88例卵巢上皮性癌行ATP-TCA体外药敏试验结果分析

该研究是探讨三磷酸腺苷生物荧光肿瘤抗癌药物药敏性分析实验（ATP-TCA）在卵巢癌患者化疗中的应用。研究选取88例卵巢上皮性癌新鲜组织行ATP-TCA体外药敏试验,分析结果、计算各种化疗药物敏感性,并与48例对照组患者进行临床近期有效率的比较。结果显示,在体外药敏试验敏感性最强的单药为紫杉醇（51.9%）,敏感性强弱依次为：紫杉醇〉卡铂〉顺铂〉吉西他滨〉拓泊替康〉多西他赛〉依托泊苷〉环磷酰胺〉博来霉素,联合用药方案敏感性较单药增加。药敏组患者临床近期有效率（85.23%）高于对照（68.75%）。ATP-TCA是一种有效的抗癌药物敏感性分析实验,可为卵巢癌患者临床化疗提供个体化的指导方案。     

COPS5 Conferred the Platinum Resistance in Epithelial Ovarian Cancer

Development of platinum resistance is one of the major causes of epithelial ovarian cancer (EOC) treatment failure. COP9 signalosome subunit 5 (COPS5) was found to take part in the progression of EOC in our previous study. Herein, we aim to uncover the potential utility of COPS5 in EOC chemoresistance. COPS5 levels were analyzed to define clinic pathologic correlates using a matched tissue microarray and online datasets. The effect of COPS5 inhibition by the lentivirus-mediated short hairpin RNA on cell viability, proliferation and migration was accessed in vitro and in vivo. Results showed that COPS5 was upregulated in patients after platinum resistance. Kaplan–Meier survival curves revealed that COPS5 overexpression was correlated with shorter PFS and OS. COPS5 downregulation inhibited the cell proliferation, migration, and reduced the sensitivity of EOC to platinum. Overall, our data indicated that COPS5 inhibition might represent a new therapeutic strategy for overcoming platinum resistance in patients with EOC.     

Circulating Exosomal miR-1290 for Diagnosis of Epithelial Ovarian Cancer

The aim of the study was to develop a new diagnostic biomarker for identifying serum exosomal miRNAs specific to epithelial ovarian cancer (EOC) and to find out target gene of the miRNA for exploring the molecular mechanisms in EOC. A total of 84 cases of ovarian masses and sera were enrolled, comprising EOC (n = 71), benign ovarian neoplasms (n = 13). We detected expression of candidate miRNAs in the serum and tissue of both benign ovarian neoplasm group and EOC group using real-time polymerase chain reaction. Immunohistochemistry were constructed using formalin fixed paraffin embedded (FFPE) tissue to detect expression level of suppressor of cytokine signaling 4 (SOCS4). In the EOC group, miRNA-1290 was significantly overexpressed in serum exosomes and tissues as compared to benign ovarian neoplasm group (fold change ≥ 2, p < 0.05). We observed area under the receiver operating characteristic curve (AUC) for miR-1290, using a cut-off of 0.73, the exosomal miR-1290 from serum had AUC, sensitivity, and specificity values of 0.794, 69.2 and 87.3, respectively. In immunohistochemical study, expression of SOCS4 in EOC was lower than that in benign ovarian neoplasm. Serum exosomal miR-1290 could be considered as a biomarker for differential diagnosis of EOC from benign ovarian neoplasm and SOCS4 might be potential target gene of miR-1290 in EOC.     

人附睾蛋白4与血清CA125联合检测在卵巢癌诊断中的应用价值

目的：探讨人附睾蛋白4（HE4）和CA125联合检测在上皮性卵巢癌临床诊断中的应用价值。方法：用化学发光法测定51例卵巢癌患者、64例卵巢良性疾病患者和50例健康对照者血清中的HE4和CA125水平,并对结果进行比较分析。结果：卵巢癌组血清中HE4和CA125水平均显著高于卵巢良性肿瘤组和健康对照组,差异有统计学意义（P〈0．05）,卵巢良性肿瘤组与健康对照组比较无显著性差异;HE4在早期卵巢癌中的阳性率高于CA125,两者联合检测可提高卯巢癌诊断的阳性率;卵巢癌组联合检测ROC曲线下面积大于单项检测曲线下面积。结论：联合检测HE4和CA125有助于卵巢癌的早期诊断。     

Twist1调控FoxM1 在上皮性卵巢癌中的表达

目的:探讨Twist1调控转录因子Fox M1在上皮性卵巢癌中的表达。方法:采用免疫组织化学SP法检测Fox M1、Twist1在上皮性卵巢癌组织中表达情况,斯皮尔曼秩相关分析其在上皮性卵巢癌组织中的表达相关性;双荧光素酶报告系统检测Twist1对Fox M1的调控作用;Real-time quantitative RT-PCR和蛋白免疫印迹技术验证Twist1对Fox M1的调控作用。结果:Twist1、Fox M1在上皮性卵巢癌组织中的阳性表达率分别是71.4%(40/56)、78.6%(44/56),明显高于正常卵巢组织,差异有统计学意义(P<0.05);且其在上皮性卵巢癌中的表达显著相关(r=0.896,P<0.01);Twist1可以结合并激活Fox M1启动子(P<0.05);上调Twist1表达可以激活Fox M1在卵巢癌细胞中的表达(P<0.05),而干扰Twist1后可以下调Fox M1的表达(P<0.05)。结论:Twist1参与调控增殖相关转录因子Fox M1在卵巢癌中的表达,可能是一个潜在的治疗靶点。     

Lipocalin2 Expressions Correlate Significantly With Tumor Differentiation in Epithelial Ovarian Cancer

We recently identified lipocalin2 (LCN2) as being upregulated in ovarian cancer cell lines. The purpose of this study was to validate LCN2 upregulation in ovarian cancers and to investigate its potential as a serum biomarker. We assayed LCN2 expression in ovarian cancers using real-time PCR and IHC. To evaluate the potential of LCN2 as a biomarker, we measured serum LCN2 levels in 54 ovarian cancers, 15 borderline and 53 benign ovarian tumors, and 90 healthy controls. SYBR green PCR and IHC showed LCN2 overexpression in ovarian cancers. LCN2 immunoreactivity was significantly associated with tumor differentiation (p=0.009), as well-differentiated tumors showed the highest LCN2 expression. Serum LCN2 level in ovarian cancer was significantly higher than in the other study groups (p<0.001), and in accordance with IHC results, it also correlated with tumor differentiation, with well-differentiated tumors having the highest value. The sensitivity and specificity of LCN2 in detecting ovarian cancer was 72.2% and 50.4%, respectively. By Cox univariate analysis, LCN2 positivity was an independent prognostic factor for overall survival (hazard ratio = 1.47, p=0.012). In conclusion, LCN2 expressions are upregulated and related to tumor differentiation in ovarian cancers and should be included in future research assessing potential biomarkers for ovarian cancer. (J Histochem Cytochem 57:513–521, 2009)     

动态监测上皮性卵巢癌患者血清CA125水平对疗效及预后的评估价值

目的:通过观察卵巢上皮性癌患者术前、术后及化疗后CA125水平变化,探讨其水平变化对患者预后的评价价值。方法:选取2012年3月至2013年2月间医院诊治的卵巢上皮性癌患者85例为研究对象,所有患者均接受规范的卵巢癌分期手术或卵巢癌细胞减灭术,术后常规进行系统化疗。比较手术及化疗后患者血清CA125水平的变化,分析患者血清CA125水平动态变化、转阴时间与患者预后关系。结果:治疗后,患者CA125水平呈明显下降趋势,差异具有统计学意义(P0.05)。T1/2≤20 d患者存活时间明显长于T1/220 d的患者,差异具有统计学意义(P0.05)。CA125转阴时间≤8周的患者存活时间长于CA125转阴时间8周的患者,差异具有统计学意义(P0.05)。其复发率明显低于CA125转阴时间8周的患者,复发时间长于CA125转阴时间8周的患者,差异具有统计学意义(P0.05)。结论:通过检测血清CA125水平变化可以对卵巢上皮性癌患者预后进行较为准确的评价。     

PARP-1 抑制剂靶向治疗上皮性卵巢癌的研究进展

简介聚二磷酸腺苷核糖聚合酶-1（PARP-1）及其功能和在DNA 损伤修复中的作用,综述PARP-1 抑制剂的作用机制、发展现状以及在上皮性卵巢癌治疗中的应用,并探讨PARP-1 抑制剂靶向治疗上皮性卵巢癌的临床试验失败原因,展望PARP-1 抑制剂的应用前景,提出需对PARP-1 抑制剂在用于治疗上皮性卵巢癌中的耐药机制和选择性展开深入研究。     

卵巢上皮性肿瘤中FKBP38 蛋白的表达研究

目的:探讨卵巢上皮性肿瘤中FK506结合蛋白38(FK506-binding protein 38,FKBP38)蛋白的表达及潜在的临床意义。方法:采用免疫组化的方法检测20例正常输卵管组织,30例卵巢上皮性良性肿瘤,27例卵巢交界性肿瘤组织,130例卵巢上皮性癌(epithelial ovarian carcinoma,EOC)组织中FKBP38蛋白的表达,并分析其表达水平与临床病理参数的关系。结果:FKBP38蛋白在卵巢上皮性癌中的表达明显低于正常输卵管组织、卵巢上皮性良性和交界性肿瘤组织,差异有统计学意义(P0.05)。FKBP38蛋白表达在根据国际妇产科联盟(International Federation of Gynecology and Obstetrics,FIGO)标准定义的不同分期的卵巢上皮性癌组织中具有统计学差异(P0.05)。FKBP38蛋白在卵巢高级别浆液性癌的表达比低级别浆液性癌中的表达显著性降低(P0.05)。但把卵巢上皮性癌按照不同年龄及不同组织学分型分层后,FKBP38蛋白表达差异无统计学意义(P0.05)。结论:FKBP38蛋白表达的下调可能与卵巢上皮性癌的发生和分化密切相关,提示FKBP38蛋白作为卵巢恶性肿瘤诊断和治疗的潜在性生物靶点需进一步探索和研究。     

Evaluation of the Cost Effectiveness of Establishing A Fine Needle Aspiration Cytology Clinic In A Hospital Out-Patient Department

In an attempt to reduce the number of inadequate smears processed by our laboratory and the false negative rate of fine needle aspiration cytodiagnosis, we have introduced a fine needle aspiration cytology service where aspirates are taken by the cytopathologist in a clinic. In the 12 month period since the introduction of this service, the number of inadequate smears fell sharply. Nine per cent of the specimens were inadequate compared with 43% of specimens from other sources. The establishment of the clinic resulted in a threefold reduction in the cost of diagnosing breast lesions.     

胃癌腹膜转移的细胞学及分子生物学检测进展

胃癌是常见的肿瘤之一,在消化道肿瘤中占首位。胃癌的临床病变缺乏特异性,大部分患者就诊时已发生了转移,多数病例就诊时已为进展期或晚期。腹膜转移是胃癌最常见的转移形式,胃癌的腹膜转移是造成患者预后差的主要原因,因此,及时地诊断腹膜转移,从而采取相应治疗,对提高患者术后生存率具有重要意义。     

In Vivo and Ex Vivo Approaches to Study Ovarian Cancer Metastatic Colonization of Milky Spot Structures in Peritoneal Adipose

High-grade serous ovarian cancer (HGSC), the cause of widespread peritoneal metastases, continues to have an extremely poor prognosis; fewer than 30% of women are alive 5 years after diagnosis. The omentum is a preferred site of HGSC metastasis formation. Despite the clinical importance of this microenvironment, the contribution of omental adipose tissue to ovarian cancer progression remains understudied. Omental adipose is unusual in that it contains structures known as milky spots, which are comprised of B, T, and NK cells, macrophages, and progenitor cells surrounding dense nests of vasculature. Milky spots play a key role in the physiologic functions of the omentum, which are required for peritoneal homeostasis. We have shown that milky spots also promote ovarian cancer metastatic colonization of peritoneal adipose, a key step in the development of peritoneal metastases. Here we describe the approaches we developed to evaluate and quantify milky spots in peritoneal adipose and study their functional contribution to ovarian cancer cell metastatic colonization of omental tissues both in vivo and ex vivo. These approaches are generalizable to additional mouse models and cell lines, thus enabling the study of ovarian cancer metastasis formation from initial localization of cells to milky spot structures to the development of widespread peritoneal metastases.     

ROMA在卵巢上皮性癌早期诊断中的研究进展

卵巢上皮性癌（Epithelial ovarian cancer,EOC）死亡率居妇科恶性肿瘤首位,早期诊断可明显改善患者预后。人附睾上皮分泌蛋白（human epididymis protein 4,HE4）对早期EOC的检测敏感性高,有助于对EOC高危患者的筛选,与CA125可互补,增加盆腔包块患者中EOC早期诊断力度。HE4与CA125联合检测及结合绝经状态预测盆腔包块患者中卵巢恶性肿瘤的发病风险模型（Risk of Ovarian Malignancy Algorithm,ROMA）,能成功预测盆腔包块患者中EOC高风险个体,对卵巢良恶性肿瘤的鉴别预测更为准确且更易被接受,有较大的临床应用价值。     

Fluid-Flow Induced Wall Shear Stress and Epithelial Ovarian Cancer Peritoneal Spreading

Epithelial ovarian cancer (EOC) is usually discovered after extensive metastasis have developed in the peritoneal cavity. The ovarian surface is exposed to peritoneal fluid pressures and shear forces due to the continuous peristaltic motions of the gastro-intestinal system, creating a mechanical micro-environment for the cells. An in vitro experimental model was developed to expose EOC cells to steady fluid flow induced wall shear stresses (WSS). The EOC cells were cultured from OVCAR-3 cell line on denuded amniotic membranes in special wells. Wall shear stresses of 0.5, 1.0 and 1.5 dyne/cm² were applied on the surface of the cells under conditions that mimic the physiological environment, followed by fluorescent stains of actin and β-tubulin fibers. The cytoskeleton response to WSS included cell elongation, stress fibers formation and generation of microtubules. More cytoskeletal components were produced by the cells and arranged in a denser and more organized structure within the cytoplasm. This suggests that WSS may have a significant role in the mechanical regulation of EOC peritoneal spreading.     

WT-1、Smac蛋白在上皮性卵巢癌中的表达和临床意义研究

目的:探讨WT-1和Smac蛋白在上皮性卵巢癌中的表达及其临床意义。方法:应用免疫组织化学染色方法检测40例正常卵巢组织,40例卵巢上皮性良性肿瘤组织,60例全面分期手术治疗的上皮性卵巢癌组织中WT-1、Smac蛋白的表达,并分析WT-1、Smac蛋白的表达与上皮性卵巢癌临床病理特征的相关性及二者之间的相关性。结果:WT-1蛋白在上皮性卵巢癌组织中的表达明显高于正常卵巢组织或卵巢上皮性良性肿瘤组织(P0.05);Smac蛋白在上皮性卵巢癌组织中表达明显低于正常卵巢组织或卵巢上皮性良性肿瘤组织(P0.05)。上皮性卵巢癌组织中WT-1、Smac蛋白的表达与肿瘤临床分期、组织分化程度、淋巴结有无转移均显著相关(P0.05)。且上皮性卵巢癌中WT-1、Smac蛋白的表达呈明显负相关性(r=-0.35,P0.05)。结论:WT-1蛋白高表达或Smac蛋白低表达可能在上皮性卵巢癌的发生、发展中发挥重要作用,检测WT-1、Smac蛋白的表达有助于上皮性卵巢癌恶性程度的判断和预后评估。     

卵巢上皮癌中ING4 基因启动子的甲基化状态及其临床意义

目的：探讨卵巢上皮癌中ING4 基因启动子的甲基化状态及其临床意义。方法：收集2005 年7 月至2012 年6 月哈尔滨医科 大学附属第一医院行全面分期手术并经病理检查确诊的150 例卵巢上皮癌组织标本,并以同期因子宫肌瘤或子宫腺肌症行子宫 全切除术或次全切除术并经病理检查确诊为正常卵巢组织的150 例标本作为对照组。采用甲基化特异性PCR（MSP）技术检测卵 巢上皮癌组织与正常卵巢组织中ING4 基因启动子的甲基化状态,蛋白印迹法检测ING4 蛋白的表达,并分析ING4 基因启动子 的甲基化状态与卵巢上皮癌临床病例特征的关系。结果：卵巢上皮癌组织中ING4 基因启动子的甲基化阳性率为42.7%（64/150）, 明显高于正常卵巢组织（4%,6/150）,差异有统计学意义（P<0.05）。ING4 基因启动子甲基化阳性的卵巢上皮癌组织中ING4蛋白 表达阴性或弱阳性;ING4 基因启动子甲基化阴性的卵巢上皮癌和正常卵巢组织中ING4 蛋白表达阳性;在64 例ING4 基因启动 子甲基化的卵巢上皮癌组织中,ING4 蛋白表达强度与ING4 基因启动子的甲基化程度呈负相关（r=-0.435,P<0.05）。卵巢上皮癌 组织中,ING4 基因甲基化的阳性率随着手术病理分期和组织学分级的增加而增加（P<0.05）;卵巢透明细胞癌（55.6%,10/18）和卵 巢子宫内膜样癌（59.3%,16/27）中ING4 基因甲基化的阳性率显著高于浆液性囊腺癌（33.9%,20/59）和粘液性囊腺癌（39.1%, 18/46）（P<0.05）;ING4基因启动子的甲基化状态与患者的年龄、有无腹水及淋巴结转移均无显著相关性（P>0.05）。结论：ING4 基 因启动子的甲基化可能促进了其在卵巢上皮癌组织中的表达失活,进而促进了卵巢上皮癌的生长和分化。     

卵巢上皮癌中ING4基因启动子的甲基化状态及其临床意义

目的：探讨卵巢上皮癌中ING4基因启动子的甲基化状态及其临床意义。方法：收集2005年7月至2012年6月哈尔滨医科大学附属第一医院行全面分期手术并经病理检查确诊的150例卵巢上皮癌组织标本,并以同期因子宫肌瘤或子宫腺肌症行子宫全切除术或次全切除术并经病理检查确诊为正常卵巢组织的150例标本作为对照组。采用甲基化特异性PCR（MSP）技术检测卵巢上皮癌组织与正常卵巢组织中ING4基因启动子的甲基化状态,蛋白印迹法检测1NG4蛋白的表达,并分析ING4基因启动子的甲基化状态与卵巢上皮癌临床病例特征的关系。结果：卵巢上皮癌组织中ING4基因启动子的甲基化阳性率为42．7％（64／150）,明显高于正常卵巢组织（4％,6／150）,差异有统计学意义（P〈0．05）。ING4基因启动子甲基化阳性的卵巢上皮癌组织中ING4蛋白表达阴性或弱阳性;1NG4基因启动子甲基化阴性的卵巢上皮癌和正常卵巢组织中ING4蛋白表达阳性;在64例1NG4基因启动子甲基化的卵巢上皮癌组织中,ING4蛋白表达强度与ING4基因启动子的甲基化程度呈负相关（r=-0．435,P〈0．05）。卵巢上皮癌组织中,1NG4基因甲基化的阳性率随着手术病理分期和组织学分级的增加而增加（P〈0．05）;卵巢透明细胞癌（55．6％,10／18）和卵巢子宫内膜样癌（59-3％,16／27）中ING4基因甲基化的阳性率显著高于浆液性囊腺癌（33．9％,20／59）和粘液性囊腺癌（39．1％,18／46）（P〈0．05）;ING4基因启动子的甲基化状态与患者的年龄、有无腹水及淋巴结转移均无显著相关性（P〉0．05）。结论：ING4基因启动子的甲基化可能促进了其在卵巢上皮癌组织中的表达失活,进而促进了卵巢上皮癌的生长和分化。     

miRNA表达谱与上皮性卵巢癌

Micro RNA(miRNA)是近年来研究发现的一种高度保守,长度大约19-25个核苷酸的非编码小分子RNA,起着调控基因表达的作用。目前认为miRNA能调控细胞周期、凋亡、分化、发育和新陈代谢等,参与肿瘤的发生与发展,因此异常表达的miRNAs表达谱有可能成为一种全新的肿瘤分子标记物。相关研究表明,miRNA能够以一种被保护的状态存在于血清及血浆中,因此miRNA表达谱的发现具有易检测性、重现性以及非侵袭性。研究显示血清及血浆中miRNA表达谱可作为上皮性卵巢癌生物信号分子,在上皮性卵巢癌早期诊断、预后判断和化疗药物应用等方面具有不可替代的作用。本文将对miRNA表达谱与上皮性卵巢癌的关系进行一个简单总结。     

Cytology of Bronchoalveolar Lavage In Some Rare Pulmonary Disorders: Pulmonary Alveolar Proteinosis and Amiodarone Pulmonary Toxicity

Cytological patterns of bronchoalveolar lavage (BAL) in pulmonary alveolar proteinosis (PAP) and amiodarone pulmonary toxicity (APT) are presented together with light and electron microscopy (EM). the differential cell count of BAL in both diseases is similar in that alveolar macrophages predominate. However, the cytology of PAP is characterized by scanty macrophages and alveolar epithelial cells in abundant periodic acid-Schiff (PAS)-positive extracellular material. the gross appearance of the BAL fluid is therefore opaque. In contrast, the cytology of APT is characterized by foamy alveolar macrophages with numerous lamellar bodies in their cytoplasm, and the BAL fluid is clear.     

Modeling the Early Steps of Ovarian Cancer Dissemination in an Organotypic Culture of the Human Peritoneal Cavity

The pattern of ovarian cancer metastasis is markedly different from that of most other epithelial tumors, because it rarely spreads hematogenously. Instead, ovarian cancer cells exfoliated from the primary tumor are carried by peritoneal fluid to metastatic sites within the peritoneal cavity. These sites, most notably the abdominal peritoneum and omentum, are organs covered by a mesothelium-lined surface. To investigate the processes of ovarian cancer dissemination, we assembled a complex three-dimensional culture system that reconstructs the lining of the peritoneal cavity in vitro. Primary human fibroblasts and mesothelial cells were isolated from human omentum. The fibroblasts were then mixed with extracellular matrix and covered with a layer of the primary human mesothelial cells to mimic the peritoneal and omental surfaces encountered by metastasizing ovarian cancer cells. The resulting organotypic model is, as shown, used to examine the early steps of ovarian cancer dissemination, including cancer cell adhesion, invasion, and proliferation. This model has been used in a number of studies to investigate the role of the microenvironment (cellular and acellular) in early ovarian cancer dissemination. It has also been successfully adapted to high throughput screening and used to identify and test inhibitors of ovarian cancer metastasis.