Publications by authors named "Christopher R Pierson"

87 Publications

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

Pediatr Dev Pathol 2021 Nov 18:10935266211049689. Epub 2021 Nov 18.

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio.

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.

Results: In non-Hirschsprung disease (non-HSCR) biopsies, submucosal nerve diameter increased with age. In patients <1 year, the average diameter was 34.1 ± 11.6 µm but increased to 50.8 ± 17.3 µm after 1 year of age. Submucosal nerves ≥40 µm in diameter were significantly associated with HSCR across all ages [HSCR = 25/28 (89.3%) vs non-HSCR = 59/151 (39.1%), p < 0.0001] and remained significant in patients <1 year of age [HSCR = 22/24 (91.7%) vs non-HSCR = 19/91 (20.9%), p < 0.0001].

Conclusions: The diameter of submucosal nerves increases with age, and ≥40 µm nerves are common after 1 year of age.
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http://dx.doi.org/10.1177/10935266211049689DOI Listing
November 2021

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

Nat Med 2021 10 4;27(10):1701-1711. Epub 2021 Oct 4.

Novartis Gene Therapies, Bannockburn, IL, USA.

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. Two symptomatic infants with SMA1 enrolled in phase III studies received onasemnogene abeparvovec. Both patients died of respiratory complications unrelated to onasemnogene abeparvovec. One patient had improved motor function and the other died shortly after administration before appreciable clinical benefit could be observed. In both patients, onasemnogene abeparvovec DNA and messenger RNA distribution were widespread among peripheral organs and in the CNS. The greatest concentration of vector genomes was detected in the liver, with an increase over that detected in CNS tissues of 300-1,000-fold. SMN protein, which was low in an untreated SMA1 control, was clearly detectable in motor neurons, brain, skeletal muscle and multiple peripheral organs in treated patients. These data support the fact that onasemnogene abeparvovec has effective distribution, transduction and expression throughout the CNS after intravenous administration and restores SMN expression in humans.
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http://dx.doi.org/10.1038/s41591-021-01483-7DOI Listing
October 2021

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

Cancer Biol Ther 2021 09 13;22(7-9):430-439. Epub 2021 Jul 13.

Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.

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. Both LLY17 and LLL12B inhibit the IL-6-induced and persistent STAT3 phosphorylation in human medulloblastoma cells. Irradiation using 4 Gy alone exhibits some inhibitory effects on medulloblastoma cell viability, and these effects are further enhanced by combining with either STAT3 inhibitor. Irradiation alone also shows certain inhibitory effects on medulloblastoma cell migration and invasion and the combination of LLY17 or LLL12B with irradiation further demonstrates greater inhibitory effects than monotherapy. STAT3 inhibitor alone or irradiation alone exhibits some suppression of medulloblastoma tumorsphere growth, and the combination of LLY17 or LLL12B and irradiation exhibits greater suppression of tumorsphere growth than monotherapy. Combining either STAT3 inhibitor with irradiation reduces the expression of STAT3 downstream targets, Cyclin D1 and Survivin, and induces apoptosis in medulloblastoma cells. These results support that combination of a potent STAT3 inhibitor such as LLY17 or LLL12B with irradiation is an effective and novel therapeutic approach for medulloblastoma.
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http://dx.doi.org/10.1080/15384047.2021.1951573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489919PMC
September 2021

PTEN somatic mutations contribute to spectrum of cerebral overgrowth.

Brain 2021 May 28. Epub 2021 May 28.

The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.

Phosphatase and tensin homolog (PTEN) regulates cell growth and survival through inhibition of the mammalian target of rapamycin (MTOR) signaling pathway. Germline genetic variation of PTEN is associated with autism, macrocephaly, and PTEN hamartoma tumor syndromes (PHTS). 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 pediatric population. Here we report two somatic variants of PTEN affecting a single patient presenting with intractable epilepsy and hemimegalencephaly that varied in clinical severity throughout the left cerebral hemisphere. High-throughput sequencing analysis of affected brain tissue identified two somatic variants in PTEN. The first variant was present in multiple cell lineages throughout the entire hemisphere and associated with mild cerebral overgrowth. The second variant was restricted to posterior brain regions and affected the opposite PTEN allele, resulting in a segmental region of more severe malformation, and the only neurons in which it was found by single-nuclei RNA-seq had a unique disease-related expression profile. This study reveals brain mosaicism of PTEN as a disease mechanism of hemimegalencephaly and furthermore demonstrates the varying effects of single- or bi-allelic disruption of PTEN on cortical phenotypes.
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http://dx.doi.org/10.1093/brain/awab173DOI Listing
May 2021

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

Acta Neuropathol Commun 2021 04 7;9(1):61. Epub 2021 Apr 7.

The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute At Nationwide Children's Hospital, 575 Children's Crossroad, Columbus, OH, 43215 , USA.

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. Histopathology showed an embryonal tumor with focal Flexner-Wintersteiner-like rosettes and loss of retinoblastoma protein (RB1) expression by immunohistochemistry. DNA array-based methylation profiling confidently classified the tumor as pineoblastoma group A/intracranial retinoblastoma. The patient was subsequently enrolled on an institutional translational cancer research protocol and underwent comprehensive molecular profiling, including paired tumor/normal exome and genome sequencing and RNA-sequencing of the tumor. Additionally, Pacific Biosciences (PacBio) Single Molecule Real Time (SMRT) sequencing was performed from comparator normal and disease-involved tissue to resolve complex structural variations. RNA-sequencing revealed multiple fusions clustered within 13q14.1-q21.3, including a novel in-frame fusion of RB1-SIAH3 predicted to prematurely truncate the RB1 protein. SMRT sequencing revealed a complex structural rearrangement spanning 13q14.11-q31.3, including two somatic structural variants within intron 17 of RB1. These events corresponded to the RB1-SIAH3 fusion and a novel RB1 rearrangement expected to correlate with the complete absence of RB1 protein expression. Comprehensive molecular analysis, including DNA array-based methylation profiling and sequencing-based methodologies, were critical for classification and understanding the complex mechanism of RB1 inactivation in this diagnostically challenging tumor.
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http://dx.doi.org/10.1186/s40478-021-01164-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025529PMC
April 2021

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

Sci Rep 2021 03 22;11(1):6517. Epub 2021 Mar 22.

Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.

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. LLL12B selectively inhibited the induction of STAT3 phosphorylation by interleukin-6 but not induction of STAT1 phosphorylation by INF-γ. LLL12B also induced apoptosis in human medulloblastoma cells. In addition, LLL12B exhibited good oral bioavailability in vivo and potent suppressive activity in tumor growth of medulloblastoma cells in vivo. Besides, combining LLL12B with cisplatin showed greater inhibition of cell viability and tumorsphere formation as well as induction of apoptosis comparing to single agent treatment in medulloblastoma cells. Furthermore, LLL12B and cisplatin combination exhibited greater suppression of medulloblastoma tumor growth than monotherapy in vivo. The present study supported that LLL12B is a novel therapeutic agent for medulloblastoma and the combination of LLL12B with a chemotherapeutic agent cisplatin may be an effective approach for medulloblastoma therapy.
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http://dx.doi.org/10.1038/s41598-021-85888-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985203PMC
March 2021

Is Upregulation of Sarcolipin Beneficial or Detrimental to Muscle Function?

Front Physiol 2021 1;12:633058. Epub 2021 Mar 1.

Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, United States.

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. We have previously shown that transgenic over-expression of SLN in skeletal muscle is not detrimental, and can promote oxidative metabolism and exercise capacity. In contrast, some studies have suggested that SLN upregulation in disease states is deleterious for muscle function and ablation of SLN can be beneficial. In this perspective article, we critically examine both published and some new data to determine the relevance of SLN expression to disease pathology. The new data presented in this paper show that SLN levels are induced in muscle during systemic bacterial () infection or lipopolysaccharides (LPS) treatment. We also present data showing that SLN expression is significantly upregulated in different types of muscular dystrophies including myotubular myopathy. These data taken together reveal that upregulation of SLN expression in muscle disease is progressive and increases with severity. Therefore, we suggest that increased SLN expression should not be viewed as the cause of the disease; rather, it is a compensatory response to meet the higher energy demand of the muscle. We interpret that higher SLN/SERCA ratio positively modulate cytosolic Ca signaling pathways to promote mitochondrial biogenesis and oxidative metabolism to meet higher energy demand in muscle.
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http://dx.doi.org/10.3389/fphys.2021.633058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956958PMC
March 2021

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

Front Neurol 2020 17;11:594550. Epub 2020 Dec 17.

Division of Neuropathology, Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, United States.

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. However, some evidence suggests that at least a subset of SIDS cases may result from a neuropathological mechanism. To explain these issues, a triple-risk hypothesis has been proposed, whereby an underlying biological abnormality in an infant facing an extrinsic risk during a critical developmental period SIDS is hypothesized to occur. Each SIDS decedent is thus thought to have a unique combination of these risk factors leading to their death. This article reviews the neuropathological literature of SIDS and uses machine learning tools to identify distinct subtypes of SIDS decedents based on epidemiological data. We analyzed US Period Linked Birth/Infant Mortality Files from 1990 to 2017 (excluding 1992-1994). Using t-SNE, an unsupervised machine learning dimensionality reduction algorithm, we identified clusters of SIDS decedents. Following identification of these groups, we identified changes in the rates of SIDS at the state level and across three countries. Through t-SNE and distance based statistical analysis, we identified three groups of SIDS decedents, each with a unique peak age of death. Within the US, SIDS is geographically heterogeneous. Following this, we found low birth weight and normal birth weight SIDS rates have not been equally impacted by implementation of clinical guidelines. We show that across countries with different levels of cultural heterogeneity, reduction in SIDS rates has also been distinct between decedents with low vs. normal birth weight. Different epidemiological and extrinsic risk factors exist based on the three unique SIDS groups we identified with t-SNE and distance based statistical measurements. Clinical guidelines have not equally impacted the groups, and normal birth weight infants comprise more of the cases of SIDS even though low birth weight infants have a higher SIDS rate.
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http://dx.doi.org/10.3389/fneur.2020.594550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773837PMC
December 2020

Neuropathology of Surgically Managed Epilepsy Specimens.

Neurosurgery 2020 12;88(1):1-14

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio.

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 study using a variety of special stains, molecular analysis, and functional studies of these resected tissues has facilitated the neuropathological characterization of these lesions. Here, we review the neuropathology of common structural lesions that cause epilepsy and are amenable to neurosurgical resection, such as hippocampal sclerosis, focal cortical dysplasia, and its associated principal lesions, including long-term epilepsy-associated tumors, as well as other malformations of cortical development and Rasmussen encephalitis.
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http://dx.doi.org/10.1093/neuros/nyaa366DOI Listing
December 2020

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

Surg Pathol Clin 2020 Dec 9;13(4):783-800. Epub 2020 Oct 9.

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, J0359, 700 Children's Drive, Columbus, OH 43205, USA; Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA; Department of Biomedical Education & Anatomy, The Ohio State University, 1645 Neil Avenue, Columbus, OH 43210, USA. Electronic address:

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. This has especially impacted the workup of embryonal tumors because molecular testing has resulted in the identification of clinically relevant tumor subgroups and new entities. This review summarizes recent developments and provides a framework to workup embryonal tumors in diagnostic practice.
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http://dx.doi.org/10.1016/j.path.2020.08.005DOI Listing
December 2020

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

J Child Neurol 2021 02 14;36(2):105-115. Epub 2020 Sep 14.

Division of Anatomy, Department of Biomedical Education & Anatomy, 2647the Ohio State University, Columbus, OH, USA.

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. All patients met SOD criteria according to the triad. Additional neuropathologic findings included malformations involving non-forebrain structures and possible secondary phenomena. Autopsies demonstrate that SOD patients often have additional neuropathologic findings beyond the triad and we feel that use of the term SOD-complex appropriately underscores this diversity and its likely clinical impact. This study suggests that autopsies enhance our understanding of SOD and may be an asset in performing needed clinical and phenotypic correlation studies.
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http://dx.doi.org/10.1177/0883073820954071DOI Listing
February 2021

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

Brain Pathol 2020 11 6;30(6):1134-1143. Epub 2020 Aug 6.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.

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. As previously described, we noted a slight bias toward male patients and a higher proportion of spinal tumors compared to adults. Thirty-eight of 50 specimens were further analyzed by next generation sequencing. Loss-of-function mutations in NF2 and chromosome 22 losses were common, but pathogenic variants in other genes (SMARCB1, FUBP1, BRAF, TERT promoter, CHEK2, SMAD and GATA3) were identified in a minority of cases. Copy number variants outside of chromosomes 22 and 1 were infrequent. H3K27 hypomethylation, a useful biomarker in adult tumors, was not found in our cohort. In exploring the correlation between mitotic count and recurrence-free survival, we found a threshold of six mitoses per 10 high powered fields as the optimal cutoff in predicting recurrence-free survival. If independently validated in larger studies, adjusted grading thresholds could enhance the clinical management of pediatric meningiomas.
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http://dx.doi.org/10.1111/bpa.12884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018050PMC
November 2020

Somatic mosaicism correlates with clinical findings in epilepsy brain tissue.

Neurol Genet 2020 Aug 17;6(4):e460. Epub 2020 Jun 17.

The Steve and Cindy Rasmussen Institute for Genomic Medicine (K.E.M., D.C.K., K.M.S., T.A.B., E.C., K.L., V.M., H.Z., P.B., J.B., J.F., N.B., A.R.M., C.E.C., P.W., R.K.W., E.R.M.), Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH; Division of Genetic and Genomic Medicine (E.C.), Nationwide Children's Hospital, Columbus, OH; Department of Neurosurgery (A.S., J.L., J.A.P.), Nationwide Children's Hospital, Columbus, OH; Department of Pathology and Laboratory Medicine (C.R.P.), Nationwide Children's Hospital, Columbus, OH; Division of Child Neurology (A.P.O.), Nationwide Children's Hospital, Columbus, OH; Department of Radiology (J.A.R., S.H.S), Nationwide Children's Hospital, Columbus, OH; Department of Pediatrics (D.C.K., V.M., C.E.C., J.L., P.W., R.K.W, E.R.M., A.P.O.), The Ohio State University College of Medicine, Columbus, OH; Department of Neurosurgery (J.L., J.A.P., A.P.O.), The Ohio State University College of Medicine, Columbus, OH; Department of Pathology (C.E.C., C.R.P.), The Ohio State University College of Medicine, Columbus, OH; and Department of Biomedical Education & Anatomy (C.R.P.), Division of Anatomy, The Ohio State University College of Medicine, Columbus, OH.

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.

Methods: We have pursued a research study to identify brain somatic mosaicism, using next-generation sequencing (NGS) technologies, in patients with treatment refractory epilepsy who have undergone surgical resection of affected brain tissue.

Results: We used an integrated combination of NGS techniques and conventional approaches (radiology, histopathology, and electrophysiology) to comprehensively characterize multiple brain regions from a single patient with intractable epilepsy. We present a 3-year-old male patient with West syndrome and intractable tonic seizures in whom we identified a pathogenic frameshift somatic variant in , present at a range of variant allele fractions (4.2%-19.5%) in 12 different brain tissues detected by targeted sequencing. The proportion of the variant correlated with severity and location of neurophysiology and neuroimaging abnormalities for each tissue.

Conclusions: Our findings support the importance of tissue-based sequencing and highlight a correlation in our patient between variant allele fractions and the severity of epileptogenic phenotypes in different brain tissues obtained from a grid-based resection of clinically defined epileptogenic regions.
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http://dx.doi.org/10.1212/NXG.0000000000000460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323482PMC
August 2020

Neuropathology of Mowat-Wilson Syndrome.

Pediatr Dev Pathol 2020 Aug 6;23(4):322-325. Epub 2020 Apr 6.

Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio.

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. Here, we report the autopsy neuropathology of a 19-year-old male patient with MWS. Autopsy neuropathology findings correlated well with the reported MWS neuroimaging data and are in keeping with data from genetically engineered MWS mouse models. This autopsy enhances our understanding of function in human brain development and demonstrates the reliability of MWS murine models.
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http://dx.doi.org/10.1177/1093526620903956DOI Listing
August 2020

ΔNp73/ETS2 complex drives glioblastoma pathogenesis- targeting downstream mediators by rebastinib prolongs survival in preclinical models of glioblastoma.

Neuro Oncol 2020 03;22(3):345-356

Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio.

Background: Glioblastoma (GBM) remains one of the least successfully treated cancers. It is essential to understand the basic biology of this lethal disease and investigate novel pharmacological targets to treat GBM. The aims of this study were to determine the biological consequences of elevated expression of ΔNp73, an N-terminal truncated isoform of TP73, and to evaluate targeting of its downstream mediators, the angiopoietin 1 (ANGPT1)/tunica interna endothelial cell kinase 2 (Tie2) axis, by using a highly potent, orally available small-molecule inhibitor (rebastinib) in GBM.

Methods: ΔNp73 expression was assessed in glioma sphere cultures, xenograft glioblastoma tumors, and glioblastoma patients by western blot, quantitative reverse transcription PCR, and immunohistochemistry. Immunoprecipitation, chromatin immunoprecipitation (ChiP) and sequential ChIP were performed to determine the interaction between ΔNp73 and E26 transformation-specific (ETS) proto-oncogene 2 (ETS2) proteins. The oncogenic consequences of ΔNp73 expression in glioblastomas were examined by in vitro and in vivo experiments, including orthotopic zebrafish and mouse intracranial-injection models. Effects of rebastinib on growth of established tumors and survival were examined in an intracranial-injection mouse model.

Results: ΔNp73 upregulates both ANGPT1 and Tie2 transcriptionally through ETS conserved binding sites on the promoters by interacting with ETS2. Elevated expression of ΔNp73 promotes tumor progression by mediating angiogenesis and survival. Therapeutic targeting of downstream ΔNp73 signaling pathways by rebastinib inhibits growth of established tumors and extends survival in preclinical models of glioblastoma.

Conclusion: Aberrant expression of ΔNp73 in GBM promotes tumor progression through autocrine and paracrine signaling dependent on Tie2 activation by ANGPT1. Disruption of this signaling by rebastinib improves tumor response to treatment in glioblastoma.
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http://dx.doi.org/10.1093/neuonc/noz190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058445PMC
March 2020

GOPC-ROS1 Fusion Due to Microdeletion at 6q22 Is an Oncogenic Driver in a Subset of Pediatric Gliomas and Glioneuronal Tumors.

J Neuropathol Exp Neurol 2019 12;78(12):1089-1099

Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital and The Ohio State University.

ROS1 is a transmembrane receptor tyrosine kinase proto-oncogene that has been shown to have rearrangements with several genes in glioblastoma and other neoplasms, including intrachromosomal fusion with GOPC due to microdeletions at 6q22.1. ROS1 fusion events are important findings in these tumors, as they are potentially targetable alterations with newer tyrosine kinase inhibitors; however, whether these tumors represent a distinct entity remains unknown. In this report, we identify 3 cases of unusual pediatric glioma with GOPC-ROS1 fusion. We reviewed the clinical history, radiologic and histologic features, performed methylation analysis, whole genome copy number profiling, and next generation sequencing analysis for the detection of oncogenic mutation and fusion events to fully characterize the genetic and epigenetic alterations present in these tumors. Two of 3 tumors showed pilocytic features with focal expression of synaptophysin staining and variable high-grade histologic features; the third tumor aligned best with glioblastoma and showed no evidence of neuronal differentiation. Copy number profiling revealed chromosome 6q22 microdeletions corresponding to the GOPC-ROS1 fusion in all 3 cases and methylation profiling showed that the tumors did not cluster together as a single entity or within known methylation classes by t-Distributed Stochastic Neighbor Embedding.
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http://dx.doi.org/10.1093/jnen/nlz093DOI Listing
December 2019

A Novel De Novo Heterozygous SCN4a Mutation Causing Congenital Myopathy, Myotonia and Multiple Congenital Anomalies.

J Neuromuscul Dis 2019 ;6(4):467-473

Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.

Background: The phenotypic spectrum of the skeletal muscle voltage-gated sodium channel gene (SCN4A) mutations has been expanding dramatically with advancements in genetic testing. Previously only known to cause autosomal dominant myotonia or periodic paralysis, now recessive mutations have been found causing congenital myopathies and congenital myasthenic syndromes.

Case Presentation: A 27-year-old woman who was born with Arnold-Chiari malformation, hydrocephalus, high-arched palate, bilateral hip dysplasia, and severe scoliosis presented for evaluation of episodic muscle stiffness and weakness. Electrodiagnostic studies revealed myopathy and widespread myotonia. Muscle histopathology showed marked fiber size variability, type I fiber predominance with minimal scattered necrosis and regeneration which was typical of a congenital myopathy with an additional finding of a lobulated structural pattern in type I fibers. Sequential individual gene testing revealed a novel de novo heterozygous c.2386 C > G, p.Leu796Val missense mutation in the SCN4A gene.

Discussion: To the best of our knowledge, this is the first report of a dominant, heterozygous mutation in SCN4A causing a complex phenotype of congenital myopathy and myotonia with multiple congenital anomalies and unique muscle pathology findings. This case is another addition to the ever expanding phenotype of SCN4A mutations.
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http://dx.doi.org/10.3233/JND-190425DOI Listing
April 2020

Mentors' perspectives on the successes and challenges of mentoring in the COG Young Investigator mentorship program: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2019 10 16;66(10):e27920. Epub 2019 Jul 16.

Division of Pediatric Hematology-Oncology, Children's Hospital of Los Angeles, Los Angeles, California.

Background: Identification and development of young investigators (YI) is critical to the long-term success of research organizations. In 2004, the Children's Oncology Group (COG) created a mentorship program to foster the career development of YIs (faculty <10 years from initial appointment). This study sought to assess mentors' long-term assessment of this program.

Procedure: In 2018, 101 past or current mentors in the COG YI mentorship program completed an online survey. Statistical comparisons were made with the Kruskal-Walis test.

Results: The response rate was 74.2%. As some mentors had multiple mentees, we report on 138 total mentee-mentor pairs. Mentors were 57.4% male, and mentees were 39.1% male. Mentors rated being mentored as a YI as important with a median rating of 90 on a scale of 1-100, interquartile range (IQR) 80-100. Most mentors reported that being mentored themselves helped their own success within COG (78.2%) and with their overall career development (92.1%). Most mentors enjoyed serving in the program (72.3%) and the median success rating (on a scale of 1-100) across the mentor-mentee pairings was 75, IQR 39-90. Success ratings did not differ by mentor/mentee gender, but improved with increased frequency of mentor-mentee interactions (P < .001). Mentor-mentee pairs who set initial goals reported higher success ratings than those who did not (P < .001). Tangible successes included current mentee COG committee involvement (45.7%), ongoing mentor-mentee collaboration (53.6%), and co-authored manuscript publication (38.4%).

Conclusion: These data indicate that mentorship is important for successful professional development. Long-term mentoring success improves when mentors and mentees set goals upfront and meet frequently.
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http://dx.doi.org/10.1002/pbc.27920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707882PMC
October 2019

Expanding the clinical history associated with syndromic Klippel-Feil: A unique case of comorbidity with medulloblastoma.

Eur J Med Genet 2019 Aug 10;62(8):103701. Epub 2019 Jun 10.

Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA; Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA.

Klippel-Feil syndrome (KFS) is an exceedingly rare constitutional disorder in which a paucity of knowledge exists about the disease and its associated morbidity and mortality. We present a 4-year-old male with KFS, who notably was also diagnosed with large-cell anaplastic medulloblastoma. We evaluated the genetic basis of co-occurring KFS and medulloblastoma and the role of MYO18B as related to medulloblastoma. Constitutional and somatic variant and copy number analyses were performed from DNA-based exome studies, along with RNA-sequencing of tumor tissue, to elucidate the genetic etiology of the co-existing disease states. We identified novel constitutional compound heterozygous frameshift variants (NM_032608.5: p.Leu2257SerfsTer16 and p.Arg2220SerfsTer74) each encoding a premature stop of translation in MYO18B, consistent with a diagnosis of KFS. We did not identify any somatic variants of known relevance or disease-relevant therapeutic targets in the tumor. The somatic copy number profile was suggestive of Group 3γ medulloblastoma. Relative to pediatric brain tumors, medulloblastoma, particularly, Group 3, had increased gene expression of MYO18B. In summary, coexisting constitutional and somatic diagnoses in this patient enabled the elucidation of the genetic etiology of KFS and provided support for the role of MYO18B in tumor suppression.
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http://dx.doi.org/10.1016/j.ejmg.2019.103701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285001PMC
August 2019

Germinoma Involving the Retina: An Unusual Presentation of Recurrent Intracranial Mixed Germ Cell Tumor.

World Neurosurg 2019 Jan 7. Epub 2019 Jan 7.

The Department of Pathology & Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH 43205 and The Department of Pathology, The Ohio State University, College of Medicine, Columbus, OH 43210 USA.

Background: We report a patient with primary central nervous system mixed malignant germ cell tumor (GCT) who presented with recurrent malignant germinomatous infiltration of the retina.

Case Description: A ten-year-old girl initially presented with a large suprasellar mixed malignant GCT with a near-complete response after initial induction chemotherapy and irradiation. Three and half years after initial therapy, she presented with progressively worsening vision in her left eye. Magnetic resonance imaging showed infiltrative changes within the left optic nerve but no discrete mass. Serum and cerebrospinal fluid (CSF) tumor markers were not elevated and CSF cytology was negative. Left optic nerve biopsy confirmed the presence of mature teratoma and pure germinoma components. She was treated with gross-total resection of the left eye and optic nerve and chemotherapy. Histopathologic evaluation of the optic nerve showed only mature teratoma elements but with pure germinoma cells infiltrating the inner layers of the retina.

Conclusions: Loco-regional extension of suprasellar GCT to the optic nerve is not uncommon; however, infiltration of the tumor into the retina is not reported in the literature. Early detection of optic pathway involvement and proper delineation of the irradiation field may prevent GCT infiltration of the retina with subsequent vision loss.
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http://dx.doi.org/10.1016/j.wneu.2018.12.143DOI Listing
January 2019

Targeting Upstream Kinases of STAT3 in Human Medulloblastoma Cells.

Curr Cancer Drug Targets 2019 ;19(7):571-582

Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, United States.

Background: Medulloblastoma is the most common malignant brain tumor in children. Despite improvement in overall survival rate, it still lacks an effective targeted treatment strategy. The Janus family of cytoplasmic tyrosine kinases (JAKs) and Src kinases, upstream protein kinases of signal transducer and activator of transcription 3 (STAT3), play important roles in medulloblastoma pathogenesis and therefore represent potential therapeutic targets.

Methods: In this report, we examined the inhibitory efficacy of the JAK1/2 inhibitor, ruxolitinib, the JAK3 inhibitor, tofacitinib and two Src inhibitors, KX2-391 and dasatinib.

Results: These small molecule drugs significantly reduce cell viability and inhibit cell migration and colony formation in human medulloblastoma cells in vitro. Src inhibitors have more potent efficacy than JAK inhibitors in inhibiting medulloblastoma cell migration ability. The Src inhibitors can inhibit both phosphorylation of STAT3 and Src while JAK inhibitors reduce JAK/STAT3 phosphorylation. We also investigated the combined effect of the Src inhibitor, dasatinib with cisplatin. The results show that dasatinib exerts synergistic effects with cisplatin in human medulloblastoma cells through the inhibition of STAT3 and Src.

Conclusion: Our results suggest that the small molecule inhibitors of STAT3 upstream kinases, ruxolitinib, tofacitinib, KX2-391, and dasatinib could be novel and attractive candidate drugs for the treatment of human medulloblastoma.
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http://dx.doi.org/10.2174/1568009618666181016165604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533162PMC
September 2020

Hepcidin, an Iron Regulatory Hormone of Innate Immunity, is Differentially Expressed in Premature Fetuses with Early-Onset Neonatal Sepsis.

Am J Perinatol 2018 07 2;35(9):865-872. Epub 2018 Feb 2.

Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.

Objective: Hepcidin, a mediator of innate immunity, binds the iron exporter ferroportin, leading to functional hypoferremia through intracellular iron sequestration. We explored hepcidin-ferroportin interactions in neonates clinically diagnosed with early-onset neonatal sepsis (EONS).

Study Design: Hepcidin and interleukin (IL)-6 were quantified by enzyme-linked immunosorbent assay (ELISA) in 92 paired cord blood-maternal blood samples in the following groups: "Yes" EONS ( = 41, gestational age [GA] 29 ± 1 weeks) and "No" EONS ( = 51, GA 26 ± 1 weeks). Placental hepcidin and ferroportin expression were evaluated by immunohistochemistry and real-time-polymerase chain reaction (RT-PCR). Liver hepcidin and ferroportin expression patterns were ascertained in autopsy specimens of neonates ( = 8) who died secondary to culture-proven sepsis.

Results: Cord blood hepcidin was significantly elevated (GA corrected,  = 0.018) and was positively correlated with IL-6 ( = 0.379,  = 0.001) in EONS. Hepcidin localized at syncytiotrophoblast and fetal vascular endothelium. Placental ferroportin, but not hepcidin mRNA correlated with cord blood hepcidin levels ( = 0.46,  = 0.039) and funisitis severity ( = 0.50,  = 0.018). Newborns who died from sepsis ( = 4) had higher hepatic hepcidin and iron sequestration, but lower ferroportin staining than those who died of nonsepsis causes ( = 4).

Conclusion: Premature fetuses with EONS have elevated circulating hepcidin, likely related to lower placenta and liver ferroportin expression. Fetal hepcidin-ferroportin interaction appears to play a role in EONS pathophysiology independent of maternal response to intrauterine inflammation.
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http://dx.doi.org/10.1055/s-0038-1626711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412256PMC
July 2018

SPEG-deficient skeletal muscles exhibit abnormal triad and defective calcium handling.

Hum Mol Genet 2018 05;27(9):1608-1617

Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Centronuclear myopathies (CNM) are a subtype of congenital myopathies (CM) characterized by skeletal muscle weakness and an increase in the number of central myonuclei. We have previously identified three CNM probands, two with associated dilated cardiomyopathy, carrying striated preferentially expressed gene (SPEG) mutations. Currently, the role of SPEG in skeletal muscle function is unclear as constitutive SPEG-deficient mice developed severe dilated cardiomyopathy and died in utero. We have generated a conditional Speg-KO mouse model and excised Speg by crosses with striated muscle-specific cre-expressing mice (MCK-Cre). The resulting litters had a delay in Speg excision consistent with cre expression starting in early postnatal life and, therefore, an extended lifespan up to a few months. KO mice were significantly smaller and weaker than their littermate-matched controls. Histopathological skeletal muscle analysis revealed smaller myofibers, marked fiber-size variability, and poor integrity and low number of triads. Further, SPEG-deficient muscle fibers were weaker by physiological and in vitro studies and exhibited abnormal Ca2+ handling and excitation-contraction (E-C) coupling. Overall, SPEG deficiency in skeletal muscle is associated with fewer and abnormal triads, and defective calcium handling and excitation-contraction coupling, suggesting that therapies targeting calcium signaling may be beneficial in such patients.
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http://dx.doi.org/10.1093/hmg/ddy068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905626PMC
May 2018

Intraocular Medulloepithelioma: AIRP Best Cases in Radiologic-Pathologic Correlation.

Radiographics 2018 Jan-Feb;38(1):194-199

From the Department of Radiology, University of Toledo Medical Center, 3000 Arlington Ave, Room 1192, Toledo, OH 43614 (O.Z.A.); Department of Pathology and Laboratory Medicine (M.S., C.R.P.), Department of Ophthalmology and Visual Sciences (D.G.S.), and Department of Radiology (L.C.M.), Nationwide Children's Hospital, Columbus, Ohio; and Department of Ophthalmology and Visual Sciences (J.R., D.G.S.), Department of Pathology (C.R.P.), and Department of Biomedical Education, Division of Anatomy (C.R.P.), Ohio State University Wexner Medical Center, Columbus, Ohio.

Editor's Note.-RadioGraphics continues to publish radiologic-pathologic case material selected from the American Institute for Radiologic Pathology (AIRP) "best case" presentations. The AIRP conducts a 4-week Radiologic Pathology Correlation Course, which is offered five times per year. On the penultimate day of the course, the best case presentation is held at the American Film Institute Silver Theater and Cultural Center in Silver Spring, Md. The AIRP faculty identifies the best cases, from each organ system, brought by the resident attendees. One or more of the best cases from each of the five courses are then solicited for publication in RadioGraphics. These cases emphasize the importance of radiologic-pathologic correlation in the imaging evaluation and diagnosis of diseases encountered at the institute and its predecessor, the Armed Forces Institute of Pathology (AFIP).
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http://dx.doi.org/10.1148/rg.2018170160DOI Listing
August 2018

Blocking interleukin-6 signaling inhibits cell viability/proliferation, glycolysis, and colony forming activity of human medulloblastoma cells.

Int J Oncol 2018 Feb 22;52(2):571-578. Epub 2017 Nov 22.

Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.

Elevated levels of the pro-inflammatory cytokine interleukin-6 (IL‑6) have tumor-promoting activity and are associated with poor survival outcomes in many cancers. Additionally, the IL‑6/GP130/STAT3 axis has been widely studied due to its pivotal role in tumor development and maintenance in a number of tissue types, including the cerebellum. However, the connection between IL‑6 signaling and medulloblastoma progression is largely unexplored. In the present study, we observed that IL‑6 induced medulloblastoma cell viability, cell proliferation and glycolysis. Furthermore, it also upregulated the expression of phosphorylated STAT3, indicating that the IL‑6/GP130/STAT3 pathway plays a central role in medulloblastoma. The FDA-approved drug bazedoxifene, a blocker of the formation of the hexameric IL‑6/IL‑6R/GP130 complex, was re-purposed in this study to inhibit the IL‑6/GP130/STAT3 signaling pathway. Bazedoxifene not only inhibited IL‑6 mediated cell viability and cell proliferation, and increased phosphorylated STAT3 expression, but it also decreased cell glycolysis, demonstrating a certain level of therapeutic efficacy in vitro. Collectively, our findings offer new insight into the molecular mechanism underlying the biological aggressiveness of medulloblastoma, the roles of IL‑6 in these processes and a possible efficacious adjuvant therapy for medulloblastoma.
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http://dx.doi.org/10.3892/ijo.2017.4211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741369PMC
February 2018

Long-term evidence that a pediatric oncology mentorship program for young investigators is feasible and beneficial in the cooperative group setting: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2018 03 28;65(3). Epub 2017 Nov 28.

Children's Hospital of Los Angeles, Los Angeles, California.

Background: Mentorship of junior faculty is an integral component of career development. The Children's Oncology Group (COG) Young Investigator (YI) Committee designed a mentorship program in 2004 whose purpose was to pair YIs (faculty ≤10 years of first academic appointment) with a senior mentor to assist with career development and involvement in COG research activities. This study reports on the committee's ability to achieve these goals.

Procedure: An online survey was sent to YIs who were registered with the program from 2004 to2015, assessing three major domains: (1) overall experience with the mentor pairing, (2) satisfaction with the program, and (3) academic accomplishments of the mentees.

Results: The response rate was 64% (110/171). Overall, YIs rated the success of their mentorship pairing as 7.2 out of 10 (median) (25th, 75th quartile 3.6, 9.6). The direct effects of the mentorship program included 70% YIs reporting a positive effect on their career, 40% reporting any grant or manuscript resulting from the pairing, 47% forming a new research collaboration, and 43% receiving appointment to a COG committee. Respondents reported success in COG with 38% authoring a manuscript on behalf of COG and 65% reporting a leadership position including seven current or past COG discipline chairs and 20 study chairs. Finally, 74% of respondents said they would consider serving as mentors in the program in the future.

Conclusion: The COG YI mentorship program has been well received by the majority of the participants and has helped to identify and train many current leaders in COG.
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http://dx.doi.org/10.1002/pbc.26878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773146PMC
March 2018

Treatment-Related Noncontiguous Radiologic Changes in Children With Diffuse Intrinsic Pontine Glioma Treated With Expanded Irradiation Fields and Antiangiogenic Therapy.

Int J Radiat Oncol Biol Phys 2017 12 24;99(5):1295-1305. Epub 2017 Aug 24.

Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee.

Purpose: We previously reported the cases of 3 children with diffuse intrinsic pontine glioma (DIPG) in whom noncontiguous treatment-related abnormalities (NCTRAs) developed in the brain after expanded-field radiation therapy (RT). To investigate the occurrence and putative mechanism of NCTRAs, we reviewed brain magnetic resonance imaging studies of patients with DIPG treated in 2 consecutive phase I clinical trials (trials 1 and 2).

Methods And Materials: The 55 children included in these trials received small-molecule inhibitors: vandetanib in trial 1 (n=32; mean age 6.4 years) and vandetanib and dasatinib in trial 2 (n=23; mean age 5.8 years). The patients also received conformal 3-dimensional RT (cumulative dose 54 Gy). For patients enrolled in trial 1, the clinical target volume (CTV) was expanded by 1 cm from the gross tumor volume. In trial 2, the expansion to form the CTV was 2 to 3 cm. A review of imaging studies was performed from the initial diagnosis through the end of progression-free survival. The imaging findings were grouped into 5 categories according to the presence, absence, location, extent, and putative mechanism of NCTRAs. Statistical analysis was performed to evaluate the association between covariates and NCTRA, cohort characterization, and survival comparisons.

Results: Overall survival was similar in both studies (P=.74). NCTRAs developed in 9 patients (39%) treated in trial 2 but in none treated in trial 1. The NCTRAs included T2-weighted hyperintensities with (n=3; radiation necrosis) or without (n=5) contrast uptake, supratentorial leukoencephalopathy (n=2), and ischemic stroke (n=1). All NCTRAs, except for 1, occurred within the CTV. Compared with nonaffected patients, patients with a NCTRA were younger (P=.003) and had had larger relative brain volumes exposed to doses >20 Gy.

Conclusions: The imaging features of NCTRAs suggest that their development is secondary to synergistic steno-occlusive vascular effects induced by the combination of RT, an expanded CTV, potent antiangiogenic therapy, young age, and, in 1 case, a genetic predisposition.
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http://dx.doi.org/10.1016/j.ijrobp.2017.08.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889052PMC
December 2017

Immune profiling of NF1-associated tumors reveals histologic subtype distinctions and heterogeneity: implications for immunotherapy.

Oncotarget 2017 Oct 30;8(47):82037-82048. Epub 2017 May 30.

Division of Hematology, Oncology, Blood and Marrow Transplant, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, USA.

Successful treatment of neurofibromatosis type 1 (NF1)-associated tumors poses a significant clinical challenge. While the primary underlying genetic defect driving RAS signaling is well described, recent evidence suggests immune dysfunction contributes to tumor pathogenesis and malignant transformation. As immunologic characterizations, prognostic and predictive of immunotherapeutic clinical response in other cancers, are not fully described for benign and malignant NF1-related tumors, we sought to define their immunologic profiles. We determined the expression of human leukocyte antigen (HLA)-A/-B/-C, β-2-microglobulin (B2M), and T cell inhibitory ligands PD-L1 and CTLA-4 by microarray gene analysis and flow cytometry. We examined HLA-A/-B/-C, B2M, and PD-L1 expression on thirty-six NF1-associated tumor samples by immunohistochemistry, and correlated these with tumoral CD4, CD8, FOXP3, CD56, and CD45RO lymphocytic infiltrates. We evaluated several tumors from a single patient, observing trends of increasing immunogenicity over time, even with disease progression. We observed similarly immunogenic profiles for malignant peripheral nerve sheath tumors (MPNST) and nodular and plexiform neurofibromas, contrasting with diffuse neurofibromas. These studies suggest that while immunotherapies may offer some benefit for MPNST and nodular and plexiform neurofibromas, tumor heterogeneity might pose a significant clinical challenge to this novel therapeutic approach.
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http://dx.doi.org/10.18632/oncotarget.18301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669868PMC
October 2017

Acanthamoeba granulomatous amoebic encephalitis after pediatric hematopoietic stem cell transplant.

Pediatr Transplant 2017 Dec 17;21(8). Epub 2017 Sep 17.

Department of Pediatrics, Division of Hematology/Oncology/BMT, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.

Acanthamoeba encephalitis is a rare, often fatal condition, particularly after HSCT, with 9 reported cases to date in the world literature. Our case was originally diagnosed with ALL at age 3 years, and after several relapses underwent HSCT at age 9 years. At 17 years of age, he was diagnosed with secondary AML for which he underwent a second allogeneic HSCT. He presented with acute-onset worsening neurological deficits on day +226 after the second transplant and a post-mortem diagnosis of Acanthamoeba encephalitis was established, with the aid of the CDC.
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http://dx.doi.org/10.1111/petr.13060DOI Listing
December 2017

Use of a Piglet Model for the Study of Anesthetic-induced Developmental Neurotoxicity (AIDN): A Translational Neuroscience Approach.

J Vis Exp 2017 06 11(124). Epub 2017 Jun 11.

Department of Anesthesiology, Ohio State University College of Medicine.

Anesthesia cannot be avoided in many cases when surgery is required, particularly in children. Recent investigations in animals have raised concerns that anesthesia exposure may lead to neuronal apoptosis, known as anesthesia-induced developmental neurotoxicity (AIDN). Furthermore, some clinical studies in children have suggested that anesthesia exposure may lead to neurodevelopmental deficits later in life. Nonetheless, an ideal animal model for preclinical study has yet to be developed. The neonatal piglet represents a valuable model for preclinical study, as they share a striking number of developmental similarities with humans. The anatomy and physiology of piglets allow for implementation of rigorous human perioperative conditions in both survival and non-survival procedures. Femoral artery catheterization allows for close monitoring, thus enabling prompt correction of any deviation of the piglet's vital signs and chemistries. In addition, there are multiple developmental similarities between piglets and human neonates. The techniques required to use piglets for experimentation will require experience to master. A pediatric anesthesiologist is a critical member of the investigative team. We describe, in a general sense, the appropriate use of a piglet model for neurodevelopmental study.
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http://dx.doi.org/10.3791/55193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608378PMC
June 2017
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