Publications by authors named "Roger J Packer"

238 Publications

Computerized Working Memory Training for Children With Neurofibromatosis Type 1 (NF1): A Pilot Study.

J Child Neurol 2021 Sep 2:8830738211038083. Epub 2021 Sep 2.

National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Introduction: The present study aimed to evaluate the feasibility and efficacy of a computerized, home-based working memory (WM) training program, in children with NF1.

Method: A pre-post design was used to evaluate changes in performance-based measures of attention and WM, and parent-completed ratings of executive functioning. Children meeting eligibility criteria completed over 9 weeks. Primary outcomes included compliance statistics and change in attention and WM scores.

Results: Thirty-one children (52% male; M age = 10.97 ± 2.51), aged 8-15, were screened for participation; 27 children (87%) evidenced WM difficulties and participated in training. On average, participants completed 19.7 out of 25 prescribed sessions, with an adherence rate of 69%. Participants demonstrated improvements in short-term memory, attention, and executive functioning (all < .05).

Conclusion: Results suggest that computerized, home-based WM training programs may be both feasible and efficacious for children with NF1 and cognitive deficits.
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http://dx.doi.org/10.1177/08830738211038083DOI Listing
September 2021

Treatment during a developmental window prevents NF1-associated optic pathway gliomas by targeting Erk-dependent migrating glial progenitors.

Dev Cell 2021 Aug 20. Epub 2021 Aug 20.

Gilbert Family Neurofibromatosis Institute, Children's National Hospital, Washington, DC 20010, USA; Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC 20010, USA; Center for Neuroscience Research, Children's National Hospital, Washington, DC 20010, USA; Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; GW Cancer Center, George Washington University, Washington, DC 20052. Electronic address:

The mechanism of vulnerability to pediatric low-grade gliomas (pLGGs)-the most common brain tumor in children-during development remains largely unknown. Using mouse models of neurofibromatosis type 1 (NF1)-associated pLGGs in the optic pathway (NF1-OPG), we demonstrate that NF1-OPG arose from the vulnerability to the dependency of Mek-Erk/MAPK signaling during gliogenesis of one of the two developmentally transient precursor populations in the optic nerve, brain-derived migrating glial progenitors (GPs), but not local progenitors. Hyperactive Erk/MAPK signaling by Nf1 loss overproduced GPs by disrupting the balance between stem-cell maintenance and gliogenesis of hypothalamic ventricular zone radial glia (RG). Persistence of RG-like GPs initiated NF1-OPG, causing Bax-dependent apoptosis in retinal ganglion cells. Removal of three Mek1/Mek2 alleles or transient post-natal treatment with a low-dose MEK inhibitor normalized differentiation of Nf1 RG-like GPs, preventing NF1-OPG formation and neuronal degeneration. We provide the proof-of-concept evidence for preventing pLGGs before tumor-associated neurological damage enters an irreversible phase.
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http://dx.doi.org/10.1016/j.devcel.2021.08.004DOI Listing
August 2021

Subgroup and subtype-specific outcomes in adult medulloblastoma.

Acta Neuropathol 2021 Nov 18;142(5):859-871. Epub 2021 Aug 18.

Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Chonnam, South Korea.

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.
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http://dx.doi.org/10.1007/s00401-021-02358-4DOI Listing
November 2021

Impact of MEK Inhibitor Therapy on Neurocognitive Functioning in NF1.

Neurol Genet 2021 Oct 6;7(5):e616. Epub 2021 Aug 6.

Children's National Medical Center (K.S.W., A.C., M.D.S., T.I., R.J.P.), Washington, DC; National Cancer Institute (P.L.W., B.C.W., M.C.R., S.M., K.S.), Bethesda, MD; Clinical Research Directorate (M.A.T.-T.), Frederick National Library for Cancer Research, MD; and Children's Hospital of Philadelphia (I.P., V.C., K.M., M.J.F.), Philadelphia.

Background And Objectives: Neurofibromatosis type 1 (NF1)-associated cognitive impairments carry significant lifelong morbidity. The lack of targeted biologic treatments remains a significant unmet need. We examine changes in cognition in patients with NF1 in the first 48 weeks of mitogen-activated protein kinase inhibitor (MEKi) treatment.

Methods: Fifty-nine patients with NF1 aged 5-27 years on an MEKi clinical trial treating plexiform neurofibroma underwent pretreatment and follow-up cognitive assessments over 48 weeks of treatment. Performance tasks (Cogstate) and observer-reported functioning (BRIEF) were the primary outcomes. Group-level (paired tests) and individual-level analyses (Reliable Change Index, RCI) were used.

Results: Analysis showed statistically significant improvements on BRIEF compared with baseline (24-week Behavioral Regulation Index: = 3.03, = 0.004, = 0.24; 48-week Metacognition Index: = 2.70, = 0.01, = 0.27). RCI indicated that more patients had clinically significant improvement at 48 weeks than expected by chance (χ = 11.95, = 0.001, odds ratio [OR] = 6.3). Group-level analyses indicated stable performance on Cogstate ( > 0.05). RCI statistics showed high proportions of improved working memory (24-week χ = 8.36, = 0.004, OR = 4.6, and 48-week χ = 9.34, = 0.004, OR = 5.3) but not visual learning/memory. Patients with baseline impairments on BRIEF were more likely to show significant improvement than nonimpaired patients (24 weeks 46% vs 8%; χ = 9.54, = 0.008, OR = 9.22; 48 weeks 63% vs 16%; χ = 7.50, = 0.02, OR = 9.0).

Discussion: Our data show no evidence of neurotoxicity in 48 weeks of treatment with an MEKi and a potential clinical signal supporting future research of MEKi as a cognitive intervention.
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http://dx.doi.org/10.1212/NXG.0000000000000616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351286PMC
October 2021

Unsupervised MRI Homogenization: Application to Pediatric Anterior Visual Pathway Segmentation.

Mach Learn Med Imaging 2020 Oct 29;12436:180-188. Epub 2020 Sep 29.

Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, DC 20010, USA.

Deep learning strategies have become ubiquitous optimization tools for medical image analysis. With the appropriate amount of data, these approaches outperform classic methodologies in a variety of image processing tasks. However, rare diseases and pediatric imaging often lack extensive data. Specially, MRI are uncommon because they require sedation in young children. Moreover, the lack of standardization in MRI protocols introduces a strong variability between different datasets. In this paper, we present a general deep learning architecture for MRI homogenization that also provides the segmentation map of an anatomical region of interest. Homogenization is achieved using an unsupervised architecture based on variational autoencoder with cycle generative adversarial networks, which learns a common space (i.e. a representation of the optimal imaging protocol) using an unpaired image-to-image translation network. The segmentation is simultaneously generated by a supervised learning strategy. We evaluated our method segmenting the challenging anterior visual pathway using three brain T1-weighted MRI datasets (variable protocols and vendors). Our method significantly outperformed a non-homogenized multi-protocol U-Net.
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http://dx.doi.org/10.1007/978-3-030-59861-7_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317430PMC
October 2020

Efficacy of Carboplatin and Isotretinoin in Children With High-risk Medulloblastoma: A Randomized Clinical Trial From the Children's Oncology Group.

JAMA Oncol 2021 Sep;7(9):1313-1321

Cancer and Blood Disorders Center, Seattle Children's, Seattle, Washington.

Importance: Brain tumors are the leading cause of disease-related death in children. Medulloblastoma is the most common malignant embryonal brain tumor, and strategies to increase survival are needed.

Objective: To evaluate therapy intensification with carboplatin as a radiosensitizer and isotretinoin as a proapoptotic agent in children with high-risk medulloblastoma in a randomized clinical trial and, with a correlative biology study, facilitate planned subgroup analysis according to World Health Organization consensus molecular subgroups of medulloblastoma.

Design, Setting, And Participants: A randomized clinical phase 3 trial was conducted from March 2007 to September 2018. Analysis was completed in September 2020. Patients aged 3 to 21 years with newly diagnosed high-risk medulloblastoma from Children's Oncology Group institutions within the US, Canada, Australia, and New Zealand were included. High-risk features included metastasis, residual disease, or diffuse anaplasia.

Interventions: Patients were randomized to receive 36-Gy craniospinal radiation therapy and weekly vincristine with or without daily carboplatin followed by 6 cycles of maintenance chemotherapy with cisplatin, cyclophosphamide, and vincristine with or without 12 cycles of isotretinoin during and following maintenance.

Main Outcomes And Measures: The primary clinical trial end point was event-free survival, using the log-rank test to compare arms. The primary biology study end point was molecular subgroup classification by DNA methylation array.

Results: Of 294 patients with medulloblastoma, 261 were evaluable after central radiologic and pathologic review; median age, 8.6 years (range, 3.3-21.2); 183 (70%) male; 189 (72%) with metastatic disease; 58 (22%) with diffuse anaplasia; and 14 (5%) with greater than 1.5-cm2 residual disease. For all participants, the 5-year event-free survival was 62.9% (95% CI, 55.6%-70.2%) and overall survival was 73.4% (95% CI, 66.7%-80.1%). Isotretinoin randomization was closed early owing to futility. Five-year event-free survival was 66.4% (95% CI, 56.4%-76.4%) with carboplatin vs 59.2% (95% CI, 48.8%-69.6%) without carboplatin (P = .11), with the effect exclusively observed in group 3 subgroup patients: 73.2% (95% CI, 56.9%-89.5%) with carboplatin vs 53.7% (95% CI, 35.3%-72.1%) without (P = .047). Five-year overall survival differed by molecular subgroup (P = .006): WNT pathway activated, 100% (95% CI, 100%-100%); SHH pathway activated, 53.6% (95% CI, 33.0%-74.2%); group 3, 73.7% (95% CI, 61.9%-85.5%); and group 4, 76.9% (95% CI, 67.3%-86.5%).

Conclusions And Relevance: In this randomized clinical trial, therapy intensification with carboplatin improved event-free survival by 19% at 5 years for children with high-risk group 3 medulloblastoma. These findings further support the value of an integrated clinical and molecular risk stratification for medulloblastoma.

Trial Registration: ClinicalTrials.gov Identifier: NCT00392327.
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http://dx.doi.org/10.1001/jamaoncol.2021.2224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299367PMC
September 2021

The 2021 WHO Classification of Tumors of the Central Nervous System: clinical implications.

Neuro Oncol 2021 08;23(8):1215-1217

Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, Gilbert Family Neurofibromatosis Institute, Children's National Hospital, Washington, DC, USA.

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http://dx.doi.org/10.1093/neuonc/noab120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328017PMC
August 2021

Characteristics of Patients ≥ 10 Years of Age with Diffuse Intrinsic Pontine Glioma: A Report from the International DIPG Registry.

Neuro Oncol 2021 Jun 11. Epub 2021 Jun 11.

The Ohio State University College of Medicine, Columbus, OH.

Background: DIPG generally occurs in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR).

Methods: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months).

Results: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years [range 10-26.8]. Median OS was 13 [2-82] months. The 1-, 3- and 5- years OS was 61.9%, 3.7%, and 1.5%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P<0.01) and present with longer symptom duration (P<0.01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and one was a LTS. The presence or absence of H3 alterations did not affect survival.

Conclusion: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.
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http://dx.doi.org/10.1093/neuonc/noab140DOI Listing
June 2021

Children's Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma.

J Clin Oncol 2021 Aug 10;39(24):2685-2697. Epub 2021 Jun 10.

Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN.

Purpose: Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume.

Methods: ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time.

Results: Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm ( = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS ( = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; = .021).

Conclusion: Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches.
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http://dx.doi.org/10.1200/JCO.20.02730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376317PMC
August 2021

Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma.

J Clin Oncol 2021 03 27;39(7):807-821. Epub 2021 Jan 27.

Division of Pediatric Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX.

Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors.

Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing.

Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving , , and . Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms.

Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.
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http://dx.doi.org/10.1200/JCO.20.01359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078396PMC
March 2021

Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial.

Nat Med 2021 01 13;27(1):165-173. Epub 2021 Jan 13.

Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.
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http://dx.doi.org/10.1038/s41591-020-01193-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275010PMC
January 2021

Visual outcomes following everolimus targeted therapy for neurofibromatosis type 1-associated optic pathway gliomas in children.

Pediatr Blood Cancer 2021 04 18;68(4):e28833. Epub 2020 Dec 18.

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

Data for visual acuity (VA) after treatment of neurofibromatosis type 1-associated optic pathway gliomas (NF1-OPGs) are limited. We retrospectively collected VA, converted to logMAR, before and after targeted therapy with everolimus for NF1-OPG, and compared to radiologic outcomes (14/18 with NF1-OPG, 25 eyes [three without quantifiable vision]). Upon completion of treatment, VA was stable in 19 eyes, improved in four eyes, and worsened in two eyes; visual and radiologic outcomes were discordant. In summary, the majority of children with NF1-OPG exhibited stabilization of their VA after everolimus treatment. A larger, prospective study will help delineate visual outcomes after targeted therapy.
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http://dx.doi.org/10.1002/pbc.28833DOI Listing
April 2021

A phase I trial of lenalidomide and radiotherapy in children with diffuse intrinsic pontine gliomas or high-grade gliomas.

J Neurooncol 2020 Sep 11;149(3):437-445. Epub 2020 Oct 11.

National Cancer Institute at the National Institutes of Health, Bethesda, MD, USA.

Purpose: This study was performed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of the immunomodulatory agent, lenalidomide, when administered daily during 6 weeks of radiation therapy to children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG) PATIENTS & METHODS: Children and young adults < 22 years of age with newly diagnosed disease and no prior chemotherapy or radiation therapy were eligible. Children with HGG were required to have an inoperable or incompletely resected tumor. Eligible patients received standard radiation therapy to a prescription dose of 54-59.4 Gy, with concurrent administration of lenalidomide daily during radiation therapy in a standard 3 + 3 Phase I dose escalation design. Following completion of radiation therapy, patients had a 2-week break followed by maintenance lenalidomide at 116 mg/m/day × 21 days of a 28-day cycle.

Results: Twenty-nine patients (age range 4-19 years) were enrolled; 24 were evaluable for dose finding (DIPG, n = 13; HGG, n = 11). The MTD was not reached at doses of lenalidomide up to 116 mg/m/day. Exceptional responses were noted in DIPG and malignant glioma (gliomatosis cerebri) notably at higher dose levels and at higher steady state plasma concentrations. The primary toxicity was myelosuppression.

Conclusion: The RP2D of lenalidomide administered daily during radiation therapy is 116 mg/m/day. Children with malignant gliomas tolerate much higher doses of lenalidomide during radiation therapy compared to adults. This finding is critical as activity was observed primarily at higher dose levels suggesting a dose response.
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http://dx.doi.org/10.1007/s11060-020-03627-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690216PMC
September 2020

JNO special issue: an update on pediatric neuro-oncology.

J Neurooncol 2020 Oct 26;150(1):1-4. Epub 2020 Aug 26.

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

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http://dx.doi.org/10.1007/s11060-020-03560-2DOI Listing
October 2020

Pediatric diffuse leptomeningeal glioneuronal tumor: Two clinical cases of successful targeted therapy.

Pediatr Blood Cancer 2020 12 25;67(12):e28478. Epub 2020 Aug 25.

Center for Neuroscience and Behavioral Medicine, Brain Tumor Institute, Washington, District of Columbia.

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http://dx.doi.org/10.1002/pbc.28478DOI Listing
December 2020

Integrated analysis of pediatric low-grade glioma: clinical implications and the path forward.

Neuro Oncol 2020 10;22(10):1413-1414

Aflac Cancer Center of Children's Healthcare of Atlanta and Emory University, Atlanta, Georgia.

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http://dx.doi.org/10.1093/neuonc/noaa187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566534PMC
October 2020

NCI-CONNECT: Comprehensive Oncology Network Evaluating Rare CNS Tumors-Histone Mutated Midline Glioma Workshop Proceedings.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa007. Epub 2020 Jan 16.

Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Histone mutations occur in approximately 4% of different cancer types. In 2012, mutations were found in the gene encoding histone variant H3.3 ( gene) in pediatric diffuse intrinsic pontine gliomas and pediatric hemispheric gliomas. Tumors with mutations in the gene are generally characterized as histone mutated gliomas (HMGs) or diffuse midline gliomas. HMGs are a rare subtype of glial tumor that is malignant and fast growing, carrying a poor prognosis. In 2017, the Beau Biden Cancer Moonshot Program appropriated $1.7 billion toward cancer care in 10 select areas. The National Cancer Institute (NCI) was granted support to focus specifically on rare central nervous system (CNS) tumors through NCI-CONNECT. Its mission is to address the challenges and unmet needs in CNS cancer research and treatment by connecting patients, providers, researchers, and advocacy organizations to work in partnership. On September 27, 2018, NCI-CONNECT convened a workshop on histone mutated midline glioma, one of the 12 CNS cancers included in its initial portfolio. Three leaders in the field provided an overview of advances in histone mutated midline glioma research. These experts shared observations and experiences related to common scientific and clinical challenges in studying these tumors. Although the clinical focus of this workshop was on adult patients, one important objective was to start a collaborative dialogue between pediatric and adult clinicians and researchers. Meeting participants identified needs for diagnostic and treatment standards, disease biology and biological targets for this cancer, disease-specific trial designs, and developed a list of action items and future direction.
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http://dx.doi.org/10.1093/noajnl/vdaa007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212875PMC
January 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

New treatment modalities in NF-related neuroglial tumors.

Childs Nerv Syst 2020 10 29;36(10):2377-2384. Epub 2020 Jun 29.

Division of Radiology, Children's National Hospital, 111 Michigan Ave, NW, Washington, DC, 20010, USA.

The management of low-grade gliomas (LGGs) and other neuroglial tumors in children with neurofibromatosis type 1 (NF1) has not changed over the past 2-3 decades. With the widespread utilization of chemotherapy for younger children with progressive LGGs, outcomes have been good for most patients who have required treatment. However, some may progress after the initiation of chemotherapy and others, although radiographically responding or with stable disease, may develop progressive neurologic and visual deterioration. Molecular-targeted therapy has become an option for patients who have progressed after receiving chemotherapy and the mTOR inhibitors and bevacizumab have already shown some degree of efficacy. However, the greatest impact has been the introduction of the MEK inhibitors. A variety of different MEK inhibitors are in clinical trials and have already demonstrated the ability to result in radiographic tumor shrinkage in the majority of children with NF1 and progressive LGGs. Because of this efficacy, the MEK inhibitors have moved rapidly from phase I studies to ongoing phase III studies comparing their benefit directly to that of chemotherapy. The long-term ability of these agents to not only control disease, but improve visual and/or neurological function, as well as their short- and long-term safety, are open questions that can only be answered by well-constructed prospective, often randomized, clinical trials.
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http://dx.doi.org/10.1007/s00381-020-04704-5DOI Listing
October 2020

Update on Pediatric Brain Tumors: the Molecular Era and Neuro-immunologic Beginnings.

Curr Neurol Neurosci Rep 2020 06 20;20(8):30. Epub 2020 Jun 20.

Brain Tumor Institute, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC, 20010, USA.

Purpose Of Review: To provide an update on the current landscape of pediatric brain tumors and the impact of novel molecular insights on classification, diagnostics, and therapeutics.

Recent Findings: Scientific understanding of the genetic basis of central nervous system tumors has expanded rapidly over the last several years. The shift in classification of tumors to a molecularly based schema, accompanied by a growing number of early phase clinical trials of therapies aimed at inhibiting tumoral genetic and epigenetic programs, as well as those attempting to harness and magnify the immune response, has allowed a deeper pathophysiologic understanding of brain tumors and simultaneously provided opportunities for novel treatment. Over the last 5 years, there has been tremendous growth in the field of pediatric neuro-oncology with increasing understanding of the genetic and epigenetic heterogeneity of CNS tumors. Attempts are underway to translate these insights into tumor-specific treatments.
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http://dx.doi.org/10.1007/s11910-020-01050-6DOI Listing
June 2020

Correction to: Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes.

Acta Neuropathol 2020 08;140(2):247

Center for Genetic Medicine Research, Children's National Medical Center, 111 Michigan Ave., NW, Washington, DC, 20010, USA.

The original version of this article unfortunately contained a mistake.
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http://dx.doi.org/10.1007/s00401-020-02162-6DOI Listing
August 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

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

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

JAMA Neurol 2020 06;77(6):755-763

Columbia University Irving Medical Center, New York, New York.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.

Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings.

Conclusions And Relevance: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.
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http://dx.doi.org/10.1001/jamaneurol.2020.0367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483960PMC
June 2020

Immunotherapy Approaches for Pediatric CNS Tumors and Associated Neurotoxicity.

Pediatr Neurol 2020 06 27;107:7-15. Epub 2020 Jan 27.

Children's National Medical Center, Brain Tumor Institute, Washington, District of Columbia; Center for Neuroscience and Behavioral Medicine, Children's National Medical Center, Washington, District of Columbia.

Treatment for brain tumors has recently shifted to using the power of the immune system to destroy cancer cells with promising results. Many immunotherapeutic approaches that have been used in adults, including checkpoint inhibitors, vaccine therapy, adoptive immunotherapy, such as chimeric antigen receptor T cell therapy, and viral therapy, are now being evaluated in children. Although these treatments work through different mechanisms, they all activate the immune system and can result in inflammation at the site of disease. This can be especially problematic in the confined area of the brain causing potentially severe neurological side effects, which are of special concern in children with central nervous system malignancies. Steroids can be helpful in the management of neurological complications but carry the risk of making immunotherapeutic approaches less effective. Alternative therapeutic interventions to mitigate side effects are being evaluated. This review describes the most common immunotherapeutic modalities that are now under study for the treatment of pediatric brain tumors, their rationale, associated neurotoxicities, and current management.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.01.004DOI Listing
June 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

Cognition, ADHD Symptoms, and Functional Impairment in Children and Adolescents With Neurofibromatosis Type 1.

J Atten Disord 2021 06 14;25(8):1177-1186. Epub 2019 Dec 14.

Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.

We examined the contribution of attention and executive cognitive processes to ADHD symptomatology in NF1, as well as the relationships between cognition and ADHD symptoms with functional outcomes. The study sample consisted of 141 children and adolescents with NF1. Children were administered neuropsychological tests that assessed attention and executive function, from which latent cognitive variables were derived. ADHD symptomatology, adaptive skills, and quality of life (QoL) were assessed using parent-rated questionnaires. Path analyses were conducted to test relationships among cognitive functioning, ADHD symptomatology, and functional outcomes. Significant deficits were observed on all outcome variables. Cognitive variables did not predict ADHD symptomatology. Neither did they predict functional outcomes. However, elevated ADHD symptomatology significantly predicted functional outcomes. Irrespective of cognitive deficits, elevated ADHD symptoms in children with NF1 negatively impact daily functioning and emphasize the importance of interventions aimed at minimizing ADHD symptoms in NF1.
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http://dx.doi.org/10.1177/1087054719894384DOI Listing
June 2021

Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1.

Ann Clin Transl Neurol 2019 12 3;6(12):2555-2565. Epub 2019 Dec 3.

Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.

Objective: Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility.

Methods: Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra-class correlation coefficients were generated between pre- and post-performances (16-week interval) on neuropsychological endpoints in the placebo group to determine test-retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error.

Results: Test-retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test-retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data.

Interpretation: These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test-retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.
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http://dx.doi.org/10.1002/acn3.50952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917317PMC
December 2019
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