胆系恶性肿瘤分子治疗的新靶点

胆系恶性肿瘤是一组与胆道相关的上皮性癌,在解剖学上分为肝内(iCCA)、肝门周围(pCCA)和远端(dCCA)亚群。到目前为止,胆系恶性肿瘤仍以手术治疗为主,但很多患者发现时已到晚期,失去了手术机会,而目前仍无有效的化疗方案。因此选择一种有效的靶向药物治疗胆系恶性肿瘤是当务之急,本文讨论了近年来在胆系恶性肿瘤分子研究的一些新的观念,这些分子可能是未来治疗胆系恶性肿瘤的重要靶点。     

胆道恶性梗阻的光动力治疗疗效观察

目的 探讨光动力治疗对胆道恶性梗阻的疗效和安全性。方法 回顾性分析我中心接受经皮光动力治疗的胆管恶性梗阻患者临床资料,根据是否联合介入、靶向或免疫治疗分为光动力组和联合组。观察治疗后肝功能变化、胆道通畅时间及术后1月内并发症。结果 共入组19位患者,光动力治疗成功率达100%。术后1月未观察到肝功能下降。最长随访时间17.7月,术后1、3、6和12月胆道通畅率分别为100%、89.5%、72%和64%,平均胆道通畅时间约6.9±0.8月（95%CI:5.2～8.7月）。BismuthⅢ型胆道通畅时间7.5±1.1月,BismuthⅣ型胆道通畅时间6.1±1.3月。单纯光动力治疗组胆道通畅时间约3.3±0.7月,联合治疗组患者胆道通畅时间约7.9±0.9月,两组差异具有统计学意义（P=0.017）。结论 光动力治疗BismuthⅢ-Ⅳ型胆道恶性梗阻安全有效,联合全身治疗可使胆道通畅时间显著延长。     

经皮经肝胆道引流与胆道金属支架置入治疗肝门部胆管癌的疗效分析

目的 对比分析经皮经肝胆道金属支架内引流和导管外引流治疗肝门部胆管癌的疗效和安全性.方法选择肝门部胆管癌患者46 例.按照不同引流方法分为金属支架内引流组27 例和导管外引流组19 例.术后7 天复查两组患者肝功能,记录患者术前术后并发症的发生情况.观察两组患者术后生存情况.结果 两组患者治疗后血清ALT?AST?GGT?ALP?TBiL和DBiL 水平均较术前显著下降,差异有统计学意义(P <0.05);相比于导管外引流组,金属支架内引流组患者ALT?AST?GGT?ALP?TBiL 和DBiL 各指标水平下降更显著,差异有统计学意义(P <0.05).金属支架内引流组患者中位生存时间为12.5 个月,略高于导管外引流组患者的(10.6 个月),但是差异无统计学意义(χ2 =2.531,P =0.112).导管外引流组并发症发生率为31.6%,显著高于金属支架内引流组的11.1%,差异有统计学意义(P<0.05).结论 经皮经肝胆道引流途径金属支架置入姑息性治疗肝门胆管癌的疗效确切,安全性高,优于于经皮经肝胆道导管外引流方法.     

Multi-step Carcinogenesis Model for Adult T-cell Leukemia

The age-specific occurrence of adult T-cell leukemia (ATL) was analyzed using 357 cases collected during nationwide surveys carried out between 1982 and 1985 in Japan. A simple Weibull distribution function fitted well as a model. The mode of ATL onset was log-linear in this model and the curves for males and females overlapped completely. The presence of age-dependent accumulation of leukemogenic events within human T-cell leukemia virus type 1-immortalized T cells was suggested prior to the development of ATL, and the approximate number of independent leukemogenic events in ATL is estimated to be five. This stochastic analysis supported a multi-step carcinogenesis as an appropriate model for ATL.     

杂色曲霉素体外对人胃粘膜的致癌作用

 河北省赞皇县是胃癌高发区，我们以往的研究表明该地区胃癌高发与杂色曲霉毒素密切相关。为进一步探讨杂色曲霉毒素对人胃粘膜的致癌作用，于本研究中，用该毒素处理体外培养的人胎儿胃粘膜。处理后18天，经流式细胞分析显示胃粘膜组织S期、G2M期细胞数和细胞增殖指数增大；接种于；γ-射线处理的新生SD大鼠皮下可存活生长，形态学是重度不典型增生。结果表明杂色曲霉毒素对人胃粘膜有致癌作用。     

Biliary tract cancers: molecular profiling as a tool for treatment decisions. A literature review

Biliary tract cancer is a quite rare disease; despite recent significant advances in imaging modalities, most of the patients have advanced disease at presentation thus making radical surgery not feasible. Many different chemotherapeutic regimens have been investigated in small uncontrolled studies, with generally disappointing results. We extensively reviewed the literature on this topic trying to give an explanation to chemoresistance in this setting of patients and considering the molecular profiling as a tool for treatment decision. This review is divided in two parts, in the first one we illustrated chemotherapy results and possible mechanisms of resistance. In the second part we analysed the new molecular targets developing an hypothesis about the future therapeutics perspectives.     

肿瘤恶病质治疗潜在分子靶点的研究进展

肿瘤恶病质是各种恶性肿瘤患者的主要并发症,常出现于肿瘤晚期,主要表现为患者体重丢失、贫血、代谢失衡及全身性器官衰竭,导致癌症患者生活质量下降,肿瘤化疗治疗效果被严重削弱,是众多癌症患者死亡的主要原因。目前,肿瘤恶病质治疗尚缺乏有效的特异针对性药物,但随着对肿瘤恶病质发生分子机制的深入研究,多个新的恶病质治疗潜在分子靶点被提出,为开发新的靶向治疗药物提供了可能。全文综述了抗肿瘤恶病质导致的肌肉减少以及脂肪降解的新分子靶点,并分类阐述其分子机制以及相关体内外实验研究成果,收集针对这些靶点的药物研究的现状,希望能为肿瘤恶病质新药开发及治疗提供研究思路和方向。     

Neogenin表达下调与神经胶质瘤发生、发展的关系

背景与目的：神经胶质瘤是中枢神经系统最常见肿瘤,其发病机制尚不明确。Neogenin表达异常与多种癌症进展及预后相关．是一个潜在的肿瘤抑制因子。本研究的目的在于阐明Neogenin在神经胶质瘤发生和进展过程中的作用。方法：通过对小鼠正常脑组织及人神经胶质瘤组织及肿瘤周边脑组织进行免疫组织化学方法染色．分析Neogenin在正常脑组织及肿瘤组织中的细胞内分布差异,以及其在胶质瘤中表达水平较其周边脑组织表达的差别：进一步分析其在不同级别胶质瘤中的表达水平差异;最后通过MSP法分析Neogenin在神经胶质瘤中的启动子甲基化水平。结果：我们发现Neogenin在小鼠脑中表达丰富,主要位于神经胶质细胞的胞膜上;Neogenin在肿瘤区域的平均表达水平较周边区域低,其在肿瘤区域主要胞浆内呈弥散分布。对69例原发胶质瘤患者的肿瘤组织进行免疫组织化学分析．进一步确认了Neogenin在神经胶质瘤中表达水平与肿瘤的恶性程度呈负相关（One-Wav ANOVA,n=69,P〈0．01）。通过甲基化特异性PCR法分析表明,Neogenin的启动子在37．5％（3／8）的人神经胶质瘤组织中存在甲基化．但是我们存3株人脑胶质瘤细胞系中未检测到Neogenin启动子甲基化现象。结论：Neogenin与神经胶质瘤的发生、发展有关,其启动子部分甲基化可能是导致Neogenin表达下渊的原因之一．这种表达下调为神经胶质瘤的起源、发展提供了选择性优势。     

乳腺癌的分子分型与个体化治疗

随着医学基础和临床研究领域的飞速发展,如今治疗乳腺癌的视野已大大拓宽,治疗手段不断丰富,新的药物更是如雨后春笋,层出叠现,治疗效果不断提高.尽管与其他实体瘤相比,我们在乳腺癌的治疗领域所取得的成绩令人瞩目,但是并非任何一种治疗方案对每例患者都有效.如何确定一种治疗方案的适宜人群,以获得最好的治疗效果,成为肿瘤医师们孜孜以求的目标.     

不同胆道引流方式对高位恶性胆道梗阻疗效的影响

 目的 探讨不同胆道引流方式对高位恶性胆道梗阻（malignant high biliary obstruction, MHBO）疗效的影响,为临床治疗方式的选择提供参考。方法 随访MHBO患者164例,其中行胆道完全外引流18例（A组）、胆道单支架植入并对侧外引流48例（B组）、胆道优势侧引流34例（C组）、胆道双支架植入64例（D组）,观察术后近、远期疗效。结果 4组患者术前ALT、AST、TBIL、DBIL与术后第3、7、14天比较,差异均有统计学意义（均P<0.05）;4组患者术后第7天的组间比较,A、B、D三组下降程度高于C组,差异均有统计学意义（均P<0.05）;4组患者术后第14天的组间比较,D组下降程度明显高于A、B、C三组,B组高于A、C两组,A组高于C组,差异均有统计学意义（均P<0.05）。4组患者术后第21天TBIL均值与术前比较,D组下降程度明显高于A、B、C三组,B组高于A、C两组,A组高于C组,差异均有统计学意义（均P<0.05）。4组患者术后生存期比较,D组中位生存期为（355.00±22.21）天,远高于A、B、C三组,差异均有统计学意义（均P<0.05）。结论 胆道双支架植入实现了胆汁的充分内引流,对迅速消除黄疸具有明显的优越性,明显的提高了患者的生存质量及延长了生存期。     

三阴性乳腺癌的分子学分类和靶向治疗

三阴性乳腺癌侵袭性高、预后差,单纯从免疫组织化学的角度来定义三阴性乳腺癌显得不够全面,临床上有必要从分子学角度对三阴性乳腺癌进行更为详细的分类,从而为临床医师有针对性的治疗提供指导。本文介绍了目前已有的三阴性乳腺癌的分子学分类方法,并对其相关靶向治疗手段作一综述。     

Intrahepatic cholangiocarcinoma: Molecular markers for diagnosis and prognosis

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver tumor with increasing incidence worldwide. The outcome of patients with iCCA is dismal owing to tumor's aggressiveness, late diagnosis and lack of effective treatment options. Detection of the tumor at early stages may make surgical resection, as only potential curative treatment, more feasible. Unfortunately, despite recent developments in imaging modalities and laboratory tests, the diagnosis of iCCA remains challenging and patients often present in advanced stages when surgery cannot be offered. Moreover, accurate assessment of disease burden is critical to optimize management strategy, including the use of adjuvant therapies and clinical trials. Identifying iCCA specific diagnostic and prognostic biomarkers has been a focus of interest among many investigators with a progressive increase in data on iCCA related to advances in “omics” technologies. We herein summarize iCCA biomarkers and define the molecular mechanisms underlying iCCA carcinogenesis, as well as highlight potential diagnostic and prognostic application of molecular biomarkers.     

Potential Novel Therapy Targets in Neuroendocrine Carcinomas of the Breast

Introduction

Neuroendocrine carcinoma (NEC) of the breast is a rare, special type of breast cancer, reportedly constituting 2% to 5% of all breast cancers. Although breast NEC does not have a specific targeted therapy, several new targeted therapies based on specific biomarkers were recently investigated in the NEC of lung and in other types of breast carcinoma, which may provide guidance to their feasibility in breast NEC.

p16,Cyclin D1在胃癌发生过程中的表达

研究ｐ１６,ＣｙｃｌｉｎＤ１在胃癌发生过程中的表达。方法：采用免疫组化ＡＢＣ法,检测胃癌、不典型增生、萎缩性胃炎及正常胃粘膜组织Ｐ１６和ＣｙｃｌｉｎＤ１的表达。结论：Ｐ１６和ＣｈｃｌｉｎＤ１在胃上皮癌变过程中起着重要作用,其在胃癌中的反向表达趋势提人才是可能存在相互抑制机制。     

Carcinogenesis Studies of Dichlorvos in Fischer Rats and B6C3F1 Mice

Dichlorvos (dichlorovinyl dimethyl phosphoric acid ester) is a cholinesterase inhibitor used widely as a contact and stomach insecticide for control of internal and external parasites. Carcinogenesis studies were conducted by administering dichlorvos in corn oil by gavage 5 times a week for 103 weeks to groups of 50 male and 50 female Fischer rats at 0, 4, or 8 mg/kg body weight, to groups of 50 male B6C3F1 mice at 0,10, or 20 mg/Ag, and to groups of 50 female B6C3F1 mice at 0, 20, or 40 mg/kg. During the course of the studies, body weights and survival rates of the male and female rats and mice were not different from those of their respective controls; females of both species appeared to gain more weight than controls. Neoplasms induced by dichlorvos included adenomas of the exocrine pancreas (male rats), mononuclear cell leukemia (male rats), and squamous cell papilloma of the forestomach (male and female mice; two other female mice had squamous cell carcinomas). Lesions observed in female rats that may have been due to dichlorvos administration included adenomas of the exocrine pancreas and fibroadenomas of the mammary gland. The results demonstrated that dichlorvos is carcinogenic for Fischer rats and B6C3F1 mice.     

Carcinogenesis and chemoprevention of biliary tract cancer in pancreaticobiliary maljunction

Pancreaticobiliary maljunction (PBM) is a high risk factor for biliary tract cancer. In PBM, since the pancreatic duct and bile duct converge outside the duodenal wall beyond the influence of the sphincter of Oddi, pancreatic juice and bile are constantly mixed, producing a variety of harmful substances. Because of this, the biliary mucosa is repeatedly damaged and repaired, which causes an acceleration of cell proliferative activity and multiple gene mutations. Histological changes such as hyperplasia, metaplasia, and dysplasia ultimately result in a high incidence of carcinogenesis. In a nationwide survey by the Japanese Study Group on PBM, coexisting biliary tract cancer was detected in 278 of the 1627 registered cases of PBM (17.1%). Of these cases, in those with dilatation of the extrahepatic bile duct, cancer was often detected not only in the gallbladder but also in the bile ducts. More than 90% of cancer cases without dilatation of the extrahepatic bile duct develop in the gallbladder. Standard treatment for PBM is a cholecystectomy and resection of the extrahepatic bile duct. However, cholecystectomy alone is performed at nearly half of institutions in Japan. Conversely, reports of carcinogenesis in the remnant bile duct or pancreas after diversion surgery are steadily increasing. One of the causes for this is believed to be an accumulation of gene mutations which were present before surgery. Anticancer drugs are ineffective in preventing such carcinogenesis following surgery, thus the postoperative administration of chemopreventive agents may be necessary.