A randomized phase III study of 72 h infusional versus bolus bleomycin in BEP (bleomycin, etoposide and cisplatin) chemotherapy to treat IGCCCG good prognosis metastatic germ cell tumours (TE-3).

BACKGROUND: Bleomycin is an integral part of combination chemotherapy in germ cell tumours. Pulmonary toxicity often necessitates drug cessation and death occurs in 1%-2% of patients. A continuous infusion of bleomycin might reduce lung toxicity when compared with the conventional weekly boluses given as part of standard BEP chemotherapy. PATIENTS AND METHODS: A phase 3 trial was conducted based on 212 men with IGCCCG good prognosis metastatic germ cell tumours with 1 : 1 randomization. They were stratified for age, smoking history and renal function. Patients received either conventional BEP with weekly bleomycin (30 000 units/week i.v. bolus) or as a 90 000 unit infusion on day 1 over 72 h. The primary endpoint was CT assessed lung toxicity, secondary endpoints included progression-free survival (PFS), changes in lung function testing and quality of life. Repeated measures mixed effects model was used to analyse the data. RESULTS: CT assessed lung toxicity for the infusional and conventional arm patients were respectively 80% versus 62% at the end of treatment and 54% versus 51% at 1-year post-treatment. There was no significant difference between the two arms for CT assessed lung toxicity (estimated regression coefficient = 1.4, 95% CI: -0.36, 3.16). Older patients had higher toxicity (coefficient = 4.81, 95% CI: 3.04, 6.58). Lung toxicity increased after 1 cycle and peaked at end of treatment (P ≤ 0.002) and then declined. Lung function testing did not predict for subsequent lung damage. The median follow-up was 2.5 years. Two-year PFS rate (infusional: 93%, conventional: 94%; hazard ratio =0.91, 95% CI: 0.33, 2.52) was similar. Cough (P = 0.002) but not shortness of breath (P ≥ 0.09) was associated with bleomycin toxicity. CONCLUSIONS: Infusional bleomycin has no advantage over standard administration. It supports abandoning routine pulmonary function testing, instead the presence of cough should be sought and the early use of CT scanning of the chest to evaluate potential lung toxicity is preferred.

Gamma-tocotrienol attenuates high-fat diet-induced obesity and insulin resistance by inhibiting adipose inflammation and M1 macrophage recruitment.

BACKGROUND AND OBJECTIVE: We have previously demonstrated that gamma tocotrienol (γT3) potently inhibits adipocyte hyperplasia in human adipose-derived stem cells (hASCs). In this study, our objective was to investigate the γT3 effects on early-onset obesity, inflammation and insulin resistance in vivo. METHODS: Young C57BL/6J mice were fed a high-fat (HF) diet supplemented with 0.05% γT3 for 4 weeks. The concentrations of γT3 in plasma and adipose tissue were measured using high-performance liquid chromatography. Effects of γT3 on body weight gain, adipose volume, plasma levels of fasting glucose, insulin (enzyme-linked immunosorbent assay (ELISA)), proinflammatory cytokines (mouse cytokine array), insulin signaling (western blotting) and gene expression (quantitative real-time PCR, qPCR) in the liver and adipose tissue were examined. Influences of γT3 on [3H]-2-deoxyglucose uptake and lipopolysaccharide (LPS)-mediated NFκB signaling (western blotting) were assessed in hASCs. Effects of γT3 on macrophage M1/M2 activation were investigated using qPCR in mouse bone marrow-derived macrophages. RESULTS: After a 4-week treatment, γT3 accumulated in adipose tissue and reduced HF diet-induced weight gain in epididymal fat, mesenteric fat and the liver. Compared with HF diet-fed mice, HF+γT3-fed mice were associated with (1) decreased plasma levels of fasting glucose, insulin and proinflammatory cytokines, (2) improved glucose tolerance and (3) enhanced insulin signaling in adipose tissue. There were substantial decreases in macrophage specific markers, and monocyte chemoattractant protein-1, indicating that γT3 reduced the recruitment of adipose tissue macrophages (ATMs). In addition, γT3 treatment in human adipocytes resulted in (1) activation of insulin-stimulated glucose uptake and (2) a significant suppression of MAP kinase and NFκB activation. In parallel, γT3 treatment led to a reduction of LPS-mediated M1 macrophage polarization. CONCLUSION: Our results demonstrated that γT3 ameliorates HF diet-mediated obesity and insulin resistance by inhibiting systemic and adipose inflammation, as well as ATM recruitment.

Mortality risk for patients receiving hemodiafiltration versus hemodialysis: European results from the DOPPS.

Hemodiafiltration (HDF) is used sporadically for renal replacement therapy in Europe but not in the US. Characteristics and outcomes were compared for patients receiving HDF versus hemodialysis (HD) in five European countries in the Dialysis Outcomes and Practice Patterns Study. The study followed 2165 patients from 1998 to 2001, stratified into four groups: low- and high-flux HD, and low- and high-efficiency HDF. Patient characteristics including age, sex, 14 comorbid conditions, and time on dialysis were compared between each group using multivariate logistic regression. Cox proportional hazards regression assessed adjusted differences in mortality risk. Prevalence of HDF ranged from 1.8% in Spain to 20.1% in Italy. Compared to low-flux HD, patients receiving low-efficiency HDF had significantly longer average duration of end-stage renal disease (7.0 versus 4.7 years), more history of cancer (15.4 versus 8.7%), and lower phosphorus (5.3 versus 5.6 mg/dl); patients receiving high-efficiency HDF had significantly more lung disease (15.5 versus 10.2%) and received a higher single-pool Kt/V (1.44 versus 1.35). High-efficiency HDF patients had lower crude mortality rates than low-flux HD patients. After adjustment, high-efficiency HDF patients had a significant 35% lower mortality risk than those receiving low-flux HD (relative risk=0.65, P=0.01). These observational results suggest that HDF may improve patient survival independently of its higher dialysis dose. Owing to possible selection bias, the potential benefits of HDF must be tested by controlled clinical trials before recommendations can be made for clinical practice.

Biochemical evidence for a P2Y-like receptor in Tetrahymena thermophila.

Extracellular nucleotides are ubiquitous signaling molecules. ATP signals through two receptor types: the ionotropic P2X receptors, and the metabotropic P2Y receptors. ATP acts as a chemorepellent in Tetrahymena thermophila, where it causes a distinct avoidance response. The intracellular mechanisms by which ATP causes avoidance in this organism, however, are unknown. In this study, we use in vivo pharmacological assays along with enzyme immuno-assays to obtain information about the ATP chemorepellent pathway and its associated second messenger systems. Our data show strong similarities between the presumed ATP receptor of T. thermophila and members of the P2Y family of receptors. The ATP response of T. thermophila appears to be coupled to phospholipase C, a defining characteristic of the P2Y receptor family. In addition, the ATP chemoresponse appears to be linked to a G(i/o) protein, nitric oxide synthase, and adenylyl cyclase, all of which are characteristic of some P2Y receptors. This is an important first step in describing the pathways involved in ATP chemoresponse of this organism.

Determination of chlorate and chlorite and mutagenicity of seafood treated with aqueous chlorine dioxide.

The use of chlorine dioxide (ClO(2)) as a potential substitute for aqueous chlorine to improve the quality of seafood products has not been approved by regulatory agencies due to health concerns related to the production of chlorite (ClO(2)(-)) and chlorate (ClO(3)(-)) as well as possible mutagenic/carcinogenic reaction products. Cubes of Atlantic salmon (Salmo salar) and red grouper (Epinephelus morio) were treated with 20 or 200 ppm aqueous chlorine or ClO(2) solutions for 5 min, and extracts of the treated fish cubes and test solutions were checked for mutagenicity using the Ames Salmonella/microsome assay. No mutagenic activity was detected in the treated fish samples or test solutions with ClO(2). Only the sample treated with 200 ppm chlorine showed weak mutagenic activity toward S. typhimurium TA 100. No chlorite residue was detected in sea scallops, mahi-mahi, or shrimp treated with ClO(2) at 3.9-34.9 ppm. However, low levels of chlorate residues were detected in some of the treated samples. In most cases, the increase in chlorate in treated seafood was time- and dose-related.