Citations

Direct Pulmonary Vein Ablation With Stenosis Prevention TherapyIntroductionThe dominant location of electrical triggers for initiating atrial fibrillation (AF) originates from the muscle sleeves inside pulmonary veins (PVs). Currently, radiofrequency ablation (RFA) is performed outside of the PVs to isolate, rather than directly ablate these tissues, due to the risk of intraluminal PV stenosis.MethodsIn 4 chronic canine experiments, we performed direct PV muscle sleeve RFA ± postablation drug‐coated balloon (DCB) treatment with paclitaxel/everolimus. Of the 4 PVs, 2 PVs were ablated and treated with DCB, 1 PV was ablated without DCB treatment (positive control), and 1 PV was left as a negative control. Local electrograms were assessed in PVs for near‐field signals and were targeted for ablation. After 12–14 weeks survival, PVs were interrogated for absence of near‐field PV potentials, and each PV was assessed for stenosis.ResultsAll canines survived the study period without cardiorespiratory complications, and remained ambulatory. In all canines, PVs that were ablated and treated with DCB remained without any significant intraluminal stenosis. In contrast, PVs that were ablated and not treated with DCB showed near or complete intraluminal stenosis. At terminal study, PV potentials remained undetectable. A blinded, histologic analysis demonstrated that ablated PVs without DCB treatment had extensive thrombus, fibrin, mineralization, and elastin disruption.ConclusionOur chronic canine data suggest that direct PV tissue ablation without subsequent stenosis is feasible with the use of postablation DCBs.

AbstractBackgroundStudies reveal that ileal pouch‐anal anastomosis (IPAA) has long‐term success. These reports, however, use well‐selected cohorts and exclude patients presenting with fulminant colitis (FC). Herein, we aimed to characterize long‐term functional outcomes in patients with fulminant ulcerative colitis (UC) undergoing IPAA.MethodsA prospective database identified patients who underwent IPAA between 1998 and 2008. Patients with FC and chronic UC were matched by age, gender, date of surgery, and follow‐up duration. Clinical and laboratory parameters, immunomodulator use at the time of surgery, and functional outcomes were compared.ResultsForty patients with FC and 73 patients with chronic UC were identified. Preoperative albumin, hemoglobin, leukocyte count, and steroid dose were significantly different for those with FC. Average survey follow‐up was 5.2 years for FC and 6.7 years for chronic UC patients. Functional outcomes were not significantly different. The 3‐year fistula‐free rate was 91.4 versus 98.6 % and the 3‐year stricture‐free rate was 79.3 versus 87.2 % for FC versus chronic UC patients, respectively.ConclusionPatients undergoing colectomy for FC secondary to UC have similar long‐term functional outcomes after IPAA despite significantly worse presentation. This study confirms that IPAA is an appropriate and durable treatment for patients with FC.

Summary Objective Patients with suspected mesial temporal lobe ( MTL ) epilepsy typically undergo inpatient video–electroencephalography ( EEG ) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography ( EC oG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory EC oG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions. Methods Ambulatory EC oG was reviewed in patients with suspected bilateral MTL epilepsy who were among a larger cohort with intractable epilepsy participating in a randomized controlled trial of responsive neurostimulation. Subjects were implanted with bilateral MTL leads and a cranially implanted neurostimulator programmed to detect abnormal interictal and ictal EC oG activity. EC oG data stored by the neurostimulator were reviewed to determine the lateralization of electrographic seizures and the interval of time until independent bilateral MTL electrographic seizures were recorded. Results Eighty‐two subjects were implanted with bilateral MTL leads and followed for 4.7 years on average (median 4.9 years). Independent bilateral MTL electrographic seizures were recorded in 84%. The average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13 days, range 0–376 days). Sixteen percent had only unilateral electrographic seizures after an average of 4.6 years of recording. Significance About one third of the subjects implanted with bilateral MTL electrodes required >1 month of chronic ambulatory EC oG before the first contralateral MTL electrographic seizure was recorded. Some patients with suspected bilateral MTL seizures had only unilateral electrographic seizures. Chronic ambulatory EC oG in patients with suspected bilateral MTL seizures provides data in a naturalistic setting, may complement data from inpatient video‐ EEG monitoring, and can contribute to treatment decisions.

Abstract Background: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and colorectal cancer. Methods: We used data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study–identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis. Results: Individuals carrying greater numbers of BMI-increasing alleles had higher colorectal cancer risk [per weighted allele OR, 1.31; 95% confidence interval (CI), 1.10–1.57]. Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for colorectal cancer (IV-OR per 5 kg/m2, 1.50; 95% CI, 1.13–2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of colorectal cancer among women (IV-OR per 5 kg/m2, 1.82; 95% CI, 1.26–2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m2, 1.18; 95% CI, 0.73–1.92). Conclusions: High BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation. Impact: Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1024–31. ©2015 AACR.

Abstract It is widely appreciated that early detection is the key to making inroads in the fight against cancers. Despite the availability of endoscopic screening, compliance is poor. The diagnosis of CRC is often made in advanced stages, and the consequence is a dismal 50% five year survival across all CRC. There is urgent need for biomarkers with performance that can meet the need of early diagnosis. Like most cancers, colorectal cancers (CRCs) express tumor antigens that can induce humoral immune response. The identification of the autoantibodies against tumor antigens may facilitate early diagnosis of CRC. The goal for this pilot project was to demonstrate the feasibility of discovering autoantibody biomarkers for colorectal cancer using Nucleic Acid Programmable Protein Arrays (NAPPA). Autoantibodies in serum samples collected from 40 patients with DNA mismatch repair proficient colorectal cancer who had died of their cancer within 18 months of their blood draw and from 40 age-gender matched healthy controls were profiled on NAPPA arrays with randomly selected 2000 human protein. The fact that p53, a tumor antigen that has been previously reported to be related to various cancers including CRC, was one of the top candidates based on the statistical analysis demonstrates the validity of our discovery platform. Besides p53, thirty-one candidate antigens were identified to have sensitivity greater than or equal to 25% at 95% specificity and fifty-one candidate antigens had an area under the ROC curve (AUC) equal to or greater than 0.6. Validation of the combined 83 unique genes selected based on these two different data analysis methods in an independent sample set in a blind fashion is on-going. This pilot study using late stage cancer samples demonstrates the feasibility and power of an immunoproteomics study using protein arrays. This approach may rapidly lead to identification of markers that could have relevance in monitoring disease progression as well as in early cancer detection. Citation Format: Gokhan Demirkan, Leah Soderberg, Garrick Wallstrom, Emily Szeto, Kristi Barker, Jie Wang, Joshua LaBaer, Noralane M. Lindor, Ji Qiu. Proteome scale identification of autoantibody biomarkers in colorectal cancer. [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 887. doi:10.1158/1538-7445.AM2014-887

Abstract Background Previous literature regarding the association between occupational exposure to agricultural pesticides and non-Hodgkin lymphoma (NHL) risk has been inconsistent, particularly when looking at specific lymphoma subtypes. Most recently, a large European case-control study showed an elevated risk of chronic lymphocytic leukemia (CLL) among those ever exposed to inorganic and organic pesticides with the strongest association among those exposed to organophosphates. However, when restricting the analysis to subjects with high confidence of exposure, these associations were attenuated (Cocco P., 2013). We used case-control data from the Mayo Clinic to evaluate whether there is an increased risk of CLL among individuals with known occupational exposure to agricultural pesticides. Methods We evaluated pesticide exposure and CLL risk in a clinic-based study of newly diagnosed CLL cases and frequency-matched controls enrolled at the Mayo Clinic from 2002-2012. 200 CLL cases and 474 controls returned a detailed farming and pesticide exposure questionnaire that was modeled after the Agricultural Health Study, where exposure was based on pesticide-specific application. Unconditional logistic regression, adjusted for age and sex, was used to estimate odds ratios (ORs) and 95% confidence intervals (CI). We evaluated the effect of each pesticide individually, by chemical class of pesticides, and by an aggregate of multiple pesticide exposure on CLL risk. Results Among those participants with detailed farming data, the mean age of CLL diagnosis was 66 years and 76% were male; for controls, the mean age at enrollment was 65 years and 66% were male. Risk of CLL was mildly elevated, but not significant, amongst those with application of any pesticide (OR 1.39; 95% C.I. 0.92-2.10). When broken down by chemical class, risk of CLL was also mildly elevated, but not significant, for application of organophosphates and carbamates (OR 1.21; 95% CI 0.84-1.73; OR 1.21; 95% 0.85-1.73, respectively). Organochlorines, phenoxy compounds, pyrethriods and triazines showed no evidence of an elevated risk, nor did we see evidence of a trend that CLL risk increases with number of pesticides applied. Discussion Our preliminary results provide inconclusive support for the role of pesticide exposure as a possible risk factor for CLL. However our sample size was small. Additional data will be incorporated, including confidence of exposure measures, as well as other modifying factors, to further evaluate these results. Citation Format: Emily J. Hallberg, Sara J. Achenbach, Kari G. Rabe, Timothy G. Call, Cristine Allmer, Tait D. Shanafelt, Mark Liebow, Neil E. Kay, James R. Cerhan, Susan L. Slager. Occupational exposure to agricultural pesticides and CLL risk. [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 274. doi:10.1158/1538-7445.AM2014-274

Abstract The Ten-eleven translocation (TET) family of dioxygenases hydroxylate 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. 5mC provides important epigenetic instructions during development, and its aberrant control is a major contributor to cellular transformation; however TET functions in regulating the epigenome, particularly in cancer, remain largely unknown. We targeted TET1, TET2, and TET3 for siRNA-mediated depletion in pluripotent human embryonic carcinoma cells and examined the impact on 5mC and 5hmC genome-wide localization. TET1, TET2, and TET3 co-regulate 5hmC at many sites, and depletion of only one of the TETs is sufficient to reduce 5hmC at these co-regulated sites, suggesting a functional co-dependence for TETs. Depletion of TET1 and TET2 had the greatest impact on 5hmC levels at high and low CpG density promoters, respectively, indicating that TETs exhibit DNA sequence-based functional specificity. All TETs prevent hypermethylation throughout the genome, especially in CpG island shores, where TET depletion resulted in prolific hypermethylation. Promoter hypermethylation resulting from TET depletion was associated with histone H2AK119 monoubiquitination, DNMT1, and DNMT3B occupancy. Surprisingly, TETs also promote cytosine methylation, as many loci became hypomethylated following TET depletion. Induction of differentiation generally caused 5hmC reduction, except at transcriptionally activated genes, which become enriched for 5hmC. Importantly, genes prone to promoter hypermethylation in cancer become depleted of intragenic 5hmC and 5mC with TET deficiency. This study highlights the multi-dimensional functions of TETs in mediating DNA methylation, hydroxymethylation, and gene expression patterns, and the results reveal that chromatin landscape and DNA sequence composition are regulators of TET function. Citation Format: Emily L. Putiri, Rochelle L. Tiedemann, Jeong-Hyeon Choi, Keith D. Robertson. Dynamics of TET methylcytosine dioxygenases in 5-methylcytosine and 5-hydroxymethylcytosine patterning in human cancer cells. [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 2319. doi:10.1158/1538-7445.AM2014-2319

Abstract Ewing sarcomas are aggressive, poorly differentiated pediatric tumors of bone and soft tissue. Ewing sarcoma affects one to three people per million every year and is the second most common pediatric bone malignancy after osteosarcoma. Approximately 85% of Ewing sarcomas harbor the EWS-FLI fusion protein, which arises from a chromosomal translocation, t(11:22)(q24:q12). EWS-FLI interacts with numerous lineage-essential transcription factors to maintain mesenchymal progenitors in an undifferentiated state. We previously showed that EWS-FLI binds the osteogenic transcription factor RUNX2, and prevents osteoblast differentiation. RUNX3 is highly homologous to RUNX2 and participates in the mesenchymal-derived bone formation. RUNX3 has been described as both a tumor suppressor and an oncogene in different tumor types. In this study, we investigated the role of RUNX3 in Ewing Sarcoma. RUNX3 was detected in all Ewing sarcoma cells examined (7/7 cell lines, and 4/4 primary tumors), whereas RUNX2 was detected in only 73% of these specimens. Immunoprecipitation experiments revealed that RUNX3 binds to EWS-FLI via its Runt domain, which is >91% identical to the Runt domain in RUNX2. The interaction between RUNX3 and EWS-FLI in cell nuclei was confirmed by immunofluorescence. Moreover, EWS-FLI interactions prevented RUNX3 from activating the transcription of a RUNX-responsive reporter, p6OSE2. To determine the role of RUNX3 in Ewing sarcoma cell growth, we stably suppressed RUNX3 expression in the Ewing sarcoma cell line A673 with shRNAs. In anchorage independent growth assays in soft agar, RUNX3-deficient A673 cells formed smaller colonies than cells expressing scrambled shRNAs. Consistent with the smaller colonies, RUNX3 suppressed cells had increased expression of the cyclin dependent kinase inhibitor p21. Taken together, these results suggest and oncogenic role for RUNX3 in Ewing sarcoma. Citation Format: Krista L. Bledsoe, Meghan E. McGee-Lawrence, Emily T. Camilleri, Andre M. Oliveira, Andre J. van Wijnen, Jennifer J. Westendorf. RUNX3 plays an oncogenic role in Ewing sarcoma cells. [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 1413. doi:10.1158/1538-7445.AM2014-1413

ABSTRACT We compared an FDA-cleared rapid (<20 min) PCR assay (Cobas Liat; Roche Diagnostics) to our routine influenza A and B real-time PCR assay (Simplexa Flu A/B & RSV Direct; Focus Diagnostics) using respiratory swabs ( n = 197). The Cobas Liat influenza A and B assays demonstrated sensitivities of 99.2% (123/124) and 100% (23/23), respectively, while showing a specificity of 100% for each target.