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While autopsy-repository programs with a variety of pediatric central nervous system (CNS) tumor types are a critical resource for preclinical neuro-oncology research, few exist and there is no published guidance on how to develop one. The goal of this prospective Pediatric Brain Tumor Repository (PBTR) study was to develop such a program at Cincinnati Children's Hospital Medical Center (CCHMC) and then publish the quantitative and experiential data as a guide to support the development of similar programs.Protocols and infrastructure were established-to educate oncologists and families, establish eligibility, obtain consent, address pre- and post-autopsy logistics (e.g., patient and tissue transportation), process and authenticate tissue samples, and collect and analyze data.Of the 129 pediatric CNS tumor patients at CCHMC who died between 2013 and 2018, 109 were eligible for our study. Of these, 74% (81 of 109) were approached for PBTR donation, and 68% (55 of 81) consented. In the final year of the study, approach and consent rates were 93% and 85%, respectively. Median time from death to autopsy (postmortem interval, PMI) was 10 h (range, 1.5-30). In the outpatient setting, PMI increased with distance (from the hospice/home where the patient died to CCHMC). In all patients, PMI appeared to be lower, when consent was obtained more than 24 h before death.Procurement of autopsy specimens need not be a barrier in neuro-oncology research. Regional centers, strict timing-of-consent, patient education, and dedicated staff are all needed to minimize PMI and, thereby, increase the value of the procured tissue for an array of basic and translational research applications.

Aims Several morphologically overlapping (myo)fibroblastic neoplasms harbour USP6 fusions, including aneurysmal bone cysts, nodular fasciitis, myositis ossificans, cranial fasciitis, fibro-osseous pseudotumour of the digits, and cellular fibroma of the tendon sheath. USP6-induced neoplasms are almost universally benign and cured by local excision. We aim to highlight the diagnostic value of USP6 fusion detection in a series of aggressive-appearing paediatric myofibroblastic tumours. Methods and results Three deep-seated, radiographically aggressive, and rapidly growing childhood myofibroblastic neoplasms were morphologically and molecularly characterised by USP6 break-apart fluorescence in-situ hybridisation (FISH), transcriptome sequencing, and targeted capture analysis. Each tumour occurred in the lower-extremity deep soft tissue of a child presenting with pain, limping, or a mass. In all three patients, imaging studies showed a solid mass that infiltrated into surrounding skeletal muscle or involved/eroded underlying bone. The biopsied tumours consisted of variably cellular myofibroblastic proliferations with variable mitotic activity that lacked overt malignant cytological features. FISH showed that all tumours had USP6 rearrangements. On the basis of these results, all three patients were treated with conservative excision with positive margins. The excised tumours had foci resembling nodular fasciitis, fibromatosis, and pseudosarcomatous proliferation. Next-generation sequencing revealed COL1A1-USP6 fusions in two tumours and a COL3A1-USP6 fusion in the third tumour. One tumour had a subclonal somatic APC in-frame deletion. No recurrence was observed during follow-up (8-40 months). Conclusion We present a series of benign, but aggressive-appearing, USP6-rearranged myofibroblastic tumours. These deep-seated tumours had concerning clinical and radiographic presentations and did not fit into one distinct histological category. These cases highlight the diagnostic value of USP6 fusion detection to identify benign nondescript tumours of this group, especially those with aggressive features, to avoid overtreatment.

Aminoacyl-tRNA synthetases (ARSs) are critical for protein translation. Pathogenic variants of ARSs have been previously associated with peripheral neuropathy and multisystem disease in heterozygotes and homozygotes, respectively. We report seven related children homozygous for a novel mutation in tyrosyl-tRNA synthetase (YARS, c.499C > A, p.Pro167Thr) identified by whole exome sequencing. This variant lies within a highly conserved interface required for protein homodimerization, an essential step in YARS catalytic function. Affected children expressed a more severe phenotype than previously reported, including poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections and chronic pulmonary disease. Related adults heterozygous for YARS p.Pro167Thr showed no evidence of peripheral neuropathy on electromyography, in contrast to previous reports for other YARS variants. Analysis of YARS p.Pro167Thr in yeast complementation assays revealed a loss-of-function, hypomorphic allele that significantly impaired growth. Recombinant YARS p.Pro167Thr demonstrated normal subcellular localization, but greatly diminished ability to homodimerize in human embryonic kidney cells. This work adds to a rapidly growing body of research emphasizing the importance of ARSs in multisystem disease and significantly expands the allelic and clinical heterogeneity of YARS-associated human disease. A deeper understanding of the role of YARS in human disease may inspire innovative therapies and improve care of affected patients.

The purpose of this study was to review a case of a septal dysembryoplastic neuroepithelial tumor (sDNT) and compare it to cases reported in the current literature. We review a case of sDNT and compare with 7 other previously noted cases in the literature. The mainstay treatment is gross total resection, and most patients achieve full clinical resolution. Septal dysembryoplastic neuroepithelial tumor (sDNT) is a rare pediatric disease most commonly presenting as intractable epilepsy or headache. sDNT has been recognized as a genotypically distinct entity from DNT. A high frequency (~ 80%) of mutations of platelet-derived growth factor receptor A (PDGFRA) has been isolated in sDNT and could form the basis for future therapy. MRI is most commonly used to radiographically diagnose the disease and usually demonstrates a lobular interventricular mass involving the septum, potentially extending to the third ventricle. Our case and literature review validates endoscopic biopsy as a diagnostic and therapeutic intervention.

Background Diffuse intrinsic pontine glioma (DIPG) is a high-grade brainstem glioma of children with dismal prognosis. There is no single unifying model about the cell of origin of DIPGs. Proliferating cells in the developing human and mouse pons, the site of DIPGs, express neural stem/progenitor cell (NPC) markers, including Sox2, nestin, vimentin, Olig2, and glial fibrillary acidic protein, in an overlapping and non-overlapping manner, suggesting progenitor cell heterogeneity in the pons. It is thought that during a restricted window of postnatal pons development, a differentiation block caused by genetic/epigenetic changes leads to unrestrained progenitor proliferation and DIPG development. Nearly 80% of DIPGs harbor a mutation in the H3F3A or the related HIST1H3B gene. Supporting the impaired differentiation model, NPCs derived from human induced pluripotent stem cells expressing the H3F3A mutation showed complete differentiation block. However, the mechanisms regulating an altered differentiation program in DIPG are unknown. Methods We established syngeneic serum-dependent and independent primary DIPG lines, performed molecular characterization of DIPG lines in vitro and in an orthotopic xenograft model, and used small hairpin RNA to examine Olig2 function in DIPG. Results The transcription factor Olig2 is highly expressed in 70%-80% of DIPGs. Here we report that Olig2 expression and DIPG differentiation are mutually exclusive events in vitro, and only DIPG cells that retained Olig2 in vitro formed robust Olig2-positive brainstem glioma with 100% penetrance in a xenograft model. Conclusion Our results indicate Olig2 as an onco-requisite factor in DIPG and propose investigation of Olig2 target genes as novel candidates in DIPG therapy.

Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m(2), 12-24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m(2). Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.

OBJECTIVE Diagnostic criteria for hippocampal malrotation (HIMAL) on brain MRI typically include a rounded hippocampus, vertical collateral sulcus, and architectural blurring. Relationship to epileptogenesis remains speculative, and usefulness for surgical guidance is unknown. The study was performed to determine the prevalence of hippocampal rotational anomalies in a cohort of pediatric patients with intractable epilepsy undergoing evaluation for surgery and to determine the significance of this finding in the context of surgical planning. METHODS Forty-eight surgically treated children with intractable epilepsy were compared with matched healthy subjects; reviewers were blinded to surgical side. Each temporal lobe was evaluated for rounded hippocampus, blurring, vertical collateral sulcus, wide choroidal fissure, enlarged temporal horn, low fornix, hippocampal signal, and findings of hippocampal sclerosis. A mesial temporal lobe (MTL) score was calculated by summing the number of features, and the collateral sulcus angle (CSA) was measured in each temporal lobe. Surgical side, pathological diagnosis, and imaging findings elsewhere in the brain were tabulated. Presence of HIMAL, associated imaging features, and MTL score were compared between sides, between epilepsy and control groups, in relationship to side of surgery, and in relationship to postoperative outcome. RESULTS Only 3 epilepsy patients (6.2%) and no controls exhibited all 3 features of HIMAL (p = 0.12). Eight of 48 (16.7%) epilepsy versus 2 of 48 (4.6%) control subjects had both a rounded hippocampus and vertical collateral sulcus (suggesting HIMAL) (p = 0.045). In control and epilepsy subjects, most findings were more prevalent on the left, and the left CSA was more vertical (p < 0.0001). Epilepsy subjects had higher MTL scores (z = −2.95, p = 0.002) and more acute CSAs (p = 0.04) than controls. Only lateralizing raw MTL score had a significant association with surgical side (p = 0.03, OR 7.33); however, this was not significant when hippocampal sclerosis cases were excluded. HIMAL findings were more prevalent and MTL scores were higher in patients with resections involving the temporal lobes. On group analysis, HIMAL findings did not predict eventual surgical side and did not predict outcome, although the numbers are small. In 4 patients the abnormally rotated hippocampus was resected and showed hippocampal sclerosis and/or dysplastic changes on histopathology. All of these patients had a good outcome after surgery. CONCLUSIONS While increased in prevalence in children with intractable epilepsy, imaging findings of HIMAL did not have preoperative lateralizing utility in this group. Findings of HIMAL (including round hippocampus, architectural blurring, and vertical collateral sulcus) did not predict outcome after surgery, although the small number of patients with these findings limits evaluation. In the small number of patients in which the malrotated hippocampus was removed, outcome was good. Further research is needed to continue to define this association in children with intractable epilepsy, focusing on a temporal lobe cohort.

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.

Summary Objective The predictive value of intraoperative electrocorticography (ECoG) in pediatric epilepsy surgery is unknown. In a population of children undergoing ECoG followed typically by invasive extraoperative monitoring (IEM) and resection, we aimed to determine the relationship between frequent ECoG abnormalities and the seizure onset zone and outcome after resection. Methods We retrospectively identified 103 children with preresection ECoG of sufficient technical quality. ECoG records were scored based on electrode location and frequency, blinded to the seizure-onset zone and outcome. Electrographic seizure and spike locations were identified. Locations of seizures and spike populations were then compared to the location of seizure-onset zone defined by IEM using subdural electrodes and resection margin. Results Electrographic seizures were identified in 11 (11%) of 103 patients. A spike population of one or more was noted in 79 (77%) of 103 patients. In 50 (63%) of 79 patients, spike populations correlated with seizure-onset zone location. The overall surgical outcome was good (ILAE 1 to 3) in 53 (52%) of 101 patients. Outcome was good in seven (78%) of nine patients when electrographic seizure location was resected. The best outcomes were obtained with resection of both the seizure-onset zone and ECoG abnormalities to include seizures and spike locations (22/33 good outcome, 67%, p = 0.008). There was a significantly better outcome in children with complete resection of ECoG-identified spike populations (14/26, 62% good outcome) compared to when none were resected (4/14, 29%, p = 0.043). Significance Electrographic seizures and frequent spikes are frequently seen on pre-resection ECoG in children. The brain locations corresponding to these discharges are highly concordant with the seizure-onset zone; resection of these regions is correlated with good seizure outcome. Further research is needed to design interventions that increase the reliability of ECoG prediction of the epileptogenic zone and obviate the need for IEM.

There is a paucity of data regarding patterns of progression in children with high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG) treated with bevacizumab (BVZ) at diagnosis. We performed a retrospective study of 20 children with HGG or DIPG who received BVZ-based therapy at diagnosis on, or according to, a bi-institutional study. Magnetic resonance imaging (MRI) characteristics of first and most recent progressions were reviewed. Comparison was made to a control group of 19 patients who never received BVZ. Imaging definitions of progressive disease (PD) were local: at primary site or within 2 cm, contiguous; diffuse: >2 cm away but contiguous with primary site, ill-defined and infiltrative; distant: new, non-contiguous disease. In the BVZ-treated group, 14 patients had DIPG, six patients had HGG. Median age was 7 years (range: 3-21). Median time to PD and follow-up were 8.8 months (range 4-21) and 11 months (range: 6-25), respectively. Among 14 patients with PD, 8 (57.1 %) had local PD, 6 (42.9 %) had local and diffuse/distant PD, at initial progression. At most recent progression, a median of 10.8 months (range 6-25) from diagnosis, 10 of 14 (71.4 %) had at least diffuse (n = 8), or distant (n = 6) PD. In the comparable control group, 15 patients had PD: 11(73.3 %) local, 4 (26.7 %) local and diffuse/distant PD at first and most recent progressions. Based on these data, we postulate that BVZ may lead to a higher incidence of distant and diffuse disease in newly-diagnosed children with HGG or DIPG who received BVZ-based therapy.

Summary Objectives Metabolic imaging studies, such as positron emission tomography (PET), allow for an assessment of physiologic functioning of the brain, and [18F]fluoro-2-deoxyglucose (FDG)–PET is now a commonly used technique in presurgical epilepsy evaluations. Focal interictal decreases in glucose consumption are often but inconsistently concordant with the ictal onset area, and the underlying mechanisms are poorly understood. The current study tests the hypothesis that areas of glucose hypometabolism, determined by FDG-PET, are associated with mitochondrial dysfunction in patients with medically intractable epilepsy associated with isolated focal cortical dysplasia (FCD). Methods Measures of electron transport chain (ETC) functioning and mitochondrial abnormalities (ETC complex biochemistry, protein kinase B subtype 1 (Akt1), glial fibrillary acidic protein (GFAP)) were assessed in surgical resection specimens that had hypometabolic abnormalities and those that were normal on FDG-PET. Determination of FDG-PET abnormalities was based on coregistration of statistical parametric mapping (SPM) results with postsurgical images. Results Twenty-two patients (11 male, 11 female; mean age at the time of surgery 10.5 ± 4.4 years), with pathologically confirmed FCD, were included in this retrospective review. Complex IV function was found to be significantly reduced in areas of hypometabolism (p = 0.014), whereas there was a trend toward a significant reduction in complex II and III function in areas of hypometabolism (p = 0.08, p = 0.059, respectively). These decreases were independent of cortical dysplasia severity (p = 0.321) and other clinical epilepsy measures. Significance This study suggests an association between glucose hypometabolism and reduced mitochondrial complex IV functioning, which is independent of the degree of cortical dysplasia. This supports the role of cellular energy failure as a potential mechanism for intractable epilepsy.

Children with high-grade glioma, including diffuse intrinsic pontine glioma (DIPG), have a poor prognosis despite multimodal therapy. Identifying novel therapeutic targets is critical to improve their outcome. We evaluated prognostic roles of telomere maintenance mechanisms in children with HGG, including DIPG. A multi-institutional retrospective study was conducted involving 50 flash-frozen HGG (35 non-brainstem; 15 DIPG) tumors from 45 children (30 non-brainstem; 15 DIPG). Telomerase activity, expression of hTERT mRNA (encoding telomerase catalytic component) and TERC (telomerase RNA template) and alternative lengthening of telomeres (ALT) mechanism were assayed. Cox Proportional Hazard regression analyses assessed association of clinical and pathological variables, TERC and hTERT levels, telomerase activity, and ALT use with progression-free or overall survival (OS). High TERC and hTERT expression was detected in 13/28 non-brainstem HGG samples as compared to non-neoplastic controls. High TERC and hTERT expression was identified in 13/15 and 11/15 DIPG samples, respectively, compared to controls. Evidence of ALT was noted in 3/11 DIPG and 10/19 non-brainstem HGG specimens. ALT and telomerase use were identified in 4/19 non-brainstem HGG and 2/11 DIPG specimens. In multivariable analyses, increased TERC and hTERT levels were associated with worse OS in patients with non-brainstem HGG, after controlling for tumor grade or resection extent. Children with HGG and DIPG, have increased hTERT and TERC expression. In children with non-brainstem HGG, increased TERC and hTERT expression levels are associated with a worse OS, making telomerase a promising potential therapeutic target in pediatric HGG.

To identify pathologic characteristics that are associated with outcome, we performed a retrospective analysis of the clinical, radiologic, and pathologic features of 44 children with isolated focal cortical dysplasia (FCD) after epilepsy surgery. Based on the International League Against Epilepsy Classification, 16 patients had FCD Type I and 28 subjects had FCD Type II. A significantly higher percentage of subjects with FCD Type IIb versus Types I and IIa were seizure-free after surgery. Akt (also known as protein kinase B) is the main downstream target of phosphatidylinositol 3'-kinase and has been implicated in epilepsy pathogenesis. Semiquantitative analysis of cortical gliosis and quantitation of Akt1-immunoreactive neurons indicated that individuals with FCD Type II were more likely to have diffuse astrogliosis and higher counts of Akt1-positive neurons versus those with FCD Type I. A logistic regression model, including Akt1-positive neurons, age at surgery, and the interaction of these factors, was significantly associated with seizure-free outcome. This study provides evidence that astrogliosis and overexpression of neuronal Akt1 protein may be important factors in the pathogenesis of FCD and suggests that the pathogenesis of FCD Type I may differ from that of FCD Type II in children.

Objectives To determine the prevalence of epilepsy and drug-resistant epilepsy in pediatric patients with focal cortical dysplasia (FCD) identified by magnetic resonance imaging (MRI). To determine clinical and imaging differences between those with drug-resistant epilepsy, drug-responsive epilepsy, and no epilepsy among children with MRI-identified FCD. Methods A keyword search of a hospital radiology database identified 97 study participants for inclusion in this retrospective study. Participants were included if they were under 18 years of age at time of database query and had an MRI between 2004 and 2013 showing FCD. Exclusion was based on imaging and clinical characteristics. Data was gathered using a chart review and supplemental questionnaire. Results In this cohort of patients with imaging findings compatible with FCD, 29% had not developed epilepsy. The prevalence of epilepsy and drug-resistant epilepsy was 71.13% (95% C.I.=61.05–79.89%) and 32.99% (95% C.I.=23.78–43.27%), respectively. Patients with epilepsy were more likely to have temporal ( p =0.029) or frontal ( p =0.044) lobe lesions and a family history of seizures ( p =0.003) than those without epilepsy. Age of seizure onset was later in those with drug-responsive epilepsy than those with drug-resistant epilepsy ( p =0.0002). A later age of seizure onset (OR=1.22, p =0.0441, 95% C.I.=1.00–1.486) and absence of developmental delay (OR=3.624, p =0.0497, 95% C.I.=1.002–13.110) predicted a less severe epilepsy phenotype. Conclusions Previous studies have only assessed patient cohorts with FCD and epilepsy, limiting the data on "asymptomatic" or "atypically presenting" FCD. Identifying a surprisingly large, novel cohort of children with FCD that had not developed epilepsy helps define prognosis and inform clinical management of children with FCD on imaging.

Diffuse intrinsic pontine glioma (DIPG), a rare, often fatal childhood brain tumor, remains a major therapeutic challenge. In 2012, investigators, funded by the DIPG Collaborative (a philanthropic partnership among 29 private foundations), launched the International DIPG Registry (IDIPGR) to advance understanding of DIPG. Comprised of comprehensive deidentified but linked clinical, imaging, histopathological, and genomic repositories, the IDIPGR uses standardized case report forms for uniform data collection; serial imaging and histopathology are centrally reviewed by IDIPGR neuro-radiologists and neuro-pathologists, respectively. Tissue and genomic data, and cell cultures derived from autopsies coordinated by the IDIPGR are available to investigators for studies approved by the Scientific Advisory Committee. From April 2012 to December 2016, 670 patients diagnosed with DIPG have been enrolled from 55 participating institutions in the US, Canada, Australia and New Zealand. The radiology repository contains 3558 studies from 448 patients. The pathology repository contains tissue on 81 patients with another 98 samples available for submission. Fresh DIPG tissue from seven autopsies has been sent to investigators to develop primary cell cultures. The bioinformatics repository contains next-generation sequencing data on 66 tumors. Nine projects using data/tissue from the IDIPGR by 13 principle investigators from around the world are now underway. The IDIPGR, a successful alliance among philanthropic agencies and investigators, has developed and maintained a highly collaborative, hypothesis-driven research infrastructure for interdisciplinary and translational projects in DIPG to improve diagnosis, response assessment, treatment and outcome for patients.

Desmoplastic infantile gangliogliomas (DIG) are intracranial tumors described in 1987 as benign lesions of infancy. A literature review and the clinical course of 3 patients reported herein suggest that the initial description should be amended. Nearly 23% of DIG cases occur in children older than 24 months. Approximately 40% of DIG cases require additional medical, radiation, and/or further surgical intervention, and 15% of infants and children develop leptomeningeal spread or die from DIG. Such adverse outcomes, combined with the recognition that DIG represents a heterogeneous disease, underscore the need for an expanded biological and molecular investigation.

The purpose of this study was to evaluate relationships between subsarcolemmal mitochondrial aggregates and electron transport chain deficiencies in skeletal muscle with the objective of establishing an association between mitochondrial accumulation and electron transport chain complex deficiency. We conducted a large-scale, retrospective study to evaluate factors associated with subsarcolemmal mitochondrial aggregates (percent) in pediatric patients who received muscle biopsies for suspected respiratory chain disorders. Patients were included if they had histochemical stains for assessment of mitochondrial pathology and had biochemical testing for muscle electron transport chain complex activities. Significant positive bivariate correlations (n = 337) were found between subsarcolemmal mitochondrial aggregate percentage and electron transport chain complexes II, IV, I + III, and II + III activities. Evaluation showed that a cutoff value of2% subsarcolemmal mitochondrial aggregates had poor overall diagnostic accuracy (mean, 32%), compared with a5% cutoff (mean, 60%). To better evaluate the effects of subsarcolemmal mitochondrial aggregates percentages, patients were stratified according to lower one-third (group 1, n = 120 plus ties) and upper one-third (group 2, n = 115 plus ties) of subsarcolemmal mitochondrial aggregates values. Although only minor clinical and pathologic differences were observed, group 1 participants had significantly lower electron transport chain complex activities than group 2 for all enzymes except complex III. Logistic regression showed over 2-fold greater odds of deficiency for electron transport chain complexes I + III (P = .01) and II + III (P = .03) for group 1 participants compared with group 2. We conclude that, contrary to the previous2.0% subsarcolemmal mitochondrial aggregates cutoff for respiratory chain disorder, patients with a low subsarcolemmal mitochondrial aggregates percentage (≤4%) are significantly more likely to have electron transport chain complex deficiency than patients with increased subsarcolemmal mitochondrial aggregates percentage (≥10%). This morphological approach for assessment of mitochondrial proliferation may assist clinicians to select further testing to rule out an electron transport chain complex deficiency in children by other methods, including direct biochemical testing of electron transport chain complex activities, measurement of muscle coenzyme Q10 content, or evaluation for a mitochondrial DNA depletion syndrome.

Glypican-3 (GPC3) is an oncofetal protein that has been demonstrated to be a useful diagnostic immunomarker for hepatocellular carcinoma and hepatoblastoma. Its expression in mesenchymal tumors of the liver, particularly undifferentiated embryonal sarcoma (UES) and mesenchymal hamartoma (MH), has not been investigated. In this study, a total of 24 UESs and 18 MHs were immunohistochemically stained for GPC3 expression. The results showed cytoplasmic staining for GPC3 in 14 (58%) UESs, of which 6 exhibited diffuse immunoreactivity and the remaining 8 showed focal positivity. The patients with GPC3-positive UES tended to be younger (mean 18 years; median 11 years) than those with GPC3-negative tumors (mean 39.4 years; median 27 years), although the difference did not reach statistical significance (P = .06). Eight MHs also exhibited GPC3 immunoreactivity (44%; 4 diffuse and 4 focal). Positive staining in all 8 cases was primarily seen in entrapped nonlesional hepatocytes with a canalicular and cytoplasmic staining pattern. In only 4 cases (22%) was GPC3 immunoreactivity also observed in the mesenchymal component. The patients with positive staining also tended to be younger (mean 2.6 years; median 1.1 years) compared with those with negative staining (mean 16.3 years; median 4.5 years), but the difference was not statistically significant (P = .15). Our data demonstrate that GPC3 is expressed in a subset of UES and MH of the liver. Caution should thus be exercised when evaluating a GPC3-expressing hepatic neoplasm, particularly on a needle biopsy when the differential diagnosis includes poorly differentiated hepatocellular carcinoma or hepatoblastoma.

Pediatric transitional cell carcinomas of the bladder are typically characterized by low-grade histology, adolescent and young adult age, and cure with surgical resection. Here, we report a high-grade transitional cell carcinoma of the bladder in a 5-year-old boy treated with a partial cystectomy and adjuvant intravesical Bacillus Calmette-Guerin.

To evaluate the diagnostic value of individual noninvasive presurgical modalities and to study their role in surgical management of nonlesional pediatric epilepsy patients.We retrospectively studied 14 children (3-18 years) with nonlesional intractable focal epilepsy. Clinical characteristics, surgical outcome, localizing features on 3 presurgical diagnostic tests (subtraction peri-ictal SPECT coregistered to MRI [SISCOM], statistical parametric mapping [SPM] analysis of [18F] FDG-PET, magnetoencephalography [MEG]), and intracranial EEG (iEEG) were reviewed. The localization of each individual test was determined for lobar location by visual inspection. Concordance of localization between each test and iEEG was scored as follows: 2=lobar concordance; 1=hemispheric concordance; 0=discordance or nonlocalization. Total concordance score in each patient was measured by the summation of concordance scores for all 3 tests.Seven (50%) of 14 patients were seizure-free for at least 12 months after surgery. One (7%) had only rare seizures and 6 (43%) had persistent seizures. MEG (79%, 11/14) and SISCOM (79%, 11/14) showed greater lobar concordance with iEEG than SPM-PET (13%, 3/14) (p0.05). SPM-PET provided hemispheric lateralization (71%, 10/14) more often than lobar localization. Total concordance score tended to be greater for seizure-free patients (4.7) than for non-seizure-free patients (3.9).Our data suggest that MEG and SISCOM are better tools for lobar localization than SPM analysis of FDG-PET in children with nonlesional epilepsy. A multimodality approach may improve surgical outcome as well as selection of surgical candidates in patients without MRI abnormalities.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) causes early-onset, slowly progressive central nervous system white matter disease, macrocephaly, and later cognitive and motor decline. We describe brain structure in a patient with MLC and proven MLC1 mutations. A male, normal at birth, had macrocephaly at 6 months followed by developmental delay. Magnetic resonance imaging showed extensive signal abnormality in cerebral white matter and subcortical progressive cystic changes in the bilateral temporal and right frontal areas. Biopsy of frontal gyrus at age 15 months showed normal gray matter. The subcortical white matter was pale due to prominent fine uniform 2- to 4-μ-thick vacuoles with a few interspersed myelinated axons and rare microglia. The vacuoles had a single-, double-, or, rarely, triple-unit membrane (resembling myelin) and contained occasional organelles but no intermediate filaments. Both normal myelinated and thinly myelinated axons were observed. The outer and occasionally the inner layers of myelin surrounding intact axons formed blebs that may represent a source for vacuoles. Genetic analysis identified 2 heterozygous mutations of intron 3 (c.322–1 G>A) and intron 7 (c.597+1G>A), the 1st leading to deletion of amino acids 60 to 89 and the 2nd to deletion of amino acids 194 to 199. Fine uniform vacuolation of white matter with wide separation of myelinated axons is the hallmark of MLC in early childhood.

Previous studies have indicated that analysis of coenzyme Q10 (CoQ10) in platelets may be clinically useful. The study objectives are to describe, validate and provide application of an HPLC-EC method for platelet CoQ10 analysis. This method analyzes oxidized (ubiquinone-10) and reduced (ubiquinol-10) forms of CoQ10 using two separate injections with the electrochemical analytical cell set at neutral and oxidizing potentials. Results showed that chromatograms were free of interfering peaks. Calibration curves were constructed over a concentration range 116-2317 nmol/L (r(2) = 0.99). The extraction recovery was >95%. The within-run precision CV% was < or =4.2%, and the day-to-day precision was < or =9.9%. Platelets were isolated by differential centrifugation, and frozen at -70 degrees C until analysis. The application of the method was used to compare accumulation of CoQ10 in platelets vs plasma in eight adult volunteers during a 28 day supplementation period (5 mg/kg/day of ubiquinol-10). Mean platelet total CoQ10 was 164 pmol/10(9) cells, and ubiquinol-10:total CoQ10 ratio was 0.56. During supplementation platelet CoQ10 levels were more consistent and predictable than plasma CoQ10 levels. The results indicate that this validated method for platelet ubiquinol-10 and ubiquinone-10 analysis is acceptable for use in the clinical laboratory, and that platelet CoQ10 may have important advantages over plasma during CoQ10 supplementation.

Coenzyme Q10 content, pathology evaluation, and electron transport chain (ETC) enzyme analysis were determined in muscle biopsy specimens of 82 children with suspected mitochondrial myopathy. Data were stratified into three groups: "probable" ETC defects, "possible" ETC defects, and disease controls. Muscle total, oxidized, and reduced coenzyme Q10 concentrations were significantly decreased in the probable defect group. Stepwise logistic regression indicated that only total coenzyme Q10 was significantly associated with probable ETC defect. Receiver operator characteristic (ROC) analysis suggested that total muscle coenzyme Q10 was the best predictor of an ETC complex abnormality. Determination of muscle coenzyme Q10 deficiency in children with suspected mitochondrial disease may facilitate diagnosis and encourage earlier supplementation of this agent.

Mechanisms responsible for progression of nonalcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH) remain poorly defined. To examine the potential contribution of adipose tissue to NAFLD progression, we performed a complete transcriptomic analysis using RNA sequencing (RNA-Seq) on intra-abdominal adipose tissue (IAT) from severely obese adolescents [ Mage16.9 ± 0.4 yr, body mass index (BMI) z-score 2.7 ± 0.1] undergoing bariatric surgery and liver biopsy categorized into three groups: no steatosis (normal, n = 8), steatosis only ( n = 13), or NASH ( n = 10) by liver histology. Age, body weight, and BMI did not differ among groups, but subjects with NASH were more insulin resistant (increased homeostatic model assessment/insulin resistance, P < 0.05 vs. other groups). RNA-Seq revealed 175 up- and 492 downregulated mRNA transcripts (≥±1.5-fold, false discovery rate

Context.—Although the early post–myelosuppressive chemotherapy pathologic changes of the marrow have been described, the rate and the histologic definition of recovery are not defined. Objective.—To study the rate of recovery of bone marrow in patients given myelosuppressive therapy for acute myelogenous leukemia, establish the histologic criteria of recovered marrow, and correlate the recovery pattern with those patients who received a bone marrow transplant by using histology, peripheral blood, immunophenotyping, and computerized morphometry and mathematical slope equation. Design.—We studied the post–myelosuppression recovery of the bone marrow to determine patterns and rate of recovery in 135 serial bone marrow biopsies of 51 patients. These patients were divided into 2 groups: 1 group of 28 cases diagnosed with acute myeloid leukemia, the majority treated with cytarabine (Ara-C) infusion for 7 days and daunorubicin intravenously daily for 3 days (7+3 regimen), and the other control group of 23 cases treated with chemotherapy or allogeneic bone marrow transplantation for a variety of hematologic malignancies. All biopsies during the recovery period were obtained before consolidation regimen. We used morphometry to calculate the cellularity and myeloid to erythroid ratio and quantified megakaryocytes CD10 versus time from day 14 onward. The absolute neutrophil and platelet counts for 28 cases were related to histologic recovery. Results.—From day 14, we noted a differential slope of recovery of these patients with no difference in male and female patients, P = .45, but a difference between younger and older patients (>58.5 years), P = .03. After regenerative hyperplasia, the cellularity plateaus, the myeloid to erythroid ratio, and the megakaryocytes even out with platelet normalization, and the early CD10+ B cells rise from day 40 onward, P = .01. The patterns of recovery after day 60 of postchemotherapy and posttransplantation patients are similar. Complete histologic and peripheral blood recovery is noted at day 38 and thereafter. Conclusions.—By linear equation using at least 2 trephine biopsy specimens, the projected rate of cellular recovery may be determined, and 5 histologic features are associated with complete histologic recovery.

Cortical dysplasia is the most common cause of pediatric refractory epilepsy. MRI detection of epileptogenic lesion is associated with good postsurgical outcome. Additional electrophysiological information is suggested to be helpful in localization of cortical dysplasia. Educational measures were taken to increase the awareness of cortical dysplasia at our institution in the context of a recent International League Against Epilepsy (ILAE 2011) classification of cortical dysplasia.To determine changes in the rate of prospective identification of cortical dysplasia on an initial radiology report and also evaluate the benefit of MRI review as part of a multidisciplinary epilepsy conference in identifying previously overlooked MRI findings.We retrospectively evaluated surgically treated children with refractory epilepsy from 2007 to 2014 with cortical dysplasia on histopathology. We analyzed the initial radiology report, preoperative MRI interpretation at multidisciplinary epilepsy conference and subsequent retrospective MRI review with knowledge of the resection site. We recorded additional electrophysiological data and the presence of lobar concordance with the MRI findings.Of 78 children (44 MRI lesional) evaluated, 18 had initially overlooked MRI findings. Comparing 2007-2010 to 2011-2014, there was improvement in the rate of overlooked findings on the initial radiology report (54% vs. 13% of lesional cases, respectively; P = 0.008). The majority (72%) were identified at a multidisciplinary conference with lobar concordance of findings with at least one additional electrophysiological investigation in 89%.Awareness of current classification schemes of cortical dysplasia and image review in the context of a multidisciplinary conference can lead to improved MRI detection of cortical dysplasia in children.

Although bevacizumab has not proven effective in adults with newly diagnosed high-grade gliomas (HGG), feasibility in newly diagnosed children with diffuse intrinsic pontine gliomas (DIPG) or HGG has not been reported in a prospective study. In a safety and feasibility study, children and young adults with newly diagnosed HGG received radiotherapy (RT) with bevacizumab (10 mg/kg: days 22, 36) and temozolomide (75-90 mg/m(2)/day for 42 days) followed by bevacizumab (10 mg/kg, days 1, 15), irinotecan (125 mg/m(2), days 1, 15) and temozolomide (150 mg/m(2)/day days 1-5). DIPG patients did not receive temozolomide. Telomerase activity, quality of life (QOL), and functional outcomes were assessed. Among 27 eligible patients (15 DIPG, 12 HGG), median age 10 years (range 3-29 years), 6 discontinued therapy for toxicity: 2 during RT (grade 4 thrombocytopenia, grade 3 hepatotoxicity) and 4 during maintenance therapy (grade 3: thrombosis, hypertension, skin ulceration, and wound dehiscence). Commonest ≥grade 3 toxicities included lymphopenia, neutropenia and leukopenia. Grade 3 hypertension occurred in 2 patients. No intracranial hemorrhages occurred. For DIPG patients, median overall survival (OS) was 10.4 months. For HGG patients, 3-year progression free survival and OS were 33 % (SE ± 14 %) and 50 % (SE ± 14 %), respectively. All 3 tested tumor samples, demonstrated histone H3.3K27M (n = 2 DIPG) or G34R (n = 1 HGG) mutations. QOL scores improved over the course of therapy. A bevacizumab-based regimen is feasible and tolerable in newly diagnosed children and young adults with HGG and DIPG.

Purpose There is wide variation in clinical practice regarding the role of electrocorticography immediately after resection (post-resection ECoG) for pediatric epilepsy surgery. Results can guide further resection of potentially epileptogenic tissue. We hypothesized that post-resection ECoG spiking represents a biomarker of the epileptogenic zone and predicts seizure outcome in children undergoing epilepsy surgery. Methods We retrospectively identified 124 children with post-resection ECoG performed on the margins of resection. ECoG records were scored in a blinded fashion based on presence of frequent spiking. For patients identified as having additional resection based on clinical post-resection ECoG interpretation, these "second-look" ECoG results were re-reviewed for ongoing discharges or completeness of resection. Frequent spike populations were grouped using a standard scoring system into three ranges: 0.1–0.5Hz, 0.5–1Hz, >1Hz. Seizure outcomes were determined at minimum 12-month followup. Results Of 124 patients who met inclusion criteria, 60 (48%) had an identified spike population on post-resection ECoG. Thirty (50%) of these had further resection based on clinical interpretation. Overall, good outcome (ILAE 1) was seen in 56/124 (45%). Completeness of resection of spiking (absence of spiking on initial post-resection ECoG or resolution of spiking after further resection) showed a trend toward good outcome (OR 2.03, p =0.099). Patients with completeness of resection had good outcome in 41/80 (51%) of cases; patients with continued spikes had good outcome in 15/44 (35%) of cases. Conclusions Post-resection ECoG identifies residual epileptogenic tissue in a significant number of children. Lower frequency or absence of discharges on initial recording showed a trend toward good outcome. Completeness of resection demonstrated on final ECoG recording did not show a significant difference in outcome. This suggests that post-resection discharges represent a prognostic marker rather than a remediable biomarker of the epileptogenic zone in all patients. Resecting residual spike-generating cortex may be beneficial in selected patients, including children with tumors.

Background and purpose: Hypoxic–ischemic injury in term neonates remains a significant cause of long-term neurological morbidity. The post-natal day 10 (P10) mouse is accepted as a model for the term human. This study was designed to assess the relationships between the duration of hypoxia–ischemia (HI) on P10 and the structural and functional neurological deficits that appear in the adult mouse as a consequence. Methods: Post-natal day 10 129T2×C57Bl/6 F1 hybrid mice were subjected to 0, 45, 60 or 75 min of hypoxia–ischemia using the Rice–Vannucci model. Beginning on P50 these mice were tested over the next 8 weeks using zero maze, locomotor activity, novel object recognition, cued, hidden and reduced Morris water mazes, delayed probe trials and response to apomorphine injection. Brain weights and histology were obtained at the end of testing. Results: The degree of structural and behavioral abnormalities in adult mice correlated with the duration of hypoxia–ischemia on P10. Useful behavioral tests for separating adult mice according to duration of hypoxia–ischemia on P10 include locomotor activity, the Morris water mazes and response to apomorphine. We found cued “learning” persisted, although latencies increased, with increasing HI time while spatial learning decayed as a function of HI time. Severe HI injury involving the ventral hippocampus resulted in excessive locomotor activity. Conclusions: After correcting for motor deficits, there is evidence for persistence of “cued” learning but not spatial learning with increasing hypoxia–ischemia time on P10 in this model system.

Granular cell astrocytomas are an uncommon morphologic variant of infiltrating gliomas characterized by relatively large tumor cells with granular cytoplasm occupying variable proportions of the tumor. These tumors are thought to be more aggressive than similar tumors with no granular cell component. The tumor occurred in a 9-year-old girl who was immunocompromised owing to liver transplantation. Histologically, the tumor corresponded to World Health Organization grade II. It extensively infiltrated the cerebellum and was composed, predominantly, of large cells with eosinophilic granular cytoplasm. These cells coexpressed glial fibrillary acidic protein and CD68. Of the 49 cases of granular cell astrocytomas reported to date, none have involved the cerebellum. To our knowledge, the tumor described herein represents the first case of cerebellar granular cell astrocytoma. Pathologic features and diagnostic pitfalls are explored.

We studied muscle biopsies of 103 pediatric patients in whom clinical suspicion for disorder of energy metabolism was highest in 13 patients, intermediate in 8 patients, and lowest in 82 patients. Electron transport complex (ETC) enzyme activity measurements were available in 96 of 103 patients. Most children with unclassified encephalopathy before biopsy had negative or equivocal morphological and biochemical evaluation for disorder of energy metabolism (72/85). The incidence of ETC abnormality and morphological abnormality in muscle from 39 patients with clinical encephalomyopathy (groups I, II, and III) was 20% and 38%, respectively. In 21 children with high or intermediate clinical suspicion of mitochondriopathy, light microscopy was confirmative in 12, ultrastructure was confirmative in 15, and major ETC abnormality was present in only 4 (29%) of 14. In 82 children with lower clinical suspicion of mitochondriopathy, morphological criteria at both the light and electron microscopic level were absent, and major abnormality of ETC activity was uncommon, in 9 (11%) of 82. Partial reductions of ETC activity occurred in 15 (18%) of 82, but are of uncertain significance. Ragged blue fibers were more prevalent in infants with mitochondriopathy than ragged red fibers. Increase of large, but not small, subsarcolemmal mitochondrial aggregates based on succinate dehydrogenase histochemistry is a useful indicator for mitochondriopathy. Thus, a distinction should be made between small aggregates (normal) and large aggregates. Using strict criteria to define pathological mitochondria, we concluded that electron microscopy is a powerful tool in the diagnosis of mitochondriopathy mainly when clinical suspicion is high. We found no consistent difference in the frequency of mitochondrial "proliferation" as currently defined or in citrate synthase activity in any group. Better patient selection in infants and children and better methods for investigation of mitochondriopathy are needed.

The aim of this study is to determine whether coenzyme Q (CoQ) muscle concentrations and redox state are associated with pathologic changes in muscle biopsy specimens. Skeletal muscle biopsies were collected (January 2002-February 2004) and underwent pathologic evaluation. Quadriceps specimens (n = 47) were stratified accordingly: Group 1, controls without evidence of pathologic abnormalities; Group 2, type I myofiber predominance; Group 3, type II myofiber atrophy; Group 4, lower motor unit disease; and Group 5, muscular dystrophy. Ubiquinol-10, ubiquinone-10, total coenzyme Q10 (CoQ10), coenzyme Q9 (CoQ9), total CoQ (CoQ9+CoQ10) concentrations were analyzed in biopsy muscle by high-performance liquid chromatography. Ubiquinone-10, total CoQ10, and total CoQ concentrations were significantly decreased in Group 5. Significant positive correlations (r congruent with 0.40) were found between muscle ubiquinone-10, total CoQ10, and total CoQ concentrations vs the percentage of myofibers having subsarcolemmal mitochondrial aggregates. CoQ redox ratio and the fraction CoQ9/total CoQ were negatively correlated with subsarcolemmal mitochondrial aggregates. A significant correlation (r = 0.328) also occurred between ubiquinol-10 concentration and citrate synthase activity. This study suggests that total CoQ concentration provides a new method for estimating mitochondrial activity in biopsy muscle; and that the muscle CoQ test is feasible and potentially useful for diagnosing CoQ deficiency states.

Objectives: Anecdotal reports have described excess hepatocyte glycogen in patients with urea cycle enzyme defects. Retrospectively, the authors evaluated the prevalence and possible cause of liver glycogen accumulation in such patients. Methods: The authors searched the files of the Division of Pathology at Cincinnati Children's Hospital from 1975 and 2004 for cases of urea cycle enzyme defects and identified 11 patients who had had liver biopsy performed and/or liver transplantation. All patients were on diets containing essential amino acids as the protein source before liver biopsy and/or transplantation. Results: All but one patient had focal or diffuse glycogen accumulation in hepatocytes in at least one specimen by light microscopic examination. Two young infants also had cholestasis. Electron microscopy performed on six patients showed diffuse or focal glycogen excess in the cytoplasm of individual hepatocytes. Biochemical studies of three patients revealed two with hepatic glycogen content in the upper normal range and one that was abnormally high. Glycolytic enzyme activities were normal in two patients, and one patient had low phosphorylase activity. Conclusions: Hepatocyte glycogen accumulation in urea cycle enzyme defects resembles that seen in glycogen storage disease but can be distinguished in most cases by non-uniformity of distribution and/or the absence of sinusoidal compression by expanded hepatocytes. We speculate that therapeutic modification of dietary protein content by restriction to essential amino acids, including leucine, may promote glycogen accumulation by increasing insulin secretion.

Objective The purpose of this study was to determine which histologic features could enable one to distinguish oral condyloma, as defined by the detection of human papillomavirus (HPV) DNA through in situ hybridization, from its mimics. Study design Thirty-two paraffin-embedded specimens from 28 patients that were clinically suggestive of oral condyloma were analyzed histologically and through in situ hybridization with a consensus HPV probe. Results HPV DNA was detected in 17/32 (53%) of the lesions; no additional positive cases were detected after polymerase chain reaction amplification. Only 5 of the 17 virus-positive cases were considered to be histopathologically unequivocal for condyloma. The histologic features significantly associated with HPV detection were nonuniform perinuclear halos, often in association with epithelial crevices (P = .02), and papillomatosis (P = .02). Each of the 17 patients who were HPV-positive had either HPV-6 or HPV-11, a finding that is similar to those for condyloma involving the penis and vulva/vagina. Conclusion Differentiation between oral condyloma and its mimics is best accomplished by using a combination of histologic, clinical, and in situ viral studies.

It has been postulated that mitochondrial dysfunction may be an important factor in epileptogenesis of intractable epilepsy. The current study tests the hypothesis that mitochondrial Complex IV (CIV) or cytochrome c oxidase dysfunction is associated with the seizure onset zone (SOZ) in patients with focal cortical dysplasia (FCD). Subjects were selected based on: age

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!

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.

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

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.