The role of HER-2/neu expression on the survival of patients with lung cancer: a systematic review of the literature

C-erbB-2 prognostic value for survival in patients with lung cancer remains controversial. We performed a systematic review of the literature to clarify its impact. Studies were identified by an electronic search in order to aggregate the survival results, after a methodological assessment using the scale of the European Lung Cancer Working Party. To be eligible, a study had to deal with c-erbB-2 assessment in lung cancer patients and to analyse survival according to c-erbB-2 expression. In total, 30 studies were eligible: 24 studies dealt with non-small-cell lung carcinoma (NSCLC), five with adenocarcinoma and one study dealt with small-cell carcinoma. In all, 31% of the patients were positive for c-erbB-2. According to c-erbB-2 expression, 13 studies were 'negative' (significant detrimental effect on survival), one 'positive' (significant survival improvement) and 16 not significant. Significant studies had a better subscore relative to analysis and results report than nonsignificant studies. In total, 86% of the significant studies and only 56% of the nonsignificant studies were evaluable for the meta-analysis. This suggests a possible bias in our aggregated results. For NSCLC, the hazard ratio was 1.55 (95% CI: 1.29-1.86) in favour of tumours that do not express c-erbB-2. In conclusion, the overexpression of c-erbB-2 might be a factor of poor prognosis for survival in NSCLC, but there is a potential bias in favour of the significant studies with an overestimation risk of the magnitude of the true effect of c-erbB-2 overexpression.     

Vocalization responses after intrathecal administration of ionotropic glutamate receptor agonists in rats

Inotropic glutamate receptors in the spinal cord (N-methyl-D-aspartic acid [NMDA], alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kainate receptors) seem to play a key role in acute pain transmission and the neuronal plasticity in chronic pain states. Vocalization responses produced by activation of these receptors on the pain pathways can be quantified semiautomatically and thus could be used as a research tool. We studied vocalization responses induced by intrathecal administration of various agonists acting at the glutamate receptors in normal rats and in the presence of peripheral inflammation and a chronic constriction injury model of neuropathic pain. The nonselective endogenous agonist, glutamate, and the NMDA receptor glycine site agonist D-serine did not produce vocalization, whereas selective agonists acting at AMPA, NMDA, and kainate receptors produced dose-related vocalization responses. The vocalization response evoked by the administration of AMPA was significantly increased in the neuropathic pain model. In conclusion, spinal administration of ionotropic glutamate receptor agonists produce short-lasting, dose-related vocalization responses that can be used as a basic research and screening tool for analgesic studies. However, peripheral inflammation or nerve injury did not substantially alter vocalization responses overall, possibly indicating that the vocalization test is not a good tool for studying the role of excitatory amino acids in these pathological pain conditions. IMPLICATIONS: Vocalization responses evoked by spinal administration of ionotropic glutamate receptor agonists can be used for experimental analgesic studies. However, pathological pain models did not substantially alter vocalization responses, possibly indicating that this test is not suitable for studying the role of spinal excitatory amino acids in central sensitization.     

Effect of mechanical ventilator weaning protocols on respiratory outcomes in infants and children: a randomized controlled trial

Context  Ventilator management protocols shorten the time required to wean adult patients from mechanical ventilation. The efficacy of such weaning protocols among children has not been studied. Objective  To evaluate whether weaning protocols are superior to standard care (no defined protocol) for infants and children with acute illnesses requiring mechanical ventilator support and whether a volume support weaning protocol using continuous automated adjustment of pressure support by the ventilator (ie, VSV) is superior to manual adjustment of pressure support by clinicians (ie, PSV). Design and Setting  Randomized controlled trial conducted in the pediatric intensive care units of 10 children's hospitals across North America from November 1999 through April 2001. Patients  One hundred eighty-two spontaneously breathing children (<18 years old) who had been receiving ventilator support for more than 24 hours and who failed a test for extubation readiness on minimal pressure support. Interventions  Patients were randomized to a PSV protocol (n = 62), VSV protocol (n = 60), or no protocol (n = 60). Main Outcome Measures  Duration of weaning time (from randomization to successful extubation); extubation failure (any invasive or noninvasive ventilator support within 48 hours of extubation). Results  Extubation failure rates were not significantly different for PSV (15%), VSV (24%), and no protocol (17%) (P = .44). Among weaning successes, median duration of weaning was not significantly different for PSV (1.6 days), VSV (1.8 days), and no protocol (2.0 days) (P = .75). Male children more frequently failed extubation (odds ratio, 7.86; 95% confidence interval, 2.36-26.2; P<.001). Increased sedative use in the first 24 hours of weaning predicted extubation failure (P = .04) and, among extubation successes, duration of weaning (P<.001). Conclusions  In contrast with adult patients, the majority of children are weaned from mechanical ventilator support in 2 days or less. Weaning protocols did not significantly shorten this brief duration of weaning.      

Preparation and physicochemical characterization of biodegradable nerve guides containing the nerve growth agent sabeluzole

The objective of this study was to develop and characterize a biodegradable drug-loaded nerve guide for peripheral nerve regeneration. Sabeluzole, a nerve growth agent, was selected as model compound. Four biodegradable polymers were selected for this study: a copolymer of polylactic acid and polycaprolactone (PCL); a copolymer of polyglycolic acid and polycaprolactone PCL; a copolymer of PCL/polydioxanone (PDO) and PDO. Placebo and drug loaded nerve guides were obtained by melt compression and melt extrusion. It was observed that melt compression and melt extrusion are feasible techniques to prepare the nerve guides. Based on the physicochemical characterization, all samples show absence of crystalline sabeluzole, indicating the formation of an amorphous dispersion. The in vitro release measurements show that the release of sabeluzole is complete, reproducible and can be controlled by the proper selection of the polymer. The release mechanism for all samples follows Fickian release behaviour.     

Parents' perspectives on physician-parent communication near the time of a child's death in the pediatric intensive care unit.

OBJECTIVE: Communicating bad news about a child's illness is a difficult task commonly faced by intensive care physicians. Greater understanding of parents' scope of experiences with bad news during their child's hospitalization will help physicians communicate more effectively. Our objective is to describe parents' perceptions of their conversations with physicians regarding their child's terminal illness and death in the pediatric intensive care unit (PICU). DESIGN: A secondary analysis of a qualitative interview study. SETTING: Six children's hospitals in the National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. PARTICIPANTS: Fifty-six parents of 48 children who died in the PICU 3-12 months before the study. INTERVENTIONS: Parents participated in audio recorded semistructured telephone interviews. Interviews were analyzed using established qualitative methods. MEASUREMENTS AND MAIN RESULTS: Of the 56 parents interviewed, 40 (71%) wanted to provide feedback on the way information about their child's terminal illness and death was communicated by PICU physicians. The most common communication issue identified by parents was the physicians' availability and attentiveness to their informational needs. Other communication issues included honesty and comprehensiveness of information, affect with which information was provided, withholding of information, provision of false hope, complexity of vocabulary, pace of providing information, contradictory information, and physicians' body language. CONCLUSIONS: The way bad news is discussed by physicians is extremely important to most parents. Parents want physicians to be accessible and to provide honest and complete information with a caring affect, using lay language, and at a pace in accordance with their ability to comprehend. Withholding prognostic information from parents often leads to false hopes and feelings of anger, betrayal, and distrust. Future research is needed to investigate whether the way bad news is discussed influences psychological adjustment and family functioning among bereaved parents.     

Role of 5-HT(2) receptors in the tryptamine-induced 5-HT syndrome in rats

We distinguished the functions of the different 5-hydroxytryptamine-2 (5-HT(2)) receptor (5-HT(2)R) subtypes in the tryptamine-induced 5-HT syndrome in rats using (1) the 5-HT(2A)R antagonist R93274 (N-[(3-p-fluorophenyl-1-propyl)-4-methyl-4-piperidinyl]-4-amino-5-iodo-2-methoxybenzamide), the 5-HT(2A/C)R antagonist R99647 (2-(dimethylaminomethyl)2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine), the 5-HT(2B/C)R antagonist SB-242084 (6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline), and several 5-HT(2)R antagonists (ketanserin, risperidone, pipamperone and mianserin); and (2) chronic 5-HT(2)R activation by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). In contrast to SB-242084, the selective 5-HT(2A)R antagonist R93274 as well as the non-selective 5-HT(2A)R antagonists (R99647, ketanserin, risperidone, pipamperone and mianserin) significantly inhibited tryptamine-induced forepaw treading and tremors, and reversed peripherally mediated cyanosis into hyperaemia; only the 5-HT(2A/C)R antagonists R99647 and mianserin inhibited the tryptamine-induced hunched back. Intermittent DOM administration (intravenously every 48 h for 12 days) did not change the centrally mediated tryptamine-induced forepaw treading, tremors and hunched back at 1, 4 or 7 days after the last DOM pretreatment. The DOM-induced head twitch response, measured immediately after every DOM injection, was not affected. In contrast, peripherally mediated cyanosis was reversed into hyperaemia in 75, 11 and 20% of all pretreated rats at 1, 4 and 7 days, respectively, after the last DOM administration. Taken together, these finding suggest that central 5-HT(2A)Rs mediate tryptamine-induced forepaw treading and tremors, that peripheral 5-HT Rs mediate tryptamine-induced cyanosis, and that 5-HT(2A)Rs mediate tryptamine-induced hunched back. Peripheral 5-HT(2C)Rs are more sensitive to desensitization after intermittent treatment with an agonist than central 5-HT(2A)Rs.     

Role of granulocyte and granulocyte-macrophage colony-stimulating factors in the treatment of small-cell lung cancer: a systematic review of the literature with methodological assessment and meta-analysis

In order to clarify the role of haematological colony-stimulating factors (CSF) in the treatment of small-cell lung cancer, we performed a systematic review of the randomised trials published on this topic. Since 1991, 12 studies were eligible, including a total of 2107 randomised patients. They were divided into three groups: (1) maintenance of dose-intensity when chemotherapy was given at conventional doses and time intervals (seven trials); (2) accelerated chemotherapy with increased dose-intensity by reducing the delay between chemotherapy cycles (five trials); (3) concentration of chemotherapy on an overall shorter duration time with a lower number of cycles (one trial). Before quantitative aggregation, we performed a methodological assessment using two previously published quality scales (Chalmers and ELCWP). The median quality scores for the pooled 12 trials was 59.9% (range: 42.2-82.0%) for the ELCWP scale and 55.8% (range: 38.0-76.8%) for the Chalmers scale. No statistically significant difference was observed between positive (significant) and negative (non-significant) studies allowing us to perform a meta-analysis. A detrimental effect on response rate was associated with CSF administration in the maintenance group (RR 0.92; 95% confidence interval [CI] 0.87-0.97) without significant effect on survival (HR 1.004; 95% CI, 0.89-1.13). In the accelerated group, no significant impact on response rate (RR 1.02; 95% CI, 0.94-1.09) or survival (HR 0.82; 95% CI, 0.67-1.00) was found. Although no difference in response rate was observed, a reduced survival was associated with concentrated chemotherapy. In conclusion, the published data do not support the routine use of haematological colony-stimulating factors in the treatment of small-cell lung cancer (SCLC).