Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy.

OBJECTIVE: To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD). METHODS: A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months. RESULTS: Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone. CONCLUSIONS: Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.

Inhaled nitric oxide in premature infants: effect on tracheal aspirate and plasma nitric oxide metabolites.

OBJECTIVE: Inhaled nitric oxide (iNO) is a potential new therapy for prevention of bronchopulmonary dysplasia and brain injury in premature infants. This study examined dose-related effects of iNO on NO metabolites as evidence of NO delivery. STUDY DESIGN: A subset of 102 premature infants in the NO CLD trial, receiving 24 days of iNO (20 p.p.m. decreasing to 2 p.p.m.) or placebo, were analyzed. Tracheal aspirate (TA) and plasma samples collected at enrollment and at intervals during study gas were analyzed for NO metabolites. RESULT: iNO treatment increased NO metabolites in TA at 20 and 10 p.p.m. (1.7- to 2.3-fold vs control) and in plasma at 20, 10, and 5 p.p.m. (1.6- to 2.3-fold). In post hoc analysis, treated infants with lower metabolite levels at entry had an improved clinical outcome. CONCLUSION: iNO causes dose-related increases in NO metabolites in the circulation as well as lung fluid, as evidenced by TA analysis, showing NO delivery to these compartments.

Visual assessment of jaundice in term and late preterm infants.

OBJECTIVE: To determine the accuracy of predischarge visual assessment of jaundice for estimating bilirubin concentration and predicting risk of significant neonatal hyperbilirubinaemia. DESIGN: Prospective cohort study. SETTING: Well Baby Nursery at the Hospital of the University of Pennsylvania. PATIENTS: 522 term and late preterm newborns. INTERVENTIONS: Nurses used a 5-point scale to grade the maximum cephalocaudal extent of jaundice prior to discharge. MAIN OUTCOME MEASURES: (1) Correlation between jaundice grade and bilirubin concentration. (2) Predictive accuracy of jaundice grade for identifying infants who developed significant hyperbilirubinaemia, defined as a bilirubin level that at any time after birth exceeded or was within 1 mg/dl (17 micromol/l) of the American Academy of Pediatrics-recommended hour-specific phototherapy treatment threshold. RESULTS: Nurses' assessment of jaundice extent was only moderately correlated with bilirubin concentration and was similar in black and non-black infants (Spearman's rho = 0.45 and 0.55, respectively (p = 0.13)). The correlation was particularly weak among infants <38 weeks' gestational age (rho = 0.29) compared with infants > or = 38 weeks' gestation (rho = 0.53, p = 0.05). Jaundice extent had poor overall accuracy for predicting risk of significant hyperbilirubinaemia (c-statistic = 0.65) but complete absence of jaundice had high sensitivity (95%) and excellent negative predictive value (99%) for ruling out the development of significant hyperbilirubinaemia. CONCLUSIONS: Clinicians should not use extent of cephalocaudal jaundice progression to estimate bilirubin levels during the birth hospitalisation, especially in late preterm infants. However, the complete absence of jaundice can be used to predict with very high accuracy which infants will not develop significant hyperbilirubinaemia.

Deregulated Wnt/beta-catenin program in high-risk neuroblastomas without MYCN amplification.

Neuroblastoma (NB) is a frequently lethal tumor of childhood. MYCN amplification accounts for the aggressive phenotype in a subset while the majority have no consistently identified molecular aberration but frequently express MYC at high levels. We hypothesized that activated Wnt/beta-catenin (CTNNB1) signaling might account for this as MYC is a beta-catenin transcriptional target and multiple embryonal and neural crest malignancies have oncogenic alterations in this pathway. NB cell lines without MYCN amplification express higher levels of MYC and beta-catenin (with aberrant nuclear localization) than MYCN-amplified cell lines. Evidence for aberrant beta-catenin-TCF transcriptional activity was demonstrated using expression profiles from 73 primary NBs. Findings included increased WNT ligands (WNT1, WNT6, WNT7A, WNT10B), DVL1 and TCF7 expression in high-risk NBs without MYCN amplification, consistent with canonical beta-catenin signaling. More directly, Patterns of Gene Expression and Gene Set Enrichment Analyses demonstrated beta-catenin target genes (for example, MYC, PPARD, NRCAM, CD44, TCF7) as coordinately upregulated in high-risk NBs without MYCN amplification in comparison to high-risk MYCN-amplified or intermediate-risk NBs, supporting pathway activation in this subset. Thus, high-risk NBs without MYCN amplification may deregulate MYC and other oncogenic genes via altered beta-catenin signaling providing a potential candidate pathway for therapeutic inhibition.

BH3 peptidomimetics potently activate apoptosis and demonstrate single agent efficacy in neuroblastoma.

The major impediment to cure for many malignancies is the development of therapy resistance with resultant tumor progression. Genetic alterations leading to subversion of inherent apoptosis pathways are common themes in therapy resistance. Bcl-2 family proteins play a critical role in regulating mitochondrial apoptosis that governs chemotherapeutic effects, and defective engagement of these pathways contributes to treatment failure. We have studied the efficacy of BH3 peptidomimetics consisting of the minimal death, or BH3, domains of the proapoptotic BH3-only proteins Bid and Bad to induce apoptosis using neuroblastoma (NB) as a model system. We demonstrate that BH3 peptides, modified with an arginine homopolymer for membrane transduction (called r8-BidBH3 and r8-BadBH3, respectively), potently induce apoptosis in NB cells, including those with MYCN amplification. Cell death is caspase 9 dependent, consistent with a requirement for the intrinsic mitochondrial pathway. Substitutions at highly conserved residues within the r8-BidBH3 peptide abolish apoptotic efficacy supporting activity through specific BH domain interactions. Concomitant exposure to r8-BadBH3 and r8-BidBH3 at sublethal monotherapy doses revealed potent synergy consistent with a competitive displacement model, whereby BH3 peptides displace sequestered BH3 proteins to induce cell death. Further, BH3 peptides demonstrate antitumor efficacy in a xenograft model of NB in the absence of additional genotoxic or trophic stressors. These data provide proof of principle that targeted re-engagement of apoptosis pathways may be of therapeutic utility, and BH3-like compounds are attractive lead agents to re-establish therapy-induced apoptosis in refractory malignancies.

Survival and complications in thalassemia.

The life expectancy of patients with thalassemia major has significantly increased in recent years, as reported by several groups in different countries. However, complications are still frequent and affect the patients' quality of life. In a recent study from the United Kingdom, it was found that 50% of the patients had died before age 35. At that age, 65% of the patients from an Italian long-term study were still alive. Heart disease is responsible for more than half of the deaths. The prevalence of complications in Italian patients born after 1970 includes heart failure in 7%, hypogonadism in 55%, hypothyroidism in 11%, and diabetes in 6%. Similar data were reported in patients from the United States. In the Italian study, lower ferritin levels were associated with a lower probability of experiencing heart failure and with prolonged survival. Osteoporosis and osteopenia are common and affect virtually all patients. Hepatitis C virus antibodies are present in 85% of multitransfused Italian patients, 23% of patients in the United Kingdom, 35% in the United States, 34% in France, and 21% in India. Hepatocellular carcinoma can complicate the course of hepatitis. A survey of Italian centers has identified 23 such cases in patients with a thalassemia syndrome. In conclusion, rates of survival and complication-free survival continue to improve, due to better treatment strategies. New complications are appearing in long-term survivors. Iron overload of the heart remains the main cause of morbidity and mortality.

Identifying newborns at risk of significant hyperbilirubinaemia: a comparison of two recommended approaches.

AIMS: To compare the predictive performance of clinical risk factor assessment and pre-discharge bilirubin measurement as screening tools for identifying infants at risk of developing significant neonatal hyperbilirubinaemia (post-discharge total serum bilirubin (TSB) >95th centile). METHODS: Retrospective cohort study of term and near term infants born in an urban community teaching hospital in Pennsylvania (1993-97). A clinical risk factor scoring system was developed and its predictive performance compared to a pre-discharge TSB expressed as a risk zone on a bilirubin nomogram. Main outcome measures were prediction model discrimination, range of predicted probabilities, and sensitivity, specificity, positive and negative predictive values, and likelihood ratios for various positivity criteria. RESULTS: The clinical risk factor scoring system developed included birth weight, gestational age <38 weeks, oxytocin use during delivery, vacuum extraction, breast feeding, and combination breast and bottle feeding. The pre-discharge bilirubin risk zone had better discrimination (c = 0.83; 95% CI 0.80 to 0.86) than the clinical risk factor score (c = 0.71; 95% CI 0.66 to 0.76) and predicted risk of significant hyperbilirubinaemia as high as 59% compared with a maximum of 44% for the clinical risk factor score. Neither the risk score nor the pre-discharge TSB risk zone predicted the outcome with > or =0.98 sensitivity without significantly compromising specificity (0.13 and 0.21, respectively). Multi-level clinical risk factor scores and TSB risk zones produced likelihood ratios of 0.15-3.25 and 0.05-9.43, respectively. CONCLUSIONS: The pre-discharge bilirubin expressed as a risk zone on an hour specific bilirubin nomogram is more accurate and generates wider risk stratification than a clinical risk factor score.

Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a Pediatric Blood and Marrow Transplant Consortium study.

Conditioning regimens for children with ALL have generally included total body irradiation (TBI), which may result in significant sequelae. The primary aim of this study was to evaluate the outcome for children with ALL undergoing allogeneic stem cell transplant (SCT) with either busulfan (Bu) or TBI regimens. Patients <21 years with ALL undergoing allogeneic SCT were eligible. Conditioning included either Bu or TBI, with etoposide 40 mg/kg and cyclophosphamide 120 mg/kg. Randomization was stratified based upon duration of remission, remission status, and prior cranial irradiation. A total of 43 patients were enrolled; 21 received Bu and 22 TBI. Median patient age was 8 years (0.5-20 years). Remission status included 12 patients in CR1, 25 in CR2, and six in CR3. At a median follow-up of 43 months, event-free survival (EFS) is 45% at 3 years, with 29% EFS in the Bu arm and 58% in the TBI arm (P=0.03). There was no significant difference between Bu and TBI for patients who received stem cells from related donors (36 vs 58%, P=0.3). However, for URD, EFS was 20% for Bu and 57% for TBI (P=0.04). Relapses were similar in both arms. This randomized prospective study suggests that Bu is inferior to TBI for pediatric patients with ALL undergoing allogeneic SCT.

Exposure to traffic among urban children injured as pedestrians.

OBJECTIVES: To explore the immediate pre-crash activities and the routine traffic exposure (street crossing and play) in a sample of urban children struck by automobiles. In particular, the traffic exposure of children who were struck while playing was compared with that of those struck while crossing streets. DESIGN: Cross sectional survey. SETTING: Urban pediatric emergency department. PATIENTS: A total of 139 children ages 4-15 years evaluated for acute injuries resulting from pedestrian-motor vehicle collisions during a 14 month period. MAIN OUTCOME MEASURES: Sites of outdoor play, daily time in outdoor play, weekly number of street crossings, pre-crash circumstance (play v walking). RESULTS: Altogether 39% of the children routinely used the street and 64% routinely used the sidewalks as play areas. The median number of street crossings per week per child was 27. There were no differences in exposures for the 29% who were hit while playing compared with the 71% who were hit while walking. Although 84% of the children walked to or from school at least one day per week, only 15% of the children were struck while on the school walking trip. The remainder were injured either while playing outdoors or while walking to other places. CONCLUSIONS: Urban children who are victims of pedestrian crashes have a high level of traffic exposure from a variety of circumstances related to their routine outdoor playing and street crossing activities. The distributions of traffic exposures were similar across the sample, indicating that the sample as a whole had high traffic exposure, regardless of the children's activity preceding the crash. Future pedestrian injury programs should address the pervasive nature of children's exposure to traffic during their routine outdoor activities.

Design and baseline characteristics for the ACE Inhibitor After Anthracycline (AAA) study of cardiac dysfunction in long-term pediatric cancer survivors.

PURPOSE: The ACE Inhibitor After Anthracycline (AAA) study is a randomized, double-blind, controlled clinical trial comparing enalapril with placebo to determine whether treatment can slow the progression of cardiac decline in patients who screen positive for anthracycline cardiotoxicity. METHODS: The primary outcome measure is the rate of decline, over time, in maximal cardiac index (in liters per minute per meters squared) at peak exercise; the secondary outcome measure is the rate of increase in left ventricular end systolic wall stress (in grams per centimeters squared). Patients >2 years off therapy and <4 years from diagnosis, aged 8 years and older, were eligible if they had received anthracyclines and had at least one cardiac abnormality identified at any time after anthracycline exposure. RESULTS: A total of 135 patients were randomized to enalapril or placebo. Baseline characteristics were similar across treatment groups. CONCLUSIONS: The AAA study will provide important information concerning the efficacy of using angiotensin-converting enzyme inhibitors to offset the effects of late anthracycline cardiotoxicity.

Elevated substance P levels in HIV-infected men.

The neuropeptide, substance P, is a potent modulator of neuroimmunoregulation. Substance P and its receptor modulate HIV infection. HIV-seropositive men had significantly higher plasma substance P levels compared with uninfected controls, which were associated with decreased CD16 and CD56 natural killer (NK) cell populations. The changes in plasma substance P levels and decreases in NK subsets did not correlate with CD4 cell levels, but a diurnal pattern was suggested for substance P. The balance between substance P expression and functions of immune cells may be important in the immunopathogenesis of HIV infection.

The validity of the interviewer severity ratings in groups of ASI interviewers with varying training.

AIMS: This study evaluated the hypothesis that the subjective interviewer severity rating (ISR) summary indices of the intake Addiction Severity Index (ASI) of less trained interviewers are less valid than those of more highly trained interviewers. DESIGN: Baseline ASIs from three completed studies whose interviewers varied in degree of initial ASI training and subsequent quality assurance monitoring were examined. Associations between baseline ISRs and three other sets of ASI summary indices not based on interviewer ratings-composite scores, clinical indices and evaluation indices-were compared for three groups of interviewers with varying amounts of training. The assumption underlying these analyses was that more reliable ISRs, found in more trained interviewers, would be more highly associated with the other more objective indices. SETTING: Methadone maintenance patients in the Philadelphia and New York City areas. PARTICIPANTS: Thirty-five interviewers with the most intense training who administered 295 interviews; 10 interviewers with an intermediate level of training who administered 763 interviews; and eight identified (and other unidentified) least trained interviewers who administered a total of 276 interviews. Measurements and methods. Four sets of summary indices from the above ASIs. Both bivariate and multivariate analyses were performed. FINDINGS: The study found that the validity of the validity of ISRs was greater in more trained interviewers. CONCLUSIONS: Greater training and subsequent monitoring of ASI interviewers generally appears to be associated with increased ISR validity.

Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282.

BACKGROUND: A phase II study of dacarbazine (DTIC), was conducted to determine the response rate, duration of response, toxicity and overall survival of patients with advanced pancreatic islet cell tumors. PATIENTS AND METHODS: Fifty patients with advanced pancreatic islet cell tumors, having progressive symptoms or evidence of rapidly advancing disease were entered on this study. DTIC was given by IV infusion at a dose of 850 mg/m2, over 60-90 minutes, repeated every four weeks. RESULTS: The response rate was 33% in 42 patients who had measurable tumor, and 34% in the 50 patients (90% confidence interval (90% CI): 23%-47%). The majority of the responses were seen in patients without prior chemotherapy. Median overall survival was 19.3 months. There were two lethal toxicities on the study, one septic shock and one myocardial infarction. Grade 4 toxicities were, hematological (5 patients), sepsis, neurological (depression and paranoid behavior) and bleeding (1 patient each). The most common toxicity was vomiting, grade 3 in 13% of patients. CONCLUSIONS: DTIC has activity in advanced previously untreated pancreatic islet cell tumors.

Association among EPHB2, TrkA, and MYCN expression in low-stage neuroblastomas.

BACKGROUND: The EPH family is the largest subfamily of receptor protein-tyrosine kinases, consisting of EPHA and EPHB subgroups. Ligands of EPH family receptors are called ephrins, which include ephrin-A and ephrin-B subgroups. We recently found that transcripts encoding the EPHB subgroup (EPHB) and the ephrin-B subgroup (EFNB) were expressed together in neuroblastoma (NB) cell lines. PROCEDURE: In this study, we examined the expression of EPHB and EFNB transcripts in 24 NB specimens representing all clinical stages. We found that several EPHB and EFNB transcripts were expressed together in all NBs examined. RESULTS: Among the transcripts examined, EPHB6 expression was most significantly associated with low stage tumors (stages 1, 2, and 4S; P = 0.0048). TrkA expression was significantly correlated with EPHB6, EFNB2, and EFNB3 expression (P < 0.01 in each case). Taken together, these data indicate that the expression of EPHB6, EFNB2, and EFNB3 may serve as prognostic indicators of favorable NBs. In the low-stage NBs without MYCN amplification, EPHB2 expression was correlated both with MYCN expression and with TrkA expression (P < 0.01 in each case). Moreover, MYCN expression was correlated with TrkA expression (P < 0.01) in the low-stage NBs. CONCLUSIONS: This observation points to the possibility that MYCN expression might contribute to favorable outcome of low-stage NBs.

High microvessel density in primitive neuroectodermal brain tumors of childhood.

Microvessel density (MVD), a measure of tumor angiogenesis, has been shown to correlate significantly with overall and progression-free survival outcomes in various cancers including astrocytic brain tumors. To assess if the MVD is an independent prognostic factor in primitive neuroectodermal tumors (PNET) of the central nervous system, formalin-fixed paraffin-embedded tumor sections of 78 children with PNET were studied by CD34 immunohistochemistry to highlight endothelial cells. Microvessel density was determined in the most active area of neovascularization according to well-established methods. While it was shown that MVD showed considerable inter-tumor variability (median 75; range 20-345 microvessels per 0.7 mm2 field), no significant associations were found between MVD and metastasis or survival outcomes. We conclude that many PNETs are highly vascular CNS tumors, indicating potent angiogenic activity. Therefore, these tumors would be good candidates for antiangiogenic strategies. However, MVD determined in the most active area of neovascularization is not a predictor of metastatic potential or survival outcomes in childhood PNET.

Effectiveness of propranolol for cocaine dependence treatment may depend on cocaine withdrawal symptom severity.

Propranolol may reduce symptoms of autonomic arousal associated with early cocaine abstinence and improve treatment outcome. This trial was an 8-week, double-blind, placebo-controlled trial of propranolol in 108 cocaine dependent subjects. The primary outcome measure was quantitative urinary benzoylecgonine levels. Secondary outcome measures included treatment retention, addiction severity index results, cocaine craving, mood and anxiety symptoms, cocaine withdrawal symptoms, and adverse events. Propranolol treated subjects had lower cocaine withdrawal symptom severity but otherwise did not differ from placebo treated subjects in any outcome measure. However, in a secondary, exploratory analysis, subjects with more severe cocaine withdrawal symptoms responded better to propranolol in comparison to placebo. In these subjects, propranolol treatment was associated with better treatment retention and lower urinary benzoylecgonine levels as compared with the placebo treatment. Propranolol may be useful only for the treatment of cocaine dependent patients with severe cocaine withdrawal symptoms.

Comparison of 5-fluorouracil alone, 5-fluorouracil with levamisole, and 5-fluorouracil with hepatic irradiation in the treatment of patients with residual, nonmeasurable, intra-abdominal metastasis after undergoing resection for colorectal carcinoma.

BACKGROUND: The authors conducted a randomized Phase III trial of three treatment regimens for patients with residual, nonmeasurable, intra-abdominal metastatic disease after undergoing resection for primary colorectal carcinoma. METHODS: To be eligible for this study, patients had to be both free of other malignancies and capable of starting their therapy within 3-6 weeks after surgery. They were required to have an Eastern Cooperative Oncology Group performance status < 3; to be chemotherapy, radiation, and immunotherapy naïve; to have adequate bone marrow, renal, and hepatic function; and to provide written, informed consent. The patients were divided into two cohorts: patients with no demonstrable hepatic metastasis (Group A) and patients with hepatic metastasis (Group B). RESULTS: The 229 patients in Group A were randomized to receive either 5-fluorouracil (5-FU) (n = 116 patients) or 5-FU with levamisole (n = 113 patients). The median survival (15.4 months and 15.3 months, respectively, for Groups A and B) was virtually identical. The two groups also were similar in terms of time to treatment progression, which was 7.9 months for group that received 5-FU alone 7.7 months for the group that received levamisole with 5-FU. The 168 patients in Group B with hepatic metastasis underwent a three-way randomization: 5-FU alone (n = 60 patients), 5-FU with levamisole (n = 54 patients), and 5-FU with hepatic irradiation (n = 54 patients). The median overall survival for the three treatment arms were similar, with 17.3 months for the group that received 5-FU alone, 16 months for the group that received 5-FU with levamisole, and 14.4 months for the group that received hepatic irradiation in addition to 5-FU: The time to treatment failure was 6.7 months, 6.8 months, and 8.3 months, respectively, for the three groups. The toxicity experienced by patients was as expected with the regimens, and no differences were observed between any of the treatment groups. The primary toxicities were hematologic and gastrointestinal. There was one treatment-related death due to adult respiratory distress syndrome, which occurred on the first day of the fourth cycle of 5-FU and levamisole. Other Grade 4 toxicities included nine patients with Grade 4 leukopenia, one patient with Grade 4 sepsis, and one patient with Grade 4 gastrointestinal toxicity, including blood loss and diarrhea. CONCLUSIONS: This study showed no treatment advantage for any of the combined modalities over 5-FU alone in this group of patients with intra-abdominal, nonmeasurable disease.

Association of plasma cortisol and chronic lung disease in preterm infants.

BACKGROUND: It has been suggested that preterm infants may have developmental immaturity of the hypothalamic-pituitary-adrenal axis, and that decreased cortisol response to stress increases risk of chronic lung disease (CLD) secondary to inflammatory lung injury. METHODS: To investigate the relationship between endogenous corticosteroid and CLD, we measured plasma cortisol during the first 28 days of life in a subset of neonates in the North American Thyrotropin-Releasing Hormone (TRH) Collaborative Trial. Analyses were performed on 314 infants, 24 to 32 weeks' gestation, whose mothers received 1 or 2 courses of antenatal corticosteroids plus TRH or placebo. RESULTS: Mean cortisol was 3.1 microg/dL (range: 0.1-17.9) at birth, reached maximal levels at 24 hours (19.4 microg/dL, range: 0.8-124.6), and decreased to 5.9 microg/dL (range: 0.2-24.7) at 14 to 28 days of age; levels during the first week were not associated with gestational age. The Clinical Risk Index for Babies (CRIB), a neonatal assessment tool that is correlated with risk of mortality, was positively associated with cortisol level on days 1 and 3 through 7. TRH versus placebo treatment did not influence cortisol levels at any time point. To examine the relationship between cortisol and adverse outcome of death or CLD at 36 weeks' postmenstrual age (CLD36), logistic regression models adjusting for known contributing clinical factors (gestational age and CRIB score) were fit. There was a statistically borderline negative association between median cortisol level at 3 to 7 days and CLD36. After adjusting for gestational age and CRIB score, the predicted probability of CLD36 was only minimally influenced by the cortisol concentration. CONCLUSION: In preterm infants, basal plasma cortisol concentration during the first week is a weak predictor for CLD36. Possible benefits as well as risks of supplemental, low-dose cortisol treatment of high-risk preterm infants remain to be determined.

Double-blind clinical trial of sertraline treatment for alcohol dependence.

Clinical studies that have evaluated serotonergic medications to reduce alcohol consumption have yielded conflicting results. These studies primarily treated patients with alcohol dependence, excluding those with a current depressive disorder, in an effort to differentiate any medication effects directly on drinking from those on mood. Yet despite the exclusion of current depression, a group of alcohol-dependent patients who are not depressed can be highly heterogeneous. For example, this subgroup can include those with a lifetime depressive disorder. If these patients were more sensitive to serotonergic medications than patients without a lifetime depressive disorder, medication effects in a subgroup of patients who were not depressed could be obscured. Thus, the purpose of this study was to examine the efficacy of sertraline for treating alcohol dependence in patient groups that were differentiated by the presence or absence of lifetime depression. This study examined the effectiveness of sertraline (200 mg/day) or placebo for 14 weeks in 100 alcohol-dependent subjects with (N = 53) or without (N = 47) a lifetime diagnosis of comorbid depression. Sertraline treatment seemed to provide an advantage in reducing drinking in alcohol-dependent patients without lifetime depression, illustrated best with a measure of drinking frequency during treatment. However, sertraline was no better than placebo in patients with a diagnosis of lifetime comorbid depression, and current depression did not change the results. Treatment with selective serotonin reuptake inhibitors may be useful in alcohol-dependent patients who are not depressed. Subtyping those with alcohol dependence on the basis of the absence versus the presence of a lifetime depressive disorder may help to resolve conflicting findings in the literature on the treatment of alcohol dependence with serotonergic medications.

Expression of the neurotrophin receptor TrkB is associated with unfavorable outcome in Wilms' tumor.

PURPOSE: Neurotrophins and their receptors regulate the proliferation, differentiation, and death of neuronal cells, and they have been implicated in the pathogenesis and prognosis of neuroblastomas and medulloblastomas. Tyrosine kinase (Trk) receptors also are expressed in extraneural tissues. PATIENTS AND METHODS: To study the role of neurotrophin receptors and ligands in Wilms' tumor (WT), we determined their expression by semiquantitative duplex reverse transcriptase polymerase chain reaction in 39 patients with primary WT. Comparison of mRNA expression levels with clinical variables was performed by use of Cox regression analysis. RESULTS: Children with WT that expressed high levels of full-length TrkB mRNA (TrkBfull) had a significantly greater risk of death than children whose tumors had little or no TrkBfull expression (hazard ratio, 9.7; P =.02). The 5-year relapse-free survival was 100% versus 65% for patients with low versus high tumor expression of TrkBfull (P <.003). Conversely, children with tumors that expressed high mRNA levels of a functionally inactive truncated TrkB receptor (TrkBtrunc) had a greater chance of survival than children with low levels of TrkBtrunc (hazard ratio, 0.08; P =.005). The 5-year relapse-free survival was 95% versus 68% for patients with high versus low levels of TrkBtrunc (P =.01). The hazard ratios for TrkBfull and TrkBtrunc remained significant after they were adjusted for tumor stage (P =.01 and P =.017, respectively). All WTs with high levels of TrkB expression also expressed the brain-derived nerve growth factor ligand. CONCLUSION: Expression of TrkBfull in WT is associated with worse outcome, perhaps because it provides an autocrine survival pathway. Conversely, TrkBtrunc expression is associated with excellent outcome, perhaps as a result of a dominant negative effect.