Publications by authors named "Jonathan L Finlay"

143 Publications

Recurrent Wnt medulloblastoma treated with marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue: a dual case report and review of the literature.

Childs Nerv Syst 2021 May 4. Epub 2021 May 4.

The Division of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, 43205, USA.

Wnt-activated medulloblastoma (MB) confers an excellent prognosis. However, specific treatment strategies for patients with relapsed Wnt-MB are unknown. We report two patients with recurrent beta-catenin nucleopositive Wnt-MB successfully treated by incorporating marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue (HDCx/AuHPCR). We also present a review of the literature for previously reported cases of relapsed Wnt-MB. We propose that patients with recurrent Wnt-MB may be treated using a multi-disciplinary approach that includes HDCx/AuHPCR with or without re-irradiation.
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http://dx.doi.org/10.1007/s00381-021-05197-6DOI 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

Evaluation of the Pediatric Neuro-Oncology Resources Available in Chile.

JCO Glob Oncol 2021 Mar;7:425-434

Division of Hematology, Oncology, Blood and Marrow Transplant, Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University, Columbus, OH.

Purpose: Pediatric neuro-oncology resources are mostly unknown in Chile. We report the human and material resources available in Chilean hospitals providing pediatric neuro-oncology services.

Methods: A cross-sectional survey was distributed to 17 hospitals providing pediatric neuro-oncology services (Programa Infantil Nacional de Drogas Antineoplásicas [PINDA] hospitals, 11; private, 6).

Results: Response rate was 71% (PINDA, 8; private, 4). Pediatric neuro-oncology services were mainly provided within general hospitals (67%). Registries for pediatric CNS tumors and chemotherapy-related toxicities were available in 100% and 67% of hospitals, respectively. CNS tumors were treated by pediatric oncologists in 92% of hospitals; none were formally trained in neuro-oncology. The most used treatment protocols were the national PINDA protocols. All WHO essential medicines for childhood cancer were available in more than 80% of the hospitals except for gemcitabine, oxaliplatin, paclitaxel, and procarbazine. The median number of pediatric neurosurgeons per hospital was two (range, 2-6). General neuroradiologists were available in 83% of the centers. Pathology specimens were sent to neuropathologists (58%), adult pathologists (25%), and pediatric pathologists (17%). Intensity-modulated radiotherapy, conformal radiotherapy, and cobalt radiotherapy were used by 67%, 58%, and 42% of hospitals, respectively. Only one private hospital performed autologous hematopoietic cell transplant for children with CNS tumors.

Conclusion: A wide range of up-to-date treatment modalities are available for children with CNS tumors. Our survey highlights future directions to improve the pediatric neuro-oncology services available in Chile such as the expansion of multidisciplinary clinics, palliative care services, long-term cancer survivorship programs, dedicated clinical research support teams, establishing standardized mechanism for sending pathologic specimen for second opinion to international specialized centers, and establishing specialized neuro-oncology training program.
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http://dx.doi.org/10.1200/GO.20.00430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081533PMC
March 2021

Validated quantitative needs assessment differences in the management of children with central nervous system cancer between Brazil, an upper middle-income country, and the United States of America, a high income country.

Pediatr Blood Cancer 2021 Jun 24;68(6):e28958. Epub 2021 Mar 24.

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

Background: Pediatric cancer cure rates differ among high-income countries (HIC) and upper middle-income countries (UMIC). We have compared individual capacities of two major referral pediatric centers from a HIC and an UMIC caring for children with central nervous system (CNS) cancer.

Methods: A quantitative needs assessment questionnaire and key informant interviews, distributed in March of 2017, were used to evaluate the treatment of children with CNS cancer at Grupo de Apoio ao Adolescente e à Criança com Câncer (GRAACC) children's cancer center in São Paulo, Brazil and Nationwide Children's Hospital (NCH) in Columbus, Ohio, United States of America (USA).

Results: Both hospitals had 24-hour pediatric oncology, nursing and intensivist coverage. Supportive care available at both institutions included social workers, psychologists, child life specialists, and physical/occupational/speech therapists. Differences included two part-time neuroradiologists and one pathologist specializing in neuropathology at IOP/GRAACC/UNIFESP, whereas eight full-time neuroradiologists and two neuropathologists at NCH/OSU. There were four pediatric neurosurgeons on staff at each hospital; however, there were only 2 operative days per week at IOP/GRAACC/UNIFESP, compared with 7 days at NCH/OSU. Additionally, time to initiation of radiation therapy at IOP/GRAACC/UNIFESP extended 2-4 weeks compared with less than 1 week at NCH/OSU.

Conclusions: Center-specific differences in resources exist in highly specialized hospitals caring for children with CNS cancer in HIC and UMIC. This quantitative needs assessment may facilitate the development of targeted strategies for effective interventions to improve on the management of children with CNS cancers.
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http://dx.doi.org/10.1002/pbc.28958DOI Listing
June 2021

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

Sci Rep 2021 Mar 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

Clinical response to dabrafenib plus trametinib in a pediatric ganglioglioma with p.T599dup mutation.

Cold Spring Harb Mol Case Stud 2021 Apr 8;7(2). Epub 2021 Apr 8.

The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43215, USA.

In this follow-up report, we present updated information regarding a previously reported pediatric patient with a World Health Organization grade I ganglioglioma harboring a p.T599dup mutation ( 4: a002618). This patient, based on our initial finding, is receiving combination targeted therapy with a selective BRAF inhibitor (dabrafenib) plus MEK inhibitor (trametinib). The combination therapy was started after the patient experienced progressive tumor growth and worsening neurological symptoms, including visual changes, headaches, and peripheral neuropathy, despite 9 months of treatment with adjuvant chemotherapy (vinblastine). The patient has been receiving dabrafenib plus trametinib for 15 months and continues to have stable disease as well as improved neurological symptoms. Although combinatorial therapy targeting BRAF and MEK using dabrafenib and trametinib, respectively, is indicated for tumors harboring a p.V600E/K mutation, our report demonstrates efficacy of this combination in a non-V600E -mutated tumor. The identification of alterations may assist clinicians in determining alternative targeted treatment strategies, especially considering the paucity of effective treatments for primary brain tumors and the poor prognosis associated with many central nervous system (CNS) diagnoses. Additional case studies or larger cohort reports will continue to clarify the efficacy of BRAF and/or MEK inhibitors in patients whose tumors harbor a alteration.
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http://dx.doi.org/10.1101/mcs.a006023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040738PMC
April 2021

Molecular insights into malignant progression of atypical choroid plexus papilloma.

Cold Spring Harb Mol Case Stud 2021 Feb 19;7(1). Epub 2021 Feb 19.

Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.

Choroid plexus tumors are rare pediatric neoplasms ranging from low-grade papillomas to overtly malignant carcinomas. They are commonly associated with Li-Fraumeni syndrome and germline mutations. Choroid plexus carcinomas associated with Li-Fraumeni syndrome are less responsive to chemotherapy, and there is a need to avoid radiation therapy leading to poorer outcomes and survival. Malignant progression from choroid plexus papillomas to carcinomas is exceedingly rare with only a handful of cases reported, and the molecular mechanisms of this progression remain elusive. We report a case of malignant transformation of choroid plexus papilloma to carcinoma in a 7-yr-old male with a germline mutation in which we present an analysis of molecular changes that might have led to the progression based on the next-generation genetic sequencing of both the original choroid plexus papilloma and the subsequent choroid plexus carcinoma. Chromosomal aneuploidy was significant in both lesions with mostly gains present in the papilloma and additional significant losses in the carcinoma. The chromosomal loss that occurred, in particular loss of Chromosome 13, resulted in the losses of two critical tumor suppressor genes, and , which might play a possible role in the observed malignant transformation.
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http://dx.doi.org/10.1101/mcs.a005272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903885PMC
February 2021

Venous thromboembolism in children with central nervous system tumors: Comparison of an institutional cohort to a national administrative database.

Pediatr Blood Cancer 2021 Mar 19;68(3):e28846. Epub 2020 Dec 19.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.

Background: Central nervous system (CNS) tumors are the second most common malignancy of childhood, and published data on venous thromboembolism (VTE) rate and risk factors for these patients are outdated or incomplete. Here, we determine the cumulative incidence and risk factors for VTE in this population.

Procedure: VTE diagnosis and associated clinical risk factors were abstracted and analyzed for two cohorts of children (0-21 years) diagnosed with CNS tumors between January 1, 2010 to September 30, 2018. The first study was a retrospective single institution cohort study. The initial observations were confirmed across multiple pediatric hospitals using the Pediatric Health Information System (PHIS) administrative database.

Results: The single-institution cohort included 338 patients aged 3 days to 20.9 years (median age, 8.6 years); VTE developed in eight (2.4%) patients. The PHIS cohort included 17 634 patients aged from 0 to 21.9 years (median: 9.5 years); VTE developed in 354 (2.0%) patients. Univariate analysis for the single-institution cohort identified central venous catheter (CVC) placement as a risk factor for VTE (odds ratio [OR] 8.40, 95% confidence interval [CI] 1.43-49.41, P = .0186). Multivariable analysis of the PHIS dataset identified CVC placement (OR 1.97, 95% CI 1.57-2.46; P < .0001), obesity (OR 2.96, 95% CI 1.21-7.26; P = .0177), and more than one hospital admission (OR 3.54, 95% CI 2.69-4.64; P < .0001) as significant predictors of VTE. VTE diagnosis was not associated with increased mortality in either cohort.

Conclusions: The VTE rate in children with CNS tumors is low (2%). CVC placement was identified as a modifiable risk factor in both cohorts.
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http://dx.doi.org/10.1002/pbc.28846DOI Listing
March 2021

Brain biomarkers and neuropsychological outcomes of pediatric posterior fossa brain tumor survivors treated with surgical resection with or without adjuvant chemotherapy.

Pediatr Blood Cancer 2021 Feb 29;68(2):e28817. Epub 2020 Nov 29.

Radiology Department, CIBORG Laboratory, Children's Hospital Los Angeles, Los Angeles, California.

Purpose: Children with brain tumors experience cognitive late effects, often related to cranial radiation. We sought to determine differential effects of surgery and chemotherapy on brain structure and neuropsychological outcomes in children who did not receive cranial radiation therapy (CRT).

Methods: Twenty-eight children with a history of posterior fossa tumor (17 treated with surgery, 11 treated with surgery and chemotherapy) underwent neuroimaging and neuropsychological assessment a mean of 4.5 years (surgery group) to 9 years (surgery + chemotherapy group) posttreatment, along with 18 healthy sibling controls. Psychometric measures assessed IQ, language, executive functions, processing speed, memory, and social-emotional functioning. Group differences and correlations between diffusion tensor imaging findings and psychometric scores were examined.

Results: The z-score mapping demonstrated fractional anisotropy (FA) values were ≥2 standard deviations lower in white matter tracts, prefrontal cortex gray matter, hippocampus, thalamus, basal ganglia, and pons between patient groups, indicating microstructural damage associated with chemotherapy. Patients scored lower than controls on visuoconstructional reasoning and memory (P ≤ .02). Lower FA in the uncinate fasciculus (R = -0.82 to -0.91) and higher FA in the thalamus (R = 0.73-0.91) associated with higher IQ scores, and higher FA in the thalamus associated with higher scores on spatial working memory (R = 0.82).

Conclusions: Posterior fossa brain tumor treatment with surgery and chemotherapy affects brain microstructure and neuropsychological functioning years into survivorship, with spatial processes the most vulnerable. Biomarkers indicating cellular changes in the thalamus, hippocampus, pons, prefrontal cortex, and white matter tracts associate with lower psychometric scores.
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http://dx.doi.org/10.1002/pbc.28817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755691PMC
February 2021

Pediatric Gliosarcoma With and Without Neurofibromatosis Type 1: A Whole-exome Comparison of 2 Patients.

J Pediatr Hematol Oncol 2020 Nov 23. Epub 2020 Nov 23.

Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

Gliosarcoma is rare among pediatric patients and among individuals with Neurofibromatosis Type 1 (NF1). Here we compare 2 pediatric gliosarcoma patients, one of whom has NF1. We performed whole-exome sequencing, methylation, and copy number analysis on tumor and blood for both patients. Whole-exome sequencing showed higher mutational burden in the tumor of the patient without NF1. Copy number analysis showed differences in chromosomal losses/gains between the tumors. Neither tumor showed O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The NF1 patient survived without progression while the other expired. This is the first reported case of gliosarcoma in a child with NF1.
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http://dx.doi.org/10.1097/MPH.0000000000002020DOI Listing
November 2020

Characterizing temporal genomic heterogeneity in pediatric low-grade gliomas.

Acta Neuropathol Commun 2020 11 5;8(1):182. Epub 2020 Nov 5.

Brain Tumor Center, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.

Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs' genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and/or targeted sequencing were performed on paired tumor samples from primary diagnostic and subsequent surgeries. Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAF mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status at recurrence occurred in 11 patients (42%), with acquisition of hemizygous CDKN2A deletion in seven and loss in four. Shorter time to progression and shorter time to subsequent surgery were observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration [median time to progression: 5.5 versus 16.0 months (p = 0.048); median time to next surgery: 17.0 months versus 29.0 months (p = 0.031)]. Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or irradiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.
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http://dx.doi.org/10.1186/s40478-020-01054-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643477PMC
November 2020

YAP1-FAM118B Fusion Defines a Rare Subset of Childhood and Young Adulthood Meningiomas.

Am J Surg Pathol 2021 03;45(3):329-340

The Steve and Cindy Rasmussen Institute for Genomic Medicine.

Meningiomas are a central nervous system tumor primarily afflicting adults, with <1% of cases diagnosed during childhood or adolescence. Somatic variation in NF2 may be found in ∼50% of meningiomas, with other genetic drivers (eg, SMO, AKT1, TRAF7) contributing to NF2 wild-type tumors. NF2 is an upstream negative regulator of YAP signaling and loss of the NF2 protein product, Merlin, results in YAP overexpression and target gene transcription. This mechanism of dysregulation is described in NF2-driven meningiomas, but further work is necessary to understand the NF2-independent mechanism of tumorigenesis. Amid our institutional patient-centric comprehensive molecular profiling study, we identified an individual with meningioma harboring a YAP1-FAM118B fusion, previously reported only in supratentorial ependymoma. The tumor histopathology was remarkable, characterized by prominent islands of calcifying fibrous nodules within an overall collagen-rich matrix. To gain insight into this finding, we subsequently evaluated the genetic landscape of 11 additional pediatric and adolescent/young adulthood meningioma patients within the Children's Brain Tumor Tissue Consortium. A second individual harboring a YAP1-FAM118B gene fusion was identified within this database. Transcriptomic profiling suggested that YAP1-fusion meningiomas are biologically distinct from NF2-driven meningiomas. Similar to other meningiomas, however, YAP1-fusion meningiomas demonstrated overexpression of EGFR and MET. DNA methylation profiling further distinguished YAP1-fusion meningiomas from those observed in ependymomas. In summary, we expand the genetic spectrum of somatic alteration associated with NF2 wild-type meningioma to include the YAP1-FAM118B fusion and provide support for aberrant signaling pathways potentially targetable by therapeutic intervention.
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http://dx.doi.org/10.1097/PAS.0000000000001597DOI Listing
March 2021

Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition.

JCO Precis Oncol 2020 20;4. Epub 2020 May 20.

Semmelweis University, Budapest, Hungary.

Purpose: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors.

Patients And Methods: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries.

Results: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of , were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( = .02).

Conclusion: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.
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http://dx.doi.org/10.1200/PO.19.00298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446502PMC
May 2020

Exploring DNA Methylation for Prognosis and Analyzing the Tumor Microenvironment in Pleomorphic Xanthoastrocytoma.

J Neuropathol Exp Neurol 2020 08;79(8):880-890

Department of Neuropathology, New York University Langone Health, New York, New York.

Pleomorphic xanthoastrocytoma (PXA) is a rare type of brain tumor that affects children and young adults. Molecular prognostic markers of PXAs remain poorly established. Similar to gangliogliomas, PXAs show prominent immune cell infiltrate, but its composition also remains unknown. In this study, we correlated DNA methylation and BRAF status with clinical outcome and explored the tumor microenvironment. We performed DNA methylation in 21 tumor samples from 18 subjects with a histological diagnosis of PXA. MethylCIBERSORT was used to deconvolute the PXA microenvironment by analyzing the associated immune cell-types. Median age at diagnosis was 16 years (range 7-32). At median follow-up of 30 months, 3-year and 5-year overall survival was 73% and 71%, respectively. Overall survival ranged from 1 to 139 months. Eleven out of 18 subjects (61%) showed disease progression. Progression-free survival ranged from 1 to 89 months. Trisomy 7 and CDKN2A/B (p16) homozygous deletion did not show any association with overall survival (p = 0.67 and p = 0.74, respectively). Decreased overall survival was observed for subjects with tumors lacking the BRAF V600E mutation (p = 0.02). PXAs had significantly increased CD8 T-cell epigenetic signatures compared with previously profiled gangliogliomas (p = 0.0019). The characterization of immune cell-types in PXAs may have implications for future development of immunotherapy.
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http://dx.doi.org/10.1093/jnen/nlaa051DOI Listing
August 2020

Neuropsychological outcomes on Head Start III: a prospective, multi-institutional clinical trial for young children diagnosed with malignant brain tumors.

Neurooncol Pract 2020 Jun 3;7(3):329-337. Epub 2020 Feb 3.

Department of Psychiatry & Behavioral Sciences, Memorial Sloan Kettering, New York, NY.

Background: Current pediatric brain tumor treatment focuses on titrating toxicity based on risk factors while simultaneously improving survivorship. The Head Start (HS) protocols I to IV (1991-present) use high-dose chemotherapy (HDCTx) with an aim of reducing or eliminating cranial irradiation in very young children, the most vulnerable to its effects.

Methods: We examined estimated Full Scale IQ, overall Adaptive Functioning, Working Memory, Processing Speed, and Verbal and Nonverbal Memory outcome data for 43 HS III patients diagnosed between ages 2 months and 7 years from 15 institutions in the United States and Canada.

Results: At a mean of 5.12 years postdiagnosis, the HS III patients performed within the average to low-average ranges across these variables; however, individual variability was noted with scores ranging from superior to impaired, and the sample as a whole performed lower than age expectations. Performance did not significantly differ by sex or ethnicity, diagnosis, or for those treated with an intravenous methotrexate dose of 400 mg/kg vs 270 mg/kg. Additionally, performance did not significantly differ by age at diagnosis or length of follow-up.

Conclusions: The results, indicating overall average to low-average neurocognitive functioning, are encouraging, though significant individual variability was noted. Those who were younger at diagnosis, received more intensive methotrexate, and were further out from treatment were not at significantly increased risk of cognitive decline within our sample, suggesting a strategy of using HDCTx and autologous hematopoietic progenitor cell rescue to reduce or eliminate irradiation may allow for continued CNS development in young children treated for a brain tumor.
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http://dx.doi.org/10.1093/nop/npz071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274184PMC
June 2020

Meta-Analysis of Treatment Modalities in Metastatic Atypical Teratoid/Rhabdoid Tumors in Children.

Pediatr Neurol 2020 07 8;108:106-112. Epub 2020 May 8.

The Ohio State University College of Medicine, Columbus, Ohio; Division of Hematology, Oncology and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio. Electronic address:

Background: Metastatic atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive central nervous system tumors that present during infancy and are associated with dismal outcomes. Patients receive multimodal treatment including surgical resection, systemic chemotherapy, and one or more of intrathecal chemotherapy (IT), marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and radiation therapy (XRT). While data regarding treatment modalities for AT/RT patients exist, no comprehensive data have been published regarding the metastatic patients.

Methods: We performed a meta-analysis of 1578 articles published through September 2018, including 44 studies with a total of 123 subjects. In addition, seven patients were included through chart review of patients treated at Nationwide Children's Hospital.

Results: Analysis of 130 patients revealed a 3-year overall survival (OS) of 25%. Age at diagnosis had a significant effect on survival (P = 0.0355); 3-year OS for infants less than 18 months was 21%, 18 to 36 months was 26%, and greater than 36 months was 36%. Location of the primary tumor, metastatic stage, and extent of surgical resection did not have a significant impact on OS. On univariate analysis, XRT (P < 0.0001), IT (P = 0.01), and AuHCR (P < 0.0001) were found to significantly improve survival. The most substantial effect was noted in patients who received AuHCR (3-year OS of 60% vs 9% in those who did not). On multivariable analysis, XRT (P = 0.0006), IT (P = 0.0124), and AuHCR (P < 0.0001) were independently associated with reduced risk of death.

Conclusions: Although more research is warranted to make generalizable conclusions, these results suggest that treatment regimens for patients with metastatic AT/RTs should include AuHCR, XRT, and IT.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.03.003DOI Listing
July 2020

Excellent outcome of young children with nodular desmoplastic medulloblastoma treated on "Head Start" III: a multi-institutional, prospective clinical trial.

Neuro Oncol 2020 12;22(12):1862-1872

Division of Pediatric Hematology-Oncology, Nationwide Children's Hospital, Columbus, Ohio, USA.

Background: "Head Start" III, was a prospective clinical trial using intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) to either avoid or reduce the dose/volume of irradiation in young children with medulloblastoma.

Methods: Following surgery, patients received 5 cycles of induction followed by myeloablative chemotherapy using carboplatin, thiotepa, and etoposide with AuHCR. Irradiation was reserved for children >6 years old at diagnosis or with residual tumor post-induction.

Results: Between 2003 and 2009, 92 children <10 years old with medulloblastoma were enrolled. Five-year event-free survival (EFS) and overall survival (OS) rates (±SE) were 46 ± 5% and 62 ± 5% for all patients, 61 ± 8% and 77 ± 7% for localized medulloblastoma, and 35 ± 7% and 52 ± 7% for disseminated patients. Nodular/desmoplastic (ND) medulloblastoma patients had 5-year EFS and OS (±SE) rates of 89 ± 6% and 89 ± 6% compared with 26 ± 6% and 53 ± 7% for classic and 38 ± 13% and 46 ± 14% for large-cell/anaplastic (LCA) medulloblastoma, respectively. In multivariate Cox regression analysis, histology was the only significant independent predictor of EFS after adjusting for stage, extent of resection, regimen, age, and sex (P <0.0001). Five-year irradiation-free EFS was 78 ± 8% for ND and 21 ± 5% for classic/LCA medulloblastoma patients. Myelosuppression was the most common toxicity, with 2 toxic deaths. Twenty-four survivors completed neurocognitive evaluation at a mean of 4.9 years post-diagnosis. IQ and memory scores were within average range overall, whereas processing speed and adaptive functioning were low-average.

Conclusion: We report excellent survival and preservation of mean IQ and memory for young children with ND medulloblastoma using high-dose chemotherapy, with most patients surviving without irradiation.
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http://dx.doi.org/10.1093/neuonc/noaa102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746930PMC
December 2020

Pineoblastoma in children less than six years of age: The Head Start I, II, and III experience.

Pediatr Blood Cancer 2020 06 18;67(6):e28252. Epub 2020 Mar 18.

The Division of Hematology, Oncology and Blood and Marrow Transplant, Nationwide Children's Hospital and The Ohio State University, Columbus, Ohio.

Background: We report the outcomes of patients with pineoblastoma and trilateral retinoblastoma syndrome enrolled on the Head Start (HS) I-III trials.

Methods: Twenty-three children were enrolled prospectively between 1991 and 2009. Treatment included maximal surgical resection followed by five cycles of intensive chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR). Irradiation following consolidation was reserved for children over six years of age or those with residual tumor at the end of induction.

Results: Median age was 3.12 years (range, 0.44-5.72). Three patients withdrew from the study treatment and two patients experienced chemotherapy-related death. Eight patients experienced progressive disease (PD) during induction chemotherapy and did not proceed to HDCx/AuHCR. Ten patients received HDCx/AuHCR; eight experienced PD post-consolidation. Seven patients received craniospinal irradiation (CSI) with a median dose of 20.7 Gy (range, 18-36 Gy) with boost(s) (median dose 27 Gy; range, 18-36 Gy); three received CSI as adjuvant therapy (two post-HDCx/AuHCR) and four upon progression/recurrence. The five-year progression-free survival (PFS) and overall survival (OS) were 9.7% (95% confidence intervals [CI]: 2.6%-36.0%) and 13% (95% CI: 4.5%-37.5%), respectively. Only three patients survived beyond five years. Favorable OS prognostic factors were CSI (hazard ratio [HR] = 0.30 [0.11-0.86], P = 0.025) and HDCx/AuHCR (HR = 0.40 [0.16-0.99], P = 0.047).

Conclusions: Within the HS I-III trials, CSI and HDCx/AuHCR were statistically associated with improved survival. The high PD rate during later induction cycles and following consolidation chemotherapy warrants consideration of fewer induction cycles prior to consolidation and the potential intensification of consolidation with multiple cycles of marrow-ablative chemotherapy and irradiation.
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http://dx.doi.org/10.1002/pbc.28252DOI Listing
June 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

Correction to: DNA methylation signature is prognostic of choroid plexus tumor aggressiveness.

Clin Epigenetics 2019 Oct 21;11(1):144. Epub 2019 Oct 21.

Genetics and Genome Biology Program, Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada.

After publication of the original article [1], authors have requested to add a 'J' as middle name for Richard Gilbertson. Hence, full name should be Richard J Gilbertson.
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http://dx.doi.org/10.1186/s13148-019-0737-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802296PMC
October 2019

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Nat Commun 2019 09 25;10(1):4343. Epub 2019 Sep 25.

Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.
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http://dx.doi.org/10.1038/s41467-019-12187-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761184PMC
September 2019

DNA methylation signature is prognostic of choroid plexus tumor aggressiveness.

Clin Epigenetics 2019 08 13;11(1):117. Epub 2019 Aug 13.

Genetics and Genome Biology Program, Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada.

Background: Histological grading of choroid plexus tumors (CPTs) remains the best prognostic tool to distinguish between aggressive choroid plexus carcinoma (CPC) and the more benign choroid plexus papilloma (CPP) or atypical choroid plexus papilloma (aCPP); however, these distinctions can be challenging. Standard treatment of CPC is very aggressive and often leads to severe damage to the young child's brain. Therefore, it is crucial to distinguish between CPC and less aggressive entities (CPP or aCPP) to avoid unnecessary exposure of the young patient to neurotoxic therapy. To better stratify CPTs, we utilized DNA methylation (DNAm) to identify prognostic epigenetic biomarkers for CPCs.

Methods: We obtained DNA methylation profiles of 34 CPTs using the HumanMethylation450 BeadChip from Illumina, and the data was analyzed using the Illumina Genome Studio analysis software. Validation of differentially methylated CpG sites chosen as biomarkers was performed using pyrosequencing analysis on additional 22 CPTs. Sensitivity testing of the CPC DNAm signature was performed on a replication cohort of 61 CPT tumors obtained from Neuropathology, University Hospital Münster, Germany.

Results: Generated genome-wide DNAm profiles of CPTs showed significant differences in DNAm between CPCs and the CPPs or aCPPs. The prediction of clinical outcome could be improved by combining the DNAm profile with the mutational status of TP53. CPCs with homozygous TP53 mutations clustered as a group separate from those carrying a heterozygous TP53 mutation or CPCs with wild type TP53 (TP53-wt) and showed the worst survival outcome. Specific DNAm signatures for CPCs revealed AK1, PER2, and PLSCR4 as potential biomarkers for CPC that can be used to improve molecular stratification for diagnosis and treatment.

Conclusions: We demonstrate that combining specific DNAm signature for CPCs with histological approaches better differentiate aggressive tumors from those that are not life threatening. These findings have important implications for future prognostic risk prediction in clinical disease management.
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http://dx.doi.org/10.1186/s13148-019-0708-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692938PMC
August 2019

Delays in diagnosis for children with newly diagnosed central nervous system tumors.

Neurooncol Pract 2018 Nov 9;5(4):227-233. Epub 2018 Mar 9.

The Division of Hematology, Oncology and BMT, Nationwide Children's Hospital, Columbus, Ohio.

Background: United States studies documenting time interval from symptom onset to definitive diagnosis for childhood central nervous system (CNS) tumors are more than a quarter-century old. The purpose of this study is to establish an accurate and contemporary Ohio baseline of the diagnostic interval for children with newly diagnosed CNS tumors.

Methods: Medical records were retrospectively reviewed for 301 children with newly diagnosed CNS tumors from January 2004 to August 2015 at Nationwide Children's Hospital. We obtained comprehensive data on 171 patients (56.8%). Records were reviewed for age, gender, tumor type, presenting symptoms, number of health care visits prior to diagnosis, time interval (in months) from onset of symptoms to definitive diagnosis, and any associated genetic syndromes.

Results: Of the 171 patients with newly diagnosed CNS tumors, 25 children (14.6%) had a known cancer predisposition syndrome (all with neurofibromatosis type 1). Among the remaining 146 children, the median and mean time intervals from symptom onset to definitive diagnosis were 42 days and 138 days (range < 1 to 2190 days), respectively.

Conclusions: We have documented and quantified the contemporary delays in diagnosis of childhood brain tumors in central Ohio to serve as a benchmark for our future planned interventions to reduce the time interval from symptom onset to diagnosis through adaptation of the United Kingdom HeadSmart program throughout the state of Ohio and ultimately throughout the United States.
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http://dx.doi.org/10.1093/nop/npy002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6655489PMC
November 2018

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

Descriptive epidemiology of germ cell tumors of the central nervous system diagnosed in the United States from 2006 to 2015.

J Neurooncol 2019 Jun 25;143(2):251-260. Epub 2019 Apr 25.

Central Brain Tumor Registry of the United States, Hinsdale, IL, USA.

Purpose: Germ cell tumors (GCT) in the central nervous system (CNS) are rare tumors that occur with highest frequency in males, Asian populations, and children less than age 20 years. Due to the rarity of these tumors, their patterns of incidence are not well-described. The aim of this study is to provide the most up-to-date data on incidence and survival patterns for CNS GCT by sex, race, and age at diagnosis.

Methods: The Central Brain Tumor Registry of the United States (CBTRUS) is the largest aggregation of population-based incidence data on primary brain and other CNS tumors in the United States, containing incidence data from 51 central cancer registries and representing 100% of the US population. The current study used the CBTRUS analytic file to examine incidence (IR) of CNS GCT from 2006 to 2015, as well as registry data from the Surveillance, Epidemiology, and End Results (SEER) program to examine survival.

Results: Males had greater IR than females in all CNS GCT histologies examined. Asian and Pacific Islanders had a significantly greater IR of CNS GCT than the other race categories. We confirmed that CNS GCT IR was greatest for those age 10-14 years and male. Overall survival rates were high for malignant CNS GCT, germinoma, mixed GCT, and malignant teratoma.

Conclusions: There is significant variation in CNS GCT incidence by sex, race, and age at diagnosis. Ascertaining accurate incidence and survival rates of CNS GCT provides vital information usable in real time for clinicians, public health planners, patients, and their families.
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http://dx.doi.org/10.1007/s11060-019-03173-4DOI Listing
June 2019

Critical review of the management of primary central nervous nongerminomatous germ cell tumors.

Pediatr Blood Cancer 2019 06 15;66(6):e27658. Epub 2019 Feb 15.

The Division of Hematology, Oncology and Blood and Marrow Transplant, Nationwide Children's Hospital and The Ohio State University, Columbus, Ohio, USA.

Multimodal strategies have significantly improved the outcomes for patients with central nervous system nongerminomatous germ cell tumors. Two large cooperative group studies have recently reported much improved outcomes compared with historical series. However, a substantial proportion of patients still attain inadequate responses to initial chemotherapy prior to irradiation, with adverse impact upon survival; optimal induction chemotherapy regimens and radiotherapy strategies are as yet unidentified. Outcomes for patients with relapsed disease remain poor. There is an obvious need to incorporate molecular studies within prospective clinical trials that will likely lead to the incorporation of targeted, more effective future treatment strategies.
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http://dx.doi.org/10.1002/pbc.27658DOI Listing
June 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

Continuous and bolus intraventricular topotecan prolong survival in a mouse model of leptomeningeal medulloblastoma.

PLoS One 2019 4;14(1):e0206394. Epub 2019 Jan 4.

Department of Pathology, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California, United states of America.

Leptomeningeal metastasis remains a difficult clinical challenge. Some success has been achieved by direct administration of therapeutics into the cerebrospinal fluid (CSF) circumventing limitations imposed by the blood brain barrier. Here we investigated continuous infusion versus bolus injection of therapy into the CSF in a preclinical model of human Group 3 medulloblastoma, the molecular subgroup with the highest incidence of leptomeningeal disease. Initial tests of selected Group 3 human medulloblastoma cell lines in culture showed that D283 Med and D425 Med were resistant to cytosine arabinoside and methotrexate. D283 Med cells were also resistant to topotecan, whereas 1 μM topotecan killed over 99% of D425 Med cells. We therefore introduced D425 Med cells, modified to express firefly luciferase, into the CSF of immunodeficient mice. Mice were then treated with topotecan or saline in five groups: continuous intraventricular (IVT) topotecan via osmotic pump (5.28 μg/day), daily bolus IVT topotecan injections with a similar daily dose (6 μg/day), systemic intraperitoneal injections of a higher daily dose of topotecan (15 μg/day), daily IVT pumped saline and daily intraperitoneal injections of saline. Bioluminescence analyses revealed that both IVT topotecan treatments effectively slowed leptomeningeal tumor growth in the brains. Histological analysis showed that they were associated with localized brain necrosis, possibly due to backtracking of topotecan around the catheter. In the spines, bolus IVT topotecan showed a trend towards slower tumor growth compared to continuous (pump) IVT topotecan, as measured by bioluminescence. Both continuous and bolus topotecan IVT showed longer survival compared to other groups. Thus, both direct IVT topotecan CSF delivery methods produced better anti-medulloblastoma effect compared to systemic therapy at the dosages used here.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206394PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319703PMC
September 2019

The Latin American Brain Tumor Board teleconference: results of a web-based survey to evaluate participant experience utilizing this resource.

Childs Nerv Syst 2019 02 14;35(2):257-265. Epub 2018 Nov 14.

The Department of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital and The Ohio State University, 700 Children's Drive, Columbus, OH, 43205, USA.

Purpose: The Latin American Brain Tumor Board (LATB) is a weekly teleconference connecting pediatric neuro-oncologists from referral centers in high-income countries with pediatric subspecialists from 20 Latin American countries since 2013. This survey explored the participants' experience utilizing this resource.

Methods: A cross-sectional electronic questionnaire was distributed to 159 participants through email and Cure4Kids.

Results: Ninety-five respondents (60%) from all the participating countries completed the survey. Sixty-one reported frequent-attendance (≥ 1 per month), 23 reported infrequent-attendance (< 1 per month), and 11 never participated. The most frequently reported attendance-barriers were the subspecialist's workload (64%), the timing of the teleconference (38%), and Internet connectivity problems (29%). Subspecialist's workload was more frequently reported as a barrier compared with other barriers, in both the frequent- and infrequent-attendance groups (p < 0.05), with the exception of the timing of the meeting in the infrequent-attendance group. More than 80% of attendees found the frequency and duration of the teleconference were sufficient. Utilizing Spanish as the primary language was reported to enhance the recommendations by 93% of the attendees. Moreover, 84% reported that the recommendations (almost) always fit the local circumstances. Furthermore, 99% of attendees found the teleconference provided a continuing medical education opportunity. Finally, 96% of attendees (almost) always found that the provided recommendations helped to improve the outcomes/quality of life of the patients.

Conclusions: The LATB teleconference provided a valuable tool for the management of pediatric brain tumors in Latin America as it provided a feasible and easy to access continued medical education opportunity for the participants.
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http://dx.doi.org/10.1007/s00381-018-4000-xDOI Listing
February 2019

Pre-irradiation intensive induction and marrow-ablative consolidation chemotherapy in young children with newly diagnosed high-grade brainstem gliomas: report of the "head-start" I and II clinical trials.

J Neurooncol 2018 Dec 3;140(3):717-725. Epub 2018 Nov 3.

Division of Pediatric Hematology/Oncology, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.

Background: The dismal outcome in children with high-grade brainstem gliomas (BSG) accentuates the need for effective therapeutic strategies. We investigated the role of intensive, including marrow-ablative, chemotherapy regimens in the treatment of young children with newly-diagnosed high-grade BSG.

Methods: Between 1991-and-2002, 15 eligible children less than 10 years of age with a diagnosis of high-grade BSG were treated on "Head-Start" I and II protocols (HSI and HSII). Treatment included Induction with 4-5 cycles of one of three intensive chemotherapy regimens followed by Consolidation with one cycle of marrow-ablative chemotherapy (thiotepa, carboplatin and etoposide) with autologous hematopoietic cell rescue (AHCR). Irradiation was required for children over 6 years of age or for those with residual tumor at the end of Consolidation.

Results: We had two long-term survivors who were found retrospectively to harbor low-grade glial tumors and thus were not included in the survival analysis. Of the remaining 13 patients, the 1-year event-free (EFS) and overall (OS) survival for these children were 31% (95% CI 9-55%) and 38% (95% CI 14-63%), respectively. Median EFS and OS were 6.6 (95% CI 2.7, 12.7) and 8.7 months (95% CI 6.9, 20.9), respectively. Eight patients developed progressive disease during study treatment (seven during Induction and one at the end of Consolidation). Ten children received focal irradiation, five for residual tumor (three following Induction and two following Consolidation) and five due to disease progression.

Conclusions: Children with high-grade BSG did not benefit from this intensive chemotherapy strategy administered prior to irradiation.
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http://dx.doi.org/10.1007/s11060-018-03003-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536888PMC
December 2018