Search Results (1,795)

The efficacy of postbiotics varies significantly between different strains and preparation processes. We aimed at evaluating the effect of an innovative postbiotic product (iPB) generated through the sequential fermentation of Lacticaseibacillus rhamnosus GG and Lacticaseibacillus paracasei NPB-01, compared to single-strain postbiotics, on epithelial barrier integrity and innate immunity in human enterocytes using a Caco-2-cell-based experimental model by measuring human enterocyte proliferation and differentiation (lactase expression), tight junction proteins (occludin and zonula occludens 1, ZO-1), and mucus protein Mucin-2 (Muc-2) expression. The modulatory action on the major innate immunity peptide, Human Beta-Defensin 2 (HBD-2), production was also assessed. The iPB exposure resulted in a higher up-regulation of human enterocyte proliferation and differentiation, as suggested by higher lactase expression, and of occludin, ZO-1, and MUC2 expression compared with the single-strain postbiotics, suggesting a beneficial synergistic action in modulating the epithelial gut barrier. Furthermore, iPB induced a higher production of HBD-2, suggesting a synergistic enhancement of innate immune response. Our findings suggested that the sequential fermentation process could act as a biotechnological catalyst, optimizing the gut-barrier-protective properties and the immunomodulatory action of Lacticaseibacillus strains. This study introduces iPB as a high-performance postbiotic candidate for the prevention and management of conditions characterized by alterations in epithelial gut barrier and innate immunity. Full article

Background: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition marked by heterogeneous behavioral symptoms and systemic comorbidities, including immune and gastrointestinal dysfunctions. Emerging studies suggest that glycosylation—a fundamental post-translational modification regulating cellular communication and immune responses—may play a role in ASD pathophysiology, yet its contribution remains underexplored. Methods: In this study, we developed an integrative transcriptomic and network analysis framework to investigate glycosylation-related gene expression changes and their functional associations in ASD. Using publicly available datasets from bulk and single-cell RNA sequencing of brain and blood tissues, we focused on four prior-knowledge gene subsets: glycogenes, extracellular matrix glycoproteins, immune response genes, and autism risk genes. Results: Differential expression and pathway enrichment analyses revealed consistent dysregulation of glycosylation pathways, including mucin-type O-glycan biosynthesis, glycosaminoglycan metabolism, GPI-anchor formation, and sialylation, across ASD tissues. These transcriptional changes were functionally linked to altered immune signaling (e.g., IL-17, Toll-like receptor, and complement pathways) and synaptic development pathways, forming a distinct glyco-immune axis. Network analysis identified key glycogenes such as GALNT10, NEU1, LMAN2L, and CHST1 as central molecular nodes, interacting with immune and neuronal regulators. Linkage disequilibrium analysis further revealed ASD-associated SNPs influencing the expression of these glycogenes in both blood and brain tissues. Conclusions: Together, these findings support a model in which disrupted glycosylation contributes to ASD pathophysiology by mediating immune dysregulation and altered neuronal connectivity. This study offers a systems-level framework to understand the molecular complexity of ASD and highlights glycogenes as potential biomarkers and targets for future therapeutic exploration. Full article

Background and Objectives: Placental vascular lesions are significant histopathological findings that indicate disruptions in uteroplacental and fetoplacental circulations and are associated with adverse pregnancy outcomes such as preeclampsia, intrauterine growth restriction (IUGR), and perinatal morbidity. This study aimed to re-examine the frequency and distribution of placental vascular lesions in placentas submitted for histopathological analysis at our center, based on criteria established by the Amsterdam Placental Workshop Group Consensus Statement. Materials and Methods: In this retrospective study, placental samples examined in the Department of Pathology at Akdeniz University Faculty of Medicine from 2016 to 2019 were analyzed. A total of 571 cases with at least one placental vascular lesion identified on histopathology were included. Hematoxylin–eosin-stained sections from all cases were re-evaluated, and maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), and other placental vascular pathologies were assessed according to the Amsterdam consensus criteria. Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 25 (IBM Corp., Armonk, NY, USA). Categorical variables were compared using the chi-square or Fisher’s exact test, while continuous variables were analyzed with the Mann–Whitney U test. Results: MVM and FVM were considered the primary outcomes of the study. MVM was identified in 95.1% of cases, whereas FVM was present in 1.9%. Among individual lesions, chorangiosis (97.2%) and villous/perivillous fibrinoid deposition (88.3%) were the most frequent findings, followed by mucinous cystic degeneration of the umbilical cord (61.5%) and dystrophic calcification (58.1%). Retroplacental hematoma was observed in 38.4% of cases. Although no significant association was found between MVM and placental weight or size, umbilical cord length was significantly shorter in MVM-positive cases (p = 0.032). In contrast, FVM showed significant associations with chorangiosis (p = 0.035) and placentomegaly (p = 0.003). The high frequency of chorangiosis may reflect a compensatory angiogenic response to chronic intrauterine hypoxia, potentially mediated by vascular growth factors, with variable effectiveness depending on the severity of the underlying condition. Conclusions: These findings suggest that placental vascular lesions are not only markers of obstetric complications but also serve as morphological indicators of fetoplacental adaptive responses. Full article

Cerebral palsy (CP) is a non-progressive neurological condition associated with neuroinflammation, motor impairments, and gastrointestinal dysfunction mediated by the gut–brain axis. Preserving the intestinal epithelial barrier integrity may represent a therapeutic strategy, and quercetin is a bioactive compound with potential intestinal protective effects. This study investigated the effects of neonatal quercetin treatment on morphometric parameters, oxidative stress markers, and epithelial barrier gene expression in an experimental CP model. Wistar rats were distributed into four groups according to health status and treatment with a vehicle (V) or quercetin (Q, 10 mg/kg, intraperitoneally): healthy control (CV and CQ) and CP (CPV and CPQ) (n = 10/group). Intestinal morphology, oxidative stress markers, and gene expression (occludin, zonulin, and mucin 2) were evaluated. CP animals showed segment-specific alterations, with structural impairment predominantly in the ileum and increased oxidative damage in the jejunum. Quercetin attenuated oxidative stress markers and modulated antioxidant enzyme activity in CP, increased jejunal tight-junction gene expression in both healthy and CP groups, and enhanced MUC2 expression only in healthy animals, without fully reversing CP-induced morphological changes. In conclusion, neonatal quercetin modulates oxidative stress and epithelial barrier-related gene expression, supporting its potential as an adjuvant strategy for intestinal barrier protection in experimental CP. Full article

Juvenile idiopathic arthritis (JIA) represents the most common cause of chronic arthritis in childhood; however, not all early-onset arthropathies are inflammatory in origin. We report the case of a 4-year-old girl initially diagnosed with oligoarticular JIA and treated with methotrexate followed by a tumor necrosis factor inhibitor, without significant clinical improvement and despite persistently normal inflammatory markers. Clinical reassessment raised suspicion of a non-inflammatory arthropathy, supported by characteristic radiographic findings including metaphyseal flaring of the distal femora and proximal tibiae. Genetic analysis identified compound heterozygous pathogenic variants in the PRG4 gene, confirming the diagnosis of camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome (OMIM #208250). PRG4 encodes lubricin, a mucin-like glycoprotein essential for boundary lubrication of articular cartilage and maintenance of synovial joint homeostasis. Loss-of-function variants disrupt joint lubrication, leading to mechanical synovial hyperplasia and chronic non-inflammatory joint effusion. This case highlights common diagnostic pitfalls in pediatric rheumatology and underscores the importance of considering genetic causes of chronic arthropathy when clinical and laboratory features are atypical for inflammatory disease. Early molecular diagnosis prevents unnecessary immunosuppressive therapy and enables appropriate multidisciplinary management. Full article

Background/Objectives: Ulcerative colitis is a chronic inflammatory bowel disease marked by a disrupted intestinal barrier and consequent aberrant immune responses. Pseudoginsenoside RT2, an ocotillol-type ginsenoside abundant in Panax herbs, represents a potential therapeutic candidate, yet its anti-ulcerative colitis efficacy and pharmacokinetic profile remain unclear. This study aimed to elucidate RT2’s therapeutic potential for ulcerative colitis through a parallel evaluation of pharmacodynamic efficacy and pharmacokinetic properties. Methods: The anti-ulcerative colitis efficacy and in vivo disposition of RT2 were investigated in a trinitrobenzene sulfonic acid-induced rat colitis model. An ultra-performance liquid chromatography–tandem mass spectrometry method was employed to delineate its pharmacokinetic characteristics and quantify its distribution in various tissues following oral administration. Results: Pharmacodynamically, RT2 demonstrated significant efficacy in the UC rat model by repairing the intestinal barrier (by promoting goblet cell regeneration and upregulating tight junction proteins and mucin) and restoring immune homeostasis (by correcting T-helper 17/regulatory T-cell imbalance and reducing pro-inflammatory cytokines while elevating anti-inflammatory cytokines). Pharmacokinetically, RT2 exhibited rapid absorption, slow elimination, and high colonic accumulation, with concentrations in the inflamed colon being significantly higher than those in healthy rats. Furthermore, the biphasic concentration–time profile may account for its prolonged systemic residence time and enhanced local exposure. In summary, through parallel efficacy and pharmacokinetic studies, this work systematically reveals its characteristics as a therapeutic agent that exhibits high colonic accumulation and acts via barrier repair and immunomodulation. Conclusions: These findings provide a theoretical foundation for the development of RT2 as a novel gut-selective drug candidate for UC. Full article

Background: Constipation is a common gastrointestinal (GI) state for which probiotics have shown promise as a relief. This study examined the laxative effects of the strain Bifidobacterium animalis subsp. lactis CECT 8145 (BPL1^®) in a loperamide-induced rat model of constipation. Methods: Fifty-nine rats were divided into control and loperamide-induced constipation groups. Animals received a 3-day intervention with either placebo or probiotic BPL1^® at two doses: 1.5 × 10⁸ CFU (colony-forming units) (low) and 3 × 10⁹ CFU (high). The study assessed several parameters to determine the probiotic’s effect, including: stool and gut characteristics, gastrointestinal transit time (GTT), gene expression and gut microbiome composition. Results: While loperamide significantly decreased stool number, weight and humidity, BPL1^® supplementation effectively restored these parameters, being more pronounced at a high dose. Microbiome analysis showed that BPL1^® at a low dose reduced the abundance of Muribaculaceae and Muribaculum gordoncarteri, associated with constipation. In addition, Muribaculaceae abundance was negatively correlated with stool humidity. Functional microbiome profiling indicated that BPL1^® suppressed pathways related to mucin degradation, vancomycin resistance and isoleucine biosynthesis while promoting L-lactate and pyridoxal-P (vitamin B6) biosynthesis, which may support gut motility and barrier integrity. Conclusions:Bifidobacterium animalis subsp. lactis BPL1^® exhibits potential as a functional probiotic for relieving constipation through improving stool excretion and consistency, inducing taxonomic changes and beneficial functional modulation of the intestinal microbiome. These findings justify further investigation into the mechanisms of BPL1^® as a probiotic for constipation management. Full article

Background: Probiotics and medicine food homology are known to offer gentle approaches to prevent obesity, although it is difficult with such approaches to satisfy consumers’ requirements to lose weight quickly. The probiotic strain Bifidobacterium animalis ssp. lactis 420 (B420) and Cordyceps militaris synergistically prevented obesity and related disorders in high-fat diet (HFD)-fed mice. Methods: The synergistic effects correlated with improved gut integrity, diminished systemic inflammation, and enhanced glucose homeostasis. Gut microbiota analysis revealed that the bloom of the commensal Akkermansia muciniphila contributed to the synergistic effects by inducing a profound shift in HFD-induced gut microbiota disorder. Results: The bloom of A. muciniphila was significantly correlated with a boost in mucin 2 within the colon, achieved through increased goblet cell quantity and elevated mucin 2 expression. To reveal the collaborating pathway, we found that Cordyceps militaris did not promote the propagation of B420 in vitro or in vivo. Moreover, heat-killed B420 could not enhance the preventive efficacy of Cordyceps militaris against obesity caused by the HFD. Conclusions: The metabolites of live B420 and Cordyceps militaris-derived metabolites in the gut microbiota collaboratively promoted the production of mucin 2. Thus, our results reveal a mechanism by which a combination of probiotics and medicine food homology enhance their therapeutic effects against obesity. Full article

Objective: In metastatic colorectal cancer (mCRC), mucinous histology has been associated with poor clinical outcomes, particularly in the presence of peritoneal metastasis. However, it remains unclear whether mucinous histology exerts a context-dependent effect on treatment outcomes by modifying the efficacy of anti-vascular endothelial growth factor (VEGF)-based therapies independently of metastatic dissemination patterns and chemotherapy backbone. Methods: We retrospectively analyzed 250 patients with mCRC treated with bevacizumab-containing systemic therapy. Tumors were classified as mucinous (n = 52) or non-mucinous (n = 198). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared using the log-rank test. Cox proportional hazards regression models were applied for univariate and multivariate analyses. Predefined subgroup analyses were conducted according to peritoneal metastasis status and chemotherapy backbone (oxaliplatin- or irinotecan-based). A 6-month landmark analysis was performed to reduce early progression bias. Interaction analyses evaluated potential effect modification between histology, peritoneal metastasis, and chemotherapy backbone. Results: Mucinous tumors were more frequently right-sided and strongly associated with peritoneal metastasis. In the overall cohort, mucinous histology was associated with significantly longer median PFS compared with non-mucinous histology (22.9 vs. 11.9 months; p < 0.001). This benefit was driven by patients with peritoneal metastasis, in whom mucinous histology was associated with markedly prolonged PFS (23.9 vs. 8.7 months; p < 0.001). No significant PFS difference according to histology was observed in patients without peritoneal metastasis. On multivariate analysis, mucinous histology remained independently associated with improved PFS (HR 0.44; 95% CI 0.25–0.78; p = 0.005), an effect preserved in the landmark cohort (HR 0.39; 95% CI 0.26–0.59; p < 0.001). A significant interaction between mucinous histology and peritoneal metastasis was observed (p for interaction = 0.040), indicating that the prognostic impact of histology differed according to metastatic pattern. No significant PFS difference or interaction was detected according to chemotherapy backbone within the mucinous subgroup. Conclusions: Among bevacizumab-treated patients with mCRC, mucinous histology—particularly in the presence of peritoneal metastasis—is associated with a pronounced PFS advantage independent of chemotherapy backbone. These findings suggest that mucinous peritoneal mCRC represents a biologically and clinically distinct subgroup that may derive context-specific and disproportionate benefit from anti-VEGF-based strategies, warranting prospective validation. Full article

Mucins are highly glycosylated proteins that form the structural basis of mucus and represent a key component of innate immunity at mucosal surfaces, particularly in the respiratory tract. Beyond their mechanical barrier function, mucins actively participate in pathogen trapping, regulation of mucociliary clearance, modulation of inflammatory responses, and maintenance of epithelial homeostasis. Dysregulation of mucin synthesis, composition, or transport contributes to mucus hypersecretion, impaired airway clearance, and chronic inflammation in respiratory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. This review summarizes current insights into mucin biology, including their biosynthesis, structure, classification, and regulation, with emphasis on the gel-forming mucins MUC5AC and MUC5B. The role of mucins in mechanical protection, host–pathogen interactions, control of inflammation, and coordination of innate immune responses is reviewed. Attention is given to the interplay between mucins, immune cells, and microbial communities in maintaining airway barrier integrity. The article further examines mucoactive therapeutic strategies aimed at restoring mucus barrier function. Expectorants, mucolytics, mucoregulators, and mucokinetic agents are reviewed with respect to their mechanisms of action and clinical relevance. Established drugs, including N-acetylcysteine, carbocysteine, dornase alfa, ambroxol, and hypertonic solutions, are considered alongside emerging molecular targets such as NF-κB-dependent regulation of mucin expression, calcium-activated chloride channels, MARCKS-mediated mucin exocytosis, purinergic signaling pathways, and NO/cGMP signaling. Non-pharmacological approaches, including airway clearance techniques and respiratory rehabilitation, are covered concisely. Conclusions: Overall, this review highlights mucins as dynamic regulators of innate immunity and underscores the need for mechanism-based, personalized mucoactive therapies to improve outcomes in chronic inflammatory airway diseases. Full article

The eye is a sensitive target of sublethal stress in aquaculture-reared fish due to its direct exposure to the aquatic environment. This study tested a photoelectrocatalytic (PEC) water treatment system, integrated into a standard recirculating aquaculture system (RAS), to improve water quality and evaluated ocular health in Oncorhynchus mykiss (rainbow trout) reared at 30 kg/m³ for 28 days, with particular emphasis on the cornea as an indicator of fish welfare. Ocular analyses focused on the cornea and retina, two anatomically and functionally distinct structures. PEC significantly reduced ammonia levels and modulated nitrate concentrations compared to the control group (CTR), represented by a standard RAS. No differences in growth performance or body condition were observed between groups. Corneal integrity was assessed using optical coherence tomography, histology, and mucous cell staining to evaluate epithelial structure and protective responses. Corneal tissue was examined to detect local oxidative effects through morphological analysis and immunohistochemistry for 8-hydroxy-2′-deoxyguanosine (8-OHdG). Alcian Blu–Periodic Acid–Schiff (AB–PAS) staining did not reveal significant differences in mucin-producing cells among groups. CTR fish exhibited epithelial disruption and increased 8-OHdG immunoreactivity, whereas fish reared in the RAS equipped with the PEC system, ensuring improved water quality, showed preserved corneal architecture despite mild oxidative stress. Molecular analysis of ocular tissues revealed no differential expression of oxidative stress-related genes, such as GPx1, GR, or sod1, in the two groups. Overall, these findings support the use of the cornea as a sensitive indicator of sublethal environmental stress in farmed fish and suggest that PEC treatment may contribute to improved water quality management and welfare monitoring in intensive aquaculture systems. Full article

The gastrointestinal mucus barrier (GIMB) is a gelatinous structure consisting primarily of mucins, water, and cathelicidin. Such a structure is the first line of defense against pathogens in the intestinal cavity and acts an important environment for the survival and reproduction of symbiotic flora. Mucin is mainly synthesized and secreted by intestinal goblet cells, forming a slime layer with different structures throughout the intestinal tract. The process of mucin synthesis and secretion is regulated by many factors, and there are some differences in the physical and chemical properties of the GIMB among animal species. Furthermore, recent studies have shown a close relationship among the mucus barrier, gastrointestinal diseases, and tumors. Soybean agglutinin (SBA) is a major glycoprotein in soybean that is closely related with the detection, prevention, and treatment of disease and cancer. Current studies indicate a close relationship between SBA and the GIMB, particularly at the molecular level and through species-specific differences in mucin glycan structures. Existing evidence shows that these differences affect the binding affinity and antinutritional effects of SBA. The novel relations between SBA and GIMB may become new targets for disease treatment. Full article

Gastric-type lesions in the duodenum, including pyloric gland adenoma and gastric foveolar metaplasia, have been increasingly recognized for their unique histogenesis and potential link through the metaplasia–neoplasia sequence. However, the coexistence of neoplastic and non-neoplastic gastric-type lesions within the same histological section has not been previously reported. Here, we present a case of a 73-year-old Japanese woman who underwent endoscopic submucosal dissection for a 34 × 20 mm elevated lesion in the duodenal bulb. Based on the preoperative biopsy results, pyloric gland adenoma was diagnosed; however, histopathological examination of the resected specimen revealed a far more complex picture. The main lesion consisted of two contiguous components: a hyperplastic polyp with gastric foveolar-type phenotype (Lesion I) and a pyloric gland adenoma mixed with gastric foveolar-type hyperplastic polyp (Lesion II). Importantly, the transitional zone between these components demonstrated histological continuity, with areas showing admixture of hyperplastic and adenomatous features within the same microscopic field. A separate hyperplastic polyp with gastric foveolar-type phenotype (Lesion III) was also identified, separated from Lesions I and II by intervening normal duodenal mucosa. All lesions shared a gastric-type mucin phenotype (MUC5AC-positive, CD10-negative), and extensive Brunner’s gland hyperplasia was observed throughout the specimen. This case provides compelling morphological evidence for a histogenetic link between non-neoplastic gastric-type hyperplasia and pyloric gland adenoma, supporting the concept of a metaplasia–neoplasia sequence in the duodenum. Furthermore, the presence of an additional separate lesion with the same phenotype suggests a field change in the development of gastric-type lesions. Full article

Purpose: The objective of this study was to engineer and optimize a mucoadhesive, positively charged stearylamine-enriched liposomal platform, termed Aminosomes, to circumvent the biophysical barriers limiting the ocular bioavailability of Brimonidine Tartrate (BT), an alpha-2 adrenergic receptor agonist for glaucoma management. Methods: Aminosomes were synthesized using a tailored ethanol injection technique and optimized via a 3² × 2¹ full factorial design. Molecular integrity and crystallinity were assessed using Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). The mucoadhesive potential was validated through a mucin interaction assay based on zeta potential shifts. In vitro release kinetics were evaluated using the dialysis membrane diffusion technique, while the therapeutic potential and ocular safety were validated through in vivo pharmacodynamic profiling of intraocular pressure (IOP) reduction, alongside comprehensive biocompatibility assessments via Draize irritancy protocol and histopathological examination. Results: The optimized Aminosomes exhibited nanometric dimensions, monodisperse size distribution, robust positive surface charge, and superior drug loading. FTIR and XRD analyses confirmed the chemical compatibility of the formulation components, as well as the successful encapsulation of BT and its transition to an amorphous state within the lipidic matrix. The mucoadhesion test demonstrated a high binding affinity for mucin. The in vitro release profile demonstrated a sustained-release pattern (78.8% over 12 h). Non-compartmental pharmacodynamic analysis of IOP-reduction data revealed a 2.8-fold increase in AUC_0–24h, 3.5-fold extension in t_1/2, and 5.2-fold prolongation in mean residence time (MRT) relative to the standard solution. Conclusions: The optimized Aminosomes demonstrated superior mucoadhesive anchoring, enhanced and sustained therapeutic flux without inducing ocular toxicity, offering a robust strategy for enhancing the pharmacodynamics of BT. Full article

Cutaneous adnexal carcinomas (CACs) comprise a diverse group of malignant tumors that show morphological differentiation toward one of the four main adnexal structures in normal skin: hair follicles, sebaceous glands, sweat-apocrine glands, and sweat-eccrine glands. These tumors can arise sporadically or may be associated with rare genetic syndromes. A total of 276 CACs cases underwent hybrid capture-based comprehensive genomic profiling (CGP) to assess all classes of genomic alterations (GA). Sequencing data were used to determine microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), genomic ancestry, and COSMIC mutational signatures. PD-L1 expression was evaluated by immunohistochemistry (TPS; Dako 22C3). Statistical analyses were performed using Fisher’s exact test, with false discovery rate correction via the Benjamini–Hochberg method. Sequencing was performed on primary cutaneous tumors in 131 cases (47.4%) and on local recurrence or metastatic site biopsies in 145 cases (52.5%). Across all groups, there was a male predominance (64–81%) and similar mean ages (59–63 years), with apocrine (APO) tumors occurring in older patients than eccrine (ECC) tumors (72 vs. 62 years; p = 0.001). Histologically, 173 tumors (62.7%) were sweat gland-derived (SWT), 55 (19.9%) sebaceous gland-derived (SEB), 14 (5.1%) hair follicle-derived (HRF), and 34 (12.3%) unclassified (UNK). Among SWT tumors, 150 (86.7%) were eccrine and 23 (13.3%) apocrine. SWT tumors included digital papillary adenocarcinomas (DPA, 6.9%), mucinous carcinomas (MC, 6.3%), porocarcinomas (POR, 11.0%), spiradenocarcinomas (SPR, 8.1%), syringoadenocarcinomas (SRNG, 5.8%), and 77 (44.5%) unclassified cases. The number of GA per tumor was highest in SEB compared with SWT tumors (7.9 vs. 4.9; p = 0.005) and lowest in DPA (2.1 vs. 5.0 in non-DPA; p = 0.03). No differences in ancestry distribution were observed. Compared with SWT tumors, SEB tumors exhibited higher frequencies of RB1 (38.2% vs. 8.1%; p < 0.0001) and TP53 alterations (76.4% vs. 43.4%; p = 0.0002), suggesting potential neuroendocrine differentiation. MC tumors showed significantly higher PTCH1 alterations than non-MC tumors (36.4% vs. 1.8%; p = 0.044). MSI-high status was most frequent in SEB tumors compared with all other groups (15.7% vs. 1.2%; p = 0.005), and gLOH > 16% was also more common in SEB than SWT tumors (19.6% vs. 7.2%; p = 0.081). The MMR signature occurred more frequently in SEB than SWT tumors (32.0% vs. 2.1%; p = 0.005). Mean TMB was elevated across most CACs types, ranging from 10.4 mutations/Mb in HRF to 38.8 mutations/Mb in MC, with the exceptions of APO (2.7 mut/Mb; p = 0.001) and DPA (1.4 mut/Mb; p = 0.003). PD-L1 expression was generally low and did not differ significantly between SWT and SEB tumors (37.0% vs. 33.3%; NS). Given the limited data on CAC treatment, this study provides a catalog of commonly observed GA. SEB tumors exhibited the highest frequency of genomic alterations. Prospective clinical trials are needed to determine the prognostic and predictive value of CAC-specific biomarkers for immune checkpoint inhibitor (ICI) response, which is essential for integrating novel therapies into the evolving treatment landscape. Full article