White matter connectivity and social functioning in survivors of pediatric brain tumor.

OBJECTIVE: Survivors of pediatric brain tumors (SPBT) are at risk for social deficits, fewer friendships, and poor peer relations. SPBT also experience reduced brain connectivity via microstructural disruptions to white matter from neurological insults. Research with other populations implicates white matter connectivity as a key contributor to poor social functioning. This case-controlled diffusion-weighted imaging study evaluated structural connectivity in SPBT and typically developing controls (TDC) and associations between metrics of connectivity and social functioning. METHODS: Diffusion weighted-imaging results from 19 SPBT and 19 TDC were analyzed using probabilistic white matter tractography. Survivors were at least 5 years post-diagnosis and 2 years off treatment. Graph theory statistics measured group differences across several connectivity metrics, including average strength, global efficiency, assortativity, clustering coefficient, modularity, and betweenness centrality. Analyses also evaluated the effects of neurological risk on connectivity among SPBT. Correlational analyses evaluated associations between connectivity and indices of social behavior. RESULTS: SPBT demonstrated reduced global connectivity compared to TDC. Several medical factors (e.g., chemotherapy, recurrence, multimodal therapy) were related to decreased connectivity across metrics of integration (e.g., average strength, global efficiency) in SPBT. Connectivity metrics were related to peer relationship quality and social challenges in the SPBT group and to social challenges in the total sample. CONCLUSIONS: Microstructural white matter connectivity is diminished in SPBT and related to neurological risk and peer relationship quality. Additional neuroimaging research is needed to evaluate associations between brain connectivity metrics and social functioning in SPBT.

The Impact of Proactive Gastrostomy Tube Placement on Treatment-related Outcomes in Young Children With High-grade Central Nervous System Tumors.

Young children undergoing treatment with intensive chemotherapy for high-grade central nervous system (CNS) tumors are at risk for malnutrition, yet no guidelines exist for the placement of enteral tubes. Prior studies evaluated the impact of proactive gastrostomy tube (GT) placement with a narrow scope of outcomes, such as weight. To examine the impact of proactive GT on comprehensive treatment outcomes, we performed a single-center, retrospective study of children younger than 60 months of age with high-grade CNS tumors treated per CCG99703 or ACNS0334 between 2015 and 2022. Of 26 patients included, 9 (35%) underwent proactive GT, 8 (30%) had rescue GT, and 9 (35%) had a nasogastric tube (NGT). Clinically significant weight loss occurred in 47% of patients with NGT during induction compared with 22% with proactive GT ( P = 0.274); however, between cohorts, there was no significant difference in antibiotic or parenteral nutrition utilization, weight loss at therapy completion, and duration of hospitalization. Therefore, proactive GT placement was modestly effective at preventing significant weight loss during induction, however, there was no clear benefit for hospitalization duration, antibiotic, or parental nutrition requirements compared with NGT. We recommend an individualized approach to GT placement for young children with CNS malignancies undergoing intensive chemotherapy.

Reduced Fusiform Gyrus Activation During Face Processing in Pediatric Brain Tumor Survivors.

OBJECTIVE: The neural mechanisms contributing to the social problems of pediatric brain tumor survivors (PBTS) are unknown. Face processing is important to social communication, social behavior, and peer acceptance. Research with other populations with social difficulties, namely autism spectrum disorder, suggests atypical brain activation in areas important for face processing. This case-controlled functional magnetic resonance imaging (fMRI) study compared brain activation during face processing in PBTS and typically developing (TD) youth. METHODS: Participants included 36 age-, gender-, and IQ-matched youth (N = 18 per group). PBTS were at least 5 years from diagnosis and 2 years from the completion of tumor therapy. fMRI data were acquired during a face identity task and a control condition. Groups were compared on activation magnitude within the fusiform gyrus for the faces condition compared to the control condition. Correlational analyses evaluated associations between neuroimaging metrics and indices of social behavior for PBTS participants. RESULTS: Both groups demonstrated face-specific activation within the social brain for the faces condition compared to the control condition. PBTS showed significantly decreased activation for faces in the medial portions of the fusiform gyrus bilaterally compared to TD youth, ps ≤ .004. Higher peak activity in the left fusiform gyrus was associated with better socialization (r = .53, p < .05). CONCLUSIONS: This study offers initial evidence of atypical activation in a key face processing area in PBTS. Such atypical activation may underlie some of the social difficulties of PBTS. Social cognitive neuroscience methodologies may elucidate the neurobiological bases for PBTS social behavior.

Guideline for Children With Cancer Receiving General Anesthesia for Procedures and Imaging.

Children with cancer and those undergoing hematopoietic stem cell transplantation frequently require anesthesia for imaging as well as diagnostic and therapeutic procedures from diagnosis through follow-up. Due to their underlying disease and side effects of chemotherapy and radiation, they are at risk for complications during this time, yet no published guideline exists for preanesthesia preparation. A comprehensive literature review served as the basis for discussions among our multidisciplinary panel of oncologists, anesthesiologists, nurse practitioners, clinical pharmacists, pediatric psychologists, surgeons and child life specialists at the Children's Hospital of Philadelphia. Due to limited literature available, this panel created an expert consensus guideline addressing anesthesia preparation for this population.

Phase 1 study of sorafenib and irinotecan in pediatric patients with relapsed or refractory solid tumors.

BACKGROUND: Sorafenib,an orally bioavailable, multitarget tyrosine kinase inhibitor, and irinotecan, a topoisomerase I inhibitor, have demonstrated activity in pediatric and adult malignancies. We evaluated the toxicity, pharmacokinetic (PK), and pharmacogenomic (PGX) profile of sorafenib with irinotecan in children with relapsed or refractory solid tumors and assessed the feasibility of incorporating patient-reported outcome (PRO) measures as an adjunct to traditional endpoints. METHODS: Sorafenib, continuous oral twice daily dosing, was administered with irinotecan, orally, once daily days 1-5, repeated every 21 days (NCT01518413). Based on tolerability, escalation of sorafenib followed by escalation of irinotecan was planned. Three patients were initially enrolled at each dose level. Sorafenib and irinotecan PK analyses were performed during cycle 1. PRO measurements were collected during cycles 1 and 2. RESULTS: Fifteen patients were evaluable. Two of three patients at dose level 2 experienced dose-limiting toxicity (DLT), grade 3 diarrhea, and grade 3 hyponatremia. Therefore, dose level 1 was expanded to 12 patients and two patients had DLT, grade 4 thrombocytopenia, grade 3 elevated lipase. Nine of 15 (60%) patients had a best response of stable disease with four patients receiving ≥6 cycles. CONCLUSIONS: The recommended dose for pediatric patients was sorafenib 150 mg/m2 /dose twice daily with irinotecan 70 mg/m2 /dose daily × 5 days every 21 days. This oral outpatient regimen was well tolerated and resulted in prolonged disease stabilization. There were no significant alterations in the PK profile of either agent when administered in combination. Patients were willing and able to report their subjective experiences with this regimen.

Clinical diagnosis of attention-deficit/hyperactivity disorder in survivors of pediatric brain tumors.

PURPOSE: Survivors of pediatric brain tumors often have neurodevelopmental late effects, such as inattention. Symptoms may mirror those of attention-deficit/hyperactivity disorder (ADHD), which affects ~ 5-8% of the general population. This retrospective study of survivors followed at a large tertiary care center examined the prevalence of a clinical diagnosis of ADHD, and risk factors associated with ADHD diagnosis and ADHD-related medication use. METHODS: A retrospective chart review of brain tumor survivors (n = 528), diagnosed between 2000 and 2015, who were at least 6 years old and 2 years from the end of tumor-directed therapy or from diagnosis, if no interventions were received. Clinical and demographic data were extracted from the medical record. RESULTS: Survivors were 55.7% male with mean age 8.15 ± 4.4 (0.0-16.0) years at brain tumor diagnosis. The most common diagnoses were low-grade glioma, medulloblastoma, and craniopharyngioma, with 52.5% of tumors supratentorial. Of the survivors, 81.3% received surgery, 40.0% radiation therapy, and 36.6% chemotherapy. Sixty-nine survivors (13.1%) had ADHD diagnoses, 105 (19.9%) had symptoms of ADHD without diagnoses, and 64 (12.1%) had ADHD medication use. ADHD diagnosis was associated with younger age at tumor diagnosis (p = 0.05) and supratentorial tumor location (p = 0.001). ADHD diagnosis was not associated with gender, tumor type, or treatment type. CONCLUSIONS: Survivors of brain tumors are at increased risk of ADHD and related symptoms. The greatest increase in risk occurs for survivors with diagnoses at younger ages and supratentorial tumors. Additional research is warranted, as select survivors may benefit from behavioral or pharmacologic ADHD treatments to optimize functioning.

Carboplatin Rechallenge After Hypersensitivity Reactions in Pediatric Patients With Low-Grade Glioma.

BACKGROUND: The high prevalence of carboplatin hypersensitivity reactions (HSR) significantly affects the treatment of pediatric patients with low-grade glioma (LGG). Rechallenging patients is an option that must balance the risks of repeat allergic reaction to the benefits of retaining an effective anti-tumor regimen. PROCEDURE: We performed a retrospective review of children with LGG treated with carboplatin and vincristine between October 2000 and April 2013, who had a documented HSR to carboplatin. Patients were re-exposed to carboplatin using either precautionary measures (prolonged infusion time and premedication with H1 antagonists, H2 antagonists, and corticosteroids), a desensitization protocol, or both. RESULTS: We report the results of our institutional experience of carboplatin re-exposure using both premedication with a prolonged infusion time and a desensitization protocol. Overall, 40 of 55 (73%) patients were successfully rechallenged with carboplatin, including 19 of 25 (76%) patients who underwent desensitization. CONCLUSION: Our results demonstrate re-exposure to be a safe alternative to abandoning carboplatin for patients with a hypersensitivity reaction. We propose a clinical algorithm for treatment.

Everolimus for Children With Recurrent or Progressive Low-Grade Glioma: Results From the Phase II PNOC001 Trial.

PURPOSE: The PNOC001 phase II single-arm trial sought to estimate progression-free survival (PFS) associated with everolimus therapy for progressive/recurrent pediatric low-grade glioma (pLGG) on the basis of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway activation as measured by phosphorylated-ribosomal protein S6 and to identify prognostic and predictive biomarkers. PATIENTS AND METHODS: Patients, age 3-21 years, with progressive/recurrent pLGG received everolimus orally, 5 mg/m2 once daily. Frequency of driver gene alterations was compared among independent pLGG cohorts of newly diagnosed and progressive/recurrent patients. PFS at 6 months (primary end point) and median PFS (secondary end point) were estimated for association with everolimus therapy. RESULTS: Between 2012 and 2019, 65 subjects with progressive/recurrent pLGG (median age, 9.6 years; range, 3.0-19.9; 46% female) were enrolled, with a median follow-up of 57.5 months. The 6-month PFS was 67.4% (95% CI, 60.0 to 80.0) and median PFS was 11.1 months (95% CI, 7.6 to 19.8). Hypertriglyceridemia was the most common grade ≥3 adverse event. PI3K/AKT/mTOR pathway activation did not correlate with clinical outcomes (6-month PFS, active 68.4% v nonactive 63.3%; median PFS, active 11.2 months v nonactive 11.1 months; P = .80). Rare/novel KIAA1549::BRAF fusion breakpoints were most frequent in supratentorial midline pilocytic astrocytomas, in patients with progressive/recurrent disease, and correlated with poor clinical outcomes (median PFS, rare/novel KIAA1549::BRAF fusion breakpoints 6.1 months v common KIAA1549::BRAF fusion breakpoints 16.7 months; P < .05). Multivariate analysis confirmed their independent risk factor status for disease progression in PNOC001 and other, independent cohorts. Additionally, rare pathogenic germline variants in homologous recombination genes were identified in 6.8% of PNOC001 patients. CONCLUSION: Everolimus is a well-tolerated therapy for progressive/recurrent pLGGs. Rare/novel KIAA1549::BRAF fusion breakpoints may define biomarkers for progressive disease and should be assessed in future clinical trials.

Vinblastine/Methotrexate for Debilitating and Progressive Plexiform Neurofibroma in Children and Young Adults with Neurofibromatosis Type 1: A Phase 2 Study.

Limited therapies exist for neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN). For this reason, the activity of vinblastine (VBL) and methotrexate (MTX) was evaluated in children and young adults with NF1 and PN. Patients ≤ 25 years of age with progressive and/or inoperable NF1-PN received VBL 6 mg/m2 and MTX 30 mg/m2 weekly for 26 weeks, followed by every 2 weeks for 26 weeks. Objective response rate was the primary endpoint. Of 25 participants enrolled, 23 were evaluable. The median age of participants was 6.6 years (range 0.3-20.7). The most frequent toxicities were neutropenia and elevation of transaminases. On two-dimensional (2D) imaging, 20 participants (87%) had stable tumor, with a median time to progression of 41.5 months (95% confidence interval 16.9, 64.9). Two of eight participants (25%) with airway involvement demonstrated functional improvements including decreased positive pressure requirements and apnea-hypopnea index. A post hoc three-dimensional (3D) analysis of PN volumes was completed on 15 participants with amenable imaging; 7 participants (46%) had progressive disease on or by the end of therapy. VBL/MTX was well-tolerated but did not result in objective volumetric response. Furthermore, 3D volumetric analysis highlighted the lack of sensitivity of 2D imaging for PN response evaluation.

Efficacy of Nivolumab in Pediatric Cancers with High Mutation Burden and Mismatch Repair Deficiency.

PURPOSE: Checkpoint inhibitors have limited efficacy for children with unselected solid and brain tumors. We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively for refractory nonhematologic cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch repair deficiency (MMRD). PATIENTS AND METHODS: Twenty patients were screened, and 10 were ultimately included in the response cohort of whom nine had TMB >10 mut/Mb (three initially eligible based on MMRD) and one patient had TMB between 5 and 10 mut/Mb. RESULTS: Delayed immune responses contributed to best overall response of 50%, improving on initial objective responses (20%) and leading to 2-year overall survival (OS) of 50% [95% confidence interval (CI), 27-93]. Four children, including three with refractory malignant gliomas are in complete remission at a median follow-up of 37 months (range, 32.4-60), culminating in 2-year OS of 43% (95% CI, 18.2-100). Biomarker analyses confirmed benefit in children with germline MMRD, microsatellite instability, higher activated and lower regulatory circulating T cells. Stochastic mutation accumulation driven by underlying germline MMRD impacted the tumor microenvironment, contributing to delayed responses. No benefit was observed in the single patient with an MMR-proficient tumor and TMB 7.4 mut/Mb. CONCLUSIONS: Nivolumab resulted in durable responses and prolonged survival for the first time in a pediatric trial of refractory hypermutated cancers including malignant gliomas. Novel biomarkers identified here need to be translated rapidly to clinical care to identify children who can benefit from checkpoint inhibitors, including upfront management of cancer. See related commentary by Mardis, p. 4701.

A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study.

To estimate the sustained (≥8 weeks) objective response rate in pediatric patients with recurrent or progressive high-grade gliomas (HGG, Stratum A) or brainstem gliomas (BSG, Stratum B) treated with the combination of O6-benzylguanine (O6BG) and temozolomide(®) (TMZ). Patients received O6BG 120 mg/m(2)/d IV followed by TMZ 75 mg/m(2)/d orally daily for 5 consecutive days of each 28-day course. The target objective response rate to consider the combination active was 17%. A two-stage design was employed. Forty-three patients were enrolled; 41 were evaluable for response, including 25 patients with HGG and 16 patients with BSG. The combination of O6BG and TMZ was tolerable, and the primary toxicities were myelosuppression and gastrointestinal symptoms. One sustained (≥8 weeks) partial response was observed in the HGG cohort; no sustained objective responses were observed in the BSG cohort. Long-term (≥6 courses) stable disease (SD) was observed in 4 patients in Stratum A and 1 patient in Stratum B. Of the 5 patients with objective response or long-term SD, 3 underwent central review with 2 reclassified as low-grade gliomas. The combination of O6BG and TMZ did not achieve the target response rate for activity in pediatric patients with recurrent or progressive HGG and BSG.

Clinical significance of NTRK family gene expression in neuroblastomas.

BACKGROUND: Neuroblastomas (NBs) are characterized by clinical heterogeneity, from spontaneous regression to relentless progression. The pattern of NTRK family gene expression contributes to these disparate behaviors. TrkA/NTRK1 is expressed in favorable NBs that regress or differentiate, whereas TrkB/NTRK2 and its ligand brain-derived neurotrophic factor (BDNF) are co-expressed in unfavorable NBs, representing an autocrine survival pathway. We determined the significance of NTRK family gene expression in a large, representative set of primary NBs. PATIENTS AND METHODS: We analyzed the expression of the following genes in 814 NBs using quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR): NTRK1, NTRK2, NTRK3, P75/NGFR, nerve growth factor (NGF), BDNF, IGFR1, and EGFR. Expression (high vs. low) was dichotomized by median expression value and compared to clinical and biological variables as well as outcome. RESULTS: High NTRK1 expression was strongly correlated with favorable age, stage, MYCN status, histology, ploidy, risk group, and outcome (P < 0.0001 for all). However, it did not add significantly to the panel of prognostic variables currently used for cooperative group trials. NTRK2 expression was associated with risk factors but not with outcome. High NGF expression was also associated with most risk factors and weakly with unfavorable outcome. CONCLUSIONS: High expression of NTRK1 is strongly associated with favorable risk factors and outcome in a large, representative population of NB patients. It did not add significantly to the current risk prediction algorithm, but it may contribute to future expression classifiers. Indeed, prospective assessment of NTRK1 and NTRK2 expression will identify tumors that would be candidates for NTRK-targeted therapy, either alone or in combination with conventional agents.

Volumetric endpoints in diffuse intrinsic pontine glioma: comparison to cross-sectional measures and outcome correlations in the International DIPG/DMG Registry.

BACKGROUND: Cross-sectional tumor measures are traditional clinical trial endpoints; however volumetric measures may better assess tumor growth. We determined the correlation and compared the prognostic impact of cross-sectional and volumetric measures of progressive disease (PD) among patients with DIPG. METHODS: Imaging and clinical data were abstracted from the International DIPG Registry. Tumor volume and cross-sectional product (CP) were measured with mint Lesion™ software using manual contouring. Correlation between CP and volume (segmented and mathematical [ellipsoid] model) thresholds of PD were assessed by linear regression. Landmark analyses determined differences in survival (via log-rank) between patients classified as PD versus non-PD by CP and volumetric measurements at 1, 3, 5, 7, and 9 months postradiotherapy (RT). Hazard ratios (HR) for survival after these time points were calculated by Cox regression. RESULTS: A total of 312 MRIs (46 patients) were analyzed. Comparing change from the previous smallest measure, CP increase of 25% (PD) correlated with a segmented volume increase of 30% (R2 = 0.710), rather than 40% (spherical model extrapolation). CP-determined PD predicted survival at 1 month post-RT (HR = 2.77), but not other time points. Segmented volumetric-determined PD (40% threshold) predicted survival at all imaging timepoints (HRs = 2.57, 2.62, 3.35, 2.71, 16.29), and 30% volumetric PD threshold predicted survival at 1, 3, 5, and 9 month timepoints (HRs = 2.57, 2.62, 4.65, 5.54). Compared to ellipsoid volume, segmented volume demonstrated superior survival associations. CONCLUSIONS: Segmented volumetric assessments of PD correlated better with survival than CP or ellipsoid volume at most time points. Semiautomated tumor volume likely represents a more accurate, prognostically-relevant measure of disease burden in DIPG.

Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) generally occur 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-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .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 1 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.

Accuracy of central neuro-imaging review of DIPG compared with histopathology in the International DIPG Registry.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. METHODS: Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, <50% pontine involvement, focally exophytic morphology, sharply defined margins, and/or marked diffusion restriction throughout. RESULTS: Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. CONCLUSIONS: The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

Differential aminoacylase expression in neuroblastoma.

Neuroblastoma, a cancer of the sympathetic nervous system, is the most common extracranial solid tumor in children. MYCN amplification and increased BDNF/TrkB signaling are features of high-risk tumors; yet, only ˜25% of malignant tumors display these features. Thus, the identification of additional biomarkers and therapeutic targets is essential. As aminoacylase 1 (ACY1), an amino acid deacetylase, is a putative tumor suppressor in small cell lung and renal cell carcinomas, we investigated whether it or the other family members aspartoacylase (ASPA, aminoacylase 2) or aminoacylase 3 (ACY3) could serve a similar function in neuroblastoma. Aminoacylase expression was examined in TrkB-positive, MYCN-amplified (SMS-KCNR and SK-N-BE) and TrkB-negative, non-MYCN-amplified (SK-N-AS, SK-N-SH, SH-SY5Y and SH-EP) neuroblastoma cell lines. Each aminoacylase exhibited distinct spatial localization (i.e., cytosolic ACY1, membrane-associated ASPA and nuclear ACY3). When SK-N-SH cells were treated with neural differentiation agents (e.g., retinoic acid and cAMP) in media containing 10% serum, ACY1 was the only aminoacylase whose expression was upregulated. ASPA was primarily expressed in SH-EP cells of a glial sublineage. ACY3 was more highly expressed in the TrkB-positive, MYCN-amplified lines. All three aminoacylases were expressed in normal human adrenal gland, a common site of neuroblastoma origin, but only ACY1 and ACY3 displayed detectable expression in primary neuroblastoma tumor. Bioinformatics data mining of Kaplan-Meier survival revealed that high ACY3 expression is correlated with poor prognosis, whereas low expression of ACY1 or ASPA is correlated with poor prognosis. These data suggest that aminoacylase expression is dysregulated in neuroblastoma.

A phase II study of metronomic oral topotecan for recurrent childhood brain tumors.

BACKGROUND: The prognosis for recurrent or refractory brain tumors in children is poor with conventional therapies. Topotecan is a topoisomerase I inhibitor with good central nervous system (CNS) penetration following oral administration. Increased efficacy of topotecan has been demonstrated with prolonged low-dose daily treatment in pre-clinical models. To investigate further this drug delivered orally in pediatric CNS malignancies, a phase II study in children with recurrent or refractory brain tumors was performed. PROCEDURE: Patients ≤ 21 years of age at diagnosis with a recurrent, progressive, or refractory primary CNS malignancy and measurable disease, were eligible. Patients enrolled into four strata: ependymoma (N = 4), high-grade glioma (HGG) (N = 6), brainstem glioma (BSG) (N = 13), and primitive neuroectodermal tumor (PNET) (N = 8). Oral topotecan was administered once daily at a dose of 0.8 mg/m(2)/day for 21 consecutive days repeated every 28 days. Response and toxicity profiles were evaluated. RESULTS: Twenty-six patients were evaluable (median age 9.2 years; 10 males). Two objective responses were observed in PNET patients with disseminated tumor at study entry. These two patients remain alive and in remission 7 and 9.5 years off study. Four other patients (two BSG, one PNET, and one HGG) had stable disease (median 4.6 months). The most common toxicities were hematologic. CONCLUSIONS: Daily oral topotecan at a dose of 0.8 mg/m(2)/day can be safely administered to children with recurrent or refractory brain tumors. This regimen identified activity in recurrent PNET. The prolonged progression free survival (PFS) in two PNET patients justifies consideration of this regimen in more advanced clinical trials.

A rare case of ectopic recurrence of a craniopharyngioma diagnosed 17 years after initial presentation.

Ectopic recurrence of craniopharyngioma 17 years after initial diagnosis is exceedingly rare in pediatric neuro-oncology. Only 23 cases of ectopic recurrence in children with craniopharyngioma are described in the literature with a median time to recurrence of 3 years. We describe a patient diagnosed at 5 years of age, presenting with neck pain and ataxia 17 years after diagnosis. Her original follow-up care was fragmented and included surveillance imaging for 10 years after surgery and endocrine management of panhypopituitarism. Rare, extremely late relapse of this tumor highlights the importance of extended multidisciplinary follow-up care that includes neuro-oncologists in a late-effects/survivorship program.

A Pilot Study of Low-Dose Craniospinal Irradiation in Patients With Newly Diagnosed Average-Risk Medulloblastoma.

PURPOSE: Medulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (non-metastatic, completely resected) medulloblastoma includes craniospinal radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival of these patients, exposing the long-term morbidities associated with radiation therapy. Prior to advances in molecular subgrouping, we sought to reduce the late effects of radiation in patients with average-risk medulloblastoma. METHODS: We performed a single-arm, multi-institution study, reducing the dose of craniospinal irradiation by 25% to 18 Gray (Gy) with the goal of maintaining the therapeutic efficacy as described in CCG 9892 with maintenance chemotherapy. RESULTS: Twenty-eight (28) patients aged 3-30 years were enrolled across three institutions between April 2001 and December 2010. Median age at enrollment was 9 years with a median follow-up time of 11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were 79% (95% confidence interval [CI] 58% to 90%) and 93% (95% CI 74% to 98%), respectively. The 5-year RFS and OS were 71% (95% CI 50% to 85%) and 86% (95% CI 66% to 94%), respectively. Toxicities were similar to those seen in other studies; there were no grade 5 toxicities. CONCLUSIONS: Given the known neurocognitive adverse effects associated with cranial radiation therapy, studies to evaluate the feasibility of dose reduction are needed. In this study, we demonstrate that select patients with average-risk medulloblastoma may benefit from a reduced craniospinal radiation dose of 18 Gy without impacting relapse-free or overall survival. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00031590.

Trk receptor expression and inhibition in neuroblastomas.

Neuroblastoma, the most common and deadly solid tumor in children, exhibits heterogeneous clinical behavior, from spontaneous regression to relentless progression. Current evidence suggests that the TRK family of neurotrophin receptors plays a critical role in these diverse behaviors. Neuroblastomas expressing TrkA are biologically favorable and prone to spontaneous regression or differentiation, depending on the absence or presence of its ligand (NGF) in the microenvironment. In contrast, TrkB-expressing tumors frequently have MYCN amplification and are very aggressive and often fatal tumors. These tumors also express the TrkB ligand (BDNF), resulting in an autocrine or paracrine survival pathway. Exposure to BDNF promotes survival, drug resistance, and angiogenesis of TrkB-expressing tumors. Here we review the role of Trks in normal development, the different functions of Trk isoforms, and the major Trk signaling pathways. We also review the roles these receptors play in the heterogeneous biological and clinical behavior of neuroblastomas, and the activation of Trk receptors in other cancers. Finally we address the progress that has been made in developing targeted therapy with Trk-selective inhibitors to treat neuroblastomas and other tumors with activated Trk expression.