Publications by authors named "Samuel David"

147 Publications

Neuroimmunological therapies for treating spinal cord injury: Evidence and future perspectives.

Exp Neurol 2021 Mar 19;341:113704. Epub 2021 Mar 19.

Division of Translational and Experimental Neuroscience, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Spinal cord injury (SCI) has a complex pathophysiology. Following the initial physical trauma to the spinal cord, which may cause vascular disruption, hemorrhage, mechanical injury to neural structures and necrosis, a series of biomolecular cascades is triggered to evoke secondary injury. Neuroinflammation plays a major role in the secondary injury after traumatic SCI. To date, the administration of systemic immunosuppressive medications, in particular methylprednisolone sodium succinate, has been the primary pharmacological treatment. This medication is given as a complement to surgical decompression of the spinal cord and maintenance of spinal cord perfusion through hemodynamic augmentation. However, the impact of neuroinflammation is complex with harmful and beneficial effects. The use of systemic immunosuppressants is further complicated by the natural onset of post-injury immunosuppression, which many patients with SCI develop. It has been hypothesized that immunomodulation to attenuate detrimental aspects of neuroinflammation after SCI, while avoiding systemic immunosuppression, may be a superior approach. To accomplish this, a detailed understanding of neuroinflammation and the systemic immune responses after SCI is required. Our review will strive to achieve this goal by first giving an overview of SCI from a clinical and basic science context. The role that neuroinflammation plays in the pathophysiology of SCI will be discussed. Next, the positive and negative attributes of the innate and adaptive immune systems in neuroinflammation after SCI will be described. With this background established, the currently existing immunosuppressive and immunomodulatory therapies for treating SCI will be explored. We will conclude with a summary of topics that can be explored by neuroimmunology research. These concepts will be complemented by points to be considered by neuroscientists developing therapies for SCI and other injuries to the central nervous system.
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http://dx.doi.org/10.1016/j.expneurol.2021.113704DOI Listing
March 2021

Mutations in the RAS/MAPK pathway drive replication repair deficient hypermutated tumors and confer sensitivity to MEK inhibition.

Cancer Discov 2021 Feb 9. Epub 2021 Feb 9.

Hematology/Oncology Hospital for Sick Children, The Hospital for Sick Children, University of Toronto

The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors which harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair deficient (RRD) cancers which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for RAS/MAPK mutations (p=10-8). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient derived RRD tumors and these tumors responded to MEK inhibition in vitro and in vivo. Treatment of patients with RAS/MAPK hypermutant gliomas reveal durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways resulting in favorable response to targeted therapies.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1050DOI Listing
February 2021

Ferroptosis Mediates Cuprizone-Induced Loss of Oligodendrocytes and Demyelination.

J Neurosci 2020 11 26;40(48):9327-9341. Epub 2020 Oct 26.

Centre for Research in Neuroscience, Research Institute of the McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada

Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS. Cuprizone (CZ), a copper chelator, is widely used to study demyelination and remyelination in the CNS, in the context of MS. However, the mechanisms underlying oligodendrocyte (OL) cell loss and demyelination are not known. As copper-containing enzymes play important roles in iron homeostasis and controlling oxidative stress, we examined whether chelating copper leads to disruption of molecules involved in iron homeostasis that can trigger iron-mediated OL loss. We show that giving mice (male) CZ in the diet induces rapid loss of OL in the corpus callosum by 2 d, accompanied by expression of several markers for ferroptosis, a relatively newly described form of iron-mediated cell death. In ferroptosis, iron-mediated free radicals trigger lipid peroxidation under conditions of glutathione insufficiency, and a reduced capacity to repair lipid damage. This was further confirmed using a small-molecule inhibitor of ferroptosis that prevents CZ-induced loss of OL and demyelination, providing clear evidence of a copper-iron connection in CZ-induced neurotoxicity. This work has wider implications for disorders, such as multiple sclerosis and CNS injury. Cuprizone (CZ) is a copper chelator that induces demyelination. Although it is a widely used model to study demyelination and remyelination in the context of multiple sclerosis, the mechanisms mediating demyelination is not fully understood. This study shows, for the first time, that CZ induces demyelination via ferroptosis-mediated rapid loss of oligodendrocytes. This work shows that chelating copper with CZ leads to the expression of molecules that rapidly mobilize iron from ferritin (an iron storage protein), that triggers iron-mediated lipid peroxidation and oligodendrocyte loss (via ferroptosis). Such rapid mobilization of iron from cellular stores may also play a role in cell death in other neurologic conditions.
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http://dx.doi.org/10.1523/JNEUROSCI.1749-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687057PMC
November 2020

Opioid prescription by gynecologic oncologists: An analysis of Medicare Part D claims.

Curr Probl Cancer 2021 Apr 17;45(2):100655. Epub 2020 Sep 17.

Division of Gynecologic Oncology, Department of Obstetrics & Gynecology and Women's Health, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York, USA; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, USA.

The use of opioids across all specialties has increased greatly over the last 2 decades and along with it, opioid misuse, overdose and death. The contribution of opioids prescribed for gynecologic cancers to this problem is unknown. Data from other surgical specialties show prescriber factors including gender, geographic location, board certification, experience, and fellowship training influence opioid prescribing. To characterize national-level opioid prescription patterns among gynecologic oncologists treating Medicare beneficiaries. The Centers for Medicare and Medicaid Services database was used to access Medicare Part D opioid claims prescribed by gynecologic oncologists in 2016. Prescription and prescriber characteristics were recorded including medication type, prescription length, number of claims, and total day supply. Region of practice was determined according to the US Census Bureau Regions. Board certification data were obtained from American Board of Obstetrics and Gynecology website. Bivariate statistical analysis and linear regression modeling were performed using Stata version 14.2. In 2016, 494 board-certified US gynecologic oncologists wrote 24,716 opioid prescriptions for a total 267,824 days of treatment (median 8 [interquartile range {IQR} 6, 11] prescribed days per claim). Gynecologic oncologists had a median of 33 opioid claims (IQR 18, 64). Male physicians had significantly more opioid prescription claims than females (P < 0.01) including after adjustment for differences in years of experience. There was no difference in prescribed days per claim between male and female physicians. Physicians in the South had the greatest number of opioid prescription claims and significantly more than physicians in all other regions (P < 0.01). Gynecologic oncologists who were board certified for >15 years had a greater number of median opioid claims (28 IQR 16, 50) than those with <5 years since board certification (22 IQR 15, 38) (P= 0.04). Physicians who were board certified in palliative care (n = 19) had significantly more opioids claims (median 40; IQR 18, 91) than those without (median 32; IQR 18, 64) (P< 0.01). In 2016, there were gender-based, regional, and experience-related variations in opioid prescribing by providers caring for Medicare-insured patients.
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http://dx.doi.org/10.1016/j.currproblcancer.2020.100655DOI Listing
April 2021

Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns.

Acta Neuropathol 2020 11 8;140(5):765-776. Epub 2020 Sep 8.

Division of Haematology/Oncology, The Hospital for Sick Children, 555 University Ave, Toronto, ON, M5G 1X8, Canada.

Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled "Wild type-C" or "Paediatric RTK 1". Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.
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http://dx.doi.org/10.1007/s00401-020-02209-8DOI Listing
November 2020

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor.

Acta Neuropathol Commun 2020 08 28;8(1):151. Epub 2020 Aug 28.

Division of Neuropathology, Department of Pathology, University of California, San Francisco, 513 Parnassus Avenue, Health Sciences West 451, San Francisco, CA, 94143, USA.

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.
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http://dx.doi.org/10.1186/s40478-020-01027-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456392PMC
August 2020

Alcohol history at the front door: what's all this social drinking about?

Future Healthc J 2020 Feb;7(Suppl 1):s74

Cwm Taf Morgannwg University Health Board, UK.

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http://dx.doi.org/10.7861/fhj.7.1.s74DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241192PMC
February 2020

Vaginal Lactobacillus species and inflammatory biomarkers in pregnancy.

Minerva Ginecol 2020 Oct 13;72(5):299-309. Epub 2020 May 13.

School of Medicine, Texas Tech University Health Sciences Center (TTUHSC) of the Permian Basin, Odessa, TX, USA -

Background: The aim of this study was to identify vaginal Lactobacillus spp. and quantify vaginal inflammatory cytokines in primigravida vs. multigravida women and pregnant vs. non-pregnant women.

Methods: Vaginal swabs were obtained from four groups of patients. A real-time PCR was carried out to identify the Lactobacillus spp. Multiplex immunoassays were performed to quantify a total of 27 cytokines using the Bio-Plex MAGPIX multiplex reader and MesoQuick Plex SQ 120 (Meso Scale Diagnostics LLC, Rockville, MD, USA). Inferential statistics using hypothesis tests were applied to detect differences in cytokine levels.

Results: Significant differences in cytokines and chemokines exist among the four populations of women studied. IP-10 is significantly higher in multigravida women as compared to primigravida women. IFN-γ, MCP-1, MIP-1β, IL-2 and IL-10 are significantly higher in non-pregnant women compared to pregnant women. L. iners was the most abundant species in multigravida, pregnant and non-pregnant patients, while L. crispatus was the most abundant species in primigravida patients. Significant differences in the levels of MIP-1β, TNF-α, PDGF-BB, VEGF-A, IL-12, and IL-10 exist between women identified with Lactobacillus species and women not identified with Lactobacillus species.

Conclusions: There were significant differences regarding cytokines, chemokines, and Lactobacillus spp. among four groups of studied patients. With these results, we increase our understanding of the role that vaginal cytokines and Lactobacillus species have during pregnancy, with the goal that this novel research will be useful for examining vaginal biomarkers in obstetrical conditions.
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http://dx.doi.org/10.23736/S0026-4784.20.04566-9DOI Listing
October 2020

Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition.

Acta Neuropathol 2020 06 17;139(6):1071-1088. Epub 2020 Apr 17.

Department of Pathology, University of California, San Francisco, CA, USA.

Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.
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http://dx.doi.org/10.1007/s00401-020-02155-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792550PMC
June 2020

Synthetic mycobacterial molecular patterns partially complete Freund's adjuvant.

Sci Rep 2020 04 3;10(1):5874. Epub 2020 Apr 3.

Department of Microbiology and Immunology, McGill University, Montréal, Canada.

Complete Freund's adjuvant (CFA) has historically been one of the most useful tools of immunologists. Essentially comprised of dead mycobacteria and mineral oil, we asked ourselves what is special about the mycobacterial part of this adjuvant, and could it be recapitulated synthetically? Here, we demonstrate the essentiality of N-glycolylated peptidoglycan plus trehalose dimycolate (both unique in mycobacteria) for the complete adjuvant effect using knockouts and chemical complementation. A combination of synthetic N-glycolyl muramyl dipeptide and minimal trehalose dimycolate motif GlcC14C18 was able to upregulate dendritic cell effectors, plus induce experimental autoimmunity qualitatively similar but quantitatively milder compared to CFA. This research outlines how to substitute CFA with a consistent, molecularly-defined adjuvant which may inform the design of immunotherapeutic agents and vaccines benefitting from cell-mediated immunity. We also anticipate using synthetic microbe-associated molecular patterns (MAMPs) to study mycobacterial immunity and immunopathogenesis.
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http://dx.doi.org/10.1038/s41598-020-62543-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125112PMC
April 2020

Benefits of physical exercise on cognition and glial white matter pathology in a mouse model of vascular cognitive impairment and dementia.

Glia 2020 09 10;68(9):1925-1940. Epub 2020 Mar 10.

Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada.

White matter (WM) pathology is a clinically predictive feature of vascular cognitive impairment and dementia (VCID). Mice overexpressing transforming growth factor-β1 (TGF) with an underlying cerebrovascular pathology when fed a high cholesterol diet (HCD) develop cognitive deficits (VCID mice) that we recently found could be prevented by physical exercise (EX). Here, we further investigated cognitive and WM pathology in VCID mice and examined the cellular substrates of the protective effects of moderate aerobic EX focusing on WM alterations. Six groups were studied: Wild-type (WT) and TGF mice (n = 20-24/group) fed standard lab chow or a 2% HCD, with two HCD-fed groups given concurrent access to running wheels. HCD had a significant negative effect in TGF mice that was prevented by EX on working and object recognition memory, the latter also altered in WT HCD mice. Whisker-evoked increases in cerebral blood flow (CBF) were reduced in HCD-fed mice, deficits that were countered by EX, and baseline WM CBF was similarly affected. VCID mice displayed WM functional deficits characterized by lower compound action potential amplitude not found in EX groups. Moreover, there was an increased number of collapsing capillaries, galectin-3-expressing microglial cells, as well as a reduced number of oligodendrocytes in the WM of VCID mice; all of which were prevented by EX. Our findings indicate that a compromised cerebral circulation precedes reduced WM vascularization, enhanced WM inflammation and impaired oligodendrogenesis that all likely account for the increased susceptibility to memory impairments in VCID mice, which can be prevented by EX. MAIN POINTS: A compromised cerebral circulation increases susceptibility to anatomical and functional white matter changes that develop alongside cognitive deficits when challenged with a high cholesterol diet; preventable by a translational regimen of exercise.
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http://dx.doi.org/10.1002/glia.23815DOI Listing
September 2020

Readability assessment of online gynecologic oncology patient education materials from major governmental, non-profit and pharmaceutical organizations.

Gynecol Oncol 2019 09 16;154(3):616-621. Epub 2019 Jul 16.

Montefiore Medical Center and Albert Einstein College of Medicine, Department of Obstetrics & Gynecology and Women's Health, Bronx, NY, United States of America; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, United States of America.

Objective: Patients are increasingly using online materials to learn about gynecologic cancer. Providers can refer patients to online educational materials produced by a number of different major medical organizations and pharmacology companies. The National Institutes of Health (NIH) and the American Medical Association (AMA) recommend that patient educational materials (PEMs) are written between a sixth and eighth grade reading level. In this study, we assess the readability of online PEMs published by major medical organizations and industry partners.

Methods: Websites from twelve websites providing educational materials for gynecologic oncology patients were surveyed. Online PEMs were identified and analyzed using seven validated readability indices. One-way ANOVA and Tukey's Honestly Significant Difference (HSD) post-hoc analysis were performed to detect differences in readability between publishers.

Results: Two-hundred and sixty PEMs were included in this analysis. Overall, PEMs were written at a mean 11th±0.6 grade reading level. Only 6.5% of articles were written at the AMA/NIH recommended reading grade level of 6th to 8th grade or below. ANOVA demonstrated a significant difference in readability between publishing associations (p<0.01). PEMs from the Centers for Disease Control had a mean 9th±1.2 grade reading level and were significantly lower than all other organizations. PEMs from The Foundation for Women's Cancer had a mean 13th±1.8 grade reading level and were significantly higher than most other organizations. PEMs from pharmaceutical companies (mean readability=10.1±1.1, N=30) required the lowest reading grade level and were significantly more readable than those from governmental organizations (11.1±1.7, p<0.05) and nonprofit medical associations (12.4±1.7, p<0.01) in ANOVA and Tukey-Kramer post hoc analysis.

Conclusions: Gynecologic oncology PEMs available from twelve major organization websites are written well above the recommended sixth to eighth grade reading difficulty level.
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http://dx.doi.org/10.1016/j.ygyno.2019.06.026DOI Listing
September 2019

IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients.

Int J Mol Sci 2019 Jun 21;20(12). Epub 2019 Jun 21.

Section of Pediatric Oncology, Children's Hospital, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.

(1) The high-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a highly malignant tumor. Preclinical models and molecular targets are urgently required for this cancer. Previous data suggest a potential role of insulin-like growth factor (IGF) signaling in HGNET-BCOR. (2) The primary HGNET-BCOR cells PhKh1 were characterized by western blot, copy number variation, and methylation analysis and by electron microscopy. The expression of and was assessed by qRT-PCR. The effect of chemotherapeutics and IGF1R inhibitors on PhKh1 proliferation was tested. The phosphorylation of IGF1R and downstream molecules was assessed by western blot. (3) Phkh1 cells showed a DNA methylation profile compatible with the DNA methylation class "HGNET-BCOR" and morphologic features of cellular cannibalism. and were highly expressed by three HGNET-BCOR tumor samples and PhKh1 cells. PhKh1 cells were particularly sensitive to vincristine, vinblastine, actinomycin D (IC < 10 nM for all drugs), and ceritinib (IC = 310 nM). Ceritinib was able to abrogate the proliferation of PhKh1 cells and blocked the phosphorylation of IGF1R and AKT. (4) IGF1R is as an attractive target for the development of new therapy protocols for HGNET-BCOR patients, which may include ceritinib and vinblastine.
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http://dx.doi.org/10.3390/ijms20123027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627083PMC
June 2019

Bioactive Lipids in Inflammation After Central Nervous System Injury.

Adv Exp Med Biol 2019 ;1127:181-194

Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.

Despite the progress made over the last decades to understand the mechanisms underlying tissue damage and neurological deficits after neurotrauma, there are currently no effective treatments in the clinic. It is well accepted that the inflammatory response in the CNS after injury exacerbates tissue loss and functional impairments. Unfortunately, the use of potent anti-inflammatory drugs, such as methylprednisolone, fails to promote therapeutic recovery and also gives rise to several undesirable side effects related to immunosuppression. The injury-induced inflammatory response is complex, and understanding the mechanisms that regulate this inflammation is therefore crucial in the quest to develop effective treatments. Bioactive lipids have emerged as potent molecules in controlling the initiation, coordination, and resolution of inflammation and in promoting tissue repair and recovery of homeostasis. These bioactive lipids are produced by cells involved in the inflammatory response, and their defective synthesis leads to persistent chronic inflammation, tissue damage, and fibrosis. The present chapter discusses recent evidence for the role of some of these bioactive lipids, in particular, eicosanoid and pro-resolving lipid mediators, in the regulation of inflammation after neurotrauma and highlights the therapeutic potential of some of these lipids in enhancing neurological outcomes after CNS injuries.
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http://dx.doi.org/10.1007/978-3-030-11488-6_12DOI Listing
August 2019

High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication-a comprehensive clinical, radiographic, pathologic, and genomic analysis.

Brain Pathol 2020 01 10;30(1):46-62. Epub 2019 Jun 10.

Department of Pathology, University of California, San Francisco, CA.

High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR ex15 ITD) is a recently proposed tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. The complete spectrum of histologic features, accompanying genetic alterations, clinical outcomes, and optimal treatment for this new tumor entity are largely unknown. Here, we performed a comprehensive assessment of 10 new cases of HGNET BCOR ex15 ITD. The tumors mostly occurred in young children and were located in the cerebral or cerebellar hemispheres. On imaging all tumors were large, well-circumscribed, heterogeneous masses with variable enhancement and reduced diffusion. They were histologically characterized by predominantly solid growth, glioma-like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. They demonstrated sparse to absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. While BCOR exon 15 internal tandem duplication was the solitary pathogenic alteration identified in six cases, four cases contained additional alterations including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. While the limited clinical follow-up in prior reports had indicated a uniformly dismal prognosis for this tumor entity, this cohort includes multiple long-term survivors. Our study further supports inclusion of HGNET BCOR ex15 ITD as a distinct CNS tumor entity and expands the known clinicopathologic, radiographic, and genetic features.
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http://dx.doi.org/10.1111/bpa.12747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859193PMC
January 2020

Ontogeny and programming of the fetal temporal cortical endocannabinoid system by moderate maternal nutrient reduction in baboons (Papio spp.).

Physiol Rep 2019 03;7(6):e14024

Department of Obstetrics and Gynecology, Texas Tech University Health sciences Center at the Permian Basin, Odessa, Texas.

Poor nutrition during pregnancy is a worldwide public health problem. Maternal nutrient reduction (MNR) is associated with maternal and fetal stress and a sex-dependent decrease in nonhuman primate (NHP) cognitive performance. Early life stress potentiates epileptogenesis in a sex-specific manner, and temporal lobe (TL) epilepsy is associated with neurocognitive disorders. The endogenous cannabinoid system (ECS) demonstrates remarkable developmental changes and plays a key role in aging-related diseases (e.g., dementia). Baboons have been studied as a natural model of epilepsy and express all ECS system components. We therefore evaluated baboon fetal temporal cortex ECS ontogenic and MNR-dependent changes. At 120 days gestational age (dGA) (term 185 days), maternal, fetal, and placental morphometry were similar between control and MNR pregnancies. MNR maternal weight gain was decreased compared with controls at 165 dGA independent of fetal sex. In male fetuses, expression of ECS synthesizing and degrading enzymes was gestational age-dependent, with the exception of fatty acid amide hydrolase (FAAH). MNR had a sex-specific effect on the protein expression of CB1R during development: CB1R protein expression was decreased in fetal temporal cortex of male fetuses at 120 and 140 dGA. Our data reveal that the MNR has sex-specific effects on temporal cortical expression of the ECS in baboon offspring and shows vulnerability of ECS in male fetuses during gestation.
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http://dx.doi.org/10.14814/phy2.14024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434170PMC
March 2019

Ceruloplasmin Plays a Neuroprotective Role in Cerebral Ischemia.

Front Neurosci 2018 8;12:988. Epub 2019 Jan 8.

Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

Ceruloplasmin (Cp) is a ferroxidase that also plays a role in iron efflux from cells. It can thus help to regulate cellular iron homeostasis. In the CNS, Cp is expressed as a membrane-anchored form by astrocytes. Here, we assessed the role of Cp in permanent middle cerebral artery occlusion (pMCAO) comparing wildtype and Cp null mice. Our studies show that the lesion size is larger and functional recovery impaired in Cp null mice compared to wildtype mice. Expression of Cp increased ninefold at 72 h after pMCAO and remained elevated about twofold at day 14. We also assessed changes in mRNA and protein expression of molecules involved in iron homeostasis. As expected there was a reduction in ferroportin in Cp null mice at 72 h. There was also a remarkable increase in DMT1 protein in both genotypes at 72 h, being much higher in wildtype mice (19.5-fold), that then remained elevated about twofold at 14 days. No difference was seen in transferrin receptor 1 (TfR1) expression, except a small reduction in wildtype mice at 72 h, suggesting that the increase in DMT1 may underlie iron uptake independent of TfR1-endosomal uptake. There was also an increase of ferritin light chain in both genotypes. Iron histochemistry showed increased iron accumulation after pMCAO, initially along the lesion border and later throughout the lesion. Immunofluorescence labeling for ferritin (a surrogate marker for iron) and GFAP or CD11b showed increased ferritin in GFAP+ astrocytes along the lesion border in Cp null mice, while CD11b+ macrophages expressed ferritin equally in both genotypes. Increased lipid peroxidation assessed by 4HNE staining was increased threefold in Cp null mice at 72 h after pMCAO; and 3-nitrotyrosine labeling showed a similar trend. Three key pro-inflammatory cytokines (IL-1β, TNFα, and IL-6) were markedly increased at 24 h after pMCAO equally in both genotypes, and remained elevated at lower levels later, indicating that the lack of Cp does not alter key inflammatory cytokine expression after pMCAO. These data indicate that Cp expression is rapidly upregulated after pMCAO, and loss of Cp results in dysregulation of iron homeostasis, increased oxidative damage, greater lesion size and impaired recovery of function.
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http://dx.doi.org/10.3389/fnins.2018.00988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331473PMC
January 2019

Functional Repair Assay for the Diagnosis of Constitutional Mismatch Repair Deficiency From Non-Neoplastic Tissue.

J Clin Oncol 2019 02 4;37(6):461-470. Epub 2019 Jan 4.

1 University of Toronto, Toronto, Ontario, Canada.

Purpose: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD.

Patients And Methods: In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome.

Results: All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days.

Conclusion: On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.
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http://dx.doi.org/10.1200/JCO.18.00474DOI Listing
February 2019

Clinicopathologic features of anaplastic myxopapillary ependymomas.

Brain Pathol 2019 01;29(1):75-84

Department of Pathology, University of California, San Francisco, CA.

Myxopapillary ependymomas (MPE) are considered benign (World Health Organization (WHO) grade I) neoplasms with favorable prognosis. However, malignant behavior occurs in a small subset. To our knowledge, only five anaplastic MPEs have been reported without consensus on diagnostic criteria. We retrieved 14 anaplastic MPEs from the pathology archives of six institutions. Each tumor included at least two of the following features: ≥5 mitoses per 10 high power fields, Ki-67 labeling index (LI) ≥10%, microvascular proliferation (MVP) and spontaneous necrosis. These features were typically encountered in the foci of hypercellularity and reduced mucin. There were eight male and six female patients (age range 6-57 years, median = 16.5). Ten tumors displayed anaplasia at initial resection, and 4 were anaplastic at a second surgery for recurrence (ranging from 9 months to 14 years following initial resection). The Ki-67 LI ranged between 8% and 40% in the anaplastic foci and <3% in the foci of classic MPE. There was documented cerebrospinal fluid (CSF) dissemination in seven cases, recurrence following an anaplastic diagnosis in three cases and bone or soft tissue invasion in two cases. One patient suffered lung metastases. Two cases evaluated by targeted next-generation sequencing and one evaluated by fluorescence in situ hybridization (FISH) showed nonspecific chromosomal gains. We conclude that although rare, anaplastic MPE occurs in both pediatric and adult patients, similar to other ependymomas. At a minimum, closer follow-up is recommended, given the concern for aggressive biologic potential. Further study is needed to determine WHO grading criteria and genetic indicators of tumor progression.
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http://dx.doi.org/10.1111/bpa.12673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444646PMC
January 2019

Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury.

PLoS Biol 2018 10 17;16(10):e2005264. Epub 2018 Oct 17.

Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, Quebec, Canada.

Infiltrating monocyte-derived macrophages (MDMs) and resident microglia dominate central nervous system (CNS) injury sites. Differential roles for these cell populations after injury are beginning to be uncovered. Here, we show evidence that MDMs and microglia directly communicate with one another and differentially modulate each other's functions. Importantly, microglia-mediated phagocytosis and inflammation are suppressed by infiltrating macrophages. In the context of spinal cord injury (SCI), preventing such communication increases microglial activation and worsens functional recovery. We suggest that macrophages entering the CNS provide a regulatory mechanism that controls acute and long-term microglia-mediated inflammation, which may drive damage in a variety of CNS conditions.
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http://dx.doi.org/10.1371/journal.pbio.2005264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205650PMC
October 2018

The genetic landscape of gliomas arising after therapeutic radiation.

Acta Neuropathol 2019 01 8;137(1):139-150. Epub 2018 Sep 8.

Department of Pathology, University of California, San Francisco, CA, USA.

Radiotherapy improves survival for common childhood cancers such as medulloblastoma, leukemia, and germ cell tumors. Unfortunately, long-term survivors suffer sequelae that can include secondary neoplasia. Gliomas are common secondary neoplasms after cranial or craniospinal radiation, most often manifesting as high-grade astrocytomas with poor clinical outcomes. Here, we performed genetic profiling on a cohort of 12 gliomas arising after therapeutic radiation to determine their molecular pathogenesis and assess for differences in genomic signature compared to their spontaneous counterparts. We identified a high frequency of TP53 mutations, CDK4 amplification or CDKN2A homozygous deletion, and amplifications or rearrangements involving receptor tyrosine kinase and Ras-Raf-MAP kinase pathway genes including PDGFRA, MET, BRAF, and RRAS2. Notably, all tumors lacked alterations in IDH1, IDH2, H3F3A, HIST1H3B, HIST1H3C, TERT (including promoter region), and PTEN, which genetically define the major subtypes of diffuse gliomas in children and adults. All gliomas in this cohort had very low somatic mutation burden (less than three somatic single nucleotide variants or small indels per Mb). The ten high-grade gliomas demonstrated markedly aneuploid genomes, with significantly increased quantity of intrachromosomal copy number breakpoints and focal amplifications/homozygous deletions compared to spontaneous high-grade gliomas, likely as a result of DNA double-strand breaks induced by gamma radiation. Together, these findings demonstrate a distinct molecular pathogenesis of secondary gliomas arising after radiation therapy and identify a genomic signature that may aid in differentiating these tumors from their spontaneous counterparts.
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http://dx.doi.org/10.1007/s00401-018-1906-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589431PMC
January 2019

The ferroxidase ceruloplasmin influences Reelin processing, cofilin phosphorylation and neuronal organization in the developing brain.

Mol Cell Neurosci 2018 10 2;92:104-113. Epub 2018 Aug 2.

Département de Chimie and Centre BioMed, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montreal, Quebec H3C 3P8, Canada. Electronic address:

Ceruloplasmin (Cp) is an important extracellular regulator of iron metabolism. We showed previously that it stimulates Reelin proteolytic processing and cell aggregation in cultures of developing neurons. Reelin is a secreted protein required for the correct positioning of neurons in the brain. It is cleaved in vivo into N-terminally-derived 300K and 180K fragments through incompletely known mechanisms. One of Reelin signaling targets is the actin-binding protein cofilin, the phosphorylation of which is diminished in Reelin-deficient mice. This work looked for in vivo evidence of a relationship between Cp, Reelin and neuronal organization during brain development by analyzing wild-type and Cp-null mice. Cp as well as the full-length, 300K and 180K Reelin species appeared together in wild-type brains at embryonic day (E) 12.5 by immunoblotting. In wild-type compared to Cp-null brains, there was more 300K Reelin from E12.5 to E17.5, a period characterized by extensive, radially directed neuronal migration in the cerebral cortex. Immunofluorescence labeling of tissue sections at E16.5 revealed the localization of Cp with radial glia and meningeal cells adjacent to Reelin-producing Cajal-Retzius neurons, underlining the proximity of Cp and Reelin. Cofilin phosphorylation was seen starting at E10.5-E12.5 and lasted longer until postnatal day 7 in wild-type than Cp-null mice. Finally, using CUX1 as a marker revealed defective accumulation of neurons in layers II/III in neonatal and adult Cp-null mice. These results combined with our earlier work point to a potentially new role of Cp in Reelin processing and signaling and neuronal organization in the cerebral cortex in vivo.
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http://dx.doi.org/10.1016/j.mcn.2018.07.005DOI Listing
October 2018

Myeloid cell responses after spinal cord injury.

J Neuroimmunol 2018 08 6;321:97-108. Epub 2018 Jun 6.

Departament de Biologia Cellular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, 08193 Bellaterra, Catalonia, Spain.

The past decade has revealed much about the complexity of the local inflammatory response after spinal cord injury (SCI). A major challenge is to distinguish between microglia and monocyte-derived macrophages (MDMs) to determine their phenotype and function. Transcriptome studies have revealed microglia-selective genes but are still limited in scope because many markers are downregulated after injury. Additionally, new genetic reporter mice are available to study microglia and MDMs. There is more evidence now for the plasticity and heterogeneity of microglia and MDMs. We also discuss the role of neutrophils that are the first peripheral cells to enter the injured CNS.
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http://dx.doi.org/10.1016/j.jneuroim.2018.06.003DOI Listing
August 2018

Saddle pulmonary embolus resulting in cardiovascular collapse requiring extracorporeal membrane oxygenation in a postoperative patient with endometrial cancer.

Gynecol Oncol Rep 2018 May 16;24:36-38. Epub 2018 Mar 16.

Montefiore Medical Center and Albert Einstein College of Medicine, Department of Obstetrics & Gynecology and Women's Health, 1825 Eastchester Road, Room 722. Bronx, NY 10463, United States.

Background: Venous thromboembolism after open gynecologic surgery is not uncommon, especially in the presence of other risk factors such as obesity, prolonged surgical time or gynecologic malignancy.

Case: We present the case of a 62 y.o. patient who underwent open hysterectomy and surgical staging for uterine serous carcinoma. She was readmitted with lower extremity edema. During her workup, she underwent cardiovascular arrest secondary to saddle pulmonary embolus requiring cardiopulmonary resuscitation and extracorporeal membrane oxygenation. After systemic and catheter directed thrombolysis, and a long hospitalization, she was discharged home in stable condition.

Conclusion: Saddle pulmonary embolus is a potentially catastrophic and fatal postoperative complication. This case demonstrates a successful implementation of directed thrombolysis, veno-arterial extracorporeal membrane oxygenation and multidisciplinary management in a case of postoperative saddle pulmonary embolus.

Précis: We report a case of an endometrial cancer patient who sustained a massive postoperative pulmonary embolus and was successfully resuscitated using extracorporeal membrane oxygenation.
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http://dx.doi.org/10.1016/j.gore.2018.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003405PMC
May 2018

The genetic landscape of ganglioglioma.

Acta Neuropathol Commun 2018 06 7;6(1):47. Epub 2018 Jun 7.

Department of Pathology, University of California, San Francisco, CA, USA.

Ganglioglioma is the most common epilepsy-associated neoplasm that accounts for approximately 2% of all primary brain tumors. While a subset of gangliogliomas are known to harbor the activating p.V600E mutation in the BRAF oncogene, the genetic alterations responsible for the remainder are largely unknown, as is the spectrum of any additional cooperating gene mutations or copy number alterations. We performed targeted next-generation sequencing that provides comprehensive assessment of mutations, gene fusions, and copy number alterations on a cohort of 40 gangliogliomas. Thirty-six harbored mutations predicted to activate the MAP kinase signaling pathway, including 18 with BRAF p.V600E mutation, 5 with variant BRAF mutation (including 4 cases with novel in-frame insertions at p.R506 in the β3-αC loop of the kinase domain), 4 with BRAF fusion, 2 with KRAS mutation, 1 with RAF1 fusion, 1 with biallelic NF1 mutation, and 5 with FGFR1/2 alterations. Three gangliogliomas with BRAF p.V600E mutation had concurrent CDKN2A homozygous deletion and one additionally harbored a subclonal mutation in PTEN. Otherwise, no additional pathogenic mutations, fusions, amplifications, or deletions were identified in any of the other tumors. Amongst the 4 gangliogliomas without canonical MAP kinase pathway alterations identified, one epilepsy-associated tumor in the temporal lobe of a young child was found to harbor a novel ABL2-GAB2 gene fusion. The underlying genetic alterations did not show significant association with patient age or disease progression/recurrence in this cohort. Together, this study highlights that ganglioglioma is characterized by genetic alterations that activate the MAP kinase pathway, with only a small subset of cases that harbor additional pathogenic alterations such as CDKN2A deletion.
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http://dx.doi.org/10.1186/s40478-018-0551-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992851PMC
June 2018

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.

Lancet Oncol 2018 06 9;19(6):785-798. Epub 2018 May 9.

Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center at the NCT Heidelberg, Heidelberg, Germany. Electronic address:

Background: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines.

Methods: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MB), SHH (MB), group 3 (MB), and group 4 (MB). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma.

Findings: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MB subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MB subgroup). Patients with germline APC mutations developed MB and accounted for most (five [71%] of seven) cases of MB that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MB. Germline TP53 mutations presented only in childhood patients in the MB subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MB, MB, and MB molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes.

Interpretation: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MB and MB because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics.

Funding: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.
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http://dx.doi.org/10.1016/S1470-2045(18)30242-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984248PMC
June 2018

Large Vessel Arteriopathy After Cranial Radiation Therapy in Pediatric Brain Tumor Survivors.

J Child Neurol 2018 04;33(5):359-366

1 Department of Pediatrics, University of California, San Francisco, CA, USA.

Among childhood cancer survivors, increased stroke risk after cranial radiation therapy may be caused by radiation-induced arteriopathy, but limited data exist to support this hypothesis. Herein, we assess the timing and presence of cerebral arteriopathy identified by magnetic resonance angiography (MRA) after cranial radiation therapy in childhood brain tumor survivors. In a cohort of 115 pediatric brain tumor survivors, we performed chart abstraction and prospective annual follow-up to assess the presence of large vessel cerebral arteriopathy by MRA. We identified 10 patients with cerebral arteriopathy. The cumulative incidence of arteriopathy 5 years post-cranial radiation therapy was 5.4% (CI 0.6%-10%) and 10 years was 16% (CI 4.6%-26%). One patient had an arterial ischemic stroke 2.4 years post-cranial radiation therapy in the distribution of a radiation-induced stenotic artery. We conclude that large vessel arteriopathies can occur within a few years of cranial radiation therapy and can become apparent on MRA in under a year.
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http://dx.doi.org/10.1177/0883073818756729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873308PMC
April 2018