Publications by authors named "Lindsay Kilburn"

27 Publications

  • Page 1 of 1

A Phase 2 Trial of Selumetinib in Children with Recurrent Optic Pathway and Hypothalamic Low-Grade Glioma without NF1: A Pediatric Brain Tumor Consortium Study.

Neuro Oncol 2021 Feb 25. Epub 2021 Feb 25.

Department of Radiology (JYJ) and Department of Hematology and Oncology (MF). Nationwide Children's Hospital, Columbus, OH.

Background: Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for alternative treatments. Sporadic (without neurofibromatosis type-1) optic pathway and hypothalamic glioma (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes.

Methods: We present results from children with recurrent/progressive OPHGs treated on a PBTC phase 2 trial evaluating efficacy of selumetinib, (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase 2 dose (25mg/m 2 /dose BID) for a maximum of 26 courses.

Results: Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%) and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia and rash.

Conclusions: Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS and visual outcomes.
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http://dx.doi.org/10.1093/neuonc/noab047DOI Listing
February 2021

Robust deep learning classification of adamantinomatous craniopharyngioma from limited preoperative radiographic images.

Sci Rep 2020 10 9;10(1):16885. Epub 2020 Oct 9.

Division of Pediatric Neurosurgery, Children's Hospital Colorado, Aurora, 80045, USA.

Deep learning (DL) is a widely applied mathematical modeling technique. Classically, DL models utilize large volumes of training data, which are not available in many healthcare contexts. For patients with brain tumors, non-invasive diagnosis would represent a substantial clinical advance, potentially sparing patients from the risks associated with surgical intervention on the brain. Such an approach will depend upon highly accurate models built using the limited datasets that are available. Herein, we present a novel genetic algorithm (GA) that identifies optimal architecture parameters using feature embeddings from state-of-the-art image classification networks to identify the pediatric brain tumor, adamantinomatous craniopharyngioma (ACP). We optimized classification models for preoperative Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and combined CT and MRI datasets with demonstrated test accuracies of 85.3%, 83.3%, and 87.8%, respectively. Notably, our GA improved baseline model performance by up to 38%. This work advances DL and its applications within healthcare by identifying optimized networks in small-scale data contexts. The proposed system is easily implementable and scalable for non-invasive computer-aided diagnosis, even for uncommon diseases.
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http://dx.doi.org/10.1038/s41598-020-73278-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547020PMC
October 2020

Harmonization of postmortem donations for pediatric brain tumors and molecular characterization of diffuse midline gliomas.

Sci Rep 2020 07 2;10(1):10954. Epub 2020 Jul 2.

Center for Genetic Medicine Research, Children's National Hospital, Washington, DC, USA.

Children diagnosed with brain tumors have the lowest overall survival of all pediatric cancers. Recent molecular studies have resulted in the discovery of recurrent driver mutations in many pediatric brain tumors. However, despite these molecular advances, the clinical outcomes of high grade tumors, including H3K27M diffuse midline glioma (H3K27M DMG), remain poor. To address the paucity of tissue for biological studies, we have established a comprehensive protocol for the coordination and processing of donated specimens at postmortem. Since 2010, 60 postmortem pediatric brain tumor donations from 26 institutions were coordinated and collected. Patient derived xenograft models and cell cultures were successfully created (76% and 44% of attempts respectively), irrespective of postmortem processing time. Histological analysis of mid-sagittal whole brain sections revealed evidence of treatment response, immune cell infiltration and the migratory path of infiltrating H3K27M DMG cells into other midline structures and cerebral lobes. Sequencing of primary and disseminated tumors confirmed the presence of oncogenic driver mutations and their obligate partners. Our findings highlight the importance of postmortem tissue donations as an invaluable resource to accelerate research, potentially leading to improved outcomes for children with aggressive brain tumors.
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http://dx.doi.org/10.1038/s41598-020-67764-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331588PMC
July 2020

Molecular-Targeted Therapy for Childhood Brain Tumors: A Moving Target.

J Child Neurol 2020 10 18;35(12):791-798. Epub 2020 Jun 18.

Brain Tumor Institute, 8404Children's National Hospital, Washington, DC, USA.

Molecular-targeted therapy is an attractive therapeutic approach for childhood brain tumors. Unfortunately, with some notable exceptions, such treatment has not yet made a major impact on survival or for that matter quality-of-life for children with brain tumors. Limitations include the specificity of any single agent to inhibit the target, the presence of multiple genetic abnormalities within a tumor, the likely presence of escape mechanisms and the frequent use of molecular-targeted therapies in relatively biologically unselected patient populations. Despite these limitations, the MEK inhibitors and the BRAF V600E inhibitors have already demonstrated efficacy and are being compared to standard therapy in trials of treatment-naïve patients. There is also great enthusiasm for molecular-targeted therapies that target selective gene fusions. Given the plasticity of epigenetic changes, the targeting of epigenetic aberrations is also a promising avenue of therapy. Because molecular-targeted therapies frequently target genes and pathways that are critical in normal brain development, the acute, subacute long-term sequelae of molecular-targeted therapies need to be carefully monitored.
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http://dx.doi.org/10.1177/0883073820931635DOI Listing
October 2020

Phase I study of vemurafenib in children with recurrent or progressive BRAF mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002).

Oncotarget 2020 May 26;11(21):1942-1952. Epub 2020 May 26.

Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.

BRAF mutation is present in a subset of pediatric brain tumors. Vemurafenib is an oral, selective ATP-competitive inhibitor of BRAF kinase. The goal of this multi-center study conducted through the Pacific Pediatric Neuro-Oncology Consortium (PNOC) was to determine the recommended phase 2 dose (RP2D) and dose limiting toxicities (DLTs) in children < 18 years with recurrent or progressive BRAF mutant brain tumors. Nineteen eligible patients were enrolled. Eleven patients had received three or more prior therapies. Data reported are from the start of treatment for the first patient (April 30 2014) through August 31 2019. The RP2D was defined as 550 mg/m twice daily after DLT criteria adjustment for rash. Related grade ≥ 3 adverse events included secondary keratoacanthoma ( = 1); rash ( =16); and fever ( = 5). Subjects received a median of 23 cycles (range 3-63). Four patients remain on treatment. Centrally reviewed best radiographic responses included 1 complete response, 5 partial responses, and 13 stable disease. The steady-state area under the curve (AUCmedian) was 604 mg*h/L (range 329-1052). Vemurafenib was given starting at 550 mg/m, twice daily which corresponds to the adult RP2D. Adverse events were graded using the NIH Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Central imaging review was performed. Pharmacokinetic sampling was performed. Vemurafenib has promising anti-tumor activity in recurrent V600E-positive brain tumors with manageable toxicity. A phase 2 study is ongoing (NCT01748149).
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http://dx.doi.org/10.18632/oncotarget.27600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260122PMC
May 2020

Response assessment in paediatric low-grade glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Lancet Oncol 2020 06;21(6):e305-e316

Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute, Boston, MA, USA.

Paediatric low-grade gliomas (also known as pLGG) are the most common type of CNS tumours in children. In general, paediatric low-grade gliomas show clinical and biological features that are distinct from adult low-grade gliomas, and the developing paediatric brain is more susceptible to toxic late effects of the tumour and its treatment. Therefore, response assessment in children requires additional considerations compared with the adult Response Assessment in Neuro-Oncology criteria. There are no standardised response criteria in paediatric clinical trials, which makes it more difficult to compare responses across studies. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop consensus recommendations for response assessment in paediatric low-grade gliomas. Final recommendations were based on literature review, current practice, and expert opinion of working group members. Consensus recommendations include imaging response assessments, with additional guidelines for visual functional outcomes in patients with optic pathway tumours. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.
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http://dx.doi.org/10.1016/S1470-2045(20)30064-4DOI Listing
June 2020

Transcriptional analyses of adult and pediatric adamantinomatous craniopharyngioma reveals similar expression signatures regarding potential therapeutic targets.

Acta Neuropathol Commun 2020 05 13;8(1):68. Epub 2020 May 13.

Division of Pediatric Neurosurgery, Children's Hospital Colorado, Aurora, USA.

Adamantinomatous craniopharyngioma (ACP) is a biologically benign but clinically aggressive lesion that has a significant impact on quality of life. The incidence of the disease has a bimodal distribution, with peaks occurring in children and older adults. Our group previously published the results of a transcriptome analysis of pediatric ACPs that identified several genes that were consistently overexpressed relative to other pediatric brain tumors and normal tissue. We now present the results of a transcriptome analysis comparing pediatric to adult ACP to identify biological differences between these groups that may provide novel therapeutic insights or support the assertion that potential therapies identified through the study of pediatric ACP may also have a role in adult ACP. Using our compiled transcriptome dataset of 27 pediatric and 9 adult ACPs, obtained through the Advancing Treatment for Pediatric Craniopharyngioma Consortium, we interrogated potential age-related transcriptional differences using several rigorous mathematical analyses. These included: canonical differential expression analysis; divisive, agglomerative, and probabilistic based hierarchical clustering; information theory based characterizations; and the deep learning approach, HD Spot. Our work indicates that there is no therapeutically relevant difference in ACP gene expression based on age. As such, potential therapeutic targets identified in pediatric ACP are also likely to have relvance for adult patients.
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http://dx.doi.org/10.1186/s40478-020-00939-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222517PMC
May 2020

Phase II study of peginterferon alpha-2b for patients with unresectable or recurrent craniopharyngiomas: a Pediatric Brain Tumor Consortium report.

Neuro Oncol 2020 11;22(11):1696-1704

Department of Hematology and Oncology, Cincinnati Children's Hospital, Cincinnati, Ohio.

Background: Craniopharyngiomas account for approximately 1.2-4% of all CNS tumors. They are typically treated with a combination of surgical resection and focal radiotherapy. Unfortunately, treatment can lead to permanent deleterious effects on behavior, learning, and endocrine function.

Methods: The Pediatric Brain Tumor Consortium performed a multicenter phase 2 study in children and young adults with unresectable or recurrent craniopharyngioma (PBTC-039). Between December 2013 and November 2017, nineteen patients (median age at enrollment, 13.1 y; range, 2-25 y) were enrolled in one of 2 strata: patients previously treated with surgery alone (stratum 1) or who received radiation (stratum 2).

Results: Eighteen eligible patients (8 male, 10 female) were treated with weekly subcutaneous pegylated interferon alpha-2b for up to 18 courses (108 wk). Therapy was well tolerated with no grade 4 or 5 toxicities. 2 of the 7 eligible patients (28.6%) in stratum 1 had a partial response, but only one response was sustained for more than 3 months. None of the 11 stratum 2 patients had an objective radiographic response, although median progression-free survival was 19.5 months.

Conclusions: Pegylated interferon alpha-2b treatment, in lieu of or following radiotherapy, was well tolerated in children and young adults with recurrent craniopharyngiomas. Although objective responses were limited, progression-free survival results are encouraging, warranting further studies.
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http://dx.doi.org/10.1093/neuonc/noaa119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690365PMC
November 2020

Implications of new understandings of gliomas in children and adults with NF1: report of a consensus conference.

Neuro Oncol 2020 06;22(6):773-784

Department of Neurology; Washington University, St Louis, Missouri, USA.

Gliomas are the most common primary central nervous system tumors occurring in children and adults with neurofibromatosis type 1 (NF1). Over the past decade, discoveries of the molecular basis of low-grade gliomas (LGGs) have led to new approaches for diagnosis and treatments. However, these new understandings have not been fully applied to the management of NF1-associated gliomas. A consensus panel consisting of experts in NF1 and gliomas was convened to review the current molecular knowledge of NF1-associated low-grade "transformed" and high-grade gliomas; insights gained from mouse models of NF1-LGGs; challenges in diagnosing and treating older patients with NF1-associated gliomas; and advances in molecularly targeted treatment and potential immunologic treatment of these tumors. Next steps are recommended to advance the management and outcomes for NF1-associated gliomas.
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http://dx.doi.org/10.1093/neuonc/noaa036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283027PMC
June 2020

Somatic Mosaicism of IDH1 R132H Predisposes to Anaplastic Astrocytoma: A Case of Two Siblings.

Front Oncol 2019 14;9:1507. Epub 2020 Jan 14.

Center for Genetic Medicine, Children's National Health System, Washington, DC, United States.

Anaplastic astrocytomas are aggressive glial cancers that present poor prognosis and high recurrence. Heterozygous IDH1 R132H mutations are common in adolescent and young adult anaplastic astrocytomas. In a majority of cases, the IDH1 R132H mutation is unique to the tumor, although rare cases of anaplastic astrocytoma have been described in patients with mosaic IDH1 mutations (Ollier disease or Maffucci syndrome). Here, we present two siblings with IDH1 R132H mutant high grade astrocytomas diagnosed at 14 and 26 years of age. Analysis of IDH mutations in the siblings' tumors and non-neoplastic tissues, including healthy regions of the brain, cheek cells, and primary teeth indicate mosaicism of IDH. Whole exome sequencing of the tumor tissue did not reveal any other common mutations between the two siblings. This study demonstrates the first example of IDH1 R132H mosaicism, acquired during early development, that provides an alternative mechanism of cancer predisposition.
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http://dx.doi.org/10.3389/fonc.2019.01507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971203PMC
January 2020

Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial.

Lancet Oncol 2019 07 28;20(7):1011-1022. Epub 2019 May 28.

Department of Haematology and Oncology, Cincinnati Children's Hospital, Cincinnati, OH, USA.

Background: Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients.

Methods: The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAF [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101.

Findings: Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported.

Interpretation: Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1.

Funding: National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(19)30277-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628202PMC
July 2019

A pilot precision medicine trial for children with diffuse intrinsic pontine glioma-PNOC003: A report from the Pacific Pediatric Neuro-Oncology Consortium.

Int J Cancer 2019 10 3;145(7):1889-1901. Epub 2019 Apr 3.

Center for Data-Driven Discovery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

This clinical trial evaluated whether whole exome sequencing (WES) and RNA sequencing (RNAseq) of paired normal and tumor tissues could be incorporated into a personalized treatment plan for newly diagnosed patients (<25 years of age) with diffuse intrinsic pontine glioma (DIPG). Additionally, whole genome sequencing (WGS) was compared to WES to determine if WGS would further inform treatment decisions, and whether circulating tumor DNA (ctDNA) could detect the H3K27M mutation to allow assessment of therapy response. Patients were selected across three Pacific Pediatric Neuro-Oncology Consortium member institutions between September 2014 and January 2016. WES and RNAseq were performed at diagnosis and recurrence when possible in a CLIA-certified laboratory. Patient-derived cell line development was attempted for each subject. Collection of blood for ctDNA was done prior to treatment and with each MRI. A specialized tumor board generated a treatment recommendation including up to four FDA-approved agents based upon the genomic alterations detected. A treatment plan was successfully issued within 21 business days from tissue collection for all 15 subjects, with 14 of the 15 subjects fulfilling the feasibility criteria. WGS results did not significantly deviate from WES-based therapy recommendations; however, WGS data provided further insight into tumor evolution and fidelity of patient-derived cell models. Detection of the H3F3A or HIST1H3B K27M (H3K27M) mutation using ctDNA was successful in 92% of H3K27M mutant cases. A personalized treatment recommendation for DIPG can be rendered within a multicenter setting using comprehensive next-generation sequencing technology in a clinically relevant timeframe.
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http://dx.doi.org/10.1002/ijc.32258DOI Listing
October 2019

Clinically Relevant and Minimally Invasive Tumor Surveillance of Pediatric Diffuse Midline Gliomas Using Patient-Derived Liquid Biopsy.

Clin Cancer Res 2018 12 15;24(23):5850-5859. Epub 2018 Oct 15.

Rese arch Center for Genetic Medicine, Children's National Health System, Washington, D.C.

Purpose: Pediatric diffuse midline glioma (DMG) are highly malignant tumors with poor clinical outcomes. Over 70% of patients with DMG harbor the histone 3 p.K27M (H3K27M) mutation, which correlates with a poorer clinical outcome, and is also used as a criterion for enrollment in clinical trials. Because complete surgical resection of DMG is not an option, biopsy at presentation is feasible, but rebiopsy at time of progression is rare. While imaging and clinical-based disease monitoring is the standard of care, molecular-based longitudinal characterization of these tumors is almost nonexistent. To overcome these hurdles, we examined whether liquid biopsy allows measurement of disease response to precision therapy.

Experimental Design: We established a sensitive and specific methodology that detects major driver mutations associated with pediatric DMGs using droplet digital PCR ( = 48 subjects, = 110 specimens). Quantification of circulating tumor DNA (ctDNA) for H3K27M was used for longitudinal assessment of disease response compared with centrally reviewed MRI data.

Results: H3K27M was identified in cerebrospinal fluid (CSF) and plasma in 88% of patients with DMG, with CSF being the most enriched for ctDNA. We demonstrated the feasibility of multiplexing for detection of H3K27M, and additional driver mutations in patient's tumor and matched CSF, maximizing the utility of a single source of liquid biome. A significant decrease in H3K27M plasma ctDNA agreed with MRI assessment of tumor response to radiotherapy in 83% (10/12) of patients.

Conclusions: Our liquid biopsy approach provides a molecularly based tool for tumor characterization, and is the first to indicate clinical utility of ctDNA for longitudinal surveillance of DMGs.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279526PMC
December 2018

A phase 1/2 dose-finding, safety, and activity study of cabazitaxel in pediatric patients with refractory solid tumors including tumors of the central nervous system.

Pediatr Blood Cancer 2018 09 11;65(9):e27217. Epub 2018 May 11.

Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: This phase 1/2 study (NCT01751308) evaluated cabazitaxel in pediatric patients. Phase 1 determined the maximum tolerated dose (MTD) in patients with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. Phase 2 evaluated activity in pediatric recurrent high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG).

Procedure: In phase 1, a 3 + 3 dose-escalation study design was followed. Cabazitaxel was administered at a starting dose of 20 mg/m . Dose-limiting toxicities (DLTs) during cycle 1 were assessed to determine the MTD. Tumor response and cabazitaxel pharmacokinetics were also assessed. In phase 2, patients received cabazitaxel at the MTD determined in phase 1. Tumor responses were assessed every 9 weeks (modified Response Assessment in Neuro-oncology criteria). Progression-free survival and cabazitaxel pharmacokinetics were evaluated, and overall survival was estimated.

Results: In phase 1, 23 patients were treated, including 19 with CNS tumors. One patient had a partial response; five had stable disease for >3 cycles. Common adverse events included fatigue, diarrhea, nausea and vomiting, febrile neutropenia, and hypersensitivity reactions. Two of three DLTs (febrile neutropenia) occurred with a dose of 35 mg/m ; the MTD was 30 mg/m . Slightly higher cabazitaxel clearance was observed compared with adult trials. In phase 2, 16 patients (eight HGG and eight DIPG) were enrolled; 11 were evaluable for response and five withdrew (three due to anaphylaxis). All 11 patients progressed within four cycles. No responses were observed; the study was stopped due to futility.

Conclusions: The safety profile of cabazitaxel was consistent with previous studies. The MTD (30 mg/m ) was higher than the adult MTD. Cabazitaxel did not demonstrate activity in recurrent/refractory HGG or DIPG.
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http://dx.doi.org/10.1002/pbc.27217DOI Listing
September 2018

A pediatric brain tumor consortium phase II trial of capecitabine rapidly disintegrating tablets with concomitant radiation therapy in children with newly diagnosed diffuse intrinsic pontine gliomas.

Pediatr Blood Cancer 2018 Feb 1;65(2). Epub 2017 Nov 1.

Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas.

Background: We conducted a phase II study of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy (RT) to assess progression-free survival (PFS) in children with newly diagnosed diffuse intrinsic pontine gliomas (DIPG).

Patients And Methods: Children 3-17 years with newly diagnosed DIPG were eligible. Capecitabine, 650 mg/m /dose BID (maximum tolerated dose [MTD] in children with concurrent radiation), was administered for 9 weeks starting the first day of RT. Following a 2-week break, three courses of capecitabine, 1,250 mg/m /dose BID for 14 days followed by a 7-day rest, were administered. As prospectively designed, 10 evaluable patients treated at the MTD on the phase I trial were included in the phase II analyses. The design was based on comparison of the PFS distribution to a contemporary historical control (n = 140) with 90% power to detect a 15% absolute improvement in the 1-year PFS with a type-1 error rate, α = 0.10.

Results: Forty-four patients were evaluable for the phase II objectives. Capecitabine and RT was well tolerated with low-grade palmar plantar erythrodyesthesia, increased alanine aminotransferase, cytopenias, and vomiting the most commonly reported toxicities. Findings were significant for earlier progression with 1-year PFS of 7.21% (SE = 3.47%) in the capecitabine-treated cohort versus 15.59% (SE = 3.05%) in the historical control (P = 0.007), but there was no difference for overall survival (OS) distributions (P = 0.30). Tumor enhancement at diagnosis was associated with shorter PFS and OS. Capecitabine was rapidly absorbed and converted to its metabolites.

Conclusion: Capecitabine did not improve the outcome for children with newly diagnosed DIPG.
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http://dx.doi.org/10.1002/pbc.26832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774861PMC
February 2018

Pediatric low-grade gliomas: implications of the biologic era.

Neuro Oncol 2017 06;19(6):750-761

Brain Tumor Center, Brain Tumor Translational Research, UC Department of Pediatrics, Cincinnati, Ohio, USA.

For the past decade, it has been recognized that pediatric low-grade gliomas (LGGs) and glial-neuronal tumors carry distinct molecular alterations with resultant aberrant intracellular signaling in the Ras-mitogen-activated protein kinase pathway. The conclusions and recommendations of a consensus conference of how best to integrate the growing body of molecular genetic information into tumor classifications and, more importantly, for future treatment of pediatric LGGs are summarized here. There is uniform agreement that molecular characterization must be incorporated into classification and is increasingly critical for appropriate management. Molecular-targeted therapies should be integrated expeditiously, but also carefully into the management of these tumors and success measured not only by radiographic responses or stability, but also by functional outcomes. These trials need to be carried out with the caveat that the long-term impact of molecularly targeted therapy on the developing nervous system, especially with long duration treatment, is essentially unknown.
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http://dx.doi.org/10.1093/neuonc/now209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464436PMC
June 2017

Separation of outer retinal layers secondary to selumetinib.

J AAPOS 2016 06 21;20(3):268-71. Epub 2016 Apr 21.

Division of Oncology, Center for Cancer and Blood Disorders, Children's National Health System, Washington, DC; The Brain Tumor Institute, Children's National Health System, Washington, DC.

New therapeutic agents targeting the mitogen-activated protein (MAP) kinase pathway, including MEK inhibitors, are currently being evaluated in phase 1 and 2 clinical trials for pediatric brain tumors. Ophthalmologic side effects from MEK inhibitors have previously only been reported in adults and included retinal vein occlusion, central retinal artery occlusion, and separation of the neurosensory retina. We report 2 patients with optic pathway gliomas who developed outer retinal layer separation visualized by optical coherence tomography while taking the MEK inhibitor selumetinib. After discontinuation of selumetinib, the outer retinal layer separation resolved without visual sequelae. One patient has been retreated with selumetinib and experienced recurrence of these findings.
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http://dx.doi.org/10.1016/j.jaapos.2016.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912405PMC
June 2016

Clinicopathology of diffuse intrinsic pontine glioma and its redefined genomic and epigenomic landscape.

Cancer Genet 2015 Jul-Aug;208(7-8):367-73. Epub 2015 May 1.

Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA; Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA. Electronic address:

Diffuse intrinsic pontine glioma (DIPG) is one of the most lethal pediatric central nervous system (CNS) cancers. Recently, a surge in molecular studies of DIPG has occurred, in large part due to the increased availability of tumor tissue through donation of post-mortem specimens. These new discoveries have established DIPGs as biologically distinct from adult gliomas, harboring unique genomic aberrations. Mutations in histone encoding genes are shown to be associated with >70% of DIPG cases. However, the exact molecular mechanisms of the tumorigenicity of these mutations remain elusive. Understanding the driving mutations and genomic landscape of DIPGs can now guide the development of targeted therapies for this incurable childhood cancer.
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http://dx.doi.org/10.1016/j.cancergen.2015.04.008DOI Listing
October 2015

A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: a pediatric brain tumor consortium study.

Neuro Oncol 2015 Feb 27;17(2):303-11. Epub 2014 Nov 27.

Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas (L.B.K., M.C., J.S., S.M.B.); Department of Biostatistics, Operations and Biostatistics Center for Pediatric Brain Tumor Consortium, St. Jude Children's Research Hospital, Memphis, Tennessee (M.K., J.M.B.); Eli Lilly and Company, Indianapolis, Indiana (R.L.D.); Division of Neuro-oncology, St. Jude Children's Research Hospital, Memphis, Tennessee (C.W., R.G.); Ann and Robert H. Lurie Children's Hospital of Chicago, Center for Cancer and Blood Disorders, Northwestern University Feinberg School of Medicine, Chicago, Illinois (S.G.); Department of Pediatrics, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (A.B.); Department of Hematology Oncology, Cincinnati Children's Hospital Medical Center,Cincinnati, Ohio (M.F.); Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (L.K.); Department of Preventive Medicine, University of Tennessee Health Science Center Memphis, Tennessee (M.K.).

Background: We sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cβ, in children with recurrent central nervous system malignancies.

Methods: Enzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m(2)) and twice daily at 440 mg/m(2)/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated. Akt pathway activity was measured in pretreatment tumor samples.

Results: Thirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m(2) given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transaminase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m(2) dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease >3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma.

Conclusion: Enzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m(2)/day administered once daily.
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http://dx.doi.org/10.1093/neuonc/nou114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288513PMC
February 2015

A phase I trial of veliparib (ABT-888) and temozolomide in children with recurrent CNS tumors: a pediatric brain tumor consortium report.

Neuro Oncol 2014 Dec 7;16(12):1661-8. Epub 2014 Jun 7.

Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).

Background: A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to (i) estimate the maximum tolerated doses (MTDs) or recommended phase II doses (RP2Ds) of veliparib and TMZ; (ii) describe the toxicities of this regimen; and (iii) evaluate the plasma pharmacokinetic parameters and extent of PARP inhibition in peripheral blood mononuclear cells (PBMCs) following veliparib.

Methods: TMZ was given once daily and veliparib twice daily for 5 days every 28 days. Veliparib concentrations and poly(ADP-ribose) (PAR) levels in PBMCs were measured on days 1 and 4. Analysis of pharmacokinetic and PBMC PAR levels were performed twice during study conduct to rationally guide dose modifications and to determine biologically optimal MTD/RP2D.

Results: Twenty-nine evaluable patients were enrolled. Myelosuppression (grade 4 neutropenia and thrombocytopenia) were dose limiting. The RP2Ds are veliparib 25 mg/m(2) b.i.d. and TMZ 135 mg/m(2)/d. Only 2 out of 12 patients treated at RP2Ds experienced dose-limiting toxicities. Although no objective response was observed, 4 patients had stable disease >6 months in duration, including 1 with glioblastoma multiforme and 1 with ependymoma. At the RP2D of veliparib, pediatric pharmacokinetic parameters were similar to those in adults.

Conclusions: Veliparib and TMZ at the RP2D were well tolerated in children with recurrent brain tumors. A phase I/II trial to evaluate the tolerability and efficacy of veliparib, TMZ, and radiation in children with newly diagnosed brainstem gliomas is in progress.
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http://dx.doi.org/10.1093/neuonc/nou103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232081PMC
December 2014

Handheld optical coherence tomography during sedation in young children with optic pathway gliomas.

JAMA Ophthalmol 2014 Mar;132(3):265-71

The Gilbert Family Neurofibromatosis Institute, Children's National Medical Center, Washington, DC2Department of Neurology, Children's National Medical Center, Washington, DC6Department of Oncology, Children's National Medical Center, Washington, DC7The B.

Importance: Monitoring young children with optic pathway gliomas (OPGs) for visual deterioration can be difficult owing to age-related noncompliance. Optical coherence tomography (OCT) measures of retinal nerve fiber layer (RNFL) thickness have been proposed as a surrogate marker of vision but this technique is also limited by patient cooperation.

Objective: To determine whether measures of circumpapillary RNFL thickness, acquired with handheld OCT (HH-OCT) during sedation, can differentiate between young children with and without vision loss from OPGs.

Design, Setting, And Participants: This cross-sectional analysis of a prospective observational study was conducted at a tertiary-care children's hospital. Children with an OPG (sporadic or secondary to neurofibromatosis type 1) who were cooperative for visual acuity testing, but required sedation to complete magnetic resonance imaging, underwent HH-OCT imaging of the circumpapillary RNFL while sedated.

Main Outcomes And Measures: Area under the curve of the receiver operating characteristic, sensitivity, specificity, positive predictive value, and negative predictive value of the average and quadrant-specific RNFL thicknesses.

Results: Thirty-three children (64 eyes) met inclusion criteria (median age, 4.8 years; range, 1.8-12.6 years). In children with vision loss (abnormal visual acuity and/or visual field), RNFL thickness was decreased in all quadrants compared with the normal-vision group (P < .001 for all comparisons). Using abnormal criteria of less than 5% and less than 1%, the area under the curve was highest for the average RNFL thickness (0.96 and 0.97, respectively) compared with specific anatomic quadrants. The highest discrimination and predictive values were demonstrated for participants with 2 or more quadrants meeting less than 5% (sensitivity = 93.3; specificity = 97.9; positive predictive value = 93.3; and negative predictive value = 97.9) and less than 1% (sensitivity = 93.3; specificity = 100; positive predictive value = 100; and negative predictive value = 98.0) criteria.

Conclusions And Relevance: Measures of RNFL thickness acquired with HH-OCT during sedation can differentiate between young children with and without vision loss from OPGs. For young children who do not cooperate with vision testing, HH-OCT measures may be a surrogate marker of vision. Longitudinal studies are needed to delineate the temporal relationship between RNFL decline and vision loss.
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http://dx.doi.org/10.1001/jamaophthalmol.2013.7649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445404PMC
March 2014

Phase I trial of capecitabine rapidly disintegrating tablets and concomitant radiation therapy in children with newly diagnosed brainstem gliomas and high-grade gliomas.

Neuro Oncol 2013 Jun 16;15(6):759-66. Epub 2013 Apr 16.

Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.

Background: We conducted a phase I study to estimate the maximum tolerated dose and describe the dose-limiting toxicities and pharmacokinetics of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy to children with newly diagnosed brainstem or high-grade gliomas.

Methods: Children 3-21 y with newly diagnosed intrinsic brainstem or high-grade gliomas were eligible for enrollment. The starting dose was 500 mg/m(2), given twice daily, with subsequent cohorts enrolled at 650 mg/m(2) and 850 mg/m(2) using a 3 + 3 phase I design. Children received capecitabine at the assigned dose daily for 9 wks starting from the first day of radiation therapy (RT). Following a 2-wk break, patients received 3 courses of capecitabine 1250 mg/m(2) twice daily for 14 days followed by a 7-day rest. Pharmacokinetic sampling was performed in consenting patients. Six additional patients with intrinsic brainstem gliomas were enrolled at the maximum tolerated dose to further characterize the pharmacokinetic and toxicity profiles.

Results: Twenty-four patients were enrolled. Twenty were fully assessable for toxicity. Dose-limiting toxicities were palmar plantar erythroderma (grades 2 and 3) and elevation of alanine aminotransferase (grades 2 and 3). Systemic exposure to capecitabine and metabolites was similar to or slightly lower than predicted based on adult data.

Conclusions: Capecitabine with concurrent RT was generally well tolerated. The recommended phase II capecitabine dose when given with concurrent RT is 650 mg/m(2), administered twice daily. A phase II study to evaluate the efficacy of this regimen in children with intrinsic brainstem gliomas is in progress (PBTC-030).
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http://dx.doi.org/10.1093/neuonc/nos315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661085PMC
June 2013

Long-term efficacy and toxicity of bevacizumab-based therapy in children with recurrent low-grade gliomas.

Pediatr Blood Cancer 2013 May 13;60(5):776-82. Epub 2012 Sep 13.

Division of Oncology, Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, District of Columbia, USA.

Background: Because definitive resection or radiotherapy for pediatric low-grade gliomas (LGGs) may be associated with severe and permanent adverse effects, medical management has taken a significant role. Bevacizumab-based therapy has demonstrated encouraging responses; however, longer-term toxicity, response durability and alternative dosing regimens have not been evaluated.

Procedure: This was a retrospective review of children with multiply recurrent, progressive LGGs treated with bevacizumab-based therapy and followed for at least 12 months after treatment completion. Toxicity was uniformly graded and imaging was centrally reviewed.

Results: All fourteen patients had failed at least two prior treatment regimens; six had dissemination. Patients received initial bevacizumab-based therapy at a median age of 5.3 years (range, 1-12 years). Median treatment duration was 12 months (range, 1-24 months). 12 patients had an objective response; 2 had stable disease. Median time to maximum response was 9 weeks (range, 7-17 weeks). No patients progressed on therapy, although 13/14 progressed after stopping bevacizumab at a median of 5 months. Four patients were re-treated with bevacizumab and all again responded or stabilized. Alternative dosing strategies were effective, including bevacizumab monotherapy and prolonging the dosing interval to 3 weeks. High-grade bevacizumab-related toxicities consisted of grade 3 proteinuria (n = 2), primary inflammatory arthritis (n = 1), and somnolence (n = 1). Toxicities resolved within 6 months of treatment cessation except one case of hypertension.

Conclusions: Bevacizumab-based therapy is successful at inducing rapid LGG response. Patients progressing off-therapy may be successfully re-treated with bevacizumab. Nearly all tumors progress once treatment is discontinued. Toxicities are not insignificant but usually reversible.
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http://dx.doi.org/10.1002/pbc.24297DOI Listing
May 2013

Insights into pediatric diffuse intrinsic pontine glioma through proteomic analysis of cerebrospinal fluid.

Neuro Oncol 2012 May 5;14(5):547-60. Epub 2012 Apr 5.

Department of Neurosurgery, Georgetown University Hospital, Research Center for Genetic Medicine, Children's National Medical Center NW, Washington, DC 20010, USA.

Diffuse intrinsic pontine glioma (DIPG) is a leading cause of brain tumor-related death in children. DIPG is not surgically resectable, resulting in a paucity of tissue available for molecular studies. As such, tumor biology is poorly understood, and, currently, there are no effective treatments. In the absence of frozen tumor specimens, body fluids--such as cerebrospinal fluid (CSF), serum, and urine--can serve as more readily accessible vehicles for detecting tumor-secreted proteins. We analyzed a total of 76 specimens, including CSF, serum, urine, and normal and tumor brainstem tissue. Protein profiling of CSF from patients with DIPG was generated by mass spectrometry using an LTQ-Orbitrap-XL and database search using the Sequest algorithm. Quantitative and statistical analyses were performed with ProteoIQ and Partek Genomics Suite. A total of 528 unique proteins were identified, 71% of which are known secreted proteins. CSF proteomic analysis revealed selective upregulation of Cyclophillin A (CypA) and dimethylarginase 1 (DDAH1) in DIPG (n = 10), compared with controls (n = 4). Protein expression was further validated with Western blot analysis and immunohistochemical assays using CSF, brain tissue, serum, and urine from DIPG and control specimens. Immunohistochemical staining showed selective upregulation of secreted but not cytosolic CypA and DDAH1 in patients with DIPG. In this study, we present the first comprehensive protein profile of CSF specimens from patients with DIPG to demonstrate selective expression of tumor proteins potentially involved in brainstem gliomagenesis. Detection of secreted CypA and DDAH1 in serum and urine has potential clinical application, with implications for assessing treatment response and detecting tumor recurrence in patients with DIPG.
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http://dx.doi.org/10.1093/neuonc/nos067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337313PMC
May 2012

Glutathione S-transferase polymorphisms are associated with survival in anaplastic glioma patients.

Cancer 2010 May;116(9):2242-9

Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

Background: Glutathione S-transferases (GSTs) are polymorphic enzymes that are responsible for glutathione conjugation of alkylators and scavenging of free radicals created by radiation. GST polymorphisms may result in altered or absent enzyme activity and have been associated with survival in patients with cancer. The authors of this report hypothesized that patients with anaplastic glioma (AG) who have GST genotypes that encode for lower activity enzymes will have longer survival than similar patients who have higher activity genotypes. The current study was performed to investigate the role of GST enzyme polymorphisms in predicting the survival of patients with AG.

Methods: The medical records of 207 patients with AG from a single cancer center were reviewed retrospectively. Polymorphisms for the GST micro1 (GSTM1), GST theta1 (GSTT1), and GST pi1 (GSTP1) enzymes were identified. Overall survival was compared using the Kaplan-Meier method and Cox proportional hazards analyses adjusting for age, sex, histology, and therapy.

Results: Among the patients with oligodendroglial tumors (n = 94), patients who had the GSTT1 null genotype had a 2.9 times increased risk of death (95% confidence interval [CI], 1.3-6.3) compared with patients who had the GSTT1 non-null genotype. Adjustment for 1p/19q status did not change the finding. In the patients who had anaplastic astrocytoma (n = 113), the patients with all GSTP1 genotypes except GSTP1 *B/*B had a 3.8 times increased risk of death (95% CI, 0.5-29.6) compared with patients who had the GSTP1 *B/*B genotype.

Conclusions: In patients with anaplastic oligodendroglial tumors, the GSTT1 null genotype may be associated with poor survival, possibly because of modifications in therapy secondary to increased toxicity. This hypothesis is under investigation. In patients with anaplastic astrocytoma, the GSTP1 *B/*B genotype may confer a survival advantage.
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http://dx.doi.org/10.1002/cncr.25006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861043PMC
May 2010

Plasma and cerebrospinal fluid pharmacokinetics of tasidotin (ILX-651) and its metabolites in non-human primates.

Cancer Chemother Pharmacol 2009 Jul 29;64(2):335-40. Epub 2008 Nov 29.

Texas Children's Cancer Center, Baylor College of Medicine, 6621 Fannin St., MC:3-3320, Houston, TX 77030, USA.

Purpose: To evaluate the plasma and cerebrospinal fluid (CSF) pharmacokinetics and CSF penetration of tasidotin and metabolites in a nonhuman primate model.

Methods: Tasidotin 0.75 mg/kg was administered intravenously. The plasma and CSF concentrations of tasidotin and its metabolites were determined. Pharmacokinetic parameters were estimated using model-independent and model-dependent methods.

Results: The mean (+/-SD) CSF:plasma AUC ratio for tasidotin was 1.1 +/- 0.4. For tasidotin, tasidotin-C-carboxylate and desprolyl-tasidotin-C-carboxylate the plasma AUCs (mean +/- SD) were 30 +/- 10, 54 +/- 19 and 12 +/- 2 microM min, and apparent plasma half-lives were 27 +/- 4, 229 +/- 73 and 100 +/- 29 min. The plasma clearance of tasidotin was 44 +/- 14 ml/min/kg. The CSF AUC and half-life of tasidotin was 28 +/- 10 microM min and 96 +/- 40 min. The model-dependent plasma clearance was 35 ml/min/kg for tasidotin and 2 ml/min/kg for tasidotin-C-carboxylate.

Conclusions: Tasidotin penetrates into the CSF well and further evaluation of its activity in the treatment of central nervous system malignancies should be considered.
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http://dx.doi.org/10.1007/s00280-008-0875-7DOI Listing
July 2009

Glutathione S-transferase M1 and T1 polymorphisms may predict adverse effects after therapy in children with medulloblastoma.

Neuro Oncol 2009 Jun 24;11(3):292-300. Epub 2008 Oct 24.

Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Glutathione S-transferases (GSTs) are polymorphic enzymes that catalyze the glutathione conjugation of alkylating agents, platinum compounds, and free radicals formed by radiation used to treat medulloblastoma. We hypothesized that GST polymorphisms may be responsible, in part, for individual differences in toxicity and responses in pediatric medulloblastoma. We investigated the relationship between GSTM1 and GSTT1 polymorphisms and survival and toxicity in 42 children with medulloblastoma diagnosed and treated at the Texas Children's Cancer Center. We conducted Kaplan-Meier analyses to determine if the GST polymorphisms were related to progression-free survival (PFS) and performed logistic regression to explore associations between GST polymorphisms and occurrence of grade 3 or greater (> or =Gr 3) myelosuppression, ototoxicity, nephrotoxicity, neurotoxicity, and intellectual impairment. Patients with at least one null genotype had a 4.3 (95% confidence interval, 1.1-16.8), 3.7 (1-13.6), and 6.4 (1.2-34) times increased risk for any > or =Gr 3 toxicity, any > or =Gr 3 toxicity excluding peripheral neuropathy, and any > or =Gr 3 toxicity requiring omission or cessation of chemotherapy, respectively. Compared with all others, patients with at least one null genotype had, on average, 27.2 (p x= 0.0002), 29 (p = 0.0004), and 21.7 (p = 0.002) lower full-scale, performance, and verbal intelligence quotient (IQ) scores, respectively. GSTM1 and GSTT1 polymorphisms may predict adverse events, including cognitive impairment after therapy, in patients with medulloblastoma. A larger study to validate these findings is under way.
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http://dx.doi.org/10.1215/15228517-2008-089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718973PMC
June 2009