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Advances in MET tyrosine kinase inhibitors in gastric cancer

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Cancer Biology & Medicine 2024年第6期21卷 484-498页

作者： Yifan Zhang Lin Shen Zhi Peng Key laboratory of Carcinogenesis and Translational Research(Ministry of Education) Department of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China State Key laboratory of Holistic Integrative Management of gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchDepartment of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths *** gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics,the management of gastric cancer calls for better-defined,biomarker-guided,molecular-based treatment *** is a receptor tyrosine kinase mediating important physiologic processes,such as embryogenesis,tissue regeneration,and wound ***,mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types,including gastric cancer,and is associated with poor patient *** such,MET-targeting therapies are being actively developed and promising progress has been demonstrated,especially with MET tyrosine kinase *** review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib,tepotinib,capmatinib,and *** on current knowledge,this review further discusses existing challenges in MET alterations testing,possible resistance mechanisms to MET inhibitors,and future directions of MET-targeting therapies.

关键词： Gastric cancer MET alterations MET tyrosine kinase inhibitors savolitinib MET testing

Helicobacter pylori and immunotherapy for gastrointestinal cancer

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The Innovation 2024年第2期5卷 51-60页

作者： Keren Jia Yang Chen Yi Xie Xicheng Wang Yajie Hu Yu Sun Yanshuo Cao Liyan Zhang Yakun Wang Zhenghang Wang Zhihao Lu Jian Li Xiaotian Zhang Lin Shen Key laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Department of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China Key laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Department of PathologyPeking University Cancer Hospital&InstituteBeijing 100142China

Helicobacter pylori infection is associated with the risk of gastrointestinal(GI)cancers;however,its impact on immunotherapy for GI cancers remains *** this study,we included 10,122 patients who underwent ^(13)C-urea breath *** 636 patients with Epstein-Barr virus–negative microsatellite-stable gastric cancer(GC)who were treated with anti-PD-1/PD-L1 therapy,***–positive patients exhibited significantly longer immune-related progression-free survival(irPFS)compared with ***–negative patients(6.97 months versus 5.03 months,p<0.001,hazard ratio[HR]0.76,95%confidence interval[CI]0.62–0.95,p=0.015).Moreover,the ***–positive group demonstrated a trend of 4 months longer median immune-related overall survival(irOS)than the ***–negative ***–positive GC displayed higher densities of PD-L1+cells and nonexhausted CD8+T cells,indicative of a“hot”tumor *** analysis revealed that ***–positive GC shared molecular characteristics similar to those of immunotherapy-sensitive ***,***–positive patients with DNA mismatch repair–deficient(dMMR)/microsatellite instability–high(MSI-H)colorectal adenocarcinoma and esophageal squamous cell carcinoma(ESCC)had shorter irPFS compared with ***–negative patients(16.13 months versus not reached,p=0.042,HR 2.26,95%CI 1.13–4.50,p=0.021 and 5.57 months versus 6.97 months,p=0.029,HR 1.59,95%CI 1.14–2.23,p=0.006,respectively).The difference in irOS between ***–positive and–negative patients had the same trend as that between dMMR/MSI-H colorectal adenocarcinoma and ESCC *** also identified a trend of shorter irPFS and irOS in ***–positive liver cancer and pancreatic cancer *** summary,our findings supported that *** infection is a beneficial factor for GC immunotherapy by shaping hot tumor ***,in dMMR/MSI-H colorectal adenocarcinoma and ESCC patients,*** adversely affects the efficacy of immunothera

关键词： immunotherapy gastrointestinal pylori

Clinicopathological significance and immunotherapeutic outcome of claudin 18.2 expression in advanced gastric cancer:A retrospective study

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Chinese Journal of Cancer Research 2024年第1期36卷 78-89页

作者： Changsong Qi Xiaoyi Chong Ting Zhou Mingyang Ma Jifang Gong Miao Zhang Jian Li Jun Xiao Xiaohui Peng Zhen Liu Zonghai Li Lin Shen Xiaotian Zhang State Key laboratory of Holistic Integrative Management of gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchDepartment of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China Key laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Department of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China CARsgen Therapeutics Co. LtdShanghai 200231China CARsgen Life Sciences Co. LtdShanghai 200131China

Objective: Immunotherapeutic outcomes and clinical characteristics of claudin 18 isoform 2 positive(CLDN18.2-positive) gastric cancer(GC) vary in different clinical studies, making it difficult to optimize antiCLDN18.2 therapy. We conducted a retrospective analysis to explore the association of CLDN18.2 expression with clinicopathological characteristics and immunotherapeutic outcomes in ***: A total of 536 advanced GC patients from 2019 to 2021 in the CT041-CG4006 and CT041-ST-01clinical trials were included in the analysis. CLDN18.2 expression on ≥40% of tumor cells(2+, 40%) and CLDN18.2 expression on ≥70% of tumor cells(2+, 70%) were considered the two levels of positively expressed GC. The clinicopathological characteristics and immunotherapy outcomes of GC patients were analyzed according to CLDN18.2 expression ***: CLDN18.2 was expressed in 57.6%(cut-off: 2+, 40%) and 48.9%(cut-off: 2+, 70%) of *** death-ligand 1(PD-L1) and CLDN18.2 were co-expressed in 19.8% [combined positive score(CPS)≥1, CLDN18.2(cut-off: 2+, 40%)] and 17.2% [CPS≥5, CLDN18.2(cut-off: 2+, 70%)] of ***18.2 expression positively correlated with younger age, female sex, non-gastroesophageal junction(nonGEJ), and diffuse phenotype(P<0.001). HER2 and PD-L1 expression were significantly lower in CLDN18.2-positive GC(both P<0.05). Uterine adnexa metastasis(P<0.001) was more frequent and liver metastasis(P<0.001)was less common in CLDN18.2-positive GC. Overall survival and immunotherapy-related progression-free survival(ir PFS) were inferior in the CLDN18.2-positive ***: CLDN18.2-positive GC is associated with poor prognosis and worse immunotherapeutic outcomes. The combination of anti-CLDN18.2 therapy, anti-PD-L1/PD-1 therapy, and chemotherapy for GC requires further investigation.

关键词： Gastric cancer claudin18.2 CT041 PD-L1 immunotherapy

Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors

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World Journal of gastrointestinal Oncology 2024年第8期16卷 3585-3599页

作者： De-Gang Li Jia-Peng Jiang Fan-Ye Chen Wei Wu Jun Fu Gong-He Wang Yu-Bo Li Department of gastrointestinal and Anorectal Surgery The First Affiliated Hospital of Guangxi University of Chinese MedicineNanning 530023Guangxi Zhuang Autonomous RegionChina

BACKGROUND gastrointestinal stromal tumors(GISTs)are typical gastrointestinal tract *** is the first-line therapy for GIST *** resistance limits the long-term effectiveness of *** regulatory effect of insulin-like growth factor 2(IGF2)has been confirmed in various cancers and is related to resistance to chemotherapy and a worse *** To further investigate the mechanism of IGF2 specific to *** IGF2 was screened and analyzed using Gene Expression Omnibus(GEO:GSE225819)*** IGF2 knockdown or overexpression by transfection,the phenotypes(proliferation,migration,invasion,apoptosis)of GIST cells were characterized by cell counting kit 8,Transwell,and flow cytometry *** used western blotting to evaluate pathway-associated and epithelial-mesenchymal transition(EMT)-associated *** injected transfected cells into nude mice to establish a tumor xenograft model and observed the occurrence and metastasis of *** Data from the GEO indicated that IGF2 expression is high in GISTs,associated with liver metastasis,and closely related to drug *** cells with high expression of IGF2 had increased proliferation and migration,invasiveness and *** of IGF2 significantly inhibited those *** addition,OEIGF2 promoted GIST metastasis in vivo in nude ***2 activated IGF1R signaling in GIST cells,and IGF2/IGF1R-mediated glycolysis was required for GIST with liver *** cells with IGF2 knockdown were sensitive to imatinib treatment when IGF2 overexpression significantly raised imatinib ***,2-deoxy-D-glucose(a glycolysis inhibitor)treatment reversed IGF2 overexpressionmediated imatinib resistance in *** IGF2 targeting of IGF1R signaling inhibited metastasis and decreased imatinib resistance by driving glycolysis in GISTs.

关键词： Insulin-like growth factor 2 gastrointestinal stromal tumors IGF1R Glycolysis Imatinib resistance

Neoadjuvant chemotherapy with capecitabine combined with oxaliplatin for mid-low locally advanced rectal cancer with negative mesorectal fascia: Long-term outcomes of a prospective trial(PKUCH-R03 trial)

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Chinese Journal of Cancer Research 2024年第4期36卷 410-420页

作者： Nan Chen Minghe Zhao Yunfeng Yao Lin Wang Yifan Peng Tingting Sun Tiancheng Zhan Jun Zhao Aiwen Wu Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Gastrointestinal Cancer Center Unit III Peking University Cancer Hospital & Institute State Key laboratory of Holistic Integrative Management of gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational Research Gastrointestinal Cancer Center Unit III Peking University Cancer Hospital & Institute

Objective: To evaluate the safety and efficacy of neoadjuvant chemotherapy(NCT) in mid-low locally advanced rectal cancer with negative mesorectal fascia(MRF).Methods: This prospective, single-arm phase Ⅱ trial was designed and conducted at Peking University Cancer Hospital. The patients who provided consent received 3 months of NCT(capecitabine and oxaliplatin, CapOX)followed by total mesorectal excision(TME). The primary endpoint was the rate of pathological complete response(pCR).Results: From January 2019 through December 2021, a total of 53 patients were enrolled, 7.5% of whom experienced grade 3-4 adverse events during NCT. The pCR rate was 17.0% for the entire cohort, and the overall rate of postoperative complications was 37.7%(1.9% of grade Ⅲa patients). The 3-year disease-free survival rate was 91.4%, and 23.5%(12/51) of the patients suffered from major low anterior resection syndrome(LARS).Postoperative complications were independently associated with major ***: For patients with mid-low rectal cancer with negative MRF, 3 months of NCT were found to yield a favorable tumor response with acceptable toxicity. With fair long-term survival, the NCT regimen could be associated with low rates of perioperative complications as well as acceptable anal function.

关键词： Neoadjuvant chemotherapy anal function disease-free survival mesorectal fascia rectal cancer

Nab-paclitaxel plus capecitabine as first-line treatment for advanced biliary tract cancers:An open-label,non-randomized,phase II clinical trial

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World Journal of Gastroenterology 2024年第30期30卷 3564-3573页

作者： Ling-Xiao Xu Jia-Jia Yuan Ran Xue Jun Zhou Department of gastrointestinal Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing)Peking University Cancer Hospital and InstituteBeijing 100142China

BACKGROUND Biliary tract cancers(BTCs)are a heterogeneous group of tumors with high malignancy,poor prognosis,and limited treatment *** To explore the efficacy and safety of nab-paclitaxel plus capecitabine as first-line treatment for advanced and metastatic *** This open-label,non-randomized,double-center,phase II clinical trial recruited systemic therapy-naive patients with unresectable or metastatic BTCs between April 2019 and June 2022 at Beijing Cancer Hospital and the First Hospital of China Medical *** patients were administered nab-paclitaxel(150 mg/m^(2),day 1)and capecitabine(2000 mg/m^(2),twice daily,days 1-7)in 14-day cycles until experiencing intolerable toxicity or disease *** primary outcome was the objective response rate(ORR).The secondary outcomes included the disease control rate(DCR),overall survival(OS),progression-free survival(PFS),and *** A total of 44 patients successfully completed the trial,with a median age of 64.00 years(interquartile range,35.00-76.00),and 26(59.09%)were *** response assessment was impeded for one patient due to premature demise from tumor *** the remaining 43 patients undergoing at least one imaging assessment,the ORR was 23.26%[95%confidence interval(CI):11.80%-38.60%],and the DCR was 69.77%(95%CI:53.90%-82.80%).The median OS was 14.1 months(95%CI:8.3-19.9),and the median PFS was 4.4 months(95%CI:2.5-6.3).A total of 41 patients(93.18%)experienced at least one adverse event(AE),with 10 patients(22.73%)encountering grade≥3 AEs,and the most frequent AEs of any grade were alopecia(79.50%),leukopenia(54.55%),neutropenia(52.27%),and liver dysfunction(40.91%),and no treatment-related deaths were *** Nab-paclitaxel plus capecitabine may be an effective and safe first-line treatment strategy for patients with advanced or metastatic BTCs.

关键词： Nab-paclitaxel Capecitabine Biliary tract cancer Objective response rate Phase II clinical trial

Exploring the potential of extrachromosomal DNA as a novel oncogenic driver

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Science China Life Sciences 2024年

作者： Huanbo Zhu Longtao Huangfu Junbing Chen Jiafu Ji Xiaofang Xing Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Division of Gastrointestinal Cancer Translational Research Laboratory Peking University Cancer Hospital &Institute Department of gastrointestinal Cancer Center Peking University Cancer Hospital & Institute Department of Liver Surgery & Transplantation Liver Cancer Institute Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education State Key laboratory of Holistic Integrative Management of gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational Research Division of Gastrointestinal Cancer Translational Research Laboratory Peking University Cancer Hospital & Institute

Extrachromosomal DNA(ecDNA) is a form of circular DNA mostly found in tumor cells. Unlike the typical chromosomal DNA, ecDNA is circular, self-replicating, and carries complete or partial gene fragments. Although ecDNA occurrence remains a rare event in cancer, recent studies have shown that oncogene amplification on ecDNA is widespread throughout many types of cancer, implying that ecDNA plays a central role in accelerating tumor evolution. ecDNA has also been associated with increased tumor mutation burden, chromosomal instability, and even tumor microenvironment remodeling. ecDNA may be crucial in influencing tumor heterogeneity, drug sensitivity,oncogenic senescence, and tumor immunogenicity, leading to a worsening prognosis for tumor patients. In this way, several clinical trials have been conducted to investigate the importance of ecDNA in clinical treatment. In this review, we summarize the biogenesis, characteristics, and current research methods of ecDNA, discuss the vital role of ecDNA-caused tumor heterogeneity in cancers, and highlight the potential role of ecDNA in cancer therapy.

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Genomic characterization of peritoneal lavage cytology-positive gastric cancer

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Chinese Journal of Cancer Research 2024年第1期36卷 66-77页

作者： Zhouqiao Wu Tingfei Gu Changxian Xiong Jinyao Shi Jingpu Wang Ting Guo Xiaofang Xing Fei Pang Ning He Rulin Miao Fei Shan Yuan Zhou Ziyu Li Jiafu Ji Key laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Gastrointestinal Cancer CenterPeking University Cancer Hospital&InstituteBeijing 100142China Department of Biomedical Informatics Department of Physiology and PathophysiologyCenter for Noncoding RNA MedicineMOE Key Lab of Cardiovascular SciencesSchool of Basic Medical SciencesPeking UniversityBeijing 100191China State Key laboratory of Holistic Integrative Management of gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchGastrointestinal Cancer CenterPeking University Cancer Hospital&InstituteBeijing 100142China

Objective: Positive peritoneal lavege cytology(CY1) gastric cancer is featured by dismal prognosis, with high risks of peritoneal metastasis. However, there is a lack of evidence on pathogenic mechanism and signature of CY1and there is a continuous debate on CY1 therapy. Therefore, exploring the mechanism of CY1 is crucial for treatment strategies and targets for CY1 gastric ***: In order to figure out specific driver genes and marker genes of CY1 gastric cancer, and ultimately offer clues for potential marker and risk assessment of CY1, 17 cytology-positive gastric cancer patients and 31matched cytology-negative gastric cancer patients were enrolled in this study. The enrollment criteria were based on the results of diagnostic laparoscopy staging and cytology inspection of exfoliated cells. Whole exome sequencing was then performed on tumor samples to evaluate genomic characterization of cytology-positive gastric ***: Least absolute shrinkage and selection operator(LASSO) algorithm identified 43 cytology-positive marker genes, while Mut Sig CV identified 42 cytology-positive specific driver genes. CD3G and CDKL2 were both driver and marker genes of CY1. Regarding mutational signatures, driver gene mutation and tumor subclone architecture, no significant differences were observed between CY1 and negative peritoneal lavege cytology(CY0).Conclusions: There might not be distinct differences between CY1 and CY0, and CY1 might represent the progression of CY0 gastric cancer rather than constituting an independent subtype. This genomic analysis will thus provide key molecular insights into CY1, which may have a direct effect on treatment recommendations for CY1and CY0 patients, and provides opportunities for genome-guided clinical trials and drug development.

关键词： Cytology gastric carcinoma peritoneal metastasis whole exome sequencing

The switch triggering the invasion process:Lipid metabolism in the metastasis of hepatocellular carcinoma

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Chinese Medical Journal 2024年第11期137卷 1271-1284页

作者： Jiaqian Zhang Zhicheng Zhang Zhangfan Wu Yufei Wang Zerui Zhang Limin Xia Department of Gastroenterology Institute of Liver and Gastrointestinal DiseasesHubei Key Laboratory of Hepato-Pancreato-Biliary DiseasesTongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430030China State Key laboratory of Holistic Integrative Management of gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi’anShaanxi 710032China

In humans,the liver is a central metabolic organ with a complex and unique histological *** carcinoma(HCC),which is a highly aggressive disease with a poor prognosis,accounts for most cases of primary liver *** an emerging hallmark of cancers,metabolic reprogramming acts as a runaway mechanism that disrupts homeostasis of the affected organs,including the ***,rewiring of the liver metabolic microenvironment,including lipid metabolism,is driven by HCC cells,propelling the phenotypes of HCC cells,including dissemination,invasion,and even metastasis in *** resulting formation of this vicious loop facilitates various malignant behaviors of HCC ***,few articles have comprehensively summarized lipid reprogramming in HCC ***,we have reviewed the general situation of the liver microenvironment and the physiological lipid metabolism in the liver,and highlighted the effects of different aspects of lipid metabolism on HCC metastasis to explore the underlying *** addition,we have recapitulated promising therapeutic strategies targeting lipid metabolism and the effects of lipid metabolic reprogramming on the efficacy of HCC systematical therapy,aiming to offer new perspectives for targeted therapy.

关键词： Hepatocellular carcinoma Invasion Metastasis Lipid metabolism Tumor microenvironment