A phase 2 study of valproic acid and radiation, followed by maintenance valproic acid and bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma or high-grade glioma.

PURPOSE: To study the efficacy and tolerability of valproic acid (VPA) and radiation, followed by VPA and bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG). METHODS: Children 3 to 21 years of age received radiation therapy and VPA at 15 mg/kg/day and dose adjusted to maintain a trough range of 85 to 115 µg/mL. VPA was continued post-radiation, and bevacizumab was started at 10 mg/kg intravenously biweekly, four weeks after completing radiation therapy. RESULTS: From September 2009 through August 2015, 20 DIPG and 18 HGG patients were enrolled (NCT00879437). During radiation and VPA, grade 3 or higher toxicities requiring discontinuation or modification of VPA dosing included grade 3 thrombocytopenia (1), grade 3 weight gain (1), and grade 3 pancreatitis (1). During VPA and bevacizumab, the most common grade 3 or higher toxicities were grade 3 neutropenia (3), grade 3 thrombocytopenia (3), grade 3 fatigue (3), and grade 3 hypertension (4). Two patients discontinued protocol therapy prior to disease progression (one grade 4 thrombosis and one grade 1 intratumoral hemorrhage). Median event-free survival (EFS) and overall survival (OS) for DIPG were 7.8 (95% CI 5.6-8.2) and 10.3 (7.4-13.4) months, and estimated one-year EFS was 12% (2%-31%). Median EFS and OS for HGG were 9.1 (6.4-11) and 12.1 (10-22.1) months, and estimated one-year EFS was 24% (7%-45%). Four patients with glioblastoma and mismatch-repair deficiency syndrome had EFS of 28.5, 16.7, 10.4, and 9 months. CONCLUSION: Addition of VPA and bevacizumab to radiation was well tolerated but did not appear to improve EFS or OS in children with DIPG or HGG.

Spontaneous Regression of Atypical Teratoid Rhabdoid Tumor Without Therapy in a Patient With Uncommon Regional Inactivation of SMARCB1 ( hSNF5/INI1).

Atypical teratoid/rhabdoid tumor (ATRT) is a high-grade central nervous system tumor, with poor prognosis despite intensive multimodal therapy. Loss of nuclear immunostaining for INI1 due to inactivation of the hSNF5/INI1 tumor suppressor gene is pathognomonic of ATRT. We present a patient with congenital ATRT, who had spontaneous tumor regression without therapy, and is disease-free 4 years later. Tumor histopathology showed rhabdoid cells characteristic of ATRT, but immunohistochemistry revealed heterogeneous loss of nuclear INI1 staining. The populations of INI1-intact and INI1-deficient cells were separated by laser microdissection, for molecular analysis with DNA sequencing and fluorescence in situ hybridization. The INI1-negative cells were found to harbor a heterozygous deletion and truncating mutation of the hSNF5/INI1 locus, while the INI1-intact cells had 2 copies of the wild-type INI1 gene. To our knowledge, this is the first report of spontaneous regression of ATRT, with molecular heterogeneity for SMARCB1 inactivation, with no radiographic signs of recurrence at 4 years after diagnosis.

ATRX protein loss and deregulation of PI3K/AKT pathway is frequent in pilocytic astrocytoma with anaplastic features.

INTRODUCTION: Pilocytic astrocytoma (PA) with anaplastic features (PAAF) is a rare entity associated with decreased survival. It is characterized by hypercellularity, atypia, brisk mitotic activity, variable necrosis, and association with a classic PA component or anaplastic transformation in a recurrent tumor with a previously-documented classic PA. MATERIALS AND METHODS: We present 5 PAAF cases with clinical, radiological, pathological, and molecular correlation. We interrogated ATRX, IDH, TP53, PTEN, EGFR, BRAF, 6q23, p16(Ink4a) by sequencing, FISH, and immunohistochemistry. RESULTS: Four tumors were located in the cerebellum, and 1 was supratentorial. All showed ATRX protein loss by immunohistochemistry, loss of heterozygosity for PTEN, and had no IDH/TP53/BRAF mutations, nor EGFR amplification. Two of 5 tumors showed BRAF duplication by pyrosequencing. All showed loss of PTEN nuclear expression in subsets of tumor cells, which was associated with variable cytoplasmic positivity for pS6. There was a relative correlation between loss of PTEN expression and pS6 cytoplasmic expression. p53 was expressed in ~ 50% of tumor cells in all tumors. P16 was variably lost in all cases. One tumor showed MYB/6q23 deletion. CONCLUSION: We confirm ATRX protein loss suggestive of ATRX alteration as well as dysregulation of the PI3K/AKT pathway and, less often, of the MAPK/ERK pathway in PAAF.
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Fetal Surgery Decreases Anesthesia-Induced Neuroapoptosis in the Mid-Gestational Fetal Ovine Brain.

BACKGROUND: Studies demonstrating an association between anesthesia and brain cell death (neuroapoptosis) in young animals were performed without accompanying surgery. This study tests the hypothesis that fetal surgery decreases anesthesia-induced neuroapoptosis. MATERIALS AND METHODS: Seventy-day-pregnant ewes received 2% isoflurane for 1 h (low dose [LD]) or 4% for 3 h (high dose [HD]) with or without fetal surgery (S). Unexposed fetuses served as controls (C). Fetal brains were processed for neuroapoptosis using anti-caspase-3 antibodies. Data were analyzed using ANOVA. RESULTS: Twenty-eight fetal sheep were evaluated. Dentate gyrus neuroapoptosis was lower in the HD+S group (13.1 ± 3.76 × 105/mm3) than in the HD (19.1 ± 1.40 × 105/mm3, p = 0.012) and C groups (18.3 ± 3.55 × 105/mm3, p = 0.035). In the pyramidal layer of the hippocampus, neuroapoptosis was lower in the HD+S group (8.11 ± 4.88 × 105/mm3) than in the HD (14.8 ± 2.82 × 105/mm3, p = 0.006) and C groups (14.1 ± 4.54 × 105/mm3, p = 0.019). The LD+S group showed a trend towards a significant decrease in neuroapoptosis in the pyramidal layer (LD+S 7.51 ± 1.48 vs. LD 13.5 ± 1.87 vs. C 14.1 ± 4.54 × 105/mm3, p = 0.07) but not in the dentate gyrus. Fetal surgery did not affect neuroapoptosis in the frontal cortex or endplate. CONCLUSIONS: Fetal surgery decreases isoflurane-induced neuroapoptosis in the dentate gyrus and the pyramidal layer of mid-gestational fetal sheep. Long-term effects of these observations on memory and learning deserve further exploration.

Progression-free survival of children with localized ependymoma treated with intensity-modulated radiation therapy or proton-beam radiation therapy.

BACKGROUND: The treatment for childhood intracranial ependymoma includes maximal surgical resection followed by involved-field radiotherapy, commonly in the form of intensity-modulated radiation therapy (IMRT). Proton-beam radiation therapy (PRT) is used at some centers in an effort to decrease long-term toxicity. Although protons have the theoretical advantage of a minimal exit dose to the surrounding uninvolved brain tissue, it is unknown whether they have the same efficacy as photons in preventing local recurrence. METHODS: A retrospective review of medical records from September 2000 to April 2013 was performed. Seventy-nine children with newly diagnosed localized intracranial ependymomas treated with either IMRT (n = 38) or PRT (n = 41) were identified, and progression-free survival (PFS) was analyzed with Kaplan-Meier and Cox multivariate analyses. RESULTS: The median age at diagnosis was 3.7 years for all patients (range, 0.4-18.7 years). There were 54 patients with infratentorial tumors (68% of the total population). Patients treated with PRT were younger (median age, 2.5 vs 5.7 years; P = .001) and had a shorter median follow-up (2.6 vs 4.9 years; P < .0001). Gross total resection (GTR) was achieved in 67 patients (85%) and was more frequent in the PRT group versus the IMRT group (93% vs 76%; P = .043). The 3-year PFS rates were 60% and 82% with IMRT and PRT, respectively (P = .031). CONCLUSIONS: Children with localized ependymomas treated with PRT have a 3-year PFS rate comparable to that of children treated with IMRT. This analysis suggests that local control is not compromised by the use of PRT. The data also support GTR as the only prognostic factor for PFS. Cancer 2017;123:2570-78. © 2017 American Cancer Society.

Utility of whole exome sequencing in evaluation of juvenile motor neuron disease.

INTRODUCTION: This case report focuses on identifying novel mutations in juvenile motor neuron disease and emphasizes the significance of whole exome sequencing (WES). METHODS: We report a 13-year-old Hispanic boy with rapidly progressive weakness, muscle atrophy, tremor, and tongue fasciculation, along with upper motor neuron findings of hyperactive gag reflex, hyperreflexia, and cog-wheel rigidity. Electromyography was suggestive of motor neuron disease. After an extensive evaluation, WES was performed. RESULTS: WES identified a heterozygous de novo variant of unknown clinical significance (VUS) in the fused-in-sarcoma gene (FUS) [c.1554_1557del]. Although initially reported as a VUS, the clinical data from our patient and data from the medical literature support that the variant is indeed disease-causing. CONCLUSIONS: The genetic etiology of amyotrophic lateral sclerosis (ALS) is heterogeneous and, as clinical sequencing for FUS was not available, WES was the only method by which a diagnosis of juvenile ALS could be made.

Repeated isoflurane exposure and neuroapoptosis in the midgestation fetal sheep brain.

BACKGROUND: Advances in surgery and technology have resulted in increased in-utero procedures. However, the effect of anesthesia on the fetal brain is not fully known. The inhalational anesthetic agent, isoflurane, other gamma amino butyric acid agonists (benzodiazepines, barbiturates, propofol, other inhalation anesthetics), and N-methyl D aspartate antagonists, eg, ketamine, have been shown to induce neuroapoptosis. The ovine model has been used extensively to study maternal-fetal physiologic interactions and to investigate different surgical interventions on the fetus. OBJECTIVE: The purpose of this study was to determine effects of different doses and duration of isoflurane on neuroapoptosis in midgestation fetal sheep. We hypothesized that repeated anesthetic exposure and high concentrations of isoflurane would result in increased neuroapoptosis. STUDY DESIGN: Time-dated, pregnant sheep at 70 days gestation (term 145 days) received either isoflurane 2% × 1 hour, 4% × 3 hours, or 2% × 1 hour every other day for 3 exposures (repeated exposure group). Euthanasia occurred following anesthetic exposure and fetal brains were processed. Neuroapoptosis was detected by immunohistochemistry using anticaspase-3 antibodies. Fetuses unexposed to anesthesia served as controls. Another midgestation group with repeated 2% isoflurane exposure was examined at day 130 (long-term group) and neuronal cell density compared to age-matched controls. Representative sections of the brain were analyzed using Aperio Digital imaging (Leica Microsystems Inc, Buffalo Grove, IL). Data, reported by number of neurons per cubic millimeter of brain tissue are presented as means and SEM. Data were analyzed using the Mann-Whitney U and Kruskal-Wallis tests as appropriate. RESULTS: A total of 34 fetuses were studied. There was no significant difference in neuroapoptosis observed in fetuses exposed to 2% isoflurane for 1 hour or 4% isoflurane for 3 hours. Increased neuroapoptosis was observed in the frontal cortex following repeated 2% isoflurane exposure compared to controls (1.57 ± 0.22 × 10(6)/mm(3) vs 1.01 ± 0.44 × 10(6)/mm(3), P = .02). Fetuses at 70 days gestation with repeated exposure demonstrated decreased frontal cortex neurons at day 130 when compared to age-matched controls (2.42 ± 0.3 × 10(5)/mm(3) vs 7.32 ± 0.4 × 10(5)/mm(3), P = .02). No significant difference in neuroapoptosis was observed between the repeated exposure group and controls in the hippocampus, cerebellum, or basal ganglia. CONCLUSION: Repeated isoflurane exposure in midgestation sheep resulted in increased frontal cortex neuroapoptosis. This persisted into late gestation as decreased neuronal cell density. While animal studies should be extrapolated to human beings with caution, our findings suggest that the number of anesthetic/sedative exposures should be considered when contemplating the risks and benefits of fetal intervention as certain fetal therapies may need to be repeated.

Activation of extracellular regulated kinase and mechanistic target of rapamycin pathway in focal cortical dysplasia.

Neuropathology of resected brain tissue has revealed an association of focal cortical dysplasia (FCD) with drug-resistant epilepsy (DRE). Recent studies have shown that the mechanistic target of rapamycin (mTOR) pathway is hyperactivated in FCD as evidenced by increased phosphorylation of the ribosomal protein S6 (S6) at serine 240/244 (S(240/244) ), a downstream target of mTOR. Moreover, extracellular regulated kinase (ERK) has been shown to phosphorylate S6 at serine 235/236 (S(235/236) ) and tuberous sclerosis complex 2 (TSC2) at serine 664 (S(664) ) leading to hyperactive mTOR signaling. We evaluated ERK phosphorylation of S6 and TSC2 in two types of FCD (FCD I and FCD II) as a candidate mechanism contributing to mTOR pathway dysregulation. Tissue samples from patients with tuberous sclerosis (TS) served as a positive control. Immunostaining for phospho-S6 (pS6(240/244) and pS6(235/236) ), phospho-ERK (pERK), and phospho-TSC2 (pTSC2) was performed on resected brain tissue with FCD and TS. We found increased pS6(240/244) and pS6(235/236) staining in FCD I, FCD II and TS compared to normal-appearing tissue, while pERK and pTSC2 staining was increased only in FCD IIb and TS tissue. Our results suggest that both the ERK and mTOR pathways are dysregulated in FCD and TS; however, the signaling alterations are different for FCD I as compared to FCD II and TS.

The antimicrobial protein, CAP37, is upregulated in pyramidal neurons during Alzheimer's disease.

Inflammation is a well-defined factor in Alzheimer's disease (AD). There is a strong need to identify the molecules contributing to neuroinflammation so that therapies can be designed to prevent immune-mediated neurotoxicity. The cationic antimicrobial protein of 37 kDa (CAP37) is an inflammatory mediator constitutively expressed in neutrophils (PMNs). In addition to antibiotic activity, CAP37 exerts immunomodulatory effects on microglia. We hypothesize that CAP37 mediates the neuroinflammation associated with AD. However, PMNs are not customarily associated with the pathology of AD. This study was therefore designed to identify non-neutrophilic source(s) of CAP37 in brains of AD patients. Brain tissues from patients and age-matched controls were analyzed for CAP37 expression using immunohistochemistry (IHC). To determine factors that induce CAP37 in AD, HCN-1A primary human neurons were treated with tumor necrosis factor-alpha (TNF-α) or amyloid ß1-40 (Aß) and analyzed by IHC. Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to confirm CAP37 expression in neurons and brain tissues. IHC revealed CAP37 in cortical neurons in temporal and parietal lobes as well as CA3 and CA4 hippocampal neurons in patients with AD. CAP37 was found in more neurons in AD patients compared with age-matched controls. qRT-PCR and Western blotting showed an increase in CAP37 transcript and protein in the AD temporal lobe, a brain region that is highly impacted in AD. qRT-PCR observations confirmed CAP37 expression in neurons. TNF-α and Aß increased neuronal expression of CAP37. These findings support our hypothesis that neuronal CAP37 may modulate the neuroinflammatory response in AD.

MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most frequent maternally inherited mitochondrial disorders. MELAS syndrome is a multi-organ disease with broad manifestations including stroke-like episodes, dementia, epilepsy, lactic acidemia, myopathy, recurrent headaches, hearing impairment, diabetes, and short stature. The most common mutation associated with MELAS syndrome is the m.3243A>G mutation in the MT-TL1 gene encoding the mitochondrial tRNA(Leu(UUR)). The m.3243A>G mutation results in impaired mitochondrial translation and protein synthesis including the mitochondrial electron transport chain complex subunits leading to impaired mitochondrial energy production. The inability of dysfunctional mitochondria to generate sufficient energy to meet the needs of various organs results in the multi-organ dysfunction observed in MELAS syndrome. Energy deficiency can also stimulate mitochondrial proliferation in the smooth muscle and endothelial cells of small blood vessels leading to angiopathy and impaired blood perfusion in the microvasculature of several organs. These events will contribute to the complications observed in MELAS syndrome particularly the stroke-like episodes. In addition, nitric oxide deficiency occurs in MELAS syndrome and can contribute to its complications. There is no specific consensus approach for treating MELAS syndrome. Management is largely symptomatic and should involve a multidisciplinary team. Unblinded studies showed that l-arginine therapy improves stroke-like episode symptoms and decreases the frequency and severity of these episodes. Additionally, carnitine and coenzyme Q10 are commonly used in MELAS syndrome without proven efficacy.

Therapeutic implications of CD1d expression and tumor-infiltrating macrophages in pediatric medulloblastomas.

Immunobiology of medulloblastoma (MB), the most common malignant brain tumor in children, is poorly understood. Although tumor cells in some MBs were recently shown to express CD1d and be susceptible to Vα24-invariant natural killer T (NKT)-cell cytotoxicity, the clinical relevance of CD1d expression in MB patients remains unknown. We investigated the expression of CD1d in pediatric MBs and correlated with molecular and clinical characteristics. Specifically, we explored if NKT cell therapy can be targeted at a subset of pediatric MBs with poorer prognosis. Particularly, infantile MBs have a worse outcome because radiotherapy is delayed to avoid neurocognitive sequelae. Immunohistochemistry for CD1d was performed on a screening set of 38 primary pediatric MBs. Gene expression of the membrane form of M2 macrophage marker, CD163, was studied in an expanded cohort of 60 tumors. Outcome data was collected prospectively. Thirteen of 38 MBs (34.2 %) expressed CD1d on immunohistochemistry. CD1d was expressed mainly on MB tumor cells, and on some tumor-associated macrophages. Majority (18/22, 82 %) of non sonic-hedgehog/Wingless-activated MBs (group 3 and 4) were CD1d-negative (p = 0.05). A subset of infantile MBs (4/9, 44.4 %) expressed CD1d. Macrophages infiltrating MB expressed CD163 apart from CD1d. Molecular subtypes demonstrated statistical differences in CD163 expression, SHH-tumors were the most enriched (p = 0.006). Molecular and clinical subtypes of pediatric MB exhibit distinct differences in CD1d expression, which have important therapeutic implications. High CD1d expression in infantile MBs offers potential new immunotherapeutic treatment with NKT cell therapy in infants, where treatment is suboptimal due delayed radiotherapy.

Genome-wide analysis of DNA copy number alterations and loss of heterozygosity in intracranial germ cell tumors.

BACKGROUNDS: Intracranial germ cell tumors (GCTs) are rare and heterogeneous with very little is known about their pathogenesis and underlying genetic abnormalities. PROCEDURES: In order to identify candidate genes and pathways which are involved in the pathogenesis of these tumors, we have profiled 62 intracranial GCTs for DNA copy number alterations (CNAs) and loss of heterozygosity (LOH) by using single nucleotide polymorphism (SNP) array and quantitative real time PCR (qPCR). RESULTS: Initially 27 cases of tumor tissues with matched blood samples were fully analyzed by SNP microarray and qPCR. Statistical analysis using the genomic identification of significant targets in cancer (GISTIC) tool identified 10 regions of significant copy number gain and 11 regions of significant copy number loss. While overall pattern of genomic aberration was similar between germinoma and nongerminomatous germ cell tumors (NGGCTs), a few subtype-specific peak regions were identified. Analysis by SNP array and qPCR was replicated using an independent cohort of 35 cases. CONCLUSIONS: Frequent aberrations of CCND2 (12p13) and RB1 (13q14) suggest that Cyclin/CDK-RB-E2F pathway might play a critical role in the pathogenesis of intracranial GCTs. Frequent gain of PRDM14 (8q13) implies that transcriptional regulation of primordial germ cell specification might be an important factor in the development of this tumor.

Multilevel thoracic hemangioma with spinal cord compression in a pediatric patient: case report and review of the literature.

PURPOSE: Vertebral hemangiomas are common benign vascular tumors of the spine. It is very rare for these lesions to symptomatically compress neural elements. If spinal cord compression does occur, it usually involves only a single level. Multilevel vertebral hemangiomas causing symptomatic spinal cord compression have never been reported in the pediatric population to the best of our knowledge. METHODS: We report the case of a 15-year-old boy presenting with progressive paraparesis due to thoracic spinal cord compression from a multilevel thoracic hemangioma (T5-T10) with epidural extension. RESULTS: Because of his progressive neurological deficit, he was initially treated with urgent multilevel decompressive laminectomies from T4 to T11. This was to be followed by radiotherapy for residual tumor, but the patient was unfortunately lost to follow-up. He re-presented 3 years later with recurrent paraparesis and progressive disease. This was treated with urgent radiotherapy with good response. As of 6 months follow-up, he has made an excellent neurological recovery. CONCLUSIONS: In this report, we present the first case of a child with multilevel vertebral hemangiomas causing symptomatic spinal cord compression and review the literature to detail the pathophysiology, management, and treatment of other cases of spinal cord compression by vertebral hemangiomas.

Fractionated radiation therapy alters energy metabolism and induces cellular quiescence exit in patient-derived orthotopic xenograft models of high-grade glioma.

Radiation is one of the standard therapies for pediatric high-grade glioma (pHGG), of which the prognosis remains poor. To gain an in-depth understanding of biological consequences beyond the classic DNA damage, we treated 9 patient-derived orthotopic xenograft (PDOX) models, including one with DNA mismatch repair (MMR) deficiency, with fractionated radiations (2 Gy/day x 5 days). Extension of survival time was noted in 5 PDOX models (P < 0.05) accompanied by γH2AX positivity in >95 % tumor cells in tumor core and >85 % in the invasive foci as well as ∼30 % apoptotic and mitotic catastrophic cell death. The model with DNA MMR (IC-1406HGG) was the most responsive to radiation with a reduction of Ki-67(+) cells. Altered metabolism, including mitochondria number elevation, COX IV activation and reactive oxygen species accumulation, were detected together with the enrichment of CD133+ tumor cells. The latter was caused by the entry of quiescent G0 cells into cell cycle and the activation of self-renewal (SOX2 and BMI1) and epithelial mesenchymal transition (fibronectin) genes. These novel insights about the cellular and molecular mechanisms of fractionated radiation in vivo should support the development of new radio-sensitizing therapies.

Intensity-modulated radiotherapy (IMRT) in pediatric low-grade glioma.

BACKGROUND: The objective of this study was to evaluate local control and patterns of failure in pediatric patients with low-grade glioma (LGG) who received treatment with intensity-modulated radiation therapy (IMRT). METHODS: In total, 39 children received IMRT after incomplete resection or disease progression. Three methods of target delineation were used. The first was to delineate the gross tumor volume (GTV) and add a 1-cm margin to create the clinical target volume (CTV) (Method 1; n = 19). The second was to add a 0.5-cm margin around the GTV to create the CTV (Method 2; n = 6). The prescribed dose to the GTV was the same as dose to the CTV for both Methods 1 and 2 (median, 50.4 grays [Gy]). The final method was dose painting, in which a GTV was delineated with a second target volume (2TV) created by adding 1 cm to the GTV (Method 3; n = 14). Different doses were prescribed to the GTV (median, 50.4 Gy) and the 2TV (median, 41.4 Gy). RESULTS: The 8-year progression-free and overall survival rates were 78.2% and 93.7%, respectively. Seven failures occurred, all of which were local in the high-dose (≥95%) region of the IMRT field. On multivariate analysis, age ≤5 years at time of IMRT had a detrimental impact on progression-free survival. CONCLUSIONS: IMRT provided local control rates comparable to those provided by 2-dimensional and 3-dimensional radiotherapy. Margins ≥1 cm added to the GTV may not be necessary, because excellent local control was achieved by adding a 0.5-cm margin (Method 2) and by dose painting (Method 3).

Implications of tumor location on subtypes of medulloblastoma.

BACKGROUND: Medulloblastoma (MB) comprises of four molecular subtypes, Sonic hedgehog (SHH), Wingless (WNT), Groups 3 and 4. WNT-subtype MBs were found to arise from midline of the brainstem occupying the fourth ventricle while SHH-subtype occupied the cerebellar hemisphere in a small subset of patients. PROCEDURE: We tested this hypothesis in a large cohort of pediatric MBs comprising of all four molecular subtypes. RESULTS: We validated in the first comprehensive analysis of tumor location of 60 human MBs representative of the four molecular subtypes, that hemispheric tumors are significantly associated with SHH-subtype MBs while midline tumors with WNT-subtype, Group 3 and 4 MBs (P < 0.001). Nearly half of SHH-subtype MBs were midline. CONCLUSIONS: Tumor location should not be generalized to MB subtypes. SHH-subtype MBs are not exclusively hemispheric and hemispheric MBs are not always SHH-activated. It is imperative to identify subtypes in conjunction with tumor location when exploring currently available targeted therapy.

Cerebral pleomorphic xanthoastrocytoma associated with NF1: an updated review with a rare atypical case from Africa.

The occurrence of cerebral pleomorphic xanthoastrocytoma (PXA) in individuals with neurofibromatosis type 1 (NF1) is very rare. We present a 10-year-old Nigerian boy with NF1 who was found to harbor a thalamic-lateral ventricular solid mass lesion whose histologic and immunohistochemical findings were in keeping with PXA. We also carried out an updated review of the PXA-NF1 literature and found only eight previous reports of this clinical disease association. These reports have been limited to only certain regions of the world, with none yet reported from Africa, South America, Australia, and Eastern Europe. As far as we know, this might be the first such report from Africa. The case we present, in addition, demonstrated some other unique clinical, radiological, and histopathologic characteristics which have been highlighted in this review.

Neurofibromatosis Type 1 Has a Wide Spectrum of Growth Hormone Excess.

Overgrowth due to growth hormone (GH) excess affects approximately 10% of patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). Our aim is to describe the clinical, biochemical, pathological, and genetic features of GH excess in a retrospective case series of 10 children and adults with NF1 referred to a tertiary care clinical research center. Six children (median age = 4 years, range of 3−5 years), one 14-year-old adolescent, and three adults (median age = 42 years, range of 29−52 years) were diagnosed with NF1 and GH excess. GH excess was confirmed by the failure to suppress GH (<1 ng/mL) on oral glucose tolerance test (OGTT, n = 9) and frequent overnight sampling of GH levels (n = 6). Genetic testing was ascertained through targeted or whole-exome sequencing (n = 9). Five patients (all children) had an OPG without any pituitary abnormality, three patients (one adolescent and two adults) had a pituitary lesion (two tumors, one suggestive hyperplasia) without an OPG, and two patients (one child and one adult) had a pituitary lesion (a pituitary tumor and suggestive hyperplasia, respectively) with a concomitant OPG. The serial overnight sampling of GH levels in six patients revealed abnormal overnight GH profiling. Two adult patients had a voluminous pituitary gland on pituitary imaging. One pituitary tumor from an adolescent patient who harbored a germline heterozygous p.Gln514Pro NF1 variant stained positive for GH and prolactin. One child who harbored a heterozygous truncating variant in exon 46 of NF1 had an OPG that, when compared to normal optic nerves, stained strongly for GPR101, an orphan G protein-coupled receptor causing GH excess in X-linked acrogigantism. We describe a series of patients with GH excess and NF1. Our findings show the variability in patterns of serial overnight GH secretion, somatotroph tumor or hyperplasia in some cases of NF1 and GH excess. Further studies are required to ascertain the link between NF1, GH excess and GPR101, which may aid in the characterization of the molecular underpinning of GH excess in NF1.