Daniel W. Cramer

The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome.

A proportion of adenocarcinomas in prophylactic adnexectomies (bilateral salpingo-oophorectomies [BSOs]) from women with BRCA mutations (BRCA positive) occur in the fallopian tube. We analyzed a consecutive series of BSOs from BRCA-positive women following an index case of fimbrial serous carcinoma. To determine if the fimbria is a preferred site of origin, we followed a protocol for Sectioning and Extensively Examining the FIMbria (SEE-FIM). Immunostaining for p53 and Ki-67 was also performed. Thirteen BRCA-positive women (cases) and 13 women undergoing BSOs for other disorders (controls) were studied. Tubal carcinoma was detected in 4 cases at the initial histologic evaluation and in no controls. A fifth carcinoma was discovered following further sectioning of the fimbriae. Three were BRCA2 positive and two BRCA1 positive. Three were in the fimbria, one in both the fimbria and proximal tube, and one involved the ampulla. Four were serous carcinomas, four were confined to the tube, and three were noninvasive (intraepithelial). No ovarian carcinomas were identified. All tumors were Ki-67 positive (>75% of cell nuclei), and excluding one endometrioid carcinoma, p53 positive (>75% cell nuclei); p53 positivity in the absence of elevated Ki-67 did not correlate with morphologic neoplasia. The fimbria was the most common location for early serous carcinoma in this series of BRCA-positive women. Protocols that extensively examine the fimbria (SEE-FIM) will maximize the detection of early tubal epithelial carcinoma in patients at risk for ovarian cancer. Investigative strategies targeting the fimbriated end of the fallopian tube should further define its role in the pathogenesis of familial and sporadic ovarian serous carcinomas.

A candidate precursor to serous carcinoma that originates in the distal fallopian tube

The tubal fimbria is a common site of origin for early (tubal intraepithelial carcinoma or TIC) serous carcinomas in women with familial BRCA1 or 2 mutations (BRCA+). Somatic p53 tumour suppressor gene mutations in these tumours suggest a pathogenesis involving DNA damage, p53 mutation, and progressive loss of cell cycle control. We recently identified foci of strong p53 immunostaining—termed ‘p53 signatures’—in benign tubal mucosa from BRCA+ women. To examine the relationship between p53 signatures and TIC, we compared location (fimbria vs ampulla), cell type (ciliated vs secretory), evidence of DNA damage, and p53 mutation status between the two entities. p53 signatures were equally common in non‐neoplastic tubes from BRCA+ women and controls, but more frequently present (53%) and multifocal (67%) in fallopian tubes also containing TIC. Like prior studies of TIC, p53 signatures predominated in the fimbriae (80–100%) and targeted secretory cells (HMFG2 + /p73−), with evidence of DNA damage by co‐localization of γ‐H2AX. Laser‐capture microdissected and polymerase chain reaction‐amplified DNA revealed reproducible p53 mutations in eight of 14 fully‐analysed p53 signatures and all of the 12 TICs; TICs and their associated ovarian carcinomas shared identical mutations. In one case, a contiguous p53 signature and TIC shared the same mutation. Morphological intermediates between the two, with p53 mutations and moderate proliferative activity, were also seen. This is the first report of an early and distinct alteration in non‐neoplastic upper genital tract mucosa that fulfils many requirements for a precursor to pelvic serous cancer. The p53 signature and its malignant counterpart (TIC) underline the significance of the fimbria, both as a candidate site for serous carcinogenesis and as a target for future research on the early detection and prevention of this disease. Copyright

The Epidemiology of Endometriosis

Abstract: Advances in understanding the epidemiology of endometriosis have lagged behind other diseases because of methodologic problems related to disease definition and control selection. Nevertheless, a better picture of the epidemiology of endometriosis has emerged over the past few decades. Prevalence estimates of the disease in clinic populations vary from about a 4% occurrence of largely asymptomatic endometriosis found in women undergoing tubal ligation to 50% of teenagers with intractable dysmenorrhea. General population incidence during the 1970s in this country has been suggested to be 1.6 per 1000 white females aged 15‐49, while a more current study based upon hospital discharges finds endometriosis as a first listed diagnosis in 1.3 per 1000 discharges in women aged 15‐44. There is a clinical impression that blacks have lower rates of endometriosis and Orientals have higher rates than whites. A variety of personal risk factors for endometriosis have also been described. Women with endometriosis may be taller and thinner. Menstrual factors reported to increase risk include dysmenorrhea, early menarche, and shorter cycle lengths. There is support for the idea that lifestyle exposures that might raise or lower estrogen levels could affect risk, including a decreased risk associated with smoking and exercise and an increased risk associated with caffeine or alcohol use. These risk factors appear to be compatible with the central importance of retrograde menstruation influenced by outflow obstruction that might affect its amount, immune factors that might affect its ability to be cleared, or hormonal stimuli that might affect its growth. In this model, dysmenorrhea could be either a disease symptom or a manifestation of outflow obstruction. Nulliparity could be either a consequence of disease or a cause since nulliparous women would not have the benefit of cervical dilation associated with labor and delivery. Since there is evidence that family history is a risk factor for disease, a challenge is how to integrate genetic factors into the model. The genetics of endometriosis might be advanced if we could identify an “endometriosis phenotype”. We propose that this may consist of early menarche, short cycles, painful periods, subfertility, and possibly tall stature that could be explained by genetic factors that predispose to poor endowment of germ cells and canalization defects of the cervix. The value of establishing an “endometriosis phenotype” is that, as candidates for genetic markers are identified, particular genotypes can be correlated with these factors even if a formal diagnosis of endometriosis has not been made. Additional well‐designed case‐control and cohort studies will be necessary to test theories related to pathogenesis, establish the precise relationship between reproductive morbidity and endometriosis, identify specific genetic factors, and establish long‐term risks.

The epidemiology of endometriosis

The epidemiologic study of endometriosis presents researchers with unique challenges. As a result, few well-designed studies have been published. The authors briefly describe the primary pathogenic hypotheses, discuss methodologic issues specific to endometriosis, and review the small body of literature addressing risk factors. Finally, they offer a brief interpretation of these findings and suggest hypotheses for future research.

A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2

Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk. We performed a genome-wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and ∼2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P < 10−8). The most significant SNP (rs3814113; P = 2.5 × 10−17) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls, confirming its association (combined data odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.79–0.86, Ptrend = 5.1 × 10−19). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77, 95% CI 0.73–0.81, Ptrend = 4.1 × 10−21).

Insulin-like growth factor-I in relation to premenopausal ductal carcinoma in situ of the breast.

We evaluated the association of plasma insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) with risk of breast cancer in a study of 94 cases of premenopausal ductal carcinoma in situ and 76 controls. Compared with women in the lowest tertile of IGF-I, women in the upper two tertiles of IGF-I had an elevated risk for ductal carcinoma in situ. Conversely, compared with women in the lowest tertile of IGFBP-3, women in the upper two tertiles of IGFBP-3 had a decreased risk for ductal carcinoma in situ. After grouping women on the basis of both IGF-I and IGFBP-3, women in the highest two tertiles of IGF-I and the lowest tertile of IGFBP-3 were at notably higher risk than women in the lowest tertile of IGF-I and the highest two tertiles of IGFBP-3 (odds ratio = 3.7; 95% confidence interval = 1.1-12.2). We conclude that the combination of high IGF-I and low IGFBP-3 may increase the risk of premenopausal ductal carcinoma in situ.Hierarchical models can provide more reasonable and stable parameter estimates than conventional analytical approaches. This technique also deals with problems of multiple comparisons and allows one to model multilevel data within a hierarchical framework. Hence, one would anticipate a surge in applying hierarchical models to epidemiologic data. Difficulties in fitting hierarchical models, however, seem to have limited their use. To help address this problem, we describe the existing software packages that one can use to fit hierarchical models. Since these packages have limited familiarity and applicability in epidemiology, we also present SAS code for analyzing epidemiologic data with hierarchical models. These results allow epidemiologists to fit hierarchical models with readily available software.

Body mass index and ovulatory infertility.

Several studies have examined the association between body mass index and infertility. We compared body mass index in 597 women diagnosed with ovulatory infertility at seven infertility clinics in the United States and Canada with 1,695 primiparous controls who recently gave birth. The obese women (body mass index > or = 27) had a relative risk of ovulatory infertility of 3.1 [95% confidence interval (CI) = 2.2-4.4], compared with women of lower body weight (body mass index 20-24.9). We found a small effect in women with a body mass index of 25-26.9 or less than 17 [relative risk (RR) = 1.2, 95% CI = 0.8-1.9; and RR = 1.6, 95% CI = 0.7-3.9, respectively). We conclude that the risk of ovulatory infertility is highest in obese women but is also slightly increased in moderately overweight and underweight women.

Statistical methods in evaluating the outcome of infertility therapy

Lack of standardization in analytic methods for assigning infertility data is attributed to inadequate classification of fertility problems, and a lack of consistent methodology in evaluating outcome of infertility therapy. A classification scheme ideally should consider types of fertility problems as well as clinical assessment of its severity. Until an adequate classification system is developed, researchers are encouraged to describe fully the nature of infertility problem examined, and present results for homogenous groups of patients. The life-table method of analysis is a useful technique for assessing infertility statistics. The starting point of this method should depend on the group examined and may be either the date of 1st visit to the clinic or the date that therapy is instituted. Approximate date of conception should be the endpoint. A mathematical model of infertility predicated on the assumption that there is a constant monthly probability of conception of fecundability can be used to derive equations with potential for clinical application.

Over-the-counter analgesics and risk of ovarian cancer

BACKGROUND Evidence that aspirin and other non-steroidal anti-inflammatory drugs reduce risk for colorectal cancer has prompted interest in their ability to prevent other cancers. We aimed to find out what effect over-the-counter analgesics have on risk of ovarian cancer. METHODS In a case-control study we compared use of over-the-counter analgesics by 563 women from eastern Massachusetts and New Hampshire, USA, who had epithelial ovarian cancer with 523 women from the general population. We calculated exposure odds ratios to estimate the effect of over-the-counter analgesics on ovarian cancer risk. Use of over-the-counter analgesics was assessed through interviews and defined as use at least once a week continuously for at least 6 months. FINDINGS The odds ratio for risk of ovarian cancer for aspirin use was 0.75 (95% CI 0.52-1.10), that for ibuprofen was 1.03 (0.64-1.64), and that for paracetamol was 0.52 (0.31-0.86), after adjusting for age, study centre, education, religion, parity, oral contraceptive use, and menstrual, arthritic, or headache pain. Relative to no use, the lower risk of ovarian cancer associated with paracetamol was more apparent for use on a daily basis, 0.39 (0.21-0.74), for more than 10 years of use, 0.40 (0.19-0.88), or for more than 20 tablet years defined as (tablets per day x years of use), 0.45 (0.20-0.99). INTERPRETATION In our data, there was a statistically significant inverse association between paracetamol use and ovarian cancer risk. There was a modest but non-significant inverse association with aspirin use and ovarian cancer and no association with ibuprofen use. Experimental studies in rodents demonstrating uterine and ovarian atrophy at high doses of paracetamol and decreased ovarian-cyst formation at lower doses suggest a biological basis for our observations.

Ovarian Cancer Biomarker Performance in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Specimens

Establishing a cancer screening biomarkers intended performance requires “phase III” specimens obtained in asymptomatic individuals before clinical diagnosis rather than “phase II” specimens obtained from symptomatic individuals at diagnosis. We used specimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to evaluate ovarian cancer biomarkers previously assessed in phase II sets. Phase II specimens from 180 ovarian cancer cases and 660 benign disease or general population controls were assembled from four Early Detection Research Network or Ovarian Cancer Specialized Program of Research Excellence sites and used to rank 49 biomarkers. Thirty-five markers, including 6 additional markers from a fifth site, were then evaluated in PLCO proximate specimens from 118 women with ovarian cancer and 474 matched controls. Top markers in phase II specimens included CA125, HE4, transthyretin, CA15.3, and CA72.4 with sensitivity at 95% specificity ranging from 0.73 to 0.40. Except for transthyretin, these markers had similar or better sensitivity when moving to phase III specimens that had been drawn within 6 months of the clinical diagnosis. Performance of all markers declined in phase III specimens more remote than 6 months from diagnosis. Despite many promising new markers for ovarian cancer, CA125 remains the single-best biomarker in the phase II and phase III specimens tested in this study. Cancer Prev Res; 4(3); 365–74. ©2011 AACR.