Gastrointestinal stromal tumors (GISTs) are the most common sarcomas of the alimentary tract and are primarily characterized by malignant progression, a major cause of mortality. AT-rich interaction domain 1A (ARID1A), a core component of the chromatin-remodeling SWI/SNF complex, has been found to correlate with GIST tumor grade, although the underlying mechanism remains unclear. Its frequent inactivation across diverse cancer types reveals pleiotropic roles that intersect multiple hallmarks of cancer. In this study, we aimed to investigate the potential relationship between ARID1A and malignant progression in GISTs, as well as the underlying mechanism. Western blotting, real-time polymerase chain reaction, and immunohistochemistry were used to assess ARID1A expression in GIST tissues. Cell Counting Kit-8 (CCK-8) assays were performed to evaluate cell proliferation. Wound-healing and Transwell assays were conducted to assess cell migration and invasion. Flow cytometry was used to analyze apoptosis and cell cycle distribution. Label-free quantitative proteomics and chromatin immunoprecipitation sequencing (ChIP-seq) were employed to identify top candidate downstream targets of ARID1A. ARID1A expression was decreased in high-risk GIST tissues. Furthermore, ARID1A knockdown in GIST cells promoted proliferation and metastasis both in vitro and in vivo, and led to reduced apoptosis and impaired cell cycle arrest. We further demonstrated that ARID1A suppresses GIST proliferation and metastasis by inhibiting MEMO1 expression and inactivating the ERK1/2 signaling pathway. Notably, this regulatory axis was observed in KIT-null GIST cells, indicating that the ARID1A-MEMO1 pathway may function independently of canonical KIT signaling. Thus, ARID1A inhibits malignant progression in GISTs, providing new insights into its role in the prevention and treatment of human GISTs and suggesting its potential as a biomarker of malignant progression in GISTs.

Gastrointestinal stromal tumor (GIST), the most common gastrointestinal mesenchymal neoplasm, remains poorly understood at the molecular level, limiting precise diagnosis and targeted therapy. This study aimed to systematically identify key GIST-associated genes through multiomic integration and experimental validation. We analyzed three GIST transcriptomic datasets from GEO, corrected batch effects via surrogate variable analysis (SVA), and identified 61 differentially expressed genes (DEGs) using limma. Weighted gene co-expression network analysis (WGCNA) highlighted progression-related modules, which were refined using random forests and LASSO regression to prioritize C3 and complement factor D (CFD), both of which showed robust diagnostic performance (AUC: 0.928 for C3; 0.955 for CFD). Experimental validation confirmed C3/CFD downregulation in GIST tissues, correlating with advanced stage and poor survival. Functional assays demonstrated their tumor-suppressive roles, inhibiting GIST cell proliferation, colony formation, and migration. CIBERSORT analysis linked C3/CFD to altered immune infiltration, while ssGSEA/GSEA implicated their involvement in lipid metabolism and oxidative phosphorylation. These findings establish C3 and CFD as critical tumor-suppressive biomarkers that modulate the immune response and reprogram metabolism, offering new avenues for GIST diagnosis and therapy.

BACKGROUND:The endoplasmic reticulum (ER) serves as a crucial hub for protein synthesis and processing, playing an essential role in maintaining protein homeostasis. Perturbations, such as hypoxia, oxidative stress, inadequate amino acid supply, Ca2+ imbalance, and acidosis, can disrupt cellular equilibrium and result in the accumulation of misfolded/unfolded proteins within the ER lumen. This triggers ER stress. In response to this stress, an unfolded protein response (UPR) is activated as a mechanism to cope with the stress and restore internal balance. The UPR is regulated by three sensors located in the ER: inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). However, the UPR can promote tumor growth in vivo by affecting tumor angiogenesis, cell migration, cell metabolism, and treatment resistance, and has a huge impact on the tumor microenvironment. MATERIALS AND METHODS:We conducted a literature review of scientific papers on the topic of ER stress in the tumor microenvironment. RESULTS AND DISCUSSION:This review focuses on the inducing factors of ER stress, the mechanism of the UPR signaling pathway induced by ER stress, and the effect of ER stress on the tumor microenvironment and immune-infiltrating cells. Tumors can regulate their evolution by affecting themselves and the tumor microenvironment through endoplasmic reticulum stress. This study reveals the important role of endoplasmic reticulum stress in the occurrence and development of tumors, and provides new ideas and potential therapeutic targets for the precision treatment of tumors. Future studies can further explore the molecular mechanism of ER stress regulating tumor microenvironment and explore its application potential in clinical diagnosis and treatment.

Background: Camrelizumab combined with chemotherapy has shown significant clinical benefits in the first-line treatment of advanced esophageal squamous cell cancer (ESCC). Despite promising results from randomized trials, there is a need for real-world evidence to understand the broader applicability and longterm outcomes of neoadjuvant treatments in diverse patient populations with ESCC. This study aimed to evaluate the efficacy and safety of neoadjuvant camrelizumab combined with chemotherapy in patients with resectable locally advanced ESCC in a real-world setting. Methods: We retrospectively reviewed clinical data from 83 patients with locally advanced, potentially resectable ESCC who received neoadjuvant camrelizumab combined with docetaxel, oxaliplatin, and S1 chemotherapy at Xijing Hospital of Digestive Diseases, Fourth Military Medical University from March 2020 to May 2023. Inclusion criteria were based on clinical stage, histological confirmation, and patient tolerance. Baseline clinical characteristics were assessed using standard diagnostic tools. Treatment involved three cycles of camrelizumab combined with chemotherapy, with efficacy and safety evaluated using and safety were assessed. Results: The median age of patients was 61 years (range, 46-75 years), and tumors were predominantly located in the middle (n=49, 59.04%) and lower (n=23, 27.71%) regions of the esophagus. Most patients were diagnosed at stages III-IV (55.42% and 38.55%, respectively), and all of the patients completed patients achieved partial response (PR), and 9 (10.84%) patients achieved stable disease (SD). The objective response rate (ORR) was 77.11% (64/83), and the disease control rate (DCR) was 87.95% (73/83). Of the 14 patients who underwent surgery, the R0 resection rate was 100%, and 28.57% (4/14) achieved pathological CR (pCR). The median follow-up time was 31.0 months, and the 3-year overall survival (OS) rate was 56.9%. The incidence of grade >= 3 adverse events was 6.02% (5/83). No deaths occurred. Conclusions: While our real-world data suggest potential benefits of neoadjuvant camrelizumab plus chemotherapy in locally advanced ESCC, the absence of a control group limits the generalizability of these findings. Further randomized studies are needed to validate these results.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract, primarily driven by KIT or PDGFRA mutations. Programmed cell death (PCD), including apoptosis, autophagy, and ferroptosis, plays a crucial role in GIST pathogenesis, progression, and treatment response. Non-coding RNAs (ncRNAs) have emerged as key regulators of PCD pathways, influencing GIST proliferation, metastasis, and drug resistance, particularly in response to tyrosine kinase inhibitors (TKIs) such as imatinib. Apoptosis suppression is strongly associated with poor prognosis, while autophagy contributes to tumor dormancy and TKI resistance. Ferroptosis, a novel iron-dependent cell death pathway, represents a promising therapeutic target. Recent evidence suggests that ncRNAs modulate these PCD pathways through interactions with key molecular regulators such as miR-494, miR-30a, and lncRNAs, which affect signaling networks including PI3K/AKT, MAPK, and mTOR. Furthermore, ncRNAs have mediated secondary resistance to imatinib by promoting autophagic flux and altering ferroptosis sensitivity. Understanding the molecular interplay between ncRNAs and PCD in GIST provides novel insights into disease mechanisms and offers potential therapeutic strategies to overcome drug resistance. Targeting ncRNA-mediated regulation of apoptosis, autophagy, and ferroptosis may enhance treatment efficacy and improve patient outcomes. Future research should focus on elucidating the mechanistic roles of ncRNAs in PCD pathways to develop innovative diagnostic and therapeutic approaches for GIST.

BackgroundSince the approval of Tyrosine kinase inhibitors (TKIs) in gastrointestinal stromal tumors (GISTs), the survival of patients with metastatic GISTs have been remarkably improved. But clinically, the adverse effects (AEs) are the major barrier to the long-term and standardized treatment and less reported.MethodsThe data was acquired from FDA Adverse Event Reporting System (FAERS) database from 2006 to 2024. TKIs were selected based on the clinical guidelines for the treatment of GISTs. AEs induced by different TKIs were analyzed using calculating reporting odds ratios (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma-Poisson shrinker (MGPS) to compare the character of safety signals of different TKIs.ResultsDisorders affecting skin and subcutaneous tissue, and the circulatory system emerged as the most common adverse events elicited by the majority of tyrosine kinase inhibitors. Meanwhile, some AEs only were observed in certain TKI. Endocrine disorders have higher risk only during the treatment with sunitinib, while avapritinib displayed unique AEs associated with nervous system disorders. Additionally, several significant signals were found on the preferred term (PT) level, including brain fog with avapritinib (ROR = 27.72), pemphigus (ROR = 30.90) with imatinib, nerve injury (ROR = 25.02) with ripretinib, tough blistering (ROR = 54.96) with sunitinib.ConclusionOur comprehensive pharmacovigilance analysis identified distinct adverse event profiles and significant drug-specific safety signals among TKIs used in GIST treatment. These findings enhance the characterization of TKI safety, revealing previously unreported or strongly associated signals and highlighting differences between agents. This evidence contributes to a better understanding of TKI-associated risks in clinical practice.

Abstract Background: Gastric cancer is characterized by high incidence and mortality rates. Survival improvement relies on the identification of novel prognostic factors and the implementation of stratified precision therapy. FAT4, a crucial tumor suppressor gene, has been shown to be mutated in various tumor types. However, our understanding of the association between FAT4 mutations and the prognosis of patients with gastric cancer is limited. Methods: In this study, the impact of the FAT4 gene on prognosis was investigated using data from the TCGA database. NGS was performed on real-world gastric adenocarcinoma patients receiving different types of treatment. The conclusions from the public database were further validated. Multivariate Cox regression analysis was conducted to ascertain the prognostic significance of the FAT4 gene in the real-world cohort. Lollipop plots were generated to analyze the mutation sites in the FAT4 gene in the two cohorts, and survival disparities among distinct mutation sites were assessed using Kaplan‒Meier curves. Moreover, GSEA and immune infiltration analysis, based on the XCELL and CIBERSORT databases, were applied to explore the associations between different FAT4 mutation sites and immune infiltration. Results: The mutational profile of FAT4 has been shown to be associated with increased survival and has been further validated by real-world next-generation sequencing (NGS) in patients with gastric adenocarcinoma. Specifically, mutations in the FAT4 cadherin 21-34 site were linked to even greater survival benefits than were mutations in cadherin 1-20 or wild-type FAT4. Patients with cadherin 21-34 mutations showed increased infiltration of immune cells, including CD4+ and CD8+ T cells, as well as M1 tumor-associated macrophages (TAMs), suggesting a potential connection between FAT4 mutations and enhanced immune infiltration. Conclusions: This study highlights the importance of the FAT4 gene in predicting gastric cancer prognosis. Further research is needed to explore its comprehensive genetic landscape and impact on patient outcomes. These findings have implications for clinical practice, informing treatment decisions based on FAT4 gene mutations.

Abstract Introduction: Gastric cancer (GC) is a complex and heterogeneous disease with variable clinical outcomes. Identifying prognostic factors that can reliably predict patient outcomes is crucial for personalized treatment strategies. In this study, we aimed to investigate the impact of mutations in the FAT4 gene as potential prognostic factors in gastric cancer. Methods: We conducted a comprehensive analysis of genomic data from a cohort of 236 gastric cancer patients to identify mutations in the FAT4 gene and validated it using the TCGA cohort. The mutational landscape of FAT4 was analyzed using next-generation sequencing (NGS) techniques. Clinical data, including patient demographics, tumor characteristics, and survival outcomes, were collected and correlated with the presence of FAT4 cadherin mutations. Results: In the real-world cohort, the occurrence of mutations of FAT4 was 19.1% (45/236), while in the TCGA cohort, it was 21.0% (89/423). Specifically, the mutation rates in the single cadherin functional domain of FAT4 were 10.2% (24/236) in the real-world cohort and 8.0% (34/423) in the TCGA cohort. The mutation rates for multiple cadherin sites were 2.5% (6/236) and 2.1% (9/423) in the real-world and TCGA cohorts, respectively. Survival analysis revealed that patients with FAT4 mutations had a significantly better prognosis compared to those with wild-type FAT4 (p=0.0357). Patients with multiple cadherin mutations had a better prognosis compared to those with single cadherin mutations in real-world cohorts (p=0.0651). No significant difference was observed in the TCGA cohort between single and multiple cadherin mutations (p = 0.2003), although FAT4 mutations exhibited a significant improvement in prognosis compared to wild-type patients in the TCGA cohort (p = 0.0226). Conclusion: Our findings indicate that FAT4 mutations confer a favorable prognosis in gastric cancer patients. The presence of FAT4 mutations was associated with improved survival compared to patients with wild-type FAT4. These findings underscore the potential value of FAT4 mutation status as a prognostic factor, guiding personalized treatment approaches for individuals with gastric cancer. Citation Format: Shu Wang, Haoyuan Wang, Yuxuan Ma, Yuhao Wang, Yan Zhao, Chaosheng Peng, Weiming Duan, Feilong Zhao, Jianjun Yang. Gastric cancer carrying FAT4 mutations associated with favorable prognosis in comparison to wild-type: Results from Real-World Cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5133.

Hypoxia is a predominant risk factor at high altitudes, and evidence suggests that high-altitude hypoxia alters the gut microbiota, which plays an essential regulatory role in memory function. However, the causal relationship between the gut microbiota and memory impairment under hypoxic conditions remains unclear. In this study, we employed a high-altitude hypoxia model combined with fecal microbiota transplantation (FMT) approach in mice to explore the effects of the gut microbiota on memory impairment in a hypoxic environment. We observed that high-altitude hypoxia exposure reduced short- and long-term memory and hippocampus-dependent fear memory abilities, along with decreased relative abundance of Ligilactobacillus and Muribaculum. Moreover, hypoxic conditions increased intestinal and blood-brain barrier permeability. FMT from hypoxia-exposed mice into naïve antibiotic-treated mice resulted in similar memory impairments, Ligilactobacillus and Muribaculum abundance changes, and increased intestinal/blood-brain barrier permeability. Correlation analysis showed a robust positive association between Ligilactobacillus and Muribaculum with hippocampus-dependent contextual fear memory. Likewise, Ligilactobacillus was positively correlated with short-term memory. Therefore, Ligilactobacillus and Muribaculum may be key microbes in reducing memory ability in hypoxia, with the intestinal and blood-brain barriers as primary pathways. Our findings provide further evidence for the potential regulatory mechanism by which gut microbiota dysbiosis may contribute to memory impairment in a high-altitude environment.

ObjectiveRamucirumab is a VEGFR2 antagonist. The aim of this trial is to evaluate the efficacy and safety of ramucirumab combined with nab-paclitaxel, lobaplatin and S-1 in neoadjuvant and conversion therapy for advanced gastric cancer.Methodsand analysis: This study is a prospective single-center, randomized controlled and open label clinical study, enrolling a total of 140 patients with advanced gastric cancer distributed across two distinct cohorts (Cohort A n=70; Cohort B n=70). The central focus of the study lies in evaluating the pathological complete response (pCR) of the cancer post-neoadjuvant or conversion therapy. Secondary endpoints encompass the assessment of the R0 resection rate subsequent to the aforementioned therapies, the occurrence of adverse events (AE), progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the total response rate and its duration, the disease control rate (DCR), and the duration of overall response (DOR).EthicsEthics approval has been obtained from the Ethics Committee at the First Affiliated Hospital (Xijing Hospital) of Air force Military Medical University (KY20232220-F-1).Trial registrationThis trial has been registered at the ClinicalTrials.gov: NCT06169410 (registration date: December 5, 2023).

Microsatellite instability-high (MSI-H) is a critical biomarker for immunotherapy, yet primary resistance remains a significant challenge. Current MSI-H detection methods evaluate the proportion of MSI-H loci, termed molecular MSI-H score, which can be affected by intratumoral heterogeneity (ITH). To address this limitation, we propose evaluating MSI-H at the cellular level to improve the prediction of immunotherapy outcomes. Using bulk tissue (TCGA-CRC) and cell line (CCLE-CRC) datasets, we identified genes highly expressed in MSI-H and MSS samples. These signatures were applied to a single-cell RNA sequencing (scCRC) dataset for enrichment analysis, enabling classification of tumor cells into MSI-H, MSS, and microsatellite dual (MSD) clusters using a Gaussian finite mixture model. Validation showed that MSI-H and MSS enrichment scores were higher in mismatch repair-deficient (MMRd) and mismatch repair-proficient (MMRp) patients, respectively. Functional enrichment analysis revealed that MSI-H cells were associated with pathways such as carboxylic acid catabolism, inflammatory responses, and IL-6/JAK2/STAT3 signaling. We developed a cellular MSI-H signature using genes specifically expressed in the MSI-H cell cluster and transformed the scCRC dataset into a cell-type-specific pseudobulk expression matrix. Using this matrix as a reference, we performed reference-based deconvolution on TCGA-CRC data. We defined the deconvolution score of MSI-H cell as cellular MSI-H score. This score strongly correlated with the molecular MSI-H score (R = 0.55, P < 0.001) and showed modest correlations with macrophage (MoMac, R = 0.14) and CD8+ T-cell (R = 0.11). To investigate its potential for clinical application, we applied the cellular MSI-H signature to the BJ-cohort, comprising 97 immunotherapy-treated gastrointestinal patients sequenced with a 395-gene panel. The cellular MSI-H score was significantly higher in responders (P = 0.002), positively correlated with tumor reduction percentage (R = 0.29, P = 0.006), and associated with improved progression-free survival (PFS) (HR: 0.00, 95% CI: 0.00-0.31, P = 0.021). In summary, the cellular MSI-H score reflects the MSI-H cell level within a tumor and demonstrates superior accuracy compared to molecular MSI-H status in predicting immunotherapy response and PFS. This underscores its potential as a more robust biomarker for guiding immunotherapy decisions.

目的 探讨小鼠在高原低氧环境中学习记忆能力和肠道菌群的特征性变化及其相关性.方法 将C57BL/6小鼠随机分为对照组和低氧组,每组7只,低氧组模拟海拔4000米环境暴露4周.旷场实验检测小鼠自主活动能力及焦虑抑郁样情绪,新物体识别和水迷宫检测学习记忆能力,16S rDNA检测小鼠肠道菌群结构变化,Spearman相关系数分析认知功能与肠道菌群的相关性.结果 与对照组相比,低氧组小鼠新物体识别辨别指数下降(P＜0.05);水迷宫目标象限停留的时间百分比降低(P＜0.05),提示高原低氧暴露后小鼠学习记忆能力下降;16S rDNA结果显示肠道菌群结构改变,多样性下降,艾克曼菌属、另枝菌属、肠杆菌属和瘤胃球菌属相对丰度增加;Spearman相关性分析发现,辨别指数、目标象限停留的时间百分比与α多样性呈正相关(P＜0.05),辨别指数与艾克曼菌属、另枝菌属的相对丰度呈负相关(R=-0.709、-0.604,P＜0.05);目标象限停留的时间百分比与艾克曼菌属、另枝菌属和瘤胃球菌属的相对丰度呈负相关(R=-0.704、-0.560、-0.547,P＜0.05).结论 高原低氧暴露导致小鼠肠道菌群结构改变.其中,艾克曼菌属、另枝菌属和瘤胃球菌属相对丰度增加与小鼠学习记忆能力下降存在相关性.

Background:Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an optimized and improved derivative of paclitaxel with superior efficacy and fewer adverse reactions, and it is widely used in the treatment of advanced gastric cancer. However, there is a paucity of data regarding the safety and efficacy of nab-paclitaxel combined with oxaliplatin (LBP) and tegafur in the treatment of patients with advanced gastric cancer.Methods:This analysis is a prospective, single-center, open-label, historically controlled real-world study designed to include 10 patients with advanced gastric cancer treated with nab-paclitaxel combined with LBP and tegafur gimeracil oteracil potassium. The primary and main efficacy outcomes are safety indicators, including the incidence of adverse drug reactions and adverse events (AEs), as well as the outliers of laboratory indicators and vital signs. The secondary efficacy outcomes are overall survival (OS), objective response rate (ORR), disease control rate (DCR), and proportion of dose suspensions, dose reductions and discontinuations.Discussion:Based on the findings of previous studies, we wished to assess the safety and efficacy of nab-paclitaxel combined with LBP and tegafur in the treatment of advanced gastric cancer. The trial requires constant contact and monitoring. The purpose is to determine a superior protocol in terms of patient survival, and pathological and objective response.Trial Registration:This trial has been registered with the Clinical Trial Registry: NCT05052931 (registration date: 2021/9/12).

Introduction:The efficacy and safety of immunotherapy have been widely recognized in gastrointestinal-related cancers. However, the efficacy of neoadjuvant camrelizumab for locally advanced esophageal squamous cell carcinoma (ESCC) has not been firmly established. This study compared the efficacy of camrelizumab in combination with neoadjuvant DCF (docetaxel, cisplatin and fluorouracil), with DCF alone for ESCC, and exploring biomarkers related to immune infiltration of the ESCC immunotherapy response. Methods:We enrolled and randomly assigned patients with stage II-IVa ESCC to two study treatments: camrelizumab combined with docetaxel, cisplatin and fluorouracil (DCF) regimen and DCF regimen alone. The tissue for multiplex immunofluorescence (mIF) was obtained before and after neoadjuvant therapy. The Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 (RECIST 1.1) and Tumor Regression Grade (TRG) was used to evaluate efficacy. Results:A total of 30 patients were enrolled in the study. Following neoadjuvant camrelizumab, the objective response rate (ORR) and the disease control rate (DCR) were 46.7% (7/15) and 95.7% (14/15), respectively. No patients reported complete remission, while ORR and DCR in the chemotherapy group were 26.7% (4/15) and 86.7% (13/15), respectively. R0 resection after neoadjuvant treatment was achieved in 3 out of 15 patients in the combined group and in all patients (15/15) in the chemotherapy group. In the combined group, M1-type tumor-associated macrophages and CD56dim NK cells were more abundant in responders than in non-responders (p < 0.05). A higher M1/M2 ratio was observed in responders (p < 0.05). With respect to the NGS, among the copy number amplified genes, the 11q13 amplicon (CCND1/FGF19/FGF4/FGF3) showed the highest frequency (47%, 7/15). Conclusions:Neoadjuvant camrelizumab combined with chemotherapy improved ORR in locally advanced ESCC. M1-type tumor-associated macrophages and CD56dim NK cells might be utilized to predict camrelizumab efficacy.

BACKGROUND:After the standardization, recording and follow-up of imatinib use that significantly prolongs survival of gastrointestinal stromal tumors (GISTs), a comprehensive reassessment of the prognosis of GISTs is necessary and more conductive to treatment options.METHODS:A total of 2185 GISTs between 2013 and 2016 were obtained from the Surveillance, Epidemiology, and End Results database and comprised our training (n = 1456) and internal validation cohorts (n = 729). The risk factors extracted from univariate and multivariate analyses were used to establish a predictive nomogram. The model was evaluated and tested in the validation cohort internally and in 159 patients with GIST diagnosed between January 2015 and June 2017 in Xijing Hospital externally.RESULTS:The median OS was 49 months (range, 0-83 months) in the training cohort and 51 months (0-83 months) in the validation cohort. The concordance index (C-index) of the nomogram was 0.777 (95% CI, 0.752-0.802) and 0.7787 (0.7785, bootstrap corrected) in training and internal validation cohorts, respectively, and 0.7613 (0.7579, bootstrap corrected) in the external validation cohort. Receiver operating characteristic curves and calibration curves for 1-, 3-, and 5-year overall survival (OS) showed a high degree of discrimination and calibration. The area under the curve showed that the new model performed better than the TNM staging system. In addition, the model could be dynamically visualized on a webpage.CONCLUSION:We developed a comprehensive survival prediction model for assessing the 1-, 3- and 5-year OS of patients with GIST in the postimatinib era. This predictive model outperforms the traditional TNM staging system and sheds light on the improvement of the prognostic prediction and the selection of treatment strategies for GISTs.

The environmental conditions in high‐altitude areas can induce gastrointestinal disorders and changes in gut microbiota. The gut microbiota is closely related to a variety of gastrointestinal diseases, although the underlying pathogenic mechanisms are not well‐identified. The present study aimed to investigate the regulatory effect of high altitude on intestinal dysfunction via gut microbiota disturbance. Forty C57BL/6J mice were divided into four groups: one plain control group (CON) and three high‐altitude exposure groups (HAE) (altitude: 4000 m a.s.l.; oxygen content: 12.7%; 1‐, 2‐ and 4‐week exposure). Another set of 40 mice was divided into two CON and two HAE subgroups. Antibiotic cocktails were administered to one CON and HAE groups and autoclaved water was administered to the second CON and HAE groups for 4 weeks, respectively. In the fecal microbiota transplantation experiment, there were four transplantation groups, which received, respectively: phosphate‐buffered saline for 2 weeks, feces from CON for 2 weeks, feces from HAE‐4W for 2 weeks, and HAE‐4W for 4 weeks. Hematoxylin and eosin staining, periodic acid–Schiff staining, a terminal deoxynucleotidyl transferase dUTP nick end labeling assay and a quantitative reverse transcriptase‐polymerase chain reaction were applied to detect changes in intestinal cellular structure, morphology, apoptosis and intestinal inflammatory response. Fecal microbiota was analyzed using 16S rDNA amplicon sequencing. A high‐altitude environment changed the ecological balance of gut microbiota in mice and caused damage to the intestinal structure and mucosal barrier. Interestingly, similar damage, which was inhibited by antibiotic cocktails at high altitude, was observed in mice transplanted with fecal microbiota from HAE. A high‐altitude environment contributes to dyshomeostasis of gut microbiota, thereby impairing the intestinal mucosal barrier, eventually inducing and exacerbating intestinal damage.

胃癌是我国第二大常见恶性肿瘤,患者死亡的主要原因是术后肿瘤细胞种植导致复发扩散.因此,在提高手术根治率的同时,降低腹腔游离癌细胞种植转移是改善患者预后的关键.腹腔热灌注治疗可以清除肿瘤切除术后腹腔内游离的癌细胞和微小病灶,预防与治疗恶性肿瘤腹腔种植性转移,从而显著降低进展期胃癌易出现的腹腔种植转移,提高患者的长期生存率,是进展期肿瘤患者治疗的有效途径之一.本文将对腹腔热灌注治疗用于进展期胃癌的研究进展进行综述.

Background:The human retinoblastoma susceptibility gene (RB1) is a tumor-suppressor gene mutated at different frequencies in many different cancers. The aim of the present study was to investigate the distribution of overall RB1 mutation and different mutation types in a range of Chinese patients with solid tumors.Methods:We investigated RB1 mutations in formalin-fixed, paraffin-embedded (FFPE) tissues of cancer patients who underwent next-generation sequencing (NGS) at 3DMed Clinical Laboratory Inc from January 1, 2017 to April 15, 2020.Results:Genomic alterations in RB1 were identified in 1,712 (7.6%) of 22,432 patients with more than 20 different cancer entities (58% males and 42% females, median age: 60 years). RB1 mutations occurred most frequently in small-cell lung cancer (SCLC; 138/165, 83.6%), followed by neuroendocrine neoplasms (40/170, 23.5%), bladder cancer (40/209, 19.1%), hepatocellular carcinoma (233/1,649, 14.1%), sarcomas (71/554, 12.8%), and esophageal cancer (32/293, 10.9%). Of these 1,712 patients, 185 (10.8%) had germline RB1 mutations. When stratified by mutational type, 1,258 (5.6%) had single-nucleotide variants (SNVs), 59 (0.3%) had fusions, and 210 (0.9%) had RB1 loss.Conclusions:Our findings indicate that RB1 alterations are widely distributed in solid cancers of many different histotypes in China, with specific mutations differing largely among different tumor types. The present study provides a comprehensive landscape of RB1 mutations in Chinese solid tumor patient and suggests a novel therapeutic target for cancer treatment.

目的 探讨肠道菌群在高原低氧环境中参与肠道损伤的作用机制.方法 将20只C57 BL/6小鼠按1∶1比例随机分为对照组和暴露组,建立6000m高原低氧模型,造模成功后收集两组小鼠粪便、血液和近端结肠组织.采用16S rDNA测定粪便中肠道菌群结构;检测小鼠血液生化指标;HE和PAS染色观察结肠肠道黏膜结构的改变;RT-qPCR测定结肠组织ZO-1、Occludin、IL-6和TNFα的mRNA表达水平.结果 与对照组相比,暴露组小鼠血细胞、血红蛋白和红细胞压积值显著升高,高原低氧模型建模成功;16 SrDNA结果显示肠道菌群紊乱、多样性下降,黏蛋白降解菌艾克曼菌,普雷沃氏菌、梭状芽胞杆菌ⅩⅧ等致病菌含量上升,短链脂肪酸产生菌罗斯氏菌、Odoribacter菌、Lachnospiracea菌、Butyricicoccus菌和欧氏菌等益生菌含量下降;HE和PAS染色结果显示结肠组织上皮连续性中断、腺体萎缩、隐窝变短、杯状细胞数量减少,提示肠道结构损伤且黏膜屏障破坏;结肠组织紧密连接蛋白Occludin和ZO-1 mRNA表达水平下降,进一步暴露组小鼠肠道黏膜受损,炎症因子IL-6和TNFα的mRNA表达量上升,可能与肠道炎症反应有关.结论 高原低氧环境导致的肠道损伤可能与肠道菌群改变有关.肠道菌群紊乱、多样性下降,致病菌相对丰度上升,益生菌相对丰度下降,菌群的这些改变造成肠道黏膜损伤,引起肠道炎症,进而出现肠道损伤,最终导致高原肠道相关疾病.

Neuroendocrine neoplasias (NENs) are a heterogeneous group of rare tumors scattered throughout the body. Surgery, locoregional or ablative therapies as well as maintenance treatments are applied in well-differentiated, low-grade NENs, whereas cytotoxic chemotherapy is usually applied in high-grade neuroendocrine carcinomas. However, treatment options for patients with advanced or metastatic NENs are limited. Immunotherapy has provided new treatment approaches for many cancer types, including neuroendocrine tumors, but predictive biomarkers of immune checkpoint inhibitors (ICIs) in the treatment of NENs have not been fully reported. By reviewing the literature and international congress abstracts, we summarize the current knowledge of ICIs, potential predicative biomarkers in the treatment of NENs, implications and efficacy of ICIs as well as biomarkers for NENs of gastroenteropancreatic system, lung NENs and Merkel cell carcinoma in clinical practice.