MET 基因在非小细胞肺癌中的表达及其意义

目的：探讨间质上皮转化因子（MET）基因 mRNA 在非小细胞肺癌（NSCLC）中的表达及其与临床病理特征的关系。方法选取2011年6月—2013年11月在中国人民解放军总医院病理确诊为 NSCLC 的48例患者,所有患者均未接受术前治疗。采用分支-DNA 液相芯片技术对获取的肿瘤组织中 MET 基因 mRNA 表达水平进行检测,分析 MET 基因 mRNA 表达水平与临床病理特征的关系。结果MET 基因 mRNA 以中度表达为主,低度、中度和高度表达的比例分别为22．9％、50．0％和27．1％。MET 基因 mRNA 表达与患者病理类型（χ2＝7．183,P ＝0．020）和 TNM分期（χ2＝24．566,P ＝0．017）有关,与性别（χ2＝0．566,P ＝0．754）、年龄（χ2＝1．857,P ＝0．395）、吸烟史（χ2＝4．959,P ＝0．084）、分化程度（χ2＝5．749,P ＝0．067）、淋巴结转移（χ2＝1．631,P ＝0．442）和远处转移（χ2＝4．261,P ＝0．119）均无关。结论 MET 基因 mRNA 在 NSCLC 中更易呈现中、高度表达,而且 MET 基因可以作为判断肿瘤病理类型的生物学标志物。     

Luminal 型乳腺癌 P53表达与临床病理特征及预后的关系

目的：探讨 Luminal 型乳腺癌 P53表达与临床病理特征及预后的关系。方法选取2009年1月至2012年12月在上海交通大学附属第一人民医院手术治疗的283例 Luminal 型乳腺癌患者作为研究对象,采用免疫组织化学法测定 P53表达。生存分析采用 Kaplan-Meier 曲线评估和 Log-rank 检验比较,并用 Cox 比例风险回归模型进行单因素和多因素分析。结果 Luminal 型乳腺癌患者 P53表达与肿瘤最大径（χ2＝6．285,P ＝0．043）、淋巴结转移（χ2＝15．881,P ＝0．000）、组织分级（χ2＝8．132,P ＝0．043）、Ki-67（χ2＝6．476,P ＝0．039）有关;而与年龄（χ2＝0．955,P ＝0．328）、月经状态（χ2＝3．808,P ＝0．051）、病理类型（χ2＝0．847,P ＝0．655）、雌激素受体（χ2＝1．867,P ＝0．172）、孕激素受体（χ2＝0．937, P ＝0．333）及人表皮生长因子受体-2（χ2＝0．110,P ＝0．741）无关。在283例患者中,P53阴性组和阳性组5年无复发生存率分别为90．7％、66．7％（χ2＝12．609,P ＝0．000）,5年总生存率分别为93．4％、84．4％（χ2＝4．153,P ＝0．042）,差异均有统计学意义。Cox 多因素分析发现,淋巴结转移（HR ＝2．484,95％CI 为1．393～4．431,χ2＝9．497,P ＝0．002）和 P53阳性（HR ＝3．627,95％CI 为1．061～12．401;χ2＝4．220,P ＝0．040）是 Luminal 型乳腺癌患者无复发生存的独立危险因素;淋巴结转移（HR ＝3．451,95％CI为1．891～6．297;χ2＝16．290,P ＝0．000）和高组织学分级（HR ＝2．806,95％CI 为1．091～7．219;χ2＝4．582,P ＝0．032）是总生存时间的独立危险因素。结论 Luminal 型乳腺癌患者 P53过表达与淋巴结转移、组织分级等预后因素相关,且 P53过表达患者预后更差。     

驱动蛋白E g5在非小细胞肺癌中的表达及其意义

目的：检测驱动蛋白Eg5在非小细胞肺癌（NSCLC）中的表达水平,并探讨其与非小细胞肺癌转移的关系。方法：选取63例非小细胞肺癌的手术切除标本和20例正常肺脏组织标本,采用免疫组化检测Eg5的表达,并分析其与非小细胞肺癌临床病理特征和转移之间的关系。结果：E g5在正常肺组织中未见明显表达,在非小细胞肺癌组织中的表达阳性率为68．3％（43／63）,且与非小细胞肺癌的肿瘤直径（χ2＝4．506,P＝0．034）、临床分期（χ2＝8．866,P＝0．012）、淋巴结转移情况（χ2＝19．52,P＜0．001）有关,差异有统计学意义;而与患者性别、年龄、分化程度等指标无明显的相关性（P＞0．05）。结论：Eg5在正常肺组织中未见明显表达,在非小细胞肺癌组织中高表达,E g5的表达与非小细胞肺癌临床分期及转移有关,E g5可预测非小细胞肺癌的淋巴结转移情况,可能作为非小细胞肺癌化学治疗的潜在靶点。     

β-catenin在胃腺癌原发灶和转移淋巴结的表达及意义

目的：探索β-catenin在胃腺癌原发灶及转移淋巴结的表达情况,判断其是否与浸润程度相关及能否为胃癌浸润转移提供依据。方法免疫组织化学法对156例胃腺癌组织、40例对应转移淋巴结、12例正常胃黏膜组织进行β-catenin检测,分析β-catenin在胃腺癌及对应转移淋巴结的表达情况,明确β-catenin的表达与胃腺癌临床病理特征之间的关系,判断原发灶与转移淋巴结β-catenin表达有无差异性。结果β-catenin在正常胃组织细胞膜的阳性表达率为100．0％（12/12）,在胃腺癌组织细胞膜的表达率为29．5％（46/156）,在转移淋巴结细胞膜的表达率为10．0％（4/40）。β-catenin阳性表达与患者的年龄（χ2＝2．160,P＝0．142）、性别（χ2＝1．229,P＝0．268）无关,与肿瘤浸润深度（χ2＝4．032,P＝0．045）、肿瘤分化程度（χ2＝6．093,P＝0．048）、肿瘤分期（χ2＝4．591,P＝0．032）、淋巴结转移（χ2＝4．485,P＝0．034）有关;β-catenin的异常表达或表达缺失在胃腺癌转移淋巴结的发生率高于原发灶组织（χ2＝6．362,P＝0．012）。结论β-catenin可帮助判断胃腺癌恶性程度、肿瘤侵袭转移能力等生物学行为。     

SRS、WBRT 及 WBRT ＋SRS 治疗1～4个脑转移瘤的 Meta 分析

目的：探讨立体定向放射外科（SRS）、全脑放疗（WBRT）及全脑放疗联合立体定向治疗1～4个脑转移瘤,并为进一步研究提供循证医学依据。方法：根据设定的纳入、排除标准,在 PubMed、Springer －link、Cancer list 数据库、中国生物医学文献数据库（CBM）、万方数据库、CNKI 知识网络服务平台及其他期刊进行相关随机对照试验检索。单变量计数资料的效应量用优势比（OR）和95％可信区间（95％CI）表示,用 Rev-man 5．2软件对数据进行异质性检验后采用固定效应模型或随机效应模型对数据进行分析。结果：共检索出1985－2014年间发表的126篇相关文献,最终得到8篇包含1213例脑转移瘤患者的随机对照试验符合所纳入的标准。SRS 与 WBRT ＋SRS 比较：WBRT ＋SRS 虽能提高脑转移瘤1年局部控制率及远处肿瘤控制率（OR ＝0．43,95％CI：0．29～0．63,P ＜0．0001;OR ＝0．42,95％CI：0．30～0．57,P ＜0．00001）;但不能提高1年生存率且不良反应及神经认知异常发生率高（OR ＝1．27,95％CI：0．93～1．73,P ＝0．14;OR ＝0．50,95％CI：0．28～0．89,P ＝0．02;OR ＝0．41,95％CI：0．21～0．78,P ＝0．006）。SRS 与 WBRT 比较：SRS 治疗脑转移瘤可明显提高患者1年生存率及1年局部肿瘤控制率,但远处肿瘤控制率与WBRT相当（OR＝2．78,95％CI：1．57～4．92,P ＝0．0004;OR ＝4．8,95％CI：2．69～8．57,P ＜0．00001;OR ＝0．52,95％CI：0．15～1．83,P ＝0．31）。WBRT ＋SRS 与单独 WRBT 比较：1年局部肿瘤控制率及1年生存率无明显差别（OR ＝1．23,95％CI：0．81～1．86,P ＝0．32;OR ＝1．21,95％CI：0．76～1．93,P ＝0．42）。结论：1～4个脑转移瘤患者,单独 SRS 是理想治疗方法。     

人非小细胞肺癌VEGFR2和NRP-1表达意义分析

目的：探讨人非小细胞肺癌（non-small-celllungcancer,NSCLC）组织中VEGFR2和NRP-1的表达情况及临床意义。方法：选取2009-01-01-2012-11-30连云港市第一人民医院手术切除并经病理确诊的NSCLC石蜡包埋标本40例和肺良性组织10例,采用免疫组化方法（IHC）测定VEGFR2、NRp-1表达,运用荧光原位杂交技术（FISH）检测VEGFR2基因（KDR）及NRP-1基因拷贝获益（copynumbergains,CNG）,最终所荻结果结合患者的临床病理资料进行分析。结果：40例NSCLC组织中VEGFR2蛋白高表达率为57．5％,NRP-1蛋白高表达率为55．0％;KDRCNG（＋）比率为32．5％,NRP-1CNG（＋）的比率为30．0％。VEGFR2蛋白在NSCLC组织中的表达与肺良性病变的阴性表达比较,差异有统计学意义,χ2=10．65,P〈0．001;NRP-1蛋白在NSCLC组织中的表达与肺良性病变的阴性表达比较,差异有统计学意义,χ2=9．82,P=0．002,且其表达与肿瘤的TNM分期、淋巴结转移和肿瘤组织分化程度有关,P〈0．05;与患者年龄和病理类型无关,P〉0．05。肺癌患者中KDRCNG（＋）与肺良性病变KDRcNG（-）比较差异有统计学意义,χ2=4．39,P=0．04;肺癌患者中NRP-1CNG（＋）与肺良性病变cNG（-）比较差异有统计学意义,χ2=3．95,P=0．04;且其与肿瘤的TNM分期、淋巴结转移和肿瘤组织分化程度有关,P〈0．05;而与患者年龄和病理类型无关,P〉0．05。结论：VEGFR2、NRP-1在NSCLC组织中均有高表达,并且它们在NSCLC发生、发展和转移中有重要意义,对临床判断NSCLC预后和指导临床抗血管生成有一定的价值。     

甘氨双唑钠对食管癌同步放化疗增敏疗效与安全性的Meta分析

目的：系统评价甘氨双唑钠（CMNa）对食管癌同步放化疗增敏作用的临床疗效和安全性。方法检索中国生物医学文献数据库、中国期刊全文数据库（CNKI）、万方医药期刊全文数据库、维普中文科技期刊数据库、PubMed、Cochrane Library、EMBase,收集同步放化疗联合 CMNa 与不联合CMNa治疗食管癌的临床随机对照试验（RCT）。根据纳入排除标准筛选文献,对符合条件的 RCT 由两位研究者独立进行资料提取和质量评价后,采用 RevMan 5．3进行 Meta 分析。结果共有4篇 RCT、262例患者纳入研究。Meta 分析结果显示同步放化疗联合 CMNa 增敏组的完全缓解率（OR ＝2．09,95％CI 为1．24～3．54,Z ＝2．76,P ＝0．006）和总有效率（OR ＝2．75,95％CI 为1．39～5．44,Z ＝2．90,P ＝0．004）均优于非增敏组,差异有统计学意义;两组1年生存率差异无统计学意义（OR ＝1．85,95％CI 为0．94～3．64,Z ＝1．77,P ＝0．08）;两组消化道不良反应（OR ＝0．92,95％CI 为0．49～1．70,Z ＝0．28,P ＝0．78）、骨髓抑制（OR ＝0．69,95％CI 为0．39～1．19,Z ＝1．33,P ＝0．18）、肝功能损伤（OR ＝0．93,95％CI 为0．48～1．79,Z ＝0．23,P ＝0．82）、放射性食管炎（OR ＝1．07,95％CI 为0．58～2．00,Z ＝0．22,P ＝0．82）、放射性肺炎（OR ＝0．76,95％CI 为0．29～1．98,Z ＝0．56,P ＝0．57）、放射性皮肤损伤（OR ＝1．11,95％CI为0．51～2．43,Z ＝0．26,P ＝0．80）的发生率差异均无统计学意义。结论同步放化疗联合 CMNa 增敏治疗食管癌近期疗效好,且不增加不良反应的发生。     

血管内皮生长因子联合nm 23检测在非小细胞肺癌诊治中的意义

 目的　研究血管内皮生长因子（VEGF） 和nm 23在非小细胞肺癌（NSCLC）组织中的表达及相互关系,探讨其在NSCLC诊治中的临床意义。方法　采用免疫组织化学链酶素抗生物素蛋白-过氧化物酶连结（SP） 法检测60 例NSCLC及癌旁正常肺组织中VEGF 和nm 23 的表达,结合临床病理因素进行分析。结果　VEGF在NSCLC组织中的阳性表达率（63.3 %,38／60）显著高于癌旁肺组织 （16.7 %,10／60）（χ2＝27.22, P＜0. 01）。nm 23在NSCLC组织中的阳性表达率（53.3 %,32／60）则显著低于癌旁肺组织中的表达（88.3 %,53／60）（χ2＝17.79,P＜0. 01）。VEGF的阳性率与淋巴结转移及组织学分级呈正相关（χ2＝15.23、χ2＝ 7.25,P < 0.05）。nm 23 与淋巴结转移呈负相关（χ2＝16.93,P < 0.01）。VEGF阳性患者2年生存率明显低于阴性患者（χ2＝5.55,P＜0.05）,nm 23则相反（χ2＝12.86,P <0.05）。VEGF与nm 23 在NSCLC中表达无相关性（χ2＝1.83,P＞0.05）。结论　VEGF 和nm 23 可能与NSCLC的发生、发展有关,检测VEGF 和nm 23 可能有助于对NSCLC生物学行为的判断,对肺癌患者的诊治和预后评估有积极意义。     

胃腺癌组织中基质金属蛋白酶-13和 p73的表达及意义

目的研究 MMP-13、抑癌基因 p73在胃腺癌组织中的表达及其与临床病理参数的关系,评估其对胃腺癌转移预后的意义。方法应用免疫组织化学 SP 法检测 MMP-13、抑癌基因 p73在143例胃腺癌组织、55例癌旁正常组织中的表达情况,并分析其与临床病理参数的关系。结果胃腺癌组织中 MMP-13的表达显著高于癌旁组织（67．13％∶16．35％）,差异有统计学意义（χ2＝41．10,P ＝0．000）;p73的表达也显著高于癌旁组织（58．74％∶12．73％）,差异有统计学意义（χ2＝33．86,P ＝0．000）。胃腺癌中 MMP-13阳性表达与胃周围淋巴结转移（χ2＝11．835,P ＝0．001）、浸润深度（χ2＝5．177,P ＝0．032）、临床分期（χ2＝11．107,P ＝0．001）有关,而与患者年龄（χ2＝0．113,P ＝0．853）、肿瘤大小（χ2＝0．338,P ＝0．591）、癌细胞分化程度（χ2＝3．628,P ＝0．072）无关。胃腺癌中 p73阳性表达与胃周围淋巴结转移（χ2＝11．440,P ＝0．001）、癌细胞分化程度（χ2＝5．407,P ＝0．025）及临床分期有关（χ2＝9．497,P ＝0．003）,而与患者年龄（χ2＝1．567,P ＝0．222）、肿瘤大小（χ2＝0．841,P ＝0．392）及浸润深度（χ2＝0．554,P ＝0．498）无关,二者在胃腺癌组织中的表达呈正相关（r ＝0．684,P ＝0．000）。结论MMP-13和 p73可能共同参与胃腺癌的发生发展过程,可作为评估胃腺癌浸润和转移的重要生物学指标。     

腹腔镜低位直肠癌根治术中保肛因素的Logistic分析

目的探讨腹腔镜低位直肠癌根治术中影响保肛的相关因素。方法回顾性分析2013年6月至2016年6月在本院行腹腔镜下局部进展期低位直肠癌根治术的93例患者的临床资料,采用Logistic回归分析影响保肛的相关因素并比较39例患者行新辅助治疗前后临床指标的差异。结果单因素分析显示性别（χ2＝4．521,P＝0．033）、肿瘤距肛缘的距离（t＝36．131,P＜0．001）、肿瘤直径（t＝7．235,P＝0．007）、局部浸润深度（χ2＝17．531,P＜0．001）和是否行新辅助治疗（χ2＝4．366,P＝0．037）是影响保肛的因素。多因素分析显示性别（OR 47．59,95％CI 2．262～1001．326,P＝0．013）、肿瘤距肛缘的距离（OR 539．28,95％CI 15．165～19177．534,P＝0．001）、局部浸润深度（OR 0．005,95％CI 0．000～0．124,P＝0．001）和是否行新辅助治疗（OR 0．019,95％CI 0．001～0．601,P＝0．024）是影响保肛的关键因素。低位直肠癌行新辅助治疗后对比治疗前：肿瘤直径缩小（P＜0．001）、肿瘤距肛缘的距离增大（P＜0．001）、局部浸润深度降低（P＜0．001）、淋巴结阳性率下降（P＝0．020）。结论性别、肿瘤距肛缘的距离、肿瘤直径、浸润深度、是否行新辅助治疗是影响腹腔镜下局部进展期低位直肠癌保肛手术的因素。新辅助治疗能够使肿瘤降期,提高保肛率。     

Expression of cell cycle markers and human papillomavirus infection in oral squamous cell carcinoma: use of fuzzy neural networks

Our aim was to evaluate in oral squamous cell carcinoma (OSCC) the relationship between some cell cycle markers and HPV infection, conditionally to age, gender and certain habits of patients, and to assess the ability of fuzzy neural networks (FNNs) in building up an adequate predictive model based on logic inference rules. Eighteen cases of OSCC were examined by immunohistochemistry for MIB-1, PCNA and survivin expression; presence of HPV DNA was investigated in exfoliated oral mucosa cells by nested PCR (nPCR, MY09-MY11/GP5-GP6), and HPV genotype was determined by direct DNA sequencing. Data were analyzed by traditional statistics (TS) and FNNs. HPV DNA was found in 9/18 OSCCs (50.0 %) without any significant higher risk of HPV infection with respect to the sociodemographic variables considered (p > 0.2), apart from tobacco smoking, reported in 44.4% of OSCC HPV-positive vs. 100% HPV-negative subjects (p = 0.029). Regarding cell cycle markers, TS and FNN revealed that survivin was expressed significantly more in HPV-negative than in HPV-positive OSCC [root mean-square error (RMSE) = 5.89 x 10(-6), % predicted 100.0]; furthermore, smoking played a protective role for survivin expression in HPV-positive cases (OR = 0.019, 95%CI 0.001-0.723, RMSE = 0.20, % of prevision 94.4). FNN, although on a small sample size, allowed us to confirm data by TS and to hypothesize a different cell cycle pattern for HPV-positive vs. HPV-negative OSCC. In the latter cases, the relevance of apoptotic vs. proliferative markers suggested that they may be related to the different supposed outcome of HPV-negative OSCC and that HPV may have a protective role in the expression level of survivin, especially in tobacco smokers.     

HPV阳性宫颈癌组织中miR-34b的表达水平及其临床意义

目的:探讨miR-34b在HPV阳性宫颈癌组织中的表达水平及其对患者的临床意义。方法:收集65例HPV阳性宫颈癌组织标本和35例正常宫颈组织标本,采用Real-time PCR法测定miR-34b的相对表达水平,分析其与患者临床病理特征的关系以及对患者诊断、预后的价值。结果:miR-34b在HPV阳性宫颈癌组织中的相对表达量明显低于正常宫颈组织,差异具有统计学意义（t=9.549,P＜0.05）;在HPV阳性宫颈癌患者中,miR-34b的相对表达量与患者的年龄、病理类型、肿瘤分级均无明显关系（P＞0.05）,与患者的肿瘤大小、FIGO分期、淋巴结是否转移显著相关,差异具有统计学意义（χ2=4.996、5.925、5.824,P＜0.05）;进行ROC曲线分析,发现miR-34b区分HPV阳性宫颈癌细胞与正常宫颈细胞的AUC为0.871（95%CI:0.773~0.970,P=0.000）,灵敏度为90.24%,特异度为79.17%;对HPV阳性宫颈癌患者随访3年,发现miR-34b高表达患者的OS、DFS均显著高于低表达患者,差异具有统计学意义（χ2=5.856、5.919,P＜0.05）。结论:miR-34b在HPV阳性宫颈癌组织中呈低表达,可能为HPV阳性宫颈癌筛查、诊断和治疗提供帮助,具体情况还有待进一步研究。     

Sexual behaviour and smoking as determinants of cervical HPV infection and of CIN3 among those infected: a case-control study nested within the Manchester cohort

To distinguish risk factors for acquisition of cervical human papillomavirus (HPV) infection from the determinants of neoplasia among infected individuals we have conducted a three-arm case-control study nested within a large population-based cohort of women (the Manchester cohort) screened for HPV at entry using L1 consensus primer PCR. The study includes 181 HPV-positive controls who did not develop high-grade cervical intraepithelial neoplasia (CIN3) during follow-up, 203 HPV-negative controls, and 199 HPV-positive cases with histologically confirmed CIN3. Detailed information on sexual, reproductive and gynaecological history, oral contraceptive use and smoking was obtained at face-to-face interview. There was a striking division between risk factors for infection and those predictive of disease. Comparing the HPV-positive against the HPV-negative controls, the only risk factors for infection were number of sexual partners (OR for six or more = 3.89; 95% Cl = 1.99-7.62), a relatively recent new sexual relationship (OR for a new partner within the previous 2 years = 4.17; 95% Cl = 2.13-8.33), and a history of previous miscarriage (OR = 2.59; 95% Cl = 1.28-5.21). The determinants of CIN3 among infected women were, in contrast, early age at first intercourse (OR for 16 years old or less = 3.23; 95% Cl = 1.33-7.69), a long time since starting a new sexual relationship (OR for 6 years or more = 4.94; 95% Cl = 2.51-9.71), and cigarette smoking, with strong evidence for a dose- response (OR for current smoking habit 20+ per day = 2.57; 95% Cl = 1.49-4.45). Oral contraceptive use was not significantly associated with either HPV infection or CIN3.     

HPV Detection and Genotyping in Vulvar Squamous Cell Carcinoma in Northern Thailand

Background: The study was aimed to evaluate the prevalence and genotype distribution of HPV infection invulvar squamous cell carcinoma (SCC) in northern Thailand and the clinicopathological difference with regardto HPV infection status. Materials and Methods: Formalin-fixed paraffin-embedded tissue samples of vulvarSCC diagnosed between January 2006 and December 2012 were collected. HPV infection was detected by nestedpolymerase chain reaction (PCR) with primers MY09/11 and GP5+/6+. HPV genotyping was performed usingthe Linear Array Genotyping Test, followed by type-specific PCR targeting the E6/E7 region of HPV16/18/52if the Linear Array test was negative. The histologic slides of vulvar lesions and the medical records werereviewed. Results: There were 47 cases of vulvar SCC included in the study (mean patient age 57.9±13.2 years).HPV infection was detected in 29 cases (62%), all of which had single HPV infections. HPV16 accounted for 23(49%). The patients with HPV-positive SCC had a significantly younger mean age than those with HPV-negativetumors (52.7 years vs 66.2 years, p<0.001). There was no significant difference in tumor stage distribution withregard to the status of HPV infection. The presence of vulvar intraepithelial neoplasia (VIN) of usual type(basaloid or warty) was significantly more frequent in HPV-positive cases compared with HPV-negative cases(62% vs 6%, p<0.001), whereas differentiated-type VIN was more common in HPV-negative cases (24% vs0%, p=0.019). Conclusions: HPV infection was detected in 62% of vulvar SCC in northern Thailand. HPV16was the predominant genotype similar to the data reported from other regions. HPV-positive SCC occurredin younger patients compared with HPV-negative SCC, and was associated with usual-type VIN. Vaccinationagainst HPV16/18 may potentially prevent almost one half of vulvar SCC in northern Thailand.     

HPV感染与p53蛋白及P-糖蛋白表达在非小细胞肺癌中的关系及其临床意义

目的:探讨人乳头瘤病毒(humanpapillomavirus,HPV)感染在非小细胞肺癌(nonsmallcelllungcancer,NSCLC)发生中的病因学意义及其与p53蛋白和P糖蛋白(Pgp)表达之间的相关性。方法:应用PCR、免疫组化方法分别检测76例NSCLC组织中HPVDNA及其E6、E7原癌蛋白、p53蛋白和Pgp的表达情况。结果:NSCLC中HPVDNA及其E6、E7原癌蛋白的检出率分别为40.8%(31/76)、43.4%(33/76),2种检测方法的符合率为78.9%(60/76);p53蛋白和Pgp的阳性率分别为63.2%(48/76)、59.2%(45/76),且HPV感染阳性组中p53蛋白的表达率为80.6%(25/31),显著高于阴性组51.1%(23/45)(P<0.05);p53蛋白表达阳性组中Pgp的表达率为68.8%(33/48),显著高于阴性组42.9%(12/28)(P<0.05);而HPV感染阳性组与阴性组间Pgp的表达无显著性差异(P>0.05)。HPV感染与高、中分化程度的NSCLC及吸烟有关。结论:HPV感染可能是NSCLC发生的另一重要病因学因素,且HPV感染可能导致p53基因突变,后者可能促进肺癌耐药性的增加。     

Epidemiological evidence of cervical intraepithelial neoplasia without the presence of human papillomavirus.

The aim of this paper was to provide epidemiological evidence to support the notion that cervical intraepithelial neoplasia (CIN) without human papillomavirus (HPV) is a true entity. If a diagnosis of HPV-negative cervical neoplasia is erroneous, one would not expect there to be any differences in risk factors between HPV-positive and HPV-negative patients. Patients at a gynaecological outpatient clinic of a university hospital [a total of 265 consecutive women with dyskaryotic cervical smears who were subsequently diagnosed with CIN I (n=37), CIN II (n=48) or CIN III (n=180)] completed a structured questionnaire regarding smoking habits and sexual history. Analysis of an endocervical swab for Chlamydia trachomatis, analysis of a cervical scrape for HPV, and morphological examination of cervical biopsy specimens were also performed. HPV was found in 205 (77.4%) out of the 265 women. Univariate analysis showed that current age (P=0.02), current smoking behaviour (P=0.002) and the number of sexual partners (P=0.02) were significantly associated with the presence of HPV. Age at first sexual intercourse, a past history of venereal disease or genital warts, and current infection with Chlamydia trachomatis were not associated with the presence of HPV. Using multivariate logistic regression analysis, the number of sexual partners and current smoking behaviour showed an independent significant association with HPV. HPV-negative and HPV-positive CIN patients differ with respect to the risk factors for HPV. These findings suggest that HPV-negative CIN is a separate true entity.     

Evidence for a causal association between human papillomavirus and a subset of head and neck cancers

BACKGROUND: High-risk human papillomaviruses (HPVs) are etiologic agents for anogenital tract cancers and have been detected in head and neck squamous cell carcinomas (HNSCCs). We investigated, retrospectively, an etiologic role for HPVs in a large series of patients with HNSCC. METHODS: Tumor tissues from 253 patients with newly diagnosed or recurrent HNSCC were tested for the presence of HPV genome by use of polymerase chain reaction (PCR)-based assays, Southern blot hybridization, and in situ hybridization. The viral E6 coding region was sequenced to confirm the presence of tumor-specific viral isolates. Exons 5-9 of the TP53 gene were sequenced from 166 specimens. The hazard of death from HNSCC in patients with and without HPV-positive tumors was determined by proportional hazards regression analysis. RESULTS: HPV was detected in 62 (25%) of 253 cases (95% confidence interval [CI] = 19%-30%). High-risk, tumorigenic type HPV16 was identified in 90% of the HPV-positive tumors. HPV16 was localized specifically by in situ hybridization within the nuclei of cancer cells in preinvasive, invasive, and lymph node disease. Southern blot hybridization patterns were consistent with viral integration. Poor tumor grade (odds ratio [OR] = 2.4; 95% CI = 1.2- 4.9) and oropharyngeal site (OR = 6.2; 95% CI = 3.1-12.1) independently increased the probability of HPV presence. As compared with HPV-negative oropharyngeal cancers, HPV-positive oropharyngeal cancers were less likely to occur among moderate to heavy drinkers (OR = 0.17; 95% CI = 0.05-0.61) and smokers (OR = 0.16; 95% CI = 0.02-1.4), had a characteristic basaloid morphology (OR = 18.7; 95% CI = 2.1-167), were less likely to have TP53 mutations (OR = 0.06; 95% CI = 0.01-0. 36), and had improved disease-specific survival (hazard ratio [HR] = 0.26; 95% CI = 0.07-0.98). After adjustment for the presence of lymph node disease (HR = 2.3; 95% CI = 1.4- 3.8), heavy alcohol consumption (HR = 2.6; 95% CI = 1.4-4.7), and age greater than 60 years old (HR = 1.4; 95% CI = 0.8-2.3), all patients with HPV-positive tumors had a 59% reduction in risk of death from cancer when compared with HPV-negative HNSCC patients (HR = 0.41; 95% CI = 0.20-0.88). CONCLUSIONS: These data extend recent molecular and epidemiologic studies and strongly suggest that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis.     

Human papillomavirus and p16 immunostaining,prevalence and prognosis of squamous carcinoma of unknown primary in the head and neck region

The prevalence of human papillomavirus (HPV) in squamous cell carcinoma of unknown primary in the head and neck (SCCUPHN), and prognosis by HPV status of SCCUPHN patients has been difficult to estimate because of the rarity of this subtype. In MEDLINE, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, EMBASE, Cochrane library and Web of Science searches, observational studies and clinical trials that reported survival rates of patients with SCCUPHN by HPV status were identified. Meta-analysis estimated the prevalence and prognosis (overall survival, OS; progression-free survival, PFS) of SCCUPHN by HPV status, and compared them to studies of oropharyngeal squamous cell carcinoma (OPSCC) from the same institutions and across continents. In 17 SCCUPHN studies (n = 1,149) and 17 institution-matched OPSCC studies (n = 6,522), the pooled HPV prevalence of SCCUPHN was 49%, which was only 10% (95%CI: 1–19%) lower than OPSCC prevalence in the underlying population. Estimated 5-year OS for HPV-negative SCCUPHN was 44% (95%CI: 36–51%) vs. HPV-positive SCCUPHN of 91% (95%CI: 86–96%); hazard ratio (HR) for OS was 3.25 (95%CI: 2.45–4.31) and PFS was 4.49 (95%CI: 2.88–7.02). HRs by HPV status for OPSCC were similar to that in SCCUPHN. While North American SCCUPHNs had higher HPV prevalence than European SCCUPHNs (OR = 2.68 (95%CI: 1.3–5.6)), HR of OS for HPV-negative vs. HPV-positive patients were similar in both continents (HRs of 3.78–4.09). Prevalence of HPV among SCCUPHN patients were lower than in OPSCC. The survival benefit conferred by being HPV-positive was similar in SCCUPHN as in OPSCCs, independent of continent.     

Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis

Human papillomavirus (HPV) has been associated with head and neck squamous cell carcinomas (HNSCC), especially of the oropharynx, with highest distribution in the tonsils. HPV infection has been associated with improved outcome, although not all the studies show consistent results. The reason for this is not clear. We reviewed all published articles and conducted a meta-analysis on the overall relationship between HPV infection and overall survival (OS) and disease-free survival (DFS) in HNSCC. Patients with HPV-positive HNSCC had a lower risk of dying (meta HR: 0.85, 95% CI: 0.7-1.0), and a lower risk of recurrence (meta HR: 0.62, 95%CI: 0.5-0.8) than HPV-negative HNSCC patients. Site-specific analyses show that patients with HPV-positive oropharyngeal tumours had a 28% reduced risk of death (meta HR: 0.72, 95%CI: 0.5-1.0) in comparison to patients with HPV-negative oropharyngeal tumours. Similar observations were made for DFS (meta HR: 0.51, 95% CI: 0.4-0.7). There was no difference in OS between HPV-positive and negative non-oropharyngeal patients. The observed improved OS and DFS for HPV-positive HNSCC patients is specific to the oropharynx; these tumours may have a distinct etiology from those tumours in non-oropharyngeal sites.     

Determinants of human papillomavirus-negative, low-grade squamous intraepithelial lesions in the atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesions triage study (ALTS)

BACKGROUND: Although low-grade squamous intraepithelial lesions (LSIL) most often are the result of infection by human papillomaviruses (HPV), a small proportion of women with LSIL have negative HPV tests. Using the Atypical Squamous Cells of Undetermined Significance/LSIL Triage Study (ALTS) population, the authors evaluated the significance of HPV-negative LSIL. METHODS: Women with cytologic interpretations of LSIL by referral Papanicolaou (Pap) tests or enrollment ThinPrep tests (range, 1195-1476 women, depending on the specimen type and the reviewer) had HPV testing performed by both Hybrid Capture 2 and polymerase chain reaction (PCR)-based linear array for 27 HPV types. RESULTS: Using 4 independent cytologic definitions of LSIL, only 3-11% of women with LSIL were found to have HPV-negative results on both HPV tests. The demographic characteristics of women with HPV-negative LSIL were consistent with those of a low-risk population; many were age > 35 years, and many reported no or only 1 recent sexual partner. The absolute risk of a histologic diagnosis of cervical intraepithelial neoplasia (CIN) Grade 3/carcinoma during the 2-year trial was lower for women with HPV-negative LSIL (range, 2-4%) compared with the absolute risks for oncogenic HPV-positive women with LSIL (range, 13-19%). However, at the next 6-month follow-up visit, 12%-32% of the women with HPV-negative LSIL had a positive HPV test. Finally, visual inspection of cervigrams demonstrated a clear association between a larger os and negative HPV test results compared with women who had HPV-positive LSIL. This may have influenced HPV sample adequacy. CONCLUSIONS: Based on the ALTS data, the authors found no evidence to support the existence of HPV-negative LSIL as a distinct biologic entity related to the risk of cervical carcinoma. Such results appear to represent cytologic misinterpretations or falsely negative HPV tests.