Could CT scan avoid unnecessary flexible bronchoscopy in children with active pulmonary tuberculosis? A retrospective study.

BACKGROUND: Systematic flexible bronchoscopy is advocated in the initial management of childhood pulmonary tuberculosis. METHODS: Our aim was to describe and to compare the systematic flexible bronchoscopy findings of 53 children (6.5 + or - 4.4 years; 52.8% boys) with active pulmonary tuberculosis to their initial clinical and radiological (chest x-ray, n=53; CT, n=45) features in an 11-year retrospective study. RESULTS: Flexible bronchoscopy was normal in 51% of cases. A severe tracheobronchial involvement (extrinsic compression >50% or obstructive endoluminal mass >25% of the lumen) was found in 10 patients. Flexible bronchoscopy guided therapy in 13 cases (steroids n=12, bronchoscopic extraction of a granuloma n=1) and permitted isolation of Mycobacterium tuberculosis in three patients (5.7%). No useful information was obtained by flexible bronchoscopy in 73.5% of cases. No correlation was found between flexible bronchoscopy findings and clinical features or x-ray findings. Conversely, a strong correlation was found between severe bronchoscopic involvement and tracheobronchial luminal narrowing on CT. The CT negative predictive value was 100% (95% CI 91% to 100%). Based on CT results, flexible bronchoscopy could have been avoided in about 60% of our patients. CONCLUSIONS: Flexible bronchoscopy remains a very relevant tool in the diagnostic and therapeutic management of childhood pulmonary tuberculosis but resulted in treatment modification or microbiological proof in a minority of our patients. We propose that flexible bronchoscopy in children with pulmonary tuberculosis be limited to those who show tracheobronchial luminal narrowing on an initial CT scan.

Intrapleural administration of pemetrexed: a pharmacokinetic study in an animal model.

BACKGROUND: Pemetrexed is a key drug for the treatment of malignant pleural mesothelioma. The intrapleural administration of pemetrexed might increase its efficacy and decrease its toxicity in comparison with intravenous administration. The aim of this study was to assess in an animal model the pharmacokinetics of pemetrexed administered intrapleurally compared with intravenously. METHODS: Thirty Wistar rats were randomly assigned to four groups defined by route (intravenous or intrapleural) and dose (10 or 100 mg/kg) of pemetrexed. After pemetrexed administration, serial plasma pemetrexed concentrations were analyzed by high performance liquid chromatography to determine the maximum plasma concentration (C(max)), the area under the plasma concentration-time curve (AUC), and the total body clearance (CL). RESULTS: The C(max) was significantly lower after intrapleural versus intravenous administration of 10 mg/kg pemetrexed (14.36 microg/ml versus 29.83 microg/ml; p = 0.008) or 100 mg/kg pemetrexed (70.64 microg/ml versus 218.64 microg/ml; p = 0.001). At either dose, the AUC and the CL did not significantly differ according to the route of administration. CONCLUSIONS: While intravenous and intrapleural administration of pemetrexed yielded similar AUC and CL, the intrapleural route yielded a significantly lower C(max). As Cmax is a determinant of pemetrexed toxicity, intrapleural administration might offer a means of widening the effective therapeutic index of the drug by improving tolerability. Future studies are needed to confirm this hypothesis in malignant pleural mesothelioma patients.

Analysis of the DYSF mutational spectrum in a large cohort of patients.

Dysferlinopathies belong to the heterogeneous group of autosomal recessive muscular dystrophies. Mutations in the gene encoding dysferlin (DYSF) lead to distinct phenotypes, mainly Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). Here, we analysed the mutational data from the largest cohort described to date, a cohort of 134 patients, included based on clinical suspicion of primary dysferlinopathy and/or dysferlin protein deficiency identified on muscle biopsy samples. Data were compiled from 38 patients previously screened for mutations in our laboratory (Nguyen, et al., 2005; Nguyen, et al., 2007), and 96 supplementary patients screened for DYSF mutations using genomic DHPLC analysis, and subsequent sequencing of detected variants, in a routine diagnostic setting. In 89 (66%) out of 134 patients, molecular analysis identified two disease causing mutations, confirming the diagnosis of primary Dysferlinopathy on a genetic basis. Furthermore, one mutation was identified in 30 patients, without identification of a second deleterious allele. We are currently developing complementary analysis for patients in whom only one or no disease-causing allele could be identified using the genomic screening procedure. Altogether, 64 novel mutations have been identified in this cohort, which corresponds to approximately 25% of all DYSF mutations reported to date. The mutational spectrum of this cohort significantly shows a higher proportion of nonsense mutations, but a lower proportion of deleterious missense changes as compared to previous series. (c) 2008 Wiley-Liss, Inc.

Influence of -308 A/G polymorphism in the tumor necrosis factor alpha gene on etanercept treatment in rheumatoid arthritis.

OBJECTIVE: To determine whether the -308 A/G tumor necrosis factor alpha (TNFalpha) gene polymorphism can predict the outcome of etanercept therapy in 86 patients with rheumatoid arthritis (RA), as already observed in patients treated with infliximab. METHODS: Eighty-six RA patients treated with etanercept were genotyped for -308 A/G TNFalpha gene polymorphism by polymerase chain reaction and melting curve analysis, using specific gene primers and probes. Patients were subdivided into group A (G/A genotype) and group G (G/G genotype). We compared clinical responses to etanercept between groups A and G after 6 months, using the Disease Activity Score in 28 joints (DAS28). After 12-month treatment, 48 of 86 patients were evaluated again. RESULTS: Of 86 patients, 18 (21%) belonged in group A and 68 (79%) belonged in group G. After 6-month treatment, 55.6% of patients in group A and 82.4% of patients in group G had DAS28 improvement >1.2 (P = 0.027 by chi-square). The mean +/- SD DAS28 improvement was 1.69 +/- 1.31 in group A and 2.23 +/- 1.19 in group G (P = 0.098 by t-test). After 1-year treatment 48 patients were tested again: 10 (21%) belonged in group A and 38 (79%) belonged in group G. Forty percent of patients in group A and 87% in group G had DAS28 improvement >1.2 (P = 0.005 by chi-square). The mean +/- SD DAS28 improvement was 1.334 +/- 1.37 in group A and 2.29 +/- 1.47 in group G (Mann-Whitney U test = 115, P = 0.0057). CONCLUSION: RA patients with a -308 G/G TNFalpha genotype respond to etanercept better than patients with a -308 A/G genotype.