Tubal ligation and ovarian cancer risk in a large cohort: Substantial variation by histological type

Histopathological and molecular studies suggest that different histological subtypes (histotypes) of ovarian cancer have different aetiologies. Few studies have been large enough to explore reliably the effect of tubal ligation (sterilization), which has been associated with a reduced overall risk of ovarian cancer, on different tumour histotypes. In a prospective study of 1.1 million UK women without prior cancer or bilateral oophorectomy, 8,035 ovarian cancers occurred during mean follow‐up of 13.8 years. Using a Cox proportional hazards model, we estimated adjusted relative risks of ovarian cancer associated with tubal ligation. Overall, there was substantial heterogeneity in tumour risk associated with tubal ligation for the four main histotypes, serous, endometrioid, mucinous and clear cell (heterogeneity: p < 0.0001). For serous tumours, the most common histotype (n = 3,515), risks differed significantly between high‐grade (RR: 0.77, 95% CI: 0.67–0.89) and low‐grade tumours (RR: 1.13, 95% CI: 0.89–1.42); heterogeneity: p = 0.007. Relative risks were almost halved for endometrioid (n = 690, RR: 0.54, 95% CI: 0.43–0.69) and clear cell tumours (n = 401, RR: 0.55, 95% CI: 0.39–0.77), but there was no association between tubal ligation and mucinous tumours (n = 836, RR: 0.99, 95% CI: 0.84–1.18). For the main tumour histotypes we found little variation of risk by timing of tubal ligation. The significant differences by tumour histotype are unlikely to be due to confounding and are consistent with hypotheses that high‐grade and low‐grade serous tumours have different origins, and that some endometrioid and clear cell tumours might arise from cells and/or carcinogens travelling through the fallopian tubes.     

Tubal ligation and risk of breast cancer

Although it has been demonstrated in previous studies that tubal ligation can have widespread effects on ovarian function, including a decrease in the risk of subsequent ovarian cancer, few studies have evaluated effects on breast cancer risk. In a population-based case-control study of breast cancer among women 20-54 years of age conducted in three geographic areas, previous tubal ligations were reported by 25.3% of the 2173 cases and 25.8% of the 1990 controls. Initially it appeared that tubal ligations might impart a slight reduction in risk, particularly among women undergoing the procedure at young ages (<25 years). However, women were more likely to have had the procedure if they were black, less educated, young when they bore their first child, or multiparous. After accounting for these factors, tubal ligations were unrelated to breast cancer risk (relative risk (RR) = 1.09, 95% confidence interval (CI) 0.9-1.3), with no variation in risk by age at, interval since, or calendar year of the procedure. The relationship of tubal ligations to risk did not vary according to the presence of a number of other risk factors, including menopausal status or screening history. Furthermore, effects of tubal ligation were similar for all stages at breast cancer diagnosis. Further studies would be worthwhile given the biologic plausibility of an association. However, future investigations should include information on type of procedure performed (since this may relate to biologic effects) as well as other breast cancer risk factors.     

Tubal ligation in relation to menopausal symptoms and breast cancer risk

Background:

Local inflammation after tubal ligation may affect ovarian function and breast cancer risk.

Methods:

We analysed tubal ligation, menopausal characteristics, and breast cancer risk in the Sister Study cohort (N=50 884 women).

Results:

Tubal ligation was associated with hot flashes (hazard ratio (HR) 1.09; 95% confidence interval (CI): 1.06–1.12) but not menopausal age (HR 0.99; 95% CI: 0.96–1.02). Tubal ligation did not have an impact on breast cancer overall (HR 0.95; 95% CI: 0.85–1.06), but had a suggested inverse relation with oestrogen receptor+/progesterone receptor+ invasive tumours (HR 0.84; 95% CI: 0.70–1.01), possibly because of subsequent hysterectomy/bilateral oophorectomy.

Conclusion:

Tubal ligation does not influence overall breast cancer risk.     

Tubal sterilization in relation to breast cancer risk

Tubal sterilization methods may damage surrounding tissue, potentially disrupting the ovarian blood supply and hormonal functioning, and may decrease breast cancer risk. We examined this hypothesis, within the Nurses' Health Study, among 77,511 women, aged 30-55 years and free of cancer at the start of follow-up in 1976. We documented 4,176 cases of invasive breast cancer from 1976 to 2000. Cox proportional hazards models, adjusting for multiple breast cancer risk factors, provided rate ratios (RR) and 95% confidence intervals (CI). Overall, tubal sterilization was not associated with breast cancer risk (RR=0.95, 95% CI=0.88-1.03). However, tubal sterilizations performed from 1970 to 1974 were inversely associated with risk (RR=0.84, 95% CI=0.73-0.97), while procedures performed in other years were not associated with risk. Among women with procedures performed in 1970-1974, those who were >or=35 years old at the time of sterilization were at the lowest risk (RR=0.81, 95% CI=0.66-0.98), while younger women had a suggested decreased risk (RR=0.87, 95% CI=0.72-1.06). Overall, tubal sterilization was not associated with breast cancer risk. However, a modest inverse association was observed at a time when the potentially destructive unipolar electrocautery method was commonly used, providing some support for an association between lower lifetime exposure to hormones and a decreased risk of breast cancer.     

Parity, tubal sterilization, hysterectomy and risk of primary fallopian tube carcinoma in Finland, 1975-2004

We studied the possible relationship among parity, female sterilization, hysterectomy and the risk of primary fallopian tube carcinoma (PFTC) in a case-control study in Finland in cases occurring between 1975 and 2004. A total of 573 PFTC cases were identified from the Finnish Cancer Registry, and 10 age-matched controls per case were randomly selected from the Finnish Central Population Registry. In multivariate analysis (including 189 PFTC cases and 1764 controls) parity was protective: the odds ratio (OR) for 1-2 deliveries was 0.63 (95% CI 0.44-0.91) and for > or =3 deliveries, 0.32 (95% CI 0.19-0.52). The OR for sterilization was 0.74 (95% CI 0.42-1.30) and for hysterectomy 1.27 (95% CI 0.73-2.21). Our findings suggest a possible hormonal background as regards the development of PFTC.     

Tubal sterilization and risk of breast cancer mortality in US women

Objective: To investigate the hypothesis that tubal sterilization is associated with a reduced risk of breast cancer. Methods: We examined this hypothesis in a large prospective study of US adults. After 14 years of mortality follow-up, 3837 deaths from breast cancer were observed in a cohort of 619,199 women who were cancer-free at study entry in 1982. Results: Cox proportional hazards models (adjusted for multiple breast cancer risk factors) showed a significant inverse association between tubal sterilization and breast cancer mortality (adjusted rate ratio (RR) = 0.82, 95% confidence interval (CI) 0.70–0.96). Women who were sterilized before age 35 had a lower risk (adjusted RR = 0.69, 95% CI 0.53–0.88) than women who were sterilized at 35 years of age or older (adjusted RR = 0.92, 95% CI 0.75–1.13). Also, sterilizations performed before 1975 resulted in a lower risk (RR = 0.75, 95% CI 0.62–0.91) than those performed during or after 1975 (RR = 0.98, 95% CI 0.74–1.29), possibly reflecting the likelihood of greater tissue damage with earlier procedures. Conclusions: These results suggest that tubal sterilization may lower subsequent risk of breast cancer, especially among women who are sterilized at a relatively young age. Additional studies are needed to confirm or refute these findings.     

Epidemiology and treatment patterns of epithelial ovarian cancer

Introduction: While ovarian cancer (OC) is relatively rare, it remains one of the most fatal cancers. Lack of robust screening methods for eOC lead to detection of most cases at advanced stages, and most patients relapse following initial treatment.

Areas covered: This review summarizes epidemiology and treatment patterns of epithelial ovarian cancer (eOC). MEDLINE, EMBASE, conference proceedings, and the Cochrane Library were searched using key terms and Medical Subject Headings for ovarian cancer, treatment patterns, and epidemiology to identify articles published from 2005–2015.

Expert commentary: To improve early detection, future studies should focus on the identification of biomarkers that can detect asymptomatic disease. Following diagnosis and eventual relapse, response to first-line platinum appears to guide physicians’ choice of subsequent therapies, but we do not understand what patients ultimately receive or its relationship to categories of response to first-line platinum. Improved understanding of later-line treatment patterns, by initial response to platinum, could correlate with overall outcomes among relapsed patients and promote development of more effective treatment guidelines. Novel treatment approaches, such as immunotherapies, would fulfill a need for an effective strategy against advanced stages of OC that results in fewer toxic side effects.     

上皮性卵巢癌组织中乙酰肝素酶的表达及其与预后的关系

目的：研究乙酰肝素酶（Hpa）在上皮性卵巢癌组织中的表达,分析其与卵巢癌临床病理特征及预后的关系。方法：采用RT-PCR和免疫组化方法检测乙酰肝素酶mRNA及蛋白在上皮性卵巢癌、卵巢良性肿瘤和正常卵巢组织中的表达。结果：Hpa mRNA在卵巢癌组织中的阳性表达率为73.33%（33/45）,相对表达水平为0.65±0.37,均明显高于卵巢良性肿瘤和正常卵巢组织（0.39±0.49/0.31±0.52）,差异有显著性（P均〈0.05）。Hpa蛋白主要定位于细胞胞质,在卵巢癌组织中染色以（＋＋）-（＋＋＋）为主（44.44%）,明显强于卵巢良性肿瘤（13.33%）和正常卵巢组织（0.00%）。有淋巴结转移的癌组织Hpa蛋白及mRNA水平均高于无淋巴结转移组,FIGO分期Ⅲ-IV的癌组织表达高于I-Ⅱ组,均有统计学意义（P〈0.01）。Log-rank分析显示Hpa表达阳性者的累积生存率明显低于阴性者,差异有显著性（P〈0.05）。结论：Hpa在上皮性卵巢癌组织中高表达,并且与卵巢癌的临床分期、淋巴结转移及病人的生存期密切相关,可作为判断上皮性卵巢癌生物学行为和预后的重要参考指标。     

上皮性卵巢癌组织中乙酰肝素酶的表达及其与预后的关系

目的 研究乙酰肝素酶(Hpa)在上皮性卵巢癌组织中的表达,分析其与卵巢癌临床病理特征及预后的关系.方法 采用RT-PCR和免疫组化方法检测乙酰肝素酶mRNA及蛋白在上皮性卵巢癌、卵巢良性肿瘤和正常卵巢组织中的表达.结果 Hpa mRNA在卵巢癌组织中的阳性表达率为73.33%(33/45),相对表达水平为0.65±0.37,均明显高于卵巢良性肿瘤和正常卵巢组织(0.39±0.49/0.31±0.52),差异有显著性(P均<0.05).Hpa蛋白主要定位于细胞胞质,在卵巢癌组织中染色以(++)-(+++)为主(44.44%),明显强于卵巢良性肿瘤(13.33%)和正常卵巢组织(0.00%).有淋巴结转移的癌组织Hpa蛋白及mRNA水平均高于无淋巴结转移组,FIGO分期Ⅲ-IV的癌组织表达高于I-Ⅱ组,均有统计学意义(P<0.01).Log-rank 分析显示Hpa 表达阳性者的累积生存率明显低于阴性者,差异有显著性(P<0.05).结论 Hpa在上皮性卵巢癌组织中高表达,并且与卵巢癌的临床分期、淋巴结转移及病人的生存期密切相关,可作为判断上皮性卵巢癌生物学行为和预后的重要参考指标.     

Fertility preservation in young women with epithelial ovarian cancer

BACKGROUND:

Surgical management of ovarian cancer consists of hysterectomy with bilateral oophorectomy. In young women, this results in the loss of reproductive function and estrogen deprivation. In the current study, the authors examined the safety of fertility‐conserving surgery in premenopausal women with epithelial ovarian cancers.

METHODS:

Women aged ≤50 years with stage IA or IC epithelial ovarian cancer who were registered in the Surveillance, Epidemiology, and End Results database were examined. Patients who underwent bilateral oophorectomy were compared with those who underwent ovarian conservation. A second analysis examined uterine conservation versus hysterectomy. Multivariate Poisson regression models were developed to describe predictors of fertility preservation. Survival was examined using Cox proportional hazards models and the Kaplan‐Meier method.

RESULTS:

In total, 1186 women, including 754 women (64%) who underwent bilateral oophorectomy and 432 women (36%) who underwent ovarian preservation, were identified. Younger age, later year of diagnosis, and residence in the eastern or western United States were associated with ovarian preservation (P < .05 for all). Women with endometrioid and clear cell histologies and stage IC disease were less likely to have ovarian conservation (P < .05). In a Cox model, ovarian preservation had no effect on survival (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.39‐1.20). Young age, later year of diagnosis, residence in the eastern or western United States, single women, mucinous tumors, and patients with stage IA disease were more likely to have uterine preservation (P < .05 for all). In a multivariate model, uterine preservation had no effect on survival (HR, 0.87; 95% CI, 0.62‐1.22).

CONCLUSIONS:

Ovarian and uterine‐conserving surgery were safe in young women who had stage IA and IC epithelial ovarian cancer. Cancer 2009. © 2009 American Cancer Society.     

卵巢上皮性癌和血小板计数增高相关性分析

Objective: To evaluate the clinical significance of platelet (PLT) count in epithelial ovarian cancer, and to inves-tigate the correlation between thrombocytosis and the incidence of epithelial ovarian cancer. Methods: We evaluated 220 epithelial ovarian tumor patients divided into early stage epithelial ovarian cancer group (n = 80), advanced stage epithelial ovarian cancer group (n = 50) and benign ovarian tumor group (n = 90) as controls, who underwent primary surgical treatment. Three groups were evaluated with the relationship between platelet counts and preoperative and postoperative CA125, histo-pathology, abdominal edema, residual tumor, and lymph node metastasis. Epithelial ovarian cancer patients were evaluated whether platelet count was decreased after surgery. Results: The mean platelet counts were (234.55±71.51)×109/L in the early stage epithelial ovarian cancer group, (308.12±111.95)×10<'9>/L in the advanced stage epithelial ovarian cancer group,and (206.28±52.62)×109/L in the benign ovarian tumor group, with a significant difference among the 3 groups (P<0.05).In the early stage epithelial ovarian cancer group, the platelet count was correlated with histopathology. In the advanced stage epithelial ovarian cancer group, there was a correlation between thrombocytosis and the incidence of that residual tumor diameter was greater than 2 cm. But there was no relationship between platelet count and histopathology, CA125, abdominal edema, or lymph node metastasis. In general the platelet count was decreased after surgery. Conclusion: An increased platelet count is commonly seen in patients with epithelial ovarian cancer, but it usually decreases after surgery. Patients with thrombocytosis have poor prognosis. Platelet count can be used as a marker for the development and prognosis of epithelial ovarian cancer.     

Continuous mitoxantrone infusion in pretreated epithelial ovarian cancer

Mitoxantrone has shown moderate activity in advanced epithelial ovarian cancer following intermittent i.v. administration. Experiments and clinical data suggest that long-term continuous drug infusion may achieve a better therapeutic result with less toxicity. This hypothesis was tested in patients with advanced ovarian cancer who had been pretreated with other agents. Mitoxantrone was infused continuously in 21-day courses beginning every 6 weeks. If severe toxicity did not occur, the infusion rate was increased by 0.1–0.2 mg/m² per day. The mitoxantrone solution proved to be stable over the 21-day infusion period. For ethical reasons an optimal two-stage design was employed. The trial was interrupted at the end of the first recruitment stage because the target of 3 responses out of 13 patients had not been achieved (only 1 patient had a partial response). Hematologic toxicity was observed in 11 patients, and 2 of them had a catheter occlusion. In conclusion, we found that 21-day of infusion of mitoxantrone apparently has no clinical benefit as compared with bolus administration in patients with advanced ovarian cancer.     

Use of antidepressants and risk of epithelial ovarian cancer

Antidepressants are widely prescribed among women to treat depression and anxiety disorders, but studies of their effects on gynecological cancer risk are sparse. We assessed associations between various antidepressants and risk of epithelial ovarian cancer. By using Danish nationwide registers, we identified all women (cases) aged 30–84 years with incident epithelial (serous, endometrioid, clear cell or mucinous) ovarian cancer during 2000–2011 (n = 4,103) and matched each case to 20 population controls (n = 58,706) by risk‐set matching. Data on drug use (including tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants, and potential confounder drugs), medical and reproductive history and socioeconomic parameters, were obtained from nationwide registries. We used conditional logistic regression models to estimate adjusted odds ratios (ORs) and two‐sided 95% confidence intervals (CIs) for epithelial ovarian cancer associated with antidepressive drug use. Compared with non‐use, use of selective serotonin reuptake inhibitors was associated with a decreased risk of ovarian cancer (OR, 0.85; 95% CI, 0.74–0.96), whereas the associations for other antidepressants were close to unity [tricyclic and related antidepressants: OR, 0.99 (95% CI, 0.78–1.26); other antidepressants: OR, 1.05 (95% CI, 0.76–1.46)]. For individual types of SSRI, reduced ORs were observed for citalopram OR, 0.78 (95% CI, 0.66–0.93), paroxetine 0.79 (95% CI, 0.56–1.12) and sertraline 0.80 (95% CI, 0.60–1.08). Among postmenopausal women, the inverse association was restricted to users of menopausal hormone therapy. In conclusion, use of selective serotonin reuptake inhibitors was associated with a decreased risk of epithelial ovarian cancer; thereby implying potential chemopreventive properties of these drugs.     

晚期上皮性卵巢癌术后辅助化疗与放疗

对晚期上皮性卵巢癌减瘤术后辅助化疗及放疗的结果进行比较分析。材料与方法对５２例已行初次减瘤术的Ⅲｃ、Ⅳ期上皮性卵巢癌病人随机分成腹腔化疗＋静脉化疗（化疗组）和放疗＋静脉化疗（放疗组）２组，给予药物及放射治疗。结果化疗及放疗２组病人５年生存率分别是２７．３％和３６．７％，无明显差异。无严重并发症。结论对控制晚期上皮性卵巢癌减瘤术后腹腔残余癌，腹腔化疗＋静脉化疗及放疗＋静脉化疗同样有效，且较术后单纯静脉化疗效果好。     

Hypodontia phenotype in patients with epithelial ovarian cancer

Background

Ovarian cancer is usually diagnosed in an advanced stage and the present clinical and diagnostic molecular markers for early OC screening are insufficient. The aim of this study was to identify potential relationship between the hypodontia and epithelial ovarian cancer (EOC).

Patients and methods

A retrospective study was conducted on 120 patients with EOC treated at the Department of Gynaecologic and Breast Oncology at the University Clinical Centre and 120 gynaecological healthy women (control group) of the same mean age. Women in both groups were reviewed for the presence of hypodontia and the patients with EOC also for clinicopathological characteristics of EOC according to hypodontia phenotype.

Results

Hypodontia was diagnosed in 23 (19.2%) of patients with EOC and 8 (6.7%) controls (p = 0.004; odds ratio [OR] = 3.32; confidence interval [CI], 1.42–7.76). There was no statistically significant difference in patients with EOC with or without hypodontia regarding histological subtype (p = 0.220); they differed in regard to FIGO stage (p = 0.014; OR =3.26; CI, 1.23–8.64) and tumour differentiation grade (p = 0.042; OR = 3.1; CI, 1.01–9.53). Also, bilateral occurrence of EOC was more common than unilateral occurrence in women with hypodontia (p = 0.021; OR = 2.9; CI, 1.15–7.36). We also found statistically significant difference between the ovarian cancer group and control group in presence of other malignant tumours in subjects (p < 0.001).

Conclusions

The results of the study suggest a statistical association between EOC and hypodontia phenotype. Hypodontia might serve as a risk factor for EOC detection.     

Maintenance therapy in epithelial ovarian cancer: from chemotherapy to targeted agents

Over the past years, although no increase in the cure rate for advanced epithelial ovarian cancer patients has been achieved, a slow prolongation in patients survival has been observed, thanks to the introduction of effective second line or salvage therapies. Attempts to disease chronicization seem therefore of value in this setting. A major effort has been pursued to establish the role of maintenance therapies for epithelial ovarian cancer patients. Although chemotherapy does not seem to have an effective role, promising results are coming from trials investigating maintenance targeted treatments, especially with antiangiogenic agents or PARP inhibitors for selected patients. The aim of this article is to review current evidences on maintenance therapy for epithelial ovarian cancer and put the results in perspective.     

ASPM and microcephalin expression in epithelial ovarian cancer correlates with tumour grade and survival

Background:

The clinico-pathological and molecular heterogeneity of epithelial ovarian cancer (EOC) complicates its early diagnosis and successful treatment. Highly aneuploid tumours and the presence of ascitic fluids are hallmarks of EOC. Two microcephaly-associated proteins, abnormal spindle-like microcephaly-associated protein (ASPM) and microcephalin, are involved in mitosis and DNA damage repair. Their expression is deregulated at the RNA level in EOC. Here, ASPM and microcephalin protein expression in primary cultures established from the ascites of patients with EOC was determined and correlated with clinical data to assess their suitability as biomarkers.

Methods:

Five established ovarian cancer cell lines, cells derived from two benign ovarian ascites samples and 40 primary cultures of EOC derived from ovarian ascites samples were analysed by protein slot blotting and/or immunofluorescence to determine ASPM and microcephalin protein levels and their cellular localisation. Results were correlated with clinico-pathological data.

Results:

A statistically significant correlation was identified for ASPM localisation and tumour grade, with high levels of cytoplasmic ASPM correlating with grade 1 tumours. Conversely, cytoplasmic microcephalin was only identified in high-grade tumours. Furthermore, low levels of nuclear microcephalin correlated with reduced patient survival.

Conclusion:

Our results suggest that ASPM and microcephalin have the potential to be biomarkers in ovarian cancer.     

上皮性卵巢癌生化复发的判定、随访及治疗研究进展

在随访上皮性卵巢癌（epithelial ovarian cancer，EOC）患者的过程中，有相当一部分患者在首次治疗结束后会经历症状体格检查、影像学检查无复发迹象，而肿瘤标志物水平明显增高的阶段。有学者认为可将此阶段描述为“生化复发”。但是肿瘤标志物界定阈值不明确，种类繁多，因此目前尚无定论。这种状况在一定程度上影响了对这一阶段患者的随访方案的制定、治疗方法的研究。本文就上皮性卵巢癌“生化复发”的标志物阈值、检测时间、排除临床复发的方法等相关问题进行综述。     

颗粒蛋白前体在离体上皮性卵巢癌细胞恶性行为中的作用及意义

目的 研究颗粒蛋白前体(PGRN)在离体上皮性卵巢癌恶性行为中的作用及意义.方法 选择40例上皮性卵巢癌患者和40例卵巢良性肿瘤患者,采用免疫组织化学染色法比较肿瘤组织中PGRN的表达情况.采用慢病毒转染SKOV3细胞系,获得PGRN高表达(PGRN高表达组)和普通表达(对照组)的细胞系,传代培养比较两组细胞的增殖能力,通过Transwell小室建立转移和侵袭模型,比较两组细胞的侵袭和转移能力.结果 上皮性卵巢癌患者的PGRN免疫组化染色评分为(8.43±1.30)分,明显高于卵巢良性肿瘤患者的(3.08±1.25)分,差异有统计学意义(P﹤0.01);对照组和PGRN高表达组的细胞数量均随时间延长而明显增多(P﹤0.01),PGRN高表达组的细胞数量多于对照组(P﹤0.05).PGRN高表达组转移细胞数目为(170.73±8.13)/HP,明显多于对照组的(102.93±8.54)/HP(P﹤0.01);PGRN高表达组侵袭细胞数目为(109.33±7.37)/HP,明显多于对照组的(53.27±5.35)/HP(P﹤0.01).结论 PGRN在上皮性卵巢癌组织中高表达,并且可以促进癌细胞增殖、侵袭和转移等恶性行为.