Gastric Cancer最新文献

{"title":"Clinical impact of gastrectomy in surgically proven stage IV gastric cancers: retrospective analysis from Korean multicenter dataset (PASS-META).","authors":"Ho-Jung Shin, Jeong Ho Song, Sung Eun Kim, In-Seob Lee, Hyoung-Il Kim, Han Hong Lee, Oh Jeong, Mi Ran Jung, Hoon Hur","doi":"10.1007/s10120-025-01676-w","DOIUrl":"https://doi.org/10.1007/s10120-025-01676-w","url":null,"abstract":"<p><strong>Background: </strong>Palliative resection for metastatic gastric cancer is not recommended in current practice guidelines; however, it is frequently performed based on clinical considerations. Prospective trials face challenges, necessitating large-scale retrospective analyses to provide clinical evidence.</p><p><strong>Methods: </strong>The PASS-META study group established a cohort of 983 patients with gastric cancer with surgically confirmed metastatic lesions treated at five major Korean institutions from 2014 to 2021, collecting 126 variables from preoperative, operative, and postoperative data through hospital records. The correlation between gastrectomy and survival outcomes was investigated using inverse probability of treatment weighting (IPTW) and standardization to estimate counterfactual outcomes.</p><p><strong>Results: </strong>Machine learning-based imputation and statistical causal survival analysis revealed that gastrectomy was found to significantly improve survival in patients with limited peritoneal metastasis (P1 or P2; RR: 0.90, 95% CI 0.85-0.94), as well as in those with distant lymph node metastasis (dLN1; RR: 0.92, 95% CI 0.91-0.94) and hepatic metastasis (H1; RR: 0.92, 95% CI 0.82-1.00), suggesting a potential survival advantage across these subgroups. No survival benefit was observed in patients with severe peritoneal metastasis (P3). Among patients with P1-P2 metastasis, extensive lymph node dissection improved the 5-year survival rates compared with limited dissection, whereas minimally invasive surgery did not affect the survival outcome. Although gastrectomy increased the postoperative hospital stay and delayed the initiation of the first postoperative chemotherapy compared to patients without gastrectomy, it did not affect the total number of chemotherapy cycles.</p><p><strong>Conclusion: </strong>This study suggests that gastrectomy offers a significant survival benefit to patients with surgically proven stage IV gastric cancer and limited peritoneal metastasis (P1/P2), distant lymph node (dLN1), or hepatic metastases (H1). Furthermore, specific surgical procedures such as extended lymph node dissection or minimally invasive surgery may be considered for patients undergoing gastrectomy.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinicopathological and genomic features of extrachromosomal DNA in gastric cancer.","authors":"Yukio Hokazono, Mihoko Saito-Adachi, Natsuko Hama, Yasushi Totoki, Hiromi Nakamura, Yasuhito Arai, Shinichi Yachida, Akihiko Fukagawa, Hirofumi Rokutan, Tetsuo Ushiku, Tatsuhiro Shibata","doi":"10.1007/s10120-025-01666-y","DOIUrl":"https://doi.org/10.1007/s10120-025-01666-y","url":null,"abstract":"<p><strong>Background: </strong>Extrachromosomal DNA (ecDNA), a form of circular DNA located outside chromosomes, is a common driver of oncogene amplification. Recent pan-cancer studies have associated ecDNA with cancer progression and poor prognosis. Moreover, its relationship with specific genomic features is becoming increasingly evident. However, the clinicopathological characteristics and underlying genomic mechanisms of ecDNA in gastric cancer remain poorly understood.</p><p><strong>Methods: </strong>We analyzed whole-genome sequencing data from 81 Japanese gastric cancer samples to identify ecDNA using AmpliconArchitect and AmpliconClassifier. Gene expression profiles were obtained through whole-transcriptome RNA sequencing (RNA-seq).</p><p><strong>Results: </strong>We found that the frequency of ecDNA occurrence was comparable across cancer stages and had a modest impact on prognosis, suggesting that ecDNA is present in early-stage disease and has a limited role in gastric cancer progression. Several immunomodulatory genes were amplified on ecDNA, and the presence of ecDNA harboring these genes was associated with the suppression of cytotoxic T cell responses, indicating a functional link between ecDNA and immune evasion. ecDNA-positive cases more frequently harbored TP53 mutations and were microsatellite stable compared to ecDNA-negative cases. Finally, ecDNA-positive tumors exhibited a high prevalence of single-base substitution signature 17, implicating that oxidative stress, potentially induced by gastric acid, plays a role in the generation of ecDNA in gastric cancer.</p><p><strong>Conclusions: </strong>These findings provide insights into the clinicogenomic features of ecDNA in gastric cancer and highlight its potential impact on disease progression and immune modulation.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Helicobacter pylori-naïve status is associated with poor prognosis and aggressive pathological features in undifferentiated-type gastric cancer: a multi-center retrospective cohort study.","authors":"Yuxuan Ren, Kefang Sun, Hanjin Yang, Lei Xu, Channi Wu, Yide Zhou, Ye Chen, Chaohui Yu, Lan Li","doi":"10.1007/s10120-025-01678-8","DOIUrl":"https://doi.org/10.1007/s10120-025-01678-8","url":null,"abstract":"<p><strong>Background: </strong>Undifferentiated-type gastric cancer (UGC) is more pathologically aggressive and progresses faster than differentiated-type gastric cancer (DGC). However, the impact of Helicobacter pylori (Hp) status on survival outcomes and clinicopathological features of UGC remains unclear.</p><p><strong>Methods: </strong>This multi-center retrospective study analyzed 571 patients pathologically confirmed UGC from January 2011 to December 2021. Clinical and histopathological features and survival outcomes were compared between Hp-naïve undifferentiated-type gastric cancer (HpNUGC) and Hp-infected undifferentiated-type gastric cancer (HpIUGC).</p><p><strong>Results: </strong>571 patients including 283 HpNUGC (49.6%) and 288 HpIUGC (50.4%) were enrolled in survival analysis. The 5-year event-free survival (EFS) and 5-year overall survival (OS) rates were significantly lower in the HpNUGC group compared to the HpIUGC group (EFS: 46.3% vs. 64.3%, P < 0.001; OS: 54.3% vs. 67.7%, P < 0.001). Hp-naïve status was associated with a 57% higher risk of disease progression, recurrence, or death, collectively termed \"events\" in this study (HR 1.57; 95% CI 1.20-2.04), and a 50% higher risk of all-cause mortality (HR 1.50, 95% CI 1.12-2.00). The HpNUGC lesions demonstrated larger tumor diameters (P < 0.001), deeper invasion depths (P < 0.001), more frequent lymphatic metastasis (P = 0.003), more advanced disease stages (P = 0.002), and higher rates of positive incision margins (P = 0.049).</p><p><strong>Conclusion: </strong>HpNUGC is associated with worse survival outcomes and exhibits more malignant pathological features compared to HpIUGC. Future prospective studies are needed to clarify the relationship between Hp status and the development and progression of UGC.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical utility impact of DNA-based cytology using droplet digital methylation-specific PCR in gastric cancer.","authors":"Hiroki Harada, Takafumi Soeno, Akira Ooki, Kanako Naito, Hiroyuki Minoura, Kota Okuno, Shohei Fujita, Mikiko Sakuraya, Tadashi Higuchi, Koshi Kumagai, Takeshi Naitoh, Yusuke Kumamoto, Naoki Hiki, Keishi Yamashita","doi":"10.1007/s10120-025-01674-y","DOIUrl":"https://doi.org/10.1007/s10120-025-01674-y","url":null,"abstract":"<p><strong>Background: </strong>Peritoneal dissemination is a major cause of poor prognosis in gastric cancer (GC). Although conventional peritoneal lavage cytology (CY) is used to detect micrometastatic peritoneal spread, its sensitivity is limited. This study aimed to evaluate the clinical utility of droplet digital methylation-specific PCR (ddMSP) targeting cancer-specific methylation for DNA-based detection of peritoneal dissemination.</p><p><strong>Methods: </strong>Peritoneal lavage fluid was prospectively collected from 400 samples in 357 GC patients, including 360 samples from 339 patients with chemotherapy-naïve tumors. DNA was extracted, bisulfite-converted, and analyzed by ddMSP targeting CDO1 and HOPX methylation. Diagnostic performance was assessed by ROC analysis, and associations with clinicopathological features and prognosis were evaluated using logistic and Cox regression models.</p><p><strong>Results: </strong>CDO1 and HOPX methylation levels were significantly elevated in CY1 cases compared with CY0 (p < 0.0001). CDO1 methylation demonstrated excellent diagnostic accuracy for CY1 (AUC: 0.93; sensitivity: 83.9%; specificity: 90.9%), while HOPX methylation showed slightly lower performance (AUC: 0.86). Multivariate analysis revealed that ddMSP CDO1-hi was independently associated with serosal invasion (pT4), and HOPX-hi with both pT4 and nodal metastasis. Furthermore, CDO1-hi status was an independent adverse prognostic factor for peritoneal dissemination-free survival (HR: 2.73, p = 0.018).</p><p><strong>Conclusions: </strong>ddMSP-based detection of CDO1 methylation provides a sensitive and specific method for identifying micrometastatic peritoneal spread in GC. This DNA-based approach may serve as a valuable prognostic biomarker and contribute to improved perioperative management in gastric cancer.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A gene-expression signature defines a subtype of Stomach Adenocarcinomas with low levels of Claudins and a high ratio of NF-YA long/NF-YA short splicing variants.","authors":"Alberto Gallo, Mirko Ronzio, Maria Barbara Campbell, Sofia Polettini, Enrico Garattini, Roberto Mantovani, Diletta Dolfini","doi":"10.1007/s10120-025-01671-1","DOIUrl":"https://doi.org/10.1007/s10120-025-01671-1","url":null,"abstract":"<p><strong>Background: </strong>Claudin-3, Claudin-4, and Claudin-7 are expressed on the surface of epithelial cells. Their absence in neoplastic cells of epithelial origin is an aggressiveness marker in different cancers. The NF-YA gene codes for the Nuclear-Transcription-Factor-Y-Subunit-A, which is overexpressed in various tumors. In tumors, the relative ratio of the two major NF-YA alternative splicing isoforms, NF-YA long and NF-YA short, is associated with a mesenchymal phenotype and a poor prognosis. Based on a high NF-YA long/NF-YA short ratio, we generated a 158-gene signature that is common to Claudin^low Breast Carcinomas (BRCA) and Stomach Adenocarcinomas (STAD).</p><p><strong>Methods: </strong>To better classify STAD Claudin^low tumors, we employed a hierarchical clustering approach based on our 158-gene signature to classify STAD into a Claudin^low subgroup. We tested the classification potential of our signature in TCGA as well as in two additional datasets of tumors. We used the deep-learning DeepCC tool and the 158-gene signature to classify the STAD cell lines available in the CCLE platform. Obtained data were validated with qRT-PCR and Western blots.</p><p><strong>Results: </strong>The 158-gene signature resulted in the selection of a STAD subgroup with effective Claudin^low expression and with a high NF-YA long/NF-YA short ratio. This Claudin^low subgroup was separated from the EMT subgroup of STAD and it is characterized by poor clinical outcome. We identified nine Claudin^low STAD cell lines with a high NF-YA long/NF-Y short ratio and validated the expression of selected markers.</p><p><strong>Conclusions: </strong>Our work supports the notion that three overlapping features-low expression of Claudin-3/4/7, high NF-YA long/NF-YA short ratio and a 158-gene signature-mark a specific subset of STAD characterized by mesenchymal features and poor prognosis.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Health-related quality-of-life outcomes with regorafenib in advanced gastric and esophagogastric junction cancer: results from the INTEGRATE trials.","authors":"Andrew J Martin, Yu Yang Soon, Katrin Marie Sjoquist, Nick Pavlakis, David Goldstein, Kohei Shitara, John R Simes","doi":"10.1007/s10120-025-01670-2","DOIUrl":"https://doi.org/10.1007/s10120-025-01670-2","url":null,"abstract":"<p><strong>Background: </strong>The INTEGRATE trials evaluated regorafenib in advanced gastric and esophagogastric junction cancer (AGOC), a poor prognosis population. In INTEGRATE 1 (I1, phase 2), regorafenib improved progression-free survival (PFS) without a clear excess decline in health-related quality of life (HRQoL). INTEGRATE 2a (I2a, phase 3) demonstrated an overall survival (OS) benefit, alone and in a pre-specified pooled analysis with I1.</p><p><strong>Aim: </strong>To evaluate HRQoL outcomes from I2a and the pooled analysis with I1.</p><p><strong>Methods: </strong>HRQoL was assessed at baseline, day 1 of each cycle, and every 8 weeks until progression, using EORTC QLQ-C30, EORTC STO22, and the participant Disease and Treatment Assessment (PtDATA). The primary endpoint was deterioration-free survival (DetFS), defined as time to a ≥ 10-point decline in QLQ-C30 physical function (DetFSPF) or global health status (DetFSGHS), progression, or death. Secondary analyses used linear mixed models (LMM). Tertiary analyses used logistic regression to evaluate symptom and side-effect prevalence (PtDATA). Pooled analyses adjusted for trial effects.</p><p><strong>Results: </strong>Of 251 I2a participants, 240 contributed HRQoL data. Regorafenib was superior on DetFSPF (HR = 0.75, 95% CI 0.58-0.99, p = 0.03) and DetFSGHS (HR = 0.68, 95% CI 0.52-0.89, p = 0.004). LMM showed no appreciable differences in HRQoL trajectories. Rash, hand-foot syndrome, numbness, and coping difficulties were more frequent with regorafenib. Pooled analyses confirmed these findings.</p><p><strong>Conclusion: </strong>Regorafenib modestly prolonged survival in AGOC without clear HRQoL deterioration. Despite more frequent toxicities, overall HRQoL was preserved. Regorafenib may offer a net clinical benefit when survival and HRQoL preferences are considered.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative efficacy and safety of tislelizumab and other programmed cell death protein 1 inhibitors in first-line treatment of advanced gastroesophageal cancers: a systematic review and network meta-analysis.","authors":"Jaffer A Ajani, Maria Alsina, Markus Moehler, Keun-Wook Lee, Wenxi Tang, Jason Steenkamp, Emily Prentiss, Kaijun Wang, Becky Hooper, Lin Zhan","doi":"10.1007/s10120-025-01660-4","DOIUrl":"https://doi.org/10.1007/s10120-025-01660-4","url":null,"abstract":"<p><strong>Background: </strong>Several programmed cell death protein-1 inhibitors are approved for the first-line treatment of advanced gastric/gastroesophageal junction cancer, including pembrolizumab, nivolumab and, more recently, tislelizumab. Since direct comparisons between these agents are lacking, advanced statistical modeling can be utilized to evaluate the relative efficacy and safety of tislelizumab compared with other first-line immunotherapy regimens in this indication.</p><p><strong>Methods: </strong>A systematic literature review was performed to identify and summarize published randomized controlled trials investigating first-line treatments in adult patients with unresectable, locally advanced, or metastatic human epidermal growth factor receptor 2-negative gastric/gastroesophageal junction cancer. Relevant trials were synthesized using a Bayesian network meta-analysis; fixed-effect models were conducted for all analyses. The network meta-analysis base case used the intent-to-treat populations for tislelizumab + chemotherapy and placebo + chemotherapy from RATIONALE-305.</p><p><strong>Results: </strong>Key comparators included nivolumab + chemotherapy (ATTRACTION-4, CheckMate 649), and pembrolizumab + chemotherapy (KEYNOTE-062, KEYNOTE-859). Tislelizumab + chemotherapy demonstrated similar efficacy compared with nivolumab + chemotherapy and pembrolizumab + chemotherapy for both overall survival and progression-free survival. Tislelizumab + chemotherapy was associated with significantly lower odds of grade ≥ 3 treatment-related adverse events compared with nivolumab + chemotherapy, and there were no statistically significant differences between tislelizumab + chemotherapy compared with pembrolizumab + chemotherapy.</p><p><strong>Conclusion: </strong>Overall, these analyses suggest that tislelizumab + chemotherapy is similarly efficacious to pembrolizumab + chemotherapy and nivolumab + chemotherapy, and is associated with a similar or lower incidence of grade ≥ 3 treatment-related adverse events in the first-line treatment of gastric/gastroesophageal junction cancer.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic postoperative prognosis and follow-up optimization for gastric cancer patients after neoadjuvant therapy: a multicenter retrospective study.","authors":"Qing Zhong, Zhi-Quan Zhang, Kai-Ning Ye, Min-Xian Zhuang, Yu-Qin Sun, Zhi-Xin Shang-Guan, Dong Wu, Cai-Ming Weng, Meng-Qi Xue, Tao-Yuan Qiu, Yi Li, Yu-Bin Ma, Fang-Hui Ding, Yong-Hong Wang, Shi-Chao Wu, Bao-Long Li, Wei Zhao, Ji-Yun Zhu, Jun-Hua Yu, Ju Wu, Wen Ye, Chao-Hui Zheng, Ping Li, Qi-Yue Chen, Li-Sheng Cai, Chang-Ming Huang, Jian-Wei Xie","doi":"10.1007/s10120-025-01672-0","DOIUrl":"https://doi.org/10.1007/s10120-025-01672-0","url":null,"abstract":"<p><strong>Background: </strong>Conditional survival (CS) estimates the probability of future survival based on time already survived. However, evidence regarding postoperative dynamic follow-up in gastric cancer patients after neoadjuvant therapy (NAT) remains limited. This study aimed to evaluate dynamic prognosis and optimize follow-up for locally advanced gastric cancer (LAGC) patients after NAT.</p><p><strong>Methods: </strong>We retrospectively analyzed 997 LAGC patients who underwent NAT followed by radical gastrectomy across multiple Chinese centers. CS was used to evaluate the probability of surviving for Y years on top of having survived for X years. Prognostic factors for overall survival (OS) and recurrence-free survival (RFS) were identified by Cox regression and incorporated into a model predicting conditional probabilities at 1, 3, and 5 years after surgery. Patients were stratified into high- and low-risk groups using an optimal cut-off of 160 points derived from the RFS nomogram.</p><p><strong>Results: </strong>The 3-year OS rate was 61.3%. CS increased with longer postoperative survival, with 3-year conditional overall survival (cOS3) rising from 62.2% at 1 year to 89.3% at 5 years. A similar trend was observed for 3-year conditional recurrence-free survival (cRFS3). Independent prognostic factors included preoperative CA19-9 level, tumor size, ypT stage, ypN stage, and perineural invasion (all P < 0.05). Recurrence analysis showed that 68.7% of high-risk patients experienced recurrence, with 91.9% of events occurring within 2 years.</p><p><strong>Conclusions: </strong>CS enables dynamic assessment of postoperative prognosis in patients with LAGC after NAT, underscoring the importance of intensified early follow-up to facilitate timely detection and intervention for recurrence.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"COPS5 inhibition synergizes with the antitumor effect of trastuzumab by PTEN upregulation in HER2-amplified gastric cancer.","authors":"Sung-Hyun Hwang, Ji-Won Kim, Haeseong Park, Andrew J Aguirre, Kui-Jin Kim, Songji Choi, Woochan Park, Jeongmin Seo, Heejung Chae, Minsu Kang, Eun Hee Jung, Koung Jin Suh, Se Hyun Kim, Jin Won Kim, Yu Jung Kim, Jee Hyun Kim, Keun-Wook Lee","doi":"10.1007/s10120-025-01669-9","DOIUrl":"https://doi.org/10.1007/s10120-025-01669-9","url":null,"abstract":"<p><strong>Background: </strong>COP9 Signalosome Subunit 5 (COPS5) is a deubiquitinating enzyme that induces chemotherapy resistance. The role of COPS5 amplification in patients with gastric cancer (GC) and its therapeutic potential in HER2-amplified GC models have not been explored.</p><p><strong>Methods: </strong>The Cancer Genome Atlas (TCGA) data were analyzed to assess the clinical relevance of COPS5 amplification in patients with GC. Functional studies using HER2-amplified GC cell lines and xenograft models evaluated the effects of COPS5 inhibition (CSN5i-3), alone or in combination with trastuzumab.</p><p><strong>Results: </strong>In the curated stomach adenocarcinoma cohort (n = 294) from TCGA datasets, COPS5 amplification was significantly more frequent in patients with HER2 amplification (10.5% vs. 2.7%, P = 0.040) and was associated with worse disease-free survival after surgery (median 12.6 vs. 45.2 months, P = 0.012) and overall survival (median 21.4 months vs. not reached, P = 0.004). In HER2-amplified GC cell lines, CSN5i-3 treatment synergized with the antiproliferative effect of trastuzumab. Mechanistically, COPS5 knockout enhanced PTEN expression by ubiquitin-mediated SNAIL degradation, suppressing the AKT downstream pathway. The combination effect was dependent on PTEN expression. Accordingly, COPS5 knockout enhanced the efficacy of AKT inhibitors. In a xenograft model, the combination of CSN5i-3 and trastuzumab demonstrated synergistic antitumor effects compared to monotherapy.</p><p><strong>Conclusions: </strong>COPS5 amplification was significantly more prevalent in patients with HER2 amplification and was associated with poor outcomes after surgery. The synergistic antiproliferative effect of COPS5 inhibition and trastuzumab was attributed to increased PTEN expression via SNAIL ubiquitination, resulting in the inhibition of the AKT pathway, warranting further clinical studies in patients with HER2-positive GC.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type 2 diabetes in patients undergoing gastric cancer surgery: areas requiring disease-specific glycemic management.","authors":"Jimin Choi, Sungsoo Park, Yeongkeun Kwon","doi":"10.1007/s10120-025-01673-z","DOIUrl":"https://doi.org/10.1007/s10120-025-01673-z","url":null,"abstract":"<p><p>This review provides a comprehensive analysis of phase-specific management strategies for type 2 diabetes (T2D) in patients undergoing gastric cancer (GC) surgery, encompassing the preoperative, intraoperative and postoperative phases within the context of oncodiabetology. In the preoperative phase, predicting T2D remission and evaluating antidiabetic medications while considering their adverse event profiles are important. These medications include metformin and sodium-glucose cotransporter 2 inhibitors, which may help prevent both T2D progression and GC advancement. Regarding surgical approaches, Roux-en-Y reconstructions are associated with better T2D remission rates than Billroth I/II reconstructions, likely because of enhanced glucose metabolism. The considerable effects of gastrectomy and reconstruction on glucose levels have led to the development of a new surgical approach, known as oncometabolic surgery. This approach integrates oncologic treatment with metabolic benefits and has gained attention as a promising strategy for managing T2D in patients undergoing GC surgery. In the postoperative phase, glucose monitoring, individualized medication adjustments, weight management, and patient education are essential for maintaining remission and preventing relapse. A comprehensive, stage-specific approach to glycemic care is crucial for improving both metabolic and oncologic outcomes in patients with GC.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}