Citations

Background Physical activity data are collected automatically by implantable cardioverter‐defibrillators ( ICD s). Though these data potentially provide a quantifiable and easily accessible measure of functional status, its relationship with survival has not been well studied. Methods and Results Patients enrolled in the Boston Scientific LATITUDE remote monitoring system from 2008 to 2012 with ICD s were eligible. Remote monitoring data were used to calculate mean daily activity at baseline (30 to 60 days after implantation), and longitudinally. Cox regression was used to examine the association between survival and increments of 30 minutes/day in both (1) mean baseline activity and (2) time‐varying activity, with both adjusted for demographic and device characteristics. A total of 98 437 patients were followed for a median of 2.2 years (mean age of 67.7±13.1 years; 71.7% male). Mean baseline daily activity was 107.5±66.2 minutes/day. The proportion of patients surviving after 4 years was significantly higher among those in the most versus least active quintile of mean baseline activity (90.5% vs. 50.0%; log‐rank P value, <0.001). Lower mean baseline activity (i.e., incremental difference of 30‐minutes/day) was independently associated with a higher risk of death (adjusted hazard ratio [ AHR ], 1.44; 95% confidence interval [ CI ], 1.427 to 1.462). Time‐varying activity was similarly associated with a higher risk of death ( AHR , 1.48; 95% CI , 1.451 to 1.508), indicating that a patient having 30 minutes per day less activity in a given month has a 48% increased hazard for death when compared to a similar patient in the same month. Conclusions Patient activity measured by ICD s strongly correlates with survival following ICD implantation.

Abstract Background: The health benefits associated with maintaining adequate circulating levels of vitamin D are well known. More recently, data have emerged supporting an inverse association between vitamin D levels and risk of several human cancers. Related to this, African Americans (AAs) are at increased risk of hypovitaminosis D due to elevated levels of melanin in the skin that reduce the conversion of cholesterol to vitamin D3 (cholecalciferol). Herein, we simultaneously assess levels of awareness regarding the health benefits of vitamin D and the prevalence of hypovitaminosis D in a metropolitan African American community. Methods: From January 2012 through August 2013, we partnered with African American churches and community organizations in the metropolitan Jacksonville, FL area to provide nine education programs focused on vitamin D and the evidence linking poor vitamin D levels with increased risk of chronic disease, including cancer. Participants were offered free vitamin D testing to estimate the prevalence of vitamin D insufficiency (&lt;25 ng/mL) and deficiency (&lt; 15 ng/mL) in this population. Moreover, participants also completed surveys prior to the events to assess their awareness of issues related to vitamin D, including the emerging link with cancer risk. Results: Out of 305 attendees, 285 agreed to provide blood samples for vitamin D screening. Of these, 262 (92%) self-identified as African American (75% female, 25% male). The median age of the AA participants was 59 years. Laboratory testing for 25(OH) vit D revealed 43% of the AA participants had normal levels of vitamin D (&gt;25 ng/mL), 35% had insufficient levels (15-24 ng/mL) and 22% had deficient levels (&lt; 15 ng/mL). Of interest, despite the high level of hypovitaminosis D (insufficient + deficient) in this population, participants reported high levels of awareness regarding vitamin D prior to the education program. For example, 82% of AA respondents correctly answered that the main source of vitamin D came from sunlight and 76% correctly answered that AAs are at risk of lower levels of vitamin D because of the amount of melanin in the skin. Moreover, 83% of AA respondents answered that maintaining proper vitamin D levels could potentially decrease risk for various chronic health conditions, including certain cancers. Finally, 75% of the AA participants reported never having had a vitamin D test discussed with them by their doctor. Conclusions: We report a high prevalence of hypovitaminosis D in a large AA community in Jacksonville, FL. Moreover, we report that despite this high prevalence, awareness of the health benefits of vitamin D are high, yet regular vitamin D testing levels appear to be very low. These data provide the foundation for developing targeted interventions to raise vitamin D levels in this community. Citation Format: Alexander Parker, Monica Albertie, Nancy Diehl, Matthew Drake. Evaluation of the prevalence of hypovitaminosis D and vitamin D awareness in African Americans living in a metropolitan southern community. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B61. doi:10.1158/1538-7755.DISP13-B61

AbstractThe population pharmacokinetic model reported here was developed using data from 2 phase 2 trials of irinotecan for treatment of malignant glioma to quantify the impact of concomitant therapy with enzyme‐inducing antiepileptic drugs (EIAEDs) on irinotecan pharmacokinetics. Patients received weekly irinotecan doses of 100 to 400 mg/m2, and plasma samples were collected and analyzed for irinotecan and its APC, SN‐38, and SN‐38G metabolites. Nonlinear mixed‐effects modeling was employed for population pharmacokinetic analysis. Concomitant therapy with phenytoin, phenobarbital, or carbamazepine increased the clearances of irinotecan, SN‐38, and SN‐38G but not APC. SN‐38 clearance was 2‐fold higher with concomitant EIAED use, resulting in 40% lower SN‐38 exposure. Evaluation of additional covariates revealed no clinically relevant effects of sex or concomitant corticosteroid use. The population pharmacokinetic model suggests that a 1.7‐fold increase in irinotecan dose may compensate for decreases in SN‐38 exposure in the presence of concomitant EIAEDs. Although slightly more conservative, this dose adjustment is consistent with those recommended based on increases in the maximally tolerated dose for malignant glioma patients receiving EIAEDs and may be an appropriate starting point for further investigation when extrapolating to other cancer types or alternative regimens.

Objectives/HypothesisInverting papillomas (IPs) are benign locally invasive tumors that most commonly present within the sinonasal cavity. Temporal bone involvement is exceedingly rare, with fewer than 30 cases reported within the English literature to date.Study DesignCase series and systematic review of the literature.MethodsFour consecutive subjects with temporal bone inverting papilloma (TBIP) were treated, and an additional 28 previously published cases were identified in the literature. Main outcome measures were disease presentation, diagnostic evaluation, management strategy, and outcome.ResultsA total of 32 cases were analyzed. The median age at diagnosis was 54 years (mean 54.1; range 19–81 years). Nineteen (59%) patients had synchronous or metachronous sinonasal IP, whereas 13 (41%) had isolated temporal bone disease without sinus involvement. Over half of the patients undergoing microsurgical resection experienced at least one recurrence. Compared to patients with a history of sinus IP, subjects with primary TBIP were younger at time of presentation (44 vs. 58 years; P = 0.012); were more commonly female (62% vs. 32%; P = 0.15); and were less likely to have intracranial spread (8% vs. 26%; P = 0.36), cranial neuropathy (8% vs. 26%; P = 0.36), human papillomavirus positivity (11% vs. 57%; P = 0.11), or associated carcinoma (0% vs. 47%; P = 0.004).ConclusionsInverting papilloma of the lateral skull base is rare and can pose a significant therapeutic challenge. Primary lesions of the temporal bone appear to follow a less aggressive clinical course when compared to those arising in association with sinonasal disease. Gross total resection is the preferred method of treatment, when feasible, given the high rate of recurrence with subtotal resection and risk of associated malignancy.Level of Evidence4. Laryngoscope, 125:2576–2583, 2015

Abstract Purpose: Mammographic breast density is an established and strong risk factor for breast cancer. Recently, a number of common genetic susceptibility loci have been identified as risk factors for breast cancer. We present the first report on the relative contribution of 76 validated breast cancer susceptibility loci, in the context of a polygenic risk score (PRS), to the breast density and breast cancer association. We also examine whether the PRS improves prediction of the Breast Cancer Surveillance Consortium (BCSC) 5-year risk model above and beyond breast density and clinical factors included in the model. Methods: The study population included 1643 cases and 2397 controls from three independent epidemiologic studies: the Mayo Mammography Health Study (MMHS), the Mayo Clinic Breast Cancer Study (MCBCS), and the Bavarian Breast Cancer Cases and Control Study (BBCC). Data collected on patients in each of the studies included clinical risk factor, BI-RADS breast density [a) almost entirely fat; b) scattered fibroglandular densities; c) heterogeneously dense; and d) extremely dense] and genotypes for the 76 breast cancer susceptibility loci known at the time of the study. We formed a PRS from the reported per-SNP odds ratios (OR) for 76 known breast cancer susceptibility loci, and evaluated whether BI-RADS density and the PRS were independent risk factors for breast cancer, when adjusted for age, 1/BMI and study. We also incorporated the PRS (OR) into the BCSC 5-year risk model and estimated 5-year risk for the MMHS nested case-control study of 339 invasive cases, 765 controls. Results: BI-RADS density (p&lt;0.0001) and PRS (p&lt;0.0001) were independent risk factors for breast cancer that together showed greater discrimination of risk (AUC=0.69) than density (AUC=0.66; ΔAUC=0.029) or PRS score alone (AUC=0.68; ΔAUC=0.013; p&lt;0.001). Relative to those with scattered fibroglandular densities and average (2nd quartile) PRS, women with extremely dense breasts and in the highest PRS quartile, had a 2.7 fold (95%CI: 1.7-4.1) increased risk of breast cancer, while those with fatty breasts and in the lowest PRS quartile had a reduced risk (OR=0.30, 95%CI: 0.18-0.51). Incorporation of the PRS into the BCSC risk model improved discrimination (ΔAUC=0.031, p=0.001), for a net reclassification improvement of 20% (95%CI: 11%-28%), split equally among cases (9%) and controls (11%). Conclusion: BI-RADS density and the PRS are both important risk factors for breast cancer that can be included in breast cancer risk models to improve prediction of this disease. Using these models to identify high and low-risk risk groups will facilitate improved tailored screening and primary prevention interventions. Citation Format: Celine M. Vachon, V. Shane Pankratz, Christopher G. Scott, Lothar Haeberle, Elad Ziv, Matthew R. Jensen, Kathleen R. Brandt, Dana H. Whaley, Janet E. Olson, Katharina Heusinger, Carolin C. Hack, Sebastian M. Jud, Matthias W. Beckmann, Jeffrey A. Tice, Kristen S. Purrington, Thomas A. Sellers, Karla Kerlikowske, Peter A. Fasching, Fergus J. Couch. The contribution of common breast cancer susceptibility loci to the breast density and breast cancer association and the Breast Cancer Surveillance Consortium (BCSC) risk model. [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 940. doi:10.1158/1538-7445.AM2014-940

Abstract Introduction: Triple negative breast cancers (TNBC) are characterized as lacking estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression and TNBC patients have higher rates of recurrence and death compared with other breast cancer subtypes. For TNBC patients who fail standard chemotherapy, there are a lack of novel drug therapies, given the absence of well-defined molecular targets. Recently, a microarray meta-analysis identified 7 triple negative subtypes, including the validation of the luminal androgen receptor (LAR) positive subtype [Lehmann, 2011]. However, microarray technology is dependent on probe-target specificity and the 7 subtypes have yet to be validated using RNA sequencing data, and the presences of recurrent genomic alterations in the 7 subtypes are unknown. METHODS: We obtained 1106 breast cancer RNA-Seq bam files from The Cancer Genome Atlas (TCGA) and aligned with Tophat v1.3. The PAM50 intrinsic gene signature was used to extract a cohort of 128 TNBC samples. Consensus clustering of genes, greater than 75th percentile of variance, was performed using Kmeans clustering in Spearman's correlation space. A nearest centroid prediction model was developed from genes differentially expressed among the clusters. Eighty independent TNBC RNA sequencing samples were obtained (British Colombia; BC) [Shah, 2012] which were calibrated to our TNBC conditional quantile normalized cohort and sub-typed by our model. RESULTS: Using RNA-Seq gene expression count data, we identified 5 clusters, all of which were stable, including the LAR cluster. Signaling pathway impact analysis (SPIA) implicated cytokine-cytokine receptor interaction, leukocyte transendothelial migration, and regulation of actin cytoskeleton pathways commonly altered in the non-LAR TNBC subtypes. In contrast, cell cycle, ECM-receptor interaction, endocrine regulated calcium reabsorption, and insulin signaling pathways were altered in the LAR versus non-LAR subtypes. Neuroactive ligand-receptor interactions were observed to be altered commonly between all sub-types. We then applied our model to the Shah, et al cohort. In this cohort, the LAR subtype was consistent with Shah's classification of ‘other’ TNBC and contained no basal samples by PAM50 intrinsic modeling. Analysis of sub-type specific mutation data from the BC cohort demonstrates an increased mutational load in ECM-related proteins, particularly the myosins, along with increased TP53 clonality in the non-LAR subtypes. CONCLUSIONS: Using TCGA RNASeq data, we have confirmed the presence of 5 major TNBC subtypes, including the LAR; which was negligible in basal composition by PAM50 intrinsic modeling. SPIA pathway analysis indicates a core set of pathways demonstrating altered expression across the TNBC sub-types and the identification of molecular targets within each subtype is ongoing. Citation Format: Kevin J. Thompson, Xiaojia Tang, Zhifu Sun, Jason P. Sinnwell, Hugues Sicotte, Douglas W. Mahoney, Steven Hart, Peter T. Vedell, Poulami Barman, Jeanette E. Eckel Passow, Eric D. Wieben, James N. Ingle, Judy C. Boughey, Liewei Wang, Richard Weinshilboum, Krishna R. Kalari, Matthew P. Goetz. Molecular classification of triple negative breast cancer via RNA-sequencing data. [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 5592. doi:10.1158/1538-7445.AM2014-5592

Abstract INTRODUCTION Next generation sequencing (NGS) of patients has significantly changed our ways to study cancer genomics as it provides precise estimates of gene expression, fusion transcripts, expressed single nucleotide variants (eSNVs), splice variants and copy number variants. The Breast Cancer Genome Guided Therapy (BEAUTY) is an ongoing clinical study in which RNA sequencing (RNAseq) and whole exome sequencing (WES) are performed prior to, during and after neoadjuvant chemotherapy. Here we report the use of these sequencing technologies to investigate gene expression levels and mutational profiles in a triple negative breast cancer (TNBC) patient enrolled in BEAUTY whose disease did not respond to neoadjuvant paclitaxel and anthracycline/cycphosphamide. METHODS Computational approaches were used to integrate WES and RNAseq data obtained before therapy (V1T), after 12 weekly paclitaxel treatments (V2T) and after anthracycline-based regimen at surgical resection (V3T) to study a single patient with persistent TNBC disease after neoadjuvant chemotherapy. RESULTS Using RNA-Seq data, we identified an inter-chromosomal fusion transcript between chromosome 20 and 22 (GNAS-TTC38) that was highly expressed at V1T, V2T and V3T. We also identified intra-chromosomal fusion transcripts that were expressed at two time points, such as fusion transcript (KANSL1-ARL17A) on chromosome 17 for V1T and V2T and fusion transcript (RBM12B-LINC00535) on chromosome 8 for V2T and V3T time points. Several gene expression changes were also observed. Gene expression analysis of V1T, V2T and V3T tumors was performed. Differential temporal gene expression profiles of 9884 genes that were significant and varying at different time points were obtained for pathway analysis. Pathway analysis of 9884 genes identified up regulation and down regulation of several transcription factors with a fold change of 2x or more. When compared to blood, DNA tumor and RNA-Seq data, we identified 81 common somatic eSNVs that were expressed in both V1T and V2T time points and we are in the process of investigating V3T data. We found alterations of key transporter domains (CD225, Coatamer_beta_C, DUF2435, Dynamitin, EI24, GLTP, LMF1, Porin_3, V-ATPase_C) in our V1T and V2T SNV data. Similar to gene expression analysis, we are in the process of obtaining the list of mutations at various time points to identify driver and passenger mutation candidate genes for this specific TNBC patient. CONCLUSIONS Our initial time-series analysis of eSNV, fusion transcripts and gene expression data demonstrate that intensive analysis for individual patients is feasible. Further investigation of drug transporters and transcription regulators may help develop personalized treatment strategies for patients with disease resistant to current regimens. Citation Format: Krishna R. Kalari, Xiaojia Tang, Kevin J. Thompson, Douglas W. Mahoney, Poulami Barman, Jason P. Sinnwell, Hugues Sicotte, Peter Vedell, Steven N. Hart, Travis J. Dockter, Katie N. Jones, Amy L. Conners, Ann M. Moyer, Daniel W. Visscher, Jia Yu, Bowen Gao, Sarah A. McLaughlin, John A. Copland, Alvaro Moreno-Aspitia, Donald W. Northfelt, Richard J. Gray, Vera J. Suman, Jeanette E. Eckel Passow, Jean-Pierre A. Kocher, Eric D. Wieben, Gianrico Farrugia, Cloann G. Schultz, James N. Ingle, Richard Weinshilboum, Matthew P. Goetz, Liewei Wang, Judy C. Boughey. Analysis of sequencing data to identify potential drug targets for an individual newly diagnosed with basal breast cancer who failed to respond to current standard neoadjuvant chemotherapy. [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 4185. doi:10.1158/1538-7445.AM2014-4185