Publications by authors named "Jason R Fangusaro"

12 Publications

  • Page 1 of 1

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

Extended diffusion weighted magnetic resonance imaging with two-compartment and anomalous diffusion models for differentiation of low-grade and high-grade brain tumors in pediatric patients.

Neuroradiology 2017 Aug 8;59(8):803-811. Epub 2017 Jul 8.

Department of Medical Imaging, Ann and Robert H. Lurie Children's Hospital of Chicago, 225 E. Chicago Ave, Chicago, IL, 60611, USA.

Purpose: The purpose of this study was to examine advanced diffusion-weighted magnetic resonance imaging (DW-MRI) models for differentiation of low- and high-grade tumors in the diagnosis of pediatric brain neoplasms.

Methods: Sixty-two pediatric patients with various types and grades of brain tumors were evaluated in a retrospective study. Tumor type and grade were classified using the World Health Organization classification (WHO I-IV) and confirmed by pathological analysis. Patients underwent DW-MRI before treatment. Diffusion-weighted images with 16 b-values (0-3500 s/mm) were acquired. Averaged signal intensity decay within solid tumor regions was fitted using two-compartment and anomalous diffusion models. Intracellular and extracellular diffusion coefficients (D and D), fractional volumes (V and V), generalized diffusion coefficient (D), spatial constant (μ), heterogeneity index (β), and a diffusion index (index_diff = μ × V/β) were calculated. Multivariate logistic regression models with stepwise model selection algorithm and receiver operating characteristic (ROC) analyses were performed to evaluate the ability of each diffusion parameter to distinguish tumor grade.

Results: Among all parameter combinations, D and index_diff jointly provided the best predictor for tumor grades, where lower D (p = 0.03) and higher index_diff (p = 0.009) were significantly associated with higher tumor grades. In ROC analyses of differentiating low-grade (I-II) and high-grade (III-IV) tumors, index_diff provided the highest specificity of 0.97 and D provided the highest sensitivity of 0.96.

Conclusions: Multi-parametric diffusion measurements using two-compartment and anomalous diffusion models were found to be significant discriminants of tumor grading in pediatric brain neoplasms.
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http://dx.doi.org/10.1007/s00234-017-1865-4DOI Listing
August 2017

Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors.

Authors:
Jonathon Torchia Brian Golbourn Shengrui Feng King Ching Ho Patrick Sin-Chan Alexandre Vasiljevic Joseph D Norman Paul Guilhamon Livia Garzia Natalia R Agamez Mei Lu Tiffany S Chan Daniel Picard Pasqualino de Antonellis Dong-Anh Khuong-Quang Aline C Planello Constanze Zeller Dalia Barsyte-Lovejoy Lucie Lafay-Cousin Louis Letourneau Mathieu Bourgey Man Yu Deena M A Gendoo Misko Dzamba Mark Barszczyk Tiago Medina Alexandra N Riemenschneider A Sorana Morrissy Young-Shin Ra Vijay Ramaswamy Marc Remke Christopher P Dunham Stephen Yip Ho-Keung Ng Jian-Qiang Lu Vivek Mehta Steffen Albrecht Jose Pimentel Jennifer A Chan Gino R Somers Claudia C Faria Lucia Roque Maryam Fouladi Lindsey M Hoffman Andrew S Moore Yin Wang Seung Ah Choi Jordan R Hansford Daniel Catchpoole Diane K Birks Nicholas K Foreman Doug Strother Almos Klekner Laszló Bognár Miklós Garami Péter Hauser Tibor Hortobágyi Beverly Wilson Juliette Hukin Anne-Sophie Carret Timothy E Van Meter Eugene I Hwang Amar Gajjar Shih-Hwa Chiou Hideo Nakamura Helen Toledano Iris Fried Daniel Fults Takafumi Wataya Chris Fryer David D Eisenstat Katrin Scheinemann Adam J Fleming Donna L Johnston Jean Michaud Shayna Zelcer Robert Hammond Samina Afzal David A Ramsay Nongnuch Sirachainan Suradej Hongeng Noppadol Larbcharoensub Richard G Grundy Rishi R Lulla Jason R Fangusaro Harriet Druker Ute Bartels Ronald Grant David Malkin C Jane McGlade Theodore Nicolaides Tarik Tihan Joanna Phillips Jacek Majewski Alexandre Montpetit Guillaume Bourque Gary D Bader Alyssa T Reddy G Yancey Gillespie Monika Warmuth-Metz Stefan Rutkowski Uri Tabori Mathieu Lupien Michael Brudno Ulrich Schüller Torsten Pietsch Alexander R Judkins Cynthia E Hawkins Eric Bouffet Seung-Ki Kim Peter B Dirks Michael D Taylor Anat Erdreich-Epstein Cheryl H Arrowsmith Daniel D De Carvalho James T Rutka Nada Jabado Annie Huang

Cancer Cell 2016 Dec;30(6):891-908

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G0A4, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G0A4, Canada; Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada. Electronic address:

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.
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http://dx.doi.org/10.1016/j.ccell.2016.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500911PMC
December 2016

Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis.

Lancet Oncol 2015 May 14;16(5):569-82. Epub 2015 Apr 14.

Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada. Electronic address:

Background: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours.

Methods: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling.

Findings: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes.

Interpretation: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours.

Funding: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.
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http://dx.doi.org/10.1016/S1470-2045(15)70114-2DOI Listing
May 2015

Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.

Nat Genet 2014 May 6;46(5):451-6. Epub 2014 Apr 6.

1] Division of Pathology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. [2] Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [3] Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. [4].

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.
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http://dx.doi.org/10.1038/ng.2936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997489PMC
May 2014

Growth hormone excess in children with neurofibromatosis type 1-associated and sporadic optic pathway tumors.

J Pediatr 2011 Mar 28;158(3):433-6. Epub 2010 Oct 28.

Division of Endocrinology, Department of Pediatrics, Children's Memorial Hospital, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Objective: To describe the clinical manifestations of growth hormone (GH) excess in children with optic pathway tumors (OPT).

Study Design: Descriptive case series of 5 children with OPT, 3 with associated neurofibromatosis type 1, referred for evaluation of accelerated linear growth. GH excess was evaluated by oral glucose tolerance tests with frequent sampling of GH levels. Precocious puberty was evaluated by basal luteinizing hormone and sex steroid hormone levels. Stimulation testing with leuprolide acetate (20 μg/kg subcutaneously) was conducted in patients with normal baseline testing.

Results: All patients had OPT involving both the hypothalamus and optic chiasm. All patients had elevated levels of the growth factor insulin-like growth factor 1 and on stimulation testing demonstrated an inability to suppress GH levels to < 1.0 ng/mL, indicating the presence of unregulated GH secretion. Additionally, all patients displayed biochemical evidence of precocious puberty.

Conclusions: GH excess may be an under-recognized occurrence in the setting of neurofibromatosis type 1 and OPT. GH excess in such patients may contribute to continued brain tumor growth. Given the potential adverse consequences of unrestrained GH excess, all children with chiasmal or hypothalamic tumors who have rapid growth should be evaluated for both precocious puberty and GH excess.
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http://dx.doi.org/10.1016/j.jpeds.2010.09.013DOI Listing
March 2011

Endocrine late effects: manifestations and treatments.

Cancer Treat Res 2009 ;150:155-82

Department of Pediatric Hematology/Oncology and Stem Cell Transplantation, Children's Memorial Hospital, Chicago, IL, USA.

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http://dx.doi.org/10.1007/b109924_11DOI Listing
September 2010

Dissecting the role of endothelial SURVIVIN DeltaEx3 in angiogenesis.

Blood 2007 Feb 12;109(4):1479-89. Epub 2006 Oct 12.

Center for Childhood Cancer, Columbus Children's Research Institute, OH 43205, USA.

The identification of alternative splice variants of Survivin that possess distinct functions from those originally identified for the main Survivin isoform has greatly increased the complexity of our understanding of the role of Survivin in different cells. Previous functional studies of the Survivin splice variants have been performed almost exclusively in cancer cells. However, Survivin has increasingly been implicated in other normal physiologic and pathophysiologic processes, including angiogenesis. In this study, we dissect the involvement of Survivin DeltaEx3 in angiogenesis. We show by confocal microscopy that a pool of endothelial Survivin DeltaEx3 is localized to membrane ruffles. We also demonstrate that Survivin DeltaEx3 is the Survivin splice variant responsible for modulating angiogenesis in vitro, in tube formation assays, and in vivo, in an in vivo angiogenesis assay. Our data indicate that Survivin DeltaEx3 may regulate angiogenesis via several mechanisms including cell invasion, migration, and Rac1 activation. Our findings identify a novel pathway regulating angiogenesis through Survivin DeltaEx3 and a novel mechanism for Rac1 activation during angiogenesis. In conclusion, our results provide new insights into the regulation of endothelial cell homeostasis and angiogenesis by the Survivin proteins.
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http://dx.doi.org/10.1182/blood-2006-02-003749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1794050PMC
February 2007

Brainstem primitive neuroectodermal tumors (bstPNET): results of treatment with intensive induction chemotherapy followed by consolidative chemotherapy with autologous hematopoietic cell rescue.

Pediatr Blood Cancer 2008 Mar;50(3):715-7

The Children's Hospital Los Angeles, New York University Medical Center, Memorial Sloan-Kettering Cancer Center, and Schneider Children's Hospital, USA.

We have evaluated the response rate and survival utilizing intensified chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and adjuvant radiation therapy in six young children with newly diagnosed brainstem primitive neuroectodermal tumors (bstPNET). Following maximum surgical resection of the tumor, patients received high dose induction chemotherapy including vincristine, cisplatin, cyclophosphamide, and etoposide. Eligible patients received a single cycle of myeloablative chemotherapy followed by AuHCR. Two patients survive at least 32 months with stable disease. This approach provides an alternative for young patients with bstPNET who in prior reports have had a uniformly fatal prognosis.
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http://dx.doi.org/10.1002/pbc.21032DOI Listing
March 2008

Survivin: an inhibitor of apoptosis in pediatric cancer.

Pediatr Blood Cancer 2006 Jul;47(1):4-13

Center for Childhood Cancer, Columbus Children's Research Institute (CCRI), Columbus, Ohio 43205, USA.

Survivin is an inhibitor of apoptosis protein (IAP) expressed in a large number of adult malignancies. Its expression levels correlate with more aggressive disease and poor clinical outcome in many of these tumors. As its expression is restricted in normal adult differentiated tissues, it has become of great interest as both a tumor prognostic marker and as a potential biologic target for future anti-cancer therapies. Survivin expression and Survivin-based therapies have been examined in many of the more common pediatric malignancies. We present an overview of Survivin function and current research exploring its biologic and therapeutic roles in pediatric tumors.
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http://dx.doi.org/10.1002/pbc.20805DOI Listing
July 2006