Human kallikrein 11: an indicator of favorable prognosis in ovarian cancer patients

OBJECTIVES: Human kallikrein 11 (hK11) is a secreted serine protease, highly expressed in hormonally regulated tissues, including the prostate and the ovary. Our preliminary studies indicate that hK11 may represent a diagnostic and prognostic biomarker for ovarian cancer. The aim of the present study was to examine the prognostic value of hK11 expression in ovarian tumors. METHODS: Using our established immunofluorometric assay, hK11 levels were quantified (ng per mg of total protein) in 134 ovarian tumor extracts and correlated with various clinicopathological variables and outcome [progression-free survival (PFS), overall survival (OS)], over a median follow-up period of 42 months. RESULTS: hK11 concentration in ovarian tumor cytosols ranged from 0 to 155 ng/mg of total protein, with a median of 1.45 ng/mg. An optimal cutoff value of 6.3 ng/mg was selected to categorize tumors as hK11-positive or negative. hK11-positive tumors were most often of early stage (Stage I/II) and grade (G1/G2) (P < 0.05). Univariate analysis revealed that patients with hK11-positive tumors had a significantly longer PFS (HR of 0.39, P = 0.005) and OS (HR of 0.44, P = 0.033). Cox multivariate analysis indicated that hK11 was an independent prognostic indicator of PFS (HR of 0.47, P = 0.042). Kaplan-Meier survival curves further confirmed that women with hK11-positive tumors have longer PFS and OS (P = 0.003 and P = 0.028, respectively). Also, a weak positive correlation was found between the expression levels of tissue hK11 and tissue CA125 (rs = 0.508; P < 0.001). CONCLUSIONS: These results further validate our initial findings that hK11 is an independent marker of favorable prognosis in ovarian cancer patients.     

Unfavorable prognostic value of human kallikrein 7 quantified by ELISA in ovarian cancer cytosols

BACKGROUND: Human tissue kallikrein 7 (gene, KLK7; protein, hK7) is a member of the kallikrein family of secreted serine proteases. Reports indicate that in ovarian cancer, KLK7 is significantly up-regulated at the mRNA level. The aim of this study was to determine whether hK7, measured quantitatively by ELISA in ovarian cancer cytosols, is a prognostic biomarker for ovarian cancer. METHODS: We used a newly developed ELISA with 2 monoclonal antibodies to quantify hK7 production in 260 ovarian tumor cytosols and correlated these data with various clinicopathologic variables and patient outcomes [progression-free survival (PFS) and overall survival (OS)] over a median follow-up period of 52 months. RESULTS: Median (range) hK7 concentration in ovarian tumor cytosols was 2.84 (0-32.8) ng/mg of total protein. Compared with healthy and benign ovarian tissues and nonovarian tumors that metastasized to the ovary, malignant ovarian tumor cytosols highly overproduced hK7 (P <0.001). We used the median value as the cutoff value to categorize tumors as hK7-positive and hK7-negative. Women with hK7-positive tumors most frequently had advanced-stage disease, higher tumor grade (G3), suboptimal debulking, and serous or undifferentiated histotype (P <0.001). Univariate analysis showed that hK7 positivity was associated with significantly shorter PFS (P = 0.01) but not OS. Kaplan-Meier survival curves confirmed an increased risk of relapse in women with hK7-positive tumors (P = 0.009). In multivariate analysis, hK7 was not significantly associated with either PFS or OS. CONCLUSIONS: hK7 is associated with other unfavorable characteristics of ovarian cancer, but it is not an independent prognosticator for ovarian cancer.     

B型超声诊断子宫颈部闭锁1例

患者女，２４岁。从未行经，但第二性征发育正常，８年来每月有规律地下腹痛１次，现腹痛来院就诊，因憋尿先行Ｂ超检查。Ｂ超显示：膀胱后方可见尿道回声，其后为阴道回声（图１），未见正常宫颈回声，代之以线状强回声与宫体相连，宫体位于下腹部偏左，大小尚可，宫腔内...     

人类激肽释放酶基因6在卵巢恶性肿瘤中的表达及其机制研究

目的 研究人组织激肽释放酶基因6（KLK6）mRNA和蛋白在卵巢肿瘤组织中的表达水平,探讨其在卵巢恶性肿瘤中的作用机制.方法 应用RT-PCR和免疫组化SP法分别检测在正常的卵巢组织、卵巢的良性肿瘤、卵巢的交界性肿瘤及卵巢的恶性肿瘤组织中KLK6的mRNA表达及蛋白的表达,探讨该基因的表达与卵巢恶性肿瘤患者的临床病理特征关系.结果 本研究显示,在卵巢癌组织中,KLK6 mRNA的表达水平与正常卵巢组织相比,显著增高;卵巢癌组织中KLK6蛋白的阳性表达率为69.4%,与正常卵巢组织（13.3%）、良性卵巢肿瘤（16.6%）和交界性卵巢肿瘤（44.0%）相比,差异有统计学意义（χ2=25.843,P＜0.001）.结论 KLK6可能参与了卵巢癌的侵袭和转移.     

Genes with bimodal expression are robust diagnostic targets that define distinct subtypes of epithelial ovarian cancer with different overall survival

In some cancer types, certain genes behave as molecular switches, with on and off expression states. These genes tend to define tumor subtypes associated with different treatments and different patient survival. We hypothesized that clinically relevant molecular switch genes exist in epithelial ovarian cancer. To test this hypothesis, we applied a bimodal discovery algorithm to a publicly available ovarian cancer expression microarray data set, GSE9891 [285 tumors: 246 malignant serous (MS), 20 endometrioid (EM), and 18 low malignant potential (LMP) ovarian carcinomas]. Genes with robust bimodal expression patterns were identified across all ovarian tumor types and also within selected subtypes: 73 bimodal genes demonstrated differential expression between LMP versus MS and EM; 22 bimodal genes distinguished MS from EM; and 14 genes had significant association with survival among MS tumors. When these genes were combined into a single survival score, the median survival for patients with a favorable versus unfavorable score was 65 versus 29 months (P < 0.0001, hazard ratio = 0.4221). Two independent data sets [high-grade, advanced-stage serous (n = 53) and advanced-stage (n = 119) ovarian tumors] validated the survival score performance. We conclude that genes with bimodal expression patterns not only define clinically relevant molecular subtypes of ovarian carcinoma but also provide ideal targets for translation into the clinical laboratory.     

Clinical significance of breast cancer susceptibility gene 1 expression in resected non-small cell lung cancer: A meta-analysis

BACKGROUNDThe clinical significance of breast cancer susceptibility gene 1 (BRCA1) in non-small cell lung cancer (NSCLC) patients undergoing surgery remains unclear up to now.AIMTo explore the relation of BRCA1 expression with clinicopathological characteristics and survival in patients with resected NSCLC. METHODSEMBASE, PubMed, Web of Science, and The Cochrane Library databases were searched to identify the relevant articles. To assess the correlation between the expression of BRCA1 and clinicopathological characteristics and prognosis of patients with resected NSCLC patients, the combined relative risks or hazard ratios (HRs) with their corresponding 95% confidence intervals [CIs] were estimated. RESULTSTotally, 11 articles involving 1041 patients were included in the meta-analysis. The results indicated that the expression of BRCA1 was significantly correlated with prognosis of resected NSCLC. Positive BRCA1 expression signified a shorter overall survival (HR = 1.60, 95%CI: 1.25-2.05; P < 0.001) and disease-free survival (HR = 1.78, 95%CI: 1.42-2.23; P < 0.001). However, no significant association of BRCA1 expression with any clinicopathological parameters was observed.CONCLUSIONBRCA1 expression indicates a poor prognosis in resected NSCLC patients. BRCA1 might serve as an independent biomarker to predict clinical outcomes and help to customize optimal adjuvant chemotherapy for NSCLC patients who had received surgical therapy.     

Cathepsin D concentration in breast cancer cytosols: correlation with disease-free interval and overall survival.

Cathepsin D (CD) is an aspartyl protease implicated in cancer metastasis. In this study of 331 patients, we show that patients with primary breast carcinomas containing high concentrations of CD have a significantly shorter disease-free interval (chi-square = 4.28, P < 0.05) and overall survival (chi-square = 7.7, P < 0.01) than patients with low concentrations. CD as a prognostic marker for overall survival was equally valuable for women younger (chi-square = 4.39, P < 0.05) and older (chi-square = 3.97, P < 0.05) than 50 years. CD was also a significant prognostic marker for overall survival within the estradiol receptor (ER)-positive subgroup of patients (chi-square = 5.79, P < 0.025), but not in the ER-negative subgroup. Patients with tumors containing high concentrations of CD and low concentrations of ER had shorter disease-free intervals (chi-square = 15.1, P < 0.001) and lower overall survival (chi-square = 20.9, P < 0.001) than patients with high concentrations of ER but low concentrations of CD.     

卵巢上皮癌合并血小板增多患者的预后分析

目的回顾性分析血小板增多症在卵巢上皮癌患者中的发生率及其对卵巢上皮癌患者预后的影响。方法选择1999年-2004年人院的卵巢上皮癌患者141例,分析术前血小板计数与患者年龄、病理类型、组织学分级、临床分期、CA125水平等临床病理因素之间的关系、同时分析比较卵巢上皮癌伴或不伴血小板增多症患者的生存时间之间的差异。结果141例患者中有42例患者（29．8％）在术前诊断时即合并血小板增多（血小板计数〉400×10^9／L）。在合并血小板增多的卵巢上皮癌组中CA125水平明显增高、晚期肿瘤比例更多、组织学分级多为中高级,接受理想减瘤术的比率更低伊均〈0．05）。此外,与无血小板增多症的患者相比,卵巢上皮癌伴血小板增多症患者的疾病无进展时间（15个月VS．28个月,P〈0．01）和总生存时间均明显缩短（29个月VS．37个月,P〈0．01）。结论卵巢上皮癌常伴有血小板增多症,后者是卵巢上皮癌患者预后不佳的标志之一。     

Prognostic significance of ultrasound derived intratumoral peak systolic velocity in epithelial ovarian cancer.

OBJECTIVE: To evaluate the prognostic significance of ultrasound derived intratumoral peak systolic velocity in epithelial ovarian cancer. DESIGN: Color Doppler imaging and pulsed Doppler spectral analysis were used in the investigation of 49 patients with epithelial ovarian cancer (19 serous, 15 mucinous, eight endometrioid, four clear cell and three Brenner cell) immediately before laparotomy. Twenty-two were stage I, six were stage II, 17 were stage III and four were stage IV. Sections of malignant tumors were analyzed for the cellular expression of thymidine phosphorylase and the intratumoral density of microvessels by immunohistochemistry using antibodies to thymidine phosphorylase and factor VIII-related antigen, respectively. Moreover, the apoptotic index was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling method. Intratumoral peak systolic velocity was tested for correlation with patients' age at diagnosis, stage of disease, presence of a residual tumor, histological subtype and grade, thymidine phosphorylase expression, apoptotic index, microvessel count and patient survival. RESULTS: Histological grade (P = 0.025), thymidine phosphorylase expression (P = 0.044), apoptotic index (P = 0.039) and microvessel count (P = 0.014) were all significantly associated with peak systolic velocity. Stage of disease (P = 0.002), presence of residual disease (P = 0.0002) and peak systolic velocity (P = 0.041) were found by univariate Cox regression analysis to be significantly associated with a poor prognosis. Multivariate Cox regression analysis revealed that stage of disease (P = 0.006) and peak systolic velocity (P = 0.008) are independent prognostic factors. CONCLUSIONS: Intratumoral peak systolic velocity could be a preoperatively pertinent prognostic predictor of survival in patients with epithelial ovarian cancer.     

The effect of low-molecular-weight heparin on cancer survival. A systematic review and meta-analysis of randomized trials

BACKGROUND: Low-molecular-weight heparins (LMWH) have an antitumor effect in vitro and in experimental animal models of malignancy. Retrospective data suggest that it might improve survival in cancer patients. OBJECTIVES: To evaluate the effect of LMWH compared to placebo or no anticoagulant intervention on the survival of cancer patients. METHODS: We conducted a systematic review of randomized trials specifically evaluating the impact of LMWH on the survival of cancer patients. DATA SOURCES WERE: MEDLINE, EMBASE, HealthSTAR, Cochrane library, gray literature and cross-referencing from reference lists. Data extraction was performed by one reviewer, and accuracy was independently verified by a second reviewer. Meta-analysis was conducted using: (i) odds ratio (OR) and relative risk (RR); (ii) survival rates using censored endpoints; and (iii) hazard ratios (HR). RESULTS: The pooled HR in all patients was 0.83 (95% CI 0.70-0.99; P = 0.03), and in patients with advanced disease it was 0.86 (95% CI 0.74-0.99; P = 0.04), both in favor of the LMWH group. The results of the OR, RR and survival meta-analysis consistently favored the LMWH group. Sensitivity analyses according to tumor type were not conducted, because of a lack of information. CONCLUSIONS: LMWH improves overall survival in cancer patients, even in those with advanced disease. Additional trials are required to define the tumor types, disease stages and dosing schedules most likely to provide the greatest survival benefit.     

乳腺癌组织KLK7 mRNA的表达及其与临床病理特征的关系

目的建立人KLK7mRNA荧光定量检测方法,对正常乳腺组织和癌组织KLK7 mRNA进行定量,分析其表达与部分临床病理特征的关系,探讨其临床意义。方法应用实时荧光定量PCR检测48例乳腺癌切除的组织中KLK7基因mRNA的表达量,并分析KLK7 mRNA的表达量与年龄、TNM分期、组织学类型、淋巴结转移、雌激素受体（ER）、孕激素受体（PR）等临床病理特征的关系。结果KLK7 mRNA在乳腺正常组织相对表达水平为0．091±0．139,在乳腺癌组织中的相对表达水平为0．107±0．122,无统计学意义（P〉0．05）。但KLK7 mRNA在有淋巴结转移的患者乳腺癌组织中的表达水平高于未转移组（P〈0．05）;在Ⅲ-Ⅳ期患者乳腺癌组织中高于Ⅰ．Ⅱ期患者（P〈0．05）;ER（＋）阳性乳腺癌组织明显低于ER（-）乳腺癌组织（P〈0．05）。KLK7 mRNA表达水平与患者年龄、组织病理分类以及孕激素受体状态无相关性（P〉0．05）。结论乳腺癌组织KLK7 mRNA表达与TNM分期、ER状态及肿瘤转移情况有关。     

Unsuspected pulmonary emboli adversely impact survival in patients with cancer undergoing routine staging multi‐row detector computed tomography scanning

Background: While symptomatic venous thromboembolism adversely impacts survival among cancer patients, the outcome of cancer patients with unsuspected pulmonary embolism (UPE) found on routine cancer staging multi‐row detector computed tomography (MDCT) scans is unknown. Objective: To determine whether UPE detected on routine staging MDCT scans impacts overall survival among cancer patients. Patients and methods: We performed a matched cohort study of cancer patients diagnosed with UPE on routine staging scans between May 2003 and August 2006. Two controls (n = 137) were individually matched by age (± 5 years), cancer type and stage for each UPE patient (n = 70). We used Cox’s proportional hazard models to compare the mortality between UPE patients and their matched controls. Results: The hazard ratio (HR) for death among UPE patients was 1.51 (95% CI 1.01–2.27, P = 0.048). Compared with their matched controls, patients with UPE more proximal than the subsegmental arterial branches had a HR for death at 6 months of 2.28 (95% CI 1.20–4.33, P = 0.011) and an overall HR of 1.70 (95% CI 1.06–2.74, P = 0.027). Survival among UPE patients with isolated subsegmental PE (ISSPE) was not significantly different than that of matched controls (HR 1.04 95% CI 0.44–2.39, P = 0.92). Conclusions: UPE identified more proximal than the subsegmental arterial branches has a significant negative impact on survival among cancer patients.     

卵巢癌中IGF-1/IGF-1R轴与临床病理特征及预后的相关性

目的研究卵巢癌中胰岛素样生长因子-1(IGF-1)/IGF-1受体(IGF-1R)轴与临床病理特征、手术预后的相关性。方法选择2015年3月至2017年12月期间在本院妇产科手术切除的卵巢癌组织、卵巢良性肿瘤组织、正常卵巢癌组织,采用免疫组化检测IGF-1、IGF-1R的阳性率,采用荧光定量PCR检测IGF-1、IGF-1R的m RNA表达水平。随访卵巢癌患者手术后的总生存期,采用Kalpan-Meier生存曲线分析总生存期的差异。结果卵巢癌组织中IGF-1、IGF-1R的阳性率、mRNA表达水平均高于卵巢良性肿瘤组织、正常卵巢癌组织,差异有统计学意义(P<0.05);FIGOⅢ~Ⅳ期、组织学分级G2-G3卵巢癌组织中IGF-1、IGF-1R的阳性率高于Ⅰ~Ⅱ期、组织学分级G1卵巢癌组织,差异有统计学意义(P<0.05);卵巢癌中IGF-1、IGF-1R阳性表达的患者总生存期较IGF-1、IGF-1R阴性表达患者缩短,差异有统计学意义(P<0.05)。结论卵巢癌中IGF-1及IGF-1R高表达与病理特征恶化、手术后总生存期缩短有关,IGF-1/IGF-1R轴参与卵巢癌的发病。