卵巢癌单克隆抗-抗独特型抗体32F2的制备及其特性研究

目的6B11是可模拟卵巢癌抗原的鼠源性抗独特型单克隆抗体,为了深入探讨其作为肿瘤疫苗的主动免疫机制,制备抗6B11的IgG型抗-抗独特型单克隆抗体并对其特性进行研究。方法以卵巢癌抗独特型抗体6B11作为免疫原,与载体钥孔槭血兰蛋白(KLH)偶联并辅以福氏佐剂,多次免疫同系Balb/c小鼠,通过杂交瘤技术将免疫脾细胞与骨髓瘤细胞Sp2/0融合;采用酶联免疫吸附实验(EL1SA)筛选杂交瘤细胞,经克隆化后建立稳定分泌鼠源性抗-抗独特型单克隆抗体的杂交瘤细胞株。秋水仙素法确认杂交瘤细胞染色体数目及形态,ELISA法鉴定抗体类型,采用非竞争酶免疫结合实验测定抗体亲和力,EL1SA、免疫组织化学方法检测抗-抗独特型单克隆抗体特异性结合抗原的性质。结果制备出一株能稳定分泌抗-抗独特型单克隆抗体的杂交瘤细胞株,命名为32F2。其染色体数目平均为103条,并有端着丝点和亚中部着丝点染色体,符合小鼠杂交瘤细胞特点。抗体类型为IgG1型,抗体亲和力约为2.3119×107L/mol,能够竞争抑制卵巢癌单克隆抗体COC166-9与原始抗原OC166-9的结合,免疫组织化学染色证实32F2鼠腹水与84.6%卵巢浆液性乳头状囊腺癌呈阳性染色,与COC166-9类似,表明32F2可与OC166-9抗原产生特异性结合。结论通过杂交瘤技术建立了分泌IgG1亚型的卵巢癌抗-抗独特型单克隆抗体的杂交瘤细胞株。对抗体的初步研究显示其能特异性结合初始抗原OC166-9,并能竞争抑制COC166-9与OC166-9的结合,属Ab1样Ab3,间接证实6B11为抗原内影像型抗体,具有模拟抗原作用。32F2的制备成功为进一步研究卵巢癌抗独特型疫苗6B11的作用机制打下了基础,并且该抗体具有潜在的临床治疗卵巢癌的价值。     

Imaging of ovarian cancer with radiolabelled monoclonal antibodies

Summary This article presents the state of the art of immunoscintigraphy (IS) of ovarian cancer. We will review the monoclonal antibodies (MoAbs) used in clinical trials: (HMFG1/2, OC125, H317, H17E2, NDOG2 and 791T/36). We conclude that none of the afore mentioned MoAbs are clearly superior and that IS cannot yet replace laparotomy for the diagnosis of overian cancer but may have a role in the follow-up of ovarian cancer, in timing second-look surgery and assessing the response/TD treatment.     

A phase II trial of EMD72000 (matuzumab), a humanized anti-EGFR monoclonal antibody, in patients with platinum-resistant ovarian and primary peritoneal malignancies

OBJECTIVE: The primary objective of this study was to determine the rate of response to matuzumab in patients with recurrent, EGFR-positive ovarian, or primary peritoneal cancer. Secondary end points included safety and tolerability, time to tumor progression, duration of response, and overall survival. METHODS: A multi-institutional single arm phase II trial. RESULTS: Of 75 women screened for the study, 37 were enrolled and treated. Median age of the treated patient population was 58 years, and most patients had more than four prior lines of chemotherapy. Therapy was well tolerated, the most common toxicities being a constellation of skin toxicities, including rash, acne, dry skin, and paronychia, as well as headache, fatigue, and diarrhea. Serious adverse events were very rare but included a single episode of pancreatitis that may have been drug related. All patients completed therapy, receiving 1 to 30 infusions of matuzumab. There were no formal responses (RR=0%, 95% CI: 0-9.5%), although 7 patients (21%) were on therapy for more than 3 months with stable disease. CONCLUSIONS: Matuzumab at the dose and schedule selected is well tolerated. In this population of very heavily pretreated patients with epithelial ovarian and primary peritoneal malignancies, there was no evidence of significant clinical activity when matuzumab was administered as monotherapy.     

Anti-tumor activity of an anti-DR5 monoclonal antibody, TRA-8, in combination with taxane/platinum-based chemotherapy in an ovarian cancer model

Objective

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates apoptosis via binding to death receptors and enhances the anti-tumor effect of conventional cancer therapies. We evaluated the efficacy of TRA-8, an agonistic antibody to DR5, combined with docetaxel and carboplatin in vitro in an intraperitoneal (IP) ovarian cancer model.

Methods

Luciferase positive ES2 cells (ES2H) were treated in 96 well plates with TRA-8, carboplatin, docetaxel, and combination therapy. Cell viability was assessed using ATP-lite assay. Apoptosis was confirmed via Western blot analysis. ES2H cells were injected IP into female athymic nude mice. Animals were sorted based on bioluminescent signal with the following treatments: 1) untreated; 2) TRA-8 alone; 3) docetaxel + carboplatin; and 4) docetaxel + carboplatin + TRA-8. Animals receiving TRA-8 antibody were injected IP with 200 μg of TRA-8 twice weekly until death. Animals receiving docetaxel + carboplatin were injected IP with 5 mg/kg and 15 mg/kg respectively every 3 weeks until death. Animals were assessed for tumor burden using bioluminescence imaging and overall survival.

Results

Combination therapy reduced viability of ES2H cells in vitro over single agent therapy. Tumor burden was lowest in the chemotherapy + TRA-8 group at days 23 (p < 0.001) and 30 (p = 0.04). Mean survival was greatest in the chemotherapy + TRA-8 group (41 days) compared to the chemotherapy only group (34 days) and control group (27 days) as determined by Kaplan-Meier analysis (p < 0.001).

Conclusion

Conventional chemotherapy combined with TRA-8 reduced cell-viability via activation of apoptotic pathways, reduced tumor burden and improved survival in this ovarian cancer model.     

Expression of MUC1 in primary and metastatic human epithelial ovarian cancer and its therapeutic significance

BACKGROUND: MUC1 is associated with cellular transformation and tumorigenicity and is considered as an important tumor-associated antigen (TAA) for cancer therapy. The objective of this study was to evaluate the patterns of MUC1 expression in primary tumors and metastatic lesions in the advanced stages of epithelial ovarian cancers (EOCs) and correlate the expression with clinicopathological features. METHODS: The expression of MUC1 was examined on frozen tissue sections from primary EOC (n=42), the matched metastatic lesions (n=30) and paraffin-embedded tissue sections from primary EOC (n=60), normal ovarian tissues (n=20) using immunohistochemistry (IHC) by monoclonal antibody (MAb) C595. RESULTS: The expression of MUC1 was found in 92% (39/42) of EOC and 90% (27/30) of the matched metastatic lesions in frozen tissue sections respectively while the expression of MUC1 was found in 95% (57/60) of EOC and 5% (1/20) of normal ovarian tissues in paraffin-embedded sections respectively. Most of the tumors showed moderate to strong intensity staining while normal ovarian tissues only showed weak intensity staining. The overexpression of MUC1 was significantly associated with various progression parameters such as tumor stage, grade, residual disease status and presence of ascites (P<0.05). CONCLUSIONS: MUC1 is overexpressed in above 90% of late stage of EOC and of metastatic lesions but not in normal ovarian tissues, and the high expression of MUC1 is correlated with EOC progression. MUC1 antigen may be a useful therapeutic target to prevent the development of incurable, recurrent metastatic EOC.     

卵巢癌中p27kip1和Cyclin D1的表达与预后因素的相关性研究

目的　探讨 p2 7kip1、CyclinD1在卵巢癌发生、发展方面的意义。 方法　应用免疫组化染色及半定量分析的方法 ,检测 5 0例卵巢癌、19例卵巢良性上皮肿瘤、13例正常卵巢组织中的p2 7kip1、CyclinD1表达 ,及它们与上皮组织的良恶性、病理组织分级、临床分期的相关性。结果　正常卵巢组和卵巢良性肿瘤组间 ,p2 7、CyclinD1表达无明显差异 ;p2 7在正常卵巢组织和卵巢良性上皮肿瘤中高表达 ,在卵巢癌中表达降低 (P <0 0 5 ) ,且随着肿瘤分级、分期增高 (恶性程度增高 ) ,阳性表达率逐渐下降 ;而CyclinD1的表达则相反 ;两者在肿瘤中的表达呈负相关。结论　p2 7kip1表达下降、CyclinD1过表达可能在卵巢癌的发生发展中起重要作用 ,检测 p2 7kip1、CyclinD1在卵巢癌中的表达可预测该肿瘤生物学行为特征 ,可以作为预后指标     

FTY720诱导卵巢癌细胞发生可逆性白噬及抗癌机制的探索

目的：体外观察FTY720对人卵巢癌细胞的生长抑制效应,探讨其独特的抗癌效应。方法：采用Mr丌法检测不同浓度（2．5,5,7．5,10,12．5,15μmol／L）FTY720作用24、48、72h后,对人卵巢癌OV2008和SKOV3细胞的生长抑制效应。以不同密度（亚饱和、饱和、过饱和）接种OV2008和SKOV3细胞,MTＴ及相差显微镜下检测细胞的形态学,并观察FTY720的抗卵巢癌效应与细胞接种密度间的关系。相差显微镜下观察FTY720诱导的可逆性自噬现象。Westernblot法检测自噬效应分子LC3的表达变化。MTT及Westernblot法分别检测mTOR抑制剂雷帕霉素（RA）、PP2A抑制剂冈田酸（OA）对FTY720抗癌效应的影响。结果：FTY720对卵巢癌OV2008、SKOV3细胞的生长抑制作用呈剂量时间依赖性,且其诱导的卵巢癌细胞毒性效应具有细胞接种密度依赖性。FTY720导致的卵巢癌细胞自噬具有可逆转性特点。RA不影响FTY720的抗卵巢癌效应,而OA则可协同FTY720的抗癌效应。结论：FTY720抑制卵巢癌细胞生长具有剂量时间依赖性,FTY720诱导的细胞密度依赖性抗癌效应、可逆性自噬现象、非mTOR途径依赖,以及其与PP2A途径发生协同抗癌效应等特点提示FTY720独特模式的抗卵巢癌效应。     

Expression of estrogen-responsive finger protein (Efp) is associated with advanced disease in human epithelial ovarian cancer

OBJECTIVE: The estrogen-responsive ring finger protein (Efp) gene, one of estrogen receptor (ER) target genes, is considered to be essential for estrogen-dependent cell proliferation. To understand the estrogenic action on ovarian cancer, we studied the relationships between Efp and ERs expressions and the correlations of Efp expression with clinicopathological parameters in epithelial ovarian cancer. METHODS: The protein expressions for Efp, ERalpha and ERbeta were examined by immunoblotting in 12 ovarian cancer cell lines. Efp mRNA expressions were evaluated by quantitative RT-PCR in 12 ovarian cancer cell lines. A total of 100 surgical specimens diagnosed as epithelial ovarian cancer were examined immunohistochemically using antibodies for Efp, ERalpha and ERbeta. RESULTS: Efp protein was detected in 8 out of 12 cell lines. In Efp protein-positive cell lines, Efp mRNA was expressed higher than that in negative (P=0.021). All of the Efp protein-positive cell lines simultaneously expressed either ERalpha or ERbeta protein. By immunohistochemical staining, Efp immunoreactivity was detected in 63 out of 100 ovarian cancer specimens and positive signals were in the cytoplasm of carcinoma cells. There were significant correlations between Efp and ERalpha, ERbeta immunoreactivity (Efp and ERalpha, P=0.022; Efp and ERbeta, P=0.032). Efp expression was significantly higher in a subgroup with serous adenocarcinoma (P=0.010) and with advanced disease (P=0.026). No significant relationship was detected between Efp immunoreactivity and overall survival. CONCLUSION: The expression of Efp was detected in human epithelial ovarian cancer and high expression of Efp was correlated with advanced disease and serous adenocarcinoma, and ERs status.     

Successful pregnancy after conservative surgery for stage IC ovarian cancer with serous borderline tumor on controlateral ovary: a case report

BACKGROUND: In invasive ovarian cancer, fertility saving surgery is confined to early-stage and low-grade disease, and only few study reported sparing fertility up to FIGO stage IC ovarian cancer. CASE: We present a rare case of a 30-year-old woman affected by IC ovarian cancer with borderline tumor on controlateral ovary who underwent "conservative" debulking surgery followed by adjuvant chemotherapy. A spontaneous planned pregnancy occurred 5 years postsurgery. At 60-month follow-up, patients have no evidence of disease. CONCLUSIONS: Nowadays, preservation of ovarian function in women with tumors in early stage should be evaluated for conservative surgery. It is important to emphasize that patients selected for conservative surgery should have complete surgical staging. Careful follow-up is mandatory to ensure safety of this procedure.     

Immunohistochemical detection of progesterone receptor in formalin-fixed and paraffin-embedded breast cancer tissue using a monoclonal antibody

Summary The potential for immunohistochemical detection of progesterone receptors (PRs) in routinely formalin-fixed and paraffin-embedded cancer tissues by use of the monoclonal antibody Mi 60-10 (mPR1, Dianova GmbH, Hamburg) was evaluated. The PR content of breast cancer tissue was investigated in 170 cases. A positive reaction to Mi 60-10 was found exclusively in the nuclei of benign or malignant epithelial cells. The distribution of PRs was heterogeneous. Immunohistochemical reaction was scored by multiplying the percentage of positive tumour cells by their prevalent degree of staining (Immunoreactive Score or IRS). The IRS values of formalin-fixed tissues (n=170) were compared with those in snap frozen tissues (n=82), with the PR content assayed by a DCC (dextran-coated charcoal) method (n=170), with histopathological grading according to Bloom and Richardson and with the menopausal status of the patient. There was an acceptable ranked correlation (r=0.74) between IRS in formalin-fixed and paraffin-embedded parts and snap frozen parts of the same carcinoma. A good correlation (r=0.72) was also found, when the semiquantitative results of immunohistochemical PR detection in formalin-fixed and paraffin-embedded tissues were compared to PR concentrations measured by a DCC method in tumor cytosols. There was an 80% concordance between the two methods for qualitative discrimination of PR-negative and PR-positive carcinomas. IRS correlated significantly with the degree of histological differentiation of the tumors (P<0.001) but not with the menopausal status of the women (P>0.05). Storage of paraffin-embedded tissues did not impair PR detection, for up to at least 5 years. Fixation of tissues in formalin only decreased the immunohistochemical detection rate if fixative acted for more than 24 h. Dedicated to the memory of the late Dr. H. Würz     

Osmotic lysis of tumor spill in ovarian cancer: A murine model

OBJECTIVE: Our purpose was to determine, in the murine model, whether human ovarian cancer cells injected intraperitoneally are subject to osmotic lysis by peritoneal lavage with sterile water, thereby decreasing the establishment of peritoneal implants. STUDY DESIGN: Preliminary experiments on six nude mice determined that the injection of 20 million cells of the SKOV-3 cell line reliably leads to the establishment of intraperitoneal tumor xenografts in the mice within 60 days. Four other nude mice functioned as sham controls undergoing peritoneal lavage with 3 to 4 ml of saline solution or sterile water to determine any adverse effects from the lavage alone. Subsequently, 36 nude (nu/nu) mice were injected intraperitoneally with 1 ml of the SKOV-3 cell line at a concentration of 20 million cells per milliliter. Alternate mice then underwent intraperitoneal lavage with either 3 to 4 ml of normal saline solution (control group) or sterile water (study group). The mice were followed up until tumor growth caused a moribund status or until 60 days after injection and then were killed. At necropsy the number and size of tumor nodules were recorded, and each mouse was assigned a composite tumor score. Statistical comparison used the χ² or Fisher's exact test for discrete variables. Time to failure analysis used the Kaplan-Meier method. RESULTS: Tumor growth occurred in 35 of 36 (97%) of the mice during the study period. In the first 30 days 89% of the saline solution group grew clinically visible tumor compared with 55% of the water group (p = 0.03). Ascites developed more frequently in the water group than in the saline solution group. The median tumor scores at death were significantly higher for the water group versus the saline solution group. Survival time, as determined by the time from injection until moribund status, was worse for the water group (p = 0.002). CONCLUSIONS: Intraperitoneal lavage with sterile water did not offer protection against the establishment of xenografts after the intraperitoneal injection of human ovarian cancer cells in the nude mouse model. (Am J Obstet Gynecol 1996;175:1489-92.)     

Meta-analysis: Circulating vitamin D and ovarian cancer risk

Objective

To review and summarize evidence from longitudinal studies on the association between circulating 25 hydroxyvitamin D (25(OH)D) and the risk of ovarian cancer (OC).

Methods

Relevant prospective cohort studies and nested case-control studies were identified by systematically searching Ovid Medline, EMBASE, and ISI Web of Knowledge databases and by cross-referencing. The following data were extracted in a standardized manner from eligible studies: first author, publication year, country, study design, characteristics of the study population, duration of follow-up, OC incidence according to circulating vitamin D status and the respective relative risks, and covariates adjusted for in the analysis. Due to the heterogeneity of studies in categorizing circulating vitamin D levels, all results were recalculated for an increase of circulating 25(OH)D by 20 ng/ml. Summary relative risks (RRs) were calculated using meta-analysis methods.

Results

Overall, ten individual-level studies were included that reported on the association between circulating vitamin D levels and OC incidence. Meta-analysis of studies on OC incidence resulted in a summary RR (95% confidence interval, CI) of 0.83 (0.63-1.08) for an increase of 25(OH)D by 20 ng/ml (P = 0.160). No indication for heterogeneity and publication bias was found.

Conclusions

A tentative inverse association of circulating 25(OH)D with OC incidence was found, which did not reach statistical significance but which requires clarification by additional studies due to potentially high clinical and public health impact.     

Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer

Background

The heritable fraction of ovarian cancer exceeds that of any other common adult cancer. Most inherited cases of ovarian cancer are due to a germline mutation in BRCA1 or BRCA2. It is important to have an accurate estimate of the proportion of ovarian cancer patients who carry a mutation and the specific factors which predict the presence of a mutation.

Methods

We tested a population-based series of 1342 unselected patients diagnosed with invasive ovarian cancer between 1995-1999 and 2002-2004 in Ontario, Canada, for germline mutations in BRCA1 and BRCA2. The two genes were tested in their entirety, using a range of techniques, including multiplex ligation-dependent probe amplification (MLPA).

Results

Among the 1342 women, 176 women carried a mutation (107 in BRCA1, 67 in BRCA2, and two in both genes) for a combined mutation frequency of 13.3%. Seven deletions were identified using MLPA (3.9% of all detected mutations). The prevalence of mutations was particularly high among women diagnosed in their forties (24.0%), in women with serous ovarian cancer (18.0%) and women of Italian (43.5%), Jewish (30.0%) or Indo-Pakistani origin (29.4%). A mutation was seen in 33.9% of women with a first-degree relative with breast or ovarian cancer and in 7.9% of women with no first-degree relative with breast or ovarian cancer. No mutation was seen in women with mucinous carcinoma.

Conclusions

BRCA1 and BRCA2 mutations are common in women with invasive ovarian cancer. All women diagnosed with invasive non-mucinous ovarian cancer should be considered to be candidates for genetic testing.     

Circulating and disseminated tumor cells in ovarian cancer: A systematic review

Objectives

Detecting circulating tumor cells (CTCs) in the peripheral blood and disseminated tumor cells (DTCs) in the bone marrow of cancer patients has proven feasible and of prognostic value in different neoplasms. However, the clinical significance of CTCs and DTCs in ovarian cancer and its association with outcome remains unclear.

Methods

A literature search in PubMed was performed from January 2000 to December 2013 for studies evaluating CTCs and/or DTCs and its association with clinicopathological characteristics and clinical outcome in ovarian cancer. The main outcome measures were progression-free survival (PFS) and overall survival (OS).

Results

Fourteen studies met the inclusion criteria. Median study size was 84 patients (range 43–216). Median follow-up was 19 months (range 5–52). Most studies were small case series (n < 100; studies; 71%). The majority of studies used an immunophenotyping approach to identify CTCs and/or DTCs, but only 3 studies (21%) used the FDA-approved Cell Search method. Despite the differences in methodology among studies the presence of CTCs and DTCs tended to be associated with higher baseline CA-125 serum levels, higher odds of residual disease after surgery, and worse survival in ovarian cancer across studies. No consistent intra-patient correlation was observed between DTCs detected in the bone marrow and CTCs detected in the blood.

Conclusions

The presence of CTCs and DTCs is associated with adverse clinicopathological characteristics and poor clinical outcomes in ovarian cancer patients. Its implementation as a valuable prognostic tool in the clinical setting requires uniform methodology and prospective validation.     

卵巢上皮性癌患者肿瘤组织和血清KLK8的表达及临床意义

目的:探讨激肽释放酶8(KLK8)在卵巢癌中的表达及其意义。方法:免疫组化法检测卵巢上皮性肿瘤组织中KLK8蛋白的表达水平,其中良性卵巢肿瘤20例、交界性卵巢肿瘤11例、卵巢癌62例,并测量其平均灰度值(A值);酶联免疫吸附(ELISA)双抗体夹心法检测血清KLK8浓度;分析卵巢癌组织中KLK8表达的A值与血清浓度值之间的相关性,比较血清KLK8、CA125检测用于卵巢癌诊断的敏感度及特异度。结果:(1)良性卵巢肿瘤、交界性卵巢肿瘤及卵巢癌中KLK8阳性表达率分别为25%(5/20)、27.3%(3/11)及66.1%(41/62),卵巢癌组阳性表达率明显高于前两组(P<0.05)。在不同临床病理特征间,差异亦有统计学意义(P<0.05);(2)血清KLK8浓度分别为4.26±0.29、5.26±0.46、6.59±0.15μg/L,差异有统计学意义(P<0.01);(3)卵巢癌组织KLK8表达的A值为156.4±14.7,与血清浓度值呈显著正相关,Spearman等级相关系数为0.608(P<0.001);(4)KLK8用于卵巢癌诊断的敏感度61.3%,特异度77.4%,与CA125差异无统计学意义(P>0.05)。结论:卵巢癌组织及血清中KLK8蛋白表达升高,并参与卵巢上皮性癌的发生发展过程,血清KLK8检测可指导卵巢癌的早期诊断。     

High-mobility group protein B1 (HMGB1) is a novel biomarker for human ovarian cancer

Background

High mobility group box l (HMGB1), a nuclear and extracellular protein, is implicated in some physiologic and pathologic conditions. In this study, we investigated the expression and function of HMGB1 in ovarian cancer.

Methods

cDNA microarray analysis was performed to compare gene expression profiles of the highly invasive and the low invasive subclones derived from the SKOV3 human ovarian cancer cell line. Immunohistochemistry (IHC) staining was performed to investigate HMGB1 expression in a total of 100 ovarian tissue specimens. In functional assays, effects of HMGB1 knockdown on the biological behavior of ovarian cancer cells were investigated.

Results

HMGB1 was overexpressed in the highly invasive subclone compared with the low invasive subclone. High HMGB1 expression was associated with poor clinicopathologic features. Knockdown of HMGB1 expression significantly suppressed ovarian cancer cell proliferation accompanied by decreased cyclin D1 and PCNA expression, and inhibited cell migration and invasion accompanied by decreased MMP2 and MMP9 activities.

Conclusion

HMGB1 is a newly identified gene overexpressed in ovarian cancer and associated with poor clinicopathologic features. HMGB1 may serve as a new biomarker and a therapeutic target for ovarian cancer in the future.     

p27kip1蛋白在卵巢上皮癌中的表达及其临床意义

目的 :研究p2 7kip1在卵巢上皮癌中的表达及其临床意义。方法 :采用免疫组化SP法检测 2 0例卵巢良性、5 8例卵巢恶性上皮性肿瘤中p2 7kip1蛋白的表达。应用Kaplan Meier法及Cox比例风险回归模型 ,分析p2 7kip1蛋白表达与卵巢上皮癌患者预后的关系。结果 :(1)卵巢良性和恶性上皮性肿瘤中p2 7kip1蛋白表达阳性率分别为75 .0 % ,4 6 .6 % ,恶性肿瘤中p2 7kip1蛋白表达阳性率明显低于良性肿瘤 ,恶性肿瘤染色阳性部位以胞浆为主 ;(2 )p2 7kip1蛋白的表达与病理学分级有关 ,与年龄、临床分期、淋巴结转移、组织学亚型无关 ;(3)卵巢上皮癌中 ,p2 7kip1蛋白的表达与bax蛋白的表达呈正相关 ,与bcl 2蛋白的表达呈负相关 ,与ki6 7蛋白无明显相关性 ;(4)p2 7kip1蛋白表达是影响卵巢上皮癌患者预后的独立因素 ,阳性者预后较好。结论 :p2 7kip1蛋白可能与卵巢上皮癌的发生有关。p2 7kip1蛋白可作为判断患者预后的指标。     

Triple synchronous primary cervical,endometrial and ovarian cancer with four different histologic patterns

Background Double synchronous primary cancers of gynecological cancers is a common event. However, triple synchronous primary gynecological cancers is an extremely rare event. Case A 50-year-old woman, para 0-0-0-0 was admitted to the hospital with a complaint of menorrhagia for 2 months. The preoperative evaluation and diagnosis was myoma uteri with bilateral ovarian tumor. Subtotal hysterectomy with bilateral salpingo-oophorectomy, and omentectomy were performed. The postoperative and pathologic findings were adenosquamous carcinoma of the endocervix, adenocarcinoma of the endometrium, low malignant potential of the right ovary and mucinous cystadenocarcinoma of the left ovary. She received a complete course of whole pelvic radiation. Unfortunately, she died from pulmonary embolism. Conclusion The occurrence of triple synchronous gynecological cancers is a rare and unique event deserving further studies     

High level of WAVE1 expression is associated with tumor aggressiveness and unfavorable prognosis of epithelial ovarian cancer

Objectives

Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) has been shown to promote cancer invasion and metastasis. However, no evidence has been found to identify the role of WAVE1 in epithelial ovarian cancer (EOC). This study aims to determine the effect of WAVE1 expression and investigate a possible relationship between WAVE1 and prognosis in EOC.

Methods

WAVE1 protein level was measured in 223 EOC specimens by immunohistochemical staining and 46 EOC specimens by Western blot analysis. Expression of WAVE1 in ovarian cancer cell lines was evaluated by Western blot analysis and immunofluorescence. Survival analysis was performed to assess the correlation between WAVE1 expression and survival.

Results

Immunohistochemical staining and Western blot analysis showed that WAVE1 was overexpressed in EOC compared with samples from a non-invasive ovarian tumor and normal ovaries (P < 0.05). Furthermore, expression of WAVE1 was significantly associated with advanced FIGO stage, poor grade, serum Ca-125 and residual tumor size (P < 0.05). By Western blot analysis, WAVE1 expression was detected in four ovarian cancer cell lines. Immunofluorescence was performed to demonstrate WAVE1 expression in SKOV3 and 3AO cell lines. Survival analysis showed that patients with low WAVE1 staining had a significantly better survival compared to patients with high WAVE1 staining (P < 0.05). In multivariate analysis, WAVE1 overexpression, advanced stage and suboptimal surgical debulking were independent prognostic factors of poor survival.

Conclusions

Our present study finds that WAVE1 overexpression is associated with an unfavorable prognosis. WAVE1 is an independent prognostic factor for EOC, which suggests that it is a novel and crucial predictor for EOC metastasis.     

Specificity and prognostic validation of a polyclonal antibody to detect Six1 homeoprotein in ovarian cancer

Objective

The presence of Six1 mRNA gene portends a poor prognosis in ovarian cancer. We describe validation of a Six1 specific antibody and evaluate its association with tumorigenicity and prognosis in ovarian cancer.

Methods

A Six1 antibody (Six1cTerm) was raised to residues downstream of the Six1 homeodomain, representing its unique C-terminus as compared to other Six family members. Cells were transfected with Six1-Six6 and Western blot was performed to demonstrate Six1 specificity. Ovarian cancer cell lines were analyzed for Six1 mRNA and Six1cTerm and tumorigenicity was evaluated. Ovarian cancer tissue microarrays (OTMA) were analyzed for Six1cTerm by immunohistochemistry and scored by two blinded observers. The metastatic tumors of 15 stage IIIC high grade serous ovarian cancers were analyzed with Six1 mRNA and Six1cTerm and expression was compared to clinical factors and survival.

Results

The Six1cTerm antibody is specific for Six1. Cell line tumorigenicity in SCID mice correlates with Six1 levels both by mRNA(p = 0.001, Mann-Whitney U test) and by protein (presence vs. absence, p = 0.05 Fischer's Exact test). Six1 protein was present in up to 54% of OTMA specimens. Six1 protein expression in omental/peritoneal metastases correlated with worsened survival in a sample (n = 15) of high grade serous stage IIIC ovarian cancers (p = 0.001).

Conclusions

The Six1cTerm antibody is specific and able to detect Six1 in cell lines and tumor tissue. Six1 protein detection is common in ovarian cancer and is associated with tumorigenicity and poor prognosis in this group of patient samples. Six1cTerm antibody should be further validated as prognostic tool.