Background and Objectives: Small gastrointestinal stromal tumors (GISTs) are defined as tumors less than 2 cm in diameter, which are often found incidentally during gastroscopy. There is controversy regarding the management of small GISTs, and a certain percentage of small GISTs become malignant during follow-up. Previous studies which used Sanger targeted sequencing have shown that the mutation rate of small GISTs is significantly lower than that of large tumors. The aim of this study was to investigate the overall mutational profile of small GISTs, including those of wild-type tumors, using whole-exome sequencing (WES) and Sanger sequencing. Methods: Thirty-six paired small GIST specimens, which were resected by endoscopy, were analyzed by WES. Somatic mutations identified by WES were confirmed by Sanger sequencing. Sanger sequencing was performed in an additional 38 small gastric stromal tumor samples for examining hotspot mutations in KIT, PDGFRA, and BRAF. Results: Somatic C-KIT/PDGFRA mutations accounted for 81% of the mutations, including three novel mutation sites in C-KIT at exon 11, across the entire small gastric stromal tumor cohort (n = 74). In addition, 15% of small GISTs harbored previously undescribed BRAF-V600E hotspot mutations. No significant correlation was observed among the genotype, pathological features, and clinical classification. Conclusions: Our data revealed a high overall mutation rate (~96%) in small GISTs, indicating that genetic alterations are common events in early GIST generation. We also identified a high frequency of oncogenic BRAF-V600E mutations (15%) in small GISTs, which has not been previously reported.

Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant genetic disorder with only a few affected families reported to date. Here, we report a case of familial GISTs harboring a novel germline mutation within exon 18 of KIT. A 58-year-old male patient presented with gastric subepithelial lesions accompanied by cutaneous hyperpigmentation, which were subsequently diagnosed as multinodular GISTs. Endoscopic surgery was initially conducted to remove the larger lesions, and pathological examinations were then conducted for the diagnosis of GISTs. Family history revealed that some other family members had similar cutaneous pigmentations. Whole-exome sequencing was used to search for potential driver mutations, and Sanger sequencing was used for mutation validation. A novel primary driver mutation of KIT (c.G2485C, p.A829P) was detected in these hereditary GISTs, which has been reported in some targeted chemotherapy-resistant GISTs. Cell models were subsequently established for the rapid screening of candidate drugs and exploring potential mechanisms. This mutation could lead to cell proliferation and imatinib resistance by ligand-independent activation of KIT; however, ripretinib administration was identified as an applicable targeted therapy for this mutation. The mutation activated the JAK/STAT3 and MAPK/ERK pathways, which could be inhibited by ripretinib administration. To the best of our knowledge, this is the first report of the KIT-A829P mutation in familial GISTs, complementing the pathogenesis of familial GISTs and providing valuable information for the precision treatment of this disease.

The burden of metabolic dysfunction‐associated steatotic liver disease (MASLD) is increasing, yet there is little understanding in the Western Pacific Region (WPR). This study aims to report the latest MASLD burden in the WPR from 1990 to 2021. This study obtained nonmalignant and total MASLD incidence, prevalence, mortality, disability‐adjusted life years (DALYs), years of life lost (YLLs), and years of healthy life lost due to disability (YLDs) from the Global Burden of Disease (GBD) database, and calculated age‐standardized ratios (ASRs) for each indicator. Estimated annual percentage changes (EAPCs) were calculated using a log‐transformed linear regression model. The age‐period‐cohort (APC) model was used to analyze regional MASLD‐related deaths; the Bayesian age‐period‐cohort (BAPC) model was used to estimate future trends from 2022 to 2050. The incidence, prevalence, deaths, and DALYs of nonmalignant MASLD in the WPR in 2021 are 12 million, 359.2 million, 10,195 cases, and 0.24 million years, respectively. The WPR has a high incidence of MASLD in younger age groups, especially in males, with the 15–19‐year‐old male group being 1215.82 per 100,000. Mongolia has the highest relative risk of deaths and DALYs, while Japan, Singapore, and China are comparatively low. The proportion of deaths and DALYs due to nonmalignant MASLD is increasing. Nonmalignant MASLD is projected to be the dominant component of resulting deaths and DALYs by 2050 in some countries. The WPR burden of MASLD is increasing, with a high prevalence in younger individuals, indicating the need for early initiation of targeted and effective MASLD prevention.

Hepatic stellate cell (HSC) activation has traditionally been described as a binary transition from vitamin A-rich quiescent cells to alpha-smooth muscle actin-positive, collagen-producing myofibroblast-like cells. Advances in single-cell RNA sequencing, single-nucleus RNA sequencing, spatial transcriptomics, and chromatin-accessibility profiling now reveal a more complex and dynamic landscape. During chronic liver injury, HSCs can adopt five overlapping activation-associated states characterized by injury sensing, inflammatory signaling, proliferation, extracellular matrix production and contractility, together with a senescent state that represents a possible fate of activated HSCs. These states differ in their molecular markers, spatial distribution, regulatory pathways, and interactions with hepatocytes, liver sinusoidal endothelial cells, macrophages, natural killer cells, and cholangiocytes. Importantly, they are not fixed lineages and may coexist or interconvert during fibrosis progression and regression. This review revisits the classical quiescent-activated framework and proposes a state-based approach for interpreting HSC heterogeneity. We summarize the defining features and translational relevance of six major HSC functional states, discuss their multicellular niches, and highlight the opportunities and limitations of function-selective therapeutic targeting. A reproducible classification that integrates molecular identity, spatial context, and causal function may help refine antifibrotic treatment strategies.