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.

A prospective study of family predictors of health-related quality of life in pediatric brain tumor survivors.

BACKGROUND: The objective of this study was to examine prospectively the associations between family functioning at the end of tumor-directed treatment and the health-related quality of life (HRQL) of pediatric brain tumor survivors (PBTSs) approximately 9 months later. PROCEDURE: Thirty-five PBTS (age 6-16 years) and their mothers completed measures of family functioning and survivor HRQL within 5 months of completing tumor-directed therapy (baseline) and again approximately 9 months later (follow-up). RESULTS: Survivor-rated general family functioning at baseline significantly predicted mother proxy- and self-reported survivor HRQL at follow-up when controlling for survivor HRQL at baseline and relevant demographic and treatment-related variables. CONCLUSIONS: Family functioning is a key factor contributing to survivor HRQL and should be screened throughout the course of tumor-directed treatment. Psychosocial interventions directed toward improving general family functioning may improve survivor well-being following the completion of treatment.

Pediatric Brain Tumors.

PURPOSE OF REVIEW: This article describes the most common pediatric brain tumors and highlights recent developments in their diagnosis and treatment strategies. RECENT FINDINGS: We are in the midst of a molecular era for pediatric brain tumors. Genetic and epigenetic profiling of tumors has impacted their diagnosis, allowing for the subgrouping of heterogeneous tumor groups and leading to the complete renaming of some tumor types. These advances are reflected in the new 2016 World Health Organization classification. For example, primitive neuroectodermal tumors have been completely eliminated and replaced by subgroups defined by the absence or presence of specific chromosomal amplification. Medulloblastomas, diffuse astrocytomas, and ependymomas now have specific subtypes that are based on defining molecular features. More recent epigenetic-based subgrouping of atypical teratoid/rhabdoid tumors have not yet made it into the official classification system, but will surely have an impact on how these tumors are regarded in future preclinical and clinical trials. SUMMARY: Genetic and epigenetic data are changing how pediatric brain tumors are diagnosed, are leading to new guidelines for how treatment outcome analyses can be organized, and are offering molecular targets that can be used for the development of novel therapies.

Neuroplastic Response After Radiation Therapy for Pediatric Brain Tumors: A Pilot Study.

PURPOSE: Clinically effective measurement of cognitive toxicity from photon radiation therapy (XRT) should be accurate, sensitive, and specific. This pilot study tested translational findings on phasic changes in children's memory systems that are sensitive and insensitive to toxic XRT effects to identify a possible neuroplastic effect. METHODS AND MATERIALS: Memory processes were prospectively tested before XRT and at 3 later time points up to 2 years in 35 children with mixed primary brain tumors who had not experienced recurrence. Memory processes were verbal-semantic, visual-semantic, and visual-perceptual, including accuracy, speed to recall, encoding, retrieval, and recognition. The mixed-effects model included time (to estimate slope), covariates (age, tumor locus, XRT field, and medications) as fixed effects, and individual random intercepts. A sensitivity analysis examined the influence of XRT dose to the hippocampi on memory. RESULTS: Retrieval from long-term verbal-semantic memory declined 2 months after completing XRT, as seen in adults, and was lowest at 1 year, which was delayed in comparison with adults. Double dissociation from visual-perceptual memory at baseline and 2 months was found, consistent with adults. Recovery was demonstrated 2 years after XRT. Patterns were unchanged when dose to hippocampus was included in the model. CONCLUSIONS: Verbal and semantic long-term retrieval is specifically sensitive to XRT-related cognitive dysfunction, without effect on visual-perceptual memory. Children reached nadir in XRT-sensitive memory 1 year after XRT and recovered by 2 years, which is later than that observed in adults. The protracted period of post-XRT injury may represent the maturation of the human hippocampus and white matter into late adolescence.

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.

Headache as a risk factor for neurovascular events in pediatric brain tumor patients.

OBJECTIVE: To determine whether severe recurrent headache is a risk factor for neurovascular events in children who received radiation for brain tumors. METHODS: This is a retrospective cohort study of children with brain tumors who received cranial irradiation at a large tertiary care center, aged 0-21 years at diagnosis, with initial treatment between January 1, 1993 and December 31, 2002, and 2 or more follow-up visits. Patients were considered to have severe recurrent headache if this appeared as a complaint on 2 or more visits. Headaches attributed to tumor progression, shunt malfunction, or infection, or appearing at the end of life, were excluded. Medical records were reviewed for events of stroke or TIA. RESULTS: Of 265 subjects followed for a median of 6.0 years (interquartile range 1.7-9.2 years), stroke or TIA occurred in 7/37 (19%) with severe headaches compared to 6/228 (3%) without these symptoms (hazard ratio 5.3, 95% confidence interval 1.8-15.9, p = 0.003). Adjusting for multiple variables did not remove the significance of this risk. Median time to first neurovascular event for the entire cohort was 4.9 years (interquartile range 1.7-5.5 years). CONCLUSIONS: Severe recurrent headache appears to be a risk factor or predictor for subsequent cerebral ischemia in pediatric brain tumor survivors treated with radiation. This finding has clinical implications for both monitoring survivors and targeting a specific population for primary stroke prevention.

Cranial irradiation increases risk of stroke in pediatric brain tumor survivors.

BACKGROUND AND PURPOSE: The purposes of this study were to determine the incidence of neurovascular events as late complications in pediatric patients with brain tumor and to evaluate radiation as a risk factor. METHODS: Patients were ascertained using the tumor database of a pediatric tertiary care center. Included patients had a primary brain tumor, age birth to 21 years, initial treatment January 1, 1993, to December 31, 2002, and at least 2 visits with neuro-oncology. Radiation exposure included: whole brain, whole brain plus a focal boost, or focal brain. The primary outcome was stroke or transient ischemic attack. RESULTS: Of 431 subjects, 14 had 19 events of stroke or transient ischemic attack over a median follow-up of 6.3 years. The incidence rate was 548/100 000 person-years. Overall, 61.5% of subjects received radiation, including 13 of 14 subjects with events. Median time from first radiation to first event was 4.9 years. The stroke/transient ischemic attack hazard ratio for any brain irradiation was 8.0 (95% CI, 1.05-62; P=0.045); for the circle of Willis, radiation was 9.0 (95% CI, 1.2-70; P=0.035); and for focal noncircle of Willis, radiation was 3.4 (95% CI, 0.21-55; P=0.38). CONCLUSIONS: The incidence of neurovascular events in this population is 100-fold higher than in the general pediatric population and cranial irradiation is an important risk factor. By defining the incidence of this late effect, physicians are better able to counsel parents regarding treatment, monitor patients at risk, and target a population for primary stroke prevention in future studies.

Phase measurement of cognitive impairment specific to radiotherapy.

PURPOSE: Memory impairment is an early-delayed effect of radiotherapy (RT). The prospective longitudinal measurement of the cognitive phase effects from RT was conducted on treated and untreated brain tumor patients. The study design investigated semantic vs. perceptual and visual vs. verbal memory to determine the most disease-specific measure of RT-related changes and understanding of the neurotoxicity from RT to the brain. METHODS AND MATERIALS: Tests of memory that had previously shown RT-related phasic changes were compared with experimental tests of memory to test hypotheses about cognition targeted to the neural toxicity of RT. The results from 41 irradiated and 29 nonirradiated patients with low-grade, supratentorial tumors were analyzed. The methods controlled for comorbid white matter risk, recurrence, interval after treatment, and age (18-69 years). The effects were examined before RT and at three points after RT to 1 year using a mixed effects model that included interval, group, surgical status, medication use, practice, and individual random effects. Four new tests of memory and other candidate cognitive tests were investigated, and a post hoc analysis of a comprehensive battery of tests was performed to identify the cognitive processes most specific to RT. RESULTS: The RT effects on memory were identified in the treated group only; among the new tests of memory and the complete neurocognitive battery, the RT effects were significant only for delayed recall (p < 0.009) and interval to recognize (p < 0.002). Tumor location was not related to the treatment effect. Memory decline was specific to retrieval of semantic memories; a double dissociation of semantic from perceptual visual memory was demonstrated in the RT group. CONCLUSIONS: These results implicate memory dependent on the semantic cortex and the hippocampal memory system. A cognitive measurement that is brief but specific to neural mechanisms is effective and feasible for studies of RT damage.

Retinal nerve fiber layer thickness in children with optic pathway gliomas.

PURPOSE: To determine the relationship of high-contrast visual acuity (VA) and low-contrast letter acuity with retinal nerve fiber layer (RNFL) thickness in children with optic pathway gliomas. DESIGN: Cross-sectional convenience sample, with prospective data collection, from a tertiary care children's hospital of patients with optic pathway gliomas associated with neurofibromatosis type 1, sporadic optic pathway gliomas, and neurofibromatosis type 1 without optic pathway gliomas. METHODS: Patients underwent best-corrected VA testing using surrounded H, O, T, V optotypes and low-contrast letter acuity (5%, 2.5%, and 1.25% low-contrast Sloan letter charts). Mean RNFL thickness (micrometers) was measured by a Stratus optical coherence tomography device (Carl Zeiss Meditec) using the fast RNFL thickness protocol. Eyes were classified as having abnormal vision if they had high-contrast VA of more than 0.1 logarithm of the minimal angle of resolution units or visual field loss. The association of subject age, glioma location, and RNFL thickness with both VA and low-contrast letter acuity scores was evaluated by 1-way analysis of variance and linear regression, using the generalized estimating equation approach to account for within-patient intereye correlations. RESULTS: Eighty-nine eyes of patients with optic pathway gliomas were included, and 41 were classified as having abnormal VA or visual field loss. Reduced RNFL thickness was associated significantly with higher logarithm of the minimal angle of resolution scores for both VA (P < .001) and all low-contrast letter acuity charts (P < .001) when accounting for age and glioma location. CONCLUSIONS: Eyes of most children with optic pathway gliomas and decreased RNFL thickness had abnormal VA or visual field loss.

The genetic landscape of the childhood cancer medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.

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.

Phase I trial of VNP40101M (Cloretazine) in children with recurrent brain tumors: a pediatric brain tumor consortium study.

PURPOSE: VNP40101M (Cloretazine), a novel DNA alkylating agent, was evaluated in a phase I study in children with recurrent brain tumors. EXPERIMENTAL DESIGN: VNP40101M was given i.v. daily for 5 consecutive days every 6 weeks for up to eight cycles. Dose escalation was done independently in patients stratified based on intensity of prior therapy (moderately pretreated, stratum I; heavily pretreated, stratum II). Correlative studies included pharmacokinetics and measurement of O(6)-alkylguanine-DNA alkyl transferase levels in peripheral blood mononuclear cells before and after treatment. RESULTS: Forty-one eligible patients (stratum I, 19; stratum II, 22) were enrolled on this study. The dose-limiting toxicity in 35 evaluable patients was myelosuppression, which occurred in 4 of 16 patients in stratum I and 3 of 19 patients in stratum II. Pharmacokinetic studies showed a median terminal half-life of 30 min (range, 14-39.5). The maximum tolerated dose in stratum I and II were 45 and 30 mg/m(2)/d daily for 5 days every 6 weeks, respectively. Peripheral blood mononuclear cells alkylguanine alkyl transferase levels did not decrease significantly after VNP40101M treatment. Central imaging review confirmed that three patients had stable disease for a median of 45 weeks (range, 37-61+) after therapy. CONCLUSIONS: The recommended dose of VNP40101M for phase II studies in children with brain tumors is 45 mg/m(2)/d in moderately pretreated and 30 mg/m(2)/d in heavily pretreated patients when administered for 5 consecutive days every 6 weeks.

The role of [18F]-fluorodeoxyglucose positron emission tomography in predicting plexiform neurofibroma progression.

BACKGROUND: The role of FDG-PET for managing patients with plexiform neurofibromas (PN) is unclear. While many PN tumors exhibit periods of rapid growth, others grow slowly or unpredictably and may have periods of relative quiescence. The ability to predict which PN are likely to progress should facilitate a more timely initiation of medical treatments. Since conventional radiographic techniques have limited prognostic value, the use of a functional imaging modality to predict tumor progression is desirable. We hypothesized that PN tumors with high metabolic activity as demonstrated by FDG-PET are more likely to progress in the following year. METHODS: All patients were clinically stable, but were considered at high-risk for progression based on anatomical location of PN. FDG-PET scans were performed within two weeks of the baseline MRI study. Standardized uptake values (SUV) were calculated for all focally active index lesions and analyzed for correlation with changes in quantitative MRI over the ensuing year. RESULTS: Fifteen of the 18 enrolled patients showed various degrees of FDG uptake as focal abnormalities, and these abnormalities corresponded to those noted on the MRI scans. Thirteen patients and 19 lesions were evaluable for PN volume change. The SUVmax ranged from 0.9 to 4 (median 1.5). There was a significant difference in the percent increase in PN volume in the following year for lesions that had an SUV > 2 compared to those with lower values (P = 0.016). CONCLUSIONS: These findings support the hypothesis that FDG-PET imaging predicts PN growth rate, and, therefore, may assist clinician decision making with regard to treatment of PN and enrollment in clinical trials.

Childhood intracranial ependymoma: twenty-year experience from a single institution.

BACKGROUND: Because few large studies of pediatric ependymoma treatment are available, the authors believed that a retrospective review of treatment outcomes from a single institution would yield potentially valuable information regarding potential prognostic factors. In this article, they report their 20-year institutional experience with this disease. METHODS: Medical records were reviews of patients with intracranial ependymoma who received their initial treatment at the Children's Hospital of Philadelphia (CHOP)/Hospital of the University of Pennsylvania (HUP) between January 1980 and December 2000. Of the 61 patients who were identified, 49 patients underwent primary therapy at CHOP/HUP and formed the basis for the study. Actuarial overall survival (OS) and progression-free survival (PFS) were determined by the Kaplan-Meier method. Univariate and multivariate analyses were performed using the log-rank test and Cox proportional-hazards models. RESULTS: With median follow-up of 110.2 months, the 5-year OS and PFS rates were 66.2% and 40.7%, respectively. Older age and higher radiation dose significantly predicted for improved OS. Anaplastic histology predicted for decreased PFS. Cervical spinal cord extension resulted in decreased OS primarily caused by failures outside the primary site. Patients who had a favorable prognosis (aged >/=3 years, no dissemination or cord extension, complete resection, and radiation dose >/=54 grays [Gy]) had 5-year OS and PFS rates of 83.1% and 60.6%, respectively. CONCLUSIONS: In this study of patients with pediatric intracranial ependymoma, OS and PFS rates were concordant with the rates published in other modern series. The finding of a dose response up to 54 Gy supported the current trend toward dose escalation. Tumor extension to the cervical spine was identified as a predictor for failure outside of the primary site. Although the survival rates were encouraging, there is still significant room for improvement in the management of this disease.

Temozolomide in children with progressive low-grade glioma.

We conducted a phase II study to assess the efficacy of oral temozolomide (TMZ) in children with progressive low-grade glioma. Thirty eligible patients were enrolled on this study. Median age at enrollment was 10 years (range, 4-18 years). Eligible patients received TMZ (200 mg/m(2) per day) by mouth for five days every four weeks. Patients received a median of nine cycles (range, 2-12 cycles) of treatment. Best responses in the 26 patients (86%) with optic pathway glioma (OPG)/pilocytic astrocytoma (PA) included partial response in 3 patients (11%), minor response in 1 (4%), stable disease in 10 (38%), and progressive disease in 12 (46%). Only one of four patients with fibrillary astrocytoma had stable disease for 29 months after TMZ. The overall disease stabilization rate in patients with OPG/PA was 54%, and disease control was maintained for a median interval of 34 months. Seventeen of 26 patients had progressive disease either on or off therapy, and three have died of disease. The two-year progression-free and overall survivals in patients with OPG/PA were 49% (95% CI, 30%-67%) and 96% (95% CI, 89%-100%), respectively. Worst toxicity related to TMZ in all 30 patients included grade 2-4 thrombocytopenia in seven patients, grade 2-4 neutropenia in seven, grade 2 skin rash in one, and intratumor hemorrhage in one. TMZ given in this schedule was successful in stabilizing disease in a significant proportion of the patients with OPG/PA, with manageable toxicity.

Gliomatosis cerebri: 20 years of experience at the Children's Hospital of Philadelphia.

BACKGROUND: Gliomatosis cerebri (GC) is a rare and typically fatal glial neoplasm of the central nervous system. In this report, the authors describe the largest cohort of children to date with GC and explore relations between potential prognostic factors, treatment, and survival. METHODS: Imaging, pathologic, and outcome data were reviewed from 13 patients who were diagnosed with GC and were treated at the Children's Hospital of Philadelphia (CHOP) between 1982 and 2005. All patients had GC confirmed by biopsy. Twelve patients received cranial irradiation, and 8 of those patients received adjuvant chemotherapy. A single patient age 1 year received chemotherapy alone. A review of the literature identified 51 pediatric patients with GC. RESULTS: The progression-free survival rate in this study was 13% (range, 1.5-43 months), and the overall survival (OS) rate was 64% (range, 6.5-67 months) at 2 years. OS was significantly shorter for patients who presented in the first decade of life (P = .04). The time to progression was prolonged significantly for patients who had no evidence of tumor enhancement on imaging studies (P = .03). When survival data from patients reported in the literature were combined with the CHOP cohort, treatment prolonged OS significantly (P = .003). CONCLUSIONS: The outcome of pediatric patients with GC was extremely poor; however, the current results indicated that treatment may prolong OS. Age < 10 years and contrast enhancement on magnetic resonance imaging studies at diagnosis may be risk factors for shorter survival in pediatric patients with GC.

Ifosfamide-induced nephrotoxicity: mechanism and prevention.

The efficacy of ifosfamide (IFO), an antineoplastic drug, is severely limited by a high incidence of nephrotoxicity of unknown etiology. We hypothesized that inhibition of complex I (C-I) by chloroacetaldehyde (CAA), a metabolite of IFO, is the chief cause of nephrotoxicity, and that agmatine (AGM), which we found to augment mitochondrial oxidative phosphorylation and beta-oxidation, would prevent nephrotoxicity. Our model system was isolated mitochondria obtained from the kidney cortex of rats treated with IFO or IFO + AGM. Oxidative phosphorylation was determined with electron donors specific to complexes I, II, III, or IV (C-I, C-II, C-III, or C-IV, respectively). A parallel study was done with (13)C-labeled pyruvate to assess metabolic dysfunction. Ifosfamide treatment significantly inhibited oxidative phosphorylation with only C-I substrates. Inhibition of C-I was associated with a significant elevation of [NADH], depletion of [NAD], and decreased flux through pyruvate dehydrogenase and the TCA cycle. However, administration of AGM with IFO increased [cyclic AMP (cAMP)] and prevented IFO-induced inhibition of C-I. In vitro studies with various metabolites of IFO showed that only CAA inhibited C-I, even with supplementation with 2-mercaptoethane sulfonic acid. Following IFO treatment daily for 5 days with 50 mg/kg, the level of CAA in the renal cortex was approximately 15 micromol/L. Taken together, these observations support the hypothesis that CAA is accumulated in renal cortex and is responsible for nephrotoxicity. AGM may be protective by increasing tissue [cAMP], which phosphorylates NADH:oxidoreductase. The current findings may have an important implication for the prevention of IFO-induced nephrotoxicity and/or mitochondrial diseases secondary to defective C-I.

Phase I trial of intrathecal spartaject busulfan in children with neoplastic meningitis: a Pediatric Brain Tumor Consortium Study (PBTC-004).

PURPOSE: A phase I trial of intrathecal Spartaject Busulfan (SuperGen, Inc., San Ramon, CA) was conducted in children with neoplastic meningitis following recurrent primary brain tumors to describe toxicities, estimate the maximum tolerated dose (MTD), and document evidence of responses to this agent. EXPERIMENTAL DESIGN: The continuous reassessment method was used to assign cohorts of patients to doses of intrathecal Spartaject Busulfan via an Ommaya reservoir and/or lumbar puncture twice weekly for 2 weeks followed by an assessment of toxicity and response. Patients with stable disease or an objective response continued to receive intrathecal Spartaject Busulfan plus systemic chemotherapy at regular intervals. Cerebrospinal fluid and blood were obtained for pharmacokinetic studies in patients with Ommaya reservoirs after the first dose of intrathecal Spartaject Busulfan. Seven evaluable patients were assigned to the starting dose of 5 mg, two patients to 7.5 mg, three patients to 10 mg, seven patients to 13 mg, and four patients to 17 mg. RESULTS: Between September 2000 and May 2003, 28 patients were enrolled in this study. Twenty-three patients (median age, 8.8 years; range, 2.5-19.5 years) were evaluable for estimating the MTD, and dose-limiting toxicities were observed in three and included grade 3 vomiting (n = 1 at 5 mg), grade 3 headache (n = 1 at 17 mg), and grade 3 arachnoiditis (n = 1 at 17 mg). Pharmacokinetic data showed that post-infusion concentrations of busulfan ranged from 50 to 150 microg/mL and declined to <1 microg/mL within 5 hours. CONCLUSIONS: Intrathecal Spartaject Busulfan was well tolerated in children with neoplastic meningitis from brain tumors, and the recommended dose for future phase II studies is 13 mg.

Anticancer effects of fenretinide in human medulloblastoma.

N-(4-hydroxyphenyl) retinamide (4-HPR, fenretinide) a synthetic retinoid is in clinical trials for the treatment of several malignancies. However, its biological effects and therapeutic value in childhood brain tumor medulloblastoma (MB) has not been investigated. In this study, we report for the first time that fenretinide (2.5-10 microM) induces apoptotic cell death in human MB cells. We observed significant inhibition of cell survival in four MB cell lines (D425MED, D458MED, D283MED and D341MED) as determined by MTT assays. These results were further supported by inhibition of anchorage-independent colony formation in soft agar. Fenretinide-induced decrease in cell viability was in part due to activation of caspase-3 dependent cell death, which was further supported by the cleavage of poly(ADP-ribose) polymerase-1 (PARP-1), a caspase-3 substrate. Cell death was partially prevented by the antioxidant, l-ascorbic acid suggesting that free radical intermediates might be involved in fenretinide effects. These results suggest that pharmacologically achievable concentrations of fenretinide are effective in killing MB cells and thus show its therapeutic potential to treat human MB.

Anticancer effects of the novel 1alpha, 25-dihydroxyvitamin D3 hybrid analog QW1624F2-2 in human neuroblastoma.

Vitamin D3 analogs are potential anti-cancer agents with theoretically wide therapeutic index, but there have been limited studies directed towards human neuroblastoma. The antiproliferative ability of the novel vitamin D3 hybrid analog QW-1624F2-2 (QW, 1-hydroxymethyl-16-ene-24, 24-F2-26, 27-bishomo-25-hydroxyvitamin D3) was examined in two human neuroblastoma-derived cell-lines. Analog QW inhibited cell-cycle progression of IMR5 cells with accumulation in G1 phase. QW induced the differentiation of CHP134 as evidenced by increased neurite length. These effects were accompanied by decreased expression of MYCN in both the cell-lines treated with QW. Furthermore, QW inhibited the migration of CHP134 cells in matrigel invasion assays, indicating its anti-invasive ability. In athymic nude mice, we found that QW was less calcemic than EB1089 (1alpha, 25-dihydroxy-22, 24-diene-24, 26,27-trishomovitamin D3). Systemic administration of QW in a mouse xenotransplantation model revealed that it is more effective than EB1089 in suppressing the growth of CHP134 flank tumors. In summary, the low-calcemic hybrid analog QW showed significant anti-tumor activity in vivo and thus exhibits potential as a novel cancer therapeutic.