Abstract Background Gastrointestinal stromal tumors (GISTs) are the most prevalent mesenchymal tumors of the gastrointestinal system; however, preoperative imaging for the accurate diagnosis of malignancy is unavailable. We conducted a meta-analysis to comprehensively confirm the value of preoperative Positron emission tomography (PET) in diagnosing the malignant potential of GISTs, aiming to guide preoperative preparation when biopsy is confined and prognostic evaluation for patients with localized primary GISTs after curative resection. Methods PubMed, Web of Science, Cochrane Library, and Embase databases were systematically searched from database inception till June 1, 2025, to retrieve articles reporting the predictive value of preoperative PET or PET/CT for GISTs. Overall sensitivity (SEN) and specificity (SPE) with 95% confidence intervals (CI) using forest plots were estimated. The chi-square and I2 tests were used to analyze significant heterogeneity. QUADAS-2 and Deek funnel plots were constructed to assess publication bias risk. Subgroup analyses were performed to investigate the sources of heterogeneity. Results Fifteen studies including 568 patients with GISTs were included. The findings demonstrated overall SEN (0.86, 95% CI: 0.74–0.93), SPE (0.87, 95% CI: 0.75–0.94), positive likelihood ratio 6.80, 95% CI: 3.09–14.96), negative likelihood ratio (0.16, 95% CI: 0.07–0.34), and the area under the receiver operating characteristics curve (0.93, 95% CI: 0.91–0.95). Subgroup analysis indicated that with cut-off values at ≥ 5, the diagnosis could have a higher accuracy (sensitivity, specificity, and area under the curve values were 0.89, 0.92, and 0.96, respectively). Conclusion Preoperative PET or PET/CT exhibited excellent diagnostic performance in predicting malignancy in GISTs and may be employed as an effective non-invasive imaging device for guiding preoperative preparation when biopsy is not possible and prognostic analysis for patients with localized primary GISTs who underwent radical surgery. Trial registration Our protocol was registered in PROSPERO (CRD42024545100) on May 9th, 2024.

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:This study aimed to compare the efficacy and safety of TLTG with the overlap technique to LATG in patients with advanced Siewert III Esophagogastric Junction Cancer and upper and middle third gastric cancer. METHODS:This single-center RCT enrolled 292 patients with the mentioned cancers, randomly assigned to TLTG overlap ( n =146) or LATG ( n =146) groups. Data on demographics, pathology, intraoperative variables, postoperative complications, recovery parameters, and 3-year survival were collected. Main outcome: postoperative complications within 30 days. Secondary outcomes: 3-year disease-free and overall survival. RESULTS:TLTG versus LATG: TLTG had shorter incision, faster flatus/defecation, reduced analgesia, less opioid use, and shorter hospital stay. Similar operation time, anastomosis time, blood loss, and lymph node harvest. TLTG had a lower overall post-op complication rate (P=0.047) and no significant difference in serious complications ( P =0.310). Variances in anastomotic stenosis occurrence at 3 months. No rehospitalization or mortality at 30 days. No significant differences in 3-month disease-free survival ( P =0.058) or overall survival ( P =0.236). CONCLUSION:The overlap method for anastomosis in TLTG is safe and feasible for advanced middle-upper-third gastric cancer, with positive short-term outcomes. This technique has the potential to be the preferred esophagojejunostomy approach in TLTG. TRIAL REGISTRATION:This trial has been registered at Chinese Clinical Trial Registry: ChiCTR1900025667 (registration date: 4 September 2019).

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.

UPP1 has been reported to be involved in the tumorigenesis of pancreatic ductal adenocarcinoma and lung adenocarcinoma. However, the role and mechanism of UPP1 in GC remain unclear. This study aims to reveal the biological function of UPP1 in GC and the mechanisms regulating GC progression. Analysis of public databases and clinical samples revealed that UPP1 was significantly upregulated in GC tissues and associated with poor prognosis. Functionally, UPP1 knockdown inhibited GC cell proliferation and migration in vitro and suppressed tumor growth in vivo. Mechanistically, UPP1 promoted metabolic reprogramming by activating hypoxia-related pathways and enhancing mitochondrial translation. UPP1/ARNT axis formed a positive feedback loop that upregulated the expression of key metabolic enzymes HK2, GLUT1, and LDHA. These upregulated enzymes modulated glycolytic and oxidative phosphorylation levels to influence cellular functions. Moreover, genetic inactivation of UPP1 sensitized tumors to metformin and doxycycline. In addition, UPP1 affected PD-L1 levels through NF-κB pathway, thereby influencing the tumor microenvironment of GC. Our findings reveal a novel role for UPP1 in linking metabolic reprogramming to immune evasion in GC. Targeting this pathway with doxycycline or metformin exploits this metabolic vulnerability and enhances anti-tumor immunity, which could be a promising strategy.

OBJECTIVE/BACKGROUND:The RNPLS-01 trial aimed to evaluate the efficacy and safety of ramucirumab (a VEGFR2 antagonist) combined with nab-paclitaxel, lobaplatin, and S-1 (RNPLS group) versus nab-paclitaxel, lobaplatin, and S-1 alone (NPLS group) in neoadjuvant therapy for advanced gastric cancer (GC), as part of the RNPLS-01 prospective randomized controlled trial. METHODS AND ANALYSIS:RNPLS-01 trial enrolled 140 patients with advanced GC across two cohorts (neoadjuvant therapy: n = 70; conversion therapy: n = 70). This report focuses on the neoadjuvant cohort where patients were randomized 1:1 to receive either RNPLS (n = 35) or NPLS (n = 35). Primary endpoint was pathological complete response (pCR). Secondary endpoints included R0 resection rate, objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). RESULTS:The RNPLS group demonstrated significant improvements in post-operative T stage ( P = 0.008), N stage ( P = 0.001), and AJCC (American Joint Committee on Cancer) clinical stage ( P = 0.003) compared to controls. The RNPLS group demonstrated significantly higher pCR rates compared to the NPLS group (22.9% vs. 2.9%, P <0.0001). The R0 resection rate was 85.7% in the RNPLS group versus 82.9% in the NPLS group. The RNPLS group achieved a significantly higher ORR compared to the NPLS group (68.6% vs. 25.7%, P = 0.001), while DCRs were comparable between the two groups (94.3% vs. 77.1%, P = 0.055). Treatment-related adverse events (TRAEs) were confined to Grade 1-2 severity, with no Grade 3-4 events reported in either group. The RNPLS group showed a TRAE incidence of 80.0%, versus 88.6% in the NPLS group ( P = 0.324). Neither group exhibited surgical complications during the study period. CONCLUSION:Ramucirumab combined with nab-paclitaxel, lobaplatin, and S-1 significantly enhances the pCR rate and ORR in neoadjuvant therapy of locally advanced GC patients, while maintaining an acceptable safety profile.

Background:The women's cancer screening program has been operational for several years in China, primarily utilizing palpation and ultrasound. Given the proven impact of BRCA1/2 mutations on the incidence of breast and ovarian cancer, the cost-effectiveness of incorporating BRCA1/2 mutation testing into these programs, either for the entire population or through enrichment based on family history of breast and ovarian cancer, remains poorly researched. Methods:We constructed a decision tree model to compare the cost-effectiveness of three strategies: symptom-based screening only (Symptom-only strategy), population-based BRCA1/2 testing (population-based strategy), and family-history-based BRCA1/2 testing (FH-based strategy). One-way and probability sensitivity analyses enabled model uncertainty evaluation. Outcomes included early and advanced stages of ovarian and breast cancer. Cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. The target population was women at 40-60 years, the time horizon was until age 70, and the perspective was payer-based. Results:The FH-based strategy was found to be cost-effective compared to the Symptom-only strategy (ICER: ¥185,710/QALY, gaining 0.26 days' life expectancy). Its cost-effectiveness was significantly influenced by the risks of ovarian and breast cancer among BRCA1/2 carriers, the prevalence of BRCA1/2 mutations in the general Chinese population, the prevalence of family history of breast and ovarian cancer among Chinese women, and the prevalence of BRCA1/2 mutations in the FH-positive population. Integrating these variable distributions, the FH-based strategy showed a 76.96% probability of cost-effectiveness. The Population-based strategy was not cost-effective, whether compared to the Symptom-only strategy (ICER: ¥504,476/QALY, gaining 2.66 days' life expectancy) or to the FH-based strategy (ICER: ¥539,476/QALY, gaining 2.41 days' life expectancy). The prevalence of BRCA1/2 mutations in the general Chinese population was identified as the primary variable affecting its cost-effectiveness. Integrating these variable distributions, the Population-based strategy had a probability of cost-effectiveness of only 0.8%. Conclusion:Incorporating family-history-based BRCA1/2 testing into breast and ovarian cancer screening programs is cost-effective in China and warrants promotion.

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 tumor (GIST) is the most common mesenchymal tumor. Imatinib, as a receptor-type tyrosine kinase inhibitor (TKI), becomes a first-line drug for adjuvant therapy and prognosis. However, patients are facing with the problem of primary and secondary drug resistance when using imatinib, which affects the effect of imatinib. Thus, it is particularly important to explore the mechanism of drug resistance. Ubiquitination and deubiquitination process have been proofed to performance as posttranslational modifications (PTMs) to influence the occurrence and progression of most tumors. Hence, we attach importance to these mechanisms and found that GIST resistance may be related to ubiquitination and deubiquitination in regulating exosome secretion, autophagy, apoptosis and ferroptosis. Through clarifying these connections, this review aims to offers insights and hope for therapeutic advancements of imatinib-resistant GIST patients and the use of specific ubiquitin modifications as markers in the future.

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.

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).

BackgroundBaseline serological biomarkers have the potential to predict the benefits of adjuvant chemotherapy in patients with gastric cancer. However, the fluctuating nature of postoperative recurrence risk makes precise treatment challenging. We aimed to develop a risk score in real-time predicting outcomes for postoperative GC patients using blood chemistry tests.Materials and methodsThis was a retrospective, multicentre, longitudinal cohort study from three cancer centres in China, with a total of 2737 GC patients in the pTNM stage Ib to III. Among them, 1651 patients with at least two serological records were assigned to the training cohort. Model validation was carried out using separate testing data with area under curve (AUC). The least absolute shrinkage and selection operator (LASSO) and random forest-recursive feature elimination (RF-RFE) algorithm were used to select the parameters.ResultsThe Cox regression model derived six risk factors to construct a composite score (low-risk: 0-2 score; high risk: 3-6 score), including CEA, CA125, CA199, haemoglobin, albumin, and neutrophil to lymphocyte ratio. The risk score accurately predicted mortality in 1000-time bootstrap (AUROCs:0.658; 95% CI: 0.645, 0.670), with the highest AUROC (0.767; 95% CI: 0.743, 0.791) after 1 year since the gastrectomy. In validation dataset, the risk score had an AUROC of 0.586 (95% CI 0.544, 0.628). Furthermore, patients with high risk at 1 month derived significant clinical benefits from adjuvant chemotherapy (P for interaction <0.0001). Compared with the low-low-low risk group, the low-low-high risk group of the long-term state chain (risk state at baseline, 6 months, 1 year) had the worse OS (HR, 6.91; 95%CI: 4.27, 11.19) and DFS (HR, 7.27; 95%CI: 4.55, 11.63).ConclusionThe dynamic risk score is an accurate and user-friendly serological risk assessment tool for predicting outcomes and assisting clinical decisions after gastrectomy.

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.

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.