No abstract

GaTATE PET was positive in a high proportion of patients with refractory neuroblastoma, correlating with SSTR 2 on IHC, with additional disease identified compared with MIBG imaging. PRRT seems safe, feasible, with responses observed in patients with progression despite multimodality treatment. These data support ongoing clinical trials in such patients.

No abstract

Intubated patients frequently become colonized by Pseudomonas aeruginosa, which is subsequently responsible for ventilator-associated pneumonia. This pathogen readily acquires resistance against available antimicrobials. Depending on the resistance mechanism selected for, resistance might either be lost or persist after removal of the selective pressure. We investigated the rapidity of selection, as well as the persistence, of antimicrobial resistance and determined the underlying mechanisms. We selected 109 prospectively collected P. aeruginosa tracheal isolates from two patients based on their prolonged intubation and colonization periods, during which they had received carbapenem, fluoroquinolone (FQ), or combined ␤-lactam-aminoglycoside therapies. We determined antimicrobial resistance phenotypes by susceptibility testing and used quantitative real-time PCR to measure the expression of resistance determinants. Within 10 days after the initiation of therapy, all treatment regimens selected resistant isolates. Resistance to ␤-lactam and FQ was correlated with ampC and mexC gene expression levels, respectively, whereas imipenem resistance was attributable to decreased oprD expression. Combined ␤-lactam-aminoglycoside resistance was associated with the appearance of small-colony variants. Imipenem and FQ resistance persisted for prolonged times once the selecting antimicrobial treatment had been discontinued. In contrast, resistance to ␤-lactams disappeared rapidly after removal of the selective pressure, to reappear promptly upon renewed exposure. Our results suggest that resistant P. aeruginosa is selected in less than 10 days independently of the antimicrobial class. Different resistance mechanisms lead to the loss or persistence of resistance after the removal of the selecting agent. Even if resistant isolates are not evident upon culture, they may persist in the lung and can be rapidly reselected.

To determine the effect of liver disease on the pharmacokinetics of rocuronium, the authors administered 0.6 mg/kg (twice the ED95) to 10 patients with liver disease and compared these results to values in 10 healthy surgical patients. Anesthesia was induced with thiopental and maintained with isoflurane (0.9%-1.1% end-tidal concentration) and nitrous oxide (60%). Venous blood samples were obtained for 6 h after rocuronium injection and plasma concentrations were measured using gas chromatography. Pharmacokinetic differences between groups were determined using a population-based pharmacokinetic analysis (NONMEM). Hepatic impairment did not alter the plasma clearance of rocuronium (217 +/- 21.8 mL/min, mean +/- SE, for both groups), but did increase the volume of the central compartment (5.96 +/- 1.01 L for controls, 7.87 +/- 1.33 L for patients with liver disease) and volume of distribution at steady state (16.4 L for controls, 23.4 L for patients with liver disease). In turn, elimination half-life was longer in patients with liver disease (111 min) compared to controls (75.4 min). The authors conclude that liver disease alters the pharmacokinetics of rocuronium by increasing its volume of distribution. The longer elimination half-life might result in a longer duration of action of rocuronium in patients with liver disease, particularly after prolonged administration.

Background -There is evidence that administration of higher doses of aminoglycosides given less frequently improves the bactericidal effect and reduces the potential to cause side effects. To investigate this, a prospectively randomised open label therapeutic trial was undertaken in stratified groups of patients with cystic fibrosis to examine the efficacy and toxic potential of an aminoglycoside dosing regimen designed to generate high peak drug concentrations at 12 hourly intervals compared with conventional dosing at eight hourly intervals. Methods -Patients in group A received tobramycin eight hourly using a dose aimed at generating a peak concentration of 10 mgIl with trough concentrations below 2 mglI, and those in group B received the total daily dose required to achieve eight hourly target concentrations administered as two equal 12 hourly doses. Clinical outcomes measured and assessed included vestibular symptoms, hearing and renal function, length of hospital stay, readmission rate, and mortality. Results -Twenty nine patients were recruited during a six month period, 20 to group A and nine to group B. The average peak tobramycin level was higher in group B (12.5 (2.2) mgIl) than in group A (7.9 (1.9) mgIl), whilst the average trough level was higher in group A (0-8 (0.3) mgIl) than in group B (0-5 (0.2) mg/l). There was a difference in the number ofototoxic events between patients in group A (seven of 18, 38c9%) and group B (none of eight), but no difference was found in other outcome measures assessed. Conclusions -These results suggest that 12 hourly high peak aminoglycoside dosing may be less toxic than equivalent eight hourly dosing, without any apparent difference in efficacy. (Thorax 1996;51:369-373) Keywords: aminoglycosides, cystic fibrosis, ototoxicity.Aminoglycoside antibiotics provide an effective and inexpensive treatment for Gram negative infections, yet their usefulness as antibiotics has been limited by their potential to cause ototoxicity and nephrotoxicity. }6ere is evidence from both human and animal models that larger doses of aminoglycosides given less frequently reduce their potential to cause such side effects.4"'7 The efficacy of larger less frequent aminoglycoside dosing regimens becomes a concern in patient groups whose clearance of the drug makes the interdose interval more critical, and these patient groups must be included in any rational analysis of this issue. Patients with cystic fibrosis represent such a group.The primary pathogens implicated in the chronic lung infection associated with cystic fibrosis are Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa, the latter being responsible for chronic infection in 70-90% of all these patients.""24 P aeruginosa undergoes phenotypic adaptation within the lungs of patients with cystic fibrosis, the most important being the emergence of mucoid strains. The aim of this study was to examine the efficacy and toxic potential of a dosing regimen oftobramycin which generate...

A significant biological effect of panobinostat, measured by acetylation status of histone H3 and H4, was achieved at a dose of 15 mg/m. PK data and drug tolerability at 15 mg/m was similar to that previously published.

No abstract