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Bariatric surgery is the most effective and durable treatment option for obesity today. More importantly, beyond weight loss, bariatric procedures have many advantageous metabolic effects including reversal of obesity-related liver disease - nonalcoholic steatohepatitis (NASH). NASH is an important comorbidity of obesity given that it is a precursor to the development of liver cirrhosis that may necessitate liver transplantation in the long run. Simultaneously, we and others have observed increased serum bile acids in humans and animals that undergo bariatric surgery. Specifically, our preclinical studies have included experimental procedures such as ‘ileal transposition' or bile diversion and established procedures such as Roux-en-Y gastric bypass and the adjustable gastric band. Importantly, these effects are not simply the result of weight loss since our data show that the resolution of NASH and increase in serum bile acids are not seen in rodents that lose an equivalent amount of weight via food restriction. In particular, we have studied the role of altered bile acid signaling, in the potent impact of a bariatric procedure termed ‘vertical sleeve gastrectomy' (VSG). In this review we focus on the mechanisms of NASH resolution and weight loss after VSG surgery. We highlight the fact that bariatric surgeries can be used as ‘laboratories' to dissect the mechanisms by which these procedures work to improve obesity and fatty liver disease. We describe key bile acid signaling elements that may provide potential therapeutic targets for ‘bariatric-mimetic technologies' that could produce benefits similar to bariatric surgery - but without the surgery!

The objective of this study was to compare the relative bioavailability of two new products with solubilized and non-solubilized over-the-counter (OTC) coenzyme Q 10 products. Nine healthy adults were given single 180 mg doses of each coenzyme Q 10 formulation at two week intervals. A commercially-marketed, non-solubilized Q 10 powder formulation (product D) was only minimally absorbed, and was excluded from the analysis of data. ANOVA comparison of maximum plasma concentrations (C max ), time of maximum concentrations (t max ), areas under the concentration-time curves from times zero to 144 hours post dose (AUC 0-144h ), and areas under the concentration-time curves from times zero to infinity (AUC 0-∞ ) were not significantly different ( P > 0.05) between test products A (LiQ-10™) and B (Q-Nol™) and the reference product C (UbiQGel®). The upper limits of the 90% confidence intervals of the log-transformed ratios (A:C and B:C) of C max, AUC 0-144h, and AUC 0-∞ were >1.25 for both test products, but significant ( P 0-144h. The results of this study indicate that LiQ-10™ has increased bioequivalence compared to the reference product, but did not reach statistical significance. Q-Nol™ has increased bioavailability compared to the reference product ( P

Patients with Duchenne muscular dystrophy (DMD) lose ambulation by age 12. Long-term steroids have lengthened ambulation by 2-5 years. Ischial weight-bearing knee ankle foot orthoses prolong ambulation for 2-3 years. We report the outcome of the ambulatory status of a patient with DMD treated with daily steroid therapy and orthoses. This male patient was diagnosed with DMD at age of 2. He has been treated with daily steroids since age 7 years. He lost the ability to arise from the floor and walk up steps at age 14 and lost ambulation by age 16. He was fitted with orthoses at age 16 following surgical correction of his lower extremity contractures and regained independent ambulation. At age 20, he was able to stand independently in his orthoses and take steps with moderate support. We conclude that a combination of daily steroids and orthoses prolongs ambulation beyond that of the natural history DMD.

Children suffering from epilepsy with suspected low-grade tumors may benefit from a surgical approach that considers the epileptogenic zone, which can be more extensive than the tumor region. This study aimed to determine the prevalence of epilepsy in children undergoing supratentorial tumor resection and the factors predictive of postoperative seizure freedom in children with low-grade tumors. Subjects 3 months to 21 years undergoing supratentorial brain tumor resection between 2007 and 2011 were included in this retrospective study. Children with supratentorial, cortically based tumors and a preoperative diagnosis of epilepsy were considered epilepsy surgery candidates. Pre- and postoperative MRI were reviewed and scored for extent of resection, adjacent dysplasia, and remaining abnormal cortex postoperatively. The prevalence of seizures in all cases of supratentorial tumors was 46/87 (53 %). Eighteen were epilepsy surgery candidates. Eight of 18 (44 %) were seizure-free postoperatively with a mean follow-up of 39 months. Children who were seizure free postoperatively had tried fewer anticonvulsants than those with continued seizures (1.7 v. 2.9, p = 0.01). Presurgical evaluation was nonstandardized, and a more extensive workup and resection were performed in children who continued to have seizures postoperatively. All epilepsy surgery candidates had low-grade tumors on histological evaluation, indicating that a surgical approach that takes into consideration the epileptogenic zone is reasonable in this population. Gross total resection should be the goal, with additional attention to resection of the epileptogenic zone when located in the noneloquent cortex.

estimated that up to 30% of patients become resistant to optimized medical therapy and are potential surgical candidates. 2 Criteria for this distinction have varied, but most agree that failure of 2 appropriate antiepileptic drugs to adequately control seizures, with more than one seizure/month over an 18-month–2-year period, constitute intractability. 2 Additional important clinical features indicating that the patient may be a surgical candidate include stereotyped, lateralizing seizures with focality of semiology, a localized “epileptogenic zone” by scalp electroencephalography (EEG), magnetoencephalography (MEG), or surface EEG, and a localized anatomical target on magnetic resonance imaging (MRI). 2 In fact, the presence of an imaging abnormality is one of the key findings that predict resistance to medical therapy and may be a critical finding in determining suitability for surgical therapy. 3 Interestingly, it is thought by many pediatric epileptologists that younger children may in fact be better candidates for epilepsy surgery than adults because of their increased neuroplasticity and the detrimental effect of repeated seizures on normal neurologic development. 4 Cortical dysplasia is the most common neuropathology noted after surgical resection for intractable epilepsy in children, and recent clinicopathologic classification systems have had a significant effect on the treatment and understanding of this disorder. 5,6 Some forms of focal cortical dysplasia (FCD) (such as type IIb) have typical imaging manifestations, whereas other types such as isolated type I cortical dysplasia have variable and often nonlocalizing imaging features. As imaging findings indicating cortical dysplasia may significantly affect selection for potential surgery, radiologists involved with the workup of these patients must be familiar with the imaging spectrum of FCD, especially in children. In this article, we review the current pathologic classification and imaging findings in cortical dysplasia with an emphasis on the pediatric population.

To describe the clinical course and pathological diagnosis of a 12-year-old female who presented with an acute syndrome of right hemispheric epilepsy and cortical dysfunction and brain MRI demonstrating atrophy of the left cerebral and right cerebellar hemispheres. The patient presented with occasional partial seizures consisting of a left calf sensation followed by left leg clonic jerking. Initial brain MRI showed left cerebral and right cerebellar atrophy with T2 hyperintensity in the left parietal region. After six months, the seizure frequency increased and semiology evolved to include frequent clonic movements of the left side of the face, arm and leg and epilepsia partialis continua (EPC) of the left arm and leg. There was progressive weakness of the left leg and, to a lesser extent, her left arm. MRI at this time demonstrated an additional T2 hyperintensity in the right frontal lobe. An extensive evaluation for paraneoplastic, mitochondrial, and genetic epilepsy syndromes was unrevealing. On biopsy evaluation, chronic T-cell mediated encephalitis was demonstrated within bilateral frontal lobes. Treatment with immunomodulatory therapy resulted in some improvement in her seizure frequency and motor function. Rasmussen's encephalitis can be a challenging diagnosis. The patient's clinical history, including EPC, with bilateral frontal lobe biopsies confirming a T-cell mediated encephalitis supports a diagnosis of bilateral Rasmussen encephalitis. This case highlights the diagnostic challenges and treatment dilemmas that arise in an adolescent presenting with bilateral inflammatory lesions of Rasmussen's encephalitis. [ Published with video sequences]

Management of pediatric chronic liver disease is limited by lack of validated noninvasive biomarkers of histological severity. We demonstrate that magnetic resonance elastography (MRE) is feasible and accurate in detecting significant hepatic fibrosis in a case series of 35 children with chronic liver disease, including severely obese children.

Background & Aims C-Jun N-terminal kinase (JNK) activation is pivotal in the development of nonalcoholic steatohepatitis (NASH). Mixed lineage kinase 3 (MLK) 3 is one of the mitogen activated protein kinase kinase kinase (MAP3K) that mediates JNK activation in the liver. Despite this concept, the role of MLK3 in modulating liver injury during nutrient excess has not been explored. Our aim was to determine if MLK3 deficient mice were protected against high fat high carbohydrate (HFHC) diet-induced NASH. Methods We employed eight-week-old Mlk3−/− male C57BL/6J mice, and wild type (WT) mice C57BL/6J as controls. Mice were fed a HFHC or a chow diet adlib for 16 weeks. Results Hepatic JNK activating phosphorylation was readily absent in the Mlk3−/− mice fed the HFHC diet, but not in WT mice. This inhibition of JNK activation was hepatoprotective. Despite a comparable increase in weight gain, hepatic steatosis by histological examination and hepatic triglyceride quantification was reduced in HFHC diet-fed Mlk3−/− mice compared with WT mice. In addition, compared with the WT mice, HFHC diet-fed Mlk3−/− mice had significantly attenuated liver injury as manifested by reduced ALT levels, hepatocyte apoptosis, markers of hepatic inflammation and indices of hepatic fibrogenesis. Conclusion Our results suggest that loss of MLK3 in mice is protective against HFHC diet-induced NASH, in a weight-independent fashion, through attenuation of JNK activation. MLK3 is a potential therapeutic target for the treatment of human NASH.

Background JDM is the most common idiopathic inflammatory myopathy in children. The Wedderburn scoring system is used to assess JDM muscle biopsies and categorizes muscle involvement into 4 domains: inflammatory, vascular, muscle fiber and connective tissue fibrosis (maximum scores: 12, 3, 10, and 2, respectively) and a 10-cm VAS measuring overall abnormality. A 10 cm VAS for chronicity (endomysial fibrosis, capillary loss and central nuclei) was also measured.

Diets high in saturated fat and fructose have been implicated in the development of obesity and nonalcoholic steatohepatitis (NASH) in humans. We hypothesized that mice exposed to a similar diet would develop NASH with fibrosis associated with increased hepatic oxidative stress that would be further reflected by increased plasma levels of the respiratory chain component, oxidized coenzyme Q9 (oxCoQ9). Adult male C57Bl/6 mice were randomly assigned to chow, high-fat (HF), or high-fat high-carbohydrate (HFHC) diets for 16 weeks. The chow and HF mice had free access to pure water, whereas the HFHC group received water with 55% fructose and 45% sucrose (wt/vol). The HFHC and HF groups had increased body weight, body fat mass, fasting glucose, and were insulin-resistant compared with chow mice. HF and HFHC consumed similar calories. Hepatic triglyceride content, plasma alanine aminotransferase, and liver weight were significantly increased in HF and HFHC mice compared with chow mice. Plasma cholesterol (P < 0.001), histological hepatic fibrosis, liver hydroxyproline content (P = 0.006), collagen 1 messenger RNA (P = 0.003), CD11b-F4/80+Gr1+ monocytes (P < 0.0001), transforming growth factor β1 mRNA (P = 0.04), and α-smooth muscle actin messenger RNA (P = 0.001) levels were significantly increased in HFHC mice. Hepatic oxidative stress, as indicated by liver superoxide expression (P = 0.002), 4-hydroxynonenal, and plasma oxCoQ9 (P < 0.001) levels, was highest in HFHC mice. Conclusion: These findings demonstrate that nongenetically modified mice maintained on an HFHC diet in addition to developing obesity have increased hepatic ROS and a NASH-like phenotype with significant fibrosis. Plasma oxCoQ9 correlated with fibrosis progression. The mechanism of fibrosis may involve fructose inducing increased ROS associated with CD11b+F4/80+Gr1+ hepatic macrophage aggregation, resulting in transforming growth factor β1–signaled collagen deposition and histologically visible hepatic fibrosis. (HEPATOLOGY 2010)

The current study evaluated 23 children (ages 2-16 years) with recurrent food intolerance and allergies for CoQ10 deficiency and mitochondrial abnormalities. Muscle biopsies were tested for CoQ10 levels, pathology, and mitochondrial respiratory chain (MRC) activities. Group 2 (age >10 years; n = 9) subjects had significantly decreased muscle CoQ10 than Group 1 (age

Background Detection of cerebral hypoxia-ischemia (H-I) and prevention of brain injury remains problematic in critically ill neonates. Near-infrared spectroscopy (NIRS), a noninvasive bedside technology could fill this role, although NIRS cerebral O(2) saturation (Sc(O2)) viability-time thresholds for brain injury have not been determined. We investigated the relationship between H-I duration at Sc(O2) 35%, a viability threshold which causes neurophysiological impairment, to neurological outcome. Methods Forty-six fentanyl-midazolam anesthetized piglets were equipped with NIRS and cerebral function monitor (CFM) to record Sc(O2) and electrocortical activity (ECA). After carotid occlusion, inspired O(2) was adjusted to produce H-I (Sc(O2) 35% with decreased ECA) for 1, 2, 3, 4, 6 or 8 h in different groups, followed by survival to assess neurological outcome by behavioral and histological examination. Results For H-I lasting 1 or 2 h, ECA and Sc(O2) during reperfusion rapidly returned to normal and neurological outcomes were normal. For H-I more than 2-3 h, ECA was significantly decreased and Sc(O2) was significantly increased during reperfusion, suggesting continued depression of tissue O(2) metabolism. As H-I increased beyond 2 h, the incidence of neurological injury increased linearly, approximately 15% per h. Conclusion A viability-time threshold for H-I injury is Sc(O2) of 35% for 2-3 h, heralded by abnormalities in NIRS and CFM during reperfusion. These findings suggest that NIRS and CFM might be used together to predict neurological outcome, and illustrate that there is a several hour window of opportunity during H-I to prevent neurological injury.

Objective Except when the diagnosis of juvenile dermatomyositis (DM) is in doubt, a case has not been made for routine muscle biopsy (MB). We sought to determine whether MB findings prior to systemic therapy have prognostic value. Methods We reviewed the hospital records and slides prepared from the initial open MB of 72 patients treated at one center between 1977 and 2002 and followed for a minimum of 2 years. None of the patients had received a course of systemic corticosteroid therapy at the time of MB. Our approach to MB evaluation was based on recent discussions with muscle pathology experts to develop criteria for assessing inflammation, vasculopathy, myofiber atrophy, regeneration, acute and chronic myopathic change, and stromal changes. Using simple and multivariate logistic regression, we tested each MB parameter for ability to predict outcome using 2 published classification systems. Results Extensive active myopathic changes (excluding regeneration) and central nuclei without basophilia predicted chronic juvenile DM. Severe arteropathic change, positive arterial direct immunofluorescence, obvious foci of severe capillary loss/endomysial fibrosis, and muscle infarcts predicted chronic juvenile DM, particularly with ulceration. Other MB parameters, regardless of severity, were not significant predictors of chronic juvenile DM versus limited disease. Conclusion A scoring system for evaluating pretreatment MB in juvenile DM that focuses on extent of necrotizing myopathy, severity of vasculopathy, and features of established chronicity such as central nucleation of nonbasophilic myofibers may provide a basis for stratification of therapeutic regimens according to risk for chronic disease. The validity of our findings should be prospectively tested.

We report a false negative histochemical reaction for myophosphorylase in the case of an 11 year old with fulminant Staphylococcus aureus. Due to increased creatine kinase levels and marked myoglobinuria a muscle biopsy was performed prior to death. The biopsy revealed rhabdomyolysis, glycogen depletion and absent myophosphorylase reactivity. Subsequent myophosphorylase quantification was normal. This unique case of a false negative myophosphorylase histochemical reaction is apparently related to sepsis.

A toddler with a persistent congenital umbilical papule is described. The papule was found to contain both omphalomesenteric and urachal remnants. This patient's findings illustrate the importance of further evaluation of umbilical lesions when conventional therapy with silver nitrate fails.

Glycogen storage disease type IV (GSD-IV) is an autosomal recessive genetic disorder due to a deficiency in the activity of the glycogen branching enzyme (GBE). A deficiency in GBE activity results in the accumulation of glycogen with fewer branching points and long, unbranched outer chains. The disorder results in a variable phenotype, including musculoskeletal, cardiac, neurological, and hepatic involvement, alone or in continuum, which can be identified at any stage of life. The classic form of GSD-IV is a hepatic presentation, which presents in the first 18 months of life with failure to thrive, hepatomegaly, and cirrhosis that progresses to liver failure, resulting in death by age 5 years. A severe congenital musculoskeletal phenotype with death in the neonatal period has also been described. We report an unusual case of congenital musculoskeletal presentation of GSD-IV with stable congenital hypotonia, gross motor delay, and severe fibro-fatty replacement of the musculature, but no hepatic or cardiac involvement. Molecular analysis revealed two novel missense mutations with amino acid changes in the GBE gene (Q236H and R262C), which may account for the mild phenotype.

Background & Aims: To characterize the spectrum of nonalcoholic fatty liver disease (NAFLD) in morbidly obese adolescents, we correlated liver histology with clinical features and compared findings with reported adult data. We hypothesized that NAFLD would be less severe as a result of younger age and shorter duration of obesity, but portal inflammation and fibrosis would be more prevalent. Methods: Cross-sectional study was made of 41 adolescent subjects, 13–19 years old (mean, 16 years), 61% female, 83% non-Hispanic white, mean body mass index 59 kg/m 2 , undergoing gastric bypass with liver biopsy. Liver biopsies were graded and staged as proposed by the NASH Clinical Research Network. Data were analyzed by using descriptive statistics, analysis of variance, and Fisher exact tests. Results: Eighty-three percent had NAFLD: 24% steatosis alone, 7% isolated fibrosis with steatosis, 32% nonspecific inflammation and steatosis, and 20% nonalcoholic steatohepatitis (NASH). Twenty-nine percent had fibrosis; none had cirrhosis. Abnormal ALT ( P = .05) and AST ( P = .01) were more prevalent in NASH. Mean fasting glucose was significantly higher in NASH ( P = .05), but prevalence of the metabolic syndrome was not significantly different. Conclusions: NAFLD was very prevalent in morbidly obese adolescents, but severe NASH was uncommon. In contrast to morbidly obese adults, lobular inflammation, significant ballooning, and perisinusoidal fibrosis were rare, whereas portal inflammation and portal fibrosis were more prevalent, even in those who did not meet criteria for NASH. These findings might support use of a modified scoring system for pediatric NASH. Presence of the metabolic syndrome in morbidly obese adolescents did not distinguish NASH from steatosis alone.

Adenomatoid odontogenic tumor (AOT) is a slow-growing, asymptomatic and uncommon lesion that arises from odontogenic epithelium with inductive effects on connective tissue. The more common variant is the follicular type, which involves an unerupted tooth and is often mistaken for a dentigerous cyst. Histopathologic examination demonstrates cuboidal or spindle-shaped epithelial cells forming aggregates or rosette-like structures with minimal connective tissue, and cuboidal or low columnar cells forming glandular duct-like structures. Treatment is complete enucleation, and recurrences are rare. We presented a case of AOT in a 14-year-old male presenting as a cystic mass around an unerupted tooth.

Tailgut cyst, or retrorectal cystic hamartoma, is a rare congenital lesion found in the presacral space. The lesion has been infrequently reported in the literature. We report the MRI findings of a tailgut cyst in a 2-year-old girl who presented with a sacral dimple and skin discoloration.

Ubiquinone-responsive multiple respiratory chain dysfunction due to coenzyme Q(10) (CoQ(10)) deficiency has been previously identified in muscle biopsies. However, previous methods are unreliable for estimating CoQ(10) redox status in tissue. We developed an accurate method for measuring tissue concentrations of reduced and oxidized coenzyme Q (CoQ).Mouse tissues were weighed in the frozen state and homogenized with cold 1-propanol on ice. After solvent extraction, centrifugation and filtration, the filtrate was subsequently analyzed by reversed-phase HPLC with coulometric detection.Reference calibration curves were used to determine reduced and oxidized coenzyme Q(9) (CoQ(9)) and CoQ(10) concentrations in tissues. The method is sensitive ( approximately 15 microg/l), reproducible (6% CV) for CoQ(9) and CoQ(10), and linear up to 20 mg/l for CoQ(9) and CoQ(10). Analytical recoveries were 90-104%. In mouse tissues the amounts of total CoQ (TQ) ranged from 261 to 1737 nmol/g of protein. Total CoQ(9) levels are comparable with the values of those previously reported. CoQ is found to be mostly in the reduced form in mouse liver ( approximately 87%), heart ( approximately 60%), and muscle tissues ( approximately 58%); in the brain, most of the CoQ is in the oxidized state ( approximately 65%).This procedure provides a precise, sensitive, and direct assay method for the determination of reduced and oxidized CoQ(9) and CoQ(10) in mouse hindleg muscle, heart, brain, and liver tissues.

BACKGROUND: Bariatric surgery is an effective method for achieving sustainable weight loss and health benefit in the morbidly obese population. Although inflammatory bowel disease (IBD) is often associated with malnutrition and weight loss, there has been a temporal increase in the prevalence of obesity among IBD patients. We evaluate the effect of IBD on post-surgical complications and health care utilization among inpatient gastric bypass procedures for obesity. METHODS: The Nationwide Inpatient Sample (NIS) was analyzed for all hospitalizations between 1998 through 2011 with accompanying Roux-en-Y gastric bypass surgery (ICD-9-CM 44.31, 44.38, 44.39) for obesity (ICD-9-CM 278, V778, V853V854, V855.4). IBD hospitalizations were identified using ICD-9-CM 555 and 556 in any diagnosis position. Logistic and linear regression analyses were used to assess the effect of IBD on post-operative complications, inpatient mortality, post-operative length of stay, and total charges. Multivariable models were adjusted for age, sex, payer source, medical comorbidities, and hospital size. RESULTS: Of 933,930 inpatient gastric bypasses for obesity, 967 were performed on IBD patients. Most gastric bypass patients were female (81.5%) with a mean age of 43.0 years. Compared with non-IBD patients, IBD patients were more likely to require conversion from laparoscopic to open surgery (odds ratio [OR] 3.30; 95% confidence interval [CI] 1.55 7.04). IBD patients were also significantly more likely to experience post-surgical complications, including seromas (OR 12.46; 95% CI 1.72 90.39), infections (OR 2.80; 95% CI 1.15 6.83), and gastrointestinal issues (e.g., vomiting, ileus, obstruction) (OR 2.77; 95% CI 1.55 4.98). There were no differences in perforation risk (OR 0.88; 95% CI 0.22 3.54), pulmonary (OR 0.73; 95% CI 0.30 1.77) or cardiovascular complications (OR 1.22; 95% CI 0.39 3.83), or death (0.52% vs. 0.22%; OR 2.04; 95% CI 0.28 14.67). Length of stay, post-operative length of stay, and total charges were similar between non-IBD and IBD hospitalizations. CONCLUSION: IBD is associated with seromas, infections, and gastrointestinal complications after bariatric surgery. Risk of other major complications, death, and hospitalization costs were otherwise similar between IBD and non-IBD patients. The rate of conversion from laparoscopic to open surgery was significantly higher in patients with IBD. Bariatric surgery remains a viable option for treatment of obesity in this special population.

Introduction Diffuse intrinsic pontine glioma (DIPG) and midline high-grade glioma (mHGG) are lethal childhood brain tumors. Spatial genomic heterogeneity has been well-described in adult HGG but has not been comprehensively characterized in pediatric HGG. We performed whole exome sequencing on 38-matched primary, contiguous, and metastatic tumor sites from eight children with DIPG (n = 7) or mHGG (n = 1) collected using a unique MRI-guided autopsy protocol. Validation was performed using Sanger sequencing, Droplet Digital polymerase-chain reaction, immunohistochemistry, and fluorescent in-situ hybridization. Results Median age at diagnosis was 6.1 years (range: 2.9–23.3 years). Median overall survival was 13.2 months (range: 11.2–32.2 months). Contiguous tumor infiltration and distant metastases were observed in seven and six patients, respectively, including leptomeningeal dissemination in three DIPGs. Histopathological heterogeneity was evident in seven patients, including intra-pontine heterogeneity in two DIPGs, ranging from World Health Organization grade II to IV astrocytoma. We found conservation of heterozygous K27M mutations in H3F3A (n = 4) or HIST1H3B (n = 3) across all primary, contiguous, and metastatic tumor sites in all DIPGs. ACVR1 (n = 2), PIK3CA (n = 2), FGFR1 (n = 2), and MET (n = 1) were also intra-tumorally conserved. ACVR1 was co-mutated with HIST1H3B (n = 2). In contrast, PDGFRA amplification and mutation were spatially heterogeneous, as were mutations in BCOR (n = 1), ATRX (n = 2), and MYC (n = 1). TP53 aberrations (n = 3 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved. Conclusion Spatial conservation of prognostically-relevant and therapeutically-targetable somatic mutations in DIPG and mHGG contrasts the significant heterogeneity of driver mutations seen in adult HGG and supports uniform implementation of diagnostic biopsy in DIPG and mHGG to classify molecular risk groups and guide therapeutic strategy. Electronic supplementary material The online version of this article (doi:10.1186/s40478-015-0269-0) contains supplementary material, which is available to authorized users.