Phase 2 Trial of Veliparib, Local Irradiation and Temozolomide in Patients with Newly Diagnosed High-Grade Glioma: A Children's Oncology Group Study.

Background: The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral poly(adenosine diphosphate-ribose) polymerase (PARP) 1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy.

Methods: We conducted a single-arm, non-randomized phase 2 clinical trial to determine whether treatment with veliparib and radiotherapy, followed by veliparib and temozolomide, improves progression-free survival in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations compared to patient level data from historical cohorts with closely matching clinical and molecular features.

A Novel, Mutually Beneficial Student-Faculty Partnership to Develop Real-Time Formative Assessments Aligning With the Preclinical Undergraduate Medical Curriculum.

Problem: A shortage of curriculum-aligned formative multiple-choice questions (FMCQs) remains despite their known learning benefits in preclinical medical education due to limitations on teaching faculty time and other reasons. In response, students often use extramural resources such as commercial or collaborative question banks; however, these options are often expensive and cannot be aligned with the content of each school's unique curriculum. In addition, students need feedback on their learning in a manner that parallels the format of summative assessments.

Novel MECP2 gene therapy is effective in a multicenter study using two mouse models of Rett syndrome and is safe in non-human primates.

The AAV9 gene therapy vector presented in this study is safe in mice and non-human primates and highly efficacious without causing overexpression toxicity, a major challenge for clinical translation of Rett syndrome gene therapy vectors to date. Our team designed a new truncated methyl-CpG-binding protein 2 (MECP2) promoter allowing widespread expression of MECP2 in mice and non-human primates after a single injection into the cerebrospinal fluid without causing overexpression symptoms up to 18 months after injection. Additionally, this new vector is highly efficacious at lower doses compared with previous constructs as demonstrated in extensive efficacy studies performed by two independent laboratories in two different Rett syndrome mouse models carrying either a knockout or one of the most frequent human mutations of Mecp2.

Molecular and spatial heterogeneity of microglia in Rasmussen encephalitis.

Rasmussen encephalitis (RE) is a rare childhood neurological disease characterized by progressive unilateral loss of function, hemispheric atrophy and drug-resistant epilepsy. Affected brain tissue shows signs of infiltrating cytotoxic T-cells, microglial activation, and neuronal death, implicating an inflammatory disease process. Recent studies have identified molecular correlates of inflammation in RE, but cell-type-specific mechanisms remain unclear.

Molecular Heterogeneity in Pediatric Malignant Rhabdoid Tumors in Patients With Multi-Organ Involvement.

Rhabdoid tumors (RTs) of the brain (atypical teratoid/rhabdoid tumor; AT/RT) and extracranial sites (most often the kidney; RTK) are malignant tumors predominantly occurring in children, frequently those with germline alterations. Here we present data from seven RTs from three pediatric patients who all had multi-organ involvement. The tumors were analyzed using a multimodal molecular approach, which included exome sequencing of tumor and germline comparator and RNA sequencing and DNA array-based methylation profiling of tumors.

Infantile metastatic ependymoma with a novel molecular profile and favorable outcome to intensive chemotherapy without irradiation: Case-based review.

Ependymal tumors are the third most common brain tumor under 14 years old. Even though metastatic disease is a rare event, it affects mostly young children and carries an adverse prognosis. The factors associated with dissemination and the best treatment approach have not yet been established and there is limited published data on how to manage metastatic disease, especially in patients under 3 years of age.

Detection of brain somatic variation in epilepsy-associated developmental lesions.

Objective: Epilepsy-associated developmental lesions, including malformations of cortical development and low-grade developmental tumors, represent a major cause of drug-resistant seizures requiring surgical intervention in children. Brain-restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified.

Methods: We enrolled 50 children who were undergoing epilepsy surgery into a translational research study.

Astroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes.

Astroblastomas (ABs) are rare brain tumors of unknown origin. We performed an integrative genetic and epigenetic analysis of AB-like tumors. Here, we show that tumors traceable to neural stem/progenitor cells (radial glia) that emerge during early to later brain development occur in children and young adults, respectively.

Clinically aggressive pediatric spinal ependymoma with novel MYC amplification demonstrates molecular and histopathologic similarity to newly described MYCN-amplified spinal ependymomas.

Primary spinal cord tumors contribute to ≤ 10% of central nervous system tumors in individuals of pediatric or adolescent age. Among intramedullary tumors, spinal ependymomas make up ~ 30% of this rare tumor population. A twelve-year-old male presented with an intradural, extramedullary mass occupying the dorsal spinal canal from C6 through T2.

Submucosal Nerve Diameter in the Rectum Increases With Age: An Important Consideration for the Diagnosis of Hirschsprung Disease.

Introduction: Hypertrophic submucosal nerves, defined as ≥40 µm in diameter, are considered supportive of a diagnosis of HSCR, but the effect of age on nerve diameter has not been well-studied. We sought to determine the distribution of the largest nerve diameter in ganglionic rectal biopsies and the significance of hypertrophic submucosal nerves in the diagnosis of Hirschsprung disease (HSCR) based on age.

Methods: Rectal biopsies performed in the evaluation of HSCR were retrospectively reviewed from 179 patients (151 ganglionic biopsies, 28 aganglionic biopsies), and the diameter of the largest submucosal nerve was measured.

Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue.

Spinal muscular atrophy type 1 (SMA1) is a debilitating neurodegenerative disease resulting from survival motor neuron 1 gene (SMN1) deletion/mutation. Onasemnogene abeparvovec (formerly AVXS-101) is a gene therapy that restores SMN production via one-time systemic administration. The present study demonstrates widespread biodistribution of vector genomes and transgenes throughout the central nervous system (CNS) and peripheral organs, after intravenous administration of an AAV9-mediated gene therapy.

STAT3 inhibitor in combination with irradiation significantly inhibits cell viability, cell migration, invasion and tumorsphere growth of human medulloblastoma cells.

Persistent activation of signal transducer and activator of transcription 3 (STAT3) is frequently reported in cancers and plays important roles in tumor progression. Therefore, directly targeting persistent STAT3 signaling is an attractive cancer therapeutic strategy. The aim of this study is to test the inhibitory efficacy of novel STAT3 small molecule inhibitors, LLY17 and LLL12B, in combination with irradiation in human medulloblastoma cells.

PTEN somatic mutations contribute to spectrum of cerebral overgrowth.

Phosphatase and tensin homologue (PTEN) regulates cell growth and survival through inhibition of the mammalian target of rapamycin (MTOR) signalling pathway. Germline genetic variation of PTEN is associated with autism, macrocephaly and PTEN hamartoma tumour syndromes. The effect of developmental PTEN somatic mutations on nervous system phenotypes is not well understood, although brain somatic mosaicism of MTOR pathway genes is an emerging cause of cortical dysplasia and epilepsy in the paediatric population.

Molecular classification of a complex structural rearrangement of the RB1 locus in an infant with sporadic, isolated, intracranial, sellar region retinoblastoma.

Retinoblastoma is a childhood cancer of the retina involving germline or somatic alterations of the RB Transcriptional Corepressor 1 gene, RB1. Rare cases of sellar-suprasellar region retinoblastoma without evidence of ocular or pineal tumors have been described. A nine-month-old male presented with a sellar-suprasellar region mass.

LLL12B, a small molecule STAT3 inhibitor, induces growth arrest, apoptosis, and enhances cisplatin-mediated cytotoxicity in medulloblastoma cells.

Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor and an oncogene product, which plays a pivotal role in tumor progression. Therefore, targeting persistent STAT3 signaling directly is an attractive anticancer strategy. The aim of this study is to test the efficacy of a novel STAT3 small molecule inhibitor, LLL12B, in suppressing medulloblastoma cells in vitro and tumor growth in vivo.

Is Upregulation of Sarcolipin Beneficial or Detrimental to Muscle Function?

Sarcolipin (SLN) is a regulator of sarco/endo plasmic reticulum Ca-ATPase (SERCA) pump and has been shown to be involved in muscle nonshivering thermogenesis (NST) and energy metabolism. Interestingly, SLN expression is significantly upregulated both during muscle development and in several disease states. However, the significance of altered SLN expression in muscle patho-physiology is not completely understood.

Revisiting the Neuropathology of Sudden Infant Death Syndrome (SIDS).

Sudden infant death syndrome (SIDS) is one of the leading causes of infant mortality in the United States (US). The extent to which SIDS manifests with an underlying neuropathological mechanism is highly controversial. SIDS correlates with markers of poor prenatal and postnatal care, generally rooted in the lack of access and quality of healthcare endemic to select racial and ethnic groups, and thus can be viewed in the context of health disparities.

Neuropathology of Surgically Managed Epilepsy Specimens.

Epilepsy is characterized as recurrent seizures, and it is one of the most prevalent disorders of the human nervous system. A large and diverse profile of different syndromes and conditions can cause perturbations in neural networks that are associated with epilepsy. Advances in neuroimaging and electrophysiological monitoring have enhanced our ability to localize the neuropathological lesions that alter the neural networks giving rise to epilepsy, whereas advances in surgical management have resulted in excellent seizure control in many patients following resections.

Histopathologic and Molecular Features of Central Nervous System Embryonal Tumors for Integrated Diagnosis Reporting.

Embryonal tumors of the pediatric central nervous system are challenging clinically and diagnostically. These tumors are aggressive, and patients often have poor outcomes even with intense therapy. Proper tumor classification is essential to patient care, and this process has undergone significant changes with the World Health Organization recommending histopathologic and molecular features be integrated in diagnostic reporting.

Neuropathology of Septo-optic Dysplasia: A Report of 4 Autopsy Cases.

Septo-optic dysplasia (SOD) is defined by the presence of 2 or more features in a diagnostic triad: (1) optic nerve hypoplasia, (2) pituitary dysfunction, and (3) midline forebrain anomalies. SOD arises due to diverse pathogenetic mechanisms including acquired and genetic factors, and it shows considerable clinical and phenotypic variability. Our knowledge of SOD is incomplete in part because of a paucity of published neuropathology data, so we reviewed the autopsy neuropathology of 4 SOD patients.

Pediatric meningioma: a clinicopathologic and molecular study with potential grading implications.

Meningiomas are common in adults (~35% of brain tumors) but rare in children, where they exhibit unique clinical, pathological and molecular features compared to adult counterparts. Thus, data generated from adult cohorts may be imperfectly suited to guiding diagnostic, prognostic and treatment decisions for children. We studied 50 meningioma patients ≤18 years with available clinical and pathological data to address the need for data obtained in the pediatric setting.

Somatic mosaicism correlates with clinical findings in epilepsy brain tissue.

Objective: Many genetic studies of intractable epilepsy in pediatric patients primarily focus on inherited, constitutional genetic deficiencies identified in patient blood. Recently, studies have revealed somatic mosaicism associated with epilepsy in which genetic variants are present only in a subset of brain cells. We hypothesize that tissue-specific, somatic mosaicism represents an important genetic etiology in epilepsy and aim to discover somatic alterations in epilepsy-affected brain tissue.

Neuropathology of Mowat-Wilson Syndrome.

Mowat-Wilson syndrome (MWS) is a syndromic form of Hirschsprung disease that is characterized by variable degrees of intellectual disability, characteristic facial dysmorphism, and a diverse set of other congenital malformations due to haploinsufficiency of . A variety of brain malformations have been described in neuroimaging studies of MWS patients, and the role of in the brain has been studied in a multitude of genetically engineered mouse models that are now available. However, a paucity of autopsy information limits our ability to correlate data from neuroimaging studies and animal models with actual MWS patient tissues.