Non-malignant Sequelae after Unconfined Power Morcellation.

STUDY OBJECTIVE: To identify the incidence of repeat surgery and subsequent findings after the performance of unconfined uterine power morcellation. DESIGN: A retrospective descriptive study (Canadian Task Force classification II-2). SETTING: Southern California Kaiser Permanente Medical Centers. PATIENTS: Women (N = 5154) who underwent laparoscopic supracervical hysterectomy with unconfined power morcellation. MEASUREMENTS AND MAIN RESULTS: Of the 5154 cases, 279 (5.41%) underwent subsequent reoperation with a median of 24 months after index surgery. The most common clinical complaint leading to laparoscopic supracervical hysterectomy was symptomatic leiomyoma (n = 135, 48.4%) and abnormal uterine bleeding (n = 94, 33.7%). The most common indication for reoperation was a symptomatic adnexal mass (n = 87, 31.2%) followed by pelvic pain (n = 83, 29.7%). The majority (n = 128, 60.4%) of subsequent non-urogynecologic-related reoperations resulted in benign pathology. Endometriosis was the primary pathologic diagnosis in 65 of 279 (23.3%) of the reoperative cases; this was not previously documented in 86% (n = 57/65) of these cases. The overall frequency of subsequent pathology was endometriosis (65/5154, 1.26%), disseminated leiomyomatosis (18/5154, 0.35%), and new malignancy (11/5154, 0.21%). CONCLUSION: Morcellation of nonmalignant tissue is not without consequence. Pathology confirmed endometriosis was documented for the first time in 20.4% of patients who underwent a second surgery. This finding raises the suspicion that morcellation and dispersion of the uterine specimen may be associated in the development of endometriosis.

Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies.

BACKGROUND: Endometriosis is a risk factor for epithelial ovarian cancer; however, whether this risk extends to all invasive histological subtypes or borderline tumours is not clear. We undertook an international collaborative study to assess the association between endometriosis and histological subtypes of ovarian cancer. METHODS: Data from 13 ovarian cancer case-control studies, which were part of the Ovarian Cancer Association Consortium, were pooled and logistic regression analyses were undertaken to assess the association between self-reported endometriosis and risk of ovarian cancer. Analyses of invasive cases were done with respect to histological subtypes, grade, and stage, and analyses of borderline tumours by histological subtype. Age, ethnic origin, study site, parity, and duration of oral contraceptive use were included in all analytical models. FINDINGS: 13 226 controls and 7911 women with invasive ovarian cancer were included in this analysis. 818 and 738, respectively, reported a history of endometriosis. 1907 women with borderline ovarian cancer were also included in the analysis, and 168 of these reported a history of endometriosis. Self-reported endometriosis was associated with a significantly increased risk of clear-cell (136 [20·2%] of 674 cases vs 818 [6·2%] of 13 226 controls, odds ratio 3·05, 95% CI 2·43-3·84, p<0·0001), low-grade serous (31 [9·2%] of 336 cases, 2·11, 1·39-3·20, p<0·0001), and endometrioid invasive ovarian cancers (169 [13·9%] of 1220 cases, 2·04, 1·67-2·48, p<0·0001). No association was noted between endometriosis and risk of mucinous (31 [6·0%] of 516 cases, 1·02, 0·69-1·50, p=0·93) or high-grade serous invasive ovarian cancer (261 [7·1%] of 3659 cases, 1·13, 0·97-1·32, p=0·13), or borderline tumours of either subtype (serous 103 [9·0%] of 1140 cases, 1·20, 0·95-1·52, p=0·12, and mucinous 65 [8·5%] of 767 cases, 1·12, 0·84-1·48, p=0·45). INTERPRETATION: Clinicians should be aware of the increased risk of specific subtypes of ovarian cancer in women with endometriosis. Future efforts should focus on understanding the mechanisms that might lead to malignant transformation of endometriosis so as to help identify subsets of women at increased risk of ovarian cancer. FUNDING: Ovarian Cancer Research Fund, National Institutes of Health, California Cancer Research Program, California Department of Health Services, Lon V Smith Foundation, European Community's Seventh Framework Programme, German Federal Ministry of Education and Research of Germany, Programme of Clinical Biomedical Research, German Cancer Research Centre, Eve Appeal, Oak Foundation, UK National Institute of Health Research, National Health and Medical Research Council of Australia, US Army Medical Research and Materiel Command, Cancer Council Tasmania, Cancer Foundation of Western Australia, Mermaid 1, Danish Cancer Society, and Roswell Park Alliance Foundation.

Perspectives on Access to Novel Therapeutics Through Clinical Trials Among Adolescents and Young Adults with Advanced Cancer: Implications for Patient-Centered Clinical Trials.

Purpose: Adolescents and young adults (AYA) with advanced cancer have unequal access to and enrollment in clinical trials. Many AYA use online platforms to share their treatment experiences. The purpose of this analysis was to explore how AYA discuss clinical trials and their access to novel therapeutics through their blogs. Methods: We studied illness blogs from 22 AYA (ages 16-38 years old) with advanced cancer who specifically discussed experiences enrolling in a clinical trial. Nearly 500 excerpts were abstracted from their blogs, and we used qualitative descriptive methodology and thematic analysis to explore their longitudinal perspectives. Results: We describe three themes: (1) "Blinded", which represents the uncertainty in treatment pathway and underrepresentation of AYA in clinical trials, (2) "Totally healthy except for the damn cancer", which represents the numerous challenges associated with meeting eligibility criteria and lack of available clinical trials, and (3) "Go ahead and send me the bill!", which represents the precarious financial challenges associated with participating with clinical trials (both direct costs and indirect costs associated with travel, time away from work) as well as the costs of novel therapeutics. Conclusions: By studying AYA online narratives, we can outline several gaps in accessing clinical trials and generate future research priorities. AYA with advanced cancer are known to have aggressive trajectories, and there are opportunities to integrate patient-reported outcomes and supportive care frameworks embedded within clinical trial study design.

Adolescent endometriosis.

PURPOSE OF REVIEW: This review will address the recent literature regarding adolescent endometriosis. RECENT FINDINGS: An increasing body of literature suggests that there are symptoms of endometriosis present in adolescents. In addition, those teens with a history of dysmenorrhea severe enough to disrupt quality of life are more likely to be diagnosed with endometriosis. SUMMARY: The issues of endometriosis progression and early diagnosis remain key issues for the adolescent.

Recent breast cancer incidence trends according to hormone therapy use: the California Teachers Study cohort.

INTRODUCTION: Recent, international declines in breast cancer incidence are unprecedented, and the causes remain controversial. Few data sources can address breast cancer incidence trends according to pertinent characteristics like hormone therapy use history. METHODS: We used the prospective California Teachers Study to evaluate changes in self-reported use of menopausal hormone therapy (HT) between 1995 to 1996 and 2005 to 2006 and age-adjusted breast cancer incidence among 74,647 participants aged 50 years or older. Breast cancer occurrence was determined by linkage with the California Cancer Registry. RESULTS: During 517,286 woman years of follow up, 565 in situ and 2,668 invasive breast cancers were diagnosed. In situ breast cancer incidence rates in this population did not change significantly from 2000 to 2002 to 2003 to 2005, whereas rates of invasive breast cancer declined significantly by 26.0% from 528.0 (95% confidence intervals (CI) = 491.1, 564.9) per 100,000 women in 2000 to 2002 to 390.6 (95% CI = 355.6, 425.7) in 2003 to 2005. The decline in invasive breast cancer incidence rates was restricted to estrogen receptor-positive tumors. In 1996 to 1999 and 2000 to 2002 invasive breast cancer incidence was higher for women who reported current HT use especially estrogen-progestin (EP) use at baseline than for never or past users; but by 2003 to 2005 rates were comparable between these groups. For women who were taking EP in 2001 to 2002,75% of whom had stopped use by 2005 to 2006, incidence had declined 30.6% by 2003 to 2005 (P = 0.001); whereas incidence did not change significantly for those who never took HT (P = 0.33). CONCLUSIONS: Few data resources can examine prospectively individual HT use and breast cancer diagnosis. Stable in situ breast cancer rates imply consistent levels of screening and suggest recent declines in invasive breast cancer to be explained predominantly by changes in HT use.

Menopausal hormone therapy use and risk of invasive colon cancer: the California Teachers Study.

Results from epidemiologic studies of hormone therapy use and colon cancer risk are inconsistent. This question was investigated in the California Teachers Study (1995-2006) among 56,864 perimenopausal or postmenopausal participants under 80 years of age with no prior colorectal cancer by using Cox proportional hazards regression. Incident invasive colon cancer was diagnosed among 442 participants. Baseline-recent hormone therapy users were at 36% lower risk for colon cancer versus baseline-never users (baseline-recent users: relative risk (RR) = 0.64, 95% confidence interval (CI): 0.51, 0.80). Results did not differ by formulation. Estimated risk was lower among baseline-recent hormone therapy users with increasing duration between 5 and 15 years of use (RR = 0.49, 95% CI: 0.35, 0.68), but the trend did not persist in the longest duration group, more than 15 years of use (RR = 0.69, 95% CI: 0.52, 0.92; P(trend) = 0.60). Long-term recreational physical activity, obesity, regular use of nonsteroidal antiinflammatory medications, and daily alcohol intake did not modify these effects; baseline-recent use was more strongly associated with colon cancer risk among women with a family history of colorectal cancer (P(heterogeneity) = 0.04). Baseline-recent hormone therapy use was inversely associated with invasive colon cancer risk among perimenopausal and postmenopausal women in the California Teachers Study.

Markers of inflammation and risk of ovarian cancer in Los Angeles County.

Factors that increase inflammation have been suggested to influence the development of ovarian cancer, but these factors have not been well studied. To further investigate this question, we studied the role of talc use, history of endometrioisis and use of non-steroidal anti-inflammatory drugs (NSAIDs) and risk of ovarian cancer in a population-based case-control study in Los Angeles County involving 609 women with newly diagnosed epithelial ovarian cancer and 688 population-based control women. Risk of ovarian cancer increased significantly with increasing frequency and duration of talc use; compared to never users risk was highest among long-duration (20+ years), frequent (at least daily) talc users (adjusted relative risk (RR) = 2.08, 95% confidence interval (CI) = 1.34-3.23). A history of physician-diagnosed endometriosis was statistically significantly associated with risk (RR = 1.66, 95% CI = 1.01-2.75). Women who were talc users and had a history of endometriosis showed a 3-fold increased risk (RR = 3.12, 95% CI = 1.36-7.22). Contrary to the hypothesis that risk of ovarian cancer may be reduced by use of NSAIDs; risk increased with increasing frequency (per 7 times/week, RR = 1.27, 95% CI = 1.14-1.43) and years of NSAID use (per 5 years of use, RR = 1.25, 95% CI = 1.10-1.42); this was consistent across types of NSAIDs. We conclude that risk of ovarian cancer is significantly associated with talc use and with a history of endometriosis, as has been found in previous studies. The NSAID finding was unexpected and suggests that factors associated with inflammation are associated with ovarian cancer risk. This result needs confirmation with careful attention to the reasons for NSAID use.

Twin gestation in a uterus didelphys with only one functional cervix: A case report.

INTRODUCTION: Twin gestation in a uterus didelphys with one fetus in each uterine cavity is rare and presents unique challenges in antepartum and intrapartum care. CASE PRESENTATION: A 35-year-old woman with a uterus didelphys became pregnant with twins, with one fetus in each uterus, after intrauterine insemination of a single visible cervix. Multiplanar ultrasonography showed the presence of one complete cervix and a second hypoplastic cervix; it was unclear whether she could deliver both twins vaginally. Her pregnancy was complicated by fetal growth restriction of twin B. At 38 weeks, the patient underwent scheduled cesarean section and delivered two viable twins. CONCLUSION: Determining the precise anatomy of Mullerian duct anomalies, including the cervix and vagina, is important for obstetrical management.

Differential gene expression by 1,25(OH)2D3 in an endometriosis stromal cell line.

Endometriosis is a common female reproductive disease characterized by invasion of endometrial cells into other organs, frequently causing pelvic pain and infertility. Alterations of the vitamin D system have been linked to endometriosis incidence and severity. To shed light on the potential mechanism for these associations, we examined the effects of 1,25(OH)2D3 on gene expression in endometriosis cells. Stromal cell lines derived from endometriosis tissue were treated with 1,25(OH)2D3, and RNA-seq was used to identify genes differentially expressed between treated and untreated cells. Gene ontology and pathway analyses were carried out using Partek Flow and Ingenuity software suites, respectively. We identified 1627 genes that were differentially expressed (886 down-regulated and 741 up-regulated) by 1,25(OH)2D3. Only one gene, CYP24A1, was strongly up-regulated (369-fold). Many genes were strongly down-regulated. 1,25(OH)2D3 treatment down-regulated several genetic pathways related to neuroangiogenesis, cellular motility, and invasion, including pathways for axonal guidance, Rho GDP signaling, and matrix metalloprotease inhibition. These findings support a role for vitamin D in the pathophysiology of endometriosis, and provide new targets for investigation into possible causes and treatments.

Up-regulation of EphB4 in mesothelioma and its biological significance.

PURPOSE: Mesothelioma is a rare malignancy that is incurable and carries a short survival despite surgery, radiation, or chemotherapy. This study was designed to identify novel targets for diagnostic, prognostic, and therapeutic approaches. EXPERIMENTAL DESIGN: The expression and functional significance of the receptor tyrosine kinase EphB4 was studied in vitro and in a murine model of mesothelioma. RESULTS: EphB4 was highly expressed in mesothelioma cell lines and primary tumor tissues but not in normal mesothelium. Knockdown of EphB4 using small interfering RNA and antisense oligodeoxynucleotide showed reduction in cell survival, migration, and invasion. EphB4 knockdown initiated a caspase-8-mediated apoptosis and down-regulation of the anti-apoptotic protein bcl-xl. EphB4 knockdown also resulted in reduced phosphorylation of Akt and down-regulation of matrix metalloproteinase-2 transcription. In addition, murine tumor xenograft studies using EphB4 oligodeoxynucleotides showed a marked reduction in tumor growth accompanied by a specific decline in EphB4 protein levels, reduced cell division, apoptosis in tumor tissue, and decreased microvascular density. CONCLUSIONS: EphB4 is expressed in mesothelioma, provides a survival advantage to tumor cells, and is therefore a potential novel therapeutic target.

Insufflation techniques in gynecologic laparoscopy.

Our objectives were to assess the safety and efficacy of different insufflation methods in women undergoing laparoscopy and to develop a model for selection of the appropriate insufflation technique based on the patient's characteristics and surgeon's experience. We performed a retrospective analysis of laparoscopic procedures on 3086 women over a 13-year period at the University of Louisville Hospital, Louisville, KY. All laparoscopic procedures were performed on an outpatient basis by residents under faculty supervision. Five different insufflation techniques were evaluated: standard transumbilical insufflation, open laparoscopy, transuterine insufflation, subcostal insufflation, and direct trocar insertion technique. Body mass index and previous abdominal surgeries were identified as the most important factors in the selection of the most successful insufflation method based on the surgeon's experience, using data mining techniques. During the first insufflation attempt, we were successful at achieving a pneumoperitoneum 94.7% of the time. This number increased to 98.1% when we switched to a second alternative insufflation method. In all, there were 5 complications out of 3086 patients (0.16%) after all insufflation techniques.

Evidence of a genetic link between endometriosis and ovarian cancer.

OBJECTIVE: To evaluate whether endometriosis-associated genetic variation affects risk of ovarian cancer. DESIGN: Pooled genetic analysis. SETTING: University hospital. PATIENT(S): Genetic data from 46,176 participants (15,361 ovarian cancer cases and 30,815 controls) from 41 ovarian cancer studies. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Endometriosis-associated genetic variation and ovarian cancer. RESULT(S): There was significant evidence of an association between endometriosis-related genetic variation and ovarian cancer risk, especially for the high-grade serous and clear cell histotypes. Overall we observed 15 significant burden statistics, which was three times more than expected. CONCLUSION(S): By focusing on candidate regions from a phenotype associated with ovarian cancer, we have shown a clear genetic link between endometriosis and ovarian cancer that warrants further follow-up. The functional significance of the identified regions and SNPs is presently uncertain, though future fine mapping and histotype-specific functional analyses may shed light on the etiologies of both gynecologic conditions.

Benign ovarian masses.

Primary tumors of the ovary are uncommon in children and the majority of these masses are not malignant. As newer diagnostic imaging techniques have increased the detection of all ovarian masses, the frequency of ovarian cancer has actually decreased. Clinical symptoms are generally not helpful in distinguishing benign from malignant masses, but radiographic criteria have been developed. Surgical treatment is aimed at ovarian preservation if the lesion proves benign.

Population distribution of lifetime risk of ovarian cancer in the United States.

BACKGROUND: In U.S. women, lifetime risk of ovarian cancer is 1.37%, but some women are at a substantially lower or higher risk than this average. METHODS: We have characterized the distribution of lifetime risk in the general population. Published data on the relative risks and their variances for five well-accepted risk and protective factors for ovarian cancer, oral contraceptive use, parity, tubal ligation, endometriosis, and first-degree family history of ovarian cancer in conjunction with a genetic risk score using genome-wide significant common, low penetrance variants were used. The joint distribution of these factors (i.e., risk/protective factor profiles) was derived using control data from four U.S. population-based studies, providing a broad representation of women in the United States. RESULTS: A total of 214 combinations of risk/protective factors were observed, and the lifetime risk estimates ranged from 0.35% [95% confidence interval (CI), 0.29-0.42] to 8.78% (95% CI, 7.10-10.9). Among women with lifetime risk ranging from 4% to 9%, 73% had no family history of ovarian cancer; most of these women had a self-reported history of endometriosis. CONCLUSIONS: Profiles including the known modifiable protective factors of oral contraceptive use and tubal ligation were associated with a lower lifetime risk of ovarian cancer. Oral contraceptive use and tubal ligation were essentially absent among the women at 4% to 9% lifetime risk. IMPACT: This work demonstrates that there are women in the general population who have a much higher than average lifetime risk of ovarian cancer. Preventive strategies are available. Should effective screening become available, higher than average risk women can be identified.

Novel three-dimensional in vitro models of ovarian endometriosis.

BACKGROUND: Endometriosis is characterized by the presence of functional endometrial tissue outside of the uterine cavity. It affects 1 in 10 women of reproductive age. This chronic condition commonly leads to consequences such as pelvic pain, dysmenorrhea, infertility and an elevated risk of epithelial ovarian cancer. Despite the prevalence of endometriosis and its impact on women's lives, there are relatively few in vitro and in vivo models available for studying the complex disease biology, pathophysiology, and for use in the preclinical development of novel therapies. The goal of this study was to develop a novel three-dimensional (3D) cell culture model of ovarian endometriosis and to test whether it is more reflective of endometriosis biology than traditional two dimensional (2D) monolayer cultures. METHODS: A novel ovarian endometriosis epithelial cell line (EEC16) was isolated from a 34-year old female with severe endometriosis. After characterization of cells using in vitro assays, western blotting and RNA-sequencing, this cell line and a second, already well characterized endometriosis cell line, EEC12Z, were established as in vitro 3D spheroid models. We compared biological features of 3D spheroids to 2D cultures and human endometriosis lesions using immunohistochemistry and real-time semi-quantitative PCR. RESULTS: In comparison to normal ovarian epithelial cells, EEC16 displayed features of neoplastic transformation in in vitro assays. When cultured in 3D, EEC16 and EEC12Z showed differential expression of endometriosis-associated genes compared to 2D monolayer cultures, and more closely mimicked the molecular and histological features of human endometriosis lesions. CONCLUSIONS: To our knowledge, this represents the first report of an in vitro spheroid model of endometriosis. 3D endometriosis models represent valuable experimental tools for studying EEC biology and the development of novel therapeutic approaches.

Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer.

HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.

Bilateral oophorectomy is not associated with increased mortality: the California Teachers Study.

OBJECTIVE: To investigate the effect of surgical menopause due to bilateral oophorectomy on mortality, in light of evidence that bilateral oophorectomy among premenopausal women rapidly reduces endogenous hormone levels, thereby modifying risks of cardiovascular disease and breast cancer. DESIGN: The California Teachers Study (CTS) is a prospective cohort study of 133,479 women initiated in 1995-1996 through a mailed, self-administered questionnaire. Relative risks and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression. SETTING: None. PATIENT(S): California Teachers Study participants who, at baseline, reported having surgical menopause due to bilateral oophorectomy (n = 9,785), were compared with participants with natural menopause (n = 32,219). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We investigated whether bilateral oophorectomy was associated with all-cause, cardiovascular, or cancer mortality, overall and by menopausal hormone therapy use status. RESULT(S): Among participants aged <45 years at menopause, multivariable relative risks were 0.86 (95% CI, 0.74-1.00), 0.85 (95% CI, 0.66-1.11), and 0.91 (95% CI, 0.67-1.23) for all-cause mortality, cardiovascular mortality, and cancer mortality, respectively. Among participants with an age at menopause of ≥45 years, multivariable relative risks were 0.87 (95% CI, 0.80-0.94), 0.83 (95% CI, 0.71-0.96), and 0.84 (95% CI, 0.72-0.98) for all-cause, cardiovascular, and cancer mortality, respectively. The association between bilateral oophorectomy and mortality did not differ by baseline status of hormone therapy use. CONCLUSION(S): Surgical menopause due to bilateral oophorectomy vs. natural menopause does not increase all-cause, cardiovascular, or cancer mortality.

Progesterone receptor gene polymorphisms and risk of endometriosis: results from an international collaborative effort.

OBJECTIVE: To investigate the association between self-reported endometriosis and the putative functional promoter +331C/T single nucleotide polymorphism and the PROGINS allele. DESIGN: Control subjects from ovarian cancer case-control studies participating in the international Ovarian Cancer Association Consortium. The majority of controls are drawn from population-based studies. SETTING: An international ovarian cancer consortium including studies from Australia, Europe, and the United States. PATIENT(S): Five thousand eight hundred twelve white female controls, of whom 348 had endometriosis, from eight ovarian cancer case-control studies. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genotypes for the +331C/T single nucleotide polymorphism and PROGINS allele and a history of endometriosis. RESULT(S): The occurrence of endometriosis was reduced in women carrying one or more copies of the +331 T allele (odds ratio=0.65; 95% confidence interval: 0.43-0.98), whereas there was no association between the PROGINS allele and endometriosis (odds ratio=0.94, 95% confidence interval 0.76-1.16). CONCLUSION(S): Additional studies of the +331C/T variant are warranted given the current finding and the equivocal results of previous studies. The +331 T allele has been shown to result in a reduced progesterone (P) receptor A to P receptor B ratio, and if the observed association with endometriosis is confirmed it would suggest that this ratio is important for this disease.

Long-term postmenopausal hormone therapy and endometrial cancer.

Estrogen-alone therapy (ET) or estrogen and progestin (EPT) as menopausal hormone therapy (HT) has been commonly used to alleviate menopausal symptoms. Treatments containing > or = 10 days per month of progestin are considered relatively safe with respect to endometrial cancer risk. However, the endometrial safety of long-term EPT regimens is uncertain. We conducted a case-control study of 311 invasive endometrial cancer cases and 570 controls nested within the California Teachers Study cohort. We used unconditional logistic regression to obtain odds ratios (OR) and 95% confidence intervals (95% CI) for the association between long-term HT use and endometrial cancer risk, and to assess the modifying effect of body mass index (BMI). Long-term (> or = 10 years) use of ET, sequential EPT with <10 days per month progestin, and continuous-combined EPT (> or = 25 days/month progestin) were all associated with an elevated risk of endometrial cancer (OR, 4.5; 95% CI, 2.5-8.1; OR, 4.4; 95% CI, 1.7-11.2; and OR, 2.1; 95% CI, 1.3-3.3, respectively; all P(trend) < 0.001). The risk associated with short-term use was elevated only for ET preparations. The association for continuous-combined EPT was confined to thinner women (BMI, <25 kg/m2; P(interaction) = 0.03). Among heavier women (BMI, > or = 25 kg/m2), use of continuous-combined EPT was associated with a statistically nonsignificant reduction in risk. These findings confirm that long-term use of ET, sequential EPT, or, among normal weight women, continuous-combined EPT is associated with increased risk of endometrial cancer.