Publications by authors named "Fredrick A Boop"

9 Publications

  • Page 1 of 1

Diagnostic delay in children with central nervous system tumors and the need to improve education.

J Neurooncol 2019 Dec 5;145(3):591-592. Epub 2019 Nov 5.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

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http://dx.doi.org/10.1007/s11060-019-03329-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927573PMC
December 2019

Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas.

Acta Neuropathol 2018 08 16;136(2):211-226. Epub 2018 Jun 16.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.
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http://dx.doi.org/10.1007/s00401-018-1877-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105278PMC
August 2018

Mortality in children with low-grade glioma or glioneuronal tumors: A single-institution study.

Pediatr Blood Cancer 2018 Jan 14;65(1). Epub 2017 Jul 14.

Division of Neuro-Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: While pediatric low-grade glioma/glioneuronal tumors (LGG/LGGNTs) are considered slow-growing, indolent tumors with excellent long-term prognosis, mortality due to the disease is not unknown. Few studies have addressed the cause of death in this population.

Methods: Retrospective review of clinicopathologic and radiologic data for children 21 years or younger with LGG/LGGNT who died at St. Jude Children's Research Hospital between April 1985 and June 2015. Our primary objective was to determine the causes and timing of mortality in affected children.

Results: For the 87 eligible patients, median age at diagnosis was 7.7 years (range, 0.21-21 years), median age at death was 14.26 years (range, 0.58-32 years), and median time to death from diagnosis was 4.02 years (range, 0.21-24 years). Midbrain/thalamus was the most common tumor location (n = 34), followed by suprasellar/hypothalamic (n = 18) and cerebrocortical (n = 13). Astrocytoma not otherwise specified (n = 24), pilocytic astrocytoma (n = 23), and fibrillary astrocytoma (n = 11) were the predominant histologic diagnoses. Causes of death included progressive primary disease (PD) (n = 43), progression of PD with histological features of a high-grade glioma at progression or at autopsy (PD-HGG) (n = 15), second cancer (n = 3), suicide (n = 4), and vehicular accident (n = 3). Among the 15 patients with PD-HGG, 12 received radiation therapy before histologic confirmation of progression.

Conclusions: PD and PD-HGG contributed to 66% of the mortality in our patient cohort. Early psychological intervention should be included as part of the multidisciplinary management approach of children with LGG/LGGNT to reduce the risk of suicide in vulnerable subjects.
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http://dx.doi.org/10.1002/pbc.26717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699960PMC
January 2018

Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology.

Acta Neuropathol 2016 06 25;131(6):833-45. Epub 2016 Jan 25.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, USA.

Low-grade neuroepithelial tumors (LGNTs) are diverse CNS tumors presenting in children and young adults, often with a history of epilepsy. While the genetic profiles of common LGNTs, such as the pilocytic astrocytoma and 'adult-type' diffuse gliomas, are largely established, those of uncommon LGNTs remain to be defined. In this study, we have used massively parallel sequencing and various targeted molecular genetic approaches to study alterations in 91 LGNTs, mostly from children but including young adult patients. These tumors comprise dysembryoplastic neuroepithelial tumors (DNETs; n = 22), diffuse oligodendroglial tumors (d-OTs; n = 20), diffuse astrocytomas (DAs; n = 17), angiocentric gliomas (n = 15), and gangliogliomas (n = 17). Most LGNTs (84 %) analyzed by whole-genome sequencing (WGS) were characterized by a single driver genetic alteration. Alterations of FGFR1 occurred frequently in LGNTs composed of oligodendrocyte-like cells, being present in 82 % of DNETs and 40 % of d-OTs. In contrast, a MYB-QKI fusion characterized almost all angiocentric gliomas (87 %), and MYB fusion genes were the most common genetic alteration in DAs (41 %). A BRAF:p.V600E mutation was present in 35 % of gangliogliomas and 18 % of DAs. Pathogenic alterations in FGFR1/2/3, BRAF, or MYB/MYBL1 occurred in 78 % of the series. Adult-type d-OTs with an IDH1/2 mutation occurred in four adolescents, the youngest aged 15 years at biopsy. Despite a detailed analysis, novel genetic alterations were limited to two fusion genes, EWSR1-PATZ1 and SLMAP-NTRK2, both in gangliogliomas. Alterations in BRAF, FGFR1, or MYB account for most pathogenic alterations in LGNTs, including pilocytic astrocytomas, and alignment of these genetic alterations and cytologic features across LGNTs has diagnostic implications. Additionally, therapeutic options based upon targeting the effects of these alterations are already in clinical trials.
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http://dx.doi.org/10.1007/s00401-016-1539-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866893PMC
June 2016

Phase II Trial of Erlotinib during and after Radiotherapy in Children with Newly Diagnosed High-Grade Gliomas.

Front Oncol 2014 1;4:67. Epub 2014 Apr 1.

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

Background: Epidermal growth factor receptor is overexpressed in most pediatric high-grade gliomas (HGG). Since erlotinib had shown activity in adults with HGG, we conducted a phase II trial of erlotinib and local radiotherapy (RT) in children with newly diagnosed HGG.

Methods: Following maximum surgical resection, patients between 3 and 21 years with non-metastatic HGG received local RT at 59.4 Gy (54 Gy for spinal tumors and those with ≥70% brain involvement). Erlotinib started on day 1 of RT (120 mg/m(2) per day) and continued for 2 years unless there was tumor progression or intolerable toxicities. The 2-year progression-free survival (PFS) was estimated for patients with intracranial anaplastic astrocytoma (AA) and glioblastoma (GBM).

Results: Median age at diagnosis for 41 patients with intracranial tumors (21 with GBM and 20 with AA) was 10.9 years (range, 3.3-19 years). The 2-year PFS for patients with AA and GBM was 15 ± 7 and 19 ± 8%, respectively. Only five patients remained alive without tumor progression. Twenty-six patients had at least one grade 3 or 4 toxicity irrespective of association with erlotinib; only four required dose modifications. The main toxicities were gastrointestinal (n = 11), dermatologic (n = 5), and metabolic (n = 4). One patient with gliomatosis cerebri who required prolonged corticosteroids died of septic shock associated with pancreatitis.

Conclusion: Although therapy with erlotinib was mostly well-tolerated, it did not change the poor outcome of our patients. Our results showed that erlotinib is not a promising medication in the treatment of children with intracranial AA and GBM.
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http://dx.doi.org/10.3389/fonc.2014.00067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978340PMC
April 2014

Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas.

Nat Genet 2013 Jun 14;45(6):602-12. Epub 2013 Apr 14.

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

The most common pediatric brain tumors are low-grade gliomas (LGGs). We used whole-genome sequencing to identify multiple new genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24 of 39 (62%) tumors. Intragenic duplications of the portion of FGFR1 encoding the tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes expressing FGFR1 with the duplication involving the TKD into the brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. FGFR1 with the duplication induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs and LGGNTs.
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http://dx.doi.org/10.1038/ng.2611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3727232PMC
June 2013

Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas.

Acta Neuropathol 2012 Aug 21;124(2):247-57. Epub 2012 Apr 21.

Laboratory of Pathology, Université Catholique de Louvain, Brussels, Belgium.

No reliable classification is in clinical use for the therapeutic stratification of children with ependymoma, such that disease risk might be identified and patients treated to ensure a combination of maximal cure rates and minimal adverse therapeutic effects. This study has examined associations between clinicopathologic and cytogenetic variables and outcome in a trial cohort of children with ependymoma, with the aim of defining a practical scheme for stratifying this heterogeneous tumor. Intracranial ependymomas (n = 146) from children treated on the RT1 trial at St. Jude Children's Research Hospital were evaluated for the status of multiple pathological features. Interphase FISH (iFISH) defined the status of loci on chromosomes 1q (EXO1), 6q (LATS1) and 9, including 9p21 (CDKN2A). Data relating to these clinicopathological and cytogenetic variables were compared with survival data in order to model disease risk groups. Extent of surgical resection was a significant determinant of outcome in both supratentorial and infratentorial compartments. Tumor cell density and mitotic count were associated with outcome among children with posterior fossa ependymomas (n = 119). Among pathologic features, only brain invasion was associated with outcome in children with supratentorial ependymomas (n = 27). For posterior fossa tumors, gain of 1q was independently associated with outcome and in combination with clinicopathological variables defined both a two-tier and three-tier system of disease risk. Among children developing posterior fossa ependymomas treated with maximal surgical resection and conformal radiotherapy, key clinicopathological variables and chromosome 1q status can be used to define tiers of disease risk. In contrast, risk factors for pediatric supratentorial tumors are limited to sub-total resection and brain invasion.
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http://dx.doi.org/10.1007/s00401-012-0981-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554251PMC
August 2012

Cross-species genomics matches driver mutations and cell compartments to model ependymoma.

Nature 2010 Jul 18;466(7306):632-6. Epub 2010 Jul 18.

Department of Developmental Neurobiology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.

Understanding the biology that underlies histologically similar but molecularly distinct subgroups of cancer has proven difficult because their defining genetic alterations are often numerous, and the cellular origins of most cancers remain unknown. We sought to decipher this heterogeneity by integrating matched genetic alterations and candidate cells of origin to generate accurate disease models. First, we identified subgroups of human ependymoma, a form of neural tumour that arises throughout the central nervous system (CNS). Subgroup-specific alterations included amplifications and homozygous deletions of genes not yet implicated in ependymoma. To select cellular compartments most likely to give rise to subgroups of ependymoma, we matched the transcriptomes of human tumours to those of mouse neural stem cells (NSCs), isolated from different regions of the CNS at different developmental stages, with an intact or deleted Ink4a/Arf locus (that encodes Cdkn2a and b). The transcriptome of human supratentorial ependymomas with amplified EPHB2 and deleted INK4A/ARF matched only that of embryonic cerebral Ink4a/Arf(-/-) NSCs. Notably, activation of Ephb2 signalling in these, but not other, NSCs generated the first mouse model of ependymoma, which is highly penetrant and accurately models the histology and transcriptome of one subgroup of human supratentorial tumour. Further, comparative analysis of matched mouse and human tumours revealed selective deregulation in the expression and copy number of genes that control synaptogenesis, pinpointing disruption of this pathway as a critical event in the production of this ependymoma subgroup. Our data demonstrate the power of cross-species genomics to meticulously match subgroup-specific driver mutations with cellular compartments to model and interrogate cancer subgroups.
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http://dx.doi.org/10.1038/nature09173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912966PMC
July 2010

Frontal sinus fractures in children.

Laryngoscope 2005 Oct;115(10):1741-5

Department of Otolaryngology--Head and Neck Surgery, University of Tennessee Health Science Center, Memphis, 38163, USA.

Objective: To review the epidemiologic characteristics, clinical course, and management of pediatric patients with frontal sinus fractures.

Methods: Retrospective review of 120 patients with maxillofacial fractures who presented to a tertiary children's hospital from 1998 to 2003 revealed 11 patients with frontal sinus fractures.

Results: The study group included 9 males and 2 females with a mean age of 9.7 (range 4-14) years. The most common mechanisms of injury were unrestrained motor vehicle accident and all-terrain vehicle accident. All patients suffered concomitant orbital fractures. Other maxillofacial fractures included sphenoid (4), naso-orbitoethmoid (3), midface (2), and mandible (1). Seven (63.6%) patients sustained significant intracranial injuries including intraparenchymal hemorrhage, expanding pneumocephalus, and subdural hematoma. The average age of patients with intracranial injury was younger than those without intracranial injury (8.1 vs. 12.8 years, P = .025). Four patients had a total of six sites of cerebrospinal fluid (CSF) leak. The most common sites of dural injury were the cribriform area (4) and frontal region (2). All patients with CSF leaks had significant intracranial injuries and required bifrontal craniotomy.

Conclusions: Pediatric frontal sinus fractures are likely to involve other maxillofacial injuries, particularly involving the orbit. Frontal sinus fractures in children are associated with increased risk of serious intracranial injury and CSF leak when compared with adults. The most common site of dural injury was the cribriform area. A multidisciplinary approach is necessary to manage concomitant injuries, obtain separation of the sinonasal tract from intracranial contents, and to restore cosmesis to the brow.
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http://dx.doi.org/10.1097/01.mlg.0000172199.50482.28DOI Listing
October 2005
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