Role of cytoreductive surgery in recurrent ovarian cancer

Cytoreductive surgery is well established in patients with primary ovarian cancer. The benefit of surgery in patients with recurrent ovarian cancer remains a controversial matter. There is a large heterogeneity in surgical results published in the literature, possibly caused by infrastructure, surgeons’ philosophy and belief in adding various surgical skills. This might also be a result of different preoperative selection procedures. Further questions to be addressed are the definition of surgical end points and whether there are predictive factors for a successful surgery. The surgical end point in recurrent ovarian cancer should be complete resection. Predictive factors could help identify patients in whom complete resection is possible.     

Survivin与卵巢癌关系的Meta分析

目的:应用Meta分析方法评估国内外有关卵巢癌组织中Survivin的表达及其临床意义。方法:通过计算机检索PubMed、CNKI等数据库全面检索国内外已发表的相关文献,最终进入系统评价的有13篇病例对照研究。应用Stata 11.0进行Meta分析,计算OR及95%CI。结果:表明Survivin的表达在卵巢癌组与卵巢良性肿瘤组,卵巢癌组与卵巢正常组织组,临床Ⅰ-Ⅱ组与临床Ⅲ-Ⅳ组,中、高分化组与低、未分化组的差异有统计学意义(P<0.05);Survivin淋巴结转移组与淋巴结未转移组的表达差异无统计学意义(P>0.05)。结论:Survivin的高表达可能在卵巢癌的发生发展中起重要作用。     

上皮源性卵巢癌干细胞的研究进展

肿瘤干细胞(cancer stem cells,CSCs)是肿瘤组织内具有自我更新能力以及无限增殖和多向分化潜能的一群细胞,对化疗药物耐受.卵巢癌干细胞(epithelial ovarian cancer stem cells,EOCSCs)在卵巢癌的发生发展、侵袭转移和耐药复发过程中都起到了重要作用.传统的肿瘤细胞减灭术联合顺铂、紫杉醇全身化疗对减小肿瘤体积,缓解临床症状具有一定的作用,但治疗后残留的EOCSCs能够短时间内重建肿瘤组织,是卵巢癌复发和难治的根本原因.深入了解EOCSCs的生物学特性,探索EOCSCs的发生发展机制,研究针对EOCSCs的靶向治疗药物,是抗肿瘤治疗的关键.     

Central nervous system metastasis from epithelial ovarian cancer- predictors of outcome

Management of central nervous system (CNS) metastases from epithelial ovarian cancer (EOC) is an unmet need. We analyzed data on 41 such patients to evaluate predictors of outcome. Between January, 2010 and December 2020, among 1028 patients with EOC treated at our institute 41 (3.98%) developed CNS metastasis. Median age of patients was 48 years, ranging from 22 to 75 years. Primary outcome measure was progression free survival (PFS). Overall survival (OS), and analysis of prognostic factors were secondary outcome measures. An intention to treat analysis was done. We also performed review the literature (n=2253) as regards to clinicopathological and radiological features, treatment received, survival outcomes and prognostic factors. Median time from diagnosis of EOC to CNS metastasis was 27 months (range: 0 to 101 months). 33(80.5%) patients had FIGO stage III-IV at baseline and serous carcinoma (75.6%) was common pathology subtype. Thirteen (31.7%) patients had isolated CNS metastasis and 28 (68.3%) had intra-abdominal disease in addition. Nineteen (46.3%) patients achieved complete response post treatment with surgery, radiation and chemotherapy. Median PFS and OS from the time of CNS metastasis is 12 (range:1 to 51) months and 33 (range: 1 to 71) months, respectively. Absence of extracranial disease and lower serum CA-125 at diagnosis of CNS metastasis were predictive of superior PFS and OS on multivariate analysis. CNS metastasis is a late event in EOC, post multiple lines of treatment. Patients with disease limited to brain and treated with surgical resection and chemoradiation have best outcome.     

ATP生物荧光技术在卵巢癌体外药敏检测中的应用

目的 评价ATP生物荧光肿瘤药敏检测与临床疗效的相关性,探讨其临床应用价值。方法 对34例卵巢癌新鲜瘤组织和腹水进行肿瘤细胞分离、原代培养,以ATP生物荧光体外药敏检测技术进行检测。结果ATP生物荧光法测定细胞数量具有相关性好(r=0.9981),量程宽(10-100000个细胞),敏感性高(最小检测10个活细胞)的优点,其检测结果与其他方法相比有较高的相关性。32例卵巢癌病人体外药敏结果表明,其整体预测值为90.6％;其中阳性预测值为94.7％,阴性预测值为84.6％,敏感性90％,特异性91.7％。各种药物体外药敏检测结果与临床资料基本相符。结论 ATP生物荧光肿瘤药敏检测结果与临床疗效具有较好的相关性。该药敏检测方法对于筛选及临床应用新药,研究和确定新的化疗方案和治疗原则,评估联合用药方案,实现肿瘤病人的个体化化疗具有指导作用。     

Dideoxy fingerprinting assay for BRCA1 mutation analysis

Since the isolation of BRCA1, the familial breast/ovarian cancer predisposition gene, much effort has been invested in characterizing the mutation spectrum. The large size of the gene and the wide distribution of its more than 100 mutations has increased the challenge of this endeavor such that traditional mutation detection techniques are inadequate. We examined the sensitivity of dideoxy fingerprinting (DDF), which combine a Sanger sequencing reaction with multiple-fragment single-strand conformation analysis (SSCA), as a mutation detection technique to screen BRCA1. Here we describe the technique and compare its sensitivity with that of SSCA in detecting 21 previously described BRCA1 sequence variants. All the variants were detected by DDF, but only 17 of 21 (81%) were observed by SSCA under standard conditions. Three of four alterations missed by SSCA were base substitutions. As a BRCA1 mutation detection technique, DDF was more sensitive than SSCA and may prove to be a useful research tool in defining the mutation spectrum within this and other genes. Mol. Carcinog. 19:176–179, 1997. © 1997 Wiley-Liss, Inc.     

卵巢癌的免疫治疗

卵巢癌作为妇女死亡的重要因素,一直受到人们的关注.手术和化学治疗目前都不能达到令人满意的效果.随着免疫学的进展,卵巢癌的免疫治疗将成为临床治疗的可选择手段之一.卵巢癌免疫治疗可分为预防性和治疗性免疫两种,同时还可分为腹腔内与全身两种给药方式.本文对卵巢癌的免疫治疗目前的一些进展,临床试验结果及发展中的一些问题与探索进行了综述.     

BRCA1 mutation testing for Japanese patients with ovarian cancer in breast cancer screening

From February 1996 to April 1998, 2967 women received screening for breast cancer in the gynecologic ambulatory practice of the Hokkaido University Hospital. In 116 Japanese women with epithelial ovarian cancer, mutation analysis of BRCA1 exon 11 in genomic DNA was performed by the stop codon (SC) assay and DNA sequence analysis. Clinicopathological factors were also investigated in these patients. The aim of this study was to examine the advantages of performing BRCA1 mutation testing for ovarian cancer patients during breast cancer screening. We achieved a high detection rate (6.0) of patients with germline mutations in BRCA1. The high frequencies of breast ovarian cancer syndrome, serous adenocarcinoma, high histological grades, advanced FIGO stages, and breast cancer as double cancer were found to be characteristic of ovarian cancer with germline mutations in BRCA1. These characteristics may assist physicians in selecting BRCA1 mutation testing for ovarian cancer patients. The mean age at diagnosis of ovarian cancer was 51.0 and 51.2 years in the groups with and without mutation, respectively, and no difference was found in age at diagnosis. All of the nine living female mutation carriers were offered the options of increased surveillance or prophylactic surgery, and all chose the former. We have performed breast cancer screening and/or ovarian cancer screening every 6 months for these carriers. This may allow another advantage in establishing a relationship of mutual trust with a patient from a series of responsible follow-ups.     

Trabectedin therapy as an emerging treatment strategy for recurrent platinum-sensitive ovarian cancer

Epithelial ovarian cancer (OC) is a common gynecologic malignancy in women. The standard treatment for OC is maximal cytoreductive surgical debulking folowed by platinum-based chemotherapy. Despite the...     

凋亡抑制蛋白与卵巢癌化疗耐药

卵巢癌是严重威胁妇女健康的恶性肿瘤之一,其病死率在妇科肿瘤中占第一位.化疗耐药是导致其治疗失败、病死率居高不下的重要原因.已有的研究表明,抗凋亡机制在肿瘤细胞发生、发展及化疗耐药中起重要作用.凋亡抑制蛋白(IAPs)是重要的细胞凋亡调节因子,在细胞凋亡中起关键作用.本文主要综述IAPs与卵巢癌化疗耐药的相关进展.     

Molecular approaches to diagnosis and management of ovarian cancer

The recent advances in the understanding of the pathogenesis of ovarian cancer have been helpful in addressing issues in diagnosis, prognosis and management. The study of ovarian tumours by novel techniques such as immunohistochemistry, fluorescent in situ hybridisation, comparative genomic hybridisation, polymerase chain reaction and new tumour markers have aided the evaluation and application of new concepts into clinical practice. The correlation of novel surrogate tumour specific features with response to treatment and outcome in patients has defined prognostic factors which may allow the future design of tailored therapy based on a molecular profile of the tumour. These have also been used to design new approaches to therapy such as antibody targeting and gene therapy. The delineation of roles of c-erbB2, c-fms and other novel receptor kinases in the pathogenesis of ovarian cancer has led initially to the development of anti-c-erbB2 monoclonal antibody therapy. The discovery of BRCA1 and BRCA2 genes will have an impact in the diagnosis and the prevention of familial ovarian cancer. The important role played by recessive genes such as p53 in cancer has raised the possibility of restoration of gene function by gene therapy. Although the pathological diagnosis of ovarian cancer is still confirmed principally on morphological features, addition of newer investigations will increasingly be useful in addressing difficult diagnostic problems. The increasingly rapid pace of discovery of genes important in disease, makes it imperative that the evaluation of their contribution in the pathogenesis of ovarian cancer is undertaken swiftly, thus improving the overall management of patients and their outcome.     

子宫内膜异位症相关性卵巢透明细胞癌和卵巢子宫内膜样癌的临床病理特征研究

目的 研究子宫内膜异位症(EM)相关性卵巢透明细胞癌(CCC)和卵巢子宫内膜样癌(EC)的临床病理特征.方法 选取CCC和EC患者共167例,根据是否为EM恶变将患者分为EM组(n=84)和非EM组(n=83).比较两组患者的年龄、生育史、EM病史、临床表现、凝血功能、血清CA125水平、超声检查结果、术中情况及术后病理特点.结果 EM组患者的发病年龄、初潮年龄均明显小于非EM组(P﹤0.01),未绝经患者所占比例明显低于非EM组(P﹤0.01);EM组患者的孕次、产次明显低于非EM组(P﹤0.001),不孕症患者所占比例明显高于非EM组(P﹤0.001);EM组中既往有EM病史的患者所占比例高于非EM组(P﹤0.05);临床表现方面,EM组患者的痛经、月经紊乱发生率均明显高于非EM组(P﹤0.01);EM组患者的PT、APTT明显短于非EM组(P﹤0.001);术后,EM组患者的血清CA125水平低于非EM组(P﹤0.05);两组患者超声检查结果比较,差异无统计学意义(P﹥0.05);EM组患者的肿瘤直径明显大于非EM组(P﹤0.001);两组患者的FIGO分期比较,差异有统计学意义(P﹤0.05),其中EM组患者中Ⅰ~Ⅱ期患者所占比例高于非EM组.结论 EM相关性CCC和EC与单纯CCC和EC存在明显不同的临床病理特征,具有确诊年龄及初潮年龄小、绝经比例更高、孕产次更低、既往有EM病史患者所占比例更高、痛经和月经紊乱表现更多、PT和APTT更短、血清CA125水平较低和临床病理分期较早等特点.     

Tibolone and risk of gynecological hormone sensitive cancer

Risk of ovarian cancer with hormone therapy is associated with use of both unopposed estrogen therapy and combined estrogen–progestin therapy, whereas for endometrial cancer addition of continuous progestin decreases the estrogen induced increased risk. Less is known about risk with use of tibolone; a synthetic steroid with estrogenic, progestagenic and androgenic properties. We assessed these associations in a prospective cohort study, including all Danish women 50–79 years of age and followed 1995–2009. National Danish Registers captured individually updated exposure information, cancer cases including histology and confounding factors. Poisson regression analyses provided multiple adjusted incidence rate ratios (IRRs). More than 900,000 women were followed for 9.8 years on average; 4,513 were diagnosed with ovarian cancer and 6,202 with endometrial cancer. Compared to women never on postmenopausal hormone therapy, current users of tibolone had an increased IRR for ovarian cancer (1.42(95% confidence interval [CI], 1.01–2.00) and serous ovarian tumors (2.21(95%CI 1.48–3.32)). The risk increased with duration of use, particularly for serous ovarian tumors. Compared to never users, the IRR of endometrial cancer was 3.56(95%CI 2.94–4.32) among current users of tibolone and 3.80(95%CI 3.08–4.69) of Type I endometrial cancer. The steepest risk increase with duration of use was for Type I tumors. In conclusion, tibolone is associated with increased risk for ovarian and endometrial cancer overall; and particular the risk of serous ovarian tumors and Type I endometrial cancer. Because the associations are stronger with increasing durations of use – and for hormone sensitive tumors – the results seem indicative of causality.     

Parp inhibitors as maintenance treatment in platinum sensitive recurrent ovarian cancer: An updated meta-analysis of randomized clinical trials according to BRCA mutational status

ObjectiveThis meta-analysis investigated the effectiveness of PARP inhibitors (PARPis) as maintenance treatment in platinum sensitive recurrent ovarian cancer (ROC), stratifying results based on BRCA mutational status into five different categories: whole population, germ-line BRCA mutated patients, somatic BRCA mutated patients, HRD patients and wild type population.MethodsPubMed, Medline, Scopus, EMBASE and clinicaltrials.gov, as well as meeting proceedings were searched for eligible studies that described RCTs testing the efficacy of PARPis as maintenance treatment in platinum sensitive ROC. Data were extracted independently and analysed using RevMan statistical software version 5.3. Primary end-point was progression free survival (PFS).ResultsThe analysis confirmed the positive effect of PARPis in patients with platinum sensitive ROC in case of germinal or somatic BRCA mutations. Specifically, HR for PFS was 0.26, 95% CI 0.21–0.31, p < 0.00001 for the mutation of BRCA gene and 0.24, 95%, CI 0.12–0.48, p < 0.0001 for the somatic alteration. In addition, in the HRD population, studies that analysed the efficacy of PARPis  reported a PFS improvement with HR 0.34, 95% CI 0.26–0.43, p < 0.00001. Finally, our analysis confirms the role of these drugs in prolonging PFS in the whole population with HR 0.36, 95% CI 0.32–0.42, p < 0.00001, although to a lesser extent, with a significant improvement even in wild type cancers with HR 0.49, 95%, CI 0.41–0.59, p < 0.00001).ConclusionsPARPis are effective regardless of BRCA mutational status. Future investigations are necessary to explore the use of different PARPis as monotherapy, comparing them among each other in terms of efficacy and toxicity, and exploring their potential re-use.     

Immunotherapy in ovarian cancer

Immunotherapy aims to develop combination approaches that simultaneously augment immunity while preventing local immune suppression. Despite advances in combinatorial chemotherapy regimens and the advent of intraperitoneal chemotherapy administration, current therapeutic options for patients with ovarian cancer are inadequate. Advances in immunotherapy offer a promising frontier for treating ovarian tumors. Multiple immunotherapeutic modalities are currently developed and tested in clinical trials. Antibody-based therapies, immune checkpoint blockade, cancer vaccines, and chimeric antigen receptor–modified T cells have demonstrated preclinical success and entered clinical testing. In this review, we discuss these promising immunotherapeutic approaches and emphasize the importance of combinatorial treatment strategies and biomarker discovery.     

抑癌基因OVCA1体外对卵巢癌细胞A2780迁移和侵袭的抑制作用

目的:探讨卵巢癌基因1[ovarian cancer gene 1,OVCA1;也称为DPH2L( diphthamide synthesis protein 2-like)基因]体外对卵巢癌细胞系A2780迁移和侵袭能力的抑制作用.方法:采用脂质体法将GFP标记的携带OVCA1的重组质粒pEGFP-OVCA1或GFP空白质粒分别转染A2780细胞后,G418筛选稳定转染细胞,有限稀释法筛选稳定转染细胞的单克隆细胞株,荧光显微镜检查绿色荧光蛋白的表达及RT-PCR方法检测A2780细胞OVCA1基因mRNA的表达.A2780-OVCA1细胞为实验组, A2780-GFP细胞和A2780细胞为对照组,采用划痕实验、Transwell体外迁移实验和Matrigel体外侵袭实验检测OVCA1对A2780细胞迁移和侵袭能力的影响.结果:重组质粒pEGFP-OVCA1转染后获得了稳定表达GFP标记OVCA1蛋白的A2780细胞株.A2780-OVCA1组划痕后的细胞迁移速度明显小于两对照组(P<0.05);A2780-OVCA1组穿过Transwell滤膜的迁移细胞数明显少于两对照组(P<0.05);A2780-OVCA1组穿过Matrigel滤膜的侵袭细胞数明显少于两对照组(P<0.05).结论:OVCA1在体外具有显著抑制卵巢癌A2780细胞迁移和侵袭的作用.     

A comparison of national cancer registry and direct follow-up in the ascertainment of ovarian cancer.

The National Health Service Central Register (NHSCR) and direct follow-up were used to document ovarian and fallopian tube cancers in 22000 women from 1986 to 1993. Direct follow-up identified 47/49 cases (96%) and the NHSCR 38/49 (78%). NHSCR ascertainment was incomplete and direct follow-up provided additional information. These findings have implications for interpretation of national cancer statistics and for use of the NHSCR in research trials.     

The diagnosis and outcome of Krukenberg tumors

BackgroundAccurate diagnostic tools are crucial to distinguish patients with Krukenberg tumors from those with ovarian cancers before decision on initial management. To address this unmet need, we aimed to evaluate the diagnostic utility of clinical, biochemical, and radiographic factors in this patient population.MethodsPatients with Krukenberg tumors or primary ovarian cancers were retrospectively identified from institutional cancer registry. Kaplan-Meier method and Cox proportional hazards models were used for survival analysis. Logistic regression evaluated clinical, biochemical, and radiographic factors; residual deep neural network model evaluated features in computed tomography images as predictors to distinguish Krukenberg tumors from ovarian cancers. Model performance was summarized as accuracy and area under the receiver operating characteristic curve (AUC).ResultsThis study included 214 patients with Krukenberg tumors with median age of 52 years. Among 104 (48.6%) patients with colorectal cancer, those who received palliative surgery had significantly higher median overall survival (48.1 versus 30.6 months, P=0.015) and progression-free survival (22.2 versus 6.7 months, P<0.001) than those with medical management only. The accuracy of radiology reports to make either diagnosis of Krukenberg tumors or primary ovarian cancers was 60.7%. In contrast, multivariable logistic regression model with age [odds ratio (OR) 2.98, P<0.001], carbohydrate antigen 125 (OR 1.57, P=0.004), and carcinoembryonic antigen (OR 0.03, P=0.031) had 87.5% [95% confidence interval (CI): 75.0–100.0%] accuracy with AUC 0.96 (95% CI: 0.87–1.00). The neural network model had 62.8% (95% CI: 51.8–74.5%) accuracy with AUC of 0.61 (95% CI: 0.53–0.72).ConclusionsWe developed a diagnostic model with clinical and biochemical features to distinguish Krukenberg tumors from primary ovarian cancers with promising accuracy.     

Photodynamic diagnosis of ovarian cancer using hexaminolaevulinate: a preclinical study

The unfailing detection of micrometastases during surgery of patients suffering from ovarian cancer is mandatory for the optimal management of this disease. Thus, the present study aimed at determining the feasibility of detecting micrometastases in an ovarian cancer model using the intraperitoneal administration of the photosensitiser precursor hexaminolaevulinate (HAL). For this purpose, HAL was applied intraperitoneally at different concentrations (4-12 mM) to immunocompetent Fischer 344 rats bearing a syngeneic epithelial ovarian carcinoma. The tumours were visualised laparoscopically using both white and blue light (D-light, Karl Storz, Tuttlingen, Germany), and the number of peritoneal micrometastases detected through HAL-induced photodiagnosis (PD) was compared to standard white light visualisation. Fluorescence spectra were recorded with an optical fibre-based spectrofluorometer and the fluorescence intensities were compared to the protoporphyrin IX (PpIX) fluorescence induced by 5-aminolevulinic acid under similar conditions. The number of metastases detected by the PD blue light mode was higher than when using standard white light abdominal inspection for all applied concentrations. Twice as many cancer lesions were detected by fluorescence than by white light inspection. The hexyl-ester derivative produced higher PpIX fluorescence than its parent substance aminolevulinic acid at the same concentration and application time. Fluorescence contrast between healthy and cancerous tissue was excellent for both compounds. To overcome poor diagnostic efficiency and to detect peritoneal ovarian carcinoma foci in the large surface area of the human peritoneal cavity, HAL fluorescence-based visualisation techniques may acquire importance in future and lead to a more correct staging of early ovarian cancer.