index of 10%. Conclusions: Extended, risk-adapted surveillance may be reasonable for small-bowel GISTs, and it may be beneficial to incorporate Ki-67 (≥5%) into site-based risk stratification. These observations remain hypothesis-generating and require validation in larger, multicenter cohorts and prospective studies. Full article

This study reports the isolation, identification, and functional characterization of lactic acid bacteria (LAB) obtained from the endogenous fermentation of Theobroma bicolor (pataxte), an understudied Mesoamerican species with unexplored biotechnological potential. Five lactic acid bacteria strains were isolated and selected for comprehensive in vitro evaluation of their probiotic attributes. The assays included antimicrobial activity (disk diffusion and minimum inhibitory concentration), tolerance to simulated gastrointestinal conditions, and comparison of survival between non-encapsulated and bigel-encapsulated cells during digestion. All five isolates demonstrated notable antimicrobial activity against Escherichia coli ATCC 25922, Salmonella Enteritidis ATCC 13076, and Staphylococcus aureus ATCC 25923. Strain S1.B exhibited exceptional resistance to acidic pH (2.0) and bile salts, reaching 3.61 ± 0.00 log (CFU/mL) after gastrointestinal simulation. The strain was identified as Lactiplantibacillus pentosus via 16S rRNA gene sequencing, marking the first documented isolation of this species from pataxte fermentation. Bigel encapsulation markedly enhanced its survival, increasing viability to 5.08 ± 0.10 log (CFU/mL). These findings identify Lactiplantibacillus pentosus 124-2 as a potential probiotic candidate originating from pataxte fermentation and highlight bigel systems as powerful vehicles for bacterial protection. Collectively, this work expands the microbial biodiversity known in Theobroma fermentations and underscores their promise for future functional food applications. Full article

The mesenchymal–epithelial transition (MET) receptor is a tyrosine kinase activated by its sole known ligand, hepatocyte growth factor (HGF). MET signaling regulates key cellular processes, including proliferation, survival, migration, motility, and angiogenesis. Dysregulation and hyperactivation of this pathway are implicated in multiple malignancies, including lung, breast, colorectal, and gastrointestinal cancers. In non–small cell lung cancer (NSCLC), aberrant activation of the MET proto-oncogene contributes to 1% of known oncogenic drivers and is associated with poor clinical outcomes. Several mechanisms can induce MET hyperactivation, including MET gene amplification, transcriptional upregulation of MET or HGF, MET fusion genes, and MET exon 14 skipping mutations. Furthermore, MET pathway activation represents a frequent mechanism of acquired resistance to EGFR- and ALK-targeted tyrosine kinase inhibitors (TKIs) in EGFR- and ALK-driven NSCLCs. Although MET has long been recognized as a promising therapeutic target in NSCLC, the clinical efficacy of MET-targeted therapies has historically lagged behind that of EGFR and ALK inhibitors. Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment of MET exon 14 skipping mutations. They have also demonstrated potential in overcoming MET-driven resistance to EGFR TKIs or ALK TKIs. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC. Full article

The objective of this research was to combine three plant-derived polysaccharides, Lycium barbarum polysaccharides (LBP), peach gum polysaccharide (PGP), and citrus pectin (CP), with alginate (SA) to co-encapsulate probiotics and investigate the survival of cells during in vitro gastrointestinal digestion, storage, and application in yogurt. The incorporation of different polysaccharides into SA all improved the encapsulation efficiencies and surface regularities of probiotic capsules. Texture analysis showed that the PGP-incorporated microspheres exhibited the highest values for hardness, springiness, and resilience, while in terms of chewiness, the highest values were observed for the LBP and CP groups. In vitro gastrointestinal digestion analysis revealed that the incorporation of different polysaccharides all further enhanced the cell survival rates, and the SA: PGP group demonstrated superior probiotic protection with the minimal viability loss of only 0.40 log CFU/g after 6h digestion. During storage, SA: PGP group also exhibited the highest stability, which still maintained 7.7 Log CFU/g of viable cells at the end of 20 days storage, and after incorporation of SA: PGP into yogurt, 7.8 Log CFU/g of viable cells were still detected at the end of 21 days storage. Full article

Helicobacter pylori infection is a primary cause of gastritis and gastric ulcers. It is crucial to find alternative therapies for H. pylori infection due to the significant side effects of current antibiotics. Heyndrickxia coagulans is an ideal probiotic due to its functionality and stability in production and storage. This study explored the anti-bacterial effects of H. coagulans BHE26 in vitro and in vivo. H. coagulans BHE26 showed notable tolerance to simulated gastric juice (pH 3.0) and 1% bile salts, highlighting its potential suitability for gastrointestinal survival. H. coagulans BHE26 was resistant to ceftriaxone but sensitive to penicillin, ampicillin, erythromycin, gentamicin, ciprofloxacin, ceftriaxone, lincomycin, tetracycline and chloramphenicol. These characteristics showed that H. coagulans BHE26 is a potential probiotic bacterium. In vitro assays demonstrated that H. coagulans BHE26 inhibited H. pylori, reduced urease activity, and displayed notable auto-aggregation and co-aggregation abilities. In vivo, administration of H. coagulans BHE26 alleviated H. pylori-induced gastric mucosal damage, significantly lowered serum anti-bacterial IgG levels, and modulated gastric microbiota composition, including an increase in Turicibacter and a decrease in Lactobacillus abundance. These results indicate that H. coagulans BHE26 alleviated H. pylori-induced inflammation, offering a novel therapeutic strategy against H. pylori infection. Full article

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. While imatinib revolutionized first-line therapy, resistance and specific mutation profiles necessitate subsequent generations of tyrosine kinase inhibitors (TKIs). Sunitinib, regorafenib, and avapritinib represent second-line, third-line, and mutation-specific therapies, respectively, offering improved precision and disease control. This review summarizes clinical trial evidence, real-world data, and translational studies evaluating the efficacy, safety, and mechanistic basis of second- and third-generation TKIs in GIST. Emphasis is placed on therapeutic sequencing, resistance mechanisms, and molecularly guided treatment selection. Sunitinib, a multitargeted TKI inhibiting KIT, PDGFR, and VEGFR, provides effective disease control in imatinib-resistant or intolerant patients. Regorafenib, a broad-spectrum multikinase inhibitor, improves progression-free survival in refractory GIST and targets additional angiogenic and oncogenic pathways. Avapritinib, a next-generation TKI, selectively inhibits PDGFRA D842V and KIT exon 17 mutations, addressing a previously untreatable, mutation-driven subgroup. Integration of these agents into treatment algorithms exemplifies a shift toward personalized therapy, with outcomes guided by mutation profiling and biomarker-driven decisions. Second- and third-generation TKIs have transformed the management of advanced GIST, extending survival and offering mutation-specific precision therapy. Ongoing research into resistance mechanisms, combination strategies, and novel inhibitors promises further optimization of patient-centered care. Full article

Weissella viridescens has been proposed as a probiotic candidate, but strain-level multi-omics evidence remains limited. The complete genome of the human-derived W. viridescens strain Wv2365 was sequenced through a hybrid assembly of Illumina and PacBio sequencing reads and compared with eight publicly available W. viridescens genomes. Pangenome analysis and functional annotation were performed, and metabolites were profiled by broadly targeted metabolomic analysis. In addition, the acid and bile tolerance, auto-aggregation and cell surface hydrophobicity, and antioxidant activity of the strain, as well as both in silico and phenotypic safety, were assessed. Wv2365 carries a single chromosome of 1.57 Mb with 41.3% G+C content. The species has an open pangenome with 803 core genes. Genomic and metabolomic features converged on carbohydrate and amino acid metabolism, including glycolysis/tricarboxylic acid (TCA) cycle and arginine pathways, and a carbohydrate-active enzyme (CAZyme) repertoire dominated by glycosyltransferases. In vitro, Wv2365 tolerated pH 3.0 and 0.3% bile, showed auto-aggregation, surface hydrophobicity, and 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radical scavenging. The strain was susceptible to 10 antibiotics tested except for its intrinsic vancomycin non-susceptibility and was non-hemolytic and gelatinase negative. No acquired antimicrobial resistance or virulence genes were found in the genome. These findings indicate that W. viridescens Wv2365 is safe with probiotic traits relevant to gastrointestinal survival, colonization, and redox balance. Full article

Hyperparathyroidism is a serious complication of chronic kidney disease (CKD) and can occur in patients not on renal replacement therapy, during dialysis therapy, or after kidney transplantation. The disease leads to an increased risk of cardiovascular events, bone loss, and fractures. Cinacalcet is a widely used drug, but its effectiveness in treating hyperparathyroidism in selected stages of chronic kidney disease remains unclear. This critical review aims to integrate findings from meta-analyses and clinical trials to assess optimal therapeutic strategies in patients suffering from CKD, who are non-dialysis-dependent, dialysis-dependent, and after kidney transplantation. The authors reviewed eligible studies, including meta-analyses, randomized controlled trials, and observational studies assessing biochemical outcomes, cardiovascular, bone, and survival outcomes with cinacalcet. Cinacalcet effectively reduced serum parathyroid hormone (PTH), calcium, and phosphorus across all CKD stages, particularly in hemodialysis patients. Combination therapy with vitamin D analogs enhanced biochemical control without increasing adverse events, although mild, transient hypocalcemia and gastrointestinal symptoms were common. In kidney transplant recipients, parathyroidectomy achieved greater normalization of PTH and calcium. Cinacalcet has been shown to reduce mortality in patients on hemodialysis and peritoneal dialysis. Full article

This study aimed to develop functional calcium alginate hydrogels incorporating Chlorella vulgaris, carob (Ceratonia siliqua L.), and encapsulated Lactobacillus acidophilus in edible jelly gums with enhanced bioactivity and probiotic viability. Laboratory-prepared jellies containing encapsulated probiotics (encapsulated LAB-Jelly) and those with free cells (LAB-Jelly) were compared with a commercial jelly sample. The formulations were evaluated for phenolic content, antioxidant capacity and antiradical activity, texture, sensory characteristics, and probiotic survival under simulated gastrointestinal conditions. The encapsulated LAB-Jelly exhibited significantly higher total phenolic content (4.6 ± 0.1 mg GAE/g) and antioxidant activity (25.9 ± 0.1 mg Fe⁺²/g) compared to the commercial product, mainly due to the presence of carob and Chlorella. Texture analysis showed lower hardness (21.8 N) but comparable elasticity (89.3%) and cohesiveness (72.8%) comparative to commercial jelly gum, while sensory evaluation confirmed their favorable acceptability and non-perceptible bead presence. Microencapsulation achieved 75% efficiency and improved probiotic survival during gastrointestinal simulation after 18 h (14% reduction in Logcfu/mL compared to 30% of the free probiotics). Overall, the combination of alginate encapsulation, Chlorella, and carob produced edible jelly gums with improved antioxidant and textural properties, offering a promising delivery system for functional foods enriched with probiotics and plant-based bioactives. Full article

Background: Clear cell renal cell carcinoma (RCC) is the most common primary tumor that metastasizes to the pancreas, and surgery is the established treatment option. The aim of this study was to compare surgical treatment options for RCC metastases to the pancreas and to assess long-term outcomes, identifying risk factors for recurrence and death. Methods: We retrospectively analyzed data from 62 patients with RCC metastases to the pancreas who underwent pancreatic surgery at the Department of Gastrointestinal Surgery, Medical University of Silesia, Katowice. Patients were divided into two groups: those who underwent local tumor removal (group A, N = 10) and those who underwent classical pancreatic resection (group B, N = 52). Demographic data, postoperative course, histological findings, and clinical outcomes—recurrence-free survival (PFS) and overall survival (OS)—were analyzed. Results: In group A, tumors were smaller (p < 0.001) and exclusively single (p = 0.100), and Clavien–Dindo complications were milder, with a predominance of grade 0 (90% vs. 28.8%; p = 0.042). In group B, blood loss was greater (p < 0.001), and hospitalization was longer (median 12.5 days vs. 10.5 days; p = 0.022) compared with group A. Group A had a longer PFS (144 months vs. 61 months; p = 0.007) and longer OS (144 months vs. 70 months; p = 0.006) compared with group B. In the entire cohort, independent factors associated with worse OS in multivariate analysis were larger tumor size (p = 0.003), lymphatic invasion (p < 0.001), vascular invasion (p < 0.001), perineural invasion (p < 0.001), R1 resection (p < 0.001), and symptoms of the metastases (p < 0.001). Conclusions: The prognosis following surgical resection of pancreatic RCC metastases is excellent: median OS is 77 months, and 5-year survival reaches 71.4%. In multivariate analysis, the type of surgical treatment is not significantly associated with OS or PFS. The choice of surgical procedure should depend on the preoperative CT results and the intraoperative assessment of the surrounding tissues. Full article