Citations

Background The characteristics of patients undergoing atrial fibrillation ( AF ) ablation and subsequent outcomes in community practice are not well described. Methods and Results Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation ( ORBIT ‐ AF ), we investigated the prevalence and impact of catheter ablation of AF . Among 9935 patients enrolled, 5.3% had previous AF ablation. Patients with AF ablation were significantly younger, more frequently male, and had less anemia, chronic obstructive pulmonary disease, and previous myocardial infarction (P<0.05 for all analyses) than those without previous catheter ablation of AF . Ablated patients were more likely to have a family history of AF , obstructive sleep apnea, paroxysmal AF , and moderate‐to‐severe symptoms (P<0.0001 for all analyses). Patients with previous ablation were more often in sinus rhythm on entry into the registry (52% vs. 32%; P<0.0001). Despite previous ablation, 46% in the ablation group were still on antiarrhythmic therapy. Oral anticoagulation was prescribed in 75% of those with previous ablation versus 76% in those without previous ablation (P=0.5). The adjusted risk of death (hazard ratio [ HR ], 0.78; 95% confidence interval [ CI ], 0.52 to 1.18; P=0.2) and cardiovascular ( CV ) hospitalization ( HR , 1.06; 95% CI , 0.90 to 1.26; P=0.5) were similar in both groups. Patients with incident AF ablation had higher risk of subsequent CV hospitalization than matched patients without incident ablation ( HR , 1.67; 95% CI , 1.24 to 2.26; P=0.0008). Conclusions In U.S. clinical practice, a minority of patients with AF are managed with catheter ablation. Subsequent to ablation, there were no significant differences in oral anticoagulation use or outcomes, including stroke/non–central nervous system embolism/transient ischemic attack or death. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01165710.

Purpose The purpose of this study was to (1) evaluate the clinical outcomes of a series of patients aged 60 years or older who underwent hip arthroscopy for labral tears with minimum 2‐year follow‐up and (2) identify risk factors for conversion to total hip arthroplasty (THA). Methods Outcome data were prospectively collected and retrospectively reviewed in patients aged 60 years or older who underwent hip arthroscopy between April 2008 and May 2012. Four patient‐reported outcome (PRO) scores, pain scores, and satisfaction ratings were collected. Conversion to THA and revision surgery rates were recorded. A subgroup analysis compared survivors with patients requiring THA. Results Minimum 2‐year follow‐up was available for 30 patients with a mean age of 63.9 years. The 2‐year survivorship rate was 70%, with 9 patients undergoing conversion to THA at a mean of 1.1 years after hip arthroscopy. Two patients required additional surgery during the study period, for a reoperation rate of 37% (11 of 30 patients). The remaining cohort showed mean improvements in all PRO scores. All scores, except the sports‐related PRO ( P = .12), improved significantly from the preoperative baseline scores. Visual analog scale scores for pain decreased from a mean of 5.0 preoperatively to 2.7 postoperatively ( P = .003). Patients who required conversion to THA had lower preoperative modified Harris Hip Scores ( P = .015), lower preoperative Hip Outcome Score–Activity of Daily Living values ( P = .01), higher pain scores ( P = .05), greater acetabular inclination ( P = .023), and more severe chondral damage ( P = .033). Conclusions Arthroscopic treatment of labral tears in patients aged 60 years or older should be approached with caution. Patients in this age group had an overall 2‐year survivorship rate of 70% and should be counseled before surgery on the possibility of subsequent conversion to THA. Patients aged 60 years or older with poor preoperative PRO scores, high pain scores, radiographic evidence of borderline dysplasia, and severe chondral damage may be poor candidates for hip arthroscopy. Level of Evidence Level IV, therapeutic case series.

Abstract Neuroblastoma, an embryonic tumor of peripheral sympathetic nervous system (PSNS), accounts for 10% of all childhood cancer deaths. We recently developed a robust zebrafish model of neuroblastoma and demonstrated that activated ALK synergizes with MYCN by inhibiting a developmentally-timed apoptotic response that is otherwise induced by MYCN. Genomic studies show that PTPN11 (encoding SHP2) is the second most frequently mutated genes in high-risk neuroblastoma. We have now used our zebrafish model to ask whether mutationally activated SHP2 functions as an oncogene in neuroblastoma. We developed a transgenic line in which ptpn11E69K is overexpressed in the PSNS under control of the dopamine-beta-hydroxylase promoter. Interestingly, ptpn11E69K synergized with MYCN to accelerate the onset of neuroblastoma in the interrenal gland (IRG), the zebrafish analogue of the adrenal medulla. Tumors began to appear at 15 weeks in transgenic fish overexpressing MYCN alone, whereas latency was shortened to 7 weeks and the penetrance was increased more than four-fold in transgenic fish coexpressing MYCN and ptpn11E69K. Coexpression of ptpn11E69K and MYCN also induced ganglioneuroma in the sympathetic ganglia, an outcome that has not been observed in transgenic fish overexpressing MYCN and activated ALK. In addition, coexpression of ptpn11E69K and MYCN induced adrenal neuroblastic hyperplasia in the IRG of all the transgenic fish at 5 weeks of age, a phenotype that has only been observed in about 50% of transgenic fish overexpressing activated ALK and MYCN or MYCN alone. Thus, these results suggest that activated SHP2 can collaborate with MYCN in neuroblastoma tumorigenesis via mechanisms different from those of activated ALK. Thus, zebrafish appears to provide a robust model system for functional genomic analysis and for the investigation of the mechanisms and pathways underlying genetic alterations identified in integrative genomic studies. Citation Format: Xiaoling Zhang, Guang Yang, A.Thomas Look, Benjamin G. Neel, Shizhen (Jane) Zhu. Activated SHP2 collaborates with MYCN in neuroblastoma tumorigenesis. [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 80. doi:10.1158/1538-7445.AM2014-80

Abstract Introduction: QSOX1 is a flavin-dependent sulfhydryl oxidase and the only known human enzyme with both disulfide generating and transferring activities. Using tissue microarrays, we previously demonstrated that QSOX1 is over-expressed in multiple tumor types including breast, pancreas, prostate and myeloma. Loss of QSOX1 leads to a significant decrease in tumor cell proliferation and invasion. The over-expression of QSOX1 in tumor cells compared to non-malignant cells combined with its role in tumor cell proliferation and invasion make it an attractive target for potential anti-neoplastic agents. Methods: Using a high throughput screening assay to detect sulfhydryl oxidase activity, we screened a library of compounds for inhibition of the QSOX1 enzyme. We used ROS-GloTM, a luciferase-based assay that detects H2O2, to determine if any compounds in the library inhibited QSOX1-mediated disulfide bond formation using reduced RNAse A as a substrate. QSOX1 generates H2O2 as a by-product of disulfide bond formation. To determine if compounds that showed activity in the enzymatic assay were also active against tumor cells, we treated pancreatic, breast, and myeloma cells with the compounds in a dose-dependent fashion, using non-malignant cells as controls. We assayed growth/viability by MTT and CellTiter-Glo assays. Invasive activity of tumor cells was assessed using matrigel-coated inserts in a modified Boyden chamber assay. Results: High throughput library screening identified 4 compounds that specifically inhibited QSOX1 activity (designated A-D) compared to a glucose oxidase counter-screen. Growth/viability assays showed that compound D suppressed the growth of tumor cells with IC50s between 300nM-750nM, depending on tumor cell line. In non-malignant cells the IC50s for compound D were more than 10-fold higher than in tumor cells. Compounds A and D also inhibited invasion of breast and pancreatic tumor cells through Matrigel. Conclusion: This is the first report of chemical compounds that inhibit QSOX1 enzymatic activity. The discovery of QSOX1 inhibitors with cellular efficacy establishes the chemical tractability of the target. Our data demonstrate that these First-In-Class compounds have potential as anti-neoplastic therapeutics via inhibition of QSOX1. Citation Format: Paul D. Hanavan, Douglas O. Faigel, Chen-Ting Ma, Eduard Sergienko, Nathalie Meurice, Joachim L. Petit, Yvette W. Ruiz, Benjamin A. Katchman, Douglas F. Lake. Small molecule inhibitors of QSOX1 suppress tumor cell growth and invasion. [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 1790. doi:10.1158/1538-7445.AM2014-1790

Abstract Purpose: The purpose of this study was to evaluate oncologists' preferences for methods to increase delivery of tobacco cessation support to cancer patients. Methods: An email list of 6844 physicians at NCI Designated Cancer Centers was generated using publically available online resources. An online survey was conducted in the fall of 2013 to assess tobacco assessment and cessation practices by physicians, barriers to providing cessation support, and methods to improve access to cessation services for cancer patients. Results of this survey are compared to similar survey findings by the American Society of Clinical Oncology (ASCO) and the International Association for the Study of Lung Cancer (IASLC). Results: Of 6844 electronically delivered survey invitations, we received 887 responses (13%). Consistent with previously published ASCO and IASLC surveys, 90% of physicians agreed that tobacco use by patients affects cancer treatment outcomes (vs. 87-92% in ASCO/IASLC), 90% of respondents reported that they ask patients about their tobacco use (vs. 90% in ASCO/IASLC), and 83% routinely advise tobacco users to quit (vs. 80-82% in ASCO/IASLC). However, only 37% of respondents regularly discussed medications, and 35% actively treated patients (vs. 39-44% in ASCO/IASLC). Most (71%) responding oncologists preferred cessation support be provided at the initial patient consult, and few (11%) were concerned about the use of tobacco cessation medications. Lack of time and lack of available resources were the dominant barriers to the administration of tobacco cessation support to cancer patients by oncologists. Only 10% of oncologists believed they were adequately trained to counsel patients on smoking cessation, but 55% reported that training for someone else in their clinic would increase tobacco cessation support. When asked what provider they prefer to administer cessation support to cancer patients, 16% reported a primary care physician, 18% reported a mid-level (nurse practitioner or physician assistant), 50% reported any other clinical staff, and only 1% preferred to personally provide cessation support. Whereas most (58%) oncologists preferred to have dedicated cessation services within their institution, 38% reported they would use dedicated services either within, or outside their institution. Conclusions: Most oncologists at NCI Designated Cancer Centers recognize the importance of tobacco cessation, but prefer to have tobacco cessation support for cancer patients provided by another trained professional. Citation Format: Alix Pommerenke, Anthony Alberg, Thomas H. Brandon, Ivana Croghan, Michael K. Cummings, Carolyn Dresler, Ellen R. Gritz, Roy Herbst, Scott Leischow, James R. Marshall, Benjamin Toll, Graham Warren. Physician preferences in tobacco cessation support for cancer patients: A survey of physicians at National Cancer Institute Designated Cancer Centers. [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 5049. doi:10.1158/1538-7445.AM2014-5049

Abstract Neuroblastoma, an embryonic tumor of peripheral sympathetic nervous system (PSNS), accounts for 10% of all childhood cancer deaths. We recently developed a robust zebrafish model of neuroblastoma and demonstrated that activated ALK synergizes with MYCN by inhibiting a developmentally-timed apoptotic response that is otherwise induced by MYCN. Genomic studies show that PTPN11 (encoding SHP2) is the second most frequently mutated genes in high-risk neuroblastoma. We have now used our zebrafish model to ask whether mutationally activated SHP2 functions as an oncogene in neuroblastoma. We developed transgenic lines in which ptpn11E69K is overexpressed in the PSNS under control of the dopamine-beta-hydroxylase promoter. Interestingly, ptpn11E69Ksynergized with MYCN to accelerate the onset of neuroblastoma in the interrenal gland, the zebrafish analogue of the adrenal medulla. Tumors began to appear at 15 weeks in transgenic fish overexpressing MYCN alone, whereas latency was shortened to 7 weeks and the penetrance was increased more than four-fold in transgenic fish co-expressing MYCN and ptpn11E69K. Co-expression of ptpn11E69K and MYCN also induced ganglioneuroma in the sympathetic ganglia, an outcome that has not been observed in transgenic fish overexpressing MYCN and activated ALK. These results suggest that activated SHP2 can collaborate with MYCN in neuroblastoma tumorigenesis via mechanisms different from those of activated ALK. Thus, zebrafish appears to provide a robust model system for functional genomic analysis and for the investigation of the mechanisms and pathways underlying mutations identified in ongoing tumor resequencing studies. Citation Format: (Jane) shizhen Zhu, Benjamin G. Neel, A. Thomas Look. Role of activated SHP2 in high-risk neuroblastoma pathogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B43.

Background Ehlers-Danlos syndrome (EDS) is a genetic disorder that affects the structural integrity of collagen within the body. This presents clinically as a connective tissue disorder with increased elasticity of joints, muscles, and ligaments. Multiple joints are affected by hypermobility and joint injury is common in these patients. It is estimated that EDS occurs once in every 5,000 births worldwide. Case review This article focuses on reconstruction of the ligamentum teres (LT) of the hip using a tibialis anterior allograft to treat severe instability and pain in a 43 year-old female with EDS. The LT reconstruction was accompanied by labral repair and capsular plication. The patient was assessed pre- and postoperatively using modified Harris Hip Score (mHHS), Hip Outcome Score Activities of Daily Living (HOS-ADLS), Hip Outcome Score Sports Specific Subscale (HOS-SSS), Non Arthritic Hip Score (NAHS), Visual Analog Scale (VAS), and satisfaction. One year following surgery the patient has reported positive outcomes in terms of pain and instability. Literature review Ligament reconstruction has been reported in patients with Ehlers-Danlos syndrome for shoulders and knees with positive results and restoration of stability. Currently there is a paucity of literature regarding patients with EDS undergoing hip procedures. In addition, reconstruction of the ligamentum teres for hip instability and pain has rarely been reported in a normal patient cohort. Clinical relevance This is the first study to report ligamentum teres reconstruction of the hip in a patient with Ehlers-Danlos syndrome and hip instability. The patient demonstrated satisfactory results 1 year from surgery.