Passive multistate surveillance for neutropenia after use of cocaine or heroin possibly contaminated with levamisole.

STUDY OBJECTIVE: To characterize the demographic, clinical, and epidemiologic features of levamisole-associated neutropenia in cocaine or heroin users. METHODS: State health departments were recruited for participation when the Centers for Disease Control and Prevention (CDC) was notified of potential cases by a clinician, a health department official, or a poison center between October 15, 2009, and May 31, 2010. A case was defined as a person with an absolute neutrophil count less than 1,000 cells/µL (or a WBC count <2,000 cells/µL) and a self-reported history or laboratory confirmation of cocaine or heroin use. Health department officials abstracted data from medical charts, attempted a patient interview, and submitted data to CDC for descriptive analysis. RESULTS: Of the 46 potential cases reported from 6 states, half met eligibility criteria and had medical chart abstractions completed (n=23; 50%). Of these, close to half of the patients were interviewed (n=10; 43%). The average age was 44.4 years; just over half were men (n=12; 52%). The majority of patients presented to emergency departments (n=19; 83%). More than half presented with infectious illnesses (n=12; 52%), and nearly half reported active skin lesions (n=10; 44%). The majority of interview respondents used cocaine greater than 2 to 3 times a week (n=9; 90%), used cocaine more than 2 years (n=6; 60%), and preferred crack cocaine (n=6; 60%). All were unaware of exposure to levamisole through cocaine and of levamisole's inherent toxicity (n=10; 100%). CONCLUSION: Physicians should suspect levamisole exposure in patients using illicit drugs, cocaine in particular, who present with unexplained neutropenia. Most patients reported chronic cocaine use and were unaware of levamisole exposure. Cocaine use is more prevalent among men; however, our results identified a higher-than-expected proportion of female users with neutropenia, suggesting women may be at higher risk. Emergency physicians and practitioners are uniquely positioned to recognize these patients early during their hospital course, elucidate a history of cocaine or other drug exposure, and optimize the likelihood of confirming exposure by arranging for appropriate drug testing.

Brief report: a phase II "window-of-opportunity" frontline study of the MTOR inhibitor, temsirolimus given as a single agent in patients with advanced NSCLC, an NCCTG study.

BACKGROUND: In an effort to evaluate the single agent activity of temsirolimus in previously untreated non-small-cell lung cancer, the North Central Cancer Treatment Group undertook a frontline "window-of-opportunity" study. METHODS: Patients received 25 mg of temsirolimus administered intravenously as a weekly 30 minute infusion, on a 4-week cycle. Based on a two-stage Fleming design, the treatment would be promising if at least four of the first 25 evaluable patients in stage I or at least six of the 50 evaluable patients at the end of stage II have a confirmed response. Fresh tumor biopsies were obtained to evaluate predictive markers of temsirolimus activity. RESULTS: A total of 55 patients were enrolled with 52 patients being evaluable. The median age was 64 years. Adverse events (grade 3/4) occurring in 33 patients included dyspnea (12%), fatigue (10%), hyperglycemia (8%), hypoxia (8%), nausea (8%), and rash/desquamation (6%). The clinical benefit rate was 35% with four patients achieving a confirmed partial response and 14 patients with stable disease for 8 weeks or more. The 24-week progression-free survival rate was 25%. Median progression-free survival and overall survival were 2.3 and 6.6 months, respectively. Expression of p70s6 kinase, phospho-p70s6 kinase, Akt, phospho-Akt, and phosphatase and tensin homolog mutation did not correlate with clinical outcome. CONCLUSIONS: Temsirolimus given as a single agent in frontline therapy in patients with non-small-cell lung cancer was tolerable and demonstrated clinical benefit but did not meet the primary objective in this study. Patient selection will be needed to enhance the efficacy.

Determination of levamisole in urine by gas chromatography-mass spectrometry.

The United States Public Health Service Substance Abuse and Mental Health Services Administration is alerting medical professionals that a substantial percentage of cocaine imported into the United States is adulterated with levamisole, a veterinary pharmaceutical that can cause blood cell disorders such as severe neutropenia and agranulocytosis. Levamisole HCl is the active ingredient in a number of veterinary drugs approved to treat worm infestations in animals. Levamisole HCl was also the active ingredient in a human drug for oral administration approved on June 18, 1990, as adjuvant treatment in combination with fluorouracil after surgical resection in patients with Duke's stage C colon cancer. This drug was withdrawn from the U.S. market around 2000, and it has not been marketed in the U.S. since then. The objective of this study was to develop a method to determine the amount of levamisole in urine samples. The procedure will be provided to state health laboratories as needed to be used in the evaluation of patients that have developed neutropenia or agranulocytosis in the setting of recent cocaine use. A gas chromatography-mass spectrometry method was validated and tested at two different laboratories, and the method limit of detection for levamisole is 1 ng/mL in urine when using a 5-mL sample. Confirmation of the stereoisomer of levamisole was done by high-performance liquid chromatography using a chiral column.

Endpoints in phase II trials for advanced non-small cell lung cancer.

INTRODUCTION: We investigated the relationships between progression-free survival (PFS), response, confirmed response, and failure-free survival (FFS) with overall survival (OS) to assess their suitability as primary endpoints in phase II trials for advanced non-small cell lung cancer. METHODS: Individual data of 284 patients from four phase II trials were pooled. Progression status and response were modeled as time dependent variables in a multivariable (adjusted for baseline age, gender, stage, and performance status) Cox proportional hazards model for OS, stratified by trial. Subsequently, Cox proportional hazards models were used to assess the impact of PFS, response, confirmed response, and FFS on subsequent survival, using landmark analysis at 8, 12, 16, 20, and 24 weeks. Model discrimination was evaluated using the concordance index (c-index). RESULTS: The overall median OS, PFS, and FFS were 9.6, 3.7, and 2.8 months, and the response and confirmed response rates were 21 and 15%, respectively. Both progression status and response as time dependent covariates were significantly associated with OS (p < 0.0001; p = 0.009). PFS and FFS at 12 weeks significantly predicted for subsequent survival with the strongest c-index and hazard ratio combination in landmark analyses (hazard ratio, c-index: PFS: 0.39, 0.67; FFS: 0.37, 0.67). The c-indices for response and confirmed response were low (0.59-0.60), indicating their inability to sufficiently discriminate subsequent patient survival outcomes. CONCLUSIONS: FFS or PFS at 12 weeks is a stronger predictor of subsequent patient survival compared with tumor response and should be routinely used as endpoints in phase II trials for advanced non-small cell lung cancer.