The degree of CB1 downregulation correlated with years of chronic cannabis smoking

cardiac insufficiency. In fact, cardiotoxicity associated with bortezomib-based regimens has been reported with a substantial variation in the incidences, ranging from 0 to 17.9% in clinical trials. However, this associated is mostly based on case reports, single arm prospective studies and retrospective analyses, there has been no systematic attempt to synthesize these data and the overall risk of cardiotoxicity associated with bortezomib has not been well determined. As a result, we conduct this study to investigate the incidence and risk of cardiotoxicity in patients treated with bortezomib. Cardiotoxicity Associated with Bortezomib Methods Data sources We conducted an independent review of citations from PubMed between January 1, 1966, and July31, 2013. Key words were bortezomib, Velcade, PS-431, clinical trials and cancer. The search was limited to prospective clinical trials published in English. We also performed independent searches using Web of Science databases between January 1, 1966, and July 31, 2013, to ensure that no clinical trials were overlooked. Additionally, we searched the clinical trial registration website to obtain information on the registered prospective trials. We also searched abstracts and virtual meeting presentations from the American Society of Clinical K 858 Oncology conferences that took place between Jan 2004 and Jan 2013. Each publication was reviewed and in cases of duplicate publication only the most complete, recent, and updated report of the clinical trial was included in the metaanalysis. We also reviewed the reference lists of the original and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19643932 review articles to identify relevant studies. Data Extraction and clinical endpoint Data abstraction was conducted independently by two investigators, and any discrepancy between the reviewers was resolved by consensus. For each study, the following information was extracted: first author’s name, year of publication, phases of trials, number of enrolled subjects, treatment arms, number of patients in treatment and controlled groups, underlying malignancy, median age, median treatment duration, median progression-free survival, adverse outcomes of interest, and dosage of bortezomib. The following adverse outcomes were considered as cardiotoxic events and were included in the analyses: left ventricular ejection fraction decline or dysfunction, CHF, cardiomyopathy, cardiac arrest and cardiac arrhythmia. Trials that reported adverse outcomes as cardiac disorders and cardiac toxicity were also included in our meta-analysis. Cardiotoxicity in these studies were assessed and recorded according to the National Cancer Institute’s common terminology criteria for adverse events, which had been widely used in cancer clinical trials. Study Selection The primary goal of our study was to determine the overall incidence of cardiotoxicity associated with bortezomib and establish the association between treatments with bortezomib and the risk of developing cardiotoxicity. Thus, only prospective phase II and III trials evaluating bortezomib in cancer patients with adequate data on cardiotoxicity were incorporated in the analysis. Phase I trials were omitted due to multiple dose level and limited sample sizes. Clinical trials that met the following criteria were included: prospective phase 2 or 3 trials involving cancer patients; participants assigned to treatment with bortezomib; and available data regarding events or incidence of cardiotoxicity and sample size. Statistical Analys