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Background Multiple studies have suggested a relationship between adult exposures to environmental organochlorines and fecundability. There is a paucity of data, however, regarding fetal exposure to organochlorines via the mother’s blood and fecundability of adult female offspring. Methods Data from a two-generation cohort of maternal fisheaters was investigated to assess female offspring fecundability. Serum concentrations of polychlorinated biphenyls (PCBs) and 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (DDE) in Michigan female anglers were serially measured between 1973 and 1991 and used to estimate in utero exposure in their female offspring using two different methods. The angler cohort included 391 women of whom 259 provided offspring information. Of 213 daughters aged 20–50, 151 participated (71 %) and provided information for time intervals of unprotected intercourse (TUI). The daughters reported 308 TUIs (repeated observations), of which 288 ended in pregnancy. We estimated the fecundability ratio (FR) for serum-PCB and serum-DDE adjusting for confounders and accounting for repeated measurements. An FR below one indicates a longer time to pregnancy. Results Compared to serum-PCB of 7.4 μg/L. Similar results were obtained using the alternative statistical method to estimate in utero serum-PCB. The association was stronger for TUIs when women planned a baby; FR = 0.50 for serum-PCB between 2.5–7.4 μg/L, [95 % CI 0.29, 0.89], and 0.30 [95 % CI 0.13, 0.68] for serum-PCB >7.4 μg/L. There was no relationship between in utero exposure to DDE and fecundability in daughters. Conclusions Decreased fecundability in female offspring of fisheaters was found to be associated with PCB exposure in utero, possibly related to endocrine disruption in the oocyte and/or other developing organs influencing reproductive capacity in adulthood. Electronic supplementary material The online version of this article (doi:10.1186/s12940-016-0175-3) contains supplementary material, which is available to authorized users.

Breast cancer remained a hidden disease among women in the United States until the 20th century. It was initially brought into the open with public revelations from individual women, which was followed by the development of support groups and ultimately the formation of political activist groups with various priorities. Those concerned with toxic environmental exposures as a potential cause of breast cancer organized, demonstrated, and lobbied for research funding and eventually became partners in the research that arose from their efforts. One representative example was the Breast Cancer and Environment Research Centers (BCERC) Project (2003–2010), supported by the National Institute of Environmental Health Sciences (NIEHS) and the National Cancer Institute (NCI). The BCERC embedded a Community Outreach and Translational Core into its formal organizational infrastructure to ensure advocate involvement in the standing scientific subcommittees of BCERC, the first project funded by NIEHS and NCI to do so. The formal integration of advocates as partners in scientific studies focused on breast cancer is embedded in a rich history of action on the part of many courageous women. This article describes the historical evolution of breast cancer activism in the United States, which provided a critical foundation for the formation of BCERC. This description is followed by a discussion of BCERC as an example of the transdisciplinary research model, a paradigm that strives for inclusion of multiple stakeholders and increased interaction between scientists from a wide spectrum of disciplines, advocates, and lay audiences in order to more effectively conduct critical research and to translate and disseminate its findings.

This study investigates associations between gene expressions of aromatase (CYP19), 17α hydroxylase (CYP17), and estrogen receptors α and β and anthropometric measurements in offspring of the Michigan fish eater cohort. Leg and trunk length, height, weight, and BMI and gene expression in peripheral blood cells were measured in offspring of the Michigan fish eater cohort. The parental generation was followed between 1973 and 1991, and maternal age, height, and weight data were collected. Female offspring were contacted in 2001/2002 and followed up in 2006/2007; offspring information included age, education, reproductive history, smoking, and exercise. Gene expression was standardized against 18S ribosomal ribonucleic acid (18SrRNA) and RNA polymerase II (RNA PolII) expressions. Mixed models assessed the statistical effect of gene expression on anthropometric outcomes, accounting for multiple offspring from one mother. Anthropometric measurements and gene expression were measured in 139 female offspring. The two length and the height measurements were correlated, as were BMI and weight. CYP19 expression was correlated with the other gene expressions and both estrogen receptor expressions were associated. For every 1 unit of ΔC(t) (18SrRNA - CYP19) or ΔC(t) (RNA PolII - CYP19), BMI was increased by 0.9 (P = 0.03) and 0.87 kg/m(2) (P = 0.04), respectively, and weight by 2.35 kg (P = 0.03) and 2.1 kg (P = 0.03), respectively. For every 1 unit of ΔC(t) (18SrRNA - CYP17), leg length was increased by 0.84 cm (P = 0.04). The results suggest that CYP17 gene expression may influence growth during childhood and adolescence while CYP19 may be associated with the concurrent measures of weight and BMI.

This study was designed to develop and validate a method for enhancing spiritual feelings, particularly in women who have received a diagnosis of breast cancer. The protocol specifically was developed to be used in functional magnetic resonance imaging (fMRI) studies. Eighteen breast cancer survivors rated pictures for their ability to enhance feelings of spirituality, happiness, and sadness. Results indicate that presenting carefully selected pictures with spiritual content (e.g., nature scenes, people engaged in contemplative behaviors) can effectively enhance spiritual feelings among breast cancer survivors. Future fMRI studies will explore the use of the protocol developed in this study for investigating neural activity during spiritual feelings and states.

Objective To determine whether prenatal exposure to dichlorodiphenyl ethylene (DDE) and polychlorinated biphenyls (PCBs) and concurrent exposure to DDE, PCBs and polybrominated diphenylethers (PBDEs) affect gene expression of aromatase ( CYP19A1 ), 17-α-hydroxylase ( CYP17A1 ), and oestrogen receptors α and β ( ESR 1 and ESR2 ). Methods Based on maternal PCB and DDE levels in the parent generation of the Michigan Fisheater Cohort determined between 1973 and 1991, individual prenatal exposures were estimated and have been published. In 2007, female adult offspring of this cohort were examined. Gene expression and concurrent lipid-adjusted exposures to DDE, PCBs and PBDEs were measured in blood and serum, respectively. Using mixed models and path analyses, gene-expression data were regressed on prenatal and concurrent exposures controlling for confounders. Results 139 daughters of Michigan fisheaters (65.3%) participated in the investigation. While prenatal PCB levels were statistically significantly associated with decreased expression of the aromatase and 17-α-hydroxylase genes, prenatal DDE levels were significantly related to increased gene expression of aromatase but not of 17-α-hydroxylase. The DDE association seems to be mediated by concurrent lipid-adjusted p,p′-DDE serum levels. Prenatal and concurrent exposure of both PCBs and DDE had comparable effects. No association was found for PBDEs or for the gene expression of ESR 1 and ESR2 . Conclusions A 40-year antecedent prenatal exposure and concurrent levels of PCBs and DDE are associated with the expression of aromatase and 17-α-hydroxylase genes. Prenatal exposures to organochlorines may instigate long-term alterations of gene expression. Mechanisms of prenatal induction of persistent gene-expression alterations are speculated to be epigenetic in nature.

Objectives We introduce and describe the Breast Cancer and the Environment Research Centers (BCERC), a research network with a transdisciplinary approach to elucidating the role of environmental factors in pubertal development as a window on breast cancer etiology. We describe the organization of four national centers integrated into the BCERC network. Data sources Investigators use a common conceptual framework based on multiple levels of biologic, behavioral, and social organization across the life span. The approach connects basic biologic studies with rodent models and tissue culture systems, a coordinated multicenter epidemiologic cohort study of prepubertal girls, and the integration of community members of breast cancer advocates as key members of the research team to comprise the network. Data extraction Relevant literature is reviewed that describes current knowledge across levels of organization. Individual research questions and hypotheses in BCERC are driven by gaps in our knowledge that are presented at genetic, metabolic, cellular, individual, and environmental (physical and social) levels. Data synthesis As data collection on the cohort, animal experiments, and analyses proceed, results will be synthesized through a transdisciplinary approach. Conclusion Center investigators are addressing a large number of specific research questions related to early pubertal onset, which is an established risk factor for breast cancer. BCERC research findings aimed at the primary prevention of breast cancer will be disseminated to the scientific community and to the public by breast cancer advocates, who have been integral members of the research process from its inception.

To investigate the effect of prenatal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyl-dichloroethylene (DDE) on weight, height and body mass index (BMI) in adult female offspring of the Michigan fisheater cohort examined between 1973 and 1991.259 mothers from the Michigan fisheater cohort were studied. Prenatal exposure to PCBs and DDE was estimated by extrapolating maternal measurements to the time that the women gave birth. 213 daughters aged 20-50 years in 2000 were identified and 83% of them participated in at least one of two repeated investigations in 2001/02 (n = 151) and 2006/07 (n = 129). To assess the effect of prenatal PCB and DDE exposure on anthropometric measurements, generalised estimating equations nested for repeated measurements (2001/02 and 2006/07) and for sharing the same mother were used. We controlled for maternal height and BMI and for daughters' age, birth weight, having been breastfed and number of pregnancies.Maternal height and BMI were significant predictors of the daughters' height, weight and BMI. Low birth weight (2500 g) was significantly associated with reduced adult offspring weight and BMI. The weight and BMI of adult offspring were statistically significantly associated with the extrapolated prenatal DDE levels of their mothers. Controlling for confounders and compared to maternal DDE levels of1.503 microg/l, offspring BMI was increased by 1.65 when prenatal DDE levels were 1.503-2.9 microg/l and by 2.88 if levels were2.9 microg/l. Prenatal PCB levels showed no effect.Prenatal exposure to the oestrogenic endocrine-disrupting chemical DDE may contribute to the obesity epidemic in women.

Purpose : Many students in the Michigan State University College of Human Medicine (CHM) are non-traditional with unique needs and experiences. To meet these needs, in 1988 CHM developed a structured Extended Curriculum Program (ECP), which allows students to take longer than 2 years to complete the preclinical curriculum. This work examined the reasons why students extended their programs, their perceptions of that experience, and the outcome with respect to satisfaction and success in their careers after graduation. Methods : The analysis used data from the college database, follow-up surveys of residency directors and graduates, surveys of graduates who extended, and the AMA Physician Masterfile. Results : Graduates who responded to the survey were evenly split between those who extended for academic reasons and those who extended for other reasons. Although feelings about extending were mixed at the time of extension, nearly all respondents agreed that extending was the right decision in the long run. Extended students continued to face academic challenges having lower basic science averages, lower USMLE Step 1 and 2 first attempt pass rates, and more instances of repeated clerkships compared to those who did not extend, however, most were able to secure a residency in the specialty they desired and had comparable career satisfaction ratings. Conclusions : The ECP allows some students to complete medical school who otherwise may not have been able to do so. This analysis has provided valuable information that was used to improve the program, allowing CHM to continue its mission of training a diverse set of students to be exemplary physicians. Keywords: extended curriculum; non-traditional medical students; accommodating life events; academic challenges; career satisfaction (Published: 15 September 2015) Citation: Med Educ Online 2015, 20: 29297 - http://dx.doi.org/10.3402/meo.v20.29297

Hormonally-linked adult reproductive and anthropometric risk factors have been well established in the etiology of postmenopausal breast cancer, though early life exposures have been evaluated only more recently. Here, we examine the evidence for associations between lifetime reproductive and anthropometric risk factors for postmenopausal breast cancer. The review finds some evidence for the hypothesis that breast cancer risk is determined by the number of susceptible stem cells, modified by the hormonal environment. The in utero experience of an infant may be associated with postmenopausal breast cancer; preeclampsia may decrease and greater birthweight increase risk, but more evidence is needed. Earlier and more rapid childhood growth appears to increase postmenopausal breast cancer risk and childhood obesity to decrease risk, but very few studies have yet examined these associations. Increased final height and earlier age at menarche are consistently associated with increased risk for postmenopausal breast cancer. Later age at first birth, decreased parity, later menopausal age, use of hormone replacement therapy (especially progestin containing), and increased postmenopausal adiposity are well-established risk factors for postmenopausal breast cancer. The effect of a woman's own pregnancy conditions and lactation are not established. Further investigation is needed to identify whether events occurring early in life modify later events or accumulate over the life course. Many aspects of this research can be conducted by examining the influence of early life events on intermediary events without the need for longitudinal data.

Background and Objective: Given the large numbers of open breast biopsies performed in women who have benign breast masses, we developed a clinical decision rule (CDR), called BREASTAID, to triage women into open biopsy or follow-up. Methods: A prospective cohort design was used to obtain data on 452 palpable breast masses evaluated at a referral clinic. Breast cancer was defined as ductal carcinoma in situ or invasive cancer at open biopsy. Separate logistic regression models were developed at three logical stages of the clinical workup. Bayes' theorem was applied in a stepwise fashion to revise model probabilities to generate a final probability of cancer. Receiver operator characteristics curves were generated to determine the optimum cut-point. Results derived from the CDR were compared with actual clinical practice. Results: A total of 452 masses in 380 women were included. Clinical practice resulted in 180 masses (39.8%) undergoing open biopsy, 41 (22.8%) of which were cancers. Age, history of breast cancer in the mother, mass size, mammography findings, and fine needle aspiration biopsy results were included in the final models. When applied to the derivation dataset, BREASTAID successfully identified 40 of 41 cancer masses (sensitivity 97.6%, 95% confidence interval [CI] 94.1–99.9), and 350 of 411 noncancer masses (specificity 85.2%, 95% CI 81.8–88.5). BREASTAID would have reduced the number of biopsies performed on the 411 benign masses from 139 to 61. Conclusions: This study demonstrated that a CDR based on routinely collected clinical variables has the potential to accurately triage women with palpable breast masses. Further validation of the rule is required before its clinical use can be considered.

Endogenous estrogen exposure has long been implicated in the causation of breast cancer through a mechanism of epithelial cell proliferation. Whether estrogen, progesterone, or both exhibit mitogenic activity and promote carcinogenesis in the human breast has been the subject of considerable debate. The purpose of this review article is to examine the evidence for the effects of hormone replacement therapy in its various forms on the biology of the postmenopausal breast both in humans and in an animal model, and to identify the gaps in knowledge that research will need to address to further understand this complex issue.

The relative effects of postmenopausal hormone replacement therapy (HRT) with estrogen alone vs. estrogen1progestin on breast cell proliferation and on breast cancer risk are controversial. A cross-sectional observational study was carried out to examine the proliferative effects of HRT with estrogen or estrogen plus the progestin, medroxyprogesterone acetate, in breast tissue of postmenopausal women. Benign breast biopsies from 86 postmenopausal women were analyzed with antiproliferating cell nuclear antigen (anti-PCNA) and Ki67 antibodies to measure relative levels of cell proliferation. Epithelial density and estrogen and progesterone receptor status were also determined. The women were categorized either as users of: 1) estrogen (E) alone; 2) estrogen1 medroxyprogesterone acetate (E1P); or 3) no HRT. Compared with no HRT, the breast epithelium of women who had received either E1P or E alone had significantly higher PCNA proliferation indices, and treatment with E1P had a significantly higher index (PCNA and Ki67) than treatment with E alone. Breast epithelial density was significantly greater in postmenopausal women treated with E and E1P, compared with no HRT. Thus, the present study shows that postmenopausal HRT with E1P was associated with greater breast epithelial cell proliferation and breast epithelial cell density than E alone or no HRT. Furthermore, with E1P, breast proliferation was localized to the terminal duct-lobular unit of the breast, which is the site of development of most breast cancers. Further studies are needed to assess the possible association between the mitogenic activity of progestins and breast cancer risk. (J Clin Endocrinol Metab 84: 4559 ‐ 4565, 1999)

Background Dichlorodiphenyl dichloroethylene (DDE) and polychlorinated biphenyls (PCBs) can be passed from mother to offspring through placental transfer or breastfeeding. Unknown is whether maternal levels can predict concentrations in adult offspring. Objectives To test the association between maternal blood levels of DDE and PCBs and adult female offspring levels of these compounds using data from the Michigan Fisheaters’Cohort. Methods DDE and PCB concentrations were determined in 132 adult daughters from 84 mothers. Prenatal exposures were estimated based on maternal DDE and PCB serum levels measured between 1973 and 1991. Levels in adult daughters were regressed on maternal and estimated prenatal exposure levels, adjusting for potential confounders using linear mixed models. Confounders included daughter’s age, birth order, birth weight, number of pregnancies, the length of time the daughter was breast-fed, the length of time the daughter breast-fed her own children, last year fish-eating status, body mass index, and lipid weight. Results The median age of the participants was 40.4 years (range 18.4–65.4, 5–95 percentiles 22.5–54.6%, respectively). Controlling for confounders and intra-familial associations, DDE and PCB concentrations in adult daughters were significantly positively associated with estimated prenatal levels and with maternal concentrations. The proportion of variance in the adult daughters’ organochlorine concentrations explained by the maternal exposure levels is approximately 23% for DDE and 43% for PCBs. The equivalent of a median of 3.67 μg/L prenatal DDE and a median of 2.56 μg/L PCBs were 15.64 and 10.49 years of fish consumption, respectively. When controlling for effects of the shared environment (e.g., fish diet) by using a subsample of paternal levels measured during the same time frames ( n =53 and n =37), we determined that the direct maternal transfer remains important. Conclusions Estimated intra-uterine DDE and PCB levels predicted concentrations in adult female offspring 40 years later. Interpretation of adverse health effects from intra-uterine exposures of persistent pollutants may need to consider the sustained impact of maternal DDE and PCB levels found in their offspring.

The medical audit of a mammography practice is a recognized method for evaluating mammography and the accuracy of mammographic interpretation [1-4]. As such, portions of the audit will become integral to the quality assurance activities of every mammography practice under the Mammography Quality Standards Act (MQSA) of 1992, administered by the Food and Drug Administration (FDA). The FDA Interim Rules, which became effective October 1, 1994, state that "each facility shall establish a system for reviewing outcome data from all mammography performed, including follow-up on the disposition of positive mammograms and correlation of surgical biopsy results with mammogram reports" [5]. It is expected that the proposed final rules, due to be released for public comment in 1995, will require collection of additional data for medical audits (public meeting of the National Mammography Advisory Committee, May 3, 1994). Although most mammography practices are now collecting clinical outcomes data on abnormal mammographic examinations, very few have established an organized and deliberate system of data collection necessary for a more complete mammography audit [6]. A detailed discussion of and recommendations for such an audit were recently published as part of the Quality Determinants of Mammography Guideline by the Agency for Healthcare Policy and Research (AHCPR) [7]. As members and consultants on the multidisciplinary panel that produced the guideline, we offer the following review of the various elements, definitions, and processes of the mammography audit. This is intended as a primer for all radiologists who will be performing some of the same audit activities for the MQSA.

Asymmetry in knowledge and power between (1) physicians and patients and (2) physician educators and their students creates a climate for possible abuse in both sets of relationships. Virtual Mentor is a monthly bioethics journal published by the American Medical Association.

The College of Human Medicine (CHM) at Michigan State University, which graduated its first class in 1972, was one of the first community-based medical schools in the country. It was established as a state-funded medical school with specific legislative directives to educate primary care physicians who would serve the needs of the state, particularly those of underserved areas. However, the model has proved challenging to sustain with the many changes to the health care system and the economic climate of Michigan. In 2006, a two-phase expansion plan was implemented, and in 2010, CHM permanently expanded the matriculating class from 106 to 200 students with the establishment of a second four-year site for medical education in Grand Rapids. This article describes what school leaders and faculty have learned as they look back at the opportunity provided by expansion as well as the growing pains and lessons learned. The community-based model met many of the mission-related goals for CHM's graduates, who represent a diverse group of practitioners whose values resonate with the school's mission. Expansion has offered an opportunity to explore new research and clinical opportunities as well as to more fully realize the potential of community partners to meet local health care needs and reinvent a robust future for community-integrated medical education.

Background and Aims: We have previously demonstrated that prenatal exposure to organochlorines is associated with gene expression of aromatase, an enzyme in estrogen synthesis. It is also known tha...

Using grounded theory, a multidisciplinary study team compared the narratives of 30 women who had recently experienced a breast cancer scare. Even though 10 women received a benign diagnosis, all women reported a difficult time prediagnosis, characterized by an array of emotions and contemplation of the meaning of life. Diagnosis separated the two groups with emotional relief dominant for the benign group and intensification of emotions for the cancer group. For those diagnosed with cancer, three factors contributed to arriving at a point of acceptance about the diagnosis and treatment: (a) sustained coping mechanisms; (b) a belief system that shifted the meaning of the cancer experience; and (c) the ability to manage non-cancer-related stressful events. Implications include the need for tailored biopsychosocial treatments that focus on reducing stress, enhancing support systems, reframing beliefs about the illness, and providing the opportunity for the women to talk about their experiences.

Background Reliable techniques to measure polychlorinated biphenyl (PCB) congeners make the clearer definition of their effects on human health possible. Given that PCBs are classified as endocrine disrupters, we sought to explore the expression of some key genes involved in sex steroid metabolism. Objectives To examine common classification schemes of PCB congeners and determine whether exposure to groups classified by mechanism of action alter the gene expression (GE) of CYP17, CYP19, and ESR1 and ESR2. Methods GE and exposure to various classifications of lipid-adjusted PCB congeners were examined in 139 daughters of the Michigan Fisheaters' Cohort. Using mixed models analyses and adjusting for age, menopausal status, and current use of oral contraceptives and hormone replacement therapy, GE data were regressed on exposure to PCB congener groupings based on mechanism of action. Results Three novel findings are elucidated: first, that up-regulation of CYP19 expression is associated with exposure to PCB groupings containing dioxin-like, potentially anti-estrogenic, immunotoxic congeners, including PCB IUPAC #74, #105, #118, #138, #156, #157, #158, #167, and #170 from this cohort. Second, that exposure to similar congeners (PCB IUPAC #105, #156, #157, #158, and #167 in this cohort) but using a classification based solely on hormonal mechanisms of action is associated with increased expression of ESR2. Third, that increased expression of CYP17 is of borderline significance when associated with exposure to PCB IUPAC #118, #138, and #156. Conclusions These findings are both counter-intuitive and intriguing. Rather than exhibiting anti-estrogenic effects alone, they suggest that these congeners up-regulate the major enzyme involved in estrogen synthesis and tend to confirm previous findings of links between AhR and ER signaling pathways. Replication of these findings, expansion of the number of genes examined, exploration of mixtures of environmental chemicals, and subsequent study of health outcomes in a larger cohort are future priorities.

Breast cancer is the most common cancer in women [1], and failure to diagnose it in a timely manner has been documented as the most common reason for a successful medical malpractice claim [2, 3]. Knowledge of the common allegations made when a malpractice suit is filed for failure to diagnose breast cancer can provide insight into the risk management of a physician’s practice and simultaneously minimize errors in patient care. Many physicians are unaware of the legal process involved in a malpractice suit until it affects them or a close colleague. At this point, an objective perspective is often impossible. Nonetheless, it is inevitable that many, if not most, physicians will find themselves a defendant in a medical malpractice suit at some point in their career for a less-than-perfect patient outcome, whether medical negligence has occurred or not. This chapter is intended to outline the common allegations of misdiagnosis or mismanagement of breast cancer, to review the process of legal proceedings common to a medical malpractice suit, to review the issues likely to arise in the defense of a case, and to provide recommendations on the steps to take when facing malpractice litigation.

A breast cancer screening program offers a community the opportunity to highlight and address an important health issue. This article has described the important elements of any such screening effort. To be successful, the program will require a multidisciplinary cadre of health care professionals working collaboratively throughout all phases of the planning, screening, and follow-up process. An agency should be identified to lead these professionals and monitor the progress of the screening effort. These screening programs can have direct and indirect benefits in the community. The direct benefits include improved access and delivery of health services, particularly those that meet state-of-the-art quality standards. The indirect benefits involve the promotion of breast cancer screening through education of women and providers about good breast health practices. As our experience in Michigan has shown, efforts featuring a broad coalition of forces can foster debate and discussion throughout the community and ultimately lead to improvements in the delivery of breast cancer screening services.

It seems paradoxical that both increased height and earlier age at menarche (which predicts for shorter stature) are both associated with increased breast cancer risk.Retrospective data from a parental cohort coupled with prospective interviews with and anthropometric measurements from their daughters were used. Multivariable linear regression analyses were conducted using mixed regression models to account for same-family participants.Controlling for birth weight, maternal height, and birth cohort, and analyzed as a group, a 1-year increase in the age at menarche predicted an increase in standing height, leg length, and trunk height of 0.76, 0.41, and 0.35 cm, respectively. However, when stratifying by birth year (prior to 1966 vs 1966 or after), these relationships were true only for those born prior to 1966.Given the height-breast cancer risk association, the emerging evidence linking breast cell proliferation to hormones associated with growth, and the finding in this study that the relationship between age at menarche and adult height no longer exists for women born in 1966 or later, it is possible that the long-established relationship between age at menarche and breast cancer risk may also no longer exist.

Progesterone (P) regulates proliferation and differentiation in the normal mammary gland in mouse, rat and human. Progesterone has also been implicated in the etiology and pathogenesis of human breast cancer. The focus of this review is on recent advances in understanding the role of the progesterone receptor (PR) and functional significance of PR isoforms, PRA and PRB, in the normal mammary gland and in mammary cancer in mouse, rat and human.

Clinical breast examination (CBE) seeks to detect breast abnormalities or evaluate patient reports of symptoms to find palpable breast cancers at an earlier stage of progression. Treatment options for earlier-stage cancers are generally more numerous, include less toxic alternatives, and are usually more effective than treatments for later-stage cancers. For average-risk women aged 40 and younger, earlier detection of palpable tumors identified by CBE can lead to earlier therapy. After age 40, when mammography is recommended, CBE is regarded as an adjunct to mammography. Recent debate, however, has questioned the contributions of CBE to the detection of breast cancer in asymptomatic women and particularly to improved survival and reduced mortality rates. Clinicians remain widely divided about the level of evidence supporting CBE and their confidence in the examination. Yet, CBE is practiced extensively in the United States and continues to be recommended by many leading health organizations. It is in this context that this report provides a brief review of evidence for CBE's role in the earlier detection of breast cancer, highlights current practice issues, and presents recommendations that, when implemented, could contribute to greater standardization of the practice and reporting of CBE. These recommendations may also lead to improved evidence of the nature and extent of CBE's contribution to the earlier detection of breast cancer.

In 1970, breast cancer presented as a palpable mass in 90% of patients.1 Recent reports demonstrate that the majority (55%-68%) of breast cancer cases continue to present with palpable masses, despite the widespread use of screening mammography.2,3 While the approach to a solid palpable breast mass is often open surgical biopsy, the malignant/benign breast biopsy ratio in the United States averages only about 1:4, or 20%.2,4 Use of this figure and the annual incidence of breast cancer predicts that more than 1 million breast biopsies will be performed in 2002. Using an average reimbursement for open breast biopsy of $2400,5 the financial cost to the healthcare system in 2002 will be more than $2.4 billion. While many physicians consider open biopsy a minor procedure with few consequences, women pay a significant emotional toll, not only because of the anxiety of the procedure itself but also because of the delay between the clinical evaluation, the operation, and the pathology result. Some women also experience disfigurement as a consequence of the procedure, and subsequent breast cancer screening interpretation can be more difficult because of tissue scarring. Competing with these issues is the acknowledged difficulty of ruling out breast cancer short of open biopsy. In addition, delay in the diagnosis of breast cancer is the most common reason for malpractice litigation in the United States.6 This reality provides strong incentives for surgeons to continue to perform the procedure, despite its low malignant/benign ratio and associated morbidities. Triple diagnosis has been used to decrease the open biopsy rate for solid breast masses, a technique that combines the results of clinical impression, mammography, and fine needle aspiration biopsy (FNAB). When all three results are concordant for benign disease, follow-up rather than biopsy is advised.7,8 However, triple diagnosis has several limitations. First, the ill-defined interpretive criterion associated with the clinical impression limits its application to experienced examiners. Triple diagnosis often ignores hypocellular FNAB results, rendering the test useless in up to 20% to 30% of cases.9 Reporting only positive or negative outcomes for the test results in loss of information, since all three components use multiple categories in their interpretation. Triple diagnosis assumes independence of the tests comprising it, but this has not been tested. Finally, the pretest likelihood of disease (as evaluated by risk factor data), is not formally assessed. Development of a clinical decision rule (CDR) that could overcome the limitations of triple diagnosis has the potential to significantly impact the healthcare of women. A CDR quantifies the contributions that various components of the history, physical examination, and basic laboratory results make toward the diagnosis.10–12 The purposes of this study are threefold: 1) to develop a CDR that will accurately predict the probability of malignancy in women with palpable solid breast masses; 2) to develop a CDR that is practical enough to be used by a general surgeon or primary care clinician; and 3) to compare the CDR to our current method of practice, which employs triple diagnosis. Termed BREASTAID (Breast Risk Evaluation And Scoring System To Aid In the Diagnosis of Mammary Masses), this article reports on these goals and the clinical results of the first stages of CDR development.

Background: A small proportion of T1 or T2 nodenegative breast cancer tumors will recur in patients by 5 years, and more by 10 years. Results of recent studies have suggested improvement in overall survival with administration of adjuvant chemotherapy to all patients. More sensitive and specific methods are needed to identify patients at highest risk for recurrence who might benefit most from adjuvant therapy, saving others from unnecessary treatment. Some investigators have suggested DNA flow cytometry as a method to discriminate patients at greatest risk for recurrence. Hypothesis: DNA flow cytometry has predictive value for breast cancer recurrence in node-negative patients. Methods: The cancer registry of a medium-sized university-affiliated hospital was used to identify patients with T1-2 N0 M0 breast cancer treated with a uniform surgical approach and no adjuvant therapy who had completed at least 5 years of follow-up or had recurrence. Flow cytometric analysis was performed on paraffin-embedded specimens. Results: Of 115 patients, 92 (80%) had disease-free survival without recurrence and 23 (20%) had recurrence. Comparison of diploid and nondiploid tumors for likelihood of recurrence revealed no association (P=.79). Furthermore, the DNA index and S-phase fraction were not significantly different between recurrent and nonrecurrent groups. Conclusions: The likelihood of recurrence of small nodenegative breast cancers after mastectomy cannot be accurately predicted on the basis of DNA flow cytometric analysis. Traditional methods for determining risks— such as nuclear and histological grade, lymph node status, and tumor size—seem to be more useful. Sentinel lymph node biopsy techniques may increase the detection of micrometastases. Arch Surg. 2000;135:1422-1426

This paper describes the history of mammography quality assurance legislation in Michigan, the first of its kind in the nation. It discusses the collaboration of multiple organizations in the legislative process as well as in the implementation of it. It describes the effect of the legislation on the quality of mammography throughout the state and summarizes the lessons learned from the process, especially as they apply to the implementation of the Mammography Quality Standards Act at the national level.

The relative effects of postmenopausal hormone replacement therapy (HRT) with estrogen alone vs. estrogen1progestin on breast cell proliferation and on breast cancer risk are controversial. A cross-sectional observational study was carried out to examine the proliferative effects of HRT with estrogen or estrogen plus the progestin, medroxyprogesterone acetate, in breast tissue of postmenopausal women. Benign breast biopsies from 86 postmenopausal women were analyzed with antiproliferating cell nuclear antigen (anti-PCNA) and Ki67 antibodies to measure relative levels of cell proliferation. Epithelial density and estrogen and progesterone receptor status were also determined. The women were categorized either as users of: 1) estrogen (E) alone; 2) estrogen1 medroxyprogesterone acetate (E1P); or 3) no HRT. Compared with no HRT, the breast epithelium of women who had received either E1P or E alone had significantly higher PCNA proliferation indices, and treatment with E1P had a significantly higher index (PCNA and Ki67) than treatment with E alone. Breast epithelial density was significantly greater in postmenopausal women treated with E and E1P, compared with no HRT. Thus, the present study shows that postmenopausal HRT with E1P was associated with greater breast epithelial cell proliferation and breast epithelial cell density than E alone or no HRT. Furthermore, with E1P, breast proliferation was localized to the terminal duct-lobular unit of the breast, which is the site of development of most breast cancers. Further studies are needed to assess the possible association between the mitogenic activity of progestins and breast cancer risk. (J Clin Endocrinol Metab 84: 4559 ‐ 4565, 1999)

This pilot study evaluates the consistency of experts' ratings of students' performances on the National Board of Medical Examiners' Computer Based Examination (CBX) cases and the relationship of those ratings to the CBX's scoring algorithm. The authors were investigating whether an automated scoring algorithm can adequately assess an examinee's management of a computer-simulated patient. In 1989-90, at the Michigan State University College of Human Medicine, eight students, completing a surgery clerkship, each managed eight CBX cases and took a computer-administered, multiple-choice examination. Six clerkship coordinators rated the students' performances in terms of overall management, efficiency, and dangerous actions. The ratings correlated highly with scores produced by the CBX's scoring system.