Citations

Abstract Background LIV-1, a multispan transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells (Sussman 2014). It has been associated with lymph node involvement and linked with malignant progression to metastasis (Manning 1994). SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE). Upon binding to cell-surface LIV-1, SGN-LIV1A is internalized and releases MMAE, which binds to tubulin and induces G2/M arrest and apoptosis. Methods A phase 1, open-label, dose-escalation study is ongoing to evaluate the safety, tolerability, antitumor activity, pharmacokinetics (PK), and the maximum tolerated dose (MTD) of SGN-LIV1A monotherapy (q3 wks IV) in women with LIV-1-positive, metastatic breast cancer (MBC) (NCT01969643). Patients (pts) with either hormone receptor-positive/HER2-negative (HR+/HER2–) or triple-negative (TN) disease were eligible if they had measurable disease and received ≥2 prior cytotoxic regimens in the metastatic setting. Pts with ≥ Grade 2 neuropathy were excluded. Response was assessed per RECIST v1.1, and pts with stable disease (SD) or better were eligible to continue treatment until disease progression or intolerable toxicity. Fresh tumor biopsies were obtained pre- and post-treatment to evaluate the LIV-1 expression-response relationship, mechanism of action, and tumor sensitivity to SGN-LIV1A. Results To date, 21 pts (17 HR+/HER2–, 4 TN) have received a median of 3 cycles (range, 1–7) of SGN-LIV1A at doses of 0.5–2.8 mg/kg. Median age was 58 yrs (range, 34–73), and pts had a median of 8 prior systemic metastatic therapies (range, 2–15). At baseline, 19 pts had visceral disease and 15 had bone involvement. No dose-limiting toxicities (DLTs) in Cycle 1 were observed in the 18 DLT-evaluable pts; MTD has not yet been identified. Treatment-emergent adverse events (AEs) reported in ≥30% of pts were primarily Grade 1/2 in severity and were: nausea (57%), fatigue and peripheral neuropathy (43% each), alopecia (38%), and vomiting (33%). Two pts discontinued treatment due to AEs (1 nausea, 1 tachycardia). Preliminary PK data suggest a linear increase in antibody-drug conjugate (ADC) exposure with increasing dose. In the 19 efficacy-evaluable pts, the overall response rate (ORR) was 11% (2 partial responses [PRs]) with clinical benefit of SD or better achieved in 63% (2 PR, 10 SD) of pts. Of note, all 4 pts with TN MBC achieved clinical benefit: 2 PR and 2 SD. Currently, the median duration of clinical benefit is 12.7 wks (range, 6.1–26.3). Four pts remain on treatment. To date, of the 179 MBC tumor specimens evaluated for LIV-1, 156 (87%) were LIV-1-positive; moderate-to-high LIV-1 expression (H-score ≥100) was present in 91% (94 of 103) of HR+/HER2– and 81% (47 of 58) of TN samples. Conclusions LIV-1 is expressed in the majority of metastatic breast cancer tissue samples, with moderate-to-high expression in both HR+/HER2- and TN disease. To date, SGN-LIV1A monotherapy has been generally well tolerated and resulted in a clinical benefit of SD or better in 63% of these heavily pre-treated pts, including 2 PRs in the 4 TN MBC pts. Response duration data continue to evolve. Clinical subtype-specific expansion cohorts are planned. Citation Format: Forero A, Burris III H, Mita M, Specht J, Weise A, Liu MC, Modi S, Pusztai L, Kostic A, Yang J, Li M, Hengel S, Miller K. Interim analysis of a phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-05.

Abstract Background: Abnormalities of the PI3kinase/AKT/mTOR signaling network are common in BC. This pathway is associated with resistance to endocrine therapies among HR+ tumors. Everolimus, an mTOR-inhibitor, increases the biological activity of endocrine therapy. S1207 evaluates the role of everolimus in combination with endocrine therapy in the adjuvant setting. Methods: Specific aims/ design: Randomized phase III double-blinded, placebo-controlled trial. Primary objective is to assess whether the addition of everolimus to standard adjuvant endocrine therapy improves invasive disease-free survival (DFS) among patients with high risk, HR+ BC. Secondary objectives include overall survival, distant recurrence-free survival, safety, adherence and QoL. Patients are randomized to receive standard adjuvant endocrine therapy in combination with one year of everolimus (10 mg PO daily) or placebo. Submission of tissue specimens/blood samples is required for translational studies Eligibility criteria: Patients with histologically confirmed HER2-negative and HR+ invasive BC treated with surgery, adjuvant chemotherapy and radiation therapy (if indicated) are eligible if they have: node-negative disease and tumors >2cm and a recurrence score (RS) >25; 1-3 positive nodes and RS >25 or grade 3 in the absence of RS; >4 positive lymph nodes regardless of RS. Patients >1 positive lymph node after completing neoadjuvant chemotherapy are eligible. Statistics/Target accrual:Parallel randomization design with equal allocation to the two treatment groups, the study will randomize 3,500 patients. All analyses are intent-to-treat with the primary analysis conducted 3 years after the last patient is randomized. The study has 90% power (with 2-sided α=0.05) to detect an effective hazard ratio of 0.75 for everolimus versus placebo, corresponding to a gain in DFS of approximately 4.3% at 5 years. All patients will be followed for 10 years. Support: NIH/NCI NCTN Grants CA180888, 180819, 180868, 180821,180822 189867, and in part by Novartis Clinical trial information: NCT01674140. Citation Format: Chavez-MacGregor M, Barlow WE, Pusztai L, Goetz MP, Rastogi P, Ganz PA, Mamounas EP, Paik S, Bandos H, Gralow J, Lew DL, Hortobagyi GN. Phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy +/- one year of everolimus in patients with high-risk, hormone receptor (HR) positive and HER2-negative breast cancer (BC): SWOG/NRG/Alliance S1207 (NCT01674140). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-11.

Although short‐term risks of living donor hepatectomy have been well defined, little is known about the longterm impact. We aimed to perform a systematic follow‐up to screen for unanticipated health consequences of liver donation. All donors who were more than 1 year from donation were invited for a systematic evaluation including physical and laboratory assessment, quality of life questionnaire, and magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP). Those unable to return were offered the questionnaire and laboratory assessment at home. Out of our total of 97 donors, 45 returned for a full assessment and 23 completed labs and survey locally (total n = 68; 70%) after a median of 5.5 years (1.5‐10.9 years) after donation. The only laboratory abnormality was a significant decrease in platelet count (median 198 ×109/L versus 224 ×109/L before donation; P < 0.001), whereas 93% of patients were still above normal limits. No late biliary strictures or other structural abnormalities were found on MRI/MRCP. Liver regeneration was complete. Spleen volume did significantly increase (median 278 cm3 versus 230 cm3 before donation; P < 0.001) without resulting in lowered platelets (P = 0.73). The most common complaints were persistent incisional numbness and changed bowel habits. Seven donors (11%) reported problems obtaining insurance. The vast majority (97%) would have donated again. In conclusion, longterm outcome following liver donation appears satisfactory. None of our donors have developed occult biliary strictures, failure of regeneration, abnormal liver function, or other important health consequences after a median of 5.5 years from surgery. These findings can be used when counseling potential donors in the future. Liver Transplantation 22 934–942 2016 AASLD

Background: Early sport specialization is not a requirement for success at the highest levels of competition and is believed to be unhealthy physically and mentally for young athletes. It also discourages unstructured free play, which has many benefits. Purpose: To review the available evidence on early sports specialization and identify areas where scientific data are lacking. Study Design: Think tank, roundtable discussion. Results: The primary outcome of this think tank was that there is no evidence that young children will benefit from early sport specialization in the majority of sports. They are subject to overuse injury and burnout from concentrated activity. Early multisport participation will not deter young athletes from long-term competitive athletic success. Conclusion: Youth advocates, parents, clinicians, and coaches need to work together with the sport governing bodies to ensure healthy environments for play and competition that do not create long-term health issues yet support athletic competition at the highest level desired.

Background: Pediatric obesity is a significant public health problem with a prevalence of 16.9% among US children. School-based obesity interventions show promise for reducing adiposity in elementary age children. This pilot study evaluated the impact of the Let’s Go! 5-2-1-0 pediatric obesity intervention program in an elementary school setting. Methods: This was a cluster randomized controlled field trial comprising 8 classrooms of second- and third-grade children. The impact of implementation of a standardized 5-2-1-0 curriculum was evaluated in the classrooms by looking at health behavior (self-reported fruit and vegetable and sugar-containing beverage intake, and screen time), physical activity (steps measured by pedometer), and body mass index (BMI). Half of the classrooms were given 5-2-1-0 teaching over a 4-month period. Results: There was no statistical difference in improvement of healthy habits, BMI, or physical activity in the intervention group compared with the control group. Conclusions: The 5-2-1-0 intervention used in this study was feasible. There was no significant change in healthy habits, likely due to the small number of participants in the study. The intervention and control sites were in different classrooms and there could be factors such as teacher enthusiasm, socioeconomic factors, and individual traits affecting habits. Future studies could use pre- and post-intervention quizzes to assess healthy habits knowledge retention, involving the environments the child participates in outside of school, using research-grade pedometers or accelerometers for measuring activity data collection, and recruiting larger samples to ensure adequate statistical power.

Polymorphisms in mitochondrial DNA (mtDNA) are used to group individuals into haplogroups reflecting human global migration and are associated with multiple diseases, including cancer. Here, we evaluate the association between mtDNA haplogroup and risk of myelodysplastic syndromes (MDS). Cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota State driver's license/identification card list. Because haplogroup frequencies vary by race and ethnicity, we restricted analyses to non‐Hispanic whites. We genotyped 15 mtSNPs that capture common European mitochondrial haplogroup variation. We used SAS v.9.3 (SAS Institute, Cary, NC) to calculate odds ratios (OR) and 95% confidence intervals (CI) overall and stratified by MDS subtype and IPSS‐R risk category. We were able to classify 215 cases with confirmed MDS and 522 controls into one of the 11 common European haplogroups. Due to small sample sizes in some subgroups, we combined mt haplogroups into larger bins based on the haplogroup evolutionary tree, including HV (H + V), JT (J + T), IWX (I + W + X), UK (U + K), and Z for comparisons of cases and controls. Using haplogroup HV as the reference group, we found a statistically significant association between haplogroup JT and MDS (OR = 0.58, 95% CI 0.36, 0.92, P = 0.02). No statistically significant heterogeneity was observed in subgroup analyses. In this population‐based study of MDS, we observed an association between mtDNA haplogroup JT and risk of MDS. While previously published studies provide biological plausibility for the observed association, further studies of the relationship between mtDNA variation and MDS are warranted in larger sample sizes. © 2016 Wiley Periodicals, Inc.

Background Endothelial dysfunction is an early stage of atherosclerosis. Single‐nucleotide polymorphisms ( SNP s) have been associated with vascular dysfunction, cardiac events, and coronary artery remodeling. We aimed to detect SNP s associated with endothelial dysfunction and determine whether these associations are sex specific. Methods and Results Six hundred forty‐three subjects without significant obstructive coronary artery disease underwent invasive coronary endothelial function assessment. We collected data from 1536 SNP s that had previously been associated with vasoreactivity, angiogenesis, inflammation, artery calcification, atherosclerotic risk factors, insulin resistance, hormone levels, blood coagulability, or with coronary heart disease. Coronary vascular reactivity was assessed by the percent change in coronary artery diameter ≤ −20% after an intracoronary bolus injection of acetylcholine on invasive coronary physiology study. SNP s significantly associated with coronary epicardial endothelial dysfunction were ADORA 1 , KCNQ 1 , and DNAJC 4 in the whole cohort, LPA , MYBPH , ADORA 3 , and PON 1 in women and KIF 6 and NFKB 1 in men ( P <0.01). Conclusions We have identified several significant SNP s that are associated with an increased risk of coronary endothelial dysfunction. These associations appear to be sex specific and may explain gender‐related differences in development of atherosclerosis.

Cardiovascular disease continues to be the leading cause of death among women in the United States, accounting for ≈1 of every 3 female deaths. Sex-specific data focused on cardiovascular disease have been increasing steadily, yet is not routinely collected nor translated into practice. This comprehensive review focuses on novel and unique aspects of cardiovascular health in women and sex differences as they relate to clinical practice in the prevention, diagnosis, and treatment of cardiovascular disease. This review also provides current approaches to the evaluation and treatment of acute coronary syndromes that are more prevalent in women, including myocardial infarction associated with nonobstructive coronary arteries, spontaneous coronary artery dissection, and stress-induced cardiomyopathy (Takotsubo Syndrome). Other cardiovascular disease entities with higher prevalence or unique considerations in women, such as heart failure with preserved ejection fraction, peripheral arterial disease, and abdominal aortic aneurysms, are also briefly reviewed. Finally, recommendations for cardiac rehabilitation are addressed.

Posttraumatic stress disorder (PTSD) has symptoms that exist along a spectrum that includes depression and the 2 disorders may coexist. Collaborative care management (CCM) has been successfully used in outpatient mental health management (especially depression and anxiety) with favorable outcomes. Despite this, there exist limited data on clinical impact of a diagnosis of PTSD on depression outcomes in CCM. The present study used a retrospective cohort design to examine the association of PTSD with depression outcomes among 2121 adult patients involved in CCM in a primary care setting. Using standardized self-report measures, baseline depression scores and 6-month outcome scores were evaluated. Seventy-six patients had a diagnosis of PTSD documented in their electronic medical record. Patients with PTSD reported more severe depressive symptoms at baseline (Patient Health Questionnaire–9 score of 17.9 vs 15.4, P < .001) than those without PTSD. Controlling for sociodemographic and clinical characteristics, a clinical diagnosis of PTSD was associated with lower odds (AOR = 0.457, CI = 0.274-0.760, P = .003) of remission at 6 months and was also associated with higher odds (AOR = 3.112, CI = 1.921-5.041, P < .001) of persistent depressive symptoms at 6 months after CCM. When coexisting with depression, a diagnosis of PTSD was associated with worse depression outcomes, when managed with CCM in primary care. Opportunities still exist for more aggressive management of depression in these patients to help improve remission as well as reduce persistent depressive symptoms.