Cardiovascular impact of near complete estrogen deprivation in premenopausal women with breast cancer: The CROWN study.

Survival with operable breast cancer has improved markedly in recent decades, however, treatment-related cardiovascular toxicities threaten to offset these gains. Ovarian function suppression paired with aromatase inhibition, for premenopausal women with hormone receptor (HR)-positive breast cancer, is a newer widely adopted therapy with the potential for significant long-term cardiovascular toxicity. Abrupt estrogen deprivation for non-cancer reasons is associated with accelerated coronary artery disease. Women with breast cancer treated with aromatase inhibition in addition to ovarian function suppression experience a dual hit with regards to estrogen exposure. The CaRdiac Outcomes With Near-complete estrogen deprivation (CROWN) study seeks to understand the early, subclinical natural history of cardiovascular compromise in young women undergoing near-complete estrogen deprivation (NCED) therapy. It is critical to understand the early subclinical development of cardiovascular disease to identify a window for therapeutic intervention before overt cardiovascular events occur. This three-site regional study (Atrium Health Wake Forest, Duke, and Virginia Commonwealth University) uses serial stress cardiac magnetic resonance (CMR) imaging and cardiac computed tomography angiography (CCTA) obtained during the initial two years of NCED therapy to study myocardial prefusion reserve (MPR), large cardiovascular vessel changes, left ventricular function, and other cardiovascular parameters. The CROWN cohort will consist of 90 premenopausal women with breast cancer, 67 with HR-positive disease receiving NCED and 23 comparators with HR-negative disease. Participants will undergo three annual CMR scans and 2 CCTA scans during the 2-year study period. After initial activation hurdles, accrual has been brisk, and the study is expected to complete accrual in December 2024. Efforts are in place to encourage participant retention with the study primary outcome, change in MPR between the two groups, to be reported in 2026 to 2027. The results of this study will enable premenopausal women with breast cancer to balance the health burdens of cancer at a young age and treatment-related cardiovascular morbidity. Finally, the tools developed here can be utilized to study cardiovascular risk across a range of cancer types and cancer therapies with the ultimate goals of both developing generalizable risk stratification tools as well as validating interventions which prevent overt cardiovascular compromise.

Cultural and linguistic adaptation of a telephone-based cognitive-behavioral therapy (CBT) intervention to treat depression and anxiety in Hispanic cancer survivors.

PURPOSE/OBJECTIVES: The purpose of this study was to transcreate a manualized cognitive-behavioral therapy (CBT) intervention to address depression and anxiety among Hispanic cancer survivors. DESIGN/RESEARCH APPROACH: Stakeholders reviewed the CBT workbook for language, content, and cultural relevance. We designed semi-structured interview guides to elicit intervention feedback. SAMPLE/PARTICIPANTS: Stakeholder participants were Hispanic cancer survivors (n = 4), bilingual mental health providers (n = 2), and oncology professionals (n = 4). METHODS: Transcreation was conducted by initial translation of the workbook followed by incorporation of stakeholder feedback. A bilingual (Spanish and English) interviewer conducted stakeholder interviews. The study team discussed themes/suggestions before refining the workbook. FINDINGS: Stakeholders reported enthusiasm for the intervention. We gathered significant feedback regarding wording, images, and resources for the workbook. CONCLUSION: Development of culturally appropriate mental health resources for Hispanic cancer survivors is critical. IMPLICATIONS FOR PSYCHOSOCIAL PROVIDERS OR POLICY: By broadening research on psychosocial care to the Hispanic population, we increase the reach of evidence-based psychological care. Future research should fully evaluate the adapted CBT intervention among Hispanic survivors.

Prediction of Postoperative Day 1 Hemoglobin Level after Cesarean Delivery.

OBJECTIVE: To create a prediction model for postoperative hemoglobin levels after cesarean delivery, which could reduce routine use of postoperative laboratory test. STUDY DESIGN: This was a secondary analysis of a retrospective cohort study of all women who underwent cesarean delivery (primary or repeat) at or more than 23 weeks' gestation at a single academic center. The cohort was randomly divided into a training cohort to develop a prediction model and a validation cohort to test the model in a 2:1 ratio. Variables with p-value <0.10 were considered for the mixed multivariable linear regression model in a backward stepwise fashion. We obtained the best cut-off point of the predicted hemoglobin level to detect severe anemia (postoperative hemoglobin level less than 7.0 g/dL) in the training cohort. A receiver operating characteristic curve with the area under a curve was created. We calculated the sensitivity and specificity of the model in the validation cohort using the best cut-off point obtained in the training cohort as well as postoperative hemoglobin of 10.0 g/dL. RESULTS: Of 2,930 women, 1,954 (66.6%) and 976 (33.3%) were randomly allocated to training and validation cohorts. The final model included preoperative hemoglobin level, preoperative platelet level, quantitative blood loss, height, weight, magnesium administration, labor, and general anesthesia. The best cut-off to predict severe anemia was predicted hemoglobin level of 8.57 g/dL in the training cohort. Using this cut-off, the sensitivity and specificity in the validation cohort were 77% (95% confidence interval [CI]: 56-91%) and 87% (95% CI: 85-89%), respectively. The use of postpartum hemorrhage yielded the sensitivity of 58% (95% CI: 37-77%) and specificity 79% (95% CI: 76-81%), respectively. CONCLUSION: We developed a validated model to predict the postoperative day 1 hemoglobin levels after cesarean delivery that could assist with identifying women who may not need postoperative laboratory tests. KEY POINTS: · Postoperative laboratory tests are routine.. · A prediction model may allow reduce routine tests.. · We developed an accurate mathematical model..

Evaluation of the Emergency Severity Index (Version 4) in Postpartum Women after Cesarean Delivery.

OBJECTIVE: The Emergency Severity Index (ESI) version 4 is a 5-level triage system (1 being the highest acuity and 5 being the lowest acuity) used in the emergency department (ED). Our goal of the study was to compare rates of readmission according to ESI in postpartum women. STUDY DESIGN: This was a secondary analysis of a retrospective cohort study of all women who presented to the ED within 6 weeks after cesarean delivery. The acuity level was assigned by triage nurses at the time of triage presentation. Our primary outcome was postpartum readmission. To examine if the addition of blood pressure to vital sign abnormalities would improve the prediction for readmission, we created a modified ESI. We identified women who had an ESI of level 3 and reassigned to a modified ESI of level 2 if blood pressure was in the severe range. Receiver operating characteristic curves with area under the curve (AUC) were created and compared between ESI and modified ESI. RESULTS: Of 439 women, ESI distribution was 0.2% ESI 1, 23.7% ESI 2, 56.0% ESI 3, 19.4% ESI 4, and 0.7% ESI 5. Readmission rates by ESI level were 100% ESI 1, 47% ESI 2, 18% ESI 3, 2% ESI 4, and 0% ESI 5 (p < 0.001). Of 246 women who were assigned an ESI of 3, total 25 had severe range blood pressures and were reassigned to a modified ESI of 2. Of these 25 women, 14 were readmitted. The AUC of the modified ESI was statistically higher than that of the standard ESI (AUC: 0.77 and 95% confidence interval: 0.72-0.82 vs. AUC: 0.73 and 95% confidence interval: 0.68-0.78; p < 0.01). CONCLUSION: The ESI was a useful tool to identify women who required postpartum readmission. Incorporation of severe range blood pressure as a parameter of acuity improved the prediction of readmission. KEY POINTS: · ESI does not consider blood pressure.. · The ESI version 4 was predictive of postpartum readmission.. · Consideration of a severe range blood pressure significantly improved the prediction of readmission..

Interpregnancy Body Mass Index Change and Risk of Intrapartum Cesarean Delivery.

OBJECTIVE: This study aimed to examine the association between interpregnancy body mass index (BMI, kg/m2) change and intrapartum cesarean delivery in multiparous women without a history of cesarean delivery. STUDY DESIGN: We conducted a retrospective cohort study of all women who had more than one singleton pregnancy at 23 weeks' gestation or greater at MedStar Washington Hospital Center from January 2009 to June 2018. We excluded women who had a history of cesarean delivery, prelabor cesarean delivery, and contraindications for vaginal delivery. Interpregnancy BMI change was calculated by the change of early pregnancy BMI measured in the office. Women were categorized according to the interpregnancy BMI change (BMI loss more than 2 kg/m2, BMI change ± 2 kg/m2, and BMI gain more than 2 kg/m2). The primary outcome was an intrapartum cesarean delivery. Multivariable logistic regression was performed to calculate adjusted odds ratio (aOR) with 95% confidence interval (CI) after adjusting for predefined covariates. RESULTS: Of 2,168 women who were analyzed, 258 (12%), 1,192 (55%), and 718 (33%) had interpregnancy BMI loss more than 2 kg/m2, BMI change ± 2 kg/m2, and BMI gain more than 2 kg/m2, respectively. Women with BMI gain more than 2 kg/m2 compared with those with BMI change ± 2 kg/m2 had increased odds of intrapartum cesarean delivery (7.4 vs. 4.5%; aOR: 1.78; 95% CI: 1.10-2.86) and cesarean delivery for arrest disorders (3.1 vs. 1.1%; aOR: 3.06; 95% CI: 1.30-7.15). Women with BMI loss more than 2 kg/m2 compared with those with BMI change ± 2 kg/m2 had similar rates of cesarean delivery. CONCLUSION: Compared with interpregnancy BMI change ± 2 kg/m2, interpregnancy BMI gain 2 kg/m2 was associated with increased odds of intrapartum cesarean delivery. KEY POINTS: · BMI gain between pregnancies was associated with intrapartum cesarean delivery.. · BMI loss between pregnancies was not associated with intrapartum cesarean delivery.. · Our study suggests that at least maintaining weight between pregnancies is beneficial..

Diabetes, Obesity, and Inflammation: Impact on Clinical and Radiographic Features of Breast Cancer.

Obesity, diabetes, and inflammation increase the risk of breast cancer, the most common malignancy in women. One of the mainstays of breast cancer treatment and improving outcomes is early detection through imaging-based screening. There may be a role for individualized imaging strategies for patients with certain co-morbidities. Herein, we review the literature regarding the accuracy of conventional imaging modalities in obese and diabetic women, the potential role of anti-inflammatory agents to improve detection, and the novel molecular imaging techniques that may have a role for breast cancer screening in these patients. We demonstrate that with conventional imaging modalities, increased sensitivity often comes with a loss of specificity, resulting in unnecessary biopsies and overtreatment. Obese women have body size limitations that impair image quality, and diabetes increases the risk for dense breast tis-sue. Increased density is known to obscure the diagnosis of cancer on routine screening mammography. Novel molecu-lar imaging agents with targets such as estrogen receptor, human epidermal growth factor receptor 2 (HER2), pyrimi-dine analogues, and ligand-targeted receptor probes, among others, have potential to reduce false positive results. They can also improve detection rates with increased resolution and inform therapeutic decision making. These emerg-ing imaging techniques promise to improve breast cancer diagnosis in obese patients with diabetes who have dense breasts, but more work is needed to validate their clinical application.

Neuromuscular ultrasound for taxane peripheral neuropathy in breast cancer.

BACKGROUND: Our study aim was to evaluate neuromuscular ultrasound (NMUS) for the assessment of taxane chemotherapy-induced peripheral neuropathy (CIPN), the dose-limiting toxicity of this agent. METHODS: This cross-sectional study of breast cancer patients with taxane CIPN measured nerve cross-sectional area (CSA) by NMUS and compared with healthy historical controls. Correlations were determined between CSA and symptom scale, nerve conduction studies, and intraepidermal nerve fiber density (IENFD). RESULTS: A total of 20 participants reported moderate CIPN symptoms at a median of 3.8 months following the last taxane dose. Sural nerve CSA was 1.2 mm2 smaller than healthy controls (P ≤ .01). Older age and time since taxane were associated with smaller sural nerve CSA. For each 1 mm2 decrease in sural nerve CSA, distal IENFD decreased by 2.1 nerve/mm (R2 0.30; P = .04). CONCLUSIONS: These data support a sensory predominant taxane neuropathy or neuronopathy and warrant future research on longitudinal NMUS assessment of CIPN.

Early and Locally Advanced Metaplastic Breast Cancer: Presentation and Survival by Receptor Status in Surveillance, Epidemiology, and End Results (SEER) 2010-2014.

BACKGROUND: Metaplastic breast cancer (MBC) is a rare disease subtype characterized by an aggressive clinical course. MBC is commonly triple negative (TN), although hormone receptor (HR) positive and human epidermal growth receptor 2 (HER2) positive cases do occur. Previous studies have reported similar outcomes for MBC with regard to HR status. Less is known about outcomes for HER2 positive MBC. MATERIALS AND METHODS: Surveillance, Epidemiology, and End Results Program data were used to identify women diagnosed 2010-2014 with MBC or invasive ductal carcinoma (IDC). Kaplan-Meier curves estimated overall survival (OS) and multivariate Cox models were fitted. For survival analyses, only first cancers were included, and 2014 diagnoses were excluded to allow for sufficient follow-up. RESULTS: Our MBC sample included 1,516 women. Relative to women with IDC, women with MBC were more likely to be older (63 vs. 61 years), black (16.0% vs. 11.1%), and present with stage III disease (15.6% vs. 10.8%). HER2 positive and HER2 negative/HR positive MBC tumors represented 5.2% and 23.0% of cases. For MBC overall, 3-year OS was greatest for women with HER2 positive MBC (91.8%), relative to women with TN (75.4%) and HER2 negative/HR positive MBC (77.1%). This difference was more pronounced for stage III MBC, for which 3-year OS was 92.9%, 47.1%, and 42.2% for women with HER2 positive, TN, and HER2 negative/HR positive MBC, respectively. A multivariate Cox model of MBC demonstrated that HER2 positive tumors (relative to TN) were associated with improved survival (hazard ratio = 0.32, 95% confidence interval [CI] 0.13-0.79). In a second Cox model of exclusively HER2 positive tumors, OS did not differ between MBC and IDC disease subtypes (hazard ratio = 1.16, 95% CI 0.48-2.81). CONCLUSION: In this contemporary, population-based study of women with MBC, HER2 but not HR status was associated with improved survival. Survival was similar between HER2 positive MBC and HER2 positive IDC. This suggests HER2 positive MBC is responsive to HER2-directed therapy, a finding that may offer insights for additional therapeutic approaches to MBC. IMPLICATIONS FOR PRACTICE: This population-based study reports recent outcomes, by receptor status, for women with metaplastic breast cancer. Survival in metaplastic breast cancer is not impacted by hormone receptor status. To the authors' knowledge, this is the first report indicating that women with human epidermal growth receptor 2 (HER2) positive metaplastic breast cancer have survival superior to women with HER2 negative metaplastic breast cancer and survival similar to women with HER2 positive invasive ductal carcinoma. This information can be used for counseling patients diagnosed with metaplastic breast cancer. Further understanding of HER2 positive metaplastic breast cancer could offer insights for the development of therapeutic approaches to metaplastic breast cancer more broadly.

Impact of vitamin D on pathological complete response and survival following neoadjuvant chemotherapy for breast cancer: a retrospective study.

BACKGROUND: There has been interest in the potential benefit of vitamin D (VD) to improve breast cancer outcomes. Pre-clinical studies suggest VD enhances chemotherapy-induced cell death. Vitamin D deficiency was associated with not attaining a pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) for operable breast cancer. We report the impact of VD on pCR and survival in an expanded cohort. METHODS: Patients from Iowa and Montpellier registries who had serum VD level measured before or during NAC were included. Vitamin D deficiency was defined as < 20 ng/mL. Pathological complete response was defined as no residual invasive disease in the breast and lymph nodes. Survival was defined from the date of diagnosis to the date of relapse (PFS) or date of death (OS). RESULTS: The study included 327 women. Vitamin D deficiency was associated with the odds of not attaining pCR (p = 0.04). Fifty-four patients relapsed and 52 patients died. In multivariate analysis, stage III disease, triple-negative (TN) subtype and the inability to achieve pCR were independently associated with inferior survival. Vitamin D deficiency was not significantly associated with survival in the overall sample; however a trend was seen in the TN (5-years PFS 60.4% vs. 72.3%, p = 0.3), and in the hormone receptor positive /human epidermal growth factor receptor 2 negative (HER2-) subgroups (5-years PFS 89% vs 78%, p = 0.056). CONCLUSION: Vitamin D deficiency is associated with the inability to reach pCR in breast cancer patients undergoing NAC.

Optogenetic stimulation of infralimbic PFC reproduces ketamine's rapid and sustained antidepressant actions.

Ketamine produces rapid and sustained antidepressant actions in depressed patients, but the precise cellular mechanisms underlying these effects have not been identified. Here we determined if modulation of neuronal activity in the infralimbic prefrontal cortex (IL-PFC) underlies the antidepressant and anxiolytic actions of ketamine. We found that neuronal inactivation of the IL-PFC completely blocked the antidepressant and anxiolytic effects of systemic ketamine in rodent models and that ketamine microinfusion into IL-PFC reproduced these behavioral actions of systemic ketamine. We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects and that these effects are associated with increased number and function of spine synapses of layer V pyramidal neurons. The results demonstrate that ketamine infusions or optogenetic stimulation of IL-PFC are sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to the effects of systemic ketamine administration.

Male Breast Cancer as a Second Primary Cancer: Increased Risk Following Lymphoma.

BACKGROUND: Male breast cancer (MBC) as a second primary cancer (SPC) has a known association with prior MBC. However, its association with non-breast index malignancies, relative to population risk, has not been previously reported. MATERIALS AND METHODS: Using Surveillance, Epidemiology, and End Results program (9 catchment area) data, we identified MBCs diagnosed from 1973-2012 as their SPC. Information regarding the index malignancy was also obtained. Standardized incidence ratios (SIR) of MBC as SPC were estimated, along with incidence rates and trends. Kaplan-Meier curves were used to estimate survival. RESULTS: Over a 38-year period, 464 MBCs were identified as SPC. The most common index malignancies were breast (SIR 30.86, 95% confidence interval [CI] 21.50-42.92, p < .001), lymphoma (SIR 1.58, 95% CI 1.08-2.22, p = .014), melanoma (SIR 1.26, 95% CI 0.80-1.89), urinary (SIR 1.05, 95% CI 0.74-1.43), colorectal (SIR 0.94, 95% CI 0.69-1.24), and prostate (SIR 0.93 95% CI 0.81-1.07). Apart from the known association with prior breast cancer, the only significant association was with lymphoma as an index cancer, although not significant with a Bonferroni correction. From 1975-2012, incidence of breast cancer as a first cancer increased at an annual percentage change of 1.3% while breast cancer as a SPC increased at 4.7% (both p values < .001). CONCLUSION: Male breast cancer as a SPC has increased markedly over 4 decades. Men with a history of lymphoma may experience higher-than-expected rates of breast SPC. These observations warrant further research, and suggest possible etiologic connections with disease biology, prior therapy, or genetics. IMPLICATIONS FOR PRACTICE: This study reports that men are presenting more frequently to the clinic with breast cancer, both as an initial cancer and as a second cancer following an earlier malignancy. We also report the novel observation that men who survive lymphoma are at increased risk of developing a subsequent breast cancer. Further work is needed to better understand possible treatment or biologic causes of this association. More immediately, these findings suggest the need for heightened vigilance for male breast cancer overall and, in particular, for male lymphoma survivors.

Systems analysis of dynamic transcription factor activity identifies targets for treatment in Olaparib resistant cancer cells.

The development of resistance to targeted therapeutics is a challenging issue for the treatment of cancer. Cancers that have mutations in BRCA, a DNA repair protein, have been treated with poly(ADP-ribose) polymerase (PARP) inhibitors, which target a second DNA repair mechanism with the aim of inducing synthetic lethality. While these inhibitors have shown promise clinically, the development of resistance can limit their effectiveness as a therapy. This study investigated mechanisms of resistance in BRCA-mutated cancer cells (HCC1937) to Olaparib (AZD2281) using TRACER, a technique for measuring dynamics of transcription factor (TF) activity in living cells. TF activity was monitored in the parental HCC1937 cell line and two distinct resistant cell lines, one with restored wild-type BRCA1 and one with acquired resistance independent of BRCA1 for 48 h during treatment with Olaparib. Partial least squares discriminant analysis (PLSDA) was used to categorize the three cell types based on TF activity, and network analysis was used to investigate the mechanism of early response to Olaparib in the study cells. NOTCH signaling was identified as a common pathway linked to resistance in both Olaparib-resistant cell types. Western blotting confirmed upregulation of NOTCH protein, and sensitivity to Olaparib was restored through co-treatment with a gamma secretase inhibitor. The identification of NOTCH signaling as a common pathway contributing to PARP inhibitor resistance by TRACER indicates the efficacy of transcription factor dynamics in identifying targets for intervention in treatment-resistant cancer and provides a new method for determining effective strategies for directed chemotherapy. Biotechnol. Bioeng. 2017;114: 2085-2095. © 2017 Wiley Periodicals, Inc.

Surgical Management of Breast Cancer in 2010-2011 SEER Registries by Hormone and HER2 Receptor Status.

BACKGROUND: Although locoregional recurrence is known to affect overall survival for operable breast cancer, the impact of receptor status on locoregional control is debated. Currently, hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status are generally not considered relevant to surgical choice. This study examines recent population-level surgical trends with regard to receptor status. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) data to identify stage I-III female breast cancers diagnosed from 2010 to 2011. Patients were categorized by HR and HER2 receptor status. Univariate and multivariate logistic regressions were used to assess factors associated with undergoing mastectomy and the choice of contralateral prophylactic mastectomy (CPM). RESULTS: The overall mastectomy rate for the 87,504 women diagnosed in 2010-2011 was 43.4 %. On multivariate analysis, the odds of receiving mastectomy was greater for HER2-positive disease with either HR-negative or HR-positive status, than for women with HER2-negative/HR-positive disease (odds ratio 1.73 and 1. 31, respectively; all p values <0.001). Age, stage, marital status, race, and year of diagnosis also correlated with mastectomy. Triple-negative breast cancer (TNBC) was associated with CPM, while HER2 status was not. The mastectomy rate, which increased overall from 2006 to 2010, has continued to increase for stage III disease but has decreased for stage I disease. Mastectomy rates overall were lower in 2011 than 2010 (p = 0.012). CONCLUSIONS: HER2-positive disease and TNBC were independent predictors of more extensive surgery in this large, recent, population-based cohort. Although mastectomy rates have continued to increase for stage III disease, mastectomy rates overall were lower in 2011 than in previous years.

Cocaine-induced endocannabinoid release modulates behavioral and neurochemical sensitization in mice.

The endocannabinoid system has been implicated in the development of synaptic plasticity induced by several drugs abused by humans, including cocaine. However, there remains some debate about the involvement of cannabinoid receptors/ligands in cocaine-induced plasticity and corresponding behavioral actions. Here, we show that a single cocaine injection in Swiss-Webster mice produces behavioral and neurochemical alterations that are under the control of the endocannabinoid system. This plasticity may be the initial basis for changes in brain processes leading from recreational use of cocaine to its abuse and ultimately to dependence. Locomotor activity was monitored with photobeam cell detectors, and accumbens shell/core microdialysate dopamine levels were monitored by high-performance liquid chromatography with electrochemical detection. Development of single-trial cocaine-induced behavioral sensitization, measured as increased distance traveled in sensitized mice compared to control mice, was paralleled by a larger stimulation of extracellular dopamine levels in the core but not the shell of the nucleus accumbens. Both the behavioral and neurochemical effects were reversed by CB1 receptor blockade produced by rimonabant pre-treatments. Further, both behavioral and neurochemical cocaine sensitization were facilitated by pharmacological blockade of endocannabinoid metabolism, achieved by inhibiting the fatty acid amide hydrolase enzyme. In conclusion, our results suggest that a single unconditioned exposure to cocaine produces sensitization through neuronal alterations that require regionally specific release of endocannabinoids. Further, the present results suggest that endocannabinoids play a primary role from the earliest stage of cocaine use, mediating the inception of long-term brain-adaptive responses, shaping central pathways and likely increasing vulnerability to stimulant abuse disorders.

Rate of contralateral prophylactic mastectomy is influenced by preoperative MRI recommendations.

BACKGROUND: Women with breast cancer increasingly undergo contralateral prophylactic mastectomy (CPM). We evaluated the relationship between preoperative magnetic resonance imaging (MRI) findings and CPM. Other clinicopathologic variables associated with CPM choice and the pathology found in the contralateral breast are also reported. METHODS: Newly diagnosed breast cancer patients were prospectively enrolled in the University of Iowa Breast Molecular Epidemiology Resource. Patients with stages 0-III breast cancer who underwent mastectomy for the index cancer were eligible for this analysis. Univariate logistic regression and a multivariate model were used to identify factors predictive of CPM. RESULTS: Among 134 patients (mean age 54.9 years), 53 (39.6 %) chose CPM. On univariate analysis, patients undergoing CPM were more likely to have a preoperative breast MRI (64.2 vs. 39.5 %, p = 0.006) and to have follow-up testing recommended for the contralateral breast (28.3 vs. 4.9 %, p = 0.001). Univariate analysis also associated CPM with younger age (p < 0.0001), BRCA testing (p < 0.0001), BRCA mutation (p = 0.034) and reconstruction performed (p = 0.001). Median age of youngest child at diagnosis varied significantly between the CPM (15.9 years) and non-CPM (24.3 years) groups (p = 0.0018). On multivariate analysis, MRI follow-up recommendation, young age, reconstruction and human epidermal growth factor receptor 2 (HER2) positivity of the index cancer were significantly associated with CPM. Of the CPM specimens, one (1.8 %) had ductal carcinoma-in situ, which had not been identified on MRI. CONCLUSIONS: Abnormal findings in the contralateral breast on preoperative MRI, as well as young age, reconstruction and HER2-positive status correlated with CPM choice in this cohort. Occult malignancy was rare.

The impact of leukoreduced red blood cell transfusion on mortality of neonates undergoing extracorporeal membrane oxygenation.

BACKGROUND: Blood products containing leukocytes have been associated with negative immunomodulatory and infectious effects. Transfusion-related acute lung injury is partially explained by leucocyte agglutination. The Food and Drug Administration has therefore recommended leukoreduction strategies for blood product transfusion. Our institution has been using leukocyte-reduced blood via filtration for neonates on Extracorporeal Membrane Oxygenation (ECMO). We hypothesized that the use of leukocyte-reduced blood would decrease mortality and morbidity of neonatal ECMO patients. METHODS: Retrospective review of noncardiac ECMO in neonates from 1984-2011, stratified into year groups I and II (≤1996 and ≥1997). Demographics, duration and type of ECMO, complications, and outcome data were collected. Blood product use data was collected. Univariate, bivariate, and multivariate analyses determined predictors of risk-adjusted mortality by year group. RESULTS: Patients (827) underwent ECMO with 65.3% (540) in group I. Overall median blood product use in mL/kg/d was 36.2 packed red blood cells (pRBC), 8.1 platelets, and 0 cyroprecipitate and/or fresh-frozen plasma. Overall mortality was 16.4%. Median pRBC used or transfused was 42.1 mL/kg/d in group I versus 19.1 mL/kg/d group II (P <0.001). On bivariate analysis, there was no difference in crude mortality between the 2 year groups (17.2% versus 16.0%, P = 0.66). However, on multivariate analysis adjusting for demographics, diagnosis, complications, and blood product use other than pRBCs, each additional transfusion of 10 mL/kg/d of pRBC was associated with a 33% increase in mortality in group I (P <0.05). Group II also showed an increase in mortality with each additional transfusion (21%) but this was not statistically significant (P = 0.07). Days on ECMO were not associated with pRBC transfusion in group I but increased in group II (additional 3 d for each 10 mL/kg/d transfused). There was no difference in infectious complications between groups I and II. CONCLUSIONS: Blood transfusion requirement has diminished in newborns undergoing ECMO at our institution. Transfusion of non leukocyte-reduced blood is associated with an increase in mortality whereas transfusion of leukocyte-reduced blood provided no benefit with a trend toward increased mortality. Further research is recommended to understand these trends.

Impact of Anti-Estrogen Therapy on Early Cardiovascular Referrals, Tests and Medications in Premenopausal Women with Operable Breast Cancer.

INTRODUCTION: Premenopausal women with high-risk hormone receptor (HR)-positive breast cancer often receive ovarian function suppression (OFS) and anti-estrogen therapy which induces near complete estrogen deprivation (NCED). This treatment improves recurrence-free survival but may increase cardiovascular risk. We sought to identify patterns of cardiovascular care and outcomes in premenopausal women with operable breast cancer. METHODS: Premenopausal women ≤ 50 years of age with stage I-III HR-positive or triple negative breast cancer (TNBC) were identified by retrospective review. We categorized women into 3 groups based on anti-estrogen therapy approach: NCED (HR + OFS), anti-estrogen therapy without OFS (HRnoOFS), and no anti-estrogen therapy (TNBC). Baseline characteristics, post-diagnosis cardiovascular events and cardiovascular actions (tests, referrals and medications) were recorded. Categorical variables were compared among the groups using chi-square and Fisher's exact tests; continuous outcomes were compared using ANOVA. RESULTS: 82, 83, and 52 women were identified in the HR + OFS, HRnoOFS, and TNBC groups respectively; mean follow-up was 5.0 years. Mean number of cardiovascular actions per year were highest in the HR + OFS group compared with HRnoOFS and TNBC groups (0.35 vs. 0.20 and 0.27, respectively; P = .036). The HR + OFS group had significantly more referrals and tests per year than the other groups. Cardiovascular medication initiation did not differ among groups. CONCLUSIONS: In this early follow-up period, there were meaningful numbers of cardiovascular actions, with women on NCED experiencing the most per year. Future work should seek to further understand the impact of anti-estrogen therapy on the cardiovascular health of premenopausal women and test strategies to mitigate cardiotoxicity.

Assessment of body composition in breast cancer patients: concordance between transverse computed tomography analysis at the fourth thoracic and third lumbar vertebrae.

Introduction: Specific body composition markers derived from L3 axial computed tomography (CT) images predict clinical cancer outcomes, including chemotherapy toxicity and survival. However, this method is only applicable to those undergoing lumbar (L3) CT scanning, which is not universally conducted in early breast cancer cases. This study aimed to evaluate CT analysis at T4 as a feasible alternative marker of body composition in breast cancer. Method: All patients participated in the Investigating Outcomes from Breast Cancer: Correlating Genetic, Immunological, and Nutritional (BeGIN) Predictors observational cohort study (REC reference number: 14/EE/1297). Staging chest-abdomen-pelvic CT scan images from 24 women diagnosed with early breast cancer at University Hospital Southampton were analysed. Adipose tissue, skeletal muscle, and muscle attenuation were measured from the transverse CT slices' cross-sectional area (CSA) at T4 and L3. Adipose tissue and skeletal muscle area measurements were adjusted for height. Spearman's rank correlation coefficient analysis was used to determine concordance between body composition measurements using CT analysis at L3 and T4 regions. Results: Derived estimates for total adipose tissue, subcutaneous adipose tissue, and intramuscular adipose tissue mass following adjustment for height were highly concordant when determined from CSAs of CT slices at T4 and L3 (Rs = 0.821, p < 0.001; Rs = 0.816, p < 0.001; and Rs = 0.830, p < 0.001). In this cohort, visceral adipose tissue (VAT) and skeletal muscle estimates following height adjustment were less concordant when measured by CT at T4 and L3 (Rs = 0.477, p = 0.039 and Rs = 0.578, p = 0.003). The assessment of muscle attenuation was also highly concordant when measured by CT at T4 and L3 (Rs = 0.840, p < 0.001). Discussion: These results suggest that the CT analysis at T4 and L3 provides highly concordant markers for total adipose, subcutaneous adipose, and intramuscular adipose estimation, but not VAT, in this breast cancer population. High concordance between T4 and L3 was also found when assessing skeletal muscle attenuation. Lower concordance was observed for the estimates of skeletal muscle area, potentially explained by differences in the quantity and proportions of axial and appendicular muscle between the thorax and abdomen. Future studies will determine the value of T4 metrics as predictive tools for clinical outcomes in breast cancer.

Protein mimetic 2D FAST rescues alpha synuclein aggregation mediated early and post disease Parkinson's phenotypes.

Abberent protein-protein interactions potentiate many diseases and one example is the toxic, self-assembly of α-Synuclein in the dopaminergic neurons of patients with Parkinson's disease; therefore, a potential therapeutic strategy is the small molecule modulation of α-Synuclein aggregation. In this work, we develop an Oligopyridylamide based 2-dimensional Fragment-Assisted Structure-based Technique to identify antagonists of α-Synuclein aggregation. The technique utilizes a fragment-based screening of an extensive array of non-proteinogenic side chains in Oligopyridylamides, leading to the identification of NS132 as an antagonist of the multiple facets of α-Synuclein aggregation. We further identify a more cell permeable analog (NS163) without sacrificing activity. Oligopyridylamides rescue α-Synuclein aggregation mediated Parkinson's disease phenotypes in dopaminergic neurons in early and post disease Caenorhabditis elegans models. We forsee tremendous potential in our technique to identify lead therapeutics for Parkinson's disease and other diseases as it is expandable to other oligoamide scaffolds and a larger array of side chains.

Quantifying the temperature dependence of glycine-betaine RNA duplex destabilization.

Glycine-betaine (GB) stabilizes folded protein structure because of its unfavorable thermodynamic interactions with amide oxygen and aliphatic carbon surface area exposed during protein unfolding. However, GB can attenuate nucleic acid secondary structure stability, although its mechanism of destabilization is not currently understood. Here we quantify GB interactions with the surface area exposed during thermal denaturation of nine RNA dodecamer duplexes with guanine-cytosine (GC) contents of 17-100%. Hyperchromicity values indicate increasing GB molality attenuates stacking. GB destabilizes higher-GC-content RNA duplexes to a greater extent than it does low-GC-content duplexes due to greater accumulation at the surface area exposed during unfolding. The accumulation is very sensitive to temperature and displays characteristic entropy-enthalpy compensation. Since the entropic contribution to the m-value (used to quantify GB interaction with the RNA solvent-accessible surface area exposed during denaturation) is more dependent on temperature than is the enthalpic contribution, higher-GC-content duplexes with their larger transition temperatures are destabilized to a greater extent than low-GC-content duplexes. The concentration of GB at the RNA surface area exposed during unfolding relative to bulk was quantified using the solute-partitioning model. Temperature correction predicts a GB concentration at 25 °C to be nearly independent of GC content, indicating that GB destabilizes all sequences equally at this temperature.