An Infant-Type Hemispheric Glioma With SOX5::ALK: A Novel Fusion.

Infant-type hemispheric glioma (IHG) is a rare pediatric brain tumor with variable response to chemotherapy and radiotherapy. Molecular insights into IHG can be useful in identifying potentially active targeted therapy. A male fetus was found to have congenital hydrocephalus at the gestational age of 37 weeks. Fetal MRI showed a 2.6 × 2.0-cm tumor located at the frontal horn of the left lateral ventricle, involving the left basal nuclei and thalamus. Tumor biopsy at the age of 2 days revealed an IHG consisting of spindle tumor cells with strong expression of GFAP and ALK. Targeted RNA sequencing detected a novel fusion gene of SOX5::ALK. After initial chemotherapy with cyclophosphamide, carboplatin, and etoposide for 2 cycles, the tumor size progressed markedly and the patient underwent a subtotal resection of brain tumor followed by treatment with lorlatinib, an ALK tyrosine kinase inhibitor with central nervous system (CNS) activity. After 3 months of treatment, reduction of tumor size was observed. After 14 months of treatment, partial response was achieved, and the infant had normal growth and development. In conclusion, we identified a case of congenital IHG with a novel SOX5::ALK fusion that had progressed after chemotherapy and showed partial response and clinical benefit after treatment with the CNS-active ALK inhibitor lorlatinib.

Brain and Spinal Tumors Originating from the Germ Line Cells.

Primary central nervous system germ cell tumors (CNS GCTs) are part of the GCTs in children and adults. This tumor entity presents with geographic variation, age, and sex predilection. There are two age peaks of incidence distribution at the first few months of life and in adolescence. CNS GCTs are heterogeneous in histopathological subtypes, locations, and tumor marker (AFP, ß-hCG) secretions. In the WHO CNS tumor classification, GCTS are classified as germinoma and nongerminomatous GCT (NGGCT) with different subtypes (including teratoma). Excluding mature teratoma, the remaining NGGCTs are malignant (NGMGCT). In teratoma, growing teratoma syndrome and teratoma with somatic-type malignancy should be highlighted. The common intracranial locations are pineal region, neurohypophysis (NH), bifocal pineal-NH, basal ganglia, and cerebral ventricle. Above 50% of intracranial GCTs (IGCTs) present obstructive hydrocephalus. Spinal tumors are rare. Age, locations, hydrocephalus, and serum/CSF titer of ß-hCG correlate with clinical manifestations. Delayed diagnosis is common in tumors arising in neurohypophysis, bifocal, and basal ganglia resulting in the increasing of physical dysfunction and hormonal deficits. Staging work-up includes CSF cytology for tumor cells and contrast-enhanced MRI of brain and spine for macroscopic metastasis before treatment commences. The therapeutic approach of CNS GCTs integrates locations, histopathology, staging, tumor marker level, and therapeutic classification. Treatment strategies include surgical biopsy/excision, chemotherapy, radiotherapy (single or combination). Secreting tumors with consistent imaging may not require histopathological diagnosis. Primary germinomas are highly radiosensitive and the therapeutic aim is to maintain high survival rate using optimal radiotherapy regimen with/without chemotherapy combination. Primary NGNGCTs are less radiosensitive. The therapeutic aim is to increase survival utilizing more intensive chemotherapy and radiotherapy. The negative prognostic factors are residue disease at the end of treatment and serum or CSF AFP level >1000 ng/mL at diagnosis. In refractory or recurrent NMGGCTs, besides high-dose chemotherapy, new therapy is necessary. Molecular profiling and analysis help for translational research. Survivors of pediatric brain tumors frequently experience cancer-related cognitive dysfunction, physical disability, pituitary hormone deficiency, and other CNS complications after cranial radiotherapy. Continuous surveillance and assessment may lead to improvements in treatment protocols, transdisciplinary interventions, after-treatment rehabilitation, and quality of life.

Giant cystic hypothalamic hamartoma in an infant associated with persistent syndrome of inappropriate antidiuretic hormone secretion.

BACKGROUND: A giant hypothalamic hamartoma (GHH) is a rare congenital malformation only reported in a few cases in the literature and is often associated with precocious puberty, gelastic seizures, or less commonly, Pallister-Hall syndrome. Persistent syndrome of inappropriate antidiuretic hormone secretion (SIADH) is very rare in infancy, and most patients with GHH do not develop persistent SIADH, usually only transient electrolyte disturbances postoperatively. Previous cases of GHH have not been associated with persistent derangements in antidiuretic hormone levels. CASE DESCRIPTION: A 7-month-old male infant presented to our hospital with a history of an intracranial cystic lesion diagnosed at 23 weeks gestational age (GA), later impressed as a solid-cystic mass at 37 weeks GA by ultrasound prenatally. Postnatal MRI after birth showed a large mass with a dorsal cyst occupying the hypothalamus, causing hydrocephalus and brainstem compression. The patient started to have subtle seizures on the seventh day after birth and eventually developed dacrystic seizures. Hyponatremia with persistent SIADH was observed at 3 months of age before surgery. He received long-term oral sodium supplementation, polytherapy of anti-epileptic medications, ventriculocystostomy for progressive enlargement of the cystic cavity, and later surgical treatment for disconnection and partial resection which confirmed a histological diagnosis of hypothalamic hamartoma. CONCLUSION: In this case study, we present a novel association of GHH with persistent SIADH and a rare presentation of a cystic component at the dorsal part of the tumor. Clinicians should be aware of this potential endocrine derangement and provide emergent treatment.

Quantitative analysis of intraoperative electrocorticography mirrors histopathology and seizure outcome after epileptic surgery in children.

BACKGROUND: Epileptic surgery is the potentially curative treatment for children with refractory seizures. The study aimed to quantify and analyze high frequency oscillation (HFO) ripples and interictal epileptiform discharges (EDs) in intraoperative electrocorticography (ECoG) between malformation of cortical dysplasia (MCD) and non-MCD children with MRI-lesional focal epilepsy, and evaluate of seizure outcomes after epileptic surgery. METHODS: The intraoperative ECoG was performed before and after lesionectomy. Quantifications of HFO ripples and interictal EDs of ECoG by frequency, amplitude, and foci of intraoperative ECoG were performed based on electrode location, and the characteristics of ECoG recordings were analyzed in each patient based on their histopathology. Seizure outcome after surgery according to their quantitative ECoG findings was analyzed. RESULTS: Frequency of EDs and HFO ripple rates in preresection ECoG were significantly higher in children with MCD compared with non-MCD (p = 0.018 and p = 0.002, respectively). Higher frequencies of EDs and ripple rates in preresection ECoG were observed in residual seizures than in seizure-free children (p = 0.045 and p = 0.005, respectively). Clinically, children with residual seizures after surgery were significantly younger at the onset, had a trend of higher seizure frequency and higher spike frequency of presurgical videoEEG. CONCLUSION: Our results suggested that quantification of intraoperative ECoG predicted seizure outcomes and reflected different ED pattern and frequencies between MCD and non-dysplastic histopathology among children who underwent resective epileptic surgery. The results of our study were encouraging and indicated that intraoperative ECoG improved the outcomes of surgery in children with epilepsy.

Multiple subependymal pseudocysts in neonates play a role in later attention deficit hyperactivity and autistic spectrum disorder.

BACKGROUND/PURPOSE: To assess the long-term neurodevelopmental outcome of normal-term neonates who were accidentally found to exhibit subependymal pseudocysts (SEPCs), frontal horn cysts, or choroid plexus cysts through cranial ultrasound (CUS) examination in a neonatal health examination. METHODS: In total, 5569 neonates received CUS examination as an item in a health examination during the first week of birth between 2002 and 2012. Among them, 5147 infants fulfilled the inclusion criteria. The participants were aged between 5 and 15 years at the time when the data were collected. We retrospectively collected these data and interpreted their statistical significance by using one-way analysis of variance, Chi-square test with Yate's correction and odds ratios. RESULTS: The presence of SEPCs was significantly correlated with developmental delay and developmental disability, particularly with attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD). The risk of ADHD or ASD was significantly higher in participants with multiple SEPCs, among whom the odds ratios for ADHD and ASD were 6.50 (95% confidence interval [CI] = 2.27-18.64) and 28.54 (95% CI = 5.98-136.36), respectively, higher than those for the total study population. CONCLUSION: Our data revealed multiple SEPCs in normal-term neonates as a risk factor for neurobehavioral outcome, particularly in ADHD and ASD. Simultaneously, the utility of CUS examination as a health examination item for neonates was confirmed.

Long-term neurocognitive outcome and auditory event-related potentials after complex febrile seizures in children.

OBJECTIVES: Whether prolonged or complex febrile seizures (FS) produce long-term injury to the hippocampus is a critical question concerning the neurocognitive outcome of these seizures. Long-term event-related evoked potential (ERP) recording from the scalp is a noninvasive technique reflecting the sensory and cognitive processes associated with attention tasks. This study aimed to investigate the long-term outcome of neurocognitive and attention functions and evaluated auditory event-related potentials in children who have experienced complex FS in comparison with other types of FS. METHODS: One hundred and forty-seven children aged more than 6 years who had experienced complex FS, simple single FS, simple recurrent FS, or afebrile seizures (AFS) after FS and age-matched healthy controls were enrolled. Patients were evaluated with Wechsler Intelligence Scale for Children (WISC; Chinese WISC-IV) scores, behavior test scores (Chinese version of Conners' continuous performance test, CPT II V.5), and behavior rating scales. Auditory ERPs were recorded in each patient. RESULTS: Patients who had experienced complex FS exhibited significantly lower full-scale intelligence quotient (FSIQ), perceptual reasoning index, and working memory index scores than did the control group but did not show significant differences in CPT scores, behavior rating scales, or ERP latencies and amplitude compared with the other groups with FS. We found a significant decrease in the FSIQ and four indices of the WISC-IV, higher behavior rating scales, a trend of increased CPT II scores, and significantly delayed P300 latency and reduced P300 amplitude in the patients with AFS after FS. CONCLUSION: We conclude that there is an effect on cognitive function in children who have experienced complex FS and patients who developed AFS after FS. The results indicated that the WISC-IV is more sensitive in detecting cognitive abnormality than ERP. Cognition impairment, including perceptual reasoning and working memory defects, was identified in patients with prolonged, multiple, or focal FS. These results may have implications for the pathogenesis of complex FS. Further comprehensive psychological evaluation and educational programs are suggested.

Antiseizure Medications Normalize Electroencephalographic Functional Connectivity and Power in Children With Benign Epilepsy With Centrotemporal Spikes.

BACKGROUND: The decision to treat children with benign epilepsy with centrotemporal spikes (BECTS) using antiseizure medications (ASM) is controversial. Our goal is to compare the effect of ASM treatment on the alteration of electroencephalographic (EEG) functional connectivity and power across four frequency bands in children with BECTS. METHODS: Children with BECTS with two-year follow-up were retrospectively divided into ASM versus non-ASM groups. The network properties of the EEGs as based on network-based statistic and graph theory were evaluated by the following indices: global efficiency, clustering coefficient, betweenness centrality, and nodal strength in four frequency bands (delta, theta, alpha, and beta). EEG power including absolute power (AP) and relative power (RP) was analyzed in four frequency bands. RESULTS: In children with BECTS with ASM treatment, there was no significant change in EEG connectivity across all bands before and after two years of ASM. In children with BECTS without ASM treatment, there was a significant increase of global efficiency, clustering coefficient, and nodal strength but not the betweenness centrality in the delta band after two years of follow-up. A decrease in AP in the delta and theta bands and a decrease in RP in the theta band were found in the ASM group after two years of treatment. CONCLUSIONS: Our results suggest that ASM may play a role in modulating the development of increasing overall brain connectivity and in downregulating overt synaptic activity, but not intrinsic focal connectivity, in the early years of BECTS. The changes in the EEG power indicate that ASM significantly normalized slow-wave band power.

Feasibility and Toxicity of Interval-Compressed Chemotherapy in Asian Children and Young Adults with Sarcoma.

Twelve Asian patients with sarcoma received interval-compressed (ic-) chemotherapy scheduled every 14 days with a regimen of vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1200-2200 mg/m2) (VDC) alternating with a regimen of ifosfamide (9000 mg/m2) and etoposide (500 mg/m2) (IE), with filgrastim (5-10 mcg/kg/day) between cycles. Carboplatin (800 mg/m2) was added for CIC-rearranged sarcoma. The patients were treated with 129 cycles of ic-VDC/IE with a median interval of 19 days (interquartile range [IQR], 15-24 days. Median nadirs (IQR) were neutrophil count, 134 (30-396) × 106/L at day 11 (10-12), recovery by day 15 (14-17) and platelet count, 35 (23-83) × 109/L at day 11 (10-13), recovery by day 17 (14-21). Fever and bacteremia were observed in 36% and 8% of cycles, respectively. The diagnoses were Ewing sarcoma (6), rhabdomyosarcoma (3), myoepithelial carcinoma (1), malignant peripheral nerve sheath tumor (1), and CIC-DUX4 Sarcoma (1). Seven of the nine patients with measurable tumors responded (one CR and six PR). Interval-compressed chemotherapy is feasible in the treatment of Asian children and young adults with sarcomas.

Age-changed normative auditory event-related potential value in children in Taiwan.

BACKGROUND/PURPOSE: Event-related potentials (ERPs) reflect higher cortical function and the P3 (P300) wave has been associated with various sensory, cognitive, and attention processes. The aims of this study were to understand the age-related change in ERPs in children between the ages of 6 and 13 years and to establish a normal reference value for Taiwanese children for use in future study of neurocognitive dysfunction in children. METHODS: Using an auditory oddball paradigm, ERPs were recorded in 63 mentally and physically normal children ages 6 to 13 years. Parietal, central, and frontal ERP long-latency components (N1, P2, N2, P3) were measured in each test participant. RESULTS: Linear regression analysis demonstrated a significant linear decrease in P3, P2, N2, and N1 latencies and a significant linear increase in P3, P2, and N1 amplitudes in children between the ages of 6 and 13 years. P3 latency was significantly longer in children ages 6-7 years than in older children. The parietal P3 latency decreases 6.7 msec per year from ages 6 to 13 years. A wide variation in P3 latency in the children ages 6-7 years and a significant increase in P3 amplitude in those ages 12-13 years were observed from our data. A significant increase in P2 amplitude was also observed in children older than 10 years. CONCLUSION: The authors conclude that there exists an age-related change in ERP latency and amplitude during childhood. A negative correlation between ERP latencies and age and a positive correlation between ERP amplitude and age were found in this study. The authors emphasize that the auditory ERP value in children is not equal to that of adults. A normative auditory ERP value in children should be established prior to clinical application.

Resting-State EEG Functional Connectivity in Children with Rolandic Spikes with or without Clinical Seizures.

Alterations in dynamic brain network function are increasingly recognized in epilepsy. Benign childhood epilepsy with centrotemporal spikes (BECTS), or benign rolandic seizures, is the most common idiopathic focal epilepsy in children. In this study, we analyzed EEG functional connectivity (FC) among children with rolandic spikes with or without clinical seizures as compared to controls, to investigate the relationship between FC and clinical parameters in children with rolandic spikes. The FC analysis based on graph theory and network-based statistics in different frequency bands evaluated global efficiency, clustering coefficient, betweenness centrality, and nodal strength in four frequency bands. Similar to BECTS patients with seizures, children with rolandic spikes without seizures had significantly increased global efficiency, mean clustering coefficient, mean nodal strength, and connectivity strength, specifically in the theta frequency band at almost all proportional thresholds, compared with age-matched controls. Decreased mean betweenness centrality was only present in BECTS patients with seizures. Age at seizure onset was significantly positively associated with the strength of EEG-FC. The decreased function of betweenness centrality was only presented in BECTS patients with clinical seizures, suggesting weaker local connectivity may lower the seizure threshold. These findings may affect treatment policy in children with rolandic spikes.

Increased Risk of Tourette Syndrome with Leukotriene Modifier Use in Children with Allergic Diseases and Asthma: A Nationwide Population-Based Study.

(1) Background: Cysteinyl leukotriene receptor antagonists (LTRAs), including montelukast and zafirlukast, are FDA-approved for treating pediatric asthma and allergic diseases. Tourette syndrome (TS), a common neuropsychiatric disorder in children, is associated with allergic diseases and asthma. In this study, we investigated the risk of TS following an LTRA prescription for pediatric allergic diseases. (2) Methods: Children younger than 18 years of age who were newly diagnosed with asthma, allergic rhinitis, or atopic dermatitis between 1 January 2005 and 31 December 2018 and who were registered in the Taiwan National Health Insurance Research Database, which comprises the medical records of nearly 23 million Taiwanese population, were enrolled. LTRA users were matched with randomly selected LTRA non-users by sex, age, asthma-diagnosis year, and urbanization level. In total, 26,984 participants with allergic disease and TS were enrolled and included in the Cox proportional hazards model analysis. (3) Results: Children with allergic disease and asthma treated with LTRAs had a higher risk for TS than LTRA non-users (adjusted hazard ratio 1.376 [95% CI: 1.232−1.536], p < 0.001). LTRA users had a significantly higher risk for TS than LTRA non-users with allergic disease. The cumulative incidence of TS was significantly higher in LTRA users than in non-users with allergic diseases and asthma (log-rank test, p < 0.0001). (4) Conclusion: A prescription of LTRAs, mainly montelukast, increased the risk of TS among children with asthma, allergic rhinitis, or atopic dermatitis. The mechanism underlying the neuropsychiatric effect of LTRAs needs further investigation.

Clinical and Molecular Features in Medulloblastomas Subtypes in Children in a Cohort in Taiwan.

Medulloblastoma (MB) was classified into four molecular subgroups: WNT, SHH, group 3, and group 4. In 2017, 12 subtypes within 4 subgroups and 8 subtypes within non-WNT/non-SHH subgroups according to the differences of clinical features and biology were announced. In this study, we aimed to identify the heterogeneity of molecular features for discovering subtype specific factors linked to diagnosis and prognosis. We retrieved 70 MBs in children to perform RNA sequencing and a DNA methylation array in Taiwan. Integrated with clinical annotations, we achieved classification of 12 subtypes of pediatric MBs in our cohort series with reference to the other reported series. We analyzed the correlation of cell type enrichment in SHH MBs and found that M2 macrophages were enriched in SHH ß, which related to good outcomes of SHH MBs. The high infiltration of M2 macrophages may be an indicator of a favorable prognosis and therapeutic target for SHH MBs. Furthermore, C11orf95-RELA fusion was observed to be associated with recurrence and a poor prognosis. These results will contribute to the establishment of a molecular diagnosis linked to prognostic indicators of relevance and help to promote molecular-based risk stratified treatment for MBs in children.

Adrenal Crisis Mimicking COVID-19 Encephalopathy in a Teenager with Craniopharyngioma.

There is an increasing number of reported cases with neurological manifestations of COVID-19 in children. Symptoms include headache, general malaise, ageusia, seizure and alterations in consciousness. The differential diagnosis includes several potentially lethal conditions including encephalopathy, encephalitis, intracranial hemorrhage, thrombosis and adrenal crisis. We report the case of a 17-year-old boy with a positive antigen test of COVID-19 who presented with fever for one day, altered mental status and seizure, subsequently diagnosed with adrenal insufficiency. He had a history of panhypopituitarism secondary to a suprasellar craniopharyngioma treated with surgical resection; he was treated with regular hormone replacement therapy. After prompt administration of intravenous hydrocortisone, his mental status returned to normal within four hours. He recovered without neurologic complications. Adrenal insufficiency can present with neurological manifestations mimicking COVID-19 encephalopathy. Prompt recognition and treatment of adrenal insufficiency, especially in patients with brain tumors, Addison's disease or those recently treated with corticosteroids, can rapidly improve the clinical condition and prevent long-term consequences.

Atypical Teratoid/Rhabdoid Tumor in Taiwan: A Nationwide, Population-Based Study.

BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly aggressive embryonal brain tumor most commonly presenting in young children. METHODS: We performed a nationwide, population-based study of AT/RT (ICD-O-3 code: 9508/3) in Taiwan using the Taiwan Cancer Registry Database and the National Death Certificate Database. RESULTS: A total of 47 cases (male/female = 29:18; median age at diagnosis, 23.3 months (IQR: 12.5-87.9)) were diagnosed with AT/RT between 1999 and 2014. AT/RT had higher prevalence in males (61.70%), in children < 36 months (55.32%), and at infratentorial or spinal locations (46.81%). Survival analyses demonstrated that patients ≥ 3 years of age (n = 21 (45%)) had a 5y-OS of 41% (p < 0.0001), treatment with radiotherapy only (n = 5 (11%)) led to a 5y-OS of 60%, treatment with chemotherapy with or without radiotherapy (n = 27 (62%)) was associated with a 5y-OS of 45% (p < 0.0001), and patients with a supratentorial tumor (n = 11 (23%)) had a 5y-OS of 51.95%. Predictors of better survival on univariate Cox proportional hazard modeling and confirmed with multivariate analysis included older age (≥1 year), supratentorial sites, and the administration of radiotherapy, chemotherapy, or both. Gender had no effect on survival. CONCLUSION: Older age, supratentorial site, and treatment with radiotherapy, chemotherapy, or both significantly improves the survival of patients with AT/RT.

Febrile seizures reduce hippocampal subfield volumes but not cortical thickness in children with focal onset seizures.

OBJECTIVES: Whether febrile seizures (FS) produce long-term injury to the hippocampus or other brain structures is a critical question concerning focal onset seizures in children. Our aims are to evaluate the effect of FS on subfields of the hippocampus, thalamic nuclei, amygdala, cortical thickness, and surface area quantitatively in children with FS who later developed focal seizures and to identify biomarkers based on MRI structures. METHODS: Children who had focal onset seizures with or without previous FS and normal 3-T MRI findings were included retrospectively. The MRI was performed within 2 years after the onset of focal seizures. Age-matched controls were also recruited. Hippocampal subfields and thalamic nuclei, amygdala volumes, cortical thickness, and cortical surface area in individual cortical regions were segmented by FreeSurfer version 7.1.1. Volumetric and morphometric data among children who had focal seizures with or without previous FS, as well as controls, were compared and correlated with clinical parameters. RESULTS: Children with a history of FS who had focal seizures exhibited smaller right cornu ammonis (CA) 1 and right molecular cell layer of the hippocampus, compared to those without FS. A larger left hippocampal fissure was also found in FS with focal seizures compared to age-matched controls. There were no statistically significant differences in each nucleus of the thalamus, amygdala, cortical thickness, and surface area of each cortical region among the three groups. A smaller whole hippocampal volume was found for the right hippocampus in children with FS and focal seizures compared to those without FS. A trend of negative correlation was found between the frequency of FS and the left and right CA1 subfield volume ratios of the hippocampus. CONCLUSIONS: We concluded that multiple episodes of FS may be associated with a trivial difference in volume reduction in the CA1 and molecular layer of the right hippocampus and an enlarged hippocampal fissure of the left hippocampus, but not with individual cortical thicknesses, surface area, thalamic nuclei, or amygdala in children with focal onset seizures.The hippocampal subfield CA1 and molecular layer of the right hippocampus may be more vulnerable than the cortices in children with focal seizures who experienced multiple FS episodes. This study highlights the minimal differences in brain volumes among children with recent onset focal seizures with or without FS history and controls, suggesting that the brain injurious aspects of the FS and recent onset focal seizures may have been previously overstated. This suggests that physicians can be reassuring about brain injury associated with these seizure types when discussing outcomes with parents and patients.

Molecular-Clinical Correlation in Pediatric Medulloblastoma: A Cohort Series Study of 52 Cases in Taiwan.

In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). In this study, we aimed to identify a molecular-clinical correlation and somatic mutation for exploring risk-adapted treatment, drug targets, and potential genetic predisposition. In total, 52 frozen tumor tissues of childhood MBs were collected. RNA sequencing (RNA-Seq) and DNA methylation array data were generated. Molecular subgrouping and clinical correlation analysis were performed. An adjusted Heidelberg risk stratification scheme was defined for updated clinical risk stratification. We selected 51 genes for somatic variant calling using RNA-Seq data. Relevant clinical findings were defined. Potential drug targets and genetic predispositions were explored. Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Genetic backgrounds of metastasis at diagnosis and extent of tumor resection were observed. The adjusted Heidelberg scheme showed its applicability. Potential drug targets were detected in the pathways of DNA damage response. Among the 10 patients with SHH MBs analyzed using whole exome sequencing studies, five patients exhibited potential genetic predispositions and four patients had relevant germline mutations. The findings of this study provide valuable information for updated risk adapted treatment and personalized care of childhood MBs in our cohort series and in Taiwan.

Upregulation of Protein Synthesis and Proteasome Degradation Confers Sensitivity to Proteasome Inhibitor Bortezomib in Myc-Atypical Teratoid/Rhabdoid Tumors.

Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and Drug Administration as a primary treatment for multiple myeloma. This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ. We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. Concomitant upregulation of the Myc pathway, protein synthesis and proteasome degradation were identified in recurrent ATRTs. Additionally, we found the proteasome-encoding genes were highly expressed in ATRTs compared with in normal brain tissues, correlated with the malignancy of tumor cells and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12 and CHLA-266). Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs.

Seizures induced by GABAB-receptor blockade in early-life induced long-term GABA(B) receptor hypofunction and kindling facilitation.

Consequences of seizures in the developing brain are not completely understood. The aim of this study was to investigate the long-term alterations of synaptic transmission and seizure susceptibility in the hippocampus after early-life seizures induced by systemic injection of a GABA(B)-receptor antagonist CGP56999A in immature rats. Experimental rats were injected with CGP56999A 1-1.5mg/kg intraperitoneally (i.p.) on postnatal day 15, while controls were injected with saline i.p. Seizures induced by CGP56999A originated mostly from the hippocampus and amygdala, and were associated with no mortality. Thirty days after seizures, laminar field potentials were recorded in the hippocampus in urethane-anesthetized rats by 16-channel silicon probes and analyzed as current source density. As compared to early-life saline-injected rats, early-life CGP56999A-induced seizure rats showed a significant decrease in paired-pulse inhibition of population spikes at 150-400 ms interpulse intervals (IPIs) in CA1, following CA3 stimulation, and at 400 ms IPI in the dentate gyrus, following medial perforant path stimulation. In a separate experiment, adolescent rats that experienced CGP56999A-induced early-life seizures showed a robust facilitation of hippocampal kindling, as compared to saline controls. In conclusion, seizures induced by GABA(B)-receptor blockade in immature rats resulted in a long-lasting loss of GABA(B)-receptor mediated paired-pulse inhibition in CA1 and dentate gyrus, which may contribute to the increase of seizure susceptibility in the hippocampus.

Seizure characteristics are related to tumor pathology in children with brain tumors.

OBJECTIVES: Brain tumors are found in 1-3% of children with newly onset of seizures. Understanding the impact of seizures on pediatric brain tumors and factors between seizures and brain tumors are crucial. This study aimed to evaluate the association of pediatric brain tumors on seizure occurrence and the relationships between seizures and the diagnosis and prognosis of brain tumors. METHODS: In a cohort of 184 children with newly diagnosed brain tumors between August 2012 and September 2017, 56 patients with brain tumor-associated seizures were evaluated for their clinical characteristics, electroencephalography (EEG), tumor pathology, response to anti-epileptic drugs (AEDs) and their seizure outcome. RESULTS: The prevalence of seizures in our cohort of children with brain tumors was 30.4% (n = 56/184). Supratentorial tumors were more commonly associated with seizures than were infratentorial tumors (89.3% vs. 10.7%; P < 0.01). Among patients with tumor-associated seizures, the tumors were most commonly located in the temporal lobe (32.1%), followed by the frontal (21.4%) and parietal lobes (16.1%) and other cortices. Thirty-four patients (60.7%) had benign tumor pathology and 22 patients (39.3%) had malignant tumor pathology; low grade astrocytoma (n = 15; 26.8%) was the most common histology type. Seizure onset at initial presentation was more frequently observed in the patients with benign tumors, whereas the patients with malignant tumors tended to have delayed seizure onset (P < 0.01). On EEGs, focal epileptiform discharges were more commonly seen in benign tumors, whereas focal and diffuse slow waves were most commonly associated with malignant tumors. Levetiracetam was the most commonly prescribed AED to treat brain-tumor-associated seizures. CONCLUSIONS: In children with brain tumors, higher seizure frequency with normal neurologic examination was more prevalent in benign tumors, whereas less frequent seizures with focal weakness and signs of increased intracranial pressure were more indicative of malignancy. Delayed onset of seizures was more often observed in the children with malignant brain tumors. Seizure characteristics play an important role in relation to tumor biology and epileptogenesis in pediatric brain tumors.

Extrarenal rhabdoid tumor presented with an immobile arm in a one-year-old boy.

Infants with an immobile arm may be easily overlooked in primary care settings. Differential diagnoses include injuries, infections, neuropathies, ischemia and rarely, neoplasms. We report the case of a one-year-old boy with weakness in his left arm after minor trauma with a diagnosis of brachial plexus palsy initially. After rehabilitation for 2months, his weakness progressed to unsteady gait and quadriparesis. MRI revealed a huge solid tumor in the left supraclavicular fossa, which also involved the left brachial plexus, upper thoracic cavity, and left paravertebral space with invasion into the spinal canal. Microscopically, the medium-large polygonal tumor cells had an eccentric eosinophilic cytoplasm and immunostaining showed a loss of nuclear INI1 expression. Array comparative genomic hybridization of the tumor tissue confirmed a segmental deletion at chromosome region 22q11.23 involving the SMARCB1 gene. The final diagnosis was cervical paravertebral malignant rhabdoid tumor with intraspinal epidural and intradural invasion, a rare case of extrarenal extracranial rhabdoid tumor (ERRT). The intraspinal part of the tumor was resected followed by interval-compressed chemotherapy with vincristine-doxorubicin-cyclophosphamide alternating with ifosfamide-etoposide (VDC/IE). The tumor showed very good partial response to four cycles of chemotherapy with gradual recovery of neurological symptoms. ERRT is a very rare and aggressive tumor that mainly occurs in infants and children and may manifest with vague neurological symptoms when it involves the spinal cord and/or peripheral nerves. A neoplasm such as ERRT originating from or involving the brachial plexus should be considered in the differential diagnosis of an immobile arm in infancy.