Citations

Background and Purpose— Incomplete platelet inhibition by aspirin (aspirin resistance) may be a reason for stroke recurrence in some patients. 11-Dehydrothromboxane B2 (11-DTB2) is a stable thromboxane A2 metabolite that reflects in vivo platelet activation. This pilot study was intended to evaluate the reproducibility of urinary 11-DTB2 over time and to look for evidence of aspirin resistance. Methods— All subjects were screened for the African American Antiplatelet Stroke Prevention Study (AAASPS) 7 to 90 days after noncardioembolic cerebral infarction. Of 83 subjects with at least 1 urine sample, 52 were enrolled in AAASPS (randomized to blinded treatment with aspirin 650 mg/d or ticlopidine 500 mg/d), and 31 were enrolled in an open-label antiplatelet therapy cohort. Subjects were followed up for 2 years, with 11-DTB2 measurements scheduled at baseline and 6, 12, and 24 months. Vascular events were cerebral infarction, myocardial infarction, or vascular death. Results— Despite considerable individual up or down fluctuations, the median 11-DTB2 change did not significantly differ from zero in any of the subgroups. However, in 6 subjects with a 4-fold decrease in aspirin dose from 1300 to 325 or 81 mg/d, the 11-DTB2 level increased from 611 to 1881 pg/mg creatinine ( P =0.06). Vascular events occurred in 7 of 61 aspirin-treated subjects, and 11-DTB2 levels did not correlate with the events. Conclusions— Fluctuations in urinary 11-DTB2 after cerebral infarction in blacks do not correlate with changes in aspirin doses, except perhaps when the dose changes by a factor of 4 or more. A larger study is needed to look further for aspirin resistance.

ABSTRACT The VERSANT hepatitis B virus (HBV) 3.0 Assay (branched DNA [bDNA]) (referred to herein as VERSANT 3.0) was evaluated at four external sites for analytical sensitivity, specificity, reproducibility, linearity of quantification, and limits of detection. In addition, each of the test evaluation sites provided HBV DNA-positive clinical samples that were previously analyzed by one of three commercially available HBV DNA quantitative tests: Digene Hybrid Capture II HBV DNA Test (Digene); VERSANT HBV DNA 1.0 Assay (bDNA) (VERSANT 1.0); and COBAS AMPLICOR HBV Monitor Test (COBAS AMPLICOR). These samples were reexamined using VERSANT 3.0. The results from these studies showed that VERSANT 3.0 has high specificity (99.3%), excellent reproducibility (between-run coefficient of variation [CV] = 1.6 to 9.4%; within-run CV = 6.5 to 20.7%), and a broad linear range of quantification (2.0 × 10 3 to 1.0 × 10 8 HBV DNA copies/ml) that facilitate the monitoring of HBV DNA levels at diagnosis and throughout the course of treatment. In general, correlation was very good between results obtained from clinical samples analyzed by VERSANT 3.0 and the comparative HBV DNA quantitative assays (VERSANT 1.0, R 2 = 0.900; Digene, R 2 = 0.985; COBAS AMPLICOR, R 2 = 0.771). The greatest differences in comparative quantitation occurred at HBV DNA levels approaching the limits of the dynamic ranges for the comparative assays. The performance characteristics of the new VERSANT 3.0 assay demonstrated that it provides a reliable and robust method for routinely monitoring serum HBV DNA levels in assessing disease activity and determining response to antiviral treatment.

Purpose Few options are available for pain relief in patients with bone metastases who fail standard treatments. We sought to determine the benefit of radiofrequency ablation (RFA) in providing pain relief for patients with refractory pain secondary to metastases involving bone. Patients and Methods Thirty-one US and 12 European patients with painful osteolytic metastases involving bone were treated with image-guided RFA using a multitip needle. Treated patients had ≥ 4/10 pain and had either failed or were poor candidates for standard treatments such as radiation or opioid analgesics. Using the Brief Pain Inventory–Short Form, worst pain intensity was the primary end point, with a 2-unit drop considered clinically significant. Results Forty-three patients were treated (median follow-up, 16 weeks). Before RFA, the mean score for worst pain was 7.9 (range, 4/10 to 10/10). Four, 12, and 24 weeks following treatment, worst pain decreased to 4.5 (P < .0001), 3.0 (P < .0001), and 1.4 (P = .0005), respectively. Ninety-five percent (41 of 43 patients) experienced a decrease in pain that was considered clinically significant. Opioid usage significantly decreased at weeks 8 and 12. Adverse events were seen in 3 patients and included (1) a second-degree skin burn at the grounding pad site, (2) transient bowel and bladder incontinence following treatment of a metastasis involving the sacrum, and (3) a fracture of the acetabulum following RFA of an acetabular lesion. Conclusion RFA of painful osteolytic metastases provides significant pain relief for cancer patients who have failed standard treatments.

Gene therapy is being investigated as a putative treatment option for cardiovascular diseases, including cerebral vasospasm. Because there is presently no information regarding gene transfer to human cerebral arteries, the principal objective of this study was to characterize adenovirus-mediated expression and function of recombinant endothelial nitric oxide synthase (eNOS) gene in human pial arteries. Pial arteries (outer diameter 500 to 1000 μm) were isolated from 30 patients undergoing temporal lobectomy for intractable seizures and were studied using histologic staining, histochemistry, electron microscopy, and isometric force recording. Gene transfer experiments were performed ex vivo using adenoviral vectors encoding genes for bovine eNOS (AdCMVeNOS) and Escherichia coli β-galactosidase (AdCMVLacZ). In transduced arteries, studied 24 hours after exposure to vectors, expression of recombinant β-galactosidase and eNOS was detected by histochemistry, localizing mainly to the adventitia (n = 4). Immunoelectron microscopy localized recombinant eNOS in adventitial fibroblasts. During contractions to U46619, bradykinin-induced relaxations were significantly augmented in AdCMVeNOS-transduced rings compared with control and AdCMVLacZ-transduced rings ( P < 0.01; n = 6). The NOS inhibitor L-nitroarginine methylester (L-NAME) caused significantly greater contraction in AdCMVeNOS-transduced rings ( P < 0.001; n = 4) and inhibited bradykinin-induced relaxations in control and transduced rings ( P < 0.001; n = 6). The current findings suggest that in AdCMVeNOS-transduced human pial arteries, expression of recombinant eNOS occurs mainly in adventitial fibroblasts where it augments relaxations to NO-dependent agonists such as bradykinin. Findings from the current study might be beneficial in future clinical applications of gene therapy for the treatment or prevention of cerebral vasospasm.

ABSTRACT The TRUGENE HCV 5′NC genotyping kit (GeneLibrarian modules 3.1.1 and 3.1.2) and VERSANT HCV genotyping assay were compared by using 96 hepatitis C virus (HCV) RNA-positive patient specimens, including HCV genotypes 1, 2, 3, 4, 5, 6, and 10. The TRUGENE HCV 5 ′ NC genotyping kit (GeneLibrarian module 3.1.2) yielded the most accurate genotyping results.

Purpose: We sought to determine the maximum-tolerated dose (MTD) and evaluate the toxicities and clinical activity of two irinotecan (CPT-11), fluorouracil (FU), leucovorin (LV), and oxaliplatin schedules in patients with advanced solid tumors. Additionally, we investigated the effect of CPT-11 on oxaliplatin pharmacokinetics. Patients and Methods: Thirteen patients (cohort 1) received intravenous CPT-11 (infusion) and FU/LV (bolus) on days 1, 8, 15, and 22 and oxaliplatin (infusion) on days 1 and 15 every 6 weeks for a total 37 courses (median, three courses) at three dose levels. Twenty-two cohort 2 patients received intravenous CPT-11/oxaliplatin (infusion, day 1) and FU/LV (90-minute bolus infusion, days 2 to 5) every 3 weeks for a total of 122 courses (median, four courses) at three dose levels. Pharmacokinetic and neurotoxicity assessments were performed at the cohort 2 MTD. Results: Dose-limiting toxicity (DLT) seen in both cohorts at the starting dose required dose de-escalation. Cohort 1 DLT included diarrhea and neutropenia. In cohort 2, diarrhea, vomiting, dehydration, neutropenia, febrile neutropenia, and paresthesias were DLTs. Antitumor activity was seen in both cohorts. In cohort 2, the total platinum area under the curve of patients increased 17% in cycle 2 (P = .048), but objective neurotoxicity was not seen. Conclusion: The toxicities resulting from the addition of oxaliplatin to CPT-11/FU/LV are significant but manageable. The MTDs for the weekly schedule are CPT-11 (75 mg/m2), oxaliplatin (50 mg/m2), FU (320 mg/m2), and LV (20 mg/m2); and, for the 3-weekly schedule, the MTDs are CPT-11 (175 mg/m2), oxaliplatin (85 mg/m2), FU (240 mg/m2), and LV (20 mg/m2). Second-cycle platinum accumulation raises the possibility for enhanced cumulative neurotoxicity with CPT-11/oxaliplatin combinations.

Abstract Exercise-induced hypoxia is an index of the severity of interstitial lung disease. We hypothesized that desaturation during a 6-minute walk test would predict mortality for patients with usual interstitial pneumonia (n = 83) and nonspecific interstitial pneumonia (n = 22). Consecutive patients with biopsy-proven disease performed a 6-minute walk test between January 1996 and December 2001. Desaturation was defined as a fall in oxygen saturation to 88% or less during the 6-minute walk test. Desaturation was common (44 of 83 usual interstitial pneumonia and 8 of 22 nonspecific interstitial pneumonia; chi square, p = 0.39). Patients with usual interstitial pneumonia or nonspecific interstitial pneumonia who desaturated had a significantly higher mortality than patients who did not desaturate (respective log-rank tests, p = 0.0018, p = 0.0089). In patients with usual interstitial pneumonia, the presence of desaturation was associated with an increased hazard of death (hazard ratio, 4.2; 95% confidence interval, 1.40, 12.56; p = 0.01) after adjusting for age, sex, smoking, baseline diffusion capacity for carbon monoxide, FVC, and resting saturation. We conclude that knowledge of desaturation during a 6-minute walk test adds prognostic information for patients with usual interstitial pneumonia and nonspecific interstitial pneumonia.

AbstractLittle effort has been made to quantitate adverse outcomes of monoclonal gammopathy of undetermined significance (MGUS) of the immunoglobulin M (IgM) class, which progresses to lymphoma or Waldenström macroglobulinemia, whereas IgA and IgG MGUS progress to multiple myeloma, primary amyloidosis (AL), or a related plasma cell disorder. From 1960 to 1994, IgM MGUS was diagnosed in 213 patients in southeastern Minnesota. The end point was progression to lymphoma or a related disorder, as assessed with the Kaplan-Meier method. The 213 patients were followed up for 1567 person-years (median, 6.3 years per patient). Lymphoma developed in 17 patients (relative risk [RR], 14.8), Waldenström macroglobulinemia in 6 (RR, 262), primary amyloidosis in 3 (RR, 16.3), and chronic lymphocytic leukemia in 3 (RR, 5.7). The relative risk of progression was 16-fold higher in the patients with IgM MGUS than in the white population of the Iowa Surveillance, Epidemiology, and End Results Program. Cumulative incidence of progression was 10% at 5 years, 18% at 10 years, and 24% at 15 years. On multivariate analysis, the serum monoclonal protein and serum albumin concentrations at diagnosis were the only risk factors for progression to lymphoma or a related disorder. Risk for progression to lymphoma or a related disorder at 10 years after the diagnosis of MGUS was 14% with an initial monoclonal protein concentration of 0.5 g/dL or less, 26% with 1.5 g/dL, 34% for 2.0 g/dL, and 41% for more than 2.5 g/dL. (Blood. 2003;102:3759-3764)