Magee-Womens Hospital

CONTEXT: Tamoxifen is approved for the reduction of breast cancer risk, and raloxifene has demonstrated a reduced risk of breast cancer in trials of older women with osteoporosis. OBJECTIVE: To compare the relative effects and safety of raloxifene and tamoxifen on the risk of developing invasive breast cancer and other disease outcomes. DESIGN, SETTING, AND PATIENTS: The National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene trial, a prospective, double-blind, randomized clinical trial conducted beginning July 1, 1999, in nearly 200 clinical centers throughout North America, with final analysis initiated after at least 327 incident invasive breast cancers were diagnosed. Patients were 19,747 postmenopausal women of mean age 58.5 years with increased 5-year breast cancer risk (mean risk, 4.03% [SD, 2.17%]). Data reported are based on a cutoff date of December 31, 2005. INTERVENTION: Oral tamoxifen (20 mg/d) or raloxifene (60 mg/d) over 5 years. MAIN OUTCOME MEASURES: Incidence of invasive breast cancer, uterine cancer, noninvasive breast cancer, bone fractures, thromboembolic events. RESULTS: There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (incidence, 4.30 per 1000 vs 4.41 per 1000; risk ratio [RR], 1.02; 95% confidence interval [CI], 0.82-1.28). There were fewer cases of noninvasive breast cancer in the tamoxifen group (57 cases) than in the raloxifene group (80 cases) (incidence, 1.51 vs 2.11 per 1000; RR, 1.40; 95% CI, 0.98-2.00). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene (RR, 0.62; 95% CI, 0.35-1.08). No differences were found for other invasive cancer sites, for ischemic heart disease events, or for stroke. Thromboembolic events occurred less often in the raloxifene group (RR, 0.70; 95% CI, 0.54-0.91). The number of osteoporotic fractures in the groups was similar. There were fewer cataracts (RR, 0.79; 95% CI, 0.68-0.92) and cataract surgeries (RR, 0.82; 95% CI, 0.68-0.99) in the women taking raloxifene. There was no difference in the total number of deaths (101 vs 96 for tamoxifen vs raloxifene) or in causes of death. CONCLUSIONS: Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003906.

BACKGROUND: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker. METHODS: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases. RESULTS: A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment. CONCLUSIONS: Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).

Table: of ContentsA. EXECUTIVE SUMMARY Updated US consensus guidelines for management of cervical screening abnormalities are needed to accommodate the 3 available cervical screening strategies: primary human papillomavirus (HPV) screening, cotesting with HPV testing and cervical cytology, and cervical cytology alone. New data indicate that a patient's risk of developing cervical precancer or cancer can be estimated using current screening test results and previous screening test and biopsy results, while considering personal factors such as age and immunosuppression. Routine screening applies only to asymptomatic individuals who do not require surveillance for prior abnormal screening results. The 2012 consensus guidelines were the first to be based on the principle of equal management for equal risk, specifically, the risk of a patient developing cervical cancer, estimated by the surrogate end point of the 5-year risk of cervical intraepithelial neoplasia (CIN) grade 3 (CIN 3) or more severe diagnoses (CIN 3+), regardless of which test combinations yielded this risk level. Introduction of risk-based guidelines in 2012 was a conceptual breakthrough, but the recommendations retained a continued reliance on complicated algorithms and insufficiently incorporated screening history. With a more nuanced understanding of how previous results affect risk, and more variables to consider, the 2019 guidelines further align management recommendations with current understanding of HPV natural history and cervical carcinogenesis. More frequent surveillance, colposcopy, and treatment are recommended for patients at progressively higher risk, whereas those at lower risk can defer colposcopy, undergo follow-up at longer surveillance intervals, and, when at sufficiently low risk, return to routine screening. Clearly defined risk thresholds to guide management are designed to continue functioning appropriately when population-level prevalence of CIN 3+ decreases because of HPV vaccination and also as new screening and triage tests are introduced. The revised guidelines provide a framework for incorporating new data and technologies as ongoing incremental recommendation revisions, minimizing the time needed to implement changes that are beneficial to patient care. B. INTRODUCTION This is the fourth American Society of Colposcopy and Cervical Pathology (ASCCP)-sponsored consensus guidelines for management of cervical cancer screening abnormalities, after the original consensus conferences in 20011 and subsequent updates in 20062 and 2012.3 An interim guidance publication providing management recommendations for primary HPV screening was released in 2015.4This document updates and replaces all previous guidance. The key difference between 2019 guidelines and previous versions is the change from primarily test results–based algorithms (e.g., "Colposcopy is recommended for patients with HPV-positive atypical squamous cells of undetermined significance [ASC-US], low-grade squamous intraepithelial lesion [LSIL]," etc.) to primarily "risk-based" guidelines (e.g., "Colposcopy is recommended for any combination of history and current test results yielding a 4.0% or greater probability of finding CIN 3+," etc.). See Box 1 for essential changes. Tables of risk estimates for possible combinations of current screening test results and screening history (including unknown history) have been generated from a prospective longitudinal cohort of more than 1.5 million patients followed for more than a decade at Kaiser Permanente Northern California (KPNC). All KPNC estimates of risk underlying guideline decisions are detailed in the accompanying article by Egemen et al.5 The applicability of these risk estimates to other United States regions and populations has been confirmed in other data sets from screening programs and clinical trials.6 Many patients, especially those with minor abnormalities, can be managed by identifying their risk level using Tables 1A to 5B in Egemen et al5 and linking it to a recommended clinical action (return to routine screening, surveillance with repeat testing at 1- or 3-year intervals, colposcopy, or treatment). To facilitate use of these tables, the same information will be accessible via smartphone app (for purchase) and web (no cost) through http://www.asccp.org. Decision aids may facilitate use of the tables.7 Common abnormalities are managed using risk estimates outlined in Section E, and rare abnormalities are managed via the result-specific consensus recommendations outlined in Sections G-K.TABLE 1: Participating OrganizationsBox 1. Essential Changes From Prior Management Guidelines 1) Recommendations are based on risk, not results. Recommendations of colposcopy, treatment, or surveillance will be based on a patient's risk of CIN 3+ determined by a combination of current results and past history (including unknown history). The same current test results may yield different management recommendations depending on the history of recent past test results. 2) Colposcopy can be deferred for certain patients. Repeat HPV testing or cotesting at 1 year is recommended for patients with minor screening abnormalities indicating HPV infection with low risk of underlying CIN 3+ (e.g., HPV-positive, low-grade cytologic abnormalities after a documented negative screening HPV test or cotest). 3) Guidance for expedited treatment is expanded (i.e., treatment without colposcopic biopsy). Expedited treatment was an option for patients with HSIL cytology in the 2012 guidelines; this guidance is now better defined. For non-pregnant patients 25 years or older, expedited treatment, defined as treatment without preceding colposcopic biopsy demonstrating CIN 2+, is preferred when the immediate risk of CIN 3+ is ≥60%, and is acceptable for those with risks between 25% and 60%. Expedited treatment is preferred for nonpregnant patients 25 years or older with high-grade squamous intraepithelial lesion (HSIL) cytology and concurrent positive testing for HPV genotype 16 (HPV 16) (i.e., HPV 16–positive HSIL cytology) and never or rarely screened patients with HPV-positive HSIL cytology regardless of HPV genotype. Shared decision-making should be used when considering expedited treatment, especially for patients with concerns about the potential impact of treatment on pregnancy outcomes. 4) Excisional treatment is preferred to ablative treatment for histologic HSIL (CIN 2 or CIN 3) in the United States. Excision is recommended for adenocarcinoma in situ (AIS). 5) Observation is preferred to treatment for CIN 1. 6) Histopathology reports based on Lower Anogenital Squamous Terminology (LAST)/World Health Organization (WHO) recommendations for reporting histologic HSIL should include CIN 2 or CIN 3 qualifiers, i.e., HSIL(CIN 2) and HSIL (CIN 3). 7) All positive primary HPV screening tests, regardless of genotype, should have additional reflex triage testing performed from the same laboratory specimen (e.g., reflex cytology). Additional testing from the same laboratory specimen is recommended because the findings may inform colposcopy practice. For example, those HPV-16 positive HSIL cytology qualify for expedited treatment. HPV 16 or 18 infections have the highest risk for CIN 3 and occult cancer, so additional evaluation (e.g., colposcopy with biopsy) is necessary even when cytology results are negative. If HPV 16 or 18 testing is positive, and additional laboratory testing of the same sample is not feasible, the patient should proceed directly to colposcopy. 8) Continued surveillance with HPV testing or cotesting at 3-year intervals for at least 25 years is recommended after treatment and initial post-treatment management of histologic HSIL, CIN 2, CIN 3, or AIS. Continued surveillance at 3-year intervals beyond 25 years is acceptable for as long as the patient's life expectancy and ability to be screened are not significantly compromised by serious health issues. The 2012 guidelines recommended return to 5-year screening intervals and did not specify when screening should cease. New evidence indicates that risk remains elevated for at least 25 years, with no evidence that treated patients ever return to risk levels compatible with 5-year intervals. 9) Surveillance with cytology alone is acceptable only if testing with HPV or cotesting is not feasible. Cytology is less sensitive than HPV testing for detection of precancer and is therefore recommended more often. Cytology is recommended at 6-month intervals when HPV testing or cotesting is recommended annually. Cytology is recommended annually when 3-year intervals are recommended for HPV or cotesting. 10) Human papilloma virus assays that are Food and Drug Administration (FDA)-approved for screening should be used for management according to their regulatory approval in the United States. (Note: all HPV testing in this document refers to testing for high-risk HPV types only). For all management indications, HPV mRNA and HPV DNA tests without FDA approval for primary screening alone should only be used as a cotest with cytology, unless sufficient, rigorous data are available to support use of these particular tests in management. The minimum amount of data required to generate a recommendation will include the patient's age and current test results, as we recognize that previous screening history is often not known. Increased precision of management guidance will be possible if information is available on test results within the past 5 years and previous precancer treatment within the past 25 years.3 Current results and past history are designed to generate the patient's risk estimate from data tables.5 Risk estimates are available for the following clinical situations: abnormal screening test results with unknown history, abnormal screening test results with medical record documentation of a preceding negative HPV test or cotest, surveillance of previous abnormal screening test results that did not require immediate colposcopic referral (e.g., follow-up after an HPV-positive cytology negative result), colposcopy/biopsy results, and follow-up surveillance tests after colposcopy or after treatment for, or resolution of, high-grade abnormalities (e.g., CIN 2+). The recognition that persistent HPV infection is necessary for developing precancer and cancer (defined as CIN 3+, which includes diagnoses of CIN 3, AIS, and cancer) underlies the 2019 guideline update. Prospective longitudinal data indicate that when a new abnormal screening test result follows a negative HPV test or cotest within the past 5 years, the estimated risk of CIN 3+ is reduced by approximately 50%.8 A negative cytology result within 3 years of a new abnormal screening test, however, does not confer a similar reduction in risk.9 The 2019 guidelines also recognize that a colposcopic examination performed according to accepted standards (e.g., using the KPNC colposcopy protocol or the ASCCP Colposcopy Standards10) confirming low-grade or normal histology reduces a patient's estimated risk of having precancer/cancer in the next 2 years.11 This allows patients with an HPV-positive ASC-US or LSIL result at their 1-year follow-up visit after a colposcopy confirming normal- or low-grade histology to return for repeat HPV or cotesting in 1 more year, rather than immediately return to colposcopy. Thus, incorporating a patient's history of previous HPV tests and colposcopy/biopsy results will permit detection and treatment of CIN 3+ while avoiding unnecessary interventions for patients with new HPV infections who are at lower risk.12 C. GUIDING PRINCIPLES Guidelines are based on several guiding principles. The first 4 guiding principles are new for 2019, whereas the others are from the 2012 guidelines. As the 2012 guidelines are familiar to providers, we changed management recommendations only when new evidence favored an altered management strategy. Note that management guidelines apply only to patients with current or previous abnormal screening test results; screening guidelines for individuals in the general population, that are not being followed for a screening abnormality, are addressed elsewhere.13,14 New 2019 Principles 1. HPV–based testing is the basis for risk estimation. The term HPV-based testing is used throughout this document and refers to use of either primary HPV testing alone or HPV testing in conjunction with cervical cytology (cotesting). Characteristics of HPV infections, including HPV type and the duration of infection, determine a patient's risk of CIN 3+.15–18 Although cytology has high specificity (apart from ASC-US) and can be helpful when estimating immediate risk, its lower sensitivity and lower negative predictive value compared with HPV testing reduces its utility for long-term risk prediction.9 The results of HPV tests alone or in conjunction with cytology are used to guide recommendations that allow lengthening of follow-up intervals and deferral of colposcopy for low-risk results. Of note, risk estimates underlying the 2019 management guidelines are based on HPV DNA testing. 2.Personalized risk-based management is possible with knowledge of current results and past history. A patient's risk of having or developing CIN 3+ is estimated based on current and previous results, as well as history of previous precancer treatment. Management recommendations use thresholds of risk.19 Recommendations of routine screening, 1-year or 3-year surveillance, colposcopy, or treatment correspond to a risk stratum, a range of risk for CIN 3+. The lower threshold of each risk stratum, called Clinical Action Threshold, defines the level at which the management recommendation changes. The Clinical Action Thresholds for each risk stratum were determined through the consensus process. Risks were estimated for all combination of current results and past history (including unknown history) for which adequate data were available at KPNC. Management can be determined via look-up tables,5 and use of the tables can be facilitated using decision aids. 3.Guidelines must allow updates to incorporate new test methods as they are validated, and to adjust for decreasing CIN3+ risks as more patients who received HPV vaccination reach screening age. The field of cervical cancer prevention is rapidly evolving, with new technologies being continually validated. Data on the validation of new technologies are being published frequently, and risk reduction from HPV vaccination is increasing as vaccine coverage increases and vaccinated individuals age into screening cohorts. Up to now, guideline revisions have required full consensus conferences, which are time-consuming, expensive, and not compatible with the rapid evolution of the field. The 2019 guidelines build a framework that allows incorporation of new technologies and modified strategies without requiring full consensus conferences, so that revisions may rapidly incorporate new findings and be quickly disseminated to optimize patient care. Clinical Action Thresholds for management created through the 2019 consensus process will remain in place, but as new tests become available and more long-term data accrue, the test combinations used to reach these thresholds will change. For example, at the 2019 consensus conference, HPV vaccination levels in the United States population currently 25 years or older were deemed too low to warrant incorporating HPV vaccination into the 2019 management recommendations. However, this is expected to change in the near future as more vaccinated patients, who have lower CIN 3+ risk, reach the age of 25 years and additional data accrue demonstrating the impact of vaccination on the CIN 3+ risk associated with abnormal test result combinations. The framework outlined here will allow guideline modification as robust data become available and are publicized. Because Clinical Action Thresholds remain constant, new data can be added while the Clinical Action Thresholds remain unchanged. This design is intentional to reduce clinician confusion associated with frequently changing guidelines. 4.Colposcopy practice must follow guidance detailed in the ASCCP Colposcopy Standards.10 Colposcopy with targeted biopsy remains the primary method of detecting precancers requiring treatment. Because patients are managed less aggressively after a colposcopic examination where CIN grade 2 or higher (CIN 2+) is not found, maximizing detection of CIN 2+ at each colposcopy visit is paramount. Evidence-based practice recommends that biopsies be taken of all discrete acetowhite areas, usually 2 to 4 biopsies at each colposcopic examination. For those at lowest risk, defined as less than HSIL cytology, no evidence of HPV 16/18 infection, and a completely normal colposcopic impression (i.e., no acetowhitening, metaplasia, or other visible abnormality, and a fully visualized squamocolumnar junction), untargeted (random) biopsies are not recommended and patients with a completely normal colposcopic impression can be observed without biopsy. To ensure that CIN 2+ is not missed, the ASCCP Colposcopy Standards emphasize the need for biopsies even when the colposcopic impression is normal but any degree of acetowhitening, metaplasia, or other abnormality is present. 2012 Principles Carried Forward 5.The primary goal of screening and management is cancer prevention through detection and treatment of cervical precancer. Numerous population-level studies indicate that incidence and mortality from cervical cancer decrease as detection and treatment of high-grade histologic cervical abnormalities (generally defined as CIN 2+) increases.20,21 Timely detection and treatment of the highest grade of precancers (CIN 3/AIS) have been the benchmark used for previous guidelines3 and remain the primary goal of the 2019 management guideline; a secondary goal (because of the relative rarity of this finding in the United States) is early diagnosis of cervical cancer to reduce related morbidity and mortality. A patient's risk of having or developing CIN 3+ is estimated based on current and previous results, as well as history of previous precancer treatment. Management recommendations are guided by risk thresholds.19 Recommendations of routine screening, 1- or 3-year surveillance, colposcopy, or treatment each correspond to a risk stratum. These risk strata (ranges of risk for CIN 3+) are defined by Clinical Action Thresholds that were determined through the consensus process (Section E). 6.Guidelines apply to all individuals with a cervix. Guidelines apply to women and transgender men with a cervix, including individuals who have undergone supracervical hysterectomy. Risk estimates were validated in individuals of diverse racial, ethnic, and socioeconomic backgrounds and shown to be comparable.6 Though not the primary focus of the 2019 guidelines, management recommendations are also provided for patients who have undergone hysterectomy with removal of the cervix and who have a previous diagnosis of histologic HSIL, CIN 2, CIN 2/3, CIN 3, and/or AIS, irrespective of whether the hysterectomy was performed for precancer treatment or another indication. 7.Equal management for equal risk. History and current test results are used to calculate a patient's current and future risk of CIN 3+. Similar risks are managed similarly, regardless of the combination of results/history used to estimate the risk. 8.Balancing benefits and harms. Providing the best care means balancing cancer prevention with overtesting and overtreatment. Preventing all cervical cancers is unfortunately not an achievable goal. Interventions to prevent cervical cancer can cause harm. The 2019 guidelines are designed to maximize cervical cancer prevention and minimize harms from overtesting and overtreating by managing patients according to their current and future risks of CIN 3+. High-risk patients require closer follow-up to maximize detection of CIN 3+, whereas low-risk patients require fewer tests and procedures. 9.Guidelines apply to asymptomatic patients that require management of abnormal cervical screening test results. Patients with symptoms such as abnormal uterine or vaginal bleeding or a visibly abnormal-appearing cervix require appropriate diagnostic testing as this may be a sign of cancer.22 This evaluation may include cervical cytology, colposcopy, diagnostic imaging, and cervical, endocervical, or endometrial biopsy. Guidelines cannot cover all clinical situations and clinical judgment is advised, especially in those circumstances which are not covered by the 2019 guidelines. 10.Guidelines are intended for use in the United States. Appropriate management may differ in countries with limited follow-up capabilities, less availability of colposcopy, limited pathology infrastructure, or different views of the trade-offs between cancer risk, cost, and overtesting/overtreatment. D. METHODS D.1 Process and Timeline The ASCCP and National Cancer Institute (NCI) established a Memorandum of Understanding in January 2017 to undertake the work of this guideline update. As with the previous 2001, 2006, and 2012 guidelines,1–3 NCI produced risk data and other scientific support for the consensus guideline process. The ASCCP sponsored the consensus effort to develop and ratify the guidelines. Stakeholder organizations representing best practice in the United States were identified and invited to participate. These included medical professional societies, patient advocacy groups, and federal agencies integral to cervical cancer screening and management of abnormal results (see Table 1). Participation of the stakeholder organizations included identifying organization representatives and, for nongovernment participants, sponsoring their travel to consensus conferences. Representatives from 19 organizations attended the initial meeting in February 2018. At that time, 7 working groups were convened. In previous consensus conferences, working groups considered test (e.g., and In the 7 working groups for the 2019 guidelines were with the goal of consensus Clinical Action The treatment which risk levels of CIN 3+ warrant expedited treatment without as well as issues. The colposcopy considered the threshold for colposcopy The surveillance created a of at intervals than currently recommended for routine screening with either HPV primary testing or cotesting and also when patients return to routine screening. Patients surveillance include those with abnormal screening results not requiring colposcopy (e.g., HPV-positive for or after colposcopy with low-grade results, or after treatment for high-grade The risk modification factors that change a patient's estimated risk or on pregnancy and immunosuppression. The high value care performed decision related to management strategies and will continue to value as the 2019 guidelines are The new technologies laboratory and technologies related to management. The created and for to and the about the guidelines and the process. groups were of 2 to including representatives of stakeholder and representatives of patient advocacy groups from through 2019 to data and develop guidelines for management. The consensus process was by a by the ASCCP and was by a of 1 NCI and 2 ASCCP representatives Because the guidelines a the guidelines process included a and process of stakeholder These included patient and a consensus meeting to guidelines, and a the consensus meeting in of CIN 3+ as Clinical for Risk For the management guidelines, we CIN 3+ as the best surrogate for cancer risk. The of CIN 3+ as used in these guidelines includes CIN 3, AIS, and the rare of cervical cancer that are in screening These management guidelines CIN 3+ risk at the time point for the clinical action being Action Thresholds for colposcopy and treatment immediate risks of CIN 3+, whereas surveillance recommendations use 5-year CIN3+ was as an of cancer because cancer is in the United and risk is by treatment. that are in robust screening programs may cancers at first screening, rare of or not by screening, or negative CIN 3+ was of CIN 2+ because it is a more the HPV type in CIN 3+ more that of cervical cancers than the range of types in CIN and CIN 2 has in the of The of CIN 3+ does have as even CIN risks of to cancer including AIS, with HPV 16 and 18 infections, and those in older patients have higher cancer risks than and those in for cervical are in use in the United States. The and the a for reporting of squamous similar to the used for reporting cervical However, the CIN is and data used to generate this of guidelines on CIN Although no is possible without use of the histologic HSIL is similar but not to CIN Data to Risks Prior guidelines on a prospective data including results of cytology, HPV colposcopy, and follow-up from which cotesting as practice in The KPNC data continue to be the data in the United States for risk of combinations of HPV DNA testing and For the 2019 guidelines, several additional were to ensure that results are to patients of diverse racial, ethnic, and socioeconomic Risk estimates were compared using screening and follow-up data from clinical a HPV and the for and National and Cervical Cancer a that includes and The populations in of abnormal screening results and the prevalence of CIN 3+. the that the risks of CIN 3+ for the combination of current results and screening history were similar in that they within the same risk for management. et the of CIN 3+ risks associated with screening test result combinations the different populations of screened patients from these data In different populations within the United States have higher or lower of CIN 3+ to factors including to screening and HPV infection patients with similar test results and screening history combinations have similar CIN 3+ risk, regardless of their or socioeconomic of Risks of how risks of CIN 3+ were for the combinations of test results, including longitudinal of tests time, are in the accompanying In for each combination of past and current test results, the risk of CIN 3+ was estimated using which of of CIN 3+ at the time of the current testing using a and CIN 3+ at subsequent testing using a These are designed to and in this means that are only available for patients to CIN3+ that in the of negative screening or abnormal screening tests that were not for colposcopy will not be in this means that the CIN 3+ is at colposcopy but the time of of CIN 3+ cannot be determined as it is asymptomatic and between testing These are designed to provide risk estimates without the data into a (e.g., of to Clinical For each combination of current test results and screening

BACKGROUND: The proportion of women who attempt vaginal delivery after prior cesarean delivery has decreased largely because of concern about safety. The absolute and relative risks associated with a trial of labor in women with a history of cesarean delivery, as compared with elective repeated cesarean delivery without labor, are uncertain. METHODS: We conducted a prospective four-year observational study of all women with a singleton gestation and a prior cesarean delivery at 19 academic medical centers. Maternal and perinatal outcomes were compared between women who underwent a trial of labor and women who had an elective repeated cesarean delivery without labor. RESULTS: Vaginal delivery was attempted by 17,898 women, and 15,801 women underwent elective repeated cesarean delivery without labor. Symptomatic uterine rupture occurred in 124 women who underwent a trial of labor (0.7 percent). Hypoxic-ischemic encephalopathy occurred in no infants whose mothers underwent elective repeated cesarean delivery and in 12 infants born at term whose mothers underwent a trial of labor (P<0.001). Seven of these cases of hypoxic-ischemic encephalopathy followed uterine rupture (absolute risk, 0.46 per 1000 women at term undergoing a trial of labor), including two neonatal deaths. The rate of endometritis was higher in women undergoing a trial of labor than in women undergoing repeated elective cesarean delivery (2.9 percent vs. 1.8 percent), as was the rate of blood transfusion (1.7 percent vs. 1.0 percent). The frequency of hysterectomy and of maternal death did not differ significantly between groups (0.2 percent vs. 0.3 percent, and 0.02 percent vs. 0.04 percent, respectively). CONCLUSIONS: A trial of labor after prior cesarean delivery is associated with a greater perinatal risk than is elective repeated cesarean delivery without labor, although absolute risks are low. This information is relevant for counseling women about their choices after a cesarean section.

OBJECTIVE: To summarize published data about abdominal sacrocolpopexy and to highlight areas about which data are lacking. DATA SOURCES: We conducted a literature search on MEDLINE using Ovid and PubMed, from January,1966 to January, 2004, using search terms "sacropexy," "sacrocolpopexy," "sacral colpopexy," "colpopexy," "sacropexy," "colposacropexy," "abdominal sacrocolpopexy" "pelvic organ prolapse and surgery," and "vaginal vault prolapse or surgery" and included articles with English-language abstracts. We examined reference lists of published articles to identify other articles not found on the electronic search. METHODS OF STUDY SELECTION: We examined all studies identified in our search that provided any outcome data on sacrocolpopexy. Because of the substantial heterogeneity of outcome measures and follow-up intervals in case studies, we did not apply meta-analytic techniques to the data. TABULATION, INTEGRATION, AND RESULTS: Follow-up duration for most studies ranged from 6 months to 3 years. The success rate, when defined as lack of apical prolapse postoperatively, ranged from 78-100% and when defined as no postoperative prolapse, from 58-100%. The median reoperation rates for pelvic organ prolapse and for stress urinary incontinence in the studies that reported these outcomes were 4.4% (range 0-18.2%) and 4.9% (range 1.2% to 30.9%), respectively. The overall rate of mesh erosion was 3.4% (70 of 2,178). Some reports found more mesh erosions when concomitant total hysterectomy was done, whereas other reports did not. There were no data to either support or refute the contentions that concomitant culdoplasty or paravaginal repair decreased the risk of failure. Most authors recommended burying the graft under the peritoneum to attempt to decrease the risk of bowel obstruction; despite this, the median rate (when reported) of small bowel obstruction requiring surgery was 1.1% (range 0.6% to 8.6%). Few studies rigorously assessed pelvic symptoms, bowel function, or sexual function. CONCLUSION: Sacrocolpopexy is a reliable procedure that effectively and consistently resolves vaginal vault prolapse. Patients should be counseled about the low, but present risk, of reoperation for prolapse, stress incontinence, and complications. Prospective trials are needed to understand the effect of sacrocolpopexy on functional outcomes.

MicroRNAs (miRNAs) are a recently discovered class of endogenous, small, noncoding RNAs that regulate about 30% of the encoding genes of the human genome. However, the role of miRNAs in vascular disease is currently completely unknown. Using microarray analysis, we demonstrated for the first time that miRNAs are aberrantly expressed in the vascular walls after balloon injury. The aberrantly expressed miRNAs were further confirmed by Northern blot and quantitative real-time polymerase chain reaction. Modulating an aberrantly overexpressed miRNA, miR-21, via antisense-mediated depletion (knock-down) had a significant negative effect on neointimal lesion formation. In vitro, the expression level of miR-21 in dedifferentiated vascular smooth muscle cells was significantly higher than that in fresh isolated differentiated cells. Depletion of miR-21 resulted in decreased cell proliferation and increased cell apoptosis in a dose-dependent manner. MiR-21-mediated cellular effects were further confirmed in vivo in balloon-injured rat carotid arteries. Western blot analysis demonstrated that PTEN and Bcl-2 were involved in miR-21-mediated cellular effects. The results suggest that miRNAs are novel regulatory RNAs for neointimal lesion formation. MiRNAs may be a new therapeutic target for proliferative vascular diseases such as atherosclerosis, postangioplasty restenosis, transplantation arteriopathy, and stroke.

PURPOSE: To determine whether adding shear-wave (SW) elastographic features could improve accuracy of ultrasonographic (US) assessment of breast masses. MATERIALS AND METHODS: From September 2008 to September 2010, 958 women consented to repeat standard breast US supplemented by quantitative SW elastographic examination in this prospective multicenter institutional review board-approved, HIPAA-compliant protocol. B-mode Breast Imaging Reporting and Data System (BI-RADS) features and assessments were recorded. SW elastographic evaluation (mean, maximum, and minimum elasticity of stiffest portion of mass and surrounding tissue; lesion-to-fat elasticity ratio; ratio of SW elastographic-to-B-mode lesion diameter or area; SW elastographic lesion shape and homogeneity) was performed. Qualitative color SW elastographic stiffness was assessed independently. Nine hundred thirty-nine masses were analyzable; 102 BI-RADS category 2 masses were assumed to be benign; reference standard was available for 837 category 3 or higher lesions. Considering BI-RADS category 4a or higher as test positive for malignancy, effect of SW elastographic features on area under the receiver operating characteristic curve (AUC), sensitivity, and specificity after reclassifying category 3 and 4a masses was determined. RESULTS: Median participant age was 50 years; 289 of 939 (30.8%) masses were malignant (median mass size, 12 mm). B-mode BI-RADS AUC was 0.950; eight of 303 (2.6%) BI-RADS category 3 masses, 18 of 193 (9.3%) category 4a lesions, 41 of 97 (42%) category 4b lesions, 42 of 57 (74%) category 4c lesions, and 180 of 187 (96.3%) category 5 lesions were malignant. By using visual color stiffness to selectively upgrade category 3 and lack of stiffness to downgrade category 4a masses, specificity improved from 61.1% (397 of 650) to 78.5% (510 of 650) (P<.001); AUC increased to 0.962 (P=.005). Oval shape on SW elastographic images and quantitative maximum elasticity of 80 kPa (5.2 m/sec) or less improved specificity (69.4% [451 of 650] and 77.4% [503 of 650], P<.001 for both), without significant improvement in sensitivity or AUC. CONCLUSION: Adding SW elastographic features to BI-RADS feature analysis improved specificity of breast US mass assessment without loss of sensitivity.

BACKGROUND: Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The pathogenesis of these tumors is unknown. Moreover, their histopathological diagnosis can be challenging, and there is no curative treatment beyond surgery. METHODS: We analyzed four adult-type GCTs using whole-transcriptome paired-end RNA sequencing. We identified putative GCT-specific mutations that were present in at least three of these samples but were absent from the transcriptomes of 11 epithelial ovarian tumors, published human genomes, and databases of single-nucleotide polymorphisms. We confirmed these variants by direct sequencing of complementary DNA and genomic DNA. We then analyzed additional tumors and matched normal genomic DNA, using a combination of direct sequencing, analyses of restriction-fragment-length polymorphisms, and TaqMan assays. RESULTS: All four index GCTs had a missense point mutation, 402C-->G (C134W), in FOXL2, a gene encoding a transcription factor known to be critical for granulosa-cell development. The FOXL2 mutation was present in 86 of 89 additional adult-type GCTs (97%), in 3 of 14 thecomas (21%), and in 1 of 10 juvenile-type GCTs (10%). The mutation was absent in 49 SCSTs of other types and in 329 unrelated ovarian or breast tumors. CONCLUSIONS: Whole-transcriptome sequencing of four GCTs identified a single, recurrent somatic mutation (402C-->G) in FOXL2 that was present in almost all morphologically identified adult-type GCTs. Mutant FOXL2 is a potential driver in the pathogenesis of adult-type GCTs.

BACKGROUND: Midurethral slings are increasingly used for the treatment of stress incontinence, but there are limited data comparing types of slings and associated complications. METHODS: We performed a multicenter, randomized equivalence trial comparing outcomes with retropubic and transobturator midurethral slings in women with stress incontinence. The primary outcome was treatment success at 12 months according to both objective criteria (a negative stress test, a negative pad test, and no retreatment) and subjective criteria (self-reported absence of symptoms, no leakage episodes recorded, and no retreatment). The predetermined equivalence margin was +/-12 percentage points. RESULTS: A total of 597 women were randomly assigned to a study group; 565 (94.6%) completed the 12-month assessment. The rates of objectively assessed treatment success were 80.8% in the retropubic-sling group and 77.7% in the transobturator-sling group (3.0 percentage-point difference; 95% confidence interval [CI], -3.6 to 9.6). The rates of subjectively assessed success were 62.2% and 55.8%, respectively (6.4 percentage-point difference; 95% CI, -1.6 to 14.3). The rates of voiding dysfunction requiring surgery were 2.7% in those who received retropubic slings and 0% in those who received transobturator slings (P=0.004), and the respective rates of neurologic symptoms were 4.0% and 9.4% (P=0.01). There were no significant differences between groups in postoperative urge incontinence, satisfaction with the results of the procedure, or quality of life. CONCLUSIONS: The 12-month rates of objectively assessed success of treatment for stress incontinence with the retropubic and transobturator approaches met the prespecified criteria for equivalence; the rates of subjectively assessed success were similar between groups but did not meet the criteria for equivalence. Differences in the complications associated with the two procedures should be discussed with patients who are considering surgical treatment for incontinence. (ClinicalTrials.gov number, NCT00325039.)

PURPOSE: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. EXPERIMENTAL DESIGN: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as >or=50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. RESULTS: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a >or=20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a >or=20% volumetric reduction in their CNS lesions. CONCLUSIONS: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.

Abstract Rosai-Dorfman-Destombes disease (RDD) is a rare non–Langerhans cell histiocytosis characterized by accumulation of activated histiocytes within affected tissues. RDD, which now belongs to the R group of the 2016 revised histiocytosis classification, is a widely heterogeneous entity with a range of clinical phenotypes occurring in isolation or in association with autoimmune or malignant diseases. Recent studies have found NRAS, KRAS, MAP2K1, and ARAF mutations in lesional tissues, raising the possibility of a clonal origin in some forms of RDD. More than 1000 reports have been published in the English literature; however, there is a lack of consensus regarding approach for the clinical management of RDD. Although in most cases RDD can be observed or treated with local therapies, some patients with refractory or multifocal disease experience morbidity and mortality. Here we provide the first consensus multidisciplinary recommendations for the diagnosis and management of RDD. These recommendations were discussed at the 32nd Histiocyte Society Meeting by an international group of academic clinicians and pathologists with expertise in RDD. We include guidelines for clinical, laboratory, pathologic, and radiographic evaluation of patients with RDD together with treatment recommendations based on clinical experience and review of the literature.

BACKGROUND: Seizures occur in 1 to 2 percent of neonates admitted to an intensive care unit. The treatment is usually with either phenobarbital or phenytoin, but the efficacy of the two drugs has not been compared directly. METHODS: From 1990 to 1995, we studied 59 neonates with seizures that were confirmed by electroencephalography. The neonates were randomly assigned to receive either phenobarbital or phenytoin intravenously, at doses sufficient to achieve free plasma concentrations of 25 microg per milliliter for phenobarbital and 3 microg per milliliter for phenytoin. Neonates whose seizures were not controlled by the assigned drug were then treated with both drugs. Seizure control was assessed by electroencephalographic criteria. RESULTS: Seizures were controlled in 13 of the 30 neonates assigned to receive phenobarbital (43 percent) and 13 of the 29 neonates assigned to receive phenytoin (45 percent; P=1.00). When combined treatment is considered, seizure control was achieved in 17 (57 percent) of the neonates assigned to receive phenobarbital first and 18 (62 percent) of those assigned to receive phenytoin first (P=0.67). The severity of the seizures was a stronger predictor of the success of treatment than was the assigned agent. Neonates with mild seizures or with seizures that were decreasing in severity before treatment were more likely to have their seizures end, regardless of the treatment assignment. CONCLUSIONS: Phenobarbital and phenytoin are equally but incompletely effective as anticonvulsants in neonates. With either drug given alone, the seizures were controlled in fewer than half of the neonates.

PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m 2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m 2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

BACKGROUND: Screening for aneuploid pregnancies is routinely performed after 15 weeks of gestation and has a sensitivity of approximately 65 percent, with a false positive rate of 5 percent. First-trimester markers of aneuploidy have been developed, but their use in combination has not been adequately evaluated in clinical practice. METHODS: We conducted a multicenter study of screening for trisomies 21 and 18 among patients with pregnancies between 74 and 97 days of gestation, based on maternal age, maternal levels of free beta human chorionic gonadotropin and pregnancy-associated plasma protein A, and ultrasonographic measurement of fetal nuchal translucency. A screening result was considered to be positive for trisomy 21 if the calculated risk was at least 1 in 270 pregnancies and positive for trisomy 18 if the risk was at least 1 in 150. RESULTS: Screening was completed in 8514 patients with singleton pregnancies. This approach to screening identified 85.2 percent of the 61 cases of Down's syndrome (95 percent confidence interval, 73.8 to 93.0), with a false positive rate of 9.4 percent (95 percent confidence interval, 8.8 to 10.1). At a false positive rate of 5 percent, the detection rate was 78.7 percent (95 percent confidence interval, 66.3 to 88.1). Screening identified 90.9 percent of the 11 cases of trisomy 18 (95 percent confidence interval, 58.7 to 99.8), with a 2 percent false positive rate. Among women 35 years of age or older, screening identified 89.8 percent of fetuses with trisomy 21, with a false positive rate of 15.2 percent, and 100 percent of fetuses with trisomy 18. CONCLUSIONS: First-trimester screening for trisomies 21 and 18 on the basis of maternal age, maternal levels of free beta human chorionic gonadotropin and pregnancy-associated plasma protein A, and measurement of fetal nuchal translucency has good sensitivity at an acceptable false positive rate.

PURPOSE: To update the 1999 American Society of Clinical Oncology (ASCO) guideline on breast cancer follow-up and management in the adjuvant setting. METHODS: An ASCO Expert Panel reviewed pertinent information from the literature through March 2006. More weight was given to studies that tested a hypothesis directly relating testing to one of the primary outcomes in a randomized design. RESULTS: The evidence supports regular history, physical examination, and mammography as the cornerstone of appropriate breast cancer follow-up. All patients should have a careful history and physical examination performed by a physician experienced in the surveillance of cancer patients and in breast examination. Examinations should be performed every 3 to 6 months for the first 3 years, every 6 to 12 months for years 4 and 5, and annually thereafter. For those who have undergone breast-conserving surgery, a post-treatment mammogram should be obtained 1 year after the initial mammogram and at least 6 months after completion of radiation therapy. Thereafter, unless otherwise indicated, a yearly mammographic evaluation should be performed. Patients at high risk for familial breast cancer syndromes should be referred for genetic counseling. The use of CBCs, chemistry panels, bone scans, chest radiographs, liver ultrasounds, computed tomography scans, [18F]fluorodeoxyglucose-positron emission tomography scanning, magnetic resonance imaging, or tumor markers (carcinoembryonic antigen, CA 15-3, and CA 27.29) is not recommended for routine breast cancer follow-up in an otherwise asymptomatic patient with no specific findings on clinical examination. CONCLUSION: Careful history taking, physical examination, and regular mammography are recommended for appropriate detection of breast cancer recurrence.

BACKGROUND: The benefits and safety of the treatment of mild chronic hypertension (blood pressure, <160/100 mm Hg) during pregnancy are uncertain. Data are needed on whether a strategy of targeting a blood pressure of less than 140/90 mm Hg reduces the incidence of adverse pregnancy outcomes without compromising fetal growth. METHODS: In this open-label, multicenter, randomized trial, we assigned pregnant women with mild chronic hypertension and singleton fetuses at a gestational age of less than 23 weeks to receive antihypertensive medications recommended for use in pregnancy (active-treatment group) or to receive no such treatment unless severe hypertension (systolic pressure, ≥160 mm Hg; or diastolic pressure, ≥105 mm Hg) developed (control group). The primary outcome was a composite of preeclampsia with severe features, medically indicated preterm birth at less than 35 weeks' gestation, placental abruption, or fetal or neonatal death. The safety outcome was small-for-gestational-age birth weight below the 10th percentile for gestational age. Secondary outcomes included composites of serious neonatal or maternal complications, preeclampsia, and preterm birth. RESULTS: A total of 2408 women were enrolled in the trial. The incidence of a primary-outcome event was lower in the active-treatment group than in the control group (30.2% vs. 37.0%), for an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<0.001). The percentage of small-for-gestational-age birth weights below the 10th percentile was 11.2% in the active-treatment group and 10.4% in the control group (adjusted risk ratio, 1.04; 95% CI, 0.82 to 1.31; P = 0.76). The incidence of serious maternal complications was 2.1% and 2.8%, respectively (risk ratio, 0.75; 95% CI, 0.45 to 1.26), and the incidence of severe neonatal complications was 2.0% and 2.6% (risk ratio, 0.77; 95% CI, 0.45 to 1.30). The incidence of any preeclampsia in the two groups was 24.4% and 31.1%, respectively (risk ratio, 0.79; 95% CI, 0.69 to 0.89), and the incidence of preterm birth was 27.5% and 31.4% (risk ratio, 0.87; 95% CI, 0.77 to 0.99). CONCLUSIONS: In pregnant women with mild chronic hypertension, a strategy of targeting a blood pressure of less than 140/90 mm Hg was associated with better pregnancy outcomes than a strategy of reserving treatment only for severe hypertension, with no increase in the risk of small-for-gestational-age birth weight. (Funded by the National Heart, Lung, and Blood Institute; CHAP ClinicalTrials.gov number, NCT02299414.).

BACKGROUND: Many surgical procedures are available for women with urinary stress incontinence, yet few randomized clinical trials have been conducted to provide a basis for treatment recommendations. METHODS: We performed a multicenter, randomized clinical trial comparing two procedures--the pubovaginal sling, using autologous rectus fascia, and the Burch colposuspension--among women with stress incontinence. Women were eligible for the study if they had predominant symptoms associated with the condition, a positive stress test, and urethral hypermobility. The primary outcomes were success in terms of overall urinary-incontinence measures, which required a negative pad test, no urinary incontinence (as recorded in a 3-day diary), a negative cough and Valsalva stress test, no self-reported symptoms, and no retreatment for the condition, and success in terms of measures of stress incontinence specifically, which required only the latter three criteria. We also assessed postoperative urge incontinence, voiding dysfunction, and adverse events. RESULTS: A total of 655 women were randomly assigned to study groups: 326 to undergo the sling procedure and 329 to undergo the Burch procedure; 520 women (79%) completed the outcome assessment. At 24 months, success rates were higher for women who underwent the sling procedure than for those who underwent the Burch procedure, for both the overall category of success (47% vs. 38%, P=0.01) and the category specific to stress incontinence (66% vs. 49%, P<0.001). However, more women who underwent the sling procedure had urinary tract infections, difficulty voiding, and postoperative urge incontinence. CONCLUSIONS: The autologous fascial sling results in a higher rate of successful treatment of stress incontinence but also greater morbidity than the Burch colposuspension. (ClinicalTrials.gov number, NCT00064662 [ClinicalTrials.gov] .).

Abstract The goal of the study was to compare cardiovascular heart disease risk factors in women with polycystic ovary syndrome (PCOS) and matched control subjects. Women with PCOS have risk factors, including anovulation, hyperandrogenism, and insulin resistance, that suggest a male coronary heart disease risk-factor profile. A total of 206 women with PCOS were recruited by using records from a large reproductive endocrinology practice. A clinical diagnosis of PCOS was made if there was a history of chronic anovulation in association with either clinical evidence of androgen excess (hirsutism) or if total testosterone level was &gt;2 nm/L or the luteinizing hormone/follicle-stimulating hormone ratio was greater than 2. The overall response rate for cases was 76%. A control population was obtained by using a combination of area voters’ registration tapes and directories of households. A control subject was matched to each case subject by age±5 years, race, and neighborhood. The response rate for recruitment of the first or second eligible control subject was 83.6%. The average age at initial interview was 35.9±7.4 years for case and 37.2±7.8 years for control subjects. Women with PCOS had significantly increased cardiovascular disease risk factors compared with control women. These included increases in body mass index, insulin, and triglyceride levels ( P &lt;.001), decreased total HDL and HDL 2 levels ( P &lt;.01), and increased total cholesterol and fasting LDL levels, waist/hip ratio, and systolic blood pressure ( P &lt;.05). After controlling for age, body mass index, and other confounding variables, differences in total cholesterol, total HDL, HDL 2 , LDL cholesterol, and triglycerides were still significant between case and control subjects. These risk factors were especially elevated in PCOS women in the early premenopausal years compared with control women, indicating that women with PCOS should be monitored for early detection and considered for appropriate clinical interventions.

BACKGROUND: Germline truncating mutations in DICER1, an endoribonuclease in the RNase III family that is essential for processing microRNAs, have been observed in families with the pleuropulmonary blastoma-family tumor and dysplasia syndrome. Mutation carriers are at risk for nonepithelial ovarian tumors, notably sex cord-stromal tumors. METHODS: We sequenced the whole transcriptomes or exomes of 14 nonepithelial ovarian tumors and noted closely clustered mutations in the region of DICER1 encoding the RNase IIIb domain of DICER1 in four samples. We then sequenced this region of DICER1 in additional ovarian tumors and in certain other tumors and queried the effect of the mutations on the enzymatic activity of DICER1 using in vitro RNA cleavage assays. RESULTS: DICER1 mutations in the RNase IIIb domain were found in 30 of 102 nonepithelial ovarian tumors (29%), predominantly in Sertoli-Leydig cell tumors (26 of 43, or 60%), including 4 tumors with additional germline DICER1 mutations. These mutations were restricted to codons encoding metal-binding sites within the RNase IIIb catalytic centers, which are critical for microRNA interaction and cleavage, and were somatic in all 16 samples in which germline DNA was available for testing. We also detected mutations in 1 of 14 nonseminomatous testicular germ-cell tumors, in 2 of 5 embryonal rhabdomyosarcomas, and in 1 of 266 epithelial ovarian and endometrial carcinomas. The mutant DICER1 proteins had reduced RNase IIIb activity but retained RNase IIIa activity. CONCLUSIONS: Somatic missense mutations affecting the RNase IIIb domain of DICER1 are common in nonepithelial ovarian tumors. These mutations do not obliterate DICER1 function but alter it in specific cell types, a novel mechanism through which perturbation of microRNA processing may be oncogenic. (Funded by the Terry Fox Research Institute and others.).

BACKGROUND: Urodynamic studies are commonly performed in women before surgery for stress urinary incontinence, but there is no good evidence that they improve outcomes. METHODS: We performed a multicenter, randomized, noninferiority trial involving women with uncomplicated, demonstrable stress urinary incontinence to compare outcomes after preoperative office evaluation and urodynamic tests or evaluation only. The primary outcome was treatment success at 12 months, defined as a reduction in the score on the Urogenital Distress Inventory of 70% or more and a response of "much better" or "very much better" on the Patient Global Impression of Improvement. The predetermined noninferiority margin was 11 percentage points. RESULTS: A total of 630 women were randomly assigned to undergo office evaluation with urodynamic tests or evaluation only (315 per group); the proportion in whom treatment was successful was 76.9% in the urodynamic-testing group versus 77.2% in the evaluation-only group (difference, -0.3 percentage points; 95% confidence interval, -7.5 to 6.9), which was consistent with noninferiority. There were no significant between-group differences in secondary measures of incontinence severity, quality of life, patient satisfaction, rates of positive provocative stress tests, voiding dysfunction, or adverse events. Women who underwent urodynamic tests were significantly less likely to receive a diagnosis of overactive bladder and more likely to receive a diagnosis of voiding-phase dysfunction, but these changes did not lead to significant between-group differences in treatment selection or outcomes. CONCLUSIONS: For women with uncomplicated, demonstrable stress urinary incontinence, preoperative office evaluation alone was not inferior to evaluation with urodynamic testing for outcomes at 1 year. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT00803959.).