Citations

Background and Purpose— We report the primary outcome of the Cerecyte Coil Trial, a randomized trial to determine whether polymer-loaded Cerecyte coils compared with Micrus bare platinum coils improved the proportion of patients with angiographic occlusion of the aneurysm at 6 months when assessed by a core laboratory. The secondary objectives were to compare the clinical outcomes and retreatment rates in the 2 groups. Methods— Five hundred patients between 18 and 70 years of age with a ruptured or unruptured target aneurysm were randomized to be treated with either Cerecyte or bare platinum coils in 23 centers worldwide. Two hundred forty-nine patients were assigned to Cerecyte coils and 251 to bare platinum coils. Analysis was by intention to treat. Results— Four hundred ninety-four patients were eligible for analysis. Four hundred eighty-one patients underwent coil treatment of their aneurysm, 227 patients with recently ruptured aneurysms and 254 with unruptured aneurysms. Four hundred thirty-three follow-up angiograms were assessed by the core laboratory; 127 of 215 (59%) and 118 of 218 (54%) in the Cerecyte and bare platinum groups, respectively, fulfilled the trial prespecified definition of success, namely that the treated aneurysm showed complete angiographic occlusion, had stable neck remnant, or improved in angiographic appearance compared with the end-of-treatment angiogram ( P =0.17). Late retreatment was performed in 25 of 452 (5.5%) patients, 17 (7.7%) Cerecyte versus 8 (3.5%) bare platinum ( P =0.064; range, 4–34 months). The clinical outcomes did not differ between the groups. Conclusion— There was no significant difference at 6 months in the angiographic outcomes between Cerecyte coils and bare platinum coils when assessed by the core laboratory. Clinical Trial Registration Information— URL: www.controlled-trials.com . Unique Identifier: ISRCTN82461286.

Abstract We performed a multi-stage genome-wide association study (GWAS) for drug response in ovarian cancer. We selected 313 chemotherapy treated patients from the Australian Ovarian Cancer Study (AOCS). Patients were treated with paclitaxel/carboplatin and the trait of interest was Progression Free Survival (PFS). We maximized power for a fixed genotyping budget by genotyping individuals from the tails of the distribution: 94 with good survival and 94 with poor survival, taking into account extent of residual disease following surgery. Patients were genotyped on Illumina HumanOmni1-Quad arrays (1140419 loci).Two further cohorts with measures of PFS and whole genome data available; 134 ovarian patients from the Mayo clinic (genotyped on Illumina HumanHap 610 arrays, 620901 loci) and 68 patients from The Cancer Genome Atlas ovarian cancer set (genotyped on Illumina Human1M arrays, 1199187 loci) were meta-analyzed with the AOCS set (stage 1). We have imputed all the stage 1 samples with reference of the 1000 Genome data to allow more direct comparison of SNPs not common to all of the arrays used (up to 6 million SNPs with good imputation quality). Based on the chemotherapy treatment received by each patient, we assigned the patients into primary and secondary analysis, with primary analysis using a more strictly defined treatment subgroup. We followed up the stage 1 findings by genotyping 26 SNPs in more than 3,000 samples collected from 8 study sites of Ovarian Cancer Association Consortium (OCAC). These 26 SNPs were mainly genotyped SNPs, chosen from 23 distinct regions showing the strongest association with chemotherapy response from either primary or secondary analysis. 2 SNPs showed nominal significance in the replication sample (chr 12: rs1861932, chr 22: rs708444). We are currently genotyping more regions to seek replication of the initial findings. In summary, we sought to identify genes that underlie individual differences in chemoresistance. In the future, typing variations in these genes will be important for personalizing drug regimes for patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4679. doi:10.1158/1538-7445.AM2011-4679

Abstract Myeloproliferative diseases (MPDs) are a subset of myeloid malignancies that are characterized by the expansion of a multipotent hematopoietic stem cell. Chronic MPDs can be classified into two categories, those harboring the BCR-ABL oncogene and those that are negative. This later category of neoplasms encompasses polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Recent discovery of activating mutations in the tyrosine kinase gene, JAK2 and constitutive activation of JAK2-STAT pathway, in large number of MPD patients has ignited considerable interest in MPD and has highlighted JAK2 as a therapeutic intervention point for drug discovery efforts. However, high-sequence homology with other JAK family members has posed a major challenge to design selective JAK2 inhibitors. Given that other JAK family members are involved in the regulation of immune function, it is important to maintain selectivity for JAK2 over these family members in order to mitigate the risks associated with undesired immunosuppression. Several JAK2 inhibitors with varying selectivity profiles are currently being evaluated in preclinical testing as well as in clinical trials for the treatment of MPD. Additionally, emerging genetic and pharmacologic evidence suggest that inhibition of the JAK2-STAT pathway may be an important therapeutic intervention point in other hematological malignancies as well as in certain solid tumors. We report here the discovery and characterization of BMS-911543, a functionally selective small molecule inhibitor of the Janus kinase family (JAK) member, JAK2. BMS-911543 is a potent and reversible inhibitor of JAK2 with a biochemical Ki of 0.48 nM. It has over 65-, 74- and 350-fold selectivity against the other JAK family members, TYK2, JAK3 and JAK1, respectively. Importantly, examination of > 450 other kinases in competition binding assays and in selected biochemical kinase assays did not reveal significant inhibitory activity for this JAK2 inhibitor, highlighting its high degree of biochemical selectivity for JAK2. Functionally, BMS-911543 displayed potent antiproliferative and pharmacodynamic (PD) effects in mutated JAK2-expressing cell lines dependent upon JAK2-STAT signaling and had little activity in cell types dependent upon other pathways such as JAK1 and JAK3. Further, single agent antiproliferative activity was not observed for BMS-911543 in a variety of solid tumor cell lines dependent upon other signaling pathways. In contrast, BMS-911543 was evaluated in colony growth assays using primary progenitor cells isolated from patients with JAK2V617F-positive myeloproliferative disease (MPD) and resulted in an increased antiproliferative response in MPD cells as compared with those from healthy volunteers. Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2-pSTAT signaling in multiple species with durable and potent pathway suppression observed after a single oral dose. Additionally, BMS-911543 was evaluated for effects in a JAK2V617F-expressing SET-2 xenograft model system and displayed a minimally effective dose of <2 mg/kg on pSTAT5 pathway suppression, which lasted up to 8 hours. To test the hypothesis that a JAK2 selective inhibitor would have less effect on immune system function, BMS-911543 was compared to pan-JAK inhibitors in a mouse model of immunosuppression. At low dose levels active in JAK2-dependent PD models, no effects were observed on antigen-induced IgG and IgM production for BMS-911543 whereas a pan-JAK family inhibitor showed pronounced effects at all dose levels tested. The mechanistic selectivity of BMS-911543 to pan-JAK family inhibitors was extended through comparative analysis of these inhibitors in whole genome gene expression profiling experiments performed in sensitive and resistant cell types. In this comparison, BMS-911543 modulated a distinct subset of transcriptional changes as compared to pan-JAK inhibitors in clinical testing, thereby defining a minimal set of transcriptional changes underlying the pharmacologic effects of JAK2 inhibition. Collectively these results define the mechanistic basis for a differential therapeutic index between selective JAK2 and pan-JAK family inhibition pre-clinically and suggest a therapeutic rationale for the further characterization of BMS-911543 in patients with MPD and in other malignancies reliant upon constitutively active JAK2 signaling. References: Levine, R.L., et al. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders (2007). Nature Rev. Cancer, 7, 673-683. Atallah, E. and Verstovsek, S. Prospect of JAK2 inhibitor therapy in myeloproliferative neoplasms. (2009). Expert Rev. Anticancer Ther. 9, 663-670. Ghoreschi, K., et al. Janus kinases in immune cell signaling. (2009). Immunol. Rev.,228, 273-287. Mesa, R.A. and Tefferi, A. Emerging drugs for the therapy of primary and post essential thrombocythemia, post polycythemia vera myelofibrosis (2009). Expert Opin. Emerging Drugs, 14, 1-9. Roll, J.D. and Reuther, G.W. CRLF2 and JAK2 in B-progenitor acute lymphoblastic leukemia: a novel association in oncogenesis. (2010) Cancer Res, 70, 7347-7352. Rui et al., Cooperative epigenetic modulation by cancer amplicon genes (2010). Cancer Cell, 18, 590-605. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr DDT01-03. doi:10.1158/1538-7445.AM2011-DDT01-03

Background —This study applied the New York State conventional coronary angioplasty (PTCA) model of clinical outcomes to evaluate whether it has relevance in the current era of stent implantation. The model was developed in 62 670 patients treated with conventional PTCA from 1991 to 1994 to risk adjust mortality and bypass surgery after PTCA. Since then, stents have become the dominant form of intervention. Whether that model remains relevant is uncertain. Methods and Results —All patients undergoing stenting at the Mayo Clinic from 1995 to 1998 were analyzed for in-hospital mortality, bypass surgery performed after attempted stenting, and longer-term mortality. No patients were excluded. The New York model was used to risk adjust and predict in-hospital and follow-up mortality. There were 3761 patients with 4063 procedural admissions for stenting; 6472 target vessel segments were attempted, and 96.1% of procedures were successful. With the New York multivariable risk factor equation, 79 in-hospital deaths were expected (1.95%); 66 deaths (1.62%) were observed. The New York model risk score in a logistic regression model was the most significant factor associated with in-hospital mortality (OR, 1.86; P <0.001). During a mean follow-up of 1.2±1.0 years, there were 154 deaths. Multivariable analysis documented 6 factors associated with subsequent mortality; New York risk score was the most significant (χ 2 =16.64, P =0.0001). Conclusions —Although the New York mortality model was developed in an era of conventional angioplasty, it remains relevant in patients undergoing stenting. The risk score derived from that model is the variable most significantly associated with not only in-hospital but also longer-term outcome.

Background —Although prompt treatment is a cornerstone of the management of acute myocardial infarction (AMI), prior studies have shown that one fourth of AMI patients arrive at the hospital >6 hours after symptom onset. It would be valuable to identify individuals at highest risk for late arrival, but predisposing factors have yet to be fully characterized. Methods and Results —Data from the Cooperative Cardiovascular Project, involving Medicare beneficiaries aged >65 years hospitalized between January 1994 and February 1996 with confirmed AMI, were used to identify patients who presented “late” (≥6 hours after symptom onset). Patient characteristics were tested for associations with late presentation by use of backward stepwise logistic regression. Among 102 339 subjects, 29.4% arrived late. Significant predictors of late arrival (odds ratio, 95% CI) included diabetes (1.11, 1.07 to 1.14) and a history of angina (1.32, 1.28 to 1.35), whereas prior MI (0.82, 0.79 to 0.85), prior angioplasty (0.80, 0.75 to 0.85), prior bypass surgery (0.93, 0.89 to 0.98), and cardiac arrest (0.52, 0.46 to 0.58) predicted early presentation. Additionally, initial evaluation at an outpatient clinic (2.63, 2.51 to 2.75) and daytime presentation (1.67, 1.59 to 1.72) predicted late arrival. Finally, female sex, black race, and poverty, which were evaluated with an 8-level race–sex–socioeconomic status interaction term, were also risk factors for delay. Conclusions —Delayed hospital presentation is a common problem among Medicare beneficiaries with AMI. Factors associated with delay include not only clinical and logistical issues but also race, sex, and socioeconomic characteristics. Education efforts designed to hasten AMI treatment should be directed at individuals with risk factors for late arrival.

Background —Coronary endothelial dysfunction is characterized by an imbalance between endothelium-derived vasodilating and vasoconstricting factors and coronary vasoconstriction in response to the endothelium-dependent vasodilator acetylcholine. Thus, the present double-blind, randomized study was designed to test the hypothesis that long-term, 6-month supplementation of l -arginine, the precursor of the endothelium-derived vasodilator NO, reverses coronary endothelial dysfunction to acetylcholine in humans with nonobstructive coronary artery disease. Methods and Results —Twenty-six patients without significant coronary artery disease on coronary angiography and intravascular ultrasound were blindly randomized to either oral l -arginine or placebo, 3 g TID. Endothelium-dependent coronary blood flow reserve to acetylcholine (10 −6 to 10 −4 mol/L) was assessed at baseline and after 6 months of therapy. There was no difference between the two study groups in clinical characteristics or in the coronary blood flow in the response to acetylcholine at baseline. After 6 months, the coronary blood flow in response to acetylcholine in the subjects who were taking l -arginine increased compared with the placebo group (149±20% versus 6±9%, P <0.05). This was associated with a decrease in plasma endothelin concentrations and an improvement in patients’ symptoms scores in the l -arginine treatment group compared with the placebo group. Conclusions —Long-term oral l -arginine supplementation for 6 months in humans improves coronary small-vessel endothelial function in association with a significant improvement in symptoms and a decrease in plasma endothelin concentrations. This study proposes a role for l -arginine as a therapeutic option for patients with coronary endothelial dysfunction and nonobstructive coronary artery disease.

Background Coronary endothelial dysfunction may occur in patients with minimally obstructive coronary artery disease and angina, and potentially may cause myocardial ischemia. Methods and Results Coronary endothelium-dependent vasodilation was examined in patients with angina and <50% coronary artery diameter (CAD) stenosis by selectively infusing acetylcholine (10 −6 mol/L to 10 −4 mol/L) into the left anterior descending coronary artery (LAD). Percent change in CAD (%ΔCAD) was measured by quantitative coronary angiography, and percent change in coronary blood flow (%ΔCBF) was calculated using intracoronary flow Doppler. Coronary endothelium-independent vasodilation was examined using intracoronary adenosine and nitroglycerin. 99m Tc sestamibi was injected intravenously just prior to the infusion of the highest dose of acetylcholine. Patients were divided blindly into three groups: Perfusion defects in non-LAD territory (group 1, n=6), no perfusion defects (group 2, n=7), and perfusion defects in the LAD territory (group 3, n=7). All patients had intact endothelium-independent vasodilation. In group 1, perfusion defects outside the LAD territory reflected an increase in %ΔCAD and %ΔCBF by 24±5% and 241±46% in the LAD. In group 2, %ΔCAD decreased by 26±5%, but %ΔCBF increased by 54±17%. In group 3, perfusion defects were within the LAD territory, reflecting a decrease in %ΔCAD and %ΔCBF by 35±5% and 51±14%, respectively. Conclusions This study demonstrates that coronary endothelial dysfunction in humans may be temporally associated with myocardial perfusion defects and supports a role for the coronary epicardial and microcirculation endothelium in regulating myocardial perfusion. Myocardial ischemia may occur in humans with impaired endothelium-dependent coronary flow reserve of the coronary epicardial and microcirculation.