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Background: Pre-exposure prophylaxis (PrEP) is highly effective at reducing the risk of human immunodeficiency virus (HIV) acquisition in at-risk individuals; however, it is largely underutilized. The Veterans Health Administration has created an HIV PrEP dashboard to identify at-risk veterans in attempt to increase PrEP enrollment., Objective: This study aimed to determine whether the use of an HIV PrEP dashboard would prove effective at increasing PrEP enrollment at a single facility., Methods: This was a single-center quality improvement project. Three pharmacists used the HIV PrEP dashboard and retrospective chart review to identify eligible patients for PrEP. A multimodal process of contacting patients was conducted. The primary objective was to evaluate the number of patients who enrolled in PrEP during the study period. Secondary objectives included evaluating the ability of the HIV PrEP dashboard to identify eligible patients, identify effective strategies to target PrEP enrollment, and compare those patients who accepted with those who declined PrEP to evaluate barriers to enrollment., Results: Of the 94 patients reviewed, 26 patients (27.7%) were found eligible for PrEP. Of the eligible patients, 3 patients (11.5%) were enrolled, and 7 patients (26.9%) declined PrEP. The others were lost to follow-up (9 of 26, 34.6%), had no action taken on a chart note to provider (6 of 26, 23.1%), or did not have a primary care provider assigned at the local facility (1 of 26, 3.9%). The 3 patients who were successfully enrolled in PrEP were all contacted and prescribed PrEP through the infectious diseases (ID) clinic. There were no statistically significant differences between the cohorts of patients who accepted and declined PrEP., Conclusions: The use of an HIV PrEP dashboard aided in identifying eligible patients for PrEP. Enrollment through the ID clinic was the most successful modality. Further research is needed to characterize barriers to PrEP uptake and to develop strategies to increase prescribing from non-ID providers., Competing Interests: Disclosure The authors declare no relevant conflicts of interest or financial relationships., (Published by Elsevier Inc.)

Background: Pre-exposure prophylaxis (PrEP) is highly effective at reducing the risk of human immunodeficiency virus (HIV) acquisition in at-risk individuals; however, it is largely underutilized. The Veterans Health Administration has created an HIV PrEP dashboard to identify at-risk veterans in attempt to increase PrEP enrollment., Objective: This study aimed to determine whether the use of an HIV PrEP dashboard would prove effective at increasing PrEP enrollment at a single facility., Methods: This was a single-center quality improvement project. Three pharmacists used the HIV PrEP dashboard and retrospective chart review to identify eligible patients for PrEP. A multimodal process of contacting patients was conducted. The primary objective was to evaluate the number of patients who enrolled in PrEP during the study period. Secondary objectives included evaluating the ability of the HIV PrEP dashboard to identify eligible patients, identify effective strategies to target PrEP enrollment, and compare those patients who accepted with those who declined PrEP to evaluate barriers to enrollment., Results: Of the 94 patients reviewed, 26 patients (27.7%) were found eligible for PrEP. Of the eligible patients, 3 patients (11.5%) were enrolled, and 7 patients (26.9%) declined PrEP. The others were lost to follow-up (9 of 26, 34.6%), had no action taken on a chart note to provider (6 of 26, 23.1%), or did not have a primary care provider assigned at the local facility (1 of 26, 3.9%). The 3 patients who were successfully enrolled in PrEP were all contacted and prescribed PrEP through the infectious diseases (ID) clinic. There were no statistically significant differences between the cohorts of patients who accepted and declined PrEP., Conclusions: The use of an HIV PrEP dashboard aided in identifying eligible patients for PrEP. Enrollment through the ID clinic was the most successful modality. Further research is needed to characterize barriers to PrEP uptake and to develop strategies to increase prescribing from non-ID providers., Competing Interests: Disclosure The authors declare no relevant conflicts of interest or financial relationships., (Published by Elsevier Inc.)

Background: Cancer treatment related fatigue (CTRF) is one of the most debilitating side effects of adjuvant radiation therapy (RT). Several studies have found that physical activity (PA) may be an effective intervention to decrease fatigue and enhance QOL in cancer survivors. The primary objective of the PEDLAR study is to test the feasibility of an easily administered 8-week structured moderate-intensity PA intervention, delivered concurrently with RT, in reducing CTRF and improving health-related QOL among African-American breast cancer patients. This study is also designed to provide pilot data on the acceptability and adherence of PA interventions in African-American women with breast cancer., Methods: It is a prospective, 2-arm, 8-week feasibility trial. Participants are randomized to either a structured, moderate-intensity aerobic training exercise regimen concurrent with radiotherapy or a control group., Results: Participants in intervention group reported high satisfaction with exercise and adherence was >75% for exercise sessions., Conclusions: African-American breast cancer patients in a moderate-intensity 75 min/wk aerobic exercise intervention had marginally lower fatigue at 8-wk follow-up compared to baseline. The control group participants had marginally higher fatigue at 8-wk follow-up compared to baseline. Participants in the intervention group reported slightly better quality of life at 8-wk follow-up compared to baseline (P = 0.06)., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 National Medical Association. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS 313 ) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes., Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS 313 and CBC risk., Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS 313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS 313 , HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS 313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively., Conclusion: The PRS 313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS 313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making., (© 2021. The Author(s).)

Background: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SET ER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA)., Patients and Methods: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SET ER/PR or RNA4 components of SET2,3., Results: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SET ER/PR index., Conclusions: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment., Competing Interests: Disclosure WFS is a co-inventor of a pending patent application for the sensitivity to endocrine therapy and co-founder with equity in Delphi Diagnostics that licensed the intellectual property. LP and WFS are co-inventors of an issued patent for the algorithm to calculate residual cancer burden that is freely available on the internet. LvV is a co-inventor of an issued patent for the MammaPrint test and holds equity in Agendia that licensed the intellectual property. The remaining authors have declared no conflicts of interest., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Objective: Women with early-stage, ER + breast cancer are recommend to receive genomic profiling tests, such as the 21-gene Recurrence Score (RS) test, to guide treatment decisions. We examined test- and treatment-related information discussed and the associations between RS categories and aspects of communication during patient-oncologist clinical encounters., Methods: As part of a larger trial, clinical encounters (N = 46) were audiorecorded and coded for 1) RS- and treatment-related information, 2) shared decision making, 3) patient active participation, and 4) oncologist patient-centered communication. We examined differences by RS category using mixed models, adjusting for nesting within oncologist., Results: Patients with a high RS were more likely to receive a chemotherapy recommendation (p < .01), hear about the risks/side effects of chemotherapy (p < .01), and offer their preferences (p = .02) than those with intermediate or low RS. Elements of shared decision making increased with RS. Oncologist patient-centered communication (M = 4.09/5, SD = .25) and patient active participation (M = 3.5/4, SD = 1.0) were high across RS., Conclusion: Findings suggest that disease severity, rather than clinical uncertainty, impact treatment recommendations and shared decision making., Practice Implications: Oncologists adjust test- and treatment-related information and shared decision making by disease severity. This information provides a framework to inform decision making in complex cancer and genomics settings., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers., Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort., Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10 -72 ). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10 -50 ). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10 -22 ) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10 -12 ) carriers. The associations in the prospective cohort were similar., Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

Background: Oncotype DX (ODX) is a genomic assay of tumor tissue that is utilized to predict the likelihood of recurrence and benefit of chemotherapy in breast cancer patients. Five to 10% of breast cancers are hereditary, and hereditary syndromes may not be uncovered through family history alone. We hypothesized that high ODX recurrence score (RS) may signal a potential hereditary cancer risk., Patients and Methods: We performed a retrospective analysis of data from hormone receptor-positive breast cancer patients who had undergone ODX and germline genetic testing. The chi-square test and Fisher exact test were used to examine univariable association between RS and germline mutation status. Multivariable logistic regression was utilized to examine if there was an association of RS with germline mutation status., Results: In univariable analysis, the association of RS with germline mutation status was significant (P < .0001). In the multivariable logistic regression model predicting germline mutation status, RS level remained significantly associated with germline mutation, in particular BRCA1 or BRCA2. The mean RS for those with non-BRCA1/2 germline mutations versus those without germline mutations was not significant (P = .38)., Conclusion: High RS is associated with germline mutation status. Breast cancer patients with high RS are more likely to harbor a mutation in the BRCA1 or BRCA2 genes. If confirmed prospectively, oncologists may consider referring patients with high RS for genetic risk assessment and counseling to inform management plans, as well as counseling of family members., (Copyright © 2020. Published by Elsevier Inc.)

Context: Symptoms affect quality of life (QOL), functional status, and cognitive function in cancer survivors, but older survivors are understudied., Objectives: The objectives of this study were to identify prototypical presystemic therapy psychoneurological symptom clusters among older breast cancer survivors and determine whether these symptom clusters predicted cognition and QOL over time., Methods: Women with newly diagnosed nonmetastatic breast cancer (n = 319) and matched noncancer controls (n = 347) aged 60+ years completed questionnaires and neuropsychological tests before systemic therapy and 12 and 24 months later. Latent class analysis identified clusters of survivors based on their pretherapy depression, anxiety, fatigue, sleep disturbance, and pain. Linear mixed-effects models examined changes in objective cognition, perceived cognition, and functional status (Instrumental Activities of Daily Living disability, functional well-being, and breast cancer-specific QOL) by group, controlling for covariates., Results: Nearly one-fifth of older survivors were classified as having high pretherapy symptoms (n = 51; 16%); the remainder had low symptoms (n = 268; 84%); both groups improved over time on all outcomes. However, compared to the low symptom group and controls, survivors with high symptoms had lower baseline objective cognition and lower perceived cognition at baseline and 24 months, lower functional well-being at baseline and 12 months, greater Instrumental Activities of Daily Living disability at baseline, and lower breast cancer-specific QOL at all time points (all P < 0.05)., Conclusion: Nearly one-fifth of older breast cancer survivors had high psychoneurological symptoms at diagnosis, which predicted clinically meaningful decrements in perceived cognition and function in the first 24 months after diagnosis. Pretreatment psychoneurological symptom clusters could identify survivors for monitoring or intervention., (Copyright © 2018 American Academy of Hospice and Palliative Medicine. All rights reserved.)

Background: Cancer related fatigue (CRF) is a common and debilitating side-effect of radiotherapy in breast cancer patients. Physical activity interventions can attenuate CRF but evidence in African-American women with breast cancer is lacking., Methods/design: The "Pedlar" Study is a prospective, 8-week structured moderate-intensity exercise intervention, delivered concurrently with radiotherapy, to reduce CRF and improve health-related quality of life among African American breast cancer patients. Forty African American women with breast cancer scheduled to receive radiation therapy at MedStar Washington Hospital Center will be randomized to one of the two trial arms: 1) a facility-based aerobic exercise utilizing a portable stationary pedal exerciser; and 2) a control group. Intervention arm participants will exercise at the hospital either before or after their radiation treatment. Assessments will be conducted at baseline, 4, and 8 weeks. The outcome variables are CRF, biomarkers of inflammation, and health-related quality of life., Discussion: The Pedlar Study will provide preliminary evidence on whether a short-term moderate-intensity exercise intervention might be effective in reducing CRF in African American women undergoing radiotherapy for breast cancer, and whether this effect is mediated by inflammation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: As genetic counseling and testing become more fully integrated into clinical care, alternative delivery models are increasingly prominent. This study examines predictors of genetic testing for hereditary breast/ovarian cancer among high-risk women in a randomized trial of in-person versus telephone-based genetic counseling., Methods: Methods include multivariable logistic regression and interaction analyses., Results: Of the 669 participants, 600 completed counseling and 523 received test results. As previously reported, participants randomized to telephone counseling were significantly less likely to be tested. In intention-to-treat analyses, completion of counseling and testing was associated with: race/ethnicity (odds ratio (OR) = 1.96, 95% confidence interval (CI): 1.20-3.20), perceived stress (OR = 0.89, 95% CI: 0.81-0.98), knowledge (OR = 1.12, 95% CI: 1.02-1.23), and randomization group (OR = 1.48, 95% CI: 1.01-2.16). Further, race/ethnicity moderated the association between randomization group and testing; minority women receiving telephone counseling were least likely to complete testing., Conclusion: Evidence for logistical and communication-based explanations for this interaction is presented. The overall increased access made possible with telephone genetic counseling should be considered in light of the possibility that this may also lead to lower rates of testing among high-risk minority women. Additional care should be taken to assess and address potential barriers when services are delivered by telephone.Genet Med 17 6, 467-475.

Background: In women with early stage, hormone receptor (HR)-positive (HR(+)) breast cancer, the 21-gene recurrence score (RS) assay quantifies recurrence risk and predicts chemotherapy responsiveness. Recent data suggest that not all women with early-stage, HR(+) disease receive this testing. We examined sociodemographic, clinical, and attitudinal factors associated with RS testing receipt and the RS testing effect on chemotherapy use in black and white patients., Patients and Methods: Women with newly diagnosed invasive, nonmetastatic breast cancer were recruited and interviewed to collect sociocultural and health care process data; clinical data were collected from charts. Of the sample (n = 359), 270 had HR(+) disease. Primary analysis focused on those with HR(+) node-negative disease (n = 143); secondary analyses included node-positive women. Logistic regression models evaluated factors associated with receipt of RS testing and chemotherapy., Results: Among women eligible for the 21-gene assay, 62 patients [43%] received RS testing. In multivariable analysis, older age (odds ratio, 1.04 per 1 year increase; 95% confidence interval, 1.01-1.08) was associated with RS testing after adjustment for covariates. Chemotherapy use was 23%. In multivariable analysis, positive attitudes about chemotherapy and greater risk of recurrence were associated with chemotherapy use (P < .05)., Conclusion: Patterns of genomic testing might vary according to age. Efforts to understand factors associated with low testing rates will be important., Competing Interests: None Conflict of Interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm that any aspect of the work covered in this manuscript that has involved either experimental animals or human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). She is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author and which has been configured to accept email from vls3@georgetown.edu., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: Patients ≥ 65 years old ("older") are often not included in randomized clinical trials (RCT), but when they are, care in an RCT might improve quality of life (QoL). We conducted a prospective comparison of QoL among older women receiving standard chemotherapy from the same cooperative group physicians in an RCT vs. an observational study ("off-trial")., Methods: Older women with invasive, non-metastatic breast cancer (n=150 RCT; 530 off-trial) were included. Linear mixed-effects models tested associations between chemotherapy on- vs. off-trial and changes in EORTC (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire) QoL scores over 24 months, controlling for pre-treatment QoL, age, education, tumor factors, comorbidity, and other covariates., Results: Anthracycline regimens were used by 58% of women treated on-trial vs. 54% of those treated off-trial. Women in the RCT reported an adjusted mean increase of 13.7 points (95% CI 10.2, 17.1) in global QoL at 24 months (vs. mid-treatment), while women treated off-trial had only an adjusted improvement of 7.0 points (95% CI 3.5, 10.4; p=.007 for difference in mean changes). Women in the RCT had significantly greater improvement in emotional function than those treated off-trial, controlling for baseline; they also had greater reductions in therapy side effects and fatigue at 24 months than women off-trial, controlling for covariates., Conclusion: There may be different QoL trajectories for older women undergoing breast cancer chemotherapy on- vs. off-trial. If confirmed, the results suggest that the extra monitoring and communication within an RCT could provide the infrastructure for interventions to address symptoms and improve QoL for the growing older cancer population., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Alcohol consumption increases the risk of breast cancer among women in the general population, but its effect on women who carry a BRCA gene mutation is unclear. We conducted a case-control study of 1925 matched pairs of predominantly premenopausal women who carry a BRCA1 or a BRCA2 mutation. Information on current alcohol consumption was obtained from a questionnaire administered during the course of genetic counselling or at the time of enrollment. A modest inverse association between breast cancer and reported current alcohol consumption was observed among women with a BRCA1 mutation (OR = 0.82, 95% CI 0.70-0.96), but not among women with a BRCA2 mutation (OR = 1.00; 95% CI 0.71-1.41). Compared to non-drinkers, exclusive consumption of wine was associated with a significant reduction in the risk of breast cancer among BRCA1 carriers (p-trend = 0.01). Alcohol consumption does not appear to increase breast cancer risk in women carrying a BRCA gene mutation., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

With the increasingly early diagnosis of breast cancer and the advent of breast tumor subtyping, the need for determining which patients need adjuvant therapy has become more pressing and more complex. While clinical and pathologic features to predict benefit are valuable, the use of molecular techniques to better determine which tumors will benefit from chemotherapy is expected to further improve outcomes, reduce long-term complications, and provide cost-effective care. We will review the primary tools in clinical use: Adjuvant!, Oncotype DX, and MammaPrint as well as intrinsic subtypes and the plans for their further assessment in the clinical trial setting. The expected benefit from these models are that treatment recommendations for women with early-stage breast cancer will become more individualized and thereby appropriate by combining standard clinicopathologic and molecular features. This concept is currently being evaluated in multiple well-designed clinical trials.

Objective: Virtual dialogue--a voice-activated, interactive computer model that enables a user to have an individual virtual conversation with a real person--was evaluated as a method to educate women about breast cancer. Virtual dialogues with breast cancer experts were developed and used in a field study by women with and without the disease to assess the method's effectiveness., Methods: In a clinical setting, subjects engaged in one-on-one virtual dialogues with an oncologist and a breast surgeon, and completed automated pre-post instruments developed to measure the feasibility of the method, and subjects' knowledge gain and acceptance of the method., Results: Seventy women, 39 with breast cancer and 31 without the disease, participated. The data demonstrated the feasibility and acceptance of the method, and significant learning gain across all subjects., Conclusion: Virtual dialogues with knowledgeable health professionals can be a new and effective method for educating women about breast cancer., Practice Implications: Virtual dialogues may systematically comfort patients while providing them with comprehensive and reliable basic information about breast cancer. The method may also give health care providers more time to address their patients' specific concerns.

Background: Women with BRCA1 or BRCA2 (BRCA1/2) mutations can reduce cancer incidence and mortality by using bilateral prophylactic oophorectomy (BPO) or bilateral prophylactic mastectomy (BPM). The availability of these risk-reduction strategies is an important consideration in the decision to undergo genetic testing., Patients and Methods: We evaluated the use of BPO and BPM in a prospective sample of 537 female BRCA1/2 mutation carriers from 17 centers in North America and Europe. These women were aged > 30 years, had no BPM, BPO, breast cancer, or ovarian cancer before the disclosure of their genetic test results and were followed for > or = 6 months., Results: Bilateral prophylactic oophorectomy is used significantly more frequently than BPM (55% vs. 21%; P < .001). Bilateral prophylactic oophorectomy was more common among women age > or = 40 years compared with women aged < 40 years (68% vs. 43%; P < .001) and among parous women compared with nulliparous women (60% vs. 39%; P < .001). There was no difference in BPM (P = .83) or BPO (P = .09) in BRCA1 versus BRCA2 carriers. Multivariate models identified age and parity as a predictor of BPO in BRCA1 carriers; age and ovarian cancer family history in BRCA2 carriers; parity and ovarian cancer family history as a predictor of BPM in BRCA1 carriers; and smoking and ovarian cancer family history in BRCA2 carriers., Conclusion: Bilateral prophylactic oophorectomy is more commonly used than BPM in unaffected BRCA1/2 mutation carriers. Parity, age, and family history can also influence BPO and BPM uptake. Consistent with current recommendations, BPO is used by the majority of parous women aged > 40 years.

Almost every woman and some men will encounter hot flushes during their lifetime. Despite the prevalence of the symptoms, the pathophysiology of hot flushes remains unknown. A decline in hormone concentrations might lead to alterations in brain neurotransmitters and to instability in the hypothalamic thermoregulatory setpoint. The most effective treatments for hot flushes include oestrogens and progestagens. However, many women and their physicians are reluctant to accept hormonal treatments. Women want non-pharmacological treatments but unfortunately such treatments are not very effective, and non-hormonal drugs are often associated with adverse effects. Results from recent studies showed that selective serotonin reuptake inhibitors and other similar compounds can safely reduce hot flushes. Moreover, the efficacy of these drugs provides new insight into the pathophysiology of hot flushes. In this critical review, we assess knowledge of the epidemiology, pathophysiology, and treatment of hot flushes.

Skin substitutes are increasingly being used in the treatment of difficult to heal wounds but their mechanisms of action are largely unknown. In this study, using histology, immunostaining, flow cytometry, enzyme-linked immunosorbent assay, and reverse transcription polymerase chain reaction, we determined the response to injury of a human bilayered skin substitute. Meshing or scalpel fenestration of the construct was found to stimulate keratinocyte migration and to decrease proliferation. By 24 h, flow cytometry of the keratinocyte component showed that meshing was associated with a 33% decrease in the number of cells in S phase (p < 0.01). An approximately 2-fold decrease in staining for Ki67, a proliferation marker, was observed with meshing of human bilayered skin substitute. The process of reepithelialization was apparent by 12 h, however, the wounded human bilayered skin substitute was healed by day 3, and a stratum corneum and fully stratified epithelium were re-established by day 4. Reverse transcription polymerase chain reaction analysis and enzyme-linked immunosorbent assays showed that the expression of acute proinflammatory cytokines (interleukins 1alpha, 6, and 8, tumor necrosis factor alpha) peaked by 12-24 h postinjury. The levels of mRNA of certain growth factors (transforming growth factor beta1, vascular endothelial growth factor, insulin-like growth factor 2) but not others (platelet-derived growth factors A and B, keratinocyte growth factor, fibroblast growth factors 1 and 7, transforming growth factor beta3) increased by 12 h and peaked by 1-3 d after injury, returning to normal by day 6. Immunostaining for tumor necrosis factor alpha and transforming growth factor beta1 paralleled these findings by reverse transcription polymerase chain reaction. We conclude that human bilayered skin substitute, as a prototypic bilayered skin substitute, is a truly dynamic living tissue, capable of responding to physical injury in a staged and specific pattern of cell migration, reepithelialization, and cytokine expression.

Background: In several case-control and prospective studies, tubal ligation has been associated with a decreased risk of invasive epithelial ovarian cancer. We aimed to assess the potential of tubal ligation in reducing the risk of ovarian cancer in women who carry predisposing mutations in the BRCA1 or BRCA2 genes., Methods: We did a matched case-control study among women from Canada, the USA, and the UK who had undergone genetic testing and who carried a pathogenic mutation in BRCA1 or BRCA2. Cases were 232 women with a history of invasive ovarian cancer, and controls were 232 women without ovarian cancer, and who had both ovaries intact. Cases and controls were matched for year of birth, country of residence, and mutation (BRCA1 or BRCA2). The odds ratio for developing ovarian cancer was estimated for tubal ligation, adjusting for oral contraceptive use, parity, history of breast cancer, and ethnic group., Findings: In an unadjusted analysis among BRCA1 carriers, significantly fewer cases than controls had ever had tubal ligation (30 of 173 [18%] vs 60 of 173 [35%], odds ratio 0.37 [95% CI 0.21-0.63]; p=0.0003). After adjustment for oral contraceptive use, parity, history of breast cancer and ethnic group, the odds ratio was 0.39 (p=0.002). Combination of tubal ligation and past use of an oral contraceptive was associated with an odds ratio of 0.28 (0.15-0.52). No protective effect of tubal ligation was seen among carriers of the BRCA2 mutation., Interpretation: Tubal ligation is a feasible option to reduce the risk of ovarian cancer in women with BRCA1 mutations who have completed childbearing.

Treatment of Vero cells with all-trans-retinoic acid (RA) decreased the production of infectious herpes simplex virus (HSV) by 1000-10000-fold when compared with control cultures. Levels of total HSV envelope glycoproteins gB, gC and gD produced following RA treatment, were comparable with those found in control cultures. Following 24 h of RA treatment, lower molecular weight variants of gB, gC and gD were produced in addition to the typical molecular mass of each protein found in control samples. Between 24 and 48 h of RA treatment, the proportion of the lower molecular mass variants increased. When control and RA treated samples were incubated with peptide N-glycosidase F (PNGase F), which removes N-glycosylated sugars, the molecular weights of the respective gB, gC and gD proteins produced were comparable in both the groups, indicating that RA did not alter the primary sequence of viral proteins during protein synthesis or increase viral protein proteolysis. RA treatment increased [3H]mannose incorporation into glycoproteins in HSV infected cells but did not change [3H]glucosamine incorporation. We conclude that RA treatment does not reduce the synthesis of three major viral envelope glycoproteins but alters their N-glycosylation and postulate that the inhibitory effect of RA is related to its action on N-glycosylation.

Background: Many breast cancer survivors suffer debilitating hot flashes. Estrogen, the drug of choice in perimenopausal women, is generally not recommenced to breast cancer survivors. Nonhormonal treatments are mostly disappointing. Anecdotal reports in our institution suggested that the selective serotonin-reuptake inhibitor, paroxetine hydrochloride, might be efficacious in alleviating hot flashes., Patients and Methods: Thirty women with prior breast cancer who were suffering at least two hot flashes a day entered a single institution pilot trial to evaluate paroxetine's efficacy in reducing the frequency and severity of hot flashes. After completing daily diaries for one week on no therapy, the women received open-label paroxetine, 10 mg daily for one week, followed by four weeks of paroxetine, 20 mg daily. The women completed hot-flash daily diaries throughout the study period, and a health-related symptom-assessment questionnaire and a quality-of-life rating scale in the first and sixth week of the study., Results: Twenty-seven women completed the six-week study period. The mean reduction of hot flash frequency was 67% (95% confidence interval (95% CI): 56%-79%). The mean reduction in hot flash severity score was 75% (95% CI: 66%-85%). There was a statistically significant improvement in depression, sleep, anxiety, and quality of life scores. Furthermore, 25 (83%) of the study participants chose to continue paroxetine therapy at the end of study. The most common adverse effect was somnolence, resulting in drug discontinuation in two women, and dose reduction in two women. One woman discontinued drug due to anxiety., Conclusions: Paroxetine hydrochloride is a promising new treatment for hot flashes in breast cancer survivors, and warrants further evaluation in a double-blind randomized placebo-controlled trial.

Informed consent for BRCA1 mutation testing will require adequate knowledge of patterns of inheritance of cancer and the benefits, limitations, and risks of DNA testing. This study examined knowledge about the inheritance of breast cancer and attitudes about genetic testing for breast-ovarian cancer susceptibility in women at increased risk. Knowledge and attitudes were measured in 407 African American and Caucasian women aged 18-75 who had at least one first-degree relative (FDR) with breast and/or ovarian cancer. The average knowledge score was 6.0 out of a total of 11 (S.D. = 2.15). Compared to Caucasian women, African American women had lower levels of knowledge and had more positive attitudes about the benefits of genetic testing. There were no significant ethnic differences in attitudes about the limitations and risks of testing, however, income was negatively associated with this outcome. Ethnic differences in knowledge and attitudes about genetic testing for breast-ovarian cancer risk may be attributable to differences in exposure to genetic information and referral by health care providers.

Recent investigations in antigen processing suggest that many hematopoietic and nonhematopoietic cell types are capable of presenting alloantigen to T lymphocytes. However, the role of certain nonclassical antigen presenting cells is blurred by their apparent ability to down-regulate the immune response as well as activate immune cells, depending upon the microenvironment and the functional state of the responding cells. In this study we examine the ability of cultured allogeneic keratinocytes to inhibit the response of naive T cells to alloantigen or to anti-CD3. Our results demonstrate that as few as 6.25 x 10(3) keratinocytes significantly inhibited T cell proliferation in response to alloantigen as well as anti-CD3-mediated stimulation (49 and 54%, respectively). HK-mediated inhibition of T cell proliferation did not require cell contact, suggesting that inhibition is mediated by cytokines or other soluble factors. This was further supported by experiments demonstrating the inducibility of HK inhibitory activity in the presence of FCS, and the partial blockage of HK inhibitory activity through the addition of indomethacin or anti-TGFbeta antibody. Interestingly, the data suggest that IL-10, a known immunomodulatory cytokine, does not play a role in the inhibitory activity seen in this system. Taken together the results suggest that HK have the potential to regulate the response of T cells to antigen presented by other APC through the production of soluble factors.

The retinoic acid (RA) isomers all-trans-RA, 9-cis-RA and 13-cis-RA as well as other retinoids were tested for their ability to reduce the yield of herpes simplex virus-1 (HSV-1). RA isomers reduced HSV-1 replication whereas the other retinoids, retinol, retinal, beta-carotene and amide derivatives of RA were not inhibitory. All-trans-RA reduced the yield of HSV-1 by 100-fold at 5 micrograms/ml but 9-cis-RA and 13-cis-RA reduced viral replication by 10-fold. At a concentration of 10 micrograms/ml all-trans-RA and 9-cis-RA reduced virus yield by 1000-fold while 13-cis-RA decreased HSV-1 production by 100-fold. RA isomers at a concentration of 10 micrograms/ml were not cytotoxic for the Vero cells used in these studies. Immunofluorescence studies showed that all-trans-RA treated cell cultures exhibited small foci of virus specific immunostaining while untreated cultures displayed intense HSV-1 immunoreactivity in virtually the entire cell population. RA-dependent inhibition of HSV-1 replication required the presence of RA with the virus. HSV-1 replication proceeded when RA was removed from infected cells. Treatment of cell cultures with RA did not induce gene expression for type-1 interferon (IFN) or for the type-1 IFN inducible genes studied suggesting that RA inhibition of HSV-1 replication is not mediated by IFN. These studies have established the ability of RA to reduce the replication of HSV-1 in vitro.

Objective: To determine the prevalence and correlates of psychiatric disorders among preschool children in a primary care pediatric sample., Method: In a two-stage design, 3,860 preschool children were screened; 510 received fuller evaluations., Results: For quantitative assessment of disorder (> or = 90th percentile), prevalence of behavior problems was 8.3%. "Probable" occurrence of an Axis I DSM-III-R disorder was 21.4% (9.1%, severe). Logistic regression analyses indicated significant demographic correlates for quantitative outcomes (older age, minority status, male sex, low socio-economic status, father absence, small family size) but not for DSM-III-R diagnoses. Maternal and family characteristics were generally not significant. Child correlates included activity level, timidity, persistence, and IQ., Conclusions: Overall prevalence of disorder was consistent with rates for older children; correlates varied by approach used for classification.