Publications by authors named "Karen D Wright"

34 Publications

Outcomes after first relapse of childhood intracranial ependymoma.

Pediatr Blood Cancer 2021 Feb 9:e28930. Epub 2021 Feb 9.

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

Background: Ependymoma is the third most common malignant CNS tumor in children. Despite multimodal therapy, prognosis of relapsed ependymoma remains poor. Approaches to therapy for relapsed ependymoma are varied. We present a single-institution retrospective review of the outcomes after first relapse of intracranial ependymoma in children.

Procedure: We performed a retrospective, IRB-approved chart review of patients with recurrent intracranial ependymoma treated at Dana-Farber/Boston Children's Cancer and Blood Disorders Center from 1990 to 2019.

Results: Thirty-four patients with relapsed intracranial ependymoma were identified. At initial diagnosis, 11 patients had supratentorial disease, 22 with posterior fossa disease and one with metastatic disease. Median time-to-first relapse was 14.9 months from initial diagnosis (range 1.4-52.5). Seven patients had metastatic disease at first relapse. Gross total resection (GTR) was associated with improved 5-year progression-free survival (PFS) relative to subtotal resection (STR) and no surgery (p = .005). Localized disease at relapse was associated with improved 5-year overall survival (OS) when compared to metastatic disease (p = .02). Irradiation at first relapse seemed to delay progression but was not associated with statistically prolonged PFS or OS. Tumor location, histology, and chromosomal 1q status did not impact outcome at first relapse, although available molecular data were limited making definitive conclusions difficult. Median time-to-second relapse was 10 months (range 0.7-124). Five-year PFS and OS after first relapse were 19.9% and 45.1%, respectively. Median PFS and OS were 10.0 and 52.5 months after first relapse, respectively.

Conclusions: Relapsed intracranial ependymoma has a poor prognosis despite multimodal therapy. Novel therapeutic strategies are desperately needed for this disease.
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http://dx.doi.org/10.1002/pbc.28930DOI Listing
February 2021

A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma.

Pediatr Blood Cancer 2021 Feb 2;68(2):e28787. Epub 2020 Nov 2.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, 450 Brookline Avenue, Boston, Massachusetts, 02215, USA.

Background: To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG).

Methods: Everolimus was administered at 5 mg/m once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients.

Results: Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression.

Conclusion: Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.
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http://dx.doi.org/10.1002/pbc.28787DOI Listing
February 2021

Increasing value of autopsies in patients with brain tumors in the molecular era.

J Neurooncol 2019 Nov 30;145(2):349-355. Epub 2019 Sep 30.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, USA.

Background: Pediatric brain tumors are associated with high morbidity and mortality, in part due to insufficient understanding of tumor biology. With limited tissue allocation for research from surgical specimens, a key barrier to improving biological understanding, brain tumor autopsies have become an increasingly valuable resource. This study reviews the brain tumor autopsy practice at our institution and describes specific emerging research utilization patterns beyond the clinical autopsy report.

Methods: We performed a retrospective analysis of brain tumor autopsies at Boston Children's Hospital (BCH) between 2007 and 2017 and reviewed their consents, neuropathology reports and final diagnoses. We reviewed the method of tissue triaging for research consented autopsies (bioregistry, frozen and fresh tissue) and documented their specific uses.

Results: Ninety-six deaths at BCH were due to brain tumors; 56 autopsies were performed (58.3%), of which 49 (87.5%) were consented for research. Tumor mapping was performed on all cases and tissue was allocated for DNA- and RNA-based sequencing studies (published and ongoing). Three tissue allocations with a postmortem interval of 8 h or less resulted in successful cell lines. Tissue from 14 autopsies was contributed to the National DIPG Registry.

Conclusion: Our institutional pediatric brain tumor autopsy clinical experience demonstrates the increased utility and wide utilization of autopsy-derived tissue for multiple types of research. These results support the increased efforts to obtain research consent for brain tumor autopsy and active collection of unfixed autopsy material in the molecular era.
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http://dx.doi.org/10.1007/s11060-019-03302-zDOI Listing
November 2019

Revisiting the Role of Radiation Therapy for Pediatric Low-Grade Glioma.

J Clin Oncol 2019 12 9;37(35):3335-3339. Epub 2019 Sep 9.

Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA.

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http://dx.doi.org/10.1200/JCO.19.01270DOI Listing
December 2019

Cutaneous reactions to targeted therapies in children with CNS tumors: A cross-sectional study.

Pediatr Blood Cancer 2019 06 28;66(6):e27682. Epub 2019 Feb 28.

Dermatology Program, Boston Children's Hospital, Boston, Massachusetts.

Background: MAPK (RAS-RAF-MEK-ERK-MAP) and mTOR inhibitors are novel treatments for pediatric central nervous system (CNS) tumors. The literature on common cutaneous adverse reactions to these therapies is sparse in the pediatric population. The aim of this study was to describe common cutaneous adverse reactions to BRAF, MEK, and mTOR inhibitors in children with CNS tumors.

Methods: In this cross-sectional study, patients younger than 21 years of age receiving BRAF, MEK, and mTOR inhibitor monotherapy for a CNS tumor were enrolled over a one-year period. Full body skin examination, photographs of dermatologic findings, and initial treatment recommendations were included at the initial visit, and follow-up skin examinations were recommended every three months.

Results: Twenty-two patients were enrolled in the study. Fifty percent (11/22) received trametinib, a MEK inhibitor, 27.3% (6/22) received dabrafenib, a BRAF inhibitor, and 22.7% (5/22) received everolimus, an mTOR inhibitor. Median age at visit was 11 years (range, 3-19). Median time from treatment initiation to skin examination was 4.5 months (range, 0-43). Ninety-six percent (21/22) of all patients had at least one skin reaction. The most common reactions across treatment groups included follicular/acneiform eruptions and xerosis. Two patients on MEK inhibitors and one patient on a BRAF inhibitor required therapy cessation due to severe cutaneous reactions.

Conclusions: Cutaneous reactions to targeted anticancer therapy in children are common, treatable, and rarely require drug dose reduction or discontinuation. Routine surveillance and early intervention may improve quality of life and facilitate continuation of life-saving therapy.
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http://dx.doi.org/10.1002/pbc.27682DOI Listing
June 2019

Anaplastic Astrocytoma in a Child With Coffin-Siris Syndrome and a Germline SMARCE1 Mutation: A Case Report.

J Pediatr Hematol Oncol 2020 04;42(3):e177-e180

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

Coffin-Siris syndrome (CSS) is a rare congenital disorder with variable clinical phenotype consisting of developmental delay and characteristic facial features. It is caused by mutations in the chromatin remodeling switch/sucrose nonfermenting complex. Although SWI/SNF genes are widely implicated in tumorigenesis, only 8 cases of neoplasm have been reported in patients with CSS. We report a case of anaplastic astrocytoma (WHO grade III) in an 18-month-old child with CSS due to a de novo germline missense SMARCE1 mutation. Additional molecular features of the tumor are described as well. The role of missense SMARCE1 mutations in tumor predisposition in children with CSS should be further investigated to better inform genetic counselling.
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http://dx.doi.org/10.1097/MPH.0000000000001361DOI Listing
April 2020

Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma.

Neuro Oncol 2018 10;20(11):1547-1555

Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets.

Methods: Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG. Surgical biopsies were performed after enrollment and prior to definitive treatment. All subjects were treated with conventional external beam radiotherapy with bevacizumab, and then stratified to receive bevacizumab with erlotinib or temozolomide, both agents, or neither agent, based on O6-methylguanine-DNA methyltransferase status and epidermal growth factor receptor expression. Whole-genome sequencing and RNA sequencing were performed but not used for treatment assignment.

Results: Fifty-three patients were enrolled at 23 institutions, and 50 underwent biopsy. The median age was 6.4 years, with 24 male and 29 female subjects. Surgical biopsies were performed with a specified technique and no deaths were attributed to the procedure. Two subjects experienced grade 3 toxicities during the procedure (apnea, n = 1; hypertension, n = 1). One subject experienced a neurologic deficit (left hemiparesis) that did not fully recover. Of the 50 tumors biopsied, 46 provided sufficient tissue to perform the study assays (92%, two-stage exact binomial 90% CI: 83%-97%).

Conclusions: Surgical biopsy of DIPGs is technically feasible, associated with acceptable risks, and can provide biologic data that can inform treatment decisions.
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http://dx.doi.org/10.1093/neuonc/noy070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176802PMC
October 2018

Establishing a Preclinical Multidisciplinary Board for Brain Tumors.

Clin Cancer Res 2018 04 4;24(7):1654-1666. Epub 2018 Jan 4.

Cancer Research UK Cambridge Institute and Department of Oncology, University of Cambridge, Cambridge, England, United Kingdom.

Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials. A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC). Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic, and efficacy studies were used to triage active compounds for combination preclinical trials with "standard-of-care" surgery and radiotherapy. Mouse models displayed distinct patterns of response to surgery, irradiation, and chemotherapy that varied with tumor subtype. Repurposing screens identified 3-hour infusions of gemcitabine as a relatively nontoxic and efficacious treatment of SEP and CPC. Combination neurosurgery, fractionated irradiation, and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP. We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing. Postirradiation gemcitabine infusion should be tested as new treatments of SEP and CPC. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884708PMC
April 2018

Irreversible growth plate fusions in children with medulloblastoma treated with a targeted hedgehog pathway inhibitor.

Oncotarget 2017 Sep 1;8(41):69295-69302. Epub 2017 Sep 1.

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

The permanent defects in bone growth observed in preclinical studies of hedgehog (Hh) pathway inhibitors were not substantiated in early phase clinical studies of vismodegib in children. Consequently, vismodegib advanced into pediatric trials for malignancies suspected of being driven by aberrant activation of the Hh pathway. In one multicenter phase II trial, vismodegib was added to the therapy regimen for newly diagnosed Hh pathway activated medulloblastoma. Herein, we report on 3 children (2 on trial and one off trial) treated with vismodegib who developed widespread growth plate fusions that persist long after cessation of therapy. Currently, all 3 patients exhibit profound short stature and disproportionate growth, and 2 subsequently developed precocious puberty. Notably, the growth plate fusions only developed after a prolonged exposure to the drug (> 140 days). These findings resulted in a major trial amendment to restrict the agent to skeletally mature patients as well as a product label warning and update. Moreover, these findings alter the risk-benefit ratio of Hh inhibitors and underscore the importance of careful study of targeted agents in children.
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http://dx.doi.org/10.18632/oncotarget.20619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642479PMC
September 2017

Rethinking childhood ependymoma: a retrospective, multi-center analysis reveals poor long-term overall survival.

J Neurooncol 2017 Oct 21;135(1):201-211. Epub 2017 Jul 21.

Pediatric Neuro-Oncology Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute and Boston Children's Hospital and Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA.

Ependymoma is the third most common brain tumor in children, but there is a paucity of large studies with more than 10 years of follow-up examining the long-term survival and recurrence patterns of this disease. We conducted a retrospective chart review of 103 pediatric patients with WHO Grades II/III intracranial ependymoma, who were treated at Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Chicago's Ann & Robert H. Lurie Children's Hospital between 1985 and 2008, and an additional 360 ependymoma patients identified from the Surveillance Epidemiology and End Results (SEER) database. For the institutional cohort, we evaluated clinical and histopathological prognostic factors of overall survival (OS) and progression-free survival (PFS) using the log-rank test, and univariate and multivariate Cox proportional-hazards models. Overall survival rates were compared to those of the SEER cohort. Median follow-up time was 11 years. Ten-year OS and PFS were 50 ± 5% and 29 ± 5%, respectively. Findings were validated in the independent SEER cohort, with 10-year OS rates of 52 ± 3%. GTR and grade II pathology were associated with significantly improved OS. However, GTR was not curative for all children. Ten-year OS for patients treated with a GTR was 61 ± 7% and PFS was 36 ± 6%. Pathological examination confirmed most recurrent tumors to be ependymoma, and 74% occurred at the primary tumor site. Current treatment paradigms are not sufficient to provide long-term cure for children with ependymoma. Our findings highlight the urgent need to develop novel treatment approaches for this devastating disease.
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http://dx.doi.org/10.1007/s11060-017-2568-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658456PMC
October 2017

Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors.

Neuro Oncol 2017 Jul;19(7):986-996

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Department of Pathology, Department of Radiology, Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts; Department of Medical Oncology, Oncologic Pathology, Department of Pediatric Oncology, Department of Cancer Biology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Pathology, Department of Neurosurgery, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Pratiti Bandopadhayay, Broad Institute of MIT and Harvard, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.

Background: Clinical genomics platforms are needed to identify targetable alterations, but implementation of these technologies and best practices in routine clinical pediatric oncology practice are not yet well established.

Methods: Profile is an institution-wide prospective clinical research initiative that uses targeted sequencing to identify targetable alterations in tumors. OncoPanel, a multiplexed targeted exome-sequencing platform that includes 300 cancer-causing genes, was used to assess single nucleotide variants and rearrangements/indels. Alterations were annotated (Tiers 1-4) based on clinical significance, with Tier 1 alterations having well-established clinical utility. OncoCopy, a clinical genome-wide array comparative genomic hybridization (aCGH) assay, was also performed to evaluate copy number alterations and better define rearrangement breakpoints.

Results: Cancer genomes of 203 pediatric brain tumors were profiled across histological subtypes, including 117 samples analyzed by OncoPanel, 146 by OncoCopy, and 60 tumors subjected to both methodologies. OncoPanel revealed clinically relevant alterations in 56% of patients (44 cancer mutations and 20 rearrangements), including BRAF alterations that directed the use of targeted inhibitors. Rearrangements in MYB-QKI, MYBL1, BRAF, and FGFR1 were also detected. Furthermore, while copy number profiles differed across histologies, the combined use of OncoPanel and OncoCopy identified subgroup-specific alterations in 89% (17/19) of medulloblastomas.

Conclusion: The combination of OncoPanel and OncoCopy multiplex genomic assays can identify critical diagnostic, prognostic, and treatment-relevant alterations and represents an effective precision medicine approach for clinical evaluation of pediatric brain tumors.
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http://dx.doi.org/10.1093/neuonc/now294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570190PMC
July 2017

The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants.

Acta Neuropathol 2017 01 17;133(1):5-12. Epub 2016 Nov 17.

Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.

Multiple independent genomic profiling efforts have recently identified clinically and molecularly distinct subgroups of ependymoma arising from all three anatomic compartments of the central nervous system (supratentorial brain, posterior fossa, and spinal cord). These advances motivated a consensus meeting to discuss: (1) the utility of current histologic grading criteria, (2) the integration of molecular-based stratification schemes in future clinical trials for patients with ependymoma and (3) current therapy in the context of molecular subgroups. Discussion at the meeting generated a series of consensus statements and recommendations from the attendees, which comment on the prognostic evaluation and treatment decisions of patients with intracranial ependymoma (WHO Grade II/III) based on the knowledge of its molecular subgroups. The major consensus among attendees was reached that treatment decisions for ependymoma (outside of clinical trials) should not be based on grading (II vs III). Supratentorial and posterior fossa ependymomas are distinct diseases, although the impact on therapy is still evolving. Molecular subgrouping should be part of all clinical trials henceforth.
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http://dx.doi.org/10.1007/s00401-016-1643-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209402PMC
January 2017

Vismodegib and Physeal Closure in a Pediatric Patient.

Pediatr Blood Cancer 2016 11 10;63(11):2058. Epub 2016 Feb 10.

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

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http://dx.doi.org/10.1002/pbc.25941DOI Listing
November 2016

A 2-Year-Old Girl with Dysmetria and Ataxia.

Brain Pathol 2016 Jan;26(1):126-7

Departments of Oncology, St. Jude Children's Research Hospital, Memphis, TN.

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http://dx.doi.org/10.1111/bpa.12341DOI Listing
January 2016

Phase I study of 5-fluorouracil in children and young adults with recurrent ependymoma.

Neuro Oncol 2015 Dec 4;17(12):1620-7. Epub 2015 Nov 4.

Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.D.W., R.J.G., A.G.); Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (V.M.D., D.C.T., C.F.S); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (A.O.-T.); Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee (N.B., R.J.G.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (B.A.O.).

Background: We report a phase I study to examine the pharmacokinetics, safety, and recommended dosage of weekly intravenous bolus 5-fluorouracil (5-FU) in children and young adults with recurrent ependymoma.

Methods: Patients 22 years of age or less with recurrent ependymoma were treated with bolus dosage 5-FU weekly for 4 weeks followed by a 2-week rest period, defining one cycle. Patients could continue on therapy for 16 cycles. The starting 5-FU dosage was 500 mg/m(2). Dose-limiting toxicity was determined after one cycle. Patients were initially enrolled according to a rolling-6 design; subsequent dose re-escalation phase was based on a 3 + 3 design.

Results: We treated patients at 400 (n = 6), 500 (n = 15), and 650 (n = 5) mg/m(2), with de-escalation due to toxicity. Twenty-three of twenty-six patients enrolled were evaluable. Five patients experienced grade 4 neutropenia (n = 2: 650 mg/m(2); n = 3: 500 mg/m(2)). One patient experienced grade 3 diarrhea. At 500 mg/m(2), the median 5-FU maximal concentration, AUC0-∞, and alpha half-life were 825 µM, 205 µM × h, and 9.9 min, respectively. Interim analysis revealed an association between hematologic toxicity and prior number of chemotherapeutic regimens (P = .03). The study was amended to re-escalate the dosage in a less heavily pretreated cohort of patients.

Conclusions: These phase I clinical data provide initial pharmacokinetic parameters to describe i.v. bolus 5-FU disposition in children with recurrent ependymoma. Tumor exposures effective in preclinical testing can be achieved with tolerable bolus dosages in patients. Bolus 5-FU is well tolerated and possesses antitumor activity.
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http://dx.doi.org/10.1093/neuonc/nov181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633933PMC
December 2015

Response to: comment on "Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections".

Cancer Chemother Pharmacol 2015 Apr 26;75(4):877-8. Epub 2015 Feb 26.

Division of Neuro-oncology, Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 260, Memphis, TN, 38105, USA,

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http://dx.doi.org/10.1007/s00280-015-2699-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401467PMC
April 2015

Pubertal development and primary ovarian insufficiency in female survivors of embryonal brain tumors following risk-adapted craniospinal irradiation and adjuvant chemotherapy.

Pediatr Blood Cancer 2015 02 18;62(2):329-334. Epub 2014 Oct 18.

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

Background: Female survivors of central nervous system (CNS) tumors are at an increased risk for gonadal damage and variations in the timing of puberty following radiotherapy and alkylating agent-based chemotherapy.

Procedure: Clinical and laboratory data were obtained from 30 evaluable female patients with newly diagnosed embryonal CNS tumors treated on a prospective protocol (SJMB 96) at St. Jude Children's Research Hospital (SJCRH). Pubertal development was evaluated by Tanner staging. Primary ovarian insufficiency (POI) was determined by Tanner staging and FSH level. Females with Tanner stage I-II and FSH > 15 mIU/ml, or Tanner stage III-V, FSH > 25 mIU/ml and FSH greater than LH were defined to have ovarian insufficiency. Recovery of ovarian function was defined as normalization of FSH without therapeutic intervention.

Results: Median length of follow-up post completion of therapy was 7.2 years (4.0-10.8 years). The cumulative incidence of pubertal onset was 75.6% by the age of 13. Precocious puberty was observed in 11.1% and delayed puberty in 11.8%. The cumulative incidence of POI was 82.8%, though recovery was observed in 38.5%.

Conclusions: Treatment for primary CNS embryonal tumors may cause variations in the timing of pubertal development, impacting physical and psychosocial development. Female survivors are at risk for POI, a subset of whom will recover function over time. Further refinement of therapies is needed in order to reduce late ovarian insufficiency. Pediatr Blood Cancer 2015;62:329-334. © 2014 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/pbc.25274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402092PMC
February 2015

Incidental diagnosis of diffuse intrinsic pontine glioma in children.

Pediatr Blood Cancer 2015 Jun 16;62(6):1081-3. Epub 2015 Jan 16.

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

Children with diffuse intrinsic pontine glioma (DIPG) have a short onset, rapidly progressive neurologic decline before diagnosis. Therefore, incidental diagnosis of such an aggressive cancer is counterintuitive, yet our experience shows DIPG may occur as part of a spectrum of incidentally diagnosed pediatric brain cancers. Although children with incidentally diagnosed DIPG may experience a longer survival, it remains a potentially deadly cancer despite treatment with radiotherapy. Histologic confirmation is warranted when feasible in such patients to confirm diagnosis. Moreover, recent advances in genome-wide analyses may suggest incidentally diagnosed DIPGs are biologically distinct from the majority of these cancers.
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http://dx.doi.org/10.1002/pbc.25408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405458PMC
June 2015

Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections.

Cancer Chemother Pharmacol 2015 Jan 24;75(1):27-35. Epub 2014 Oct 24.

Division of Neuro-oncology, Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 260, Memphis, TN, 38105, USA,

Purpose: High-dose methotrexate (HD-MTX) has been used to treat children with central nervous system tumors. Accumulation of MTX within pleural, peritoneal, or cardiac effusions has led to delayed excretion and increased risk of systemic toxicity. This retrospective study analyzed the association of intracranial post-resection fluid collections with MTX plasma disposition in infants and young children with brain tumors.

Methods: Brain MRI findings were analyzed for postoperative intracranial fluid collections in 75 pediatric patients treated with HD-MTX and for whom serial MTX plasma concentrations (MTX) were collected. Delayed plasma excretion was defined as (MTX) ≥1 μM at 42 hours (h). Leucovorin was administered at 42 h and then every 6 h until (MTX) <0.1 μM. Population and individual MTX pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling.

Results: Fifty-eight patients had intracranial fluid collections present. Population average (inter-individual variation) MTX clearance was 96.0 ml/min/m² (41.1 CV %) and increased with age. Of the patients with intracranial fluid collections, 24 had delayed excretion; only 2 of the 17 without fluid collections (P < 0.04) had delayed excretion. Eleven patients had grade 3 or 4 toxicities attributed to HD-MTX. No significant difference was observed in intracranial fluid collection, total leucovorin dosing, or hydration fluids between those with and without toxicity.

Conclusions: Although an intracranial fluid collection is associated with delayed MTX excretion, HD-MTX can be safely administered with monitoring of infants and young children with intracranial fluid collections. Infants younger than 1 year may need additional monitoring to avoid toxicity.
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http://dx.doi.org/10.1007/s00280-014-2614-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282603PMC
January 2015

Successful treatment of pediatric plasmacytoid dendritic cell tumors with a contemporary regimen for acute lymphoblastic leukemia.

Pediatr Blood Cancer 2013 Jul 15;60(7):E38-41. Epub 2013 Feb 15.

Department of Oncology, St. Jude Children's Research Hospital, University of Tennessee College of Medicine, Memphis, Tennessee 38105, USA.

Dendritic cell leukemia (DCL) or hematodermic tumor is an uncommon subtype of acute leukemia. In contrast to adult cases, children tend to have a less aggressive course. The diagnosis of DCL should be considered when its characteristic morphologic features are present and leukemic cells co-express CD4 and CD56. Cases of DCL among pediatric patients have been reported to respond to therapeutic regimens for acute lymphoblastic leukemia, but details regarding the specifics of therapy are lacking.
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http://dx.doi.org/10.1002/pbc.24483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146405PMC
July 2013

Current treatment options for pediatric and adult patients with ependymoma.

Curr Treat Options Oncol 2012 Dec;13(4):465-77

Division of Neuro-oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place - Mailstop 260, Memphis, TN, 38105, USA.

Opinion Statement: Survival rates for patients with ependymoma, a glial tumor arising from the ependymal cells lining the ventricles of the brain and spinal cord canal, have changed little during the past decade. Contemporary "standard" therapy for children and adults with ependymoma consists of maximal surgical resection followed by focal irradiation except in cases of disseminated disease. Despite refinements in radiotherapy techniques and improvements in survival for patients with gross totally resected, nonanaplastic disease, many therapeutic challenges remain, especially for patients with unresectable, macroscopic, metastatic, or anaplastic disease. Moreover, radiotherapy to the developing central nervous system, especially in patients younger than age 5 years, can have potential long-term neurocognitive and neuroendocrine sequelae. Chemotherapy has not played a role in most treatment regimens for ependymoma to date, but due to the ongoing therapeutic challenges for a subset of patients, this modality is being reinvestigated in a few ongoing studies. Early recognition of patients who will not respond to primary therapy is imperative to modify treatment regimens, such as intensification with the addition of adjuvant chemotherapy, the use of novel experimental therapies, or their combination. Refinements in patient stratification schemes that are based on a combination of clinical variables and molecular profiles also require improved knowledge of tumor biology. Several molecular alterations have been identified already, some of which may be of prognostic significance. Furthermore, disruption of molecular alterations in signaling pathways involved in the development and maintenance of ependymoma by using novel molecularly targeted therapies may improve outcomes and reduce toxicity for patients with ependymoma.
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http://dx.doi.org/10.1007/s11864-012-0205-5DOI Listing
December 2012

Necrosis after craniospinal irradiation: results from a prospective series of children with central nervous system embryonal tumors.

Int J Radiat Oncol Biol Phys 2012 Aug;83(5):e655-60

Cleveland Clinic, Cleveland, OH, USA.

Purpose: Necrosis of the central nervous system (CNS) is a known complication of craniospinal irradiation (CSI) in children with medulloblastoma and similar tumors. We reviewed the incidence of necrosis in our prospective treatment series.

Patients And Methods: Between 1996 and 2009, 236 children with medulloblastoma (n = 185) or other CNS embryonal tumors (n = 51) received postoperative CSI followed by dose-intense cyclophosphamide, vincristine, and cisplatin. Average risk cases (n = 148) received 23.4 Gy CSI, 36 Gy to the posterior fossa, and 55.8 Gy to the primary; after 2003, the treatment was 23.4 Gy CSI and 55.8 Gy to the primary. All high-risk cases (n = 88) received 36-39.6 Gy CSI and 55.8 Gy primary. The primary site clinical target volume margin was 2 cm (pre-2003) or 1 cm (post-2003). With competing risk of death by any cause, we determined the cumulative incidence of necrosis.

Results: With a median follow-up of 52 months (range, 4-163 months), eight cases of necrosis were documented. One death was attributed. The median time to the imaging evidence was 4.8 months and to symptoms 6.0 months. The cumulative incidence at 5 years was 3.7% ± 1.3% (n = 236) for the entire cohort and 4.4% ± 1.5% (n = 196) for infratentorial tumor location. The mean relative volume of infratentorial brain receiving high-dose irradiation was significantly greater for patients with necrosis than for those without: ≥ 50 Gy (92.12% ± 4.58% vs 72.89% ± 1.96%; P=.0337), ≥ 52 Gy (88.95% ± 5.50% vs 69.16% ± 1.97%; P=.0275), and ≥ 54 Gy (82.28% ± 7.06% vs 63.37% ± 1.96%; P=.0488), respectively.

Conclusions: Necrosis in patients with CNS embryonal tumors is uncommon. When competing risks are considered, the incidence is 3.7% at 5 years. The volume of infratentorial brain receiving greater than 50, 52, and 54 Gy, respectively, is predictive for necrosis.
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http://dx.doi.org/10.1016/j.ijrobp.2012.01.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529413PMC
August 2012

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

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

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

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

Isochromosome 17q, MYC amplification and large cell/anaplastic phenotype in a case of medullomyoblastoma with extracranial metastases.

Pediatr Blood Cancer 2012 Sep 6;59(3):561-4. Epub 2011 Dec 6.

Department of Oncology, Division of Neuro-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, USA.

Medullomyoblastoma (MMB) is a rare variant of medulloblastoma, a member of the family of central nervous system (CNS) embryonal tumors. The outcome of standard therapy for CNS embryonal tumors is often unpredictable in the setting of MMB. Here, we present the clinical course and treatment of an almost 4-year-old girl with MMB that was characterized by MYC amplification, isochromosome 17q and large cell/anaplastic histopathology.
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http://dx.doi.org/10.1002/pbc.24002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392450PMC
September 2012

A procedure to statistically evaluate agreement of differential expression for cross-species genomics.

Bioinformatics 2011 Aug 22;27(15):2098-103. Epub 2011 Jun 22.

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

Motivation: Animal models play a pivotal role in translation biomedical research. The scientific value of an animal model depends on how accurately it mimics the human disease. In principle, microarrays collect the necessary data to evaluate the transcriptomic fidelity of an animal model in terms of the similarity of expression with the human disease. However, statistical methods for this purpose are lacking.

Results: We develop the agreement of differential expression (AGDEX) procedure to measure and determine the statistical significance of the similarity of the results of two experiments that measure differential expression across two groups. AGDEX defines a metric of agreement and determines statistical significance by permutation of each experiment's group labels. Additionally, AGDEX performs a comprehensive permutation-based analysis of differential expression for each experiment, including gene-set analyses and meta-analytic integration of results across studies. As an example, we show how AGDEX was recently used to evaluate the similarity of the transcriptome of a novel model of the brain tumor ependymoma in mice to that of a subtype of the human disease. This result, combined with other observations, helped us to infer the cell of origin of this devastating human cancer.

Availability: An R package is currently available from www.stjuderesearch.org/site/depts/biostats/agdex and will shortly be available from www.bioconductor.org.
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http://dx.doi.org/10.1093/bioinformatics/btr362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137228PMC
August 2011

Sequencing of local therapy affects the pattern of treatment failure and survival in children with atypical teratoid rhabdoid tumors of the central nervous system.

Int J Radiat Oncol Biol Phys 2012 Apr 19;82(5):1756-63. Epub 2011 May 19.

Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Purpose: To assess the pattern of treatment failure associated with current therapeutic paradigms for childhood atypical teratoid rhabdoid tumors (AT/RT).

Methods And Materials: Pediatric patients with AT/RT of the central nervous system treated at our institution between 1987 and 2007 were retrospectively evaluated. Overall survival (OS), progression-free survival, and cumulative incidence of local failure were correlated with age, sex, tumor location, extent of disease, and extent of surgical resection. Radiotherapy (RT) sequencing, chemotherapy, dose, timing, and volume administered after resection were also evaluated.

Results: Thirty-one patients at a median age of 2.3 years at diagnosis (range, 0.45-16.87 years) were enrolled into protocols that included risk- and age-stratified RT. Craniospinal irradiation with focal tumor bed boost (median dose, 54 Gy) was administered to 18 patients. Gross total resection was achieved in 16. Ten patients presented with metastases at diagnosis. RT was delayed more than 3 months in 20 patients and between 1 and 3 months in 4; 7 patients received immediate postoperative irradiation preceding high-dose alkylator-based chemotherapy. At a median follow-up of 48 months, the cumulative incidence of local treatment failure was 37.5% ± 9%; progression-free survival was 33.2% ± 10%; and OS was 53.5% ± 10%. Children receiving delayed RT (≥1 month postoperatively) were more likely to experience local failure (hazard ratio [HR] 1.23, p = 0.007); the development of distant metastases before RT increased the risk of progression (HR 3.49, p = 0.006); and any evidence of disease progressionbefore RT decreased OS (HR 20.78, p = 0.004). Disease progression occurred in 52% (11/21) of children with initially localized tumors who underwent gross total resection, and the progression rate increased proportionally with increasing delay from surgery to RT.

Conclusions: Delayed RT is associated with a higher rate of local and metastatic disease progression in children with AT/RT. Current treatment regimens for pediatric patients with AT/RT are distinctly age stratified; novel protocols investigating RT volumes and sequencing are needed.
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http://dx.doi.org/10.1016/j.ijrobp.2011.02.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530399PMC
April 2012

Successful treatment of early detected trilateral retinoblastoma using standard infant brain tumor therapy.

Pediatr Blood Cancer 2010 Sep;55(3):570-2

Department of Oncology, Division of Neuro-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, USA.

Trilateral retinoblastoma is characterized by the presence of retinoblastoma with an intracranial tumor. The incidence is low and prognosis poor. Due to the paucity of information regarding successful treatment, we report the case of a 6 month old female referred for leukocoria and found to have an associated suprasellar tumor and pineal enhancement. The patient, treated with standard infant brain tumor therapy, remains alive without signs of active disease 35 months after diagnosis; no surgery or irradiation was used. Early diagnosis of trilateral retinoblastoma may facilitate the use of less intensive therapeutic approaches and result in excellent outcomes in these patients.
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http://dx.doi.org/10.1002/pbc.22545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115715PMC
September 2010

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

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

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

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

To infinium, and beyond!

Cancer Cell 2010 May;17(5):419-20

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

Glioblastoma (GBM) is a malignant brain tumor that kills most patients within 2 years. In this issue of Cancer Cell, Noushmehr et al., through The Cancer Genome Atlas (TCGA) project, provide one of the first integrated views of the GBM methylome, adding to our increasingly comprehensive understanding of this disease.
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http://dx.doi.org/10.1016/j.ccr.2010.04.020DOI Listing
May 2010