艾立布林治疗晚期乳腺癌疗效和安全性的多中心真实世界研究

目的探讨真实世界艾立布林治疗晚期乳腺癌的疗效及安全性。方法选取2019年12月至2020年12月就诊于北京市朝阳区三环肿瘤医院、山东省肿瘤医院、北京大学肿瘤医院、包头市肿瘤医院、中国医科大学附属盛京医院及中国医学科学院肿瘤医院的晚期乳腺癌患者。生存分析采用Kaplan-Meier法和Log rank检验, 多因素分析采用Cox回归模型。结果 77例患者中位无进展生存时间为5个月, 客观缓解率(ORR)为33.8%, 疾病控制率(DCR)为71.4%。三阴性乳腺癌患者ORR为23.1%, DCR为57.7%;Luminal型乳腺癌患者ORR为40.0%, DCR为77.8%;人表皮生长因子受体2过表达型乳腺癌患者ORR为33.3%, DCR为83.3%。艾立布林为一线至二线治疗患者的ORR为50.0%, DCR为66.7%;三线至四线治疗患者的ORR为29.4%, DCR为76.5%;五线至十一线治疗患者的ORR为28.6%, DCR为71.4%。艾立布林单药治疗组患者的ORR为40.0%, DCR为66.0%;联合化疗或靶向治疗组患者的ORR为22.2%, DCR为81.5%。在辅助治...     

高级别胃肠胰神经内分泌肿瘤-NET G3的临床病理特征分析

  目的  分析高级别胃肠胰神经内分泌肿瘤（high-grade G3 gastroenteropancreatic neuroendocrine tumors，GEP NET G3）的临床病理特征及生存预后影响因素。  方法  回顾性分析2012年9月至2019年7月间北京大学肿瘤医院收治的86例GEP NET G3，收集临床病理及随访资料，采用单因素Log-rank检验和多因素Cox回归模型进行预后影响因素分析。  结果  86例GEP NET G3的原发肿瘤部位包括胰腺（40例）、胃肠（37例）以及原发肿瘤不明（9例）。镜检肿瘤均分化良好，呈器官样、巢状生长，局灶可见假腺样、细条索样或缎带样结构。免疫组织化学分析显示，肿瘤的Ki-67指数范围为21%~60%，中位值为30%，生长抑素受体2（somatostatin receptor type 2，SSTR2）的阳性率为83.9%（26/31），在检测病例中没有发现微卫星不稳定和P53异常表达（分别为0/24、0/11）。生存分析表明，获得随访的76例患者，27例患者死亡，中位生存时间为48.6（26.6~70.6）个月，确诊时有无远处转移和能否进行根治性手术切除对患者的总生存影响差异有统计学意义（P < 0.05），但患者的年龄、性别、原发肿瘤部位、确诊时血清神经元特异性烯醇化酶（neuron specific enolase，NSE）水平以及Ki-67指数对患者的总生存影响无显著差异（P>0.05）。多因素分析显示，确诊时有远处转移是影响患者生存的独立危险因素（P=0.01；HR=7.33，95% CI:1.56~34.10）。  结论  GEP NET G3的确诊依赖于组织病理学和免疫组织化学检测，易发生远处转移是其临床特点和主要的预后影响因素。      

早期胃癌内镜治疗后追加外科手术病例特点、适应证和术式选择

内镜治疗技术的发展进一步推动了早期胃癌的微创治疗。然而，随之而来的问题是，部分接受内镜治疗的病人会出现非治愈性切除。早期胃癌内镜治疗后非治愈性病人的后续处理原则值得进一步关注。结合欧洲肿瘤内科学会（ESMO）、美国国家综合癌症网络（NCCN）及日本胃癌学会等国际指南及相关临床研究并回顾分析单中心数据后可得出结论，eCura-C的病人具有相对较高的癌残留风险，在与病人充分沟通后可考虑追加手术，但仍有较高的术后病理学无癌残留的风险。术式选择和切除范围可参考早期胃癌相关规定。如何准确预测非治愈性病人的淋巴结转移仍是未来的重点。前哨淋巴结活检及腹腔镜内镜联合手术是未来的发展方向。     

放射线联合p53基因及内皮抑素治疗小鼠前列腺癌皮下移植瘤

Objective To test the hypothesis that p53 gene therapy combined with endostatin can enhance tumor response to radiation therapy of RM-1 mouse xenograft prostate cancer and to investigate its mechanism. Methods A mouse prostate cancer model was established. Then mice with xenograft tumor were randomly divided into group A (control), B (radiation), C (radiation and rAdp53), D (radiation and rh-endostatin) and E (radiation and rAdp53 and rh-endostatin). On day 1, rAdp53 was injected intra-tumorously with 1 × 1010 vp per animal to group C and E. From day 1 to 14, rh-endostatin was given 15 mg/kg intraperitoneally daily to group D and E. On day 4 single fraction of 15 Gy was given to tumors in groups B, C, D and E. Normal saline was injected intra-tumorously or intraperitoneaUy accordingly as control. No treatment was done to group A. Tumor volume was measured daily. Samples were collected on Days 5, 10 and 15. Ki67, CD31, p53 and VEGF were detected by means of immunohistochemistry. Results (1) Radiation alone, radiation combined with intra-tumorous injection of Adp53 and/or intraperitoneal injection of rh-endostatin resulted in tumor growth arrest of RM-1 cells in vivo (P = 0.000). Radiation combined with both rAdp53 and rh-endostatin was the most effective treatment (P < 0.05). (2) All the four treatment groups had a decreased expression of mutant type P53 (P = 0.000). The expression of Ki67 in groups B and C were equal (P 0.05) and increasing (P = 0.000), respectively. Group D had a up-down-up curve (P < 0.05), but group E had a up-down one. On day 5 the expresion of VEGF in group E was the lowest (P < 0.05). An increased expression of MVD compared with the control was shown, and MVD in groups C, D and E were always higher than that in the control (P < 0.05). Conclusions The limitation of radiotherapy could be overcome by combination with beth p53 gene therapy and endostatin on the growth of mouse prostate cancer cell. Radiation, rAdp53 and endostatin have their own role but they can be interacted with each other.     

细胞荧光素酶报告基因试验受CpG岛甲基化状态影响

Objective To investigate the effects of methylation status of CpG islands of endogenous E-cadherin (CDH1) gene on the promoter activity of corresponding genes in reporter assays. Methods The methylation statuses of CpG island of CDHI in 8 different cell lines were detected by methylation-specific PCR. CDH1 protein was analyzed by Western blotting. Two sets of pGL3 reporter vectors with different genotypes/haplotypes of the CDH1 promoter were constructed [pGI3-A(-73)/-C(-73)pGL3-H1/-H4]and used to transfect these cell lines. The differences between these promoter reporter vectors were analyzed by t-test. Results (1) CDH1 CpG island was unmethylated in AGS, MCF7, MKN74, and PC-3 cell lines,expressed in MCF7, MKN74, and PC-3 ,but not in AGS. Expression of CDH1 was silenced by methylation in HeLa, BGC823, A549, and RKO cell lines. (2) In the four CDH1 -unmethylated MCFT, M KN74, PC-3, and AGS cell lines ,the promoter activities of pGI3-C(-73)(as 0. 78±0. 10,0. 17±0.01,0. 11±0. 01,1.19±0. 18)were significantly higher than those of pGL3-A(-73)(as 0. 30±0. 08,0. 07±0. 01,0. 07±0. 01,0. 39±0. 04) (t values are -6. 298, -12. 349, -8. 128, -7.388, and P<0. 01). However, in the four C DH1 -methylated HeLa, BGC823, A549, and RKO cell lines, the promoter activity of pGL3-C(-73)(as 0. 09±0. 02,0. 13±0. 02,0. 05±0. 01,0. 01±0. 00) was significantly lower than that of pGL3-A(-73)(as 0. 16±0. 01,0.25±0.01,0. 11±0.03,0.03±0.00) (t valued at 5.958,11. 189,3. 661,13. 866,and P<0.05). (3) In the unmethylated MKN74 and methylated RKO cell lines, the promoter activities of pGI3-H1/-H4 were obviously and contrarily different(as 1.57±0. 23/0. 94±0. 06 and 0. 38±0. 02/0. 50±0. 04 ,t values were 4. 577 and -4. 915 ,P values were 0. 010 and 0. 003). Conclusion The methylation status of CpG island of the target gene in the tested cell lines affects the promoter activity in Reporter Assay significantly. The most active one may be the most suppressive one.     

环氧化酶-2基因启动子甲基化及表达与胃黏膜病变的关系

目的 探讨环氧化酶2(COX-2)基因启动子区甲基化水平和蛋白表达与胃黏膜病变的关系,并对其相关的影响因素进行研究.方法 以1201例患有不同胃黏膜病变的高危人群为研究对象,采用免疫组织化学方法榆测COX-2表达,用亚硫酸氢钠-变性高效液相色谱(DHPLC)对COX-2启动子甲基化率进行定量分析,采用13C尿素呼气实验(13C-UBT)对幽门螺旋杆菌(H priori)感染状况进行测定.结果 COX-2甲基化率中位数随胃黏膜病变的加重逐渐升高,在浅表性胃炎和慢性萎缩性胃炎(SG/CAG)、肠上皮化生(IM)及不确定性异型增生和异璎增生(Ind DYS/DYS)病变中分别为10.6%、11.8%、13.8%,各病变组之间差异有统计学意义(X2=8.312,P=0.016).分层分析显示,在H pylori感染阴性病例中,COX-2甲基化率仍随病变加重明显升高,在SG/CAG、IM、Ind DYS/DYS病变中其中位数分别为8.8%、10.6%、14.1%(X2=6.629,P=0.036).进一步分析发现,COX-2甲基化率随着COX-2表达强度的增强而降低,由COX-2弱阳性表达的13.3%降至强阳性表达的7.6%(X2=10.400,P=0.015).结论 COX-2启动子甲基化水平与胃黏膜病变程度及H pylori感染状况密切相关,并与COX-2表达强度呈负相关,说明COX-2启动子区异常甲基化可能在胃黏膜病变的演变过程中起重要作用.     

放射线联合p53基因及内皮抑素治疗小鼠前列腺癌皮下移植瘤

Objective To test the hypothesis that p53 gene therapy combined with endostatin can enhance tumor response to radiation therapy of RM-1 mouse xenograft prostate cancer and to investigate its mechanism. Methods A mouse prostate cancer model was established. Then mice with xenograft tumor were randomly divided into group A (control), B (radiation), C (radiation and rAdp53), D (radiation and rh-endostatin) and E (radiation and rAdp53 and rh-endostatin). On day 1, rAdp53 was injected intra-tumorously with 1 × 1010 vp per animal to group C and E. From day 1 to 14, rh-endostatin was given 15 mg/kg intraperitoneally daily to group D and E. On day 4 single fraction of 15 Gy was given to tumors in groups B, C, D and E. Normal saline was injected intra-tumorously or intraperitoneaUy accordingly as control. No treatment was done to group A. Tumor volume was measured daily. Samples were collected on Days 5, 10 and 15. Ki67, CD31, p53 and VEGF were detected by means of immunohistochemistry. Results (1) Radiation alone, radiation combined with intra-tumorous injection of Adp53 and/or intraperitoneal injection of rh-endostatin resulted in tumor growth arrest of RM-1 cells in vivo (P = 0.000). Radiation combined with both rAdp53 and rh-endostatin was the most effective treatment (P < 0.05). (2) All the four treatment groups had a decreased expression of mutant type P53 (P = 0.000). The expression of Ki67 in groups B and C were equal (P 0.05) and increasing (P = 0.000), respectively. Group D had a up-down-up curve (P < 0.05), but group E had a up-down one. On day 5 the expresion of VEGF in group E was the lowest (P < 0.05). An increased expression of MVD compared with the control was shown, and MVD in groups C, D and E were always higher than that in the control (P < 0.05). Conclusions The limitation of radiotherapy could be overcome by combination with beth p53 gene therapy and endostatin on the growth of mouse prostate cancer cell. Radiation, rAdp53 and endostatin have their own role but they can be interacted with each other.     

消化道肿瘤免疫相关不良事件的临床分析

目的探讨消化系统恶性肿瘤中免疫检查点抑制剂(immune checkpoint inhibitors, ICIs）导致免疫相关不良事件(immune-related adverse events, irAEs)的特征及危险因素。方法 回顾性分析2019年4月至2021年10月北京大学肿瘤医院诊治的95例接受ICIs治疗的消化系统恶性肿瘤患者的临床资料和irAEs发生情况。irAEs、内分泌irAEs危险因素分析采用二元Logistic回归分析。结果 95例患者共应用ICIs治疗458例次,中位应用3例次(范围：1~33例次）。irAEs的发生率为55.8%,3~4级irAEs发生率为9.5%。最常见的irAEs为皮肤irAEs(27.4%）和内分泌irAEs(22.1%）。内分泌irAEs中甲状腺功能减退最常见(16.8%）,肾上腺皮质功能减退(2.1%）和垂体炎(1.1%）少见。多数irAEs发生于免疫治疗初期,78.2%发生于12周内。过敏反应、皮肤irAEs最早发生,中位发生时间分别为2周(范围：0.9～3.1周）和3.8周(范围：0.9～17.9周）,内分泌irAEs中位发生时间为6.9周(范围：3.0～52.1周）。多因素分析显示,女性(OR=5.197, 95%CI：1.166～23.154, P=0.031)和微卫星高度不稳定(microsatellite instability-high,MSI-H） (OR=35.048, 95%CI：2.756～445.787, P=0.006)是内分泌irAEs发生风险增加的独立危险因素,免疫治疗联合化学药物治疗(OR=0.107, 95%CI：0.021～0.412, P=0.001）是内分泌irAEs的独立保护性因素。结论在消化系统恶性肿瘤中应用ICIs具有较好的安全性。女性和MSI-H患者出现内分泌irAEs风险增加,联合化学药物治疗可能降低内分泌irAEs发生风险。     

全球针对家族史高危人群的结直肠癌筛查指南推荐意见的系统综述

目的 对全球现有结直肠癌家族史高危人群筛查指南的更新进展及推荐意见进行系统总结和评价。方法 以“结直肠癌”“筛查”“指南”“共识”“推荐”“家族史”以及“colorectal cancer”“screening”“guideline”“recommendation”“family history”为关键词,并补充其自由词,系统检索中国知网、万方数据知识服务平台、PubMed、Embase、Cochrane Library、Web of Science,并且同时检索官网刊登的结直肠癌筛查指南/共识作为补充,语种限定为中文和英文。截至2022年5月24日,共20篇有效文献。对纳入文献的基本信息、针对家族史人群的推荐意见等进行摘录整理及汇总描述。结果 在20篇文献中,大多数国家/地区/机构根据结直肠癌家族史人群的亲属关系等级,对筛查起止年龄、筛查方式及筛查周期提出建议。多数指南针对有1例60岁前患结直肠癌一级亲属的人群,推荐筛查起始年龄为40岁或比患病亲属诊断年龄提前10年,推荐的筛查方式多为结肠镜。结论 目前全球多数结直肠癌家族史高危人群筛查指南主要针对一级亲属家族史、以结肠镜作为主要筛查方式。本文将为我国针对结直肠癌家族史高危人群筛查策略的更新提供参考依据,进而完善结直肠癌筛查与早诊早治实践。