PURPOSE: This study aimed to characterize the clinicopathological, immunophenotypic, and molecular features of gastrointestinal stromal tumors (GISTs) harboring NTRK fusions and to evaluate their diagnostic, prognostic, and therapeutic implications. METHODS: Twenty-six cases of KIT/PDGFRA/SDH/BRAF wild-type GISTs were evaluated using pan-TRK immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) for NTRK1/2/3, and next-generation sequencing (NGS). Transcriptome analysis was performed on all NTRK fusion-positive cases. Seven KIT-mutant GISTs served as controls. Clinicopathological parameters, IHC profiles, genetic alterations, and treatment responses were analyzed, supplemented by a literature review. RESULTS: Five of the 26 wild-type GISTs harbored NTRK fusions, all confirmed by NGS as ETV6::NTRK3. Pan-TRK IHC showed 100% sensitivity and 66.7% specificity. All five patients were male; four tumors were intestinal and one gastric. Four cases were high-risk and one very low-risk. Two cases recurred post-resection, showing additional mutations and copy number variations (CNVs). Preliminary evidence from transcriptome sequencing pointed to the possibility that NTRK fusion-positive GISTs represented a heterogeneous group and showed similarities in their molecular profiles to common KIT-mutant GISTs. Both recurrent patients received multi-line TKI therapy (imatinib, sunitinib, regorafenib, ripretinib) with disease progression; one subsequently achieved remission with larotrectinib. CONCLUSION: NTRK fusion-positive GISTs are rare and exhibit distinct clinicopathological characteristics. FISH and NGS are reliable detection methods, while pan-TRK IHC has limited specificity. Co-occurring genetic alterations may confer aggressive behavior. These tumors respond to TRK inhibition but are resistant to conventional TKIs, underscoring the need for molecularly guided therapy.

11537 Background: Cytoreductive surgery may improve outcomes in patients with locally advanced or metastatic gastrointestinal stromal tumors (GIST) after progression on imatinib. Ripretinib has shown a high objective response rate (ORR) and a favorable safety profile in advanced GIST, suggesting its potential for tumor downstaging and enabling surgical intervention. This study evaluated the efficacy and safety of ripretinib as preoperative therapy in patients with imatinib-resistant, potentially resectable advanced GIST. Methods: This single-arm, multicenter, exploratory study (NCT05132738) enrolled patients with imatinib-resistant, locally advanced or recurrent metastatic GIST who met the following criteria: 1) ≤5 evaluable lesions on CT/MRI; 2) resection deemed high-risk by multidisciplinary team (MDT) assessment (meeting one of the following): a) The maximum diameter of a single lesion is ≥10 cm; b) Organ function damage surgery is required; c) Multiple organ resection surgery is required. Patients received ripretinib 150 mg once daily (QD) up to 6 months before surgery. The primary endpoint was the no evidence of disease rate (NED Rate). Secondary endpoints included the R0/R1 resection rate, surgery rate, and ORR. Results: As of January 2026, 20 patients were enrolled, with a median age of 58 years (range: 31-74). The most common primary tumor site was the small intestine (70%). The median sum of target lesion diameters was 10.8 cm (range: 3.2-33.7). The median duration of preoperative ripretinib was 5 months (range: 2-6). The median best percentage change in the sum of target lesion diameters was -20.5% (range: -47.2% to +56.0%). 8 patients (40.0%) achieved a partial response (PR) and 10 patients (50.0%) had stable disease (SD). Median time to response was 2.0 months (range: 2.0-6.0). 70% (14/20) of patients underwent surgery and the NED rate was 92.9% (13/14). Of the 13 patients who achieved R0 resection, 8 (61.5%) have maintained NED to date. Only 1 patient experienced intestinal fistula as a surgical complication, which was unrelated to ripretinib treatment. After surgery, 6 patients continued ripretinib therapy, while 3 switched to imatinib therapy and 5 switched to sunitinib therapy. With a median follow-up of 20.4 months (range: 8.1–47.6), the median overall survival (OS) was immature. Conclusions: These findings demonstrate that preoperative ripretinib effectively reduced tumor burden in patients with imatinib-resistant, potentially resectable advanced GIST, and facilitated successful surgery intervention. Notably, the approach achieved a high NED rate and a low surgical complication rate, supporting ripretinib as a safe and effective preoperative treatment option. Clinical trial information: NCT05132738 .

The regulatory role of TGF-β-induced epithelial-mesenchymal transition (EMT) in cancer cell dissemination is well established, but the involvement of N6-methyladenosine (m6A) in TGF-β signaling remains obscure. Here, we unveil, for the first time, the m6A modification profile in TGF-β-induced gastric cancer (GC) EMT and identify zinc finger protein ZNF460 as a critical mediator of the EMT process. The presence of ZNF460 greatly enhances the EMT process, as well as the invasion and spread of GC cells. Mechanistically, the activation of ZNF460 during the EMT process is mediated by METTL16-dependent m6A methylation of ZNF460 mRNA. ZNF460 interacts with histone deubiquitinase USP22 and histone demethylase PHF8 to form a stable complex, which transcriptionally activates SOX4, thereby contributing to the tumor EMT and metastasis. In addition, the ZNF460/USP22/PHF8 complex enhances the transcriptional activity of METTL16 in the nucleus, thus forming a positive feedback loop. Clinically, elevated ZNF460, alone or in combination with overexpression of METTL16 and SOX4, is predictive of poor prognosis. Collectively, our findings identify a novel oncogenic epitranscriptomic axis of METTL16/ZNF460/SOX4 which is involved in generating the EMT phenotype and regulating GC metastasis.

Accurate prediction of the recurrence risk of localized primary gastrointestinal stromal tumors (GISTs) after complete surgical resection is crucial for determining adjuvant treatment and surveillance strategies. Traditional risk-stratification schemes often exhibit heterogeneity and may not provide sufficient prognostic information. Therefore, the authors' objective was to develop a pathomics nomogram that integrates digital pathology and machine-learning algorithms to improve predictive accuracy. The authors enrolled 421 eligible participants (253 in the training cohort, and 168 in the external validation cohort) from four medical centers. Four distinct machine-learning methods were evaluated, and the one that demonstrated optimal performance in the validation cohort was selected to develop the pathomics model. Subsequently, stepwise multivariate Cox regression analysis was performed to construct a machine-learning-based pathomics nomogram (the MLPNom). The MLPNom exhibited superior predictive performance compared with traditional risk criteria (concordance index values: training cohort, 0.892; validation cohort, 0.964). The time-dependent area under the curve values for the MLPNom were notably higher than those for traditional risk criteria (5-year area under the curve values: training cohort, 0.919; validation cohort, 0.959). Calibration curves and Brier scores confirmed the excellent calibration of the MLPNom. Decision curve analysis further underscored the utility of the MLPNom in clinical decision making for GISTs. Furthermore, the MLPNom identified three distinct prognostic subgroups that retained their significance after stratification based on diverse clinicopathologic factors. The MLPNom demonstrates robust discrimination and calibration in predicting recurrence-free survival in localized primary gastric and small intestinal GISTs after complete surgical resection. This may complement traditional risk criteria and aid in selecting patients for adjuvant imatinib therapy.

Rationale: Gastrointestinal stromal tumors (GIST), the most common mesenchymal tumors of the gastrointestinal tract, are primarily driven by activating mutations in the KIT intracellular segment. The standard treatment with imatinib frequently results in acquired resistance due to secondary mutations. Besides mutations, KIT is also overexpressed in GIST. An aptamer that specifically binds to the extracellular segment of KIT (unaffected by these mutations) was promising in drug delivery and may overcome imatinib resistance. Methods: The microtubule inhibitor VcMMAE (mc-vc-PAB-MMAE) was conjugated with an optimized KIT-targeting aptamer (KIT-d) to generate an aptamer-drug conjugate (ApDC) named KIT-d-MMAE. This ApDC was then evaluated for its binding specificity, internalization via endocytosis, and cytotoxicity towards KIT-positive GIST cells. The therapeutic efficacy of KIT-d-MMAE was evaluated through both in vitro and in vivo experiments. Results: KIT-d-MMAE exhibited specific binding and efficient internalization into KIT-positive GIST cells, including imatinib-resistant lines, inducing targeted cytotoxic effects. In animal studies, KIT-d-MMAE significantly suppressed tumor growth in GIST-T1 subcutaneous and liver metastasis models. Notably, in imatinib-resistant GIST-430/654 and multi-TKI-resistant patient-derived xenograft (PDX) models, KIT-d-MMAE demonstrated superior antitumor efficacy compared to imatinib. Additionally, therapeutic effects were also observed in genetically engineered mouse models, indicating effective inhibition of spontaneous tumor formation and progression. Conclusion: The aptamer-based drug delivery not only provides an innovative approach to overcome drug resistance but also simplifies treatment regimens, offering new therapeutic hope and marking a significant advancement in targeted therapy for GIST patients.

Gastrointestinal stromal tumor (GISTs) are clinically heterogenous exhibiting varying degrees of disease aggressiveness in individual patients. We comprehensively describe the genomic and transcriptomic landscape of a cohort of 117 GISTs including 31 low-risk, 18 intermediate-risk, 29 high-risk, 34 metastatic and 5 neoadjuvant GISTs from 105 patients. GISTs have notably low tumor mutation burden but widespread copy number variations. Aggressive GISTs harbor remarkably more genomic aberrations than low-/intermediate-risk GISTs. Complex genomic alterations, chromothripsis and kataegis, occur selectively in aggressive GISTs. Despite the paucity of mutations, recurrent inactivating YLPM1 mutations are identified (10.3%, 7 of 68 patients), enriched in high-risk/metastatic GIST and functional study further demonstrates YLPM1 inactivation promotes GIST proliferation, growth and oxidative phosphorylation. Spatially and temporally separated GISTs from individual patients demonstrate complex tumor heterogeneity in metastatic GISTs. Finally, four prominent subtypes are proposed with different genomic features, expression profiles, immune characteristics, clinical characteristics and subtype-specific treatment strategies. This large-scale analysis depicts the landscape and provides further insights into GIST pathogenesis and precise treatment. Gastrointestinal stromal tumours (GISTs) are clinically heterogeneous, with varying degrees of aggressiveness. Here, the authors describe the genomic and transcriptomic landscape of 117 GISTs from 105 patients; they find four molecular subtypes as well as recurrent inactivating YLPM1 mutations in high-risk/metastatic GIST.

BACKGROUND:Chromosome gains or localized amplifications are frequently observed in human gastric cancer (GC) and are major causes of aberrant oncogene activation. However, the significance of long non-coding RNAs (LncRNAs) in the above process is largely unknown.METHODS:The copy number aberrations (CNAs) data of GC samples were downloaded and analyzed from the TCGA database. qRT-PCR and fluorescence in situ hybridization were used to evaluate the expression of Linc01711 in GC. The effects of Linc01711 on GC progression were investigated through in vitro and in vivo assays. The mechanism of Linc01711 action was explored through transcriptome sequencing, chromatin immunoprecipitation sequencing, RNA immunoprecipitation, RNA pull-down and chromatin isolation by RNA purification (ChIRP) assays.RESULTS:We report for the first time a novel DNA copy number amplification-driven LncRNA on chromosome 20q13, designated Linc01711 in human GC, which is highly associated with malignant features. Functionally, Linc01711 significantly accelerates the proliferation and metastasis of GC. Mechanistically, Linc01711 acts as a modular scaffold to promote the binding of histone acetyltransferase HBO1 and histone demethylase KDM9. By coordinating the localization of the HBO1/KDM9 complex, Linc01711 specifies the histone modification pattern on the target genes, such as LPCAT1, and consequently facilitates the cholesterol synthesis, thereby contributing to tumor progression.CONCLUSIONS:Our findings suggest that copy number amplification-driven Linc01711 may serve as a promising prognostic predictor for GC patients and targeting Linc01711-related cholesterol metabolism pathway may be meaningful in anticancer strategies.

Ferroptosis, as a novel-induced programmed cell death, plays critical roles in the pathogenesis of cancers. However, the promising biomarkers of ferroptosis in gastrointestinal stromal tumor (GIST) remain to be elucidated. Herein, the expression of ferroptosis-related genes was analyzed in GIST. Among the 64 ferroptosis-related genes, transferrin receptor (TFRC) expression presented a remarkable upregulation in high-risk patients through Gene Expression Omnibus (GEO) dataset analysis, as well as its significant change after imatinib was treated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of TFRC-relevant genes revealed that TFRC expression was closely associated with cell growth pathways and metabolism-related pathways. Furthermore, patients at high risk of recurrence were more likely to exhibit high TFRC expression by immunohistochemistry. Additionally, high TFRC expression indicated an undesirable state of patient relapse, which could serve as a powerful significant independent predictor of recurrence-free survival (RFS). In summary, we systematically summarize the expression characteristics and clinical relevance of TFRC and show that TFRC can be used as a prognostic factor, which can be considered a potential therapeutic target in GIST.

e16089 Background: Immunotherapy has demonstrated promising efficacy and favorable safety profile for unresectable or metastatic gastric cancer (GC) by several high-quality studies. However, few have examined the immunotherapy efficacy for locally advanced GC (LAGC) in the perioperative setting, especially as adjuvant therapy after D2 resection. Here, a phase II trial reports the adjuvant efficacy of camrelizumab with docetaxel plus S-1 in patients (pts) with PD-L1 positive, deficient mismatch repair (dMMR) or Epstein-Barr virus (EBV) positive LAGC (NCT04152889). Methods: This is a single-center, prospective, open-label and single-arm phase II study. Chemotherapy-naive adult pts receiving D2 resection and histologically confirmed as PD-L1 positive (CPS > 5), dMMR or EBV positive LAGC (stage III) were enrolled. Pts received camrelizumab (200mg, D1), docetaxel (40mg/m 2 , D1, free at first course) and S-1 (80-120mg, D1-14) every 3 weeks for seven courses, sequenced by camrelizumab (200mg, D1) and S-1 (80-120mg, D1-14) every 3 weeks for up to one year, until disease relapse or intolerable toxicity. Primary endpoint was 1-year relapse-free survival (RFS). Herein, the safety and efficacy data after 1-year postoperative therapy courses were reported. Results: From Jan. 2020 to Jan. 2022, 19 pts (median age 59 years, range 34-75, 13 men and 6 women) were enrolled, of whom 15 were CPS > 5, 3 were dMMR, and 1 was EBV positive. pTNM stage IIIA, B and C were 10 (52.6%), 3 (15.8%) and 6 (31.6%), respectively. The cut-off date for the final follow-up data was Feb. 1, 2023 with a median follow-up period for surviving patients of 25.1 months. All 19 pts had experienced treatment related adverse events (TRAEs), of whom, grade 3-4 TRAEs occurred in 9 (47.4%), 2 pts (10.5%) discontinued therapy, and 11 pts (57.9%) delayed the therapy. Furthermore, the OS rate of 19 pts at 1/2 years was 100% and 88.9%, while the RFS rate at 1/2 years was 100% and 92.3%, respectively. The dead and recurrent cases all belonged to PD-L1 positive subgroup. Conclusions: Adjuvant therapy of camrelizumab with docetaxel plus S-1 shows acceptable safety and promising efficacy for PD-L1 positive, dMMR, or EBV positive stage III GC pts after D2 resection. Clinical trial information: NCT04152889 .

OBJECTIVES:Research on long noncoding RNAs (lncRNAs) has been conducted in different areas of oncology. Currently, the biological significance of lncRNAs and their regulatory features in gastrointestinal stromal tumors (GIST) remain largely unknown. We have previously identified SPRY4-IT1 overexpression in GIST through lncRNA sequencing of GIST tissues. Coincidentally, SPRY4-IT1 is an intron of the SPRY4 gene, and SPRY4 is specifically highly expressed in GIST. Thus the aim of the present study was to investigate the role of lncRNA SPRY4-IT1 in GIST pathogenesis.METHODS:Herein, we screened for SPRY4-IT1 and analyzed its possible phenotypes using Gene set enrichment analysis (GSEA). The phenotypes of GIST were verified using CCK-8, colony formation, and wound-healing assays. The ceRNA mechanism was determined by the location of lncRNA SPRY4-IT1, and its relationship to the Ago2 protein. The SPRY4-IT1/miR-101-5p/ZEB1 axis was predicted using online software and sequencing. Luciferase and pull-down assays were performed for verification. Pathway-associated and phenotype-associated proteins were detected by western blotting.RESULTS:Sequencing analysis revealed 117 differentially expressed lncRNAs in GIST and normal gastric tissue samples. Accordingly, SPRY4-IT1 was screened out and its phenotype was predicted by GSEA. Mechanistically, SPRY4-IT1 was identified as a competing endogenous RNA (ceRNA) that downregulated miR-101-5p and upregulated ZEB1, which activated extracellular signal-regulated kinase (ERK) signaling to stimulate GIST proliferation, invasion, and epithelial-mesenchymal transition. Although this effect was regulated by a negative feedback loop through SPRY4, it was still controlled by SPRY4-IT1.CONCLUSIONS:In GIST, we revealed a ceRNA mechanism by which SPRY4-IT1 modulates ZEB1 by sponging miR-101-5p, eventually driving tumor cell proliferation, migration, and epithelial-mesenchymal transition (EMT).

Objective:To investigate the short-term efficacy of laparoscopic total gastrec-tomy with hand-sewn esophagojejunostomy versus Roux-en-Y anastomosis.Methods:The propen-sity score matching and retrospective cohort study was conducted. The clinicopathological data of 159 patients who underwent laparoscopic total gastrectomy in Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine from October 2014 to July 2021 were collected. There were 107 males and 52 females, aged 63(range, 28?79)years. Of 159 patients, 71 cases undergoing totally laparoscopic total gastrectomy with hand-sewn esophagojejunostomy were allocated into totally laparoscopic group and 88 cases undergoing laparoscopic-assisted total gastrectomy with Roux-en-Y anastomosis were allocated into laparoscopic-assisted group, respectively. Observation indicators: (1) propensity score matching and comparison of general data of patients between the two groups after matching; (2) intraoperative and postoperative conditions; (3) perioperative complications. Propensity score matching was done by the 1:1 nearest neighbor matching method. Measurement data with normal distribution were expressed as Mean± SD, and t test was used for comparison between groups. Measurement data with skewed distribution were expressed as M(range), and the Mann-Whitney U test was used for comparison between groups. Count data were expressed as absolute numbers or percentages, and comparison between groups was analyzed using the chi-square test or Fisher's exact probability method. The rank sum test was used for comparison of ordinal data. Results:(1) Propensity score matching and comparison of general data of patients between the two groups after matching. Of 159 patients, 112 cases were successfully matched, including 56 cases in the totally laparoscopic group and 56 cases in the laparoscopic-assisted group. Before propensity score matching, age, cases with tumor located in cardia or gastric body in the totally laparoscopic group were 61(range, 30?76)years, 26, 45, respectively. The above indicators in the laparoscopic-assisted group were 65(range, 28?79)years, 50, 38, respectively. There were significant differences in the above indicators between the two groups ( Z=?2.89, χ2=6.43, P<0.05). After propensity score matching, the males and females, age, body mass index, cases of American Society of Anesthesiologists classification Ⅰ, Ⅱ, Ⅲ and Ⅳ, tumor diameter, cases with tumor located in cardia or gastric body, cases in TNM stage Ⅰ, Ⅱ and Ⅲ of patients in the totally laparoscopic group were 40, 16, (62±9)years, (22.7±2.8)kg/m 2, 22, 26, 7, 1, 3.5(range, 0.6?17.0)cm, 24, 32, 22, 9, 25. The above indicators of patients in the laparoscopic-assisted group were 38, 18, (62±10)years, (22.7±3.2)kg/m 2, 19, 32, 5, 0, 4.0(range, 0.6?15.0)cm, 23, 33, 21, 7, 28, respectively. There was no significant difference in the above indicators between the two groups ( χ2=0.17, t=?0.09, ?0.04, Z=?0.12, ?0.82, χ2=0.04, Z=?0.42, P>0.05). The elimination of age and tumor location confounding bias ensured comparability between the two groups. (2) Intraoperative and postoperative conditions: after propensity score matching, the total operation time, time of esophagojejunostomy, postopera-tive 24-hour pain numerical score and time to first out-off bed activities were (310±49)minutes, (37±10)minutes, 2.3±0.8 and (2.4±0.7)days for patients in the totally laparoscopic group, versus (344±77)minutes, (44±12)minutes, 3.1±1.2 and (2.9±1.0)days in the laparoscopic-assisted group, showing significant differences between the two groups ( t=?2.85, ?3.05, ?4.20, ?3.10, P<0.05). (3) Perioperative complications: after propensity score matching, 6 cases of the patients in the totally laparoscopic group had Clavien-Dindo grade 2 or higher complications, including 2 cases of anas-tomotic leak, 1 case of anastomotic stenosis, 1 case of pleural effusion, 1 case of abdominal infection and 1 case of intestinal obstruction. The incidence of Clavien-Dindo grade 2 or higher complications was 10.7%(6/56). In the laparoscopic-assisted group, 5 patients had Clavien-Dindo grade 2 or higher complications, including 2 cases of anastomotic leak, 1 case of abdominal infection, 1 case of intestinal obstruction and 1 case of cholangitis. The incidence of Clavien-Dindo grade 2 or higher complications was 8.9%(5/56). There was no significant difference in the incidence of Clavien-Dindo grade 2 or higher complications between the two groups ( χ2=0.10, P>0.05). Patients with anas-tomotic leak were improved after puncture and drainage, secondary surgery and conservative treat-ment, and other complications were improved after symptomatic treatment. Conclusions:Com-pared with Roux-en-Y anastomosis in laparoscopic total gastrectomy, the time of hand-sewn esophagojejunostomy and esophago-jejunal anastomosis are shorter, patients have less postopera-tive pain and faster postoperative recovery. Both methods have good peri-operative safety.

Objective:To investigate the application value of laparoscopic intra-gastric surgery (LIGS) in the treatment of gastrointestinal stromal tumors (GIST) around the cardia.Methods:The retrospective and descriptive study was conducted. The clinicopathological data of 5 patients who underwent LIGS for GIST around the cardia in the Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine from January 2019 to December 2021 were collected. There were 3 males and 2 females, aged 52(range, 35?69)years. All patients underwent LIGS. Observation indicators: (1) intraoperative and postoperative conditions; (2) follow-up. Follow-up was conducted using tele-phone interview or outpatient examination. Patients were followed up once every 3 months to detect long-term complications and tumor recurrence up to April 1st, 2022. Measurement data with skewed distribution were represented as M(range) and count data were described as absolute numbers. Results:(1) Intraoperative and postoperative conditions. All 5 patients underwent LIGS successfully, without conversion to laparotomy or changes in surgical methods. Intraoperative tumor exploration showed that the tumor was located on the lesser curvature of the cardia in 3 patients and on the posterior wall of the gastric fundus in 2 patients. The distance between the tumor and the dentate line of the cardia was 1.5(range, 1.0?3.0)cm. Of the 5 patients, 3 cases with tumor patholo-gically evaluable margins as 0.3, 0.8, and 1.5 cm and 2 cases without tumor pathologically evaluable margins but the tumor had an intact capsule. The operation time, volume of intraoperative blood loss, time to postoperative first anal exsufflation, time to postoperative initial fluid diet intake, time to extubation and duration of postoperative hospital stay were 75(range, 65?112)minutes, 25(range, 15?70)mL, 2(range, 1?3)days, 3(range, 2?4)days, 4(range, 3?5)days and 6(range, 5?8)days in the 5 patients. There was no short-term postoperative complication such as bleeding, anastomotic leakage, and gastroparesis in the 5 patients and results of postoperative histopathological examina-tion showed GIST in all 5 patients, with tumor diameter as 3.0(range, 1.8?5.5)cm. There were 2 patients with tumor diameter ≤2.0 cm and 3 patients with tumor diameter ≥3.0 cm. The 5 patients were classified as very low risk in 2 cases, low risk in 2 cases, and intermediate risk in 1 case. (2) Follow-up. All 5 patients were followed up after operation, with the follow-up time of 9(range, 3?15)months. During the follow-up, there was no long-term complication such as dysphagia and gastroesophageal reflux, and no recurrence or metastasis of tumor occurred in patients by computed tomography examinations.Conclusion:LIGS can be used for the treatment of GIST around the cardia.

Objective:To investigate the clinical efficacy and prognostic influencing factors of radical surgery for duodenal gastrointestinal stromal tumor (GIST).Methods:The retrospective cohort study was conducted. The clinicopathological data of 741 duodenal GIST patients who under-went radical surgery in 17 medical centers, including 121 cases in Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 121 cases in Chinese PLA General Hospital, 116 cases in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 77 cases in Fudan University Shanghai Cancer Center, 77 cases in West China Hospital, Sichuan University, 31 cases in Guangdong Provincial People′s Hospital, 24 cases in Fujian Cancer Hospital, 22 cases in Fujian Medical University Union Hospital, 25 cases in Shengjing Hospital of China Medical University, 19 cases in Xiangya Hospital, Central South University, 23 cases in Zhejiang Cancer Hospital, 17 cases in Liaoning Cancer Hospital＆Institute, 17 cases in the First Affiliated Hospital of Xiamen University, 15 cases in Sun Yat-sen University Cancer Center, 14 cases in the First Affiliated Hospital of Nanjing Medical University, 14 cases in Zhongshan Hospital Affiliated to Xiamen University and 8 cases in General Hospital of Chinese People′s Liberation Army Air Force, from January 2010 to April 2020 were collected. There were 346 males and 395 females, aged 55(range, 17?86)years. Observation indicators: (1) neoadjuvant treatment; (2) surgical and postoperative situations; (3) follow-up; (4) stratified analysis. Follow-up was conducted using outpatient examination or telephone interview. Patients were followed up once every 3?6 months during neoadjuvant therapy and once every 6?12 months after radical surgery to detect tumor recurrence and survival of patient up to April 2022. Measurement data with normal distribution were represented as Mean± SD. Measurement data with skewed distribution were represented as M(range), and comparison between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using chi-square test or Fisher exact probability. The Kaplan-Meier method was used to draw survival curves and calculate survival rates. Log-rank test was used for survival analysis. The COX regression model was used for univariate and multivariate analyses. Propensity score matching was done by the 1∶1 nearest neighbor matching method, and the matching tolerance was 0.02. Results:(1) Neoadjuvant therapy. Of the 741 patients, 34 cases received neoadjuvant therapy for 8(range, 3?44)months. Cases assessed as partial response, stable disease and progressive disease before the radical surgery of the 34 cases were 21, 9, 4, respectively. The tumor diameter of the 34 patients before the neoadjuvant therapy and before the radical surgery were 8.0(range, 3.0?26.0)cm and 5.3(range, 3.0?18.0)cm, with the regression rate as 31.9%(range, ?166.7% to 58.3%). (2) Surgical and postoperative situations. Of the 741 patients, 34 cases underwent radical surgery after receiving neoadjuvant therapy, and 707 cases underwent radical surgery directly. All the 741 patients underwent radical surgery successfully, in which 633, 102 and 6 cases received open surgery, laparoscopic surgery and endoscopic treatment, respectively. Of the 633 cases receiving open surgery and the 102 cases receiving laparoscopic surgery, cases with surgical resection range as pancreatoduodenectomy (PD) was 238, and cases with surgical resection range as duodenal limited resection, including duodenal wedge resection, distal gastrectomy, segmental duodenal resection, local resection of duodenal tumor or segmental duodenum combined with subtotal gastrectomy, was 497, 226, 55, 204, 12. Of the 741 patients, 131 cases had post-operative complications including 113 cases with grade Ⅰ?Ⅱ complications and 18 cases with ≥ grade Ⅲ complications of the Clavien-Dindo classification. The duration of postoperative hospital stay of the 741 patients was 13(range, 4?120)days. Of the 707 patients receiving direct radical surgery, 371 cases were evaluated as extremely low risk, low risk, medium risk of the modified National Institutes of Health (NIH) risk classification after surgery, and 336 cases were evaluated as high risk in which 205 cases receive postoperative adjuvant imatinib therapy with the treatment time as 24(range, 6?110)months. (3) Follow-up. All the 741 patients were followed up for 58(range, 7?150)months. During the follow-up, 110 patients had tumor recurrence and metastasis. The 1-, 3-, 5-year overall survival rates and 1-, 3-, 5-year disease-free survival rates of the 741 patients were 100.0%, 98.6%, 94.5% and 98.4%, 90.9%, 84.9%, respectively. The 1-, 3-, 5-year overall survival rates and 1-, 3-, 5-year disease-free survival rates of the 707 patients receiving direct radical surgery were 100.0%, 98.5%, 94.3% and 98.4%, 91.1%, 85.4%, respectively. (4) Stratified analysis. ① Analysis of prognostic factors in patients undergoing radical surgery directly. Results of univariate analysis showed that primary tumor location, tumor diameter, mitotic count, modified NIH risk classification and tumor gene information were related factors affecting the overall survival of 707 patients with primary duodenal GIST who underwent direct radical surgery ( hazard ratio=0.43, 0.18, 0.22, 0.06, 0.29, 95% confidence intervals as 0.20?0.93, 0.09?0.35, 0.10?0.50, 0.03?0.12, 0.09?0.95, P<0.05). The primary tumor location, tumor diameter, mitotic count, modified NIH risk classification were related factors affecting the disease-free survival of 707 patients with primary duodenal GIST who underwent direct radical surgery ( hazard ratio=0.65, 0.25, 0.25, 0.10, 95% confidence intervals as 0.41?1.03, 0.17?0.37, 0.15?0.42, 0.07?0.15, P<0.05). Results of multivariate analysis showed that primary tumor located at the horizontal segment of duodenum, mitotic count >5/50 high power field, tumor gene KIT exon 9 mutation were independent risk factors affecting the overall survival of 365 patients with primary duodenal GIST after removing 342 patients without tumor gene information who underwent direct radical surgery ( hazard ratio=2.85, 2.73, 3.13, 95% confidence intervals as 1.12?7.20, 1.07?6.94, 1.23?7.93, P<0.05). Tumor diameter >5 cm and mitotic count >5/50 high power field were independent risk factors affecting the disease-free survival of 707 patients with primary duodenal GIST who underwent direct radical surgery ( hazard ratio=3.19, 2.98, 95% confidence intervals as 2.05?4.97, 1.99?4.45, P<0.05). ② Effect of postoperative adjuvant therapy on prognosis of high-risk patients of modified NIH risk classification. Of the 336 patients evaluated as high risk of the modified NIH risk classification, the 5-year overall survival rate and 5-year disease-free survival rate were 94.6% and 77.3% in the 205 cases with postoperative adjuvant therapy, versus 83.2% and 64.4% in the 131 cases without postoperative adjuvant therapy, showing significant differences between them ( χ2=8.39, 4.44, P<0.05). Of the 205 patients evaluated as high risk of the modified NIH risk classification who received postoperative adjuvant therapy, there were 106 cases receiving postoperative adjuvant therapy <36 months, with the 5-year overall survival rate and 5-year disease-free survival rate were 87.1% and 58.7%, and there were 99 cases receiving post-operative adjuvant therapy ≥36 months, with the 5-year overall survival rate and 5-year disease-free survival rate were 100.0% and 91.5%. There were significant differences in the 5-year overall survival rate and 5-year disease-free survival rate between the 106 patients and the 99 patients ( χ2=13.92, 29.61, P<0.05). ③ Comparison of clinical efficacy of patients with different surgical methods. Before propensity score matching, cases with primary tumor located at bulb, descending, horizontal, ascending segment of duodenum, cases with tumor diameter ≤5 cm and >5 cm were 95, 307, 147, 34, 331, 252, in the 583 patients receiving open surgery with complete clinical data, versus 15, 46, 17, 5, 67, 16 in the 83 patients receiving laparoscopic surgery with complete clinical data, showing no significant difference in the primary tumor location ( χ2=0.94, P>0.05), and a significant difference in the tumor diameter ( χ2=17.33, P<0.05) between them. After propensity score matching, the above indicator were 16, 39, 20, 8, 67, 16 in the 83 patients receiving open surgery, versus 15, 46, 17, 5, 67, 16 in the 83 patients receiving laparoscopic surgery, showing no significant difference between them ( χ2=1.54, 0.00, P>0.05). Cases with postoperative complications, cases with grade Ⅰ?Ⅱ complica-tions and ≥grade Ⅲ complications of the Clavien-Dindo classification, duration of postoperative hospital stay, the 5-year overall survival rate and 5-year disease-free survival rate were 17, 12, 5, 11(range, 5?120)days, 92.0%, 100.0% in the 83 patients receiving open surgery, versus 9, 7, 2, 11(range, 5?41)days, 91.6%, 97.3% in the 83 patients receiving laparoscopic surgery, showing no signi-ficant difference in postoperative complications, duration of postoperative hospital stay, the 5-year overall survival rate and 5-year disease-free survival rate ( χ2=2.91, Z=3 365.50, χ2=3.02, 1.49, P>0.05) between them. There was no significant difference in complications of the Clavien-Dindo classification between them ( P>0.05). ④ Comparison of clinical efficacy of patients with primary tumor located at the descending segment of duodenum who underwent surgery with different surgical resection scopes. Before propensity score matching, cases with tumor diameter ≤5 cm and >5 cm, cases with tumor located at opposite side of mesangium and mesangium were 71, 85, 28, 128 in the 156 patients with primary tumor located at the descending segment of duodenum who underwent PD with complete clinical data, versus 92, 41, 120, 13 in the 133 patients with primary tumor located at the descending segment of duodenum who underwent duodenal limited resection with complete clinical data, showing significant differences between them ( χ2=16.34, 150.10, P<0.05). After propensity score matching, the above indicator were 28, 13, 16, 25 in the 41 patients with primary tumor located at the descending segment of duodenum who underwent PD with complete clinical data, versus 28, 13, 16, 25 in the 41 patients with primary tumor located at the descending segment of duodenum who underwent duodenal limited resection with complete clinical data, showing no significant difference between them ( χ2=0.00, 0.00, P>0.05). Cases with postopera-tive complications, cases with grade Ⅰ?Ⅱ complications and ≥grade Ⅲ compli-cations of the Clavien-Dindo classification, duration of postoperative hospital stay, the 5-year overall survival rate and 5-year disease-free survival rate were 13, 11, 2, 15(range, 9?62)days, 94.2%, 64.3% in the 41 patients with primary tumor located at the descending segment of duodenum who underwent PD with complete clinical data, versus 9, 8, 0, 15(range, 7?40)days, 100.0%, 78.8% in the 41 patients with primary tumor located at the descending segment of duodenum who underwent duodenal limited resection with complete clinical data, showing no significant difference in post-operative complica-tions, the 5-year overall survival rate and 5-year disease-free survival rate ( χ2=0.99, 0.34, 1.86, P>0.05) between them. There was no significant difference in complications of the Clavien-Dindo classification ( P>0.05) and there was a significant difference in duration of postopera-tive hospital stay ( Z=614.50, P<0.05) between them. Conclusions:The clinical efficacy of radical surgery for duodenal GIST are ideal. Primary tumor located at the horizontal segment of duodenum, mitotic count >5/50 high power field, tumor gene KIT exon 9 mutation are independent risk factors affec-ting the overall survival of patients undergoing direct radical surgery and tumor diameter >5 cm and mitotic count >5/50 high power field are independent risk factors affecting the disease-free survival of patients. There is no significant difference in the short-term efficacy and long-term prognosis between patients undergoing open surgery and laparoscopic surgery. For patients with primary tumor located at the descending segment of duodenum, the duration of postoperative hospital stay is longer in patients undergoing PD compared with patients undergoing duodenal limited resection. For patients evaluated as high risk of the modified NIH risk classification, posto-perative adjuvant therapy and treatment time ≥36 months are conducive to improving the prognosis of patients.

Complete surgical resection, accessible therapeutic targets and effective tyrosine kinase inhibitors (TKIs) have not completely cured gastrointestinal stromal tumours (GISTs), with most patients suffering from residual tumours and recurrence. The existence of nerve infiltration in GIST provides a way for tumour cells to escape local resection and systemic targeted therapy, which may challenge the previous understanding of its behaviour patterns and inspire the development of more radical excision and more precise targeted therapy. Moreover, tumour dormancy has emerged as a major cause of drug resistance and tumour relapse. Among these pathways, the nerve-tumour regulatory axis GDNF-GFRA1 is activated in GISTs, assists tumour cells in achieving dormancy and protects them from apoptosis under environmental stress by enhancing autophagic flux. The concrete mechanism is that the GDNF-regulating interaction between GFRA1 and the lysosomal calcium channel MCOLN1 activates Ca2+-dependent TFEB signalling. Activated TFEB transcriptionally regulates intracellular lysosome levels, which could achieve feedback upregulation of cellular autophagy flux during TKI treatment. This dormancy-transition axis fills parts of the mechanistic vacancy before the onset of secondary mutations, and strategies for TKIs combined with targeting GFRA1-dependent autophagy have distinct promise as prospective clinical therapies.

目的:对1例胃肠间质瘤(gastrointestinal stromal tumor,GIST)伴肝巨大转移患者的诊疗过程进行总结和分析,探讨联合肝脏离断和门静脉结扎二步肝切除术(associating liver partition and portal vein ligation for staged hepatectomy,ALPPS)在胃肠间质瘤肝转移患者中的应用价值.方法:报道1例GIST伴肝巨大转移患者的诊治经过,并结合相关文献进行分析.结果:1例GIST伴肝巨大转移患者在接受标准一线和二线靶向治疗后出现疾病进展,经多学科团队讨论决定实施ALPPS,完整切除全部进展肿瘤,术后恢复良好.术后5个月CT复查未见肿瘤复发和转移.结论:在多学科团队协作下,采用ALPPS治疗孤立性巨大肝转移GIST是可行且安全的.

BackgroundGastric cancer occupies the fourth highest morbidity rate of cancers worldwide. A higher incidence of gastric cancer had been found in East Asia compared to the other regions. Gastrectomy with radical lymph node dissection is the cornerstone of curative treatment for Stage III gastric cancer, and postoperative systemic chemotherapy with docetaxel, S-1 improved patients’ disease-free survival rates. However, advances in immunotherapy bring innovations in the management of patients with gastric cancer. The objective of this study was to explore the efficacy and safety of camrelizumab in combination with docetaxel + S-1, sequenced by camrelizumab + S-1 in stage III gastric cancer patients who are EBV positive, with defective mismatch repair and CPS ≥5.Methods and analysisThis prospective, open-label, single-arm trial was performed at Renji Hospital. In this study, a total of 70 adult patients aged 18–80 years with Stage III (PD-1+/MSI-H/EBV+/dMMR) gastric cancer confirmed by post-operative pathology will be enrolled after screening. Participants will receive the specific chemotherapy regimen until 1 year after the operation or until tumor recurrence or metastasis. The primary outcome is the 3-year disease-free survival rate measured by the Clopper-Pearson method and 95% confidence intervals. The secondary outcomes include overall survival, incidence and severity of adverse effects, and laboratory abnormalities. The data will be analyzed by the Kaplan-Meier method and log-rank test. The patients will be followed up every 3 months with imaging investigation until clinical remission.Ethics and disseminationAll participants will provide informed consent. The protocol has been approved by the Shanghai Jiaotong University School of Medicine, Renji Hospital Ethics Committee (KY2019-191). The results will be disseminated through peer-reviewed manuscripts, reports and presentations.Clinical Trial RegistrationClinicalTrials.gov, identifier: ChiCTR1900027123. Registration date November 2019; first enrolment December 2019; expected end date December 2021; trial status: Ongoing.Brief AbstractA clinical trial for Stage III (PD-1+/MSI-H/EBV+/dMMR) gastric cancer patients who accepted anti-PD-1 therapy combined with docetaxel + S-1 as the first-line treatment and explored improvements in three-year disease-free survival rate.