Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development.

Precancer or intraepithelial neoplasia (IEN) is a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer and that predicts for a substantial likelihood of developing invasive cancer. The AACR Task Force on the Treatment and Prevention of IEN has delineated the relationship between IEN and cancer risk as well as the clinical benefit that can be derived from reducing IEN burden. Although several effective endoscopic and surgical treatments for IEN have become standard medical practice, these interventions can confer morbidity and do not treat the entire epithelial field at risk. The incidence of many epithelial cancers is continuing to rise, the number of individuals at risk is increasing with the aging population, and the rapid advancement of imaging and molecular diagnostics is bringing to light precancers that were heretofore clinically silent. There is therefore an urgent need to rapidly develop new treatment and prevention agents for IEN. The AACR IEN Task Force recommends focusing on established precancers as the target for new agent development because of the close association between dysplasia and invasive cancer and because a convincing reduction in IEN burden provides patient benefit by reducing cancer risk and/or by decreasing the need for invasive interventions. The IEN Task Force proposes several clinical trial designs that provide practical and feasible approaches to the rapid development of new agents to treat and prevent precancer.     

2017年美国预防服务工作组甲状腺癌筛查推荐声明解读

近10年来,甲状腺癌的发病率增长较快,高于其他肿瘤,但死亡率却没有相应改变。甲状腺结节已成为常见的临床问题,甲状腺结节的过度诊断和过度治疗也随之增加。2017年美国预防服务工作组（US Preventive Services Task Force, USPSTF）发布了甲状腺癌筛查推荐声明更新。声明指出：反对在无症状人群中进行甲状腺癌筛查。本文对2017年USPSTF甲状腺癌筛查推荐声明的更新部分给予解读。     

2002—2011年上海市原卢湾区居民卵巢癌的发病和死亡资料分析

背景与目的：卵巢癌是世界范围内死亡率较高的妇科肿瘤之一。该研究旨在了解上海市原卢湾区2002—2011年间卵巢癌的发病率和死亡率。方法：系统收集整理上海市肿瘤登记报告中原卢湾区户籍人群2002年1月—2011年12月卵巢癌的发病和死亡资料,计算卵巢癌发病率、死亡率及标化率,并应用年均变化百分率计算其年均率值并进行趋势分析。结果：上海市原卢湾区2002—2011年间共报告新发卵巢癌病例236例,占同期全区女性恶性肿瘤的3.76%。2002—2011年间卵巢癌发病率相对平稳。死亡患者数111例,占同期全区女性恶性肿瘤死亡的3.05%。10年间卵巢癌的死亡率变化也不大。结论：2002—2011年间上海市原卢湾区户籍人群女性卵巢癌的发病率与死亡率趋于平稳。高龄者是高危发病人群。发病及死亡在各年龄段均可发生,亟待寻找有效的预防和治疗措施。     

遗传性卵巢癌基因筛查及家族成员管理研究进展

卵巢癌是发生率居于全球女性第三位、死亡率居于首位的妇科恶性肿瘤,其中10%~15%由胚系突变导致,称为遗传性卵巢癌（hereditary ovarian cancer）。遗传性卵巢癌是一种常染色体显性遗传病,它的发生与BRCA1/2等基因突变有关。对家族中的先证者进行基因检测,识别卵巢癌易感基因胚系突变,鉴定遗传性卵巢癌,可以使患者受益于个性化治疗,同时提示家庭成员进行基因筛查,以找出家族中高危致病基因突变的携带者,对携带者实施肿瘤的早期监测和干预。这对于降低疾病发病率和死亡率,改善长期预后有重要临床意义。本文总结现有文献,并就遗传性卵巢癌家族成员基因筛查中的主要基因相关临床意义和管理策略进行综述。     

Boosting the apoptotic response of high-grade serous ovarian cancers with CCNE1 amplification to paclitaxel in vitro by targeting APC/C and the pro-survival protein MCL-1

Ovarian cancer exhibits the highest mortality rate among gynecological malignancies. Antimitotic agents, such as paclitaxel, are frontline drugs for the treatment of ovarian cancer. They inhibit microtubule dynamics and their efficiency relies on a prolonged mitotic arrest and the strong activation of the spindle assembly checkpoint (SAC). Although ovarian cancers respond well to paclitaxel, the clinical efficacy is limited due to an early onset of drug resistance, which may rely on a compromised mitosis exit associated with weakend intrinsic apoptosis. Accordingly, we aimed at overcoming SAC silencing that occurs rapidly during paclitaxel-induced mitotic arrest. To do this, we used a specific anaphase-promoting complex/cyclosome (APC/C) inhibitor to prevent a premature mitotic exit upon paclitaxel treatment. Furthermore, we investigated the role of the antiapoptotic BCL-2 family member MCL-1 in determining the fate of ovarian cancer cells lines with CCNE1 amplification that are challenged with clinically relevant dose of paclitaxel. Using time-laps microscopy, we demonstrated that APC/C and MCL-1 inhibition under paclitaxel prevents mitotic slippage in ovarian cancer cell lines and restores death in mitosis. Consistent with this, the combinatorial treatment reduced the survival of ovarian cancer cells in 2D and 3D cell models. Since a therapeutic ceiling has been reached with taxanes, it is of utmost importance to develop alternative strategies to improve the patient's survival. Thus, our study provides not only elements to understand the causes of taxane resistance in CCNE1-amplified ovarian cancers but also suggests a new combinatorial strategy that may improve paclitaxel-based efficacy in this highly lethal gynecological disease.     

从三焦膜腠理论探析晚期卵巢癌-腹膜转移及中医维持治疗

卵巢癌在妇科三大恶性肿瘤中致死率最高，腹膜转移-肠梗阻-死亡是晚期卵巢癌主要转归模式。中医药维持治疗晚期卵巢癌疗效确切，但理论基础尚需进一步完善。本文溯本求源，在三焦-膜腠理论指导下，结合临床体会，提出卵巢癌-腹膜转移的三焦定位，及三焦功能失调在卵巢癌发生及转移中的作用，并提出疏利三焦气机、和调脏腑气血，清化伏毒是中医维持治疗卵巢癌的主要策略，从三焦-膜腠系统角度丰富了卵巢癌中医理论，为卵巢癌治疗提供新思路。     

Incidence and mortality in epithelial ovarian cancer by family history of any cancer

BACKGROUND:

Practically all data on familial risk in ovarian and other cancers are based on incident cancer, whereas familiality in cancer mortality is largely unknown. If fatal forms of cancer are a highly familial subtype, then familial risk for mortality may exceed that of incidence, which is relevant for clinical decision making and counseling.

METHODS:

Ovarian cancer patients in the nationwide Swedish Family Cancer Database were classified according to fatal and nonfatal (incident) family history. Familial risks for incident and fatal ovarian cancer were calculated for offspring based on their parental or sibling family history of any cancer using standardized incidence ratios (SIRs) for incidence and standardized mortality ratios (SMRs) for mortality. Offspring without family history were referents.

RESULTS:

The database included 24,757 mothers and 8138 daughters with ovarian cancer. When a mother had ovarian cancer, the SIR for incident ovarian cancer in daughters was 2.69, and when a sister had ovarian cancer it was 3.49. The SMRs for fatal cancer by fatal cancer in probands were 3.39 and 5.80, respectively. For fatal serous cancers among siblings, the SMR was 6.16, compared with 10.01 for the endometrioid type. Ovarian cancer was associated with maternal (SIR, 1.22; SMR, 1.56) and sororal breast cancer (SIR, 1.27). Another discordant association was between ovarian and paternal prostate cancer (SIR, 1.12; SMR, 1.66).

CONCLUSIONS:

Fatal familial risks were higher for concordant ovarian, ovarian‐breast, and ovarian‐prostate cancers than the corresponding incident risks. This may suggest that highly fatal subtypes exist for these cancers, calling for genetic dissection. Cancer 2011. © 2011 American Cancer Society.     

Possible role for green tea in ovarian cancer prevention

Ovarian cancer is the leading cause of death from gynecologic cancer. Tea, especially green tea, has shown promise in the prevention of several cancers. Green tea contains a number of compounds, including polyphenols, that have chemopreventive properties. There is much evidence from in vitro and animal studies suggesting that components of tea are associated with decreased risk or progression of ovarian cancer. However, epidemiologic studies have generated inconsistent results. Recent research conducted in China reported reduced risk of ovarian cancer and increased survival post diagnosis with green tea consumption. This review presents emerging evidence and the authors' perspectives on the role of green tea in ovarian cancer prevention.     

Tumor Infiltrating Lymphocytes in Ovarian Cancer

Several improvements in ovarian cancer treatment have been achieved in recent years, both in surgeryand in combination chemotherapy with targeting. However, ovarian tumors remain the women’s cancers withhighest mortality rates. In this scenario, a pivotal role has been endorsed to the immunological environmentand to the immunological mechanisms involved in ovarian cancer behavior. Recent evidence suggests a loss ofthe critical balance between immune-activating and immune-suppressing mechanisms when oncogenesis andcancer progression occur. Ovarian cancer generates a mechanism to escape the immune system by producinga highly suppressive environment. Immune-activated tumor infiltrating lymphocytes (TILs) in ovarian tumortissue testify that the immune system is the trigger in this neoplasm. The TIL mileau has been demonstrated tobe associated with better prognosis, more chemosensitivity, and more cases of optimal residual tumor achievedduring primary cytoreduction. Nowadays, scientists are focusing attention on new immunologically effectivetumor biomarkers in order to optimize selection of patients for recruitment in clinical trials and to identifyrelationships of these biomarkers with responses to immunotherapeutics. Assessing this point of view, TILsmight be considered as a potent predictive immunotherapy biomarker.     

Fertility-Sparing Approaches in Gynecologic Cancers: A Review of ESGO Task Force Activities

Preservation of fertility has become a very important issue in gynecologic oncology of the young. Owing to the clinical importance of appropriate management of young patients with gynecologic cancer, the European Society of Gynecological Oncology (ESGO) decided in 2007 to launch the Task Force for Fertility Preservation in Gynecologic Cancer. This task force is supposed to promote knowledge of infertility induced by treatment of gynecologic cancers among health care workers and the public through national and international collaboration among oncologists, reproductive specialists, and allied health workers to promote research and education and to develop new strategies for fertility preservation. This article summarizes all the past and current activities of this task force.     

A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer

Ovarian cancer ranks fifth in both cancer incidence and mortality among women in the United States. Defects in the mismatch-repair (MMR) pathway that arise through genetic and/or epigenetic mechanisms may be important etiologically in a reasonable proportion of ovarian cancers. Genetic mechanisms of MMR dysfunction include germline and somatic mutations in the MMR proteins. Germline mutations cause hereditary nonpolyposis colorectal cancer (HNPCC), which is the third most common cause of inherited ovarian cancer after BRCA1 and BRCA2 mutations. An epigenetic mechanism known to cause inactivation of the MMR system is promoter hypermethylation of 1 of the MMR genes, mutL homolog 1 (MLH1). Various laboratory methods, in addition to clinical and histopathologic criteria, can be used to identify MMR-deficient ovarian cancers. Such methods include microsatellite instability analysis, immunohistochemistry, MLH1 promoter hypermethylation testing, and germline mutation analysis. In this review, the authors describe the existing literature regarding the molecular, clinical, and histologic characteristics of MMR-deficient ovarian cancers along with the possible effect on survival and treatment response. By further defining the profile of MMR-deficient ovarian cancers and their associated etiologic mechanisms, there may be a greater potential to distinguish between those of hereditary and sporadic etiology. The ability to make such distinctions may be of diagnostic, prognostic, and therapeutic utility.     

上皮性卵巢癌组织病理学及分子生物学研究进展

上皮性卵巢癌是最为常见的卵巢恶性肿瘤,根据组织病理学特征和分化程度可分为多种亚型.组织学类型和分化程度是决定肿瘤行为及预后的关键因素,了解不同亚型上皮性卵巢癌组织病理学和分子生物学特点,可为选择早期筛查的肿瘤标记物和制订针对性治疗方案提供参考.     

上皮性卵巢癌组织病理学及分子生物学研究进展

上皮性卵巢癌是最为常见的卵巢恶性肿瘤,根据组织病理学特征和分化程度可分为多种亚型.组织学类型和分化程度是决定肿瘤行为及预后的关键因素,了解不同亚型上皮性卵巢癌组织病理学和分子生物学特点,可为选择早期筛查的肿瘤标记物和制订针对性治疗方案提供参考.     

The paradoxical expression of maspin in ovarian carcinoma.

Maspin is a noninhibitory member of the serpin family that is down-regulated in breast carcinoma but overexpressed in pancreatic carcinoma. There are no published data regarding the role of maspin in ovarian carcinoma, which is the focus of the present study. Ovarian cell lines (normal and cancer) and tumors (80 invasive, 14 benign, and 10 low malignant potential) were evaluated for maspin expression and localization. Normal ovarian surface epithelial cells had low levels of maspin. Two of four ovarian cancer cell lines (OVCAR3 and SKOV3) expressed maspin, whereas the cell line EG had weak expression, and 222 had no detectable maspin. Subcellular fractionation studies revealed that the two maspin-positive ovarian cancer cell lines contained maspin in both the nuclear and cytosolic compartments. Wild-type maspin was transfected into the aggressive ovarian cancer cell lines SKOV3 and 222. The in vitro invasive activity of the maspin-transfected cell lines was 44-68% lower than respective controls. The histopathology analysis revealed that among the ovarian tumors examined, 57 (71%) were ranked positive for maspin. Thirty (37%) of the invasive tumors overexpressed maspin. Invasive cancers were more likely to have predominantly cytoplasmic staining compared with benign and low-malignant-potential tumors. Maspin overexpression was significantly associated with a high tumor grade (P = 0.004), the presence of ascites (P = 0.02), a lower likelihood of optimal surgical cytoreduction (P = 0.04), and a shorter duration of overall survival (median survival, 6.33 versus 2.67 years; P = 0.003). The Cox proportional hazards multivariate model revealed that maspin overexpression and high stage were independent predictors of survival. Thus, maspin was found to be overexpressed in a substantial proportion of ovarian tumors, which may serve as an adverse prognostic factor; however, its localization may provide new clues as to its activity and function. These paradoxical results may offer new insights regarding the role of maspin in ovarian cancer progression that may also impact diagnosis and treatment strategies.     

卵巢癌一级预防研究进展

卵巢癌是严重危害女性健康的恶性肿瘤之一，其死亡率居妇科恶性肿瘤首位。目前遗传易感是卵巢癌较明确的高危因素，其他可能的因素包括激素使用、疾病/生殖相关因素及生活方式等。根据卵巢癌发生的不同风险等级，可将人群分为高风险人群和普通人群，本文就两个人群的筛查策略、干预措施两方面分别进行研究进展追踪。常规筛查不能提高普通人群卵巢癌的检出率，也无法提高卵巢癌生存。加强卵巢癌高风险人群肿瘤预防意识，进行有效筛查及干预，是降低卵巢癌发病率及死亡率的重要手段。     

Evidence-based policy recommendations on cancer screening and prevention

Ideally, practice guidelines for cancer prevention should reflect the available empirical evidence. Although the most persuasive arguments for the efficacy of an intervention come from randomized controlled trials (RCTs), such studies are not always feasible because of ethical or logistical reasons. The advent of evidence-based medicine has underscored the need for consortia of researchers specialized in reviewing the biomedical literature on a systematic basis, ranking studies according to their design, quality, and generalizability of results. This review summarizes the recommendations and policies on screening and prevention of specific types of cancers from North American and international organizations such as: the National Cancer Institute's Physicians's Data Query Program, the US Preventive Services Task Force, the Canadian Task Force on the Preventive Health Care Force, and the Cochrane Collaboration.     

Role of genetic polymorphisms and ovarian cancer susceptibility

The value of identifying women with an inherited predisposition to epithelial ovarian cancer has become readily apparent with the identification of the BRCA1, and BRCA2 genes. Women who inherit a deleterious mutation in either of these genes have a very high lifetime risk of ovarian cancer (10–60%) and to some extent, increased risks of fallopian tube and peritoneal cancer. These highly lethal cancers are almost completely prevented by prophylactic salpingoophorectomy. BRCA1/2 mutation testing has become the accepted standard of care in families with a strong history of breast and/or ovarian cancer. This approach has the potential to reduce ovarian cancer mortality by about 10%.Although the ability to perform genetic testing for BRCA1 and 2 represents a significant clinical advance, the frequency of mutations in these high penetrance ovarian cancer susceptibility genes is low in most populations. There is evidence to suggest that ovarian cancer susceptibility might be affected by common low penetrance genetic polymorphisms like it was shown for several common disorders like diabetes or breast cancer. Although such polymorphisms would increase risk to a lesser degree, they could contribute to the development of a greater proportion of ovarian cancers by virtue of their higher frequencies in the population. It has been shown that the most powerful approach to studying low penetrance genes is an association study rather than a linkage study design. This review describes the efforts that have been made in this field by individual case–control studies and through multi‐center collaborations as part of international consortia such as the Ovarian Cancer Association Consortium (OCAC).     

The significance of ovarian fibrosis

Ovarian aging is associated with significant changes in the structural organization of collagen, resulting in ovarian fibrosis. In many other tissues, fibrosis increases risks associated with tumorigenesis and metastasis. Thus, it is possible that ovarian fibrosis increases the risk of ovarian cancer by creating a microenvironment more permissive to tumor growth. In this research perspective, we review the impact of female reproduction on the development of ovarian fibrosis and the contributions of genetic and hormonal disruptions such as BRCA mutation, polycystic ovarian syndrome, and infertility to structural changes in the ovary and their relative risk of ovarian cancer. We also explore new fundamental questions in the field of ovarian fibrosis and possible prevention strategies such as metformin.     

Primary peritoneal and ovarian cancers: an epidemiological comparative analysis

We performed case–control analyses using data from the North Carolina Ovarian Cancer Study to determine risk factors that distinguish primary peritoneal cancer (PPC) from epithelial ovarian cancer (EOC). Our risk factor analyses were restricted to invasive serous cancers including 495 EOC cases, 62 PPC cases and 1,086 control women. Logistic regression analyses were used to calculate adjusted odds ratios and 95% confidence intervals for risk factor associations. Although many case–control associations for the invasive serous PPC cases were similar to those of the invasive serous EOC cases, some differences were observed including a twofold increase in risk of invasive serous PPC in women who were ≥35 years at last pregnancy, whereas a decreased risk was observed for invasive serous EOC risk. We could not confirm a previous report of an association between tubal ligation and PPC, a factor consistently associated with a decreased risk of EOC. The difference in the risk factor associations between invasive serous PPC and EOC cancers suggests divergent molecular development of peritoneal and ovarian cancers. A larger study to determine risk factors for invasive serous PPC is warranted.     

The epidemiology of ovarian cancer

Although no unequivocally effective ovarian cancer prevention strategies have emerged, epidemiologic studies have identified high-risk populations. The striking international variation (apparently a fivefold difference) can probably be explained on the basis of differential parity, differing classification measures, and differences in the underlying population age distribution. United States age-adjusted mortality has increased slightly in the past 30 years, and the cancer remains predominantly a disease of older adult white women of northern European extraction. The increases in age-specific mortality and age-adjusted mortality over time may be related to a decrease in average family size. Pregnancy, especially pregnancy before age 25 years, and use of oral contraceptives are protective; the risk of ovarian cancer increases with increasing years of ovulation. A positive family history is also associated with a substantial increase in ovarian cancer risk. Survivors of ovarian cancer are more susceptible to cancers of the breast, endometrium, and colon than are similarly-aged normal women, most probably because all four cancers share some common risk factor(s). Various alkylating agents are clearly leukemogenic in survivors of ovarian cancer, an observation that suggests caution in the use of adjuvant chemotherapy in women at relatively low risk of relapse.