Citations

Background— A paradoxical increase in the uncorrected QT interval during infusion of low-dose epinephrine appears pathognomonic for type 1 long-QT syndrome (LQT1). We sought to determine the diagnostic accuracy of this response among patients referred for clinical evaluation of congenital long-QT syndrome (LQTS). Methods and Results— From 1999 to 2002, 147 genotyped patients (125 untreated and 22 undergoing β-blocker therapy) had an epinephrine QT stress test that involved a 25-minute infusion protocol (0.025 to 0.3 μg · kg −1 · min −1 ). A 12-lead ECG was monitored continuously, and repolarization parameters were measured. The sensitivity, specificity, and positive and negative predictive values for the paradoxical QT response (defined as a ≥30-ms increase in QT during infusion of ≤0.1 μg · kg −1 · min −1 epinephrine) was determined. The 125 untreated patients (44 genotype negative, 40 LQT1, 30 LQT2, and 11 LQT3) constituted the primary analysis. The median baseline corrected QT intervals (QTc) were 444 ms (gene negative), 456 ms (LQT1), 486 ms (LQT2), and 473 ms (LQT3). The median change in QT interval during low-dose epinephrine infusion was −23 ms in the gene-negative group, 78 ms in LQT1, −4 ms in LQT2, and −58 ms in LQT3. The paradoxical QT response was observed in 37 (92%) of 40 patients with LQT1 compared with 18% (gene-negative), 13% (LQT2), and 0% (LQT3; P <0.0001) of the remaining patients. Overall, the paradoxical QT response had a sensitivity of 92.5%, specificity of 86%, positive predictive value of 76%, and negative predictive value of 96% for LQT1 status. Secondary analysis of the subset undergoing β-blocker therapy indicated inferior diagnostic utility in this setting. Conclusions— The epinephrine QT stress test can unmask concealed type 1 LQTS with a high level of accuracy.

AbstractMetastatic renal cell carcinoma (RCC) is an aggressive disease refractory to most existing therapeutic modalities. Identifying new markers for disease progression and drug targets for RCC will benefit this unmet medical need. We report a subset of clear cell and papillary cell RCC aberrantly expressing the lymphocyte activation marker CD70, a member of the tumor necrosis factor superfamily. Importantly, CD70 expression was found to be maintained at the metastatic sites of RCC. Anti-CD70 antibody-drug conjugates (ADC) consisting of auristatin phenylalanine phenylenediamine (AFP) or monomethyl auristatin phenylalanine (MMAF), two novel derivatives of the anti-tubulin agent auristatin, mediated potent antigen-dependent cytotoxicity in CD70-expressing RCC cells. Cytotoxic activity of these anti-CD70 ADCs was associated with their internalization and subcellular trafficking through the endosomal-lysosomal pathway, disruption of cellular microtubule network, and G2-M phase cell cycle arrest. The efficiency of drug delivery using anti-CD70 as vehicle was illustrated by the much enhanced cytotoxicity of antibody-conjugated MMAF compared with free MMAF. Hence, ADCs targeted to CD70 can selectively recognize RCC, internalize, and reach the appropriate subcellular compartment(s) for drug release and tumor cell killing. In vitro cytotoxicity of these ADCs was confirmed in xenograft models using RCC cell lines. Our findings provide evidence that CD70 is an attractive target for antibody-based therapeutics against metastatic RCC and suggest that anti-CD70 ADCs can provide a new treatment approach for advanced RCC patients who currently have no chemotherapeutic options. (Cancer Res 2006; 66(4): 2328-37)

ABSTRACT The Invader 1.0 assay (Invader HCV Genotyping Assay, version 1.0; Third Wave Technologies, Inc., Madison, WI) has been developed for the rapid differentiation of hepatitis C virus (HCV) genotypes 1 to 6 based on sequence variation within the HCV 5′ noncoding (NC) region. In the present study, we evaluated the compatibility of Invader 1.0 with the COBAS MONITOR (COBAS AMPLICOR HCV MONITOR Test, version 2.0; Roche Molecular Systems, Inc., Branchburg, NJ), COBAS AMPLICOR (COBAS AMPLICOR Hepatitis C Virus Test, version 2.0; Roche Molecular Systems, Inc.), and COBAS TaqMan (COBAS TaqMan HCV Test; Roche Molecular Systems, Inc.) assays. The minimum HCV RNA titers required for successful HCV genotyping (≥90% success rate) were 1,000 IU/ml for COBAS MONITOR, 100 IU/ml for COBAS AMPLICOR, and 10 IU/ml for COBAS TaqMan. Invader 1.0 results obtained from unpurified COBAS TaqMan amplification products of 111 retrospectively selected clinical serum specimens (genotypes 1 to 6, with virus titers ranging from 15.1 to 2.1 × 10 7 IU/ml) showed 98% concordance with results obtained from the TRUGENE HCV 5 ′ NC Genotyping Kit (Bayer HealthCare LLC, Tarrytown, NY), used in conjunction with COBAS AMPLICOR. Although the assay is sensitive, accurate, and easy to perform, additional optimization of the Invader 1.0 interpretive software (Invader Data Analysis Worksheet) may be necessary to reduce potential misidentification of HCV genotypes in low-titer specimens. In summary, Invader 1.0 is compatible with a variety of commercially available PCR-based HCV 5′ NC region amplification assays and is suitable for routine HCV genotyping in clinical laboratories.

Objective: To review the literature concerning the physiology of the endocannabinoid system, current drug development of cannabinoid agonists, and current clinical research on the use of cannabinoid agonists for analgesia. Data Sources: Articles were identified through a search of MEDLINE (1966–August 2005) using the key words cannabis, cannabinoid, cannabi*, cannabidiol, nabilone, THC, pain, and analgesia. No search limits were included. Additional references were located through review of the bibliographies of the articles identified. Study Selection and Data Extraction: Studies of cannabinoid agonists for treatment of pain were selected and were not limited by pain type or etiology. Studies or reviews using animal models of pain were also included. Articles that related to the physiology and pharmacology of the endocannabinoid system were evaluated. Data Synthesis: The discovery of cannabinoid receptors and endogenous ligands for these receptors has led to increased drug development of cannabinoid agonists. New cannabimimetic agents have been associated with fewer systemic adverse effects than delta-9-tetrahydrocannabinol, including recent development of cannabis medicinal extracts for sublingual use (approved in Canada), and have had promising results for analgesia in initial human trials. Several synthetic cannabinoids have also been studied in humans, including 2 cannabinoid agonists available on the international market. Conclusions: Cannabinoids provide a potential approach to pain management with a novel therapeutic target and mechanism. Chronic pain often requires a polypharmaceutical approach to management, and cannabinoids are a potential addition to the arsenal of treatment options.