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Application of immune checkpoint inhibitors and microsatellite instability in gastric cancer
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作者 Shi-Yan Yan Jian-Gao Fan 《World Journal of Gastroenterology》 SCIE CAS 2024年第21期2734-2739,共6页
In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology.We focus specifically on the application of immune checkpoint inhibitors(ICIs)and microsatellite... In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology.We focus specifically on the application of immune checkpoint inhibitors(ICIs)and microsatellite instability(MSI)in gastric cancer(GC).The four pillars of GC management have long been considered,including surgery,chemotherapy,radiotherapy and targeted therapy.However,immunotherapy has recently emerged as a“fifth pillar”,and its use is rapidly expanding.There are four principal strategies for tumor immunotherapy:ICIs,tumor vaccines,adoptive immunotherapy and nonspecific immunomodulators.Of them,ICIs are the most advanced and widespread type of cancer immunotherapy for GC.Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy.In particular,inhibition of the PD-1/PD-L1 axis with ICIs,including nivolumab and pembrolizumab,has emerged as a novel treatment strategy for advanced GC.Unfortunately,these therapies are sometimes associated with often subtle,potentially fatal immune-related adverse events(irAEs),including dermatitis,diarrhea,colitis,endocrinopathy,hepatotoxicity,neuropathy and pneumonitis.We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges,emergency department revisits,and downstream complications.Recent studies have revealed that MSI-high or mismatch-repair-deficient tumors,regardless of their primary site,have a promising response to ICIs.So,it is important to detect MSI before applying ICIs for treatment of GC. 展开更多
关键词 Gastric cancer Immune checkpoint inhibitors microsatellite instability IMMUNOTHERAPY Immune-related adverse events
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Tislelizumab in previously treated,locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors
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作者 Jian Li Ye Xu +22 位作者 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 《Chinese Journal of Cancer Research》 SCIE CAS CSCD 2024年第3期257-269,共13页
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-de... 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. 展开更多
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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Comparative effectiveness of immunotherapy and chemotherapy in patients with metastatic colorectal cancer stratified by microsatellite instability status
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作者 Chen-Gu Niu Jing Zhang +2 位作者 Aniket-Vijay Rao Utsav Joshi Patrick Okolo 《World Journal of Clinical Oncology》 2024年第4期540-547,共8页
BACKGROUND Immunotherapy have demonstrated promising outcomes in patients with high microsatellite instability(MSI)(MSI-H)metastatic colorectal cancer.However,the comparative effectiveness of Immunotherapy and chemoth... BACKGROUND Immunotherapy have demonstrated promising outcomes in patients with high microsatellite instability(MSI)(MSI-H)metastatic colorectal cancer.However,the comparative effectiveness of Immunotherapy and chemotherapy for patients with low MSI(MSI-L),and microsatellite stable(MSS)metastatic colorectal cancer remains unclear.AIM To investigate immunotherapy vs chemotherapy for treatment of MSI-L/MSS metastatic colorectal cancer,and to evaluate the success of immunotherapy against chemotherapy in managing MSI-H metastatic colorectal cancer during a follow-up of 50 months.METHODS We conducted a retrospective cohort study using the National Cancer Database(NCDB)to evaluate the overall survival(OS)of patients with metastatic colorectal cancer treated with immunotherapy or chemotherapy.The study population was stratified by MSI status(MSI-H,MSI-L,and MSS).Multivariable Cox proportional hazard models were used to assess the association between treatment modality and OS,adjusting for potential confounders.RESULTS A total of 21951 patients with metastatic colorectal cancer were included in the analysis,of which 2358 were MSI-H,and 19593 were MSI-L/MSS.In the MSI-H cohort,immunotherapy treatment(n=142)was associated with a significantly improved median OS compared to chemotherapy(n=860).After adjusting for potential confounders,immunotherapy treatment remained significantly associated with better OS in the MSI-H cohort[adjusted hazard ratio(aHR):0.57,95%confidence interval(95%CI):0.43-0.77,P<0.001].In the MSS cohort,no significant difference in median OS was observed between immunotherapy treatment and chemotherapy(aHR:0.94,95%CI:0.69-1.29,P=0.715).CONCLUSION In this population-based study using the NCDB,immunotherapy treatment was associated with significantly improved OS compared to chemotherapy in patients with MSI-H metastatic colorectal cancer,but not in those with MSI-L/MSS metastatic colorectal cancer.Further studies are warranted to determine the optimal therapeutic approach for patients with MSI-L/MSS metastatic colorectal cancer. 展开更多
关键词 IMMUNOTHERAPY CHEMOTHERAPY Metastatic colorectal cancer microsatellite instability National cancer database
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纳武利尤单抗联合伊匹木单抗治疗MSI-H晚期结肠癌1例报道 被引量:1
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作者 聂畅波 叶颖雪 胡海 《现代肿瘤医学》 CAS 2024年第3期540-544,共5页
本文报告1例晚期结肠癌患者,既往术后标本免疫组化结果提示错配修复完整(proficient mismatch repair, pMMR),予术后化疗等全身治疗后病情进展。随后行二代测序(next-generation sequencing, NGS)提示该患者微卫星高度不稳定(microsatel... 本文报告1例晚期结肠癌患者,既往术后标本免疫组化结果提示错配修复完整(proficient mismatch repair, pMMR),予术后化疗等全身治疗后病情进展。随后行二代测序(next-generation sequencing, NGS)提示该患者微卫星高度不稳定(microsatellite instability-high, MSI-H)以及高水平的肿瘤突变负荷值(tumor mutation burden, TMB)。 展开更多
关键词 晚期结肠癌 二代测序(NGS) 微卫星高度不稳定(msi-H) 免疫治疗
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PD-1单抗治疗一例dMMR/MSI-H/TMB-H型结肠癌伴颅内转移瘤患者临床完全缓解
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作者 项涛 张航瑜 +1 位作者 方维佳 陈文斌 《浙江大学学报(医学版)》 CAS CSCD 北大核心 2024年第1期58-63,共6页
一例70岁男性患者,在接受右半肠癌根治性手术1年后出现了记忆丧失和认知功能下降的症状,头颅磁共振成像检查发现脑部肿块,手术后经病理检查确诊为结肠腺癌转移。原发灶及颅内转移瘤免疫组织化学检测均提示为错配修复缺陷。原发结肠肿瘤... 一例70岁男性患者,在接受右半肠癌根治性手术1年后出现了记忆丧失和认知功能下降的症状,头颅磁共振成像检查发现脑部肿块,手术后经病理检查确诊为结肠腺癌转移。原发灶及颅内转移瘤免疫组织化学检测均提示为错配修复缺陷。原发结肠肿瘤组织基因检测证实为微卫星高度不稳定伴有高肿瘤突变负荷,肿瘤突变负荷为77.7 muts/Mb。患者结肠癌根治术和颅内转移瘤术后均接受了辅助化疗,但在颅内转移瘤切除术和化疗结束后1个月颅内转移复发。患者接受帕博利珠单抗治疗后结果颅内转移瘤消退并达到临床完全缓解。 展开更多
关键词 肠癌 微卫星高度不稳定 高肿瘤突变负荷 脑转移 程序性死亡受体1单抗 病例报告
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IVIM全容积定量参数与直肠腺癌神经脉管侵犯、MSI状态及Ki-67指数的相关性研究
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作者 蒋雯丽 蒋伟 +4 位作者 韦鑫 陈媛媛 刘欣杰 陈金华 陈维娟 《磁共振成像》 CAS CSCD 北大核心 2024年第9期80-85,93,共7页
目的探讨体素内不相干运动(intravoxel incoherent motion,IVIM)全肿瘤容积参数与直肠腺癌患者神经侵犯(perineural invasion,PNI)、脉管侵犯(lymphovascular invasion,LVI)、微卫星不稳定性(microsatellite instability,MSI)状态及Ki-6... 目的探讨体素内不相干运动(intravoxel incoherent motion,IVIM)全肿瘤容积参数与直肠腺癌患者神经侵犯(perineural invasion,PNI)、脉管侵犯(lymphovascular invasion,LVI)、微卫星不稳定性(microsatellite instability,MSI)状态及Ki-67指数的相关性。材料与方法回顾性分析136例直肠腺癌患者的影像资料和临床资料,测量病灶IVIM全容积参数包括真实扩散系数(D)、伪扩散系数(D*)及灌注分数(f)。根据病理报告中的LVI状态、PNI状态、MSI及Ki-67指数进行分组,采用独立样本t检验或Mann-Whitney U检验分析各定量参数与肿瘤病理学特征的关系。结果直肠腺癌PNI阴性组D值[(1.174±0.164)×10^(-3) mm^(2)/s]显著低于阳性组[(1.270±0.206)×10^(-3) mm^(2)/s](t=-3.033,P=0.003),LVI阴性组f值0.172(0.158,0.193)显著低于阳性组0.188(0.168,0.237)(Z=-2.435,P=0.015),Ki-67低表达组f值(0.175±0.035)显著低于高表达组(0.188±0.038)(t=-2.097,P=0.038),MSI高组和MSI低组的D、D*、f值差异无统计学意义(P>0.05)。结论IVIM全容积定量参数能够在一定程度上反映直肠腺癌的病理学特征,可作为术前评估直肠腺癌生物学行为的重要影像学指标。 展开更多
关键词 直肠肿瘤 腺癌 磁共振成像 体素内不相干运动 神经侵犯 脉管侵犯 微卫星不稳定性状态 Ki-67
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Discrepancy among microsatellite instability detection methodologies in non-colorectal cancer:Report of 3 cases
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作者 ElifŞenocak Taşçı İbrahim Yıldız +1 位作者 Sibel Erdamar LeylaÖzer 《World Journal of Clinical Cases》 SCIE 2023年第13期3105-3113,共9页
BACKGROUND Microsatellite instability(MSI)is a predictive biomarker for cancer immunotherapy.The tumor-agnostic nature of MSI makes it a denominator for immunotherapy in several solid tumors.It can be assessed using n... BACKGROUND Microsatellite instability(MSI)is a predictive biomarker for cancer immunotherapy.The tumor-agnostic nature of MSI makes it a denominator for immunotherapy in several solid tumors.It can be assessed using next-generation sequencing(NGS),fluorescent multiplex PCR,and immunohistochemistry(IHC).CASE SUMMARY Here,we report 3 cases with discordant MSI results detected using different methods.A cholangiocellular carcinoma case revealed proficient mismatch repair(MMR)by IHC but high MSI(MSI-H)by liquid NGS.A cervical cancer case revealed deficient MMR by IHC,microsatellite stable by PCR,and MSI-H by NGS.Lastly,an endometrial cancer case revealed proficient MMR by IHC but MSI-H by NGS.CONCLUSION IHC for MMR status is the first choice due to several advantages.However,in cases of indeterminate IHC results,molecular testing by MSI-PCR is preferred.Recently,NGS-based MSI assays are being widely used to detect MSI-H tumors.All three methods have high accuracy;however,the inconsistencies between them may lead to misdiagnosis. 展开更多
关键词 DISCORDANCE IMMUNOHISTOCHEMISTRY microsatellite instability Nextgeneration sequencing Case report
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Bat 26 Microsatellite Instability in Oral Cavity Cancers in Senegal
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作者 Mame Diarra Samb Fatimata Mbaye +2 位作者 Mouhamadou Makhtar Ndiaye Silly Toure Mbacke Sembene 《Journal of Cancer Therapy》 CAS 2023年第1期25-37,共13页
Oral cavity cancers are part of head and neck cancers. They have become frequent in the world in general and Senegal in particular. This study evaluates microsatellite instability tumors in oral cavity cancers in Sene... Oral cavity cancers are part of head and neck cancers. They have become frequent in the world in general and Senegal in particular. This study evaluates microsatellite instability tumors in oral cavity cancers in Senegal. Forty cancerous tissues, 20 healthy tissues, and 12 blood tissues were included in this study. These tissues were collected from each patient during the biopsy after obtaining consent. DNA extraction, Polymerase Chain Reaction (PCR) and sequencing were carried out to obtain sequences. Mutation surveyor, Bioedit and Dnasp software were used to perform our analyses. High instability was found in 57.5% of patients with cancer. Moreover, 90% of the patients had the same motif on healthy and cancerous tissue. Furthermore, 26.12%, 20.72%, and 11.71% polymorphic sites were found in cancerous, healthy and blood tissue respectively. Thus, a similarity between cancerous and healthy tissues seems to exist. This implies that instability of the Bat 26 microsatellite could occur early in the occurrence of oral cavity cancers. 展开更多
关键词 CANCER Oral Cavity microsatellite instability Bat 26 Senegal
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能谱CT影像组学预测结直肠癌MSI状态的应用研究
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作者 张红霞 田为中 +1 位作者 夏建国 杨维柘 《泰州职业技术学院学报》 2024年第4期85-89,共5页
目的研究基于能谱CT成像静脉期单能量序列影像组学模型,用于预测结直肠癌微卫星不稳定(MSI)状态。方法回顾性收集2019年7月至2022年8月在泰州市人民医院经手术切除或穿刺活检病理确诊为结直肠癌患者97例(男性57例、女性40例)。根据免疫... 目的研究基于能谱CT成像静脉期单能量序列影像组学模型,用于预测结直肠癌微卫星不稳定(MSI)状态。方法回顾性收集2019年7月至2022年8月在泰州市人民医院经手术切除或穿刺活检病理确诊为结直肠癌患者97例(男性57例、女性40例)。根据免疫组化MSI表达结果进行分组:MSI组34例、微卫星稳定(MSS)组63例。以DICOM格式将静脉期1.25mm原始图像数据传至GEAW4.7后处理工作站,生成碘基物质分解图、70keV、100keV单能量图,导入ITK-SNAP开源软件,手动勾画感兴趣区(ROI),利用Pyradiomics工具进行影像组学特征提取,采用mRMR(最大相关和最小冗余)和LASSO(最小绝对收缩选择算子)算法对训练组的影像组学特征进行降维,获取关键的影像组学特征,建立预测肿瘤生物学行为的影像组学模型。采用受试者工作特征(ROC)曲线下面积(AUC)来评估模型的诊断效能。使用校正曲线对模型的校正性能进行评估,应用决策曲线评价模型在训练组中的临床实用性。结果静脉期单能量70keV序列、100keV序列、碘基物质分解图共三种模型各提取了1218个特征,其中70keV单能量序列特征分类性能最佳。结论基于能谱CT成像的单能量模型可以有效地区分结直肠癌MSI和MSS状态患者,可以作为术前预测结直肠癌患者MSI状态的重要影像生物标志物,为指导临床医生制定个体化治疗方案及评估患者预后提供新思路。 展开更多
关键词 能谱CT成像 影像组学 结直肠癌 微卫星不稳定性
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结直肠癌组织中MMR蛋白表达、MSI、RAS和BRAF基因突变与临床病理特征的关系
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作者 向林果 谭憬一 +2 位作者 姚远 孙雪琴 张阳丽 《检验医学与临床》 CAS 2024年第1期1-7,共7页
目的 探讨结直肠癌患者癌组织中错配修复(MMR)蛋白表达、微卫星不稳定性(MSI)、大鼠肉瘤(RAS)基因和致癌同源体B1(BRAF)基因突变与临床病理特征的关系。方法 选取该院2022年1-12月接受根治手术治疗的352例结直肠癌患者的肿瘤组织和血液... 目的 探讨结直肠癌患者癌组织中错配修复(MMR)蛋白表达、微卫星不稳定性(MSI)、大鼠肉瘤(RAS)基因和致癌同源体B1(BRAF)基因突变与临床病理特征的关系。方法 选取该院2022年1-12月接受根治手术治疗的352例结直肠癌患者的肿瘤组织和血液标本、42例非肠癌患者的实体瘤组织和血液标本,采用免疫组化法检测MMR蛋白表达,一代测序片段分析法检测MSI,实时荧光定量聚合酶链反应检测KRAS、NRAS和BRAF基因突变状态,分析MMR蛋白表达、MSI和3种基因突变状态与结直肠癌临床病理特征的关系。结果 352例CRC患者肿瘤组织中检出MMR缺陷(dMMR)29例(8.2%),高度微卫星不稳定(MSI-H)26例(7.4%),KRAS基因突变161例(45.7%),NRAS基因突变13例(3.7%),BRAF基因突变11例(3.1%)。与dMMR有关因素为低龄、黏液腺癌、原发于右半结肠癌(P<0.05);与MSI-H相关因素包括低龄、肿瘤家族史、原发于右半结肠癌(P<0.05);KRAS和NRAS基因高突变率分别与黏液腺癌和淋巴结转移有关(P<0.05);BRAF基因高突变率与低分化和原发于右半结肠癌有关(P<0.05)。BRAF基因突变与dMMR和MSI-H有关(P<0.05)。结论 MMR蛋白表达,MSI,以及KRAS、NRAS和BRAF基因突变与不同的临床病理特征有关。通过这5种分子标志物的联合检测可以对肿瘤进行分子分型,进一步为结直肠癌患者的个体化精准诊疗提供理论依据。 展开更多
关键词 结直肠癌 大鼠肉瘤基因 致癌同源体B1基因 错配修复蛋白 微卫星不稳定性 基因突变
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Study on the Correlation between the Expression of Angiogenic Factor VEGF and Microsatellite Instability in Gastric Adenocarcinoma
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作者 刘文韬 陈国玉 +1 位作者 夏建国 杨力 《Journal of Nanjing Medical University》 2004年第2期94-97,共4页
Objective: To investigate the correlation between the microsatellite instability (MSI) and the expression of vascular endothelial growth factor (VEGF) in gastric adenocarcinoma. Methods: PCR SSCP method was used to d... Objective: To investigate the correlation between the microsatellite instability (MSI) and the expression of vascular endothelial growth factor (VEGF) in gastric adenocarcinoma. Methods: PCR SSCP method was used to detect MSI of thirty cases with gastric adenocarcinoma at five loci in each patient. Expression of VEGF was examined by the method of immunohistochemistry. Results: The positive of MSI was in 13 patients out of 30 patients (43.4%) in our study. Positive VEGF Immunostaining was detected in 18 patients (60.0%). VEGF was decreased in microsatellite instability high (MSI H) gastric adenocarcinoma. Conclusion: MSI H and microsatellite stable (MSS) gastric adenocarcinoma may follow a different pathway of angiogenesis. The low frequency of VEGF expression among MSI H cancer may partially explain why these cancers are less aggressive. 展开更多
关键词 gastric adenocarcinoma microsatellite instability vascular endothelial growth factor ANGIOGENESIS
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Characterization of six tumorsuppressor genes and microsatellite instability in hepatocellular carcinomain southern African blacks 被引量:21
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作者 Martins C Kedda MA Kew MC 《World Journal of Gastroenterology》 SCIE CAS CSCD 1999年第6期470-476,共7页
AIM To analyse cumulative loss of heterozygosity (LOH) of chromosomal regions and tumor suppressor genes in hepatocellular carcinomas (HCCs) from 20 southern African blacks. METHODS p53, RB1, BRCA1, BRCA2, WT1 and E c... AIM To analyse cumulative loss of heterozygosity (LOH) of chromosomal regions and tumor suppressor genes in hepatocellular carcinomas (HCCs) from 20 southern African blacks. METHODS p53, RB1, BRCA1, BRCA2, WT1 and E cadherin genes were analysed for LOH, and p53 gene was also analysed for the codon 249 mutation, in tumor and adjacent non tumorous liver tissues using molecular techniques and 10 polymorphic microsatellite markers. RESULTS p53 codon 249 mutation was found in 25% of the subjects, as was expected, because many patients were from Mozambique, a country with high aflatoxin B 1 exposure. LOH was found at the RB1, BRCA2 and WT1 loci in 20%(4/*!20) of the HCCs, supporting a possible role of these genes in HCC. No LOH was evident in any of the remaining genes. Reports of mutations of p53 and RB1 genes in combination, described in other populations, were not confirmed in this study. Change in microsatellite repeat number was noted at 9/*!10 microsatellite loci in different HCCs, and changes at two or more loci were detected in 15%(3/*!20) of subjects. CONCLUSION We propose that microsatellite/genomic instability may play a role in the pathogenesis of a subset of HCCs in black Africans. 展开更多
关键词 carcinoma hepatocellular southern African BLACKS CUMULATIVE LOH TUMOR SUPPRESSOR genes microsatellite genomic instability liver neoplasms
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Potential roles of tumor suppressor genes and microsatellite instability in hepatocellular carcinogenesis in southern African blacks 被引量:13
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作者 Roberts LR LaRusso NF 《World Journal of Gastroenterology》 SCIE CAS CSCD 2000年第1期37-41,共5页
MAJOR POINTS OF THE COMMENTED ARTICLECumulative loss of heterozygosity(LOH)ofchromosomal regions and tumor suppressor geneshas been reported in hepatocellular carcinomas(HCCs) from China,Japan,and Korea.In thisissue o... MAJOR POINTS OF THE COMMENTED ARTICLECumulative loss of heterozygosity(LOH)ofchromosomal regions and tumor suppressor geneshas been reported in hepatocellular carcinomas(HCCs) from China,Japan,and Korea.In thisissue of the World Journal of Gastroenterology,Martins et al report an analysis of LOH andmicrosatellite instability in HCCs from a group of 展开更多
关键词 SUBJECT headings liver NEOPLASMS carcinoma HEPATOCELLULAR tumor supressor gene microsatellite instability
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Era of universal testing of microsatellite instability in colorectal cancer 被引量:18
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作者 Xuchen Zhang Jia Li 《World Journal of Gastrointestinal Oncology》 SCIE CAS 2013年第2期12-19,共8页
Colorectal cancer (CRC) incidence and mortality are constantly decreasing, but CRC still remains the third most prevalent cancer and the third most common cause of cancer death in both males and females in the United ... Colorectal cancer (CRC) incidence and mortality are constantly decreasing, but CRC still remains the third most prevalent cancer and the third most common cause of cancer death in both males and females in the United States. Recent rapid declines in CRC incidence rates have largely been attributed to increases in screening that can detect and remove precancerous polyps, and the decrease in death rates for CRC largely reflects improvements in early detection, treatment and the understanding of molecular/genetic basis of CRC. One of the important molecular/genetic findings is the presence of microsatellite instability (MSI) in CRCs. Many studies have shown the importance of MSI testing in diagnosing Lynch syndrome and predicting prognosis and response to chemotherapeutic agents in CRCs. Increased emphasis has been placed on the importance of MSI testing for all newly diagnosed individuals with CRCs. Both immunohistochemical staining (IHC) and polymerase chain reaction (PCR)-based MSI testing show high sensitivity and specificity in detecting MSI. The current clinical guidelines and histopathology features are indicative of, but not reliable in diagnosing Lynch syndrome and CRCs with MSI. Currently, there are evidences that universal testing for MSI starting with either IHC or PCR-based MSI testing is cost effective, sensitive, specific and is getting widely accepted. 展开更多
关键词 COLORECTAL cancer LYNCH syndrome UNIVERSAL TESTING DNA MISMATCH repair microsatellite instability
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Microsatellite instability,MMR gene expression and proliferation kinetics in colorectal cancer with famillial predisposition 被引量:14
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作者 Bao Ping Wu Ya Li Zhang +2 位作者 Dian Yuan Zhou Chun Fang Gao Zhuo Sheng Lai 《World Journal of Gastroenterology》 SCIE CAS CSCD 2000年第6期902-905,共4页
INTRODUCTIONGenetic instability is a conunon property of manyhuman cancers,including those of HNPCC.A novel form of genetic instability involving somaticalterations,such as deletions and insertions insimple repeated s... INTRODUCTIONGenetic instability is a conunon property of manyhuman cancers,including those of HNPCC.A novel form of genetic instability involving somaticalterations,such as deletions and insertions insimple repeated sequences,has been found.Microsatellitcs are relatively short runs of tandemlyrepeated sequences scattered throughout 展开更多
关键词 colorectal neoplasms microsatellite instability gene expression FAMILIAL PREDISPOSITION proliferation kinetics immunohistochemistry POLYMERASE chain reaction flow CYTOMETRY
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Helicobacter pylori and EBV in gastric carcinomas:Methylation status and microsatellite instability 被引量:6
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作者 Adriana Camargo Ferrasi Nídia Alice Pinheiro +7 位作者 Silvia Helena Barem Rabenhorst Otávia Luisa Caballero Maria Aparecida Marchesan Rodrigues Fabrício de Carvalho Celso Vieira de Souza Leite Marcia Valéria Pitombeira Ferreira Marcos Aurélio Pessoa Barros Maria Inês de Moura Campos Pardini 《World Journal of Gastroenterology》 SCIE CAS CSCD 2010年第3期312-319,共8页
AIM:To verify the methylation status of CDH1, DAPK, COX2, hMLH1 and CDKN2A genes and to evaluate their association with Helicobacter pylori (H. pylori)-cagA+ and Epstein Barr virus (EBV) infections in gastric adenocar... AIM:To verify the methylation status of CDH1, DAPK, COX2, hMLH1 and CDKN2A genes and to evaluate their association with Helicobacter pylori (H. pylori)-cagA+ and Epstein Barr virus (EBV) infections in gastric adenocarcinomas.METHODS: Methylation-specific PCR (MSP) assay was performed in 89 primary gastric carcinomas (intestinal and diffuse types). Microsatellite instability (MSI) analysis was performed using the BAT26 primer set and PCR products were analyzed with the ABI PRISM 3100 Genetic Analyzer using Genescan 3.7 software (Applied Biosystems). Detection of H. pylori and genotyping were performed by PCR, using specifi c primers for ureaseC and cagA genes. The presence of EBV was assessed by in situ hybridization. Statistical analyses were performed using the χ2 or Fisher's exact test.RESULTS: The most frequent hypermethylated gene was COX-2 (63.5%) followed by DAPK (55.7%), CDH1 (51%), CDKN2A (36%) and hMLH1 (30.3%). Intestinal and diffuse adenocarcinomas showed different methylation profiles and there was an association between methylation of E-CDH1 and H. pylori-cagA+ in the intestinal adenocarcinoma type. MSI was correlated with hMLH1 methylation. There was an inverse correlation between DAPK hypermethylation and MSI.CONCLUSION: We found a strong association between CDH1 methylation and H. pylori-cagA+ in intestinal-type gastric cancer, association of MSI and better prognosis and an heterogeneous COX-2 overexpression. 展开更多
关键词 Gastric cancer METHYLATION microsatellite instability Helicobacter pylori Epstein Barr virus
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Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer 被引量:16
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作者 Hiroyuki Yamamoto Yasushi Adachi +4 位作者 Hiroaki Taniguchi Hiroaki Kunimoto Katsuhiko Nosho Hiromu Suzuki Yasuhisa Shinomura 《World Journal of Gastroenterology》 SCIE CAS CSCD 2012年第22期2745-2755,共11页
There is an increasing understanding of the roles that microsatellite instability (MSI) plays in Lynch syndrome (by mutations) and sporadic (by mainly epigenetic changes) gastrointestinal (GI) and other cancer... There is an increasing understanding of the roles that microsatellite instability (MSI) plays in Lynch syndrome (by mutations) and sporadic (by mainly epigenetic changes) gastrointestinal (GI) and other cancers. Defi- cient DNA mismatch repair (MMR) results in the strong mutator phenotype known as MSI, which is the hall- mark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syn- drome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2, less frequently MSH6, and rarely PMS2. MSI is also observed in about 15% of sporadic colorectal, gastric, and en-dometrial cancers and in lower frequencies in a minor- ity of other cancers where it is often associated with the hypermethylation of the IVlLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of m/R-IEE has been shown to downregulate expression of MLH1, IVlSH2, and MSH6. Thus, a subset of MSI-positive (MSI+) cancers without known MMR defects may result from m/R-1E5 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular func- tions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epi- genetic modifier genes, such as HDAC2, but also miRNA processing machinery genes, including TARBP2 and XPO5, were found to be mutated in MSI+ GI cancers. Thus, a subset of MSI+ colorectal cancers (CRCs) has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic dif- ferences exist between MSI+ and MSI- cancers. Mo- lecular signatures of miRNA expression apparently have the potential to distinguish between MSI+ and MSI- CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets. 展开更多
关键词 microsatellite instability MICRORNA DNA mis-match repair Frameshiff mutation MicroRNA processing
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Causes and consequences of microsatellite instability in gastric carcinogenesis 被引量:15
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作者 Sérgia Velho Maria Sofia Fernandes +2 位作者 Marina Leite Ceu Figueiredo Raquel Seruca 《World Journal of Gastroenterology》 SCIE CAS 2014年第44期16433-16442,共10页
Loss of DNA mismatch repair(MMR) function, due to somatic or germline epi/genetic alterations of MMR genes leads to the accumulation of numerous mutations across the genome, creating a molecular phenotype known as mic... Loss of DNA mismatch repair(MMR) function, due to somatic or germline epi/genetic alterations of MMR genes leads to the accumulation of numerous mutations across the genome, creating a molecular phenotype known as microsatellite instability(MSI). In gastric cancer(g C), MSI occurs in about 15% to 30% of the cases. This review summarizes the current knowledge on the molecular mechanisms underlying the acquisition of MSI in g C as well as on the clinic, pathologic and molecular consequences of the MSI phenotype. Additionally, current therapeutic strategies for g C and their applicability in the MSI subset are also discussed. 展开更多
关键词 Gastric cancer microsatellite instability Mismatch repair genes ONCOGENES Helicobacter pylori
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Genetic changes of p53,K-ras,and microsatellite instability in gallbladder carcinoma in high-incidence areas of Japan and Hungary 被引量:9
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作者 Masayuki Nagahashi Yoichi Ajioka +10 位作者 Istvan Lang Zoltan Szentirmay Miklos Kasler Hiroto Nakadaira Naoyuki Yokoyama Gen Watanabe Ken Nishikura Toshifumi Wakai Yoshio Shirai Katsuyoshi Hatakeyama Masaharu Yamamoto 《World Journal of Gastroenterology》 SCIE CAS CSCD 2008年第1期70-75,共6页
AIM: To disclose geographic differences in genetic changes involved in gallbladder carcinogenesis between two distinct high-incidence areas of Japan and Hungary. METHODS: We examined 42 cases of gallbladder carcinom... AIM: To disclose geographic differences in genetic changes involved in gallbladder carcinogenesis between two distinct high-incidence areas of Japan and Hungary. METHODS: We examined 42 cases of gallbladder carcinoma: 22 Japanese and 20 Hungarian cases, p53 mutations at exons 5 to 8 and K-ras mutations at codon 12 were tested by direct sequencing. Microsatellite instability was determined from fluorescent dye-labeled PCR amplifications of flve-microsatellite markers (BAT-25, BAT-26, D2S123, DSS346, and D17S250). RESULTS: Mutations of p53 were detected in 11 of 22 Japanese cases and 6 of 18 Hungarian cases (11/22 vs 6/18, P = 0.348). Transition at CpG sites was found in none of 11 Japanese cases and 2 of 6 Hungarian cases; the difference was marginally significant (0/11 vs 2/6,P = 0.110). K-ras mutations were detected in only one of the Hungarian cases. Eight of 19 (42.1%) ]apanese cases were MSI-high (presence of novel peaks in more than one of the five loci analyzed), whereas only 1 of 15 (6.7%) Hungarian cases was MSI-high (P = 0.047). CONCLUSION: It appears that the p53 mutations and MSI differ in patients with gallbladder carcinoma between two distinct high-incidence areas. Geographic variation might exist in the process of gallbladder carcinogenesis. 展开更多
关键词 GALLBLADDER Gallbladder Neoplasms K-RAS microsatellite instability P53
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Telomerase activity in colorectal cancer,prognostic factor and implications in the microsatellite instability pathway 被引量:8
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作者 M Vidaurreta ML Maestro +4 位作者 S Rafael S Veganzones MT Sanz-Casla J Cerdán M Arroyo 《World Journal of Gastroenterology》 SCIE CAS CSCD 2007年第28期3868-3872,共5页
AIM: To determine whether the telomerase activity is related to the Microsatellite instability (MSI) genetic pathway and whether it means a difference in the survival.METHODS: The population consisted of 97 colore... AIM: To determine whether the telomerase activity is related to the Microsatellite instability (MSI) genetic pathway and whether it means a difference in the survival.METHODS: The population consisted of 97 colorectal cancer patients. MSI determination was performed in accordance with the NCI criteria using PCR and Genescan. Telomerase activity was determined by the TRAP-assay, an ELISA procedure based on the amplification of telomeric repeat sequences.RESULTS: 6.2% showed high MSI (MSI-H), 10.3% showed low MSI (MSI-L) and 83.5% did not show this alteration (MSS). Positive telomerase activity was detected in 92.8% of the patients. 83.3% of MSI-H tumors showed positive telomerase against 93.8% of MSS tumors. In the overall survival analysis the absence of telomerase activity conferred a better prognosis.CONCLUSION: Previous works have shown that tumors which develop via the MSI pathway present a better prognosis. No link between telomerase activity and MSl status is observed, although sample sizes are small. Patients with telomerase negative tumors had better overall survival than patients with telomerase positive tumors. 展开更多
关键词 microsatellite instability TELOMERASE Colorectal cancer PROGNOSIS
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