Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890

Up-regulation of GABA(B) receptors by chronic administration of the GABA(B) receptor antagonist SCH 50,911

Chronic treatment of mice with the specific gamma-aminobutyrie acid(B) (GABA(B)) receptor antagonist (2S)(+)-5.5-(dimethyl-2-morpholineacetic acid (SCH 50,911) increased both the number of GABA(B) receptors in the whole brain (measured as [H-1]CGP 54626 [S-(R,R)]-3-[[1-(3,4-dichlorophenyl)amino]-2-hydroxypropyl](cyclohexylmethyl)phosphinic acid hydrochloride binding) and the ability of bacloten to activate GABA(B) receptor coupled G-protein (measured as % reduction of the EC50 of baclofen to activate [S-15]GTP gamma S binding). The results indicate that persistent blockade of GABA(B) receptors leads to their compensatory up-regulation and suggest that GABA(B) receptors are tonically activated by endogenous GABA. (c) 2005 Elsevier B.V. All rights reserved

GHB-C rats: the control line of GHB-sensitive (GHB-S) and GHB-resistant (GHB-R) rats

Gamma-hydroxybutyric acid (GHB)-sensitive (GHB-S) and GHB-resistant (GHB-R) rats have been selectively bred for their opposite sensitivity to the sedative/hypnotic effect of GHB. This opposite sensitivity has been found to generalize to the GABA(B) receptor agonist, baclofen. A control line [named GHB-control (GHB-C)] has been derived from the foundation stock of GHB-S and GHB-R rats. GHB-C rats have been bred without any evaluation of their sensitivity to GHB. The experiments described here were designed to evaluate the sensitivity of GHB-C rats, from the 13th generation, to the sedative/hypnotic effect of GHB (1 g/kg, i.p.) and baclofen (20 mg/kg, i.p.). All measures (onset, sleep time and r = sleep time/onset) of sensitivity to GHB- and baclofen-induced sedation/hypnosis in GHB-C rats were significantly different from and intermediate to those recorded in GHB-S and GHB-R rats. Furthermore, these values were similar to those recorded in the foundation stock. These results suggest that GHB-C rats may constitute a valid control line for GHB-S and GHB-R rats, representing the "general population" from which GHB-S and GHB-R rats were derived. Furthermore, the relative equidistance of sensitivity to GHB- and baclofen-induced sedation/hypnosis of GHB-C rats from those of GHB-S and GHB-R rats suggests that genetic factors contributes to the development of both sensitivity in GHB-S rats and resistance in GHB-R rats

Evaluation for the withdrawal syndrome from gamma-hydroxybutyric acid (GHB), gamma-butyrolactone (GBL), and 1,4-butanediol (1,4-BD) in different rat lines.

A severe and life-threatening gamma-hydroxybutyric acid (GHB) withdrawal syndrome, clinically similar to the alcohol withdrawal syndrome, is increasingly being reported in GHB addicts. We investigated for the occurrence of withdrawal in Wistar and Sprague-Dawley rats, and in the selectively bred lines of GHB-sensitive (GHB-S) and Sardinian alcohol-preferring (sP) rats, following chronic administration of GHB, gamma-butyrolactone (GBL), and/or 1,4-butanediol (1,4-BD). Using validated rodent alcohol withdrawal scoring scales, little to no spontaneous or pharmacologically precipitated withdrawal effects were observed in Wistar, Sprague-Dawley, or GHB-S rats. Conversely, sP rats displayed both spontaneous and precipitated audiogenic seizures following abrupt cessation of chronic GHB or 1,4-BD administration and following pharmacological challenge with the GABA(B) receptor-selective antagonist, SCH 50911, respectively

Differential G-protein coupling to GABAB receptor in limbic areas of alcohol-preferring and -nonpreferring rats

The function of the gamma-aminobutyric acid(B) (GABAB) receptor, measured as baclofen-stimulated [35S]GTPgammaS binding, was evaluated in some brain regions of Sardinian alcohol-preferring (sP) and -nonpreferring (sNP) rats. EC50 value of baclofen-stimulated [35S]GTPgammaS in limbic areas was approximately 125% higher in alcohol-naive sP than sNP rats; voluntarily consumed alcohol reduced the EC50 value to a level similar to that of alcohol-naive sNP rats. These results suggest the presence of a genetically determined lower function of the GABAB receptor in limbic areas of sP than sNP rats; this differential functioning of the GABAB receptor may contribute to the opposite preference for alcohol in these rat lines

Reducing effect of the positive allosteric modulators of the GABAB receptor, CGP7930 and GS39783, on alcohol intake in alcohol-preferring rats

The gamma-aminobutyric acidB (GABA(B)) receptor full agonists, baclofen and CGP44532, have been found to suppress different aspects of alcohol drinking behavior, including acquisition and maintenance, in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to assess whether this capability extends to the recently synthesized, positive allosteric modulators of the GABA(B) receptor, 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783). In the "acquisition" experiments, CGP7930 (0, 25, 50 and 100 mg/kg; i.g.) and GS39783 (0, 6.25, 12.5 and 25 mg/kg; i.g.) were administered for 5 consecutive days to alcohol-naive sP rats. In the "maintenance" experiments, (0, 50 and 100 mg/kg; i.g.) and GS39783 (0, 50 and 100 mg/kg; i.g.) were administered for 5 consecutive days to alcohol-experienced sP rats. Alcohol intake was evaluated under the standard, homecage 2-bottle "alcohol (10%, v/v) vs water" regimen with unlimited access for 24 h/day. Both CGP7930 and GS39783 dose-dependently suppressed the acquisition of alcohol drinking behavior. In the "maintenance" experiments, CGP7930 and GS39783 reduced daily alcohol intake by 30-40% only at the highest dose when compared to vehicle-treated rats; this effect tended to vanish on continuing treatment. The results of the present study suggest that positive allosteric modulation of the GABA(B) receptor produced an effect on alcohol drinking behavior similar to that produced by GABA(B) receptor full agonists. These data also suggest that positive allosteric modulation of the GABA(B) receptor may constitute a potential strategy for developing new drugs for treating alcohol dependence

Baclofen-induced reduction of alcohol reinforcement in alcohol-preferring rats

Recent studies have demonstrated that treatment with the gamma-aminobutyric acid (GABA(B)) receptor agonist, baclofen, reduces alcohol intake in selectively bred Sardinian alcohol-preferring rats tested under the homecage two-bottle "alcohol versus water" choice regimen. This study was designed to investigate whether baclofen also reduces alcohol-reinforcing effects in Sardinian alcohol-preferring rats. To this aim, sP rats were trained to lever press for oral alcohol (15%, vol/vol) or sucrose (0.3%, wt/vol; included as alternative reinforcer to evaluate the specificity of baclofen effect on alcohol reinforcement) under a fixed ratio schedule of 4. Once steady levels of alcohol or sucrose self-administration behavior were established, the effects of acutely administered baclofen (0, 1.7, and 3 mg/kg, intraperitoneal [ip]) and naloxone (0, 1, and 3 mg/kg, ip; included as reference compound) on alcohol- or sucrose-reinforced responding were evaluated. Baclofen administration dose dependently, although not specifically, reduced alcohol-reinforced responding to an extent comparable to that of naloxone. Baclofen also produced a dose-dependent and specific delay in the onset of alcohol-reinforced responding, suggesting that it suppressed the rats' motivation to start drinking alcohol. These data are discussed in terms of adding further support to the hypothesized involvement of the GABA(B) receptor in the neural system mediating alcohol reinforcement. These data are also in agreement with the results of recent preliminary clinical studies suggesting that baclofen may have therapeutic efficacy in the treatment of alcohol dependence