Citations

The 15q13.3 microdeletion syndrome (OMIM #612001) is characterized by a wide range of phenotypic features, including intellectual disability, seizures, autism, and psychiatric conditions. This deletion is inherited in approximately 75% of cases and has been found in mildly affected and normal parents, consistent with variable expressivity and incomplete penetrance. The common deletion is approximately 2 Mb and contains several genes; however, the gene(s) responsible for the resulting clinical features have not been clearly defined. Recently, four probands were reported with small deletions including only the CHRNA7 gene. These patients showed a wide range of phenotypic features similar to those associated with the larger 15q13.3 microdeletion. To further correlate genotype and phenotype, we queried our database of >15,000 patients tested in the Mayo Clinic Cytogenetics Laboratory from 2008 to 2011 and identified 19 individuals (10 probands and 9 family members) with isolated heterozygous CHRNA7 gene deletions. All but two infants displayed multiple features consistent with 15q13.3 microdeletion syndrome. We also identified the first de novo deletion confined to CHRNA7 as well as the second known case with homozygous deletion of CHRNA7 only. These results provide further evidence implicating CHRNA7 as the gene responsible for the clinical findings associated with 15q13.3 microdeletion.

Abstract Quiescin-sulfhydryl oxidase (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins. We previously mapped a peptide in plasma from pancreatic ductal adenocarcinoma patients back to an overexpressed QSOX1 parent protein in tumor cells. It is not known why, or in what capacity, pancreatic tumors overexpress QSOX1. To begin to address this question, we first showed through immunohistochemistry that QSOX1 is overexpressed in patients diagnosed with pancreatic cancer, while it is not expressed in adjacent normal tissue or infiltrating lymphocytes. To determine the potential advantages QSOX1 might provide to tumor cells we knocked down QSOX1 using shRNA that suppressed both short and long isoforms of the protein. Loss of QSOX1 expression suppressed cell growth over time, while changes in cell cycle and apoptotic markers were minimal. However, QSOX1 shRNA dramatically inhibited the abilities of BxPC3 and Panc-1 pancreatic tumor cells to invade through Matrigel in a modified Boyden chamber assay. Mechanistically, gelatin zymography indicated that QSOX1 may play an important role in intracellular processing and extracellular activation of MMP-2 and MMP-9. Taken together, our results suggest that pancreatic tumors that express QSOX1 demonstrate an invasive phenotype through MMP activation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B60.

Abstract Mortality from prostate cancer in 2011 is estimated at 33,720 deaths in United States which occurs primarily in advanced disease stages. The cornerstone treatment of advanced prostate cancer is androgen deprivation, first established by Huggins and Hodges in 1941. Since then, recognition for the central role of the androgen axis and the androgen receptor (AR) during prostate tumorigenesis and progression, has been accepted. The arrest of the androgen-dependent growth stimulus by surgical or medical castration (with LHRH analogues or antagonists) is the result of reduced circulating androgens including dihydro-testosterone (DHT), which induces apoptotic regression of androgen-dependent cancer cells. This control however is short lived with the emergence of castration-resistant prostate cancer (CRPC). Despite achieving sub-castrate levels of circulating androgens as a result of castration, the androgen-AR axis continues to play an active role in tumor progression. A functional AR, despite the paucity of circulating androgens, is evidenced by the elevation of AR mRNA and re-expression of some androgen-regulated genes during clinical castration, indicative of a persistently activated AR cell signaling pathway. Furthermore, although testosterone and DHT are depleted in serum following traditional androgen deprivation therapy, significant levels of androgens have been measured in locally CRPC tissue1 as well as in metastatic CRPC tissue2. These androgens continue to regulate AR transcriptional activity and stimulate expression of androgen-regulated genes thereby re-invigorating tumor progression. Indeed, a number of molecular and cellular changes have been shown to facilitate activation of the AR under these conditions: amplification of the AR gene allow the receptor to respond to lower levels of androgens; splice variants of the AR exhibit constitutive activity; increased expression of several co-activator proteins enhance activation of the AR; other signaling pathways, including Akt-PI3 Kinase and MAP Kinase, activate the AR; and gain-of-function mutations in the AR allow the receptor to become “promiscuous” and then bind to ligands other than DHT, including anti-androgens3 and weaker sex steroids such as androstenedione. Abiraterone acetate, a selective steroidal irreversible inhibitor of CYP17 (17 hydroxylase/C17,20-lyase) blocks two important enzymatic activities in the synthesis of testosterone4. In a phase III trial in patients progressing on docetaxel chemotherapy, the combination of abiraterone plus prednisone resulted in an improvement in overall survival compared to patients receiving prednisone plus placebo (14.8 months vs 10.9 months, HR=0.646;P<0.001)5. The PSA response to the active drug combination was 38% vs 10% for the placebo group. A second phase III trial testing abiraterone with prednisone vs placebo and prednisone in the castration resistant stage in patients who are chemotherapy naïve has completed accrual (COU-AA-302; NCT00887198). These results re-enforce the rationale behind previous similar clinical attempts in which non-selective and reversible inhibitors of sex steroid biosynthesis such as ketoconazole in combination with hydrocortisone were used6 to target androgen biosynthesis after failure of androgen deprivation therapy. Ketoconazole inhibits the cholesterol side chain cleavage enzyme 11 beta hydroxylase as well as CYP 17, albeit reversibly7. While no overall survival difference for the study group was demonstrated in this study, an increased survival was observed in patients treated with ketoconazole experiencing PSA responses (35% with a 50% decline in PSA). Interestingly, CYP 17 inhibition with abiraterone in CRPC patients may retain activity even in patients previously treated with ketoconazole8. Adverse events with abiraterone use include hypokalemia, hypertension, peripheral edema and headaches all sequelae of secondary mineralocorticoid excess which can be minimized with the use of combination prednisone. Additional drugs in development include Ortrenol (previously named TAK-700; Millenium Pharmaceuticals, Cambridge, MA/Takeda, Osaka, Japan), which inhibits CYP 17, 20 lyase more potently than 17-hydroxylase. Two on-going large phase III studies with ortrenol in combination with prednisone in chemotherapy naïve (ClinicalTrials.gov Identifier: NCT 01193244) and in the post docetaxel chemotherapy (ClinicalTrials.gov Identifier: NCT01193257) CRPC populations will evaluate response of the study combination vs prednisone plus placebo with overall survival as the primary endpoint. Another novel drug is ToK-001 (Tokai Pharmaceuticals, Cambridge, MA) which is a combined inhibitor of CYP 17 and AR currently in early clinical phase II trials. Resistance to abiraterone has been observed in patients initially responding to the drug. Xenograft models suggest that the resistance may occur through upregulation of CYP17A1 and/or induction of AR and AR splice variants that confer ligand independent AR transactivation9. Targeting the AR with next generation AR inhibitors has also emerged as a potential therapeutic maneuver in CRPC. MDV310010 (Medivation, San Francisco, CA), a second generation anti-androgen, is now in phase III clinical trials. This new diarylthiohydantoin compound targets AR by binding over-expressed AR with an affinity that is several fold greater than previously obtained with anti-androgens (bicalutamide and flutamide). Another drug, ARN-509 (Aragon, San Diego, CA) is currently in phase I/II clinical trials (NCT01171898) and further development of this drug is to be determined based on the completion of the on-going dose establishing trial. Both these drugs disrupt the nuclear translocation of AR and impair DNA binding to androgen response elements and recruitment of co-activators and thus have multi-functional anti-tumor capabilities10. Results of a phase III study with the primary endpoint of overall survival evaluating MDV3100 vs placebo in the post chemotherapy, castration resistant stage which has completed accrual is now awaited (NCT00974311). Another phase III study is currently accruing patients after androgen deprivation failure who are chemotherapy naïve evaluating MDV3100 vs placebo also with the primary endpoint of overall survival (NCT01212991). In conclusion, the AR signaling axis remains active during the progression to CRPC and should be considered to be a viable target for therapy. References: 1. Mohler JL. Castration-recurrent prostate cancer is not androgen-independent. Adv Exp Med Biol. 2008;617:223–234. 2. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447–4454. 3. Dehm SM, Tindall DJ. Molecular regulation of androgen action in prostate cancer. J Cell Biochem. 2006;99:333–344. 4. Reid AH, Attard G, Barrie E, de Bono JS. CYP17 inhibition as a hormonal strategy for prostate cancer. Nat Clin Pract Urol. 2008;5:610–620. 5. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005. 6. Small EJ, Halabi S, Dawson NA, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2004;22:1025–1033. 7. Haidar S, Ehmer PB, Barassin S, Batzl-Hartmann C, Hartmann RW. Effects of novel 17alpha-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J Steroid Biochem Mol Biol. 2003;84:555–562. 8. Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2010;28:1481–1488. 9. Mostaghel EA, Marck BT, Plymate SR, et al. Resistance to CYP17A1 Inhibition with Abiraterone in Castration-Resistant Prostate Cancer: Induction of Steroidogenesis and Androgen Receptor Splice Variants. Clinical cancer research: an official journal of the American Association for Cancer Research. 2011;17:5913–5925. 10. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–790. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr CN08-01.

Background —Patients with treated diabetes in the randomized-trial segment of the Bypass Angioplasty Revascularization Investigation (BARI) who were randomized to initial revascularization with PTCA had significantly worse 5-year survival than patients assigned to CABG. This treatment difference was not seen among diabetic patients eligible for BARI who opted to select their mode of revascularization. We hypothesized that differences in patient characteristics, assessed and unmeasured, together with the treatment selection in the registry, at least partially account for this discrepancy. Methods and Results —Among diabetics taking insulin or oral hypoglycemic drugs at entry, angiographic and clinical presentations were comparable between randomized and registry patients. However, more registry patients were white, and registry diabetics tended to be more educated and more physically active and to report better quality of life. Procedural characteristics and in-hospital complications were comparable. The 5-year all-cause mortality rate was 34.5% in randomized diabetic patients assigned to PTCA versus 19.4% in CABG patients ( P =0.0024; relative risk [RR]=1.87); corresponding cardiac mortality rates were 23.4% and 8.2%, respectively ( P =0.0002; RR=3.10). The CABG benefit was more apparent among patients requiring insulin. In the registry, all-cause mortality was 14.4% for PTCA versus 14.9% for CABG ( P =0.86, RR=1.10), with corresponding cardiac mortality rates of 7.5% and 6.0%, respectively ( P =0.73; RR=1.07). These RRs in the registry increased to 1.29 and 1.41, respectively, after adjustment for all known differences between treatment groups. Conclusions —BARI registry results are not inconsistent with the finding in the randomized trial that initial CABG is associated with better long-term survival than PTCA in treated diabetic patients with multivessel coronary disease suitable for either surgical or catheter-based revascularization.

Background —In a previous randomized trial, the 12F laser sheath removed pacing leads via the implant vein more successfully than traditional mechanical tools alone. Two larger sizes of laser sheath, the 14F and 16F models, were developed to extract defibrillator leads and large-diameter pacing leads implanted for the chronic. These devices use pulsed ultraviolet laser light to core though fibrotic tissue grown over the lead body to free the lead from the vasculature. A mandatory prospective registry studied the safety and effectiveness profiles of the larger laser sheaths vis-à-vis the 12F laser sheath. Methods and Results —In this study, 863 patients underwent extraction of 1285 leads at 52 sites. Patients treated with the 14F device tended to have older leads than the 12F population; the 16F population, which comprised mostly defibrillator patients, were younger, had younger leads, and were more often male than the 12F population. Clinical success (extracting the entire lead or the lead body minus the distal electrode) was observed in 91% to 92% of cases for all device sizes. The overall complication rate was 3.6%, with 0.8% perioperative mortality. Incidence of complications was independent of laser sheath size. Conclusions —The 14F and 16F laser sheaths offer an extraction option for larger long-term transvenous pacemaker and defibrillator leads that is as safe and effective as the 12F laser sheath.

Abstract Aims For patients with refractory atrial fibrillation (AF) undergoing atrioventricular nodal ablation (AVNA), initial single-chamber right ventricular (RV)-only pacing is standard. Given the deleterious effects of chronic RV-only pacing, the impact of an initial biventricular (BiV) pacing strategy post-ablation is of interest. Methods and results We conducted a meta-analysis to determine the effect of BiV vs. RV-only pacing in patients undergoing AVNA for refractory atrial fibrillation. A search of multiple electronic databases identified 921 reports, which included four randomized controlled trials (n = 534). Mean New York Heart Association (NYHA) class was 2.3 and mean left ventricular ejection fraction (LVEF) was 44%. When compared with RV-only pacing, BiV pacing was not associated with reduced mortality [risk ratio 0.85, 95% confidence interval (CI) 0.40–1.82, P = 0.68]. In three studies comprised of patients with left ventricular systolic dysfunction (mean EF 41 ± 3%), BiV pacing demonstrated a non-significant reduction in cardiac mortality (risk ratio 0.59, 95% CI 0.25–1.39; P = 0.23). Compared with RV-only pacing, BiV pacing was associated with significant improvement in symptoms [Minnesota Living with Heart Failure Questionnaire (MLWHFQ) 2.72 points fewer, 95% CI 1.45–3.99] and increased LVEF (+2.6%, 95% CI 1.69–3.44), but no significant change in 6 min walk distance (6MWD) (5.02 ms more, 95% CI −1.56 to 11.59; P = 0.13). Conclusions In patients with refractory AF undergoing AVNA, BiV pacing was not associated with significantly improved survival when compared with RV-only pacing. A modest, but significant improvement in structural and functional response to BiV pacing was observed.

Abstract Aims This study aimed to evaluate the predictive value of a baseline speckle tracking strain rate imaging-derived discoordination index for response to cardiac resynchronization therapy (CRT). Methods and results Ninety-seven patients with QRS ≥120 ms and left ventricular (LV) ejection fraction ≤35% were prospectively followed after CRT in the Mayo CRT Registry. The LV discoordination index (stretch/shortening or thinning/thickening during ejection) was calculated from three types of deformation, radial, circumferential, and longitudinal, using two-dimensional speckle tracking strain rate imaging. The benefit of CRT was evaluated by reverse remodelling (i.e. reduction of LV end-systolic volume ≥15% at 6-month follow-up) and survival. The optimal cut-off value of the baseline discoordination index in discriminating responders from non-responders was determined by receiver operating characteristic curve analysis. Significant differences in baseline indices between responders and non-responders were noted for radial and circumferential discoordination indices. A mid-ventricular radial discoordination index (RDI-M) >38% best predicted responders, especially in patients with ischaemic cardiomyopathy (area under the curve 0.86 for all patients, sensitivity 80%, and specificity 91%). Death occurred in 28 patients over a median follow-up of 3.2 years. When adjusted for confounding variables, lack of significant discoordination (RDI-M <38%) before CRT was associated with a particularly high mortality (hazard ratio 7.05, 95% confidence interval 2.45–26.0). Conclusion LV discoordination assessed by speckle tracking RDI-M imaging was able to predict reverse remodelling at 6 months and survival of patients who received CRT.

Background— Postmarket medical device surveillance in the United States depends largely on voluntary reporting of adverse events. Consequently, early safety signals may be missed, exposing patients to potentially hazardous products. The aim of this study was to assess the feasibility of using an automated safety surveillance tool to detect early signals that a marketed implantable cardiac device was underperforming. Methods and Results— For this purpose, we performed simulated prospective monthly full-cohort and propensity-matched comparative survival analyses on our 3-center database of Sprint Fidelis and Quattro Secure implantable cardioverter-defibrillator leads, using a commercially available automated surveillance tool that was preset to trigger an alert if the log rank probability value was <0.05. During the study, 84 of 1035 Fidelis (8.1%) and 23 of 1675 Quattro (1.4%) leads failed. The simulated full-cohort analysis triggered a sustained alert for Fidelis leads beginning 13 months after the first implant and 2 years before Fidelis leads were removed from the market. Of the 1035 patients who had Fidelis leads, up to 969 (93.6%) were successfully matched to Quattro patients. In the propensity-matched analysis, the alert triggered 22 months after the first Fidelis implant and more than 1 year before the lead was recalled. Conclusions— An active automated safety surveillance system could have identified this implantable cardiovascular device problem substantially sooner than was achieved through existing postmarket surveillance methods. Such a tool, when applied to clinical registries and remote monitoring databases, may limit the exposure of large populations to underperforming and potentially hazardous cardiovascular devices.