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Advances in MET tyrosine kinase inhibitors in gastric cancer

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 Oncology Peking University Cancer Hospital & Institute State Key Laboratory of Holistic Integrative Management of gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational Research Department of Gastrointestinal Oncology Peking University Cancer Hospital & Institute

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally. Because 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 strategies. MET is a receptor tyrosine kinase mediating important physiologic processes, such as embryogenesis, tissue regeneration, and wound healing. However, 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 outcomes. As such, MET-targeting therapies are being actively developed and promising progress has been demonstrated, especially with MET tyrosine kinase inhibitors. This 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 crizotinib. Building 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 testing MET tyrosine kinase inhibitors savolitinib

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Clinical efficacy and pathological outcomes of transanal endoscopic intersphincteric resection for low rectal cancer

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World Journal of gastrointestinal oncology 2024年第3期16卷 933-944页

作者： Zhi-Wen Xu Jing-Tao Zhu Hao-Yu Bai Xue-Jun Yu Qing-Qi Hong Jun You Department of gastrointestinal oncology Surgery The First Affiliated Hospital of Xiamen UniversitySchool of MedicineXiamen UniversityXiamen 361000Fujian ProvinceChina

BACKGROUND Transanal endoscopic intersphincteric resection(ISR)surgery currently lacks sufficient clinical research and reporting.AIM To investigate the clinical effectiveness of transanal endoscopic ISR,in order to promote the clinical application and development of this technique.METHODS This study utilized a retrospective case series design.Clinical and pathological data of patients with lower rectal cancer who underwent transanal endoscopic ISR at the First Affiliated Hospital of Xiamen University between May 2018 and May 2023 were included.All patients underwent transanal endoscopic ISR as the surgical approach.We conducted this study to determine the perioperative recovery status,postoperative complications,and pathological specimen charac-teristics of this group of patients.RESULTS This study included 45 eligible patients,with no perioperative mortalities.The overall incidence of early complications was 22.22%,with a rate of 4.44%for Clavien-Dindo grade≥III events.Two patients(4.4%)developed anastomotic leakage after surgery,including one case of grade A and one case of grade B.Postoperative pathological examination confirmed negative circumferential resection margins and distal resection margins in all patients.The mean distance between the tumor lower margin and distal resection margin was found to be 2.30±0.62 cm.The transanal endoscopic ISR procedure consistently yielded high quality pathological specimens.CONCLUSION Transanal endoscopic ISR is safe,feasible,and provides a clear anatomical view.It is associated with a low incidence of postoperative complications and favorable pathological outcomes,making it worth further research and application.

关键词： Intersphincteric resection Transanal Rectal cancer Complications Endoscopic

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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 GC.Methods: 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 status.Results: CLDN18.2 was expressed in 57.6%(cut-off: 2+, 40%) and 48.9%(cut-off: 2+, 70%) of patients.Programmed 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 patients.CLDN18.2 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 group.Conclusions: 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

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Surgical treatment of inflammatory bowel disease:From the gastroenterologist’s stand-point

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World Journal of gastrointestinal Surgery 2024年第5期16卷 1235-1254页

作者： John K Triantafillidis Inflammatory Bowel Disease Unit “Metropolitan General”HospitalHolargos 15562AtticaGreece Hellenic Society of gastrointestinal oncology Haidari 12461AthensGreece

Treatment of ulcerative colitis(UC)and Crohn’s disease(CD)represents,in the majority of cases,a real challenge to the gastroenterologist’s abilities and skills as well as a clinical test concerning his/her levels of medical knowledge and experience.During the last two decades,our pharmaceutical arsenal was significantly strengthened,especially after the introduction of the so-called biological agents,drugs which to a large extent not only improved the results of conservative treatment but also changed the natural history of the disease.However,colectomy is still necessary for some patients with severe UC although smaller compared to the past,precisely because of the improvements achieved in the available conservative treatment.Nevertheless,surgeries to treat colon dysplasia and cancer are increasing to some extent.At the same time,satisfactory improvements in surgical techniques,the pre-and post-operative care of patients,as well as the selection of the appropriate time for performing the surgery have been noticed.Regarding patients with CD,the improvement of conservative treatment did not significantly change the need for surgical treatment since two-thirds of patients need to undergo surgery at some point in the course of their disease.On the other hand,the outcome of the operation has improved through good preoperative care as well as the wide application of more conservative surgical techniques aimed at keeping as much of the bowel in situ as possible.This article discusses the indications for surgical management of UC patients from the gastroenterologist’s point of view,the results of the emerging new techniques such as transanal surgery and robotics,as well as alternative operations to the classic ileo-anal-pouch anastomosis.The author also discusses the basic principles of surgical management of patients with CD based on the results of the relevant literature.The self-evident is emphasized,that is,to achieve an excellent therapeutic result in patients with severe inflammatory bowel disease in today’s era;t

关键词： Inflammatory bowel disease Ulcerative colitis Crohn’s disease Surgery Treatment Ileo-anal-pouch anastomosis Indications Techniques

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Prognostic significance of grade of malignancy based on histopathological differentiation and Ki-67 in pancreatic ductal adenocarcinoma

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Cancer Biology & Medicine 2024年第5期21卷 416-432页

作者： Yuexiang Liang Guannan Sheng Yu Guo Yiping Zou Hanhan Guo Zhifei Li Shaofei Chang Quan Man Song Gao Jihui Hao Department of Pancreatic Cancer Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and TherapyTianjin Tianjin's Clinical Research Center for Cancer Department of gastrointestinal oncology The First Affiliated Hospital of Hainan Medical University Department of gastrointestinal Pancreatic Surgery Shanxi Provincial People's Hospital

Objective: Tumor cell malignancy is indicated by histopathological differentiation and cell proliferation. Ki-67, an indicator of cellular proliferation, has been used for tumor grading and classification in breast cancer and neuroendocrine tumors. However, its prognostic significance in pancreatic ductal adenocarcinoma(PDAC) remains uncertain.Methods: Patients who underwent radical pancreatectomy for PDAC were retrospectively enrolled, and relevant prognostic factors were examined. Grade of malignancy(GOM), a novel index based on histopathological differentiation and Ki-67, is proposed, and its clinical significance was evaluated.Results: The optimal threshold for Ki-67 was determined to be 30%. Patients with a Ki-67 expression level > 30% rather than ≤ 30% had significantly shorter 5-year overall survival(OS) and recurrence-free survival(RFS). In multivariate analysis, both histopathological differentiation and Ki-67 were identified as independent prognostic factors for OS and RFS. The GOM was used to independently stratify OS and RFS into 3 tiers, regardless of TNM stage and other established prognostic factors. The tumor-nodemetastasis-GOM stage was used to stratify survival into 5 distinct tiers, and surpassed the predictive performance of TNM stage for OS and RFS.Conclusions: Ki-67 is a valuable prognostic indicator for PDAC. Inclusion of the GOM in the TNM staging system may potentially enhance prognostic accuracy for PDAC.

关键词： Ki-67 Pancreatic ductal adenocarcinoma TNM stage differentiation prognosis

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Identification of breath volatile organic compounds to distinguish pancreatic adenocarcinoma,pancreatic cystic neoplasm,and patients without pancreatic lesions

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World Journal of gastrointestinal oncology 2024年第3期16卷 894-906页

作者： Kasenee Tiankanon Nuttanit Pungpipattrakul Thanikan Sukaram Roongruedee Chaiteerakij Rungsun Rerknimitr Division of Gastroenterology Faculty of MedicineChulalongkorn UniversityBangkok 10330Thailand Center of Excellence for Innovation and Endoscopy in gastrointestinal oncology King Chulalongkorn Memorial HospitalThai Red Cross SocietyBangkok 10330Thailand

BACKGROUND Volatile organic compounds(VOCs)are a promising potential biomarker that may be able to identify the presence of cancers.AIM To identify exhaled breath VOCs that distinguish pancreatic ductal adenocar-cinoma(PDAC)from intraductal papillary mucinous neoplasm(IPMN)and healthy volunteers.METHODS We collected exhaled breath from histologically proven PDAC patients,radiological diagnosis IPMN,and healthy volunteers using the ReCIVA®device between 10/2021-11/2022.VOCs were identified by thermal desorption-gas chromatography/field-asymmetric ion mobility spectrometry and compared between groups.RESULTS A total of 156 participants(44%male,mean age 62.6±10.6)were enrolled(54 PDAC,42 IPMN,and 60 controls).Among the nine VOCs identified,two VOCs that showed differences between groups were dimethyl sulfide[0.73 vs 0.74 vs 0.94 arbitrary units(AU),respectively;P=0.008]and acetone dimers(3.95 vs 4.49 vs 5.19 AU,respectively;P<0.001).After adjusting for the imbalance parameters,PDAC showed higher dimethyl sulfide levels than the control and IPMN groups,with adjusted odds ratio(aOR)of 6.98(95%CI:1.15-42.17)and 4.56(1.03-20.20),respectively(P<0.05 both).Acetone dimer levels were also higher in PDAC compared to controls and IPMN(aOR:5.12(1.80-14.57)and aOR:3.35(1.47-7.63),respectively(P<0.05 both).Acetone dimer,but not dimethyl sulfide,performed better than CA19-9 in PDAC diagnosis(AUROC 0.910 vs 0.796).The AUROC of acetone dimer increased to 0.936 when combined with CA19-9,which was better than CA19-9 alone(P<0.05).CONCLUSION Dimethyl sulfide and acetone dimer are VOCs that potentially distinguish PDAC from IPMN and healthy participants.Additional prospective studies are required to validate these findings.

关键词： Volatile organic compound Pancreas Adenocarcinoma Pancreatic intraductal neoplasms Breathing

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Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors

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Chinese Journal of Cancer Research 2024年第3期36卷 257-276页

作者： Jian Li Ye Xu Aimin Zang Yunong Gao Quanli Gao Yanqiao Zhang Dong Wang Jianming Xu Ying Yuan Haiping Jiang Jieer Ying Chunmei Shi Yanhong Deng Jing Wang Tianshu Liu Yi Huang Xiaoping Qian Yueyin Pan Ying Cheng Sheng Hu Jin Wang Mengyue Shi Ke Wang Han Hu Lin Shen Department of Medical oncology the First Affiliated Hospital Zhejiang University School of Medicine Department of Medical oncology Cancer Hospital of the University of Chinese Academy of Sciences Department of Medical oncology Fujian Medical University Union Hospital Department of oncology the Sixth Affiliated Hospital Sun Yat-sen University Department of Medical oncology Hunan Cancer Hospital Department of Medical oncology Zhongshan HospitalFudan University Department of Immunotherapy Hubei Cancer Hospital Department of Medical oncology the Affiliated Hospital of Nanjing University Medical School Department of Medical oncology Anhui Provincial Hospital Department of Medical oncology Jilin Cancer Hospital State Key Laboratory of Holistic Integrative Management of gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational Research Department of Gastrointestinal Oncology Peking University Cancer Hospital&Institute Department of Medical oncology Hubei Cancer Hospital Clinical Development BeiGene(Shanghai)Co. Ltd. Biostatistics BeiGene(Beijing)Co. Ltd. Department of oncology Fudan University Shanghai Cancer Center Department of Medical oncology Affiliated Hospital of Hebei University Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Department of Gynecology Peking University Cancer Hospital&Institute Department of Immunotherapy Henan Cancer Hospital Department of gastrointestinal oncology Affiliated Cancer Hospital of Harbin Medical University Department of gastrointestinal oncology Chongqing University Cancer Hospital Department of gastrointestinal oncology the Fifth Medical Center Chinese PLA General Hospital Department of Medical oncology the Second Affiliated Hospital Zhejiang University School of Medicine

Objective: The open-label, phase Ⅱ RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody) as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-deficient(dMMR) tumors.Methods: Adults with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled. Patients received tislelizumab 200 mg intravenously every 3 weeks. Objective response rate(ORR; primary endpoint), duration of response(DoR), and progression-free survival(PFS) were assessed by independent review committee(Response Evaluation Criteria in Solid Tumors v1.1).Results: Eighty patients were enrolled and treated; 75(93.8%) patients had measurable disease at baseline. Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease(n=79; 98.8%). At primary analysis(data cutoff July 8, 2021; median follow-up 15.2 months), overall ORR [46.7%; 95% confidence interval(95% CI), 35.1-58.6; one-sided P<0.0001] and ORR across tumor-specific subgroups [colorectal(n=46):39.1%(95% CI, 25.1–54.6); gastric/gastroesophageal junction(n=9): 55.6%(95% CI, 21.2-86.3); others(n=20):60.0%(95% CI, 36.1-80.9)] were significantly greater with tislelizumab vs. a prespecified historical control ORR of 10%; five(6.7%) patients had complete responses. Median DoR, PFS, and overall survival were not reached with long-term follow-up(data cutoff December 5, 2022; median follow-up 28.9 months). Tislelizumab was well tolerated with no unexpected safety signals. Treatment-related adverse events(TRAEs) of grade ≥3 occurred in 53.8% of patients; 7.5% of patients discontinued treatment due to TRAEs.Conclusions: Tislelizumab demonstrated a significant ORR improvement in patients with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

关键词： Biomarkers DNA mismatch repair immune checkpoint inhibitors microsatellite instability phase II clinical trials programmed cell death 1 receptor

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Lymphatic vessel:origin,heterogeneity,biological functions,and therapeutic targets

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Signal Transduction and Targeted Therapy 2024年第2期9卷 442-478页

作者： Zhaoliang Hu Xushi Zhao Zhonghua Wu Bicheng Qu Minxian Yuan Yanan Xing Yongxi Song Zhenning Wang Department of Surgical oncology and General Surgery The First Hospital of China Medical UniversityKey Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors(China Medical University)Ministry of Education155 North Nanjing StreetHeping DistrictShenyang 110001China

Lymphatic vessels,comprising the secondary circulatory system in human body,play a multifaceted role in maintaining homeostasis among various tissues and organs.They are tasked with a serious of responsibilities,including the regulation of lymph absorption and transport,the orchestration of immune surveillance and responses.Lymphatic vessel development undergoes a series of sophisticated regulatory signaling pathways governing heterogeneous-origin cell populations stepwise to assemble into the highly specialized lymphatic vessel networks.Lymphangiogenesis,as defined by new lymphatic vessels sprouting from preexisting lymphatic vessels/embryonic veins,is the main developmental mechanism underlying the formation and expansion of lymphatic vessel networks in an embryo.However,abnormal lymphangiogenesis could be observed in many pathological conditions and has a close relationship with the development and progression of various diseases.Mechanistic studies have revealed a set of lymphangiogenic factors and cascades that may serve as the potential targets for regulating abnormal lymphangiogenesis,to further modulate the progression of diseases.Actually,an increasing number of clinical trials have demonstrated the promising interventions and showed the feasibility of currently available treatments for future clinical translation.Targeting lymphangiogenic promoters or inhibitors not only directly regulates abnormal lymphangiogenesis,but improves the efficacy of diverse treatments.In conclusion,we present a comprehensive overview of lymphatic vessel development and physiological functions,and describe the critical involvement of abnormal lymphangiogenesis in multiple diseases.Moreover,we summarize the targeting therapeutic values of abnormal lymphangiogenesis,providing novel perspectives for treatment strategy of multiple human diseases.

关键词： therapeutic origin specialized

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Improving the value of molecular testing:current status and opportunities in colorectal cancer precision medicine

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Cancer Biology & Medicine 2024年第1期21卷 21-28页

作者： Haiyun Li Linwei Guo Chenchen Wang Xin Hu Ye Xu Department of Colorectal Surgery Fudan University Shanghai Cancer CenterShanghai 200032China Department of oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China Department of gastrointestinal Medical oncology Fudan University Shanghai Cancer CenterShanghai 200032China Precision Cancer Medical Center Affiliated with Fudan University Shanghai Cancer Center Shanghai 201315China

Colorectal cancer(CRC)is the second leading cause of cancer-related deaths worldwide1.Surgical radical resection with adjuvant chemotherapy remains the primary treatment choice for CRC,but the 5-year postoperative survival rate is only approximately 60%,and approximately one-third of patients with CRC experience recurrence within 2 years of surgery2.Fortunately,the transformation of high-throughput sequencing has accelerated the development of precision medicine.For example,KRAS mutations indicate resistance to anti-epidermal growth factor receptor(EGFR)-targeted therapies in CRC3.Furthermore,molecular-guided individualized therapy has brought new promise in major clinical areas and challenges,such as novel biomarkers predicting sensitivity and resistance to immunotherapy for microsatellite stable(MSS)CRC.

关键词： cancer chemotherapy colorectal

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Prioritization of risk genes in colorectal cancer by integrative analysis of multi-omics data and gene networks

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Science China(Life Sciences) 2024年第1期67卷 132-148页

作者： Ming Zhang Xiaoyang Wang Nan Yang Xu Zhu Zequn Lu Yimin Cai Bin Li Ying Zhu Xiangpan Li Yongchang Wei Shaokai Zhang Jianbo Tian Xiaoping Miao Department of Epidemiology and Biostatistics School of Public HealthDepartment of Gastrointestinal OncologyZhongnan Hospital of Wuhan UniversityDepartment of Radiation OncologyRenmin Hospital of Wuhan UniversityTaiKang Center for Life and Medical SciencesWuhan UniversityWuhan 430071China Research Center of Public Health Renmin hospital of Wuhan UniversityWuhan UniversityWuhan 430060China Department of Cancer Epidemiology The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer HospitalHenan Engineering Research Center of Cancer Prevention and ControlHenan International Joint Laboratory of Cancer PreventionZhengzhou 450008China Department of gastrointestinal Surgery Renmin Hospital of Wuhan UniversityWuhan 430060China Department of Radiation oncology Renmin Hospital of Wuhan UniversityWuhan 430060China Department of gastrointestinal oncology Hubei Cancer Clinical Study CenterZhongnan Hospital of Wuhan UniversityWuhan 430062China Department of Epidemiology and Biostatistics School of Public HealthTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430073China Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Medical UniversityNanjing 211166China

Genome-wide association studies(GWASs)have identified over 140 colorectal cancer(CRC)-associated loci;however,target genes at the majority of loci and underlying molecular mechanisms are poorly understood.Here,we utilized a Bayesian approach,integrative risk gene selector(iRIGS),to prioritize risk genes at CRC GWAS loci by integrating multi-omics data.As a result,a total of 105 high-confidence risk genes(HRGs)were identified,which exhibited strong gene dependencies for CRC and enrichment in the biological processes implicated in CRC.Among the 105 HRGs,CEBPB,located at the 20q13.13 locus,acted as a transcription factor playing critical roles in cancer.Our subsequent assays indicated the tumor promoter function of CEBPB that facilitated CRC cell proliferation by regulating multiple oncogenic pathways such as MAPK,PI3K-Akt,and Ras signaling.Next,by integrating a fine-mapping analysis and three independent case-control studies in Chinese populations consisting of 8,039 cases and 12,775 controls,we elucidated that rs1810503,a putative functional variant regulating CEBPB,was associated with CRC risk(OR=0.90,95%CI=0.86–0.93,P=1.07×10^(−7)).The association between rs1810503 and CRC risk was further validated in three additional multi-ancestry populations consisting of 24,254 cases and 58,741 controls.Mechanistically,the rs1810503 A to T allele change weakened the enhancer activity in an allele-specific manner to decrease CEBPB expression via longrange promoter-enhancer interactions,mediated by the transcription factor,REST,and thus decreased CRC risk.In summary,our study provides a genetic resource and a generalizable strategy for CRC etiology investigation,and highlights the biological implications of CEBPB in CRC tumorigenesis,shedding new light on the etiology of CRC.

关键词： susceptibility genes gene screening models multi-omics GWAS CEBPB long-range promoter-enhancer interactions

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