Publications by authors named "Ana Guerreiro Stucklin"

20 Publications

  • Page 1 of 1

Opportunities for the treatment of NF1-associated low-grade gliomas: how to decide on the best treatment options for patients?

Neuro Oncol 2020 10;22(10):1415-1416

Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1093/neuonc/noaa201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566433PMC
October 2020

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma.

Nat Med 2020 05 27;26(5):720-731. Epub 2020 Apr 27.

The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.
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http://dx.doi.org/10.1038/s41591-020-0827-2DOI Listing
May 2020

Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas.

Cancer Cell 2020 04;37(4):569-583.e5

Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Neurosurgery, The Hospital for Sick Children, Toronto ON, Canada.

Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.
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http://dx.doi.org/10.1016/j.ccell.2020.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169997PMC
April 2020

Clinical impact of combined epigenetic and molecular analysis of pediatric low-grade gliomas.

Neuro Oncol 2020 10;22(10):1474-1483

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

Background: Both genetic and methylation analysis have been shown to provide insight into the diagnosis and prognosis of many brain tumors. However, the implication of methylation profiling and its interaction with genetic alterations in pediatric low-grade gliomas (PLGGs) are unclear.

Methods: We performed a comprehensive analysis of PLGG with long-term clinical follow-up. In total 152 PLGGs were analyzed from a range of pathological subtypes, including 40 gangliogliomas. Complete molecular analysis was compared with genome-wide methylation data and outcome in all patients. For further analysis of specific PLGG groups, including BRAF p.V600E mutant gliomas, we compiled an additional cohort of clinically and genetically defined tumors from 3 large centers.

Results: Unsupervised hierarchical clustering revealed 5 novel subgroups of PLGG. These were dominated by nonneoplastic factors such as tumor location and lymphocytic infiltration. Midline PLGG clustered together while deep hemispheric lesions differed from lesions in the periphery. Mutations were distributed throughout these location-driven clusters of PLGG. A novel methylation cluster suggesting high lymphocyte infiltration was confirmed pathologically and exhibited worse progression-free survival compared with PLGG harboring similar molecular alterations (P = 0.008; multivariate analysis: P = 0.035). Although the current methylation classifier revealed low confidence in 44% of cases and failed to add information in most PLGG, it was helpful in reclassifying rare cases. The addition of histopathological and molecular information to specific methylation subgroups such as pleomorphic xanthoastrocytoma-like tumors could stratify these tumors into low and high risk (P = 0.0014).

Conclusion: The PLGG methylome is affected by multiple nonneoplastic factors. Combined molecular and pathological analysis is key to provide additional information when methylation classification is used for PLGG in the clinical setting.
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http://dx.doi.org/10.1093/neuonc/noaa077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566385PMC
October 2020

Pediatric hemispheric high-grade glioma: targeting the future.

Cancer Metastasis Rev 2020 03;39(1):245-260

Department of Neurology, University of California, San Francisco, 625 Nelson Rising Lane, Box 0663, San Francisco, CA, 94158, USA.

Pediatric high-grade gliomas (pHGGs) are a group of tumors affecting approximately 0.85 children per 100,000 annually. The general outcome for these tumors is poor with 5-year survival rates of less than 20%. It is now recognized that these tumors represent a heterogeneous group of tumors rather than one entity. Large-scale genomic analyses have led to a greater understanding of the molecular drivers of different subtypes of these tumors and have also aided in the development of subtype-specific therapies. For example, for pHGG with NTRK fusions, promising new targeted therapies are actively being explored. Herein, we review the clinico-pathologic and molecular classification of these tumors, historical treatments, current management strategies, and therapies currently under investigation.
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http://dx.doi.org/10.1007/s10555-020-09850-5DOI Listing
March 2020

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

TGF-β Determines the Pro-migratory Potential of bFGF Signaling in Medulloblastoma.

Cell Rep 2018 06;23(13):3798-3812.e8

Paediatric Neuro-Oncology Research Group, Department of Oncology, Children's Research Center, University Children's Hospital Zürich, August-Forel Strasse 1, CH-8008 Zürich, Switzerland. Electronic address:

The microenvironment shapes cell behavior and determines metastatic outcomes of tumors. We addressed how microenvironmental cues control tumor cell invasion in pediatric medulloblastoma (MB). We show that bFGF promotes MB tumor cell invasion through FGF receptor (FGFR) in vitro and that blockade of FGFR represses brain tissue infiltration in vivo. TGF-β regulates pro-migratory bFGF function in a context-dependent manner. Under low bFGF, the non-canonical TGF-β pathway causes ROCK activation and cortical translocation of ERK1/2, which antagonizes FGFR signaling by inactivating FGFR substrate 2 (FRS2), and promotes a contractile, non-motile phenotype. Under high bFGF, negative-feedback regulation of FRS2 by bFGF-induced ERK1/2 causes repression of the FGFR pathway. Under these conditions, TGF-β counters inactivation of FRS2 and restores pro-migratory signaling. These findings pinpoint coincidence detection of bFGF and TGF-β signaling by FRS2 as a mechanism that controls tumor cell invasion. Thus, targeting FRS2 represents an emerging strategy to abrogate aberrant FGFR signaling.
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http://dx.doi.org/10.1016/j.celrep.2018.05.083DOI Listing
June 2018

Cerebellar tumors.

Handb Clin Neurol 2018 ;155:289-299

Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland. Electronic address:

The cerebellum is the most common site of presentation of central nervous system tumors in children but exceedingly rare in adults. Children often present with acute symptoms related to increased intracranial pressure, requiring urgent surgical intervention. The differential diagnosis is broad and includes a variety of benign and malignant entities. Cerebellar low-grade gliomas are the most common and benign, slow-growing tumors, for which surgical resection alone is curative. Embryonal tumors, on the other hand - most commonly medulloblastomas - are highly aggressive and treatment includes intensive postsurgical radiotherapy and chemotherapy. Driven by multiple genomewide profiling studies, the field of neuro-oncology is making great strides towards understanding how different tumors develop and embarking on a new generation of molecularly informed clinical trials.
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http://dx.doi.org/10.1016/B978-0-444-64189-2.00019-6DOI Listing
October 2018

A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases.

Cell 2018 02;172(5):1050-1062.e14

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Toronto General Research Institute, University Health Network, Toronto, ON, Canada.

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.
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http://dx.doi.org/10.1016/j.cell.2018.01.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346737PMC
February 2018

Review of molecular classification and treatment implications of pediatric brain tumors.

Curr Opin Pediatr 2018 02;30(1):3-9

The Arthur and Sonia Labatt Brain Tumour Research Centre and the Developmental & Stem Cell Biology Program, The Hospital for Sick Children.

Purpose Of Review: Brain tumors are the most common solid tumors and leading cause of cancer-related death in children. The advent of large-scale genomics has resulted in a plethora of profiling studies that have mapped the genetic and epigenetic landscapes of pediatric brain tumors, ringing in a new era of precision diagnostics and targeted therapies. In this review, we highlight the most recent findings, focusing on studies published after 2015, and discuss how new evidence is changing the care of children with brain tumors.

Recent Findings: Genome-wide and epigenome-wide profiling data have revealed distinct tumor entities within, virtually, all pediatric brain tumor groups including medulloblastoma; ependymoma; high-grade and low-grade gliomas; atypical teratoid/rhabdoid tumors; and other embryonal tumors, previously called CNS primitive neuroectodermal tumors. Whenever integrated with clinical information, many molecular alterations emerge as powerful prognostic markers and should thus be used to stratify patients and tailor therapies.

Summary: Optimal integration of this newly emerging knowledge in a timely and meaningful way into clinical care is a remarkable task and a matter of active debate. The historical morphology-based classification of tumors is being replaced by a genetic-based classification, and the first generation of molecularly informed clinical trials is underway.
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http://dx.doi.org/10.1097/MOP.0000000000000562DOI Listing
February 2018

Advances in Genomics Explain Medulloblastoma Behavior at the Bedside.

Neurosurgery 2017 Sep;64(CN_suppl_1):21-26

Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1093/neuros/nyx248DOI Listing
September 2017

Multiplex Detection of Pediatric Low-Grade Glioma Signature Fusion Transcripts and Duplications Using the NanoString nCounter System.

J Neuropathol Exp Neurol 2017 Jul;76(7):562-570

Department of Cancer and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Divisions of Pathology and Genome Diagnostics, Department of Paediatric Laboratory Medicine; and Division of Hematology and Oncology, The Division of Hematology and Oncology should be followed by Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada. Hospital for Sick Children, Toronto, Ontario, Canada; Department of Radiation Oncology, Tata Memorial Hospital, Parel, Mumbai, India; and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.

Previous studies identified recurrent fusion and duplication events in pediatric low-grade glioma (pLGG). In addition to their role in diagnosis, the presence of these events aid in dictating therapy and predicting patient survival. Clinically, BRAF alterations are most commonly identified using fluorescent in situ hybridization (FISH). However, this method is costly, labor-intensive and does not identify nonBRAF events. Here, we evaluated the NanoString nCounter gene expression system for detecting 32 of the most commonly reported fusion/duplication events in pLGG. The assay was validated on 90 pLGG samples using FISH as the gold standard and showed sensitivity and specificity of 97% and 98%, respectively. We next profiled formalin-fixed paraffin-embedded preserved biopsy specimens from 429 pLGG cases. 171 (40%) of the cases within our cohort tested positive for a fusion or duplication event contained within our panel. These events, in order of prevalence, were KIAA1549-BRAF 16;9 (89/171, 52.0%), KIAA1549-BRAF 15;9 (42/171, 24.6%), KIAA1549-BRAF 16;11 (14/171, 8.2%), FGFR1-TACC1 17;7 (13/171, 7.6%), MYBL1 duplication (5/171, 2.9%), KIAA1549-BRAF 18;10 (4/171, 2.3%), KIAA1549-BRAF 15;11 (2/171, 1.2%), FAM131B-BRAF 2;9 (1/171, 0.6%), and RNF130-BRAF 3;9 (1/171, 0.6%). This work introduces NanoString as a viable clinical replacement for the detection of fusion and duplication events in pLGG.
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http://dx.doi.org/10.1093/jnen/nlx042DOI Listing
July 2017

Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas.

J Clin Oncol 2017 Sep 20;35(25):2934-2941. Epub 2017 Jul 20.

Alvaro Lassaletta, Michal Zapotocky, Matthew Mistry, Vijay Ramaswamy, Marion Honnorat, Rahul Krishnatry, Ana Guerreiro Stucklin, Nataliya Zhukova, Anthony Arnoldo, Scott Ryall, Catriona Ling, Tara McKeown, Jim Loukides, James T. Rutka, Peter Dirks, Michael D. Taylor, Shiyi Chen, Ute Bartels, Annie Huang, Eric Bouffet, Cynthia Hawkins, and Uri Tabori, The Hospital for Sick Children, Toronto; Adam Fleming, McMaster Children's Hospital, McMaster University, Hamilton; Shayna Zelcer, Children's Hospital of Western Ontario, London, Ontario; David Eisenstat and Bev Wilson, Stollery Children's Hospital, University of Alberta, Edmonton, Alberta; Anne Sophie Carret, Hospital Sainte Justine; Nada Jabado, McGill University, Montreal; Valerie Larouche, Centre Hospitalier Universitaire de Québec, Québec City, Quebec, Canada; Ofelia Cruz and Carmen de Torres, Hospital Sant Joan de Déu, Barcelona, Spain; Cheng-Ying Ho, University of Maryland School of Medicine, Baltimore, MD; Roger J. Packer, Children's National Health System, Washington, DC; Ruth Tatevossian, Ibrahim Qaddoumi, Julie H. Harreld, James D. Dalton, and David W. Ellison, St Jude Children's Research Hospital, Memphis, TN; Jean Mulcahy-Levy and Nicholas Foreman, Children's Hospital Colorado, Aurora, CO; Matthias A. Karajannis, Shiyang Wang, and Matija Snuderl, New York University Langone Medical Center, New York, NY; Amulya Nageswara Rao and Caterina Giannini, The Mayo Clinic, Rochester, MN; Mark Kieran and Keith L. Ligon, Dana-Farber Cancer Institute, Boston Children's Hospital, Boston, MA; Maria Luisa Garre, Paolo Nozza, Samantha Mascelli, and Alessandro Raso, Istituto Giannina Gaslini, Genoa, Italy; Sabine Mueller and Theodore Nicolaides, University of California, San Francisco, San Francisco, CA; Karen Silva and Romain Perbet, Hospices Civils de Lyon; Alexandre Vasiljevic, Cécile Faure Conter, and Didier Frappaz, Institute of Pediatric Hematology and Oncology, Lyon, France; Sarah Leary and Courtney Crane, Seattle Children's Hospital, Seattle, WA; Aden Chan and Ho-Keung Ng, The Chinese University of Hong Kong, Hong Kong; Zhi-Feng Shi and Ying Mao, Huashan Hospital, Fudan University, Shanghai, People's Republic of China; Elizabeth Finch, University of North Carolina, School of Medicine, Chapel Hill, NC; Peter Hauser, Semmelweis University, Budapest, Hungary; and David Sumerauer and Lenka Krskova, University Hospital Motol, Charles University, 2nd Medical School, Prague, Czech Republic.

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.
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http://dx.doi.org/10.1200/JCO.2016.71.8726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791837PMC
September 2017

Tailoring Medulloblastoma Treatment Through Genomics: Making a Change, One Subgroup at a Time.

Annu Rev Genomics Hum Genet 2017 08 5;18:143-166. Epub 2017 May 5.

Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; email:

After more than a decade of genomic studies in medulloblastoma, the time has come to capitalize on the knowledge gained and use it to directly improve patient care. Although metastatic and relapsed disease remain poorly understood, much has changed in how we define medulloblastoma, and it has become evident that with conventional therapies, specific groups of patients are currently under- or overtreated. In this review, we summarize the latest insights into medulloblastoma biology, focusing on how genomics is affecting patient stratification, informing preclinical studies of targeted therapies, and shaping the new generation of clinical trials.
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http://dx.doi.org/10.1146/annurev-genom-091416-035434DOI Listing
August 2017

Profound clinical and radiological response to BRAF inhibition in a 2-month-old diencephalic child with hypothalamic/chiasmatic glioma.

Pediatr Blood Cancer 2016 11 11;63(11):2038-41. Epub 2016 Jul 11.

Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Infants with low-grade glioma (LGG) have a poor survival. BRAFV600E mutation has been identified in pediatric LGG; however, the use of BRAF inhibitors in infants has never been reported. A 2-month-old with V600E mutant hypothalamic/chiasmatic glioma progressed on chemotherapy resulting in profound visual loss, massive ascites, and diencephalic syndrome. Initiation of dabrafenib resulted in rapid and sustained disappearance of clinical symptoms and a profound sustained cytoreduction. BRAF inhibition was safely tolerated with dramatic clinicoradiological response, suggesting early targeted therapy is a viable option in infants with LGG. A re-evaluation of current management paradigms in this population is warranted to leverage the potential benefit of upfront-targeted therapies.
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http://dx.doi.org/10.1002/pbc.26086DOI Listing
November 2016

Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study.

Cancer 2016 Apr 10;122(8):1261-9. Epub 2016 Mar 10.

Division of Hematology/Oncology, University of Toronto, Toronto, Canada.

Background: The determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown.

Methods: This study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database.

Results: At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% ± 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P < .001) and a thalamic location (P < .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P = .001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P = .012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P < .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes.

Conclusions: The course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients.
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http://dx.doi.org/10.1002/cncr.29907DOI Listing
April 2016

The Changing Landscape of Pediatric Low-Grade Gliomas: Clinical Challenges and Emerging Therapies.

Neuropediatrics 2016 Apr 14;47(2):70-83. Epub 2016 Jan 14.

Division of Oncology, University Children's Hospital of Zurich, Zurich, Switzerland.

Pediatric low-grade gliomas (PLGGs) are the most common brain tumors in children. Though histologically benign and associated with excellent outcome, patients with unresectable lesions--mostly young children with midline tumors--experience multiple progressions and are at increased risk for long-term neurological sequelae. PLGGs in children with underlying genetic predisposition syndromes--especially neurofibromatosis type 1 and tuberous sclerosis--have a distinct natural history and biology with important treatment implications. Given the complexity of medical issues, optimal management requires a large network of health care providers; treatment decisions must address both tumor control and potential side effects of the therapy. Current treatment strategies often fail to induce sustained tumor regression and many children require several lines of therapy, highlighting the need for novel therapies. Here, we review the current management of PLGG and discuss how new molecular targets--in particular alterations of the Ras/MAPK pathway--are rapidly changing our approach to PLGG.
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http://dx.doi.org/10.1055/s-0035-1570491DOI Listing
April 2016

BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma.

J Clin Oncol 2015 Mar 9;33(9):1015-22. Epub 2015 Feb 9.

Matthew Mistry, Nataliya Zhukova, Daniele Merico, Rahul Krishnatry, Mary Shago, James Stavropoulos, Noa Alon, Peter N. Ray, Vilma Navickiene, Joshua Mangerel, Marc Remke, Vijay Ramaswamy, Ana Guerreiro Stucklin, Martin Li, Edwin J. Young, Cindy Zhang, Pedro Castelo-Branco, Doua Bakry, Suzanne Laughlin, James T. Rutka, Peter B. Dirks, Michael D. Taylor, Mark Greenberg, David Malkin, Annie Huang, Eric Bouffet, Cynthia E. Hawkins, and Uri Tabori; The Hospital for Sick Children; Matthew Mistry, Patricia Rakopoulos, Rahul Krishnatry, Joshua Mangerel, Pawel Buczkowicz, Ana Guerreiro Stucklin, Doua Bakry, Adam Shlien, Mark Greenberg, David Malkin, Annie Huang, Eric Bouffet, Cynthia E. Hawkins, and Uri Tabori, University of Toronto; Jason D. Pole, Pediatric Oncology Group of Ontario, Toronto, Ontario; Jennifer Chan, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; Pedro Castelo-Branco, Universidade do Algarve, Faro, Portugal; Keith L. Ligon, Dana-Farber/Boston Children's Cancer Center, Boston, MA.

Purpose: To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG).

Patients And Methods: We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained.

Results: sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P < .001 and P < .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024).

Conclusion: BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG.
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http://dx.doi.org/10.1200/JCO.2014.58.3922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356711PMC
March 2015
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