Citations

Background Patient sex and age may influence rates of death after receiving an implantable cardioverter‐defibrillator for primary prevention. Differences in outcomes other than mortality and whether these differences vary by heart failure symptoms, etiology, and left ventricular ejection fraction are not well characterized. Methods and Results We studied 2954 patients with left ventricular ejection fraction ≤0.35 undergoing first‐time implantable cardioverter‐defibrillator for primary prevention within the Cardiovascular Research Network; 769 patients (26%) were women, and 2827 (62%) were aged >65 years. In a median follow‐up of 2.4 years, outcome rates per 1000 patient‐years were 109 for death, 438 for hospitalization, and 111 for heart failure hospitalizations. Procedure‐related complications occurred in 8.36%. In multivariable models, women had significantly lower risks of death (hazard ratio 0.67, 95% CI 0.56 to 0.80) and heart failure hospitalization (hazard ratio 0.82, 95% CI 0.68 to 0.98) and higher risks for complications (hazard ratio 1.38, 95% CI 1.01 to 1.90) than men; patients aged >65 years had higher risks of death (hazard ratio 1.55, 95% CI 1.30 to 1.86) and heart failure hospitalization (hazard ratio 1.25, 95% CI 1.05 to 1.49) than younger patients. Age and sex differences were generally consistent in strata according to symptoms, etiology, and severity of left ventricular systolic dysfunction, except the higher risk of complications in women, which differed by New York Heart Association classification ( P =0.03 for sex–New York Heart Association interaction), and the risk of heart failure hospitalization in older patients, which differed by etiology of heart failure ( P =0.05 for age–etiology interaction). Conclusions The burden of adverse outcomes after receipt of an implantable cardioverter‐defibrillator for primary prevention is substantial and varies according to patient age and sex. These differences in outcome generally do not vary according to baseline heart failure characteristics.

Abstract Background: Microsatellite instability (MSI) and BRAF mutation status are associated with colorectal cancer survival, whereas the role of body mass index (BMI) is less clear. We evaluated the association between BMI and colorectal cancer survival, overall and by strata of MSI, BRAF mutation, sex, and other factors. Methods: This study included 5,615 men and women diagnosed with invasive colorectal cancer who were followed for mortality (maximum: 14.7 years; mean: 5.9 years). Prediagnosis BMI was derived from self-reported weight approximately one year before diagnosis and height. Tumor MSI and BRAF mutation status were available for 4,131 and 4,414 persons, respectively. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated from delayed-entry Cox proportional hazards models. Results: In multivariable models, high prediagnosis BMI was associated with higher risk of all-cause mortality in both sexes (per 5-kg/m2; HR, 1.10; 95% CI, 1.06–1.15), with similar associations stratified by sex (Pinteraction: 0.41), colon versus rectum (Pinteraction: 0.86), MSI status (Pinteraction: 0.84), and BRAF mutation status (Pinteraction: 0.28). In joint models, with MS-stable/MSI-low and normal BMI as the reference group, risk of death was higher for MS-stable/MSI-low and obese BMI (HR, 1.32; P value: 0.0002), not statistically significantly lower for MSI-high and normal BMI (HR, 0.86; P value: 0.29), and approximately the same for MSI-high and obese BMI (HR, 1.00; P value: 0.98). Conclusions: High prediagnosis BMI was associated with increased mortality; this association was consistent across participant subgroups, including strata of tumor molecular phenotype. Impact: High BMI may attenuate the survival benefit otherwise observed with MSI-high tumors. Cancer Epidemiol Biomarkers Prev; 24(8); 1229–38. ©2015 AACR.

A mouse model for ALS A G4C2 repeat expansion in C9ORF72 is known to be the major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). However, a lack of animal models recapitulating key disease features has hindered efforts to understand and prevent c9FTD/ALS-related neurodegeneration. Until now. Chew et al. describe a mouse model that mimics both neuropathological and clinical phenotypes of c9FTD/ALS. Science , this issue p. 1151

Abstract Background: Physical activity is associated with a lower incidence of colorectal cancer; however, the relationship of physical activity with colorectal cancer survival is not yet clear. We evaluated the association between prediagnostic physical activity and colorectal cancer survival, overall and accounting for tumor markers associated with colorectal cancer survival: BRAF and KRAS mutation status and microsatellite instability (MSI) status. Methods: Participants were 20- to 74-year-old colorectal cancer patients diagnosed between 1998 and 2007 from the population-based Seattle Colon Cancer Family Registry (S-CCFR). Self-reported physical activity in the years preceding colorectal cancer diagnosis was summarized as average metabolic equivalent task hours per week (MET-h/wk; n = 1,309). Somatic BRAF and KRAS mutations and MSI status were evaluated on a subset of patients (n = 1043). Cox regression was used to estimate HRs and 95% confidence intervals (CI) for overall and disease-specific survival after adjusting for relevant confounders. Stratified analyses were conducted across categories of BRAF, KRAS, and MSI, as well as tumor stage and site. Results: Higher prediagnostic recreational physical activity was associated with significantly more favorable overall survival (HR for highest vs. lowest category, 0.70; 95% CI, 0.52–0.96); associations were similar for colorectal cancer–specific survival. Results consistently indicated a favorable association with physical activity across strata defined by tumor characteristics. Conclusion: Individuals who were physically active before colorectal cancer diagnosis experienced better survival than those who were inactive or minimally active. Impact: Our results support existing physical activity recommendations for colorectal cancer patients and suggest that the beneficial effect of activity is not specific to a particular molecular phenotype of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1130–7. ©2015 AACR.

This quality improvement project demonstrates that RN Care Managers, in a chronic pain programme, can assess for a family history of substance abuse in 5–10 min. Information informs treatment based on specific high risk criteria. Benefits include heightened awareness of the genetic and environmental risks associated with a family history of substance abuse, an opportunity to participate in motivational interventions to prevent or minimize consequences of substance use disorders, and likely substantial overall health‐care cost savings.

Abstract Carney's triad (CTr) is a non-hereditary condition, primarily seen in young women, characterized by gastrointestinal stromal tumors (GIST), extra-adrenal paragangliomas and pulmonary chondromas. Most CTr patients present with GIST and pulmonary chondroma (incomplete CTr). A marked decrease in the enzymatic activity of succinate dehydrogenase (SDH) has been detected in these tumors, but the presence or absence of SDH mutations in CTr is controversial. A related disease, known as Carney-Stratakis Syndrome (CSS), has no female predisposition and presents with extra-adrenal paragangliomas and GIST tumors, without pulmonary chondromas. In distinction to CTr, CSS is hereditary due to germline SDH mutations in the enzyme's subunits (SDHA, SDHB, SDHC and SDHD) with corresponding decreased SDH activity in associated tumors. We have investigated 64 patients with CTr for germline mutations and/or deletions in the SDH subunit genes; four patients were found to have germline mutations in SDHB or SDHC. All four patients had multifocal gastric GIST and pulmonary chondromas at diagnosis; two subsequently developed paragangliomas, confirmed by biopsy. One of the patients with CTr and a SDHB mutation had a nephew with the same mutation and a neuroblastoma, confirming a previously reported association of neuroblastoma with gist (JMG 2009; 46:215, and AJMG 2010; 152A: 1531). We conclude that few CTr patients maybe more correctly classified as having CSS; the genetic distinction of CTr from CSS needs further study. [S.A.B. and P.X. should be regarded as joint first authors.] Citation Format: Sosipatros A. Boikos, Paraskevi Xekouki, Fabio R. Faucz, Karel Pacak, Margarita Raygada, Karen Adams, Evan Szarek, Evan Ball, Su Young Kim, Elena Fumagalli, Lee J. Helman, J Aidan Carney, Constantine A. Stratakis. Few Carney's Triad patients have mutations in two subunits of the succinate dehydrogenase enzyme (SDHB, SDHC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 568. doi:10.1158/1538-7445.AM2014-568

Abstract The three-dimensional (3D) structure of the cell and its nucleus is intricately associated with cellular function. Aberrations and heterogeneity in cellular and nuclear morphology serve as diagnostically important cues to identify malignant transformation. However, current cytopathology practice is predominantly based on a qualitative, 2D assessment of cellular morphology that may bias the diagnosis. We utilized the Cell-CT® platform to perform single-cell, optical tomography imaging and generate 3D cell images with isotropic, sub-micron spatial resolution. We developed custom image analysis tools to accurately quantify 3D cell and nuclear morphology. We used these measures to characterize the morphological heterogeneity within and among epithelial cell populations, and to identify morphological descriptors that are reliably predictive of cell state. We assessed the efficacy of our approach relative to conventional 2D assessment (at 40x magnification) to detect malignant transformation in immortalized and primary normal-cancer cell line pairs from human esophagus and breast epithelia. We observed the 3D method of assessment to provide a consistently superior performance (sensitivity and specificity) in predicting malignant transformation. Further, some widely used diagnostic parameters, such as nuclear size or nucleus-to-cytoplasm ratio, did not always exhibit the highest predictive power in 3D space. The availability of 3D morphological information also provided novel insights on intra-population morphological heterogeneity in both normal and cancer cell populations. Our results emphasize the need to incorporate 3D morphological information into standard pathological practice. Citation Format: Vivek Nandakumar, Stephanie Helland, Jessica H. Han, Geriann Davis, Brian A. Ashcroft, Thai H. Tran, Ting Li, Karen S. Anderson, Rahul Pannala, Joseph R. Mikhael, David E. Fleischer, Roger H. Johnson, Kimberly J. Bussey, Deirdre R. Meldrum. Quantifying three-dimensional cellular morphology and its heterogeneity in epithelial cancers by single-cell optical tomography. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4297. doi:10.1158/1538-7445.AM2014-4297

Abstract Treatment of glioblastoma multiforme (GBM) continues to be a challenge due to its infiltrative nature, tumor heterogeneity, and lack of therapeutic agents that penetrate the blood-brain barrier (BBB). While the primary tumor is permeable to some degree, the ability of GBM cells to invade areas of parenchyma with an intact BBB indicates development of BBB-penetrable compounds is a necessity. The multifunctional protein MDM2 holds promise as a therapeutic target in a variety of cancers and plays a critical role in controlling cell survival, invasion, and DNA repair. MDM2 antagonists such as nutlin3a and RG7112 are being used to interrogate the impact of modulating MDM2 function in combination with front-line therapy. Our objective was to investigate whether MDM2 antagonists, alone or in combination with temozolomide (TMZ), can augment cell death in orthotopic GBM xenograft models. In vitro data indicate that TMZ and nutlin3a are synergistic in decreasing cell viability in wild type (wt) p53 U87-MG, primary human wt p53 GBM10 and mutant (mt) p53 GBM43 cells. Pharmacodynamic studies demonstrated that the mechanism of action for promoting cell death following exposure to TMZ/nutlin3a was multifactorial. Comet assays indicated that repair of TMZ-mediated DNA damage was significantly delayed in wt and mt p53 GBM cells treated with TMZ/nutlin3a compared to TMZ alone and the base excision repair protein Ape1 was downregulated in cells treated with TMZ/nutlin3a. Pharmacokinetic studies guided development of rational dosing regimens in which 2-3 five-day cycles of TMZ followed by nutlin3a 4 hours later were investigated. In ectopic U87-MG xenografts, nutlin3a sensitized xenografts to TMZ-mediated cell death. Orthotopic studies employing U87-MG, GBM10, and GBM43 tumors are being utilized to determine if nutlin3a levels detectable in the brain via HPLC-MS/MS(API 4000) are sufficient to modulate MDM2 function in the context of TMZ and increase survival. In the TMZ-resistant GBM10 (wtp53, MGMTpos, and PTENnull) orthotopic model, there was a modest increase in median survival from 63 days with TMZ to 73 days with TMZ/nutlin3a. Higher and more sustained brain levels of MDM2 antagonists will likely be necessary to improve survival. The MDM2 antagonist RG7112 has an improved PK profile and structural analysis of RG7112 and nutlin3a via QikProp 3.0 (www.schrodinger.com) indicates that RG7112 also has an improved predicted brain/blood partition coefficient (plog BB) compared to nutlin3a (RG7112 = -0.17; nutlin3a = -0.415). Studies are in progress to assess the brain penetration of RG7112 and its effect on GBM growth in vivo. Taken together, our data suggest that modulation of MDM2 function in the context of cytotoxic therapy has the potential to alter mechanisms involved in DNA repair that can promote cell death and improve survival. Citation Format: Haiyan Wang, Shanbao Cai, Barbara J. Bailey, Lawrence M. Gelbert, M. Reza Saadatzadeh, Aaron A. Cohen-Gadol, Jann N. Sarkaria, Paul Territo, Taxiarchis M. Georgiadis, T. Zachary Gunter, Samy Meroueh, Eric C. Long, David R. Jones, Lindsey D. Mayo, Shannon Harlan, Karen E. Pollok. Sensitization of temozolomide-mediated glioblastoma cell death by targeting MDM2: Assessment of PD biomarkers, brain penetration, and efficacy in humanized orthotopic xenograft models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2741. doi:10.1158/1538-7445.AM2014-2741

Abstract Background: The development of novel chemotherapeutic agents has significantly improved the prognosis and survival of patients with breast cancer. ER positive or luminal tumors represent around two thirds of all breast cancers and these cancers are comprised of different histologies including differing gene expression and mutational profiles. This study examined biomarkers involved in immune evasion including PD-L1 and its association with other biological pathways as potential treatment options for luminal breast cancer patients. Methods: We analyzed 1311 breast samples using a multiplatform approach including whole genome mRNA expression (HumanHT-12 v4 BeadChip Illumina Inc., San Diego, CA), protein expression (immunohistochemistry), gene copy number changes (in situ hybridization) and gene sequencing and an additional 304 breast samples were tested for PD-1 and PD-L1 by IHC. The mRNA expression data was based on whole tumor and represents cell type heterogeneity. Heat map analysis was done to look at differential gene expression between the PD-L1 high vs low luminal breast cancers. Results: Based on expression of ER, PR and HER2 by IHC, we subdivided the data into sub- cohorts. Elevated mRNA expression of immune markers including PD-L1, CTLA4, B7H-3, and IDO1 was noted in the ER+HER2- luminal population including ER+ PR- and ER+PR+ cohort. Positive correlation was found between PD-L1 and other immune regulators including CTLA-4, B7-H3 and IDO1 (Spearman correlations of 0.49, 0.36 and 0.46). Protein expression of PD-L1 was found to be specific to the HER2 negative cohort with no expression in the HER2 positive cohort regardless of ER status. Within the ER+HER2- cohort, PD-L1 expression was 5% {ER+PR+ was 5% (4/81) and the ER+PR- was 6% (2/34)}. In contrast, PD-L1 expression was higher in the triple negative cohort, 17% (13/75). The expression of PD-1 on the other hand was present throughout the different cohorts. PD-1 expression ranged from 43% in the ER+HER2- cohort {41% (14/34) in ER+PR-HER2-; 43% (35/81) in ER+PR+HER2-} to 33% in the ER+HER2+ cohort {44% (4/9) in ER+PR-Her2+; and 17% (1/6) in ER+PR+HER2+}. In the ER-HER2+ cohort PD-L1 expression was 75%{6/8 in ER-PR-HER2+ and 0/0 in ER-PR+HER+} and 63%(47/75) in the triple negative cohort. Pathway analysis of the PD-L1 negative vs positive luminal population identified 127 genes involved in various cancer pathways including EGFR and VEGF signaling network (P=7.47e-09). Conclusions: The expression of immune regulatory targets in the breast cancer population suggests that immune- targeted therapies with anti PD-1/PD-L1, CTLA4, B7-H3 and IDO1 may be effective especially in the luminal cohort. Our study further shows that ER+HER2- breast cancer patients may be better candidates for immunotherapy with checkpoint inhibitors as compared to ER+HER2+ due to lack of PD-L1 expression in the HER2 positive cohort. Further validation of our findings is ongoing. Citation Format: Gargi D Basu, Anatole Ghazalpour, Randal Vader, Sandeep Reddy, Karen Anderson, Ann McCullough, Barbara Pockaj. Expression of novel immunotherapeutic targets in luminal breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-04-08.