Citations

SummaryBackgroundThe optimal methadone dosing regimen for children undergoing spinal surgery is uncertain because of sparse pediatric pharmacokinetic data and a paucity of analgesic effect data. The minimum effective analgesic concentration of methadone in opioid naïve adults is 58 mcg·L−1.MethodsAdolescents aged 12–19 years undergoing idiopathic scoliosis correction were administered 0.25 mg·kg−1 racemic methadone IV prior to surgical incision. Arterial blood samples for methadone assay were obtained at 0 min, 5 min, 10 min, 15 min, 20 min, 40 min, 1 h, 2 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h, and 48 h. Compartment analysis was undertaken using nonlinear mixed effects models. Parameter estimates were standardized to a 70‐kg person using allometric models.ResultsA three‐compartment linear disposition model best described observed time–concentration profiles. Population parameter estimates (between‐subjects variability) were central volume (V1) 19.1 (126%) L 70 kg−1, peripheral volumes of distribution V2 65.5 (60%) L 70 kg−1, V3 485 (23%) L 70 kg−1, clearance (CL) 9.3 (11%) L·h−1·70 kg−1, and inter‐compartment clearances Q2 282 (95%) L·h−1 70 kg−1, Q3 139 (42%) L·h−1 70 kg−1. The terminal elimination half‐life was 44.4 h. The mean observed methadone concentration was <58 mcg·L−1 by the first hour after administration.ConclusionsCurrent pharmacokinetic parameter estimates in adolescents are similar to those reported in adults. Methadone undergoes rapid redistribution after bolus administration. This may result in plasma concentrations that provide inadequate analgesia postoperatively. We would suggest following the bolus (0.25 mg.kg‐1) with an infusion (0.1–0.15 mg·kg−1·h−1 for 4 h) during spinal surgery to ensure adequate plasma concentrations for 24 h.

Abstract Purpose: Lung cancer in never-smokers (LCINS) is increasingly recognized as a distinct disease from that in ever-smokers owing to substantial differences in etiology, clinical characteristics, and prognosis. Therefore, we aimed to identify prognostic markers specific for LCINS. Experimental Design: First, 11,930 single-nucleotide polymorphisms (SNP) in 904 inflammation-related genes were genotyped, and their associations with overall survival in 411 patients with LCINS at MD Anderson Cancer Center were analyzed. Next, validation of the top 27 SNPs in 311 patients with LCINS at Mayo Clinic was conducted. Results: Three SNPs (IL17RA:rs879576, BMP8A:rs698141, and STY:rs290229) were validated (P &lt; 0.05), and two SNPs (CD74:rs1056400 and CD38:rs10805347) reached borderline significance (P = 0.08) in the Mayo Clinic population. We validated a survival-tree created in the MD Anderson population exploring gene–gene interactions in the Mayo Clinic population. This survival-tree stratified patients into subsets with significantly different risks of death: patients with the rs1056400_GG/rs698141_GA + AA genotype had significantly higher risk of death in both MD Anderson (HR:2.32, 95%CI: 1.58–3.41) and Mayo (HR:1.97, 95%CI: 1.11–3.50) populations compared with those with the rs1056400_GG/rs698141_GG or rs1056400_GA + AA genotype. We evaluated these five SNPs in 996 ever-smokers from MD Anderson and found no significant associations. Conclusions: Our study provides strong evidence that inflammation-related genetic variations can affect clinical outcomes in LCINS, which may lead to significant biologic insight into these outcomes. Clin Cancer Res; 18(21); 5983–91. ©2012 AACR.

Summary Background Corticosteroid treatment for autoimmune hepatitis has been shown by randomised controlled clinical trials to ameliorate symptoms, normalise liver tests, improve histological findings and extend survival. Nevertheless, suboptimal responses to corticosteroid treatment still occur. Aim To describe the current definitions, frequencies, clinical relevance and treatment options for suboptimal responses, and to discuss alternative medications that have been used off‐label for these occurrences. Methods Literature search was made for full‐text papers published in English using the keyword ‘autoimmune hepatitis’. Authors' personal experience and investigational studies also helped to identify important contributions to the literature. Results Suboptimal responses to standard therapy include treatment failure (7%), incomplete response (14%), drug toxicity (13%) and relapse after drug withdrawal (50–86%). The probability of a suboptimal response prior to treatment is higher in young patients and in patients with a severe presentation, jaundice, high MELD score at diagnosis, multilobular necrosis or cirrhosis, antibodies to soluble liver antigen, or inability to improve by clinical indices within two weeks or by MELD score within 7 days of conventional corticosteroid treatment. Management strategies have been developed for the adverse responses and nonstandard drugs, including mycophenolate mofetil, budesonide, ciclosporin, tacrolimus, sirolimus and rituximab, are emerging as rescue therapies or alternative frontline agents. Conclusions Once diagnosed, the suboptimal response should be treated by a highly individualised and well‐monitored regimen, preferentially using first‐line therapy. Nonstandard drugs warrant consideration as salvage or second‐line therapies.

We present the unusual case of a 74 year-old female with a history of breast cancer who presented with acute painless orbital swelling and vertical diplopia. MRI revealed a focal enhancing mass within the superior rectus muscle. As the concern for metastatic disease was high, surgical biopsy was performed and revealed an unusual mimicker of metastatic disease, the parasitic infection dirofilariasis.