Citations

Abstract Aims Hypothesis 1 of the Surgical Treatment for Ischemic Heart Failure (STICH) trial enrolled 1212 patients with an LVEF of ≤35% and CAD amenable to coronary artery bypass grafting (CABG). Patients were randomized to CABG and optimal medical therapy (MED) or MED alone. The objective was to assess whether or not patients with diabetes mellitus (DM) enrolled in the STICH trial would have greater benefit from CABG than patients without DM. Methods and results The characteristics and clinical outcomes of patients with and without DM randomized to CABG and MED or MED alone were compared. DM was present in 40%. At baseline, patients with DM had more triple vessel CAD, higher LVEF, and smaller left ventricular volumes. In patients with DM, the primary outcome of all-cause mortality occurred in 39% of patients in the MED group and 39% in the CABG group [hazard ratio (HR) with CABG 0.96, 95% confidence interval (CI) 0.73–1.26]. In patients without DM, the primary outcome occurred in 41% of patients in the MED group and 32% in the CABG group (HR with CABG 0.80, 95% CI 0.63–1.02). While numerically it would appear that the treatment effect of CABG is blunted in patients with DM, there was no significant interaction between DM and treatment group on formal statistical testing. Conclusions Patients with DM enrolled in the STICH trial had more triple vessel disease, smaller hearts, and higher LVEF than those without DM. CABG did not exert greater benefit in patients with DM.

Context Although primary bone tumors are extremely rare, the literature suggests that there are variations in the epidemiologic characteristics in different populations. The most frequently cited epidemiologic characteristics of primary bone tumors are derived from a large US series (Mayo Clinic), with no comparable study thus far performed in China. Objective To identify any potential epidemiologic differences between Chinese patients and a US series of patients. Design We performed a comparison study between 9200 patients treated at Beijing Ji Shui Tan Hospital (JST) and 10 165 patients treated at Mayo Clinic (MC), Rochester Minnesota. Detailed epidemiologic features were analyzed. Results We found that giant cell tumor and osteosarcoma have significantly higher incidences in the JST than the MC patients (P < .001). However, JST patients had a significantly lower incidence of Ewing sarcoma, chordoma, fibrosarcoma, myeloma, and malignant lymphoma (P < .001). For most benign and malignant bone tumors, the Chinese cohort had a more distinct male predominance than the US cohort. Malignant bone tumors had a monomodal age distribution in the JST patient group, with a bimodal age distribution in the MC cohort. Also, there were was a predilection for tumors of the femur and tibia among the JST patients (P < .001). Conclusions Our data confirm that epidemiologic variations of primary bone tumors exist in different populations. Factors that may contribute to these observed differences are proposed and discussed.

Abstract A 68-year-old avid deer hunter with ischemic cardiomyopathy underwent left ventricular assist device (LVAD) implantation for destination therapy two years ago. He was living an active lifestyle, tracking deer and fishing in a Midwestern forest in November. His wife removed an engorged tick on his thorax. A few days later, he experienced fever, confusion, and ataxia and was hospitalized with septic shock and ventricular fibrillation. The LVAD site had no signs of trauma, drainage, warmth, or tenderness. A peripheral blood smear revealed intraleukocytic anaplasma microcolony inclusions. After completing 14 days of doxycycline, he recovered. Typical non-device-associated infections in LVAD recipients include pneumonia, urinary tract infection, or Clostridium difficile colitis. Human granulocytic anaplasmosis (HGA) is a very atypical non-LVAD infection, and the incidence of tickborne illnesses in LVAD recipients is unknown.

Abstract BACKGROUND Metformin, a widely used anti-diabetic drug, is being considered as a highly promising agent for treatment and prevention of many types of cancer, including breast cancer. Although the exact mechanism of action of metformin is unknown, it is thought that metformin is an AMPK activator. To better individualize metformin therapy and explore additional underlying molecular mechanism associated with metformin action, we conducted a metformin pharmacogenomic study using 266 genomic data-enriched lymphoblastoid cell lines (LCLs). METHODS Genome-wide microarray data were generated for all LCLs, including 1.3 million SNPs, 485K DNA methylation probes and 54K mRNA expression probe sets. Metformin cytotoxicity assay was performed using MTS assay. Genome-wide association (GWA) analyses and integrated analyses using all the genomic data and metformin cytotoxicity (IC50 value) were performed to identify top candidate genes for functional validation in breast cancer cell lines, MDA-MB 231 and Hs578T, using siRNA screening approach. Further mechanistic study was performed to investigate the role of candidates in regulation of AMPK activity. RESULTS GWA analyses in LCLs identified 198 mRNA expression probe sets and 210 DNA methylation probes associated with metformin IC50 with p-value <10-4, respectively. Analysis of 1.3 million SNPs found 12 loci (a region containing at least 1 SNP of p-value <10-5 and 1 SNP of p-value <10-3 within 50kb) that were associated with metformin IC50. Integrated SNP loci-mRNA expression-IC50 analysis indicated that the SNP loci on chromosome 16 was associated with metformin IC50 through a trans-regulation of expression of 7 genes with p-value <10-4. Integrated methylation-mRNA expression-IC50 analysis showed that 15 DNA methylation probes in 6 genes were associated with metformin IC50 through both cis- and trans-regulation of expression of 48 genes with p-value <10-4, including 4 methylation probes in 3 of those 6 genes that were cis-correlated with its own gene expression. Ingenuity pathway analysis of top 62 candidate genes identified four major pathways and 55 genes within those pathways were selected for functional validation in breast cancer cell lines. The knockdown experiment showed that down regulation of 25 genes significantly altered metformin sensitivity in MDA-MB231, and 14 of them also showed the same effect in Hs578T. Preliminary mechanistic experiment indicated that knockdown of 7 genes significantly reduced AMPK activity in MDA-MB231 and 3 of them had same effect in Hs578T. CONCLUSIONS GWAS using a genomic data-enriched LCL model system, together with functional validation in breast cancer cell lines, could help us to identify novel genetic and epigenetic biomarkers involved in metformin response and help us to better understand the mechanisms of metformin in cancer treatment. Citation Format: Nifang Niu, Xianglin Tan, Brooke L. Fridley, Daniel J. Schaid, Ryan P. Abo, Anthony Batzler, Erin E. Carlson, Gregory Jenkins, Sebastian Moran, Holger Andrea Heyn, Manel Esteller Badosa, Liewei Wang. Metformin pharmacogenomics: A genome-wide associate study to identify genetic and epigenetic biomarkers involved in metformin response. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2271. doi:10.1158/1538-7445.AM2013-2271

Abstract Introduction: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC, which is the most prevalent kidney cancer among adults. Of the patients who develop this disease, over 1/3 will already present with advanced or metastatic disease during initial diagnosis due to the lack of symptoms in early stages. RCC demonstrates considerable resistance to radiation and traditional chemotherapeutics. Despite advances in the development of targeted anti-cancer treatments, no current drug therapy leads to significant improvement in long term survival in patients with advanced disease with the rare exception of those who respond to immunotherapy. Additionally, patients inevitably develop drug resistance. Therefore new molecular targets for therapy are sorely needed. Our group has identified stearoyl coA desaturase (SCD1) as a novel molecular target in ccRCC. We examined its role in tumor cell growth and viability in vitro and in vivo independently as well as in combination with current FDA approved regimens. Methods: Patient normal and ccRCC tissue samples and cell lines were examined for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through use of a small molecule inhibitor were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Therapeutic models of synergy were evaluated utilizing pharmacologic inhibition of SCD1 with the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus. Results: Our studies identify increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decrease tumor cell proliferation and induce apoptosis in vitro and in vivo. Upon gene array, quantitative real-time PCR, and protein analysis of SCDi treated or SCD1 lentiviral knockdown samples, induction of endoplasmic reticulum (ER) stress response signaling was observed, providing mechanistic insight for SCD1 activity in ccRCC. Furthermore, combinatorial application of SCDi with temsirolimus synergistically inhibits tumor growth in vitro and in vivo. Conclusions: Increased SCD1 expression supports ccRCC viability and therefore we propose it as a novel molecular target for therapy either independently or in combination with an mTOR inhibitor for patients whose disease cannot be remedied with surgical intervention, such as in cases of advanced or metastatic disease. These findings support the further evaluation of targeting SCD1 as an anti-cancer strategy in a phase I clinical trial. Citation Format: Christina A. von Roemeling, Laura Marlow, Thomas Caulfield, Kevin Wu, Winston Tan, Han Tun, John A. Copland, Adam Mathias, Chuck Harrison, Louis Dawson, Beth Hollister. Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-210. doi:10.1158/1538-7445.AM2013-LB-210

Abstract Background: NPC is endemic to Asia and over 40% of cases harbor PIK3CA amplification. MK2206 is an allosteric AKT inhibitor with activity in NPC in vitro. Methods: Pts who had progressed after palliative chemotherapy (chemo) for metastatic or recurrent NPC, received oral MK-2206 at 200 mg on Days 1, 8, 15 & 22 of each 28-day cycle until disease progression. Plasma samples were collected at serial time points during cycle 1 for EBV DNA analysis, archived tumor samples were collected where feasible. The primary dual endpoints (2-stage design) consisted of RECIST-defined tumor response rate (RR) and 6-month (m) progression-free survival (PFS) rate. Secondary endpoints were overall survival (OS), PFS and adverse events (AEs). Results: Of the 21 pts enrolled, the median age was 47 years (range: 32-67), 91% were male, 81% had prior radiotherapy and 81% had > 1 prior line of palliative chemo. At the time of analysis, 20 out of 21 pts have ended treatment. The best responses were: 1 partial response (PR, 5%) lasting 4 ms; 10 stable disease (SD, 50%), 9 progressive disease (PD, 45%). The 6-m PFS rate was 38.9% (95% CI: 18.1-59.3%) and median PFS was 2.7 ms (95% CI: 0.9-7.2 ms). The 6-m OS rate was 67.9% (95% CI: 41.8-84.1%) and median survival has not been reached. In 7 pts who had SD more than or equal to 6 ms, the duration of treatment ranged from 6.4-13.9 ms. Of the 21 pts evaluable for AEs, 12 pts (57%) had at least one grade 3 AE [[Unable to Display Character: –]] macular rash (6 pts - 29%), dysphagia (2 pts - 10%), hyperglycemia (2 pts - 10%) (see Table 1). The tumor samples of 7 pts were analyzed by FISH; 3 showed PIK3CA amplification, including 1 pt with chromosome 3 polysomy. Amongst these pts, 1 had SD more than 6ms, 1 had SD more than 12 ms, and 1 is still on treatment. Pts who had SD less than 6 m or PD did not have PIK3CA amplification. Conclusions: MK2206 is well tolerated and has signs of activity in unselected pts with NPC. Preliminary results suggest that PIK3CA amplification may be related to prolonged disease stabilization from MK2206, and analysis for other PIK3CA gene alterations in more samples will be undertaken. Result of the plasma EBV DNA result will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B273. Citation Format: Brigette B. Ma, Boon Cher Goh, Wan Teck Lim, Eng Huat Tan, Gilberto de Lima Lopes, Edwin P. Hui, Ann D. King, Kwok Wai Lo, Herbert Loong, Leung Li, Nathan Foster, Michael Kam, Sing Fai Leung, Charles Erlichman, Anthony TC Chan. Multicenter Phase II study of MK-2206 in previously treated patients (pts) with recurrent and metastatic nasopharyngeal carcinoma (NPC): Mayo Clinic Phase II Consortium (Protocol: MC1079). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B273.