Cardiotoxicity screening of long-term, breast cancer survivors-The CAROLE (Cardiac-Related Oncologic Late Effects) Study.

BACKGROUND: Long-term breast cancer survivors are at risk for cardiotoxicity after treatment, but there is insufficient evidence to provide long-term (~10 years) cardiovascular disease (CVD) screening recommendations. We sought to evaluate a tri-modality CVD screening approach. METHODS: This single-arm, feasibility study enrolled 201 breast cancer patients treated ≥6 years prior without CVD at diagnosis. Patients were sub-grouped: cardiotoxic (left-sided) radiation (RT), cardiotoxic (anthracycline-based) chemotherapy, both cardiotoxic chemotherapy and RT, and neither cardiotoxic treatment. Patients underwent electrocardiogram (EKG), transthoracic echocardiogram with strain (TTE with GLS), and coronary artery calcium computed tomography (CAC CT). The primary endpoint was preclinical or clinical CVD. RESULTS: Median age was 50 (29-65) at diagnosis and 63 (37-77) at imaging; median interval was 11.5 years (6.7-14.5). Among sub-groups, 44% had no cardiotoxic treatment, 31.5% had cardiotoxic RT, 16% had cardiotoxic chemotherapy, and 8.5% had both. Overall, 77.6% showed preclinical and/or clinical CVD and 51.5% showed clinical CVD. Per modality, rates of any CVD and clinical CVD were, respectively: 27.1%/10.0% on EKG, 50.0%/25.3% on TTE with GLS, and 50.8%/45.8% on CAC CT. No statistical difference was seen among the treatment subgroups (NS, χ2 test, p = 0.58/p = 0.15). CONCLUSION: This study identified a high incidence of CVD in heterogenous long-term breast cancer survivors, most >10 years post-treatment. Over half had clinical CVD findings warranting follow-up and/or intervention. Each imaging test independently contributed to the detection rate. This provides early evidence that long-term cardiac screening may be of value to a wider group of breast cancer survivors than previously recognized.

Emergency Medical Services Providers' Knowledge, Practices, And Barriers To Stroke Management.

PURPOSE: Many strokes are not recognized by emergency medical services (EMS) providers and many providers do not prenotify emergency departments (EDs) of incoming stroke patients. The objectives of this project were to survey EMS providers to (1) assess knowledge of prehospital care related to stroke identification, time window for intravenous tissue plasminogen activator (IV tPA) administration, and comprehensive stroke centers in our health system, (2) gain insight from EMS providers regarding barriers to providing prenotification, information they provide for a prenotification, and optimal methods of providing feedback, and (3) provide EMS providers with stroke care and management information. METHODS: A survey was administered to EMS providers at four hospital EDs. The survey included questions related to knowledge of prehospital stroke care and barriers to providing prenotification. EMS providers were also provided a one-page flyer with information related to prehospital stroke care. Descriptive statistics were used to describe results. RESULTS: Of 301 EMS providers surveyed, 96.0% report that they use the Cincinnati Prehospital Stroke Scale to identify stroke, and 11.0% correctly identified the time window for IV tPA administration for acute ischemic stroke as within 4.5 hrs from the last known well time. The majority (82.7%) correctly identified the comprehensive stroke center in our health system. Barriers to providing prenotification included short transport time (40.5%), information being lost in dispatch (39.5%), and not having direct communication with ED staff (30.2%). Most reported wanting to receive feedback on the stroke patients they transported (93.7%), and 49.5% reported that the optimal method of providing feedback is via a mobile application. CONCLUSION: Deficits in stroke care knowledge among EMS providers were identified. Short transport time, inability to communicate with ED staff, and information lost in dispatch were cited as barriers to providing prenotification. Most EMS providers desire real-time feedback regarding patients via a mobile application.

BPTF Maintains Chromatin Accessibility and the Self-Renewal Capacity of Mammary Gland Stem Cells.

Chromatin remodeling is a key requirement for transcriptional control of cellular differentiation. However, the factors that alter chromatin architecture in mammary stem cells (MaSCs) are poorly understood. Here, we show that BPTF, the largest subunit of the NURF chromatin remodeling complex, is essential for MaSC self-renewal and differentiation of mammary epithelial cells (MECs). BPTF depletion arrests cells at a previously undefined stage of epithelial differentiation that is associated with an incapacity to achieve the luminal cell fate. Moreover, genome-wide analysis of DNA accessibility following genetic or chemical inhibition, suggests a role for BPTF in maintaining the open chromatin landscape at enhancers regions in MECs. Collectively, our study implicates BPTF in maintaining the unique epigenetic state of MaSCs.

BO-1055, a novel DNA cross-linking agent with remarkable low myelotoxicity shows potent activity in sarcoma models.

DNA damaging agents cause rapid shrinkage of tumors and form the basis of chemotherapy for sarcomas despite significant toxicities. Drugs having superior efficacy and wider therapeutic windows are needed to improve patient outcomes. We used cell proliferation and apoptosis assays in sarcoma cell lines and benign cells; γ-H2AX expression, comet assay, immunoblot analyses and drug combination studies in vitro and in patient derived xenograft (PDX) models. BO-1055 caused apoptosis and cell death in a concentration and time dependent manner in sarcoma cell lines. BO-1055 had potent activity (submicromolar IC50) against Ewing sarcoma and rhabdomyosarcoma, intermediate activity in DSRCT (IC50 = 2-3µM) and very weak activity in osteosarcoma (IC50 >10µM) cell lines. BO-1055 exhibited a wide therapeutic window compared to other DNA damaging drugs. BO-1055 induced more DNA double strand breaks and γH2AX expression in cancer cells compared to benign cells. BO-1055 showed inhibition of tumor growth in A673 xenografts and caused tumor regression in cyclophosphamide resistant patient-derived Ewing sarcoma xenografts and A204 xenografts. Combination of BO-1055 and irinotecan demonstrated synergism in Ewing sarcoma PDX models. Potent activity on sarcoma cells and its relative lack of toxicity presents a strong rationale for further development of BO-1055 as a therapeutic agent.