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Purpose Thalidomide, originally developed as a sedative, was subsequently identified to have antiangiogenic properties. Lenalidomide is an antiangiogenic and immunomodulatory agent that has been utilized in the treatment of patients with brain tumors. We studied the pharmacokinetics and cerebrospinal fluid (CSF) penetration of thalidomide and lenalidomide in a nonhuman primate model. Methods A dose of 50 mg of thalidomide or 20 mg of lenalidomide was administered once orally to each of three rhesus monkeys. Plasma and CSF samples were obtained at specified intervals, and the thalidomide or lenalidomide concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods. CSF penetration was calculated as area under the concentration–time curve (AUC) CSF/AUC plasma. Results For thalidomide, the median apparent clearance (Cl/F) was 2.9 mL/min/kg, the median plasma AUC was 80 μM h, and the median terminal half-life (t ½ ) was 13.3 h. For lenalidomide, the median Cl/F was 8.7 mL/min/kg, the median AUC was 9 μM h, and the median t ½ was 5.6 h. Thalidomide was detected in the CSF of all animals, with a median penetration of 42%. Lenalidomide was detected in the CSF of 2 of 3 animals, with a CSF penetration of 11% in each. Conclusion Thalidomide and lenalidomide penetrate into the CSF after oral administration of clinically relevant doses. Plasma exposure to lenalidomide was similar in our model to that observed in studies involving children who have brain tumors. These results support further development of lenalidomide for the treatment of central nervous system malignancies.

Abstract BACKGROUND: Previous studies using recombinant human bone morphogenetic protein-2 (rhBMP-2) in the adult lumbar spine have shown consistently good results. There have been no pediatric case series. OBJECTIVE: To determine the safety and efficacy of rhBMP-2 use in posterior instrumented fusions of the pediatric population. METHODS: A retrospective review of 19 consecutive pediatric patients who underwent posterior occiptocervical, cervical, thoracic, lumbar, or lumbosacral spine fusion from October 1, 2007, to June 30, 2008, at Texas Children's Hospital was performed. The average age was approximately 12 years old (range, 9 months to 20 years). The minimum follow-up was 17 months (average of 19 months, range: 17–25 months), with computed tomography (CT) evaluation and grading of fusion by an independent radiologist at 3 months after surgery. RESULTS: The average CT grade was 3, indicating bilateral bridging bone. No pseudoarthroses or loss of correction was identified clinically or radiographically at 3 months and latest follow-up. There was one complication of bony overgrowth and restenosis of the spinal canal necessitating reoperation, and two superficial wound infections. There were no deep wound infections. CONCLUSION: Early outcomes using rhBMP-2 in the pediatric population show that it is a safe and efficacious adjunct to posterior spine fusions of the occipitocervical, cervical, thoracic, lumbar, and lumbosacral spine. It dependably results in the development of stable bridging bone at 3 months after surgery with good maintenance of correction and stability in long-term follow-up. Lessons learned from the case of unexpected bony overgrowth are discussed.

Locomotor training (LT) enhances walking in adult experimental animals and humans with mild-to-moderate spinal cord injuries (SCIs). The animal literature suggests that the effects of LT may be greater on an immature nervous system than on a mature nervous system. The purpose of this study was to evaluate the effects of LT in a child with chronic, incomplete SCI. The subject was a nonambulatory 4 1/2-year-old boy with an American Spinal Injury Association Impairment Scale (AIS) C Lower Extremity Motor Score (LEMS) of 4/50 who was deemed permanently wheelchair-dependent and was enrolled in an LT program 16 months after a severe cervical SCI. A pretest-posttest design was used in the study. Over 16 weeks, the child received 76 LT sessions using both treadmill and over-ground settings in which graded sensory cues were provided. The outcome measures were ASIA Impairment Scale score, gait speed, walking independence, and number of steps. One month into LT, voluntary stepping began, and the child progressed from having no ability to use his legs to community ambulation with a rolling walker. By the end of LT, his walking independence score had increased from 0 to 13/20, despite no change in LEMS. The child's final self-selected gait speed was 0.29 m/s, with an average of 2,488 community-based steps per day and a maximum speed of 0.48 m/s. He then attended kindergarten using a walker full-time. A simple, context-dependent stepping pattern sufficient for community ambulation was recovered in the absence of substantial voluntary isolated lower-extremity movement in a child with chronic, severe SCI. These novel data suggest that some children with severe, incomplete SCI may recover community ambulation after undergoing LT and that the LEMS cannot identify this subpopulation.

Purpose ABT-888 inhibits poly(ADP-ribose) polymerase (PARP) and may enhance the efficacy of chemotherapy and radiation in CNS tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of ABT-888 in a non-human primate (NHP) model that is highly predictive of human CSF penetration. Methods ABT-888, 5 mg/kg, was administered orally to three NHPs. Serial blood and CSF samples were obtained. Plasma and CSF concentrations of ABT-888 were measured using LC/MS/MS, and the resulting concentration versus time data were evaluated using non-compartmental and compartmental PK methods. Results The CSF penetration of ABT-888 was 57 ± 7% (mean ± SD). The peak ABT-888 concentration in the plasma was 0.62 ± 0.18 μM. Plasma and CSF AUC₀₋∞ were 3.7 ± 1.7 and 2.1 ± 0.8 μM h. PARP inhibition in peripheral blood mononuclear cells was evident 2 h after ABT-888 administration. Conclusion The CSF penetration of ABT-888 after oral administration was 57%. Plasma and CSF concentrations were in the range that has been shown to inhibit PARP activity in vivo in humans.

Little to no pediatric or neurosurgical literature has been published about the complications of ventriculoperitoneal shunt procedures for hydrocephalus associated with vein of Galen malformations in childhood. The interventional neuroradiology literature, however, suggests that ventriculoperitoneal shunting as first-line treatment for hydrocephalus in children with vein of Galen malformations is fraught with short- and long-term dangers, including status epilepticus, intraventricular hemorrhage, subdural hematoma and hygroma, venous infarction, malignant dystrophic calcification, and worsening developmental delay. We present a single pediatric case where a ventriculoperitoneal shunt procedure for symptomatic hydrocephalus seemed to be the major contributing factor to the rapid neurological deterioration and eventual death of an infant with a vein of Galen malformation. Based on this experience and our review of the literature, we suggest the use of endovascular embolization of the vein of Galen malformation to reestablish a balance in hydrovenous dynamics as first-line treatment rather than directly addressing hydrocephalus with CSF diversion. The ventriculoperitoneal shunt procedure should be reserved for cases with symptomatic hydrocephalus in which the patient is a poor candidate for embolization, or for cases where endovascular therapy has already been maximized. The role of endoscopy in the treatment of hydrocephalus associated with vein of Galen malformations is not clear.

The authors report a rare case of primary disseminated intradural malignant peripheral nerve sheath tumor (MPNST) of the spine in a 5-year-old child without neurofibromatosis type I (NF-I). This child presented with abdominal pain and gait disturbance. MRI revealed a large intradural extramedullary tumor at C4–5 with dissemination to the thoracic spine, cauda equina and leptomeninges. Following a 2-level cervical laminectomy, the tumor was biopsied and debulked. Based on pathological and immunohistological findings, the tumor was diagnosed as an MPNST. Because of the rarity of this pathological entity, a review of the literature was performed. The reported clinical outcomes for adult and pediatric patients with intradural MPNST are very poor. No established standard for the treatment of these tumors exists. We report the first pediatric case – without or with NF-I – of disseminated intradural MPNST primarily localized proximal to the conus medullaris. It must always be considered in the differential diagnosis for intradural extramedullary tumors of the pediatric spine, along with neurofibromas and schwannomas, even in children without NF-I.

Intracranial germ cell tumours are rare tumours affecting mainly male adolescents, mainly in Asia; here the authors identify frequent mutations in the KIT/RAS and AKT/mTOR signalling pathways as well as rare germline variants in JMJD1C, suggesting potential therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway. Analysis of a rare brain tumour Relatively little is known about intracranial germ cell tumours (IGCTs) — rare tumours affecting principally male adolescents and mainly in Asia. Using exome sequencing, deep-targeted sequencing and SNP array the authors examined 62 IGCT patients and identified frequent mutations in the KIT/RAS and AKT/mTOR signalling pathways as well as rare germline variants in JMJD1C, a histone demethylase and coactivator of the androgen receptor. This study suggests potential therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway. Intracranial germ cell tumours (IGCTs) are a group of rare heterogeneous brain tumours that are clinically and histologically similar to the more common gonadal GCTs. IGCTs show great variation in their geographical and gender distribution, histological composition and treatment outcomes. The incidence of IGCTs is historically five- to eightfold greater in Japan and other East Asian countries than in Western countries 1 , with peak incidence near the time of puberty 2 . About half of the tumours are located in the pineal region. The male-to-female incidence ratio is approximately 3–4:1 overall, but is even higher for tumours located in the pineal region 3 . Owing to the scarcity of tumour specimens available for research, little is currently known about this rare disease. Here we report the analysis of 62 cases by next-generation sequencing, single nucleotide polymorphism array and expression array. We find the KIT/RAS signalling pathway frequently mutated in more than 50% of IGCTs, including novel recurrent somatic mutations in KIT , its downstream mediators KRAS and NRAS , and its negative regulator CBL . Novel somatic alterations in the AKT/mTOR pathway included copy number gains of the AKT1 locus at 14q32.33 in 19% of patients, with corresponding upregulation of AKT1 expression. We identified loss-of-function mutations in BCORL1 , a transcriptional co-repressor and tumour suppressor. We report significant enrichment of novel and rare germline variants in JMJD1C , which codes for a histone demethylase and is a coactivator of the androgen receptor, among Japanese IGCT patients. This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potentially promising therapeutic strategies focusing on the inhibition of KIT/RAS activation and the AKT1/mTOR pathway.

The growth pattern of pilocytic astrocytoma (PAs) is unpredictable. Gene expression profiling has recently demonstrated an inverse relationship between myelin basic protein (MBP) expression and progression free survival (PFS) in PAs. We present here the pattern of expression of oligodendroglial differentiation markers (ODMs) in PAs by immunohistochemistry and their correlation with PI and PFS. Sixty-four cases of PA were reviewed and representative sections were stained for Ki-67 and ODMs, including MBP, platelet-derived growth factor receptor-α (PDGFR-α), Olig-1, and Olig-2. Sections were graded semi-quantitatively for intensity (I: 0–3+) and extent (E: 0–4+) of staining. PI was expressed as a percentage of Ki-67 positive cells. Immunoreactivity of MBP, PDGFR-α, Olig-1, and Olig-2 was observed in 84, 56, 97, and 75% of cases, respectively. There was a statistically significant inverse correlation between MBP expression and PI ( r 2  = .696, p   = .014). A positive correlation was observed between PDGFR-α and PI ( r 2  = .727, p   = .011). Further analysis showed a significant difference in PFS between low expressors [I + E score ≤ 3] and high expressors (I + E score ≥ 4) for PDGFR-α with p   < .001. Notably, there was a significant difference in PFS between high expressors of MBP and high expressors of PDGFR-α with p   < .001. These results suggest that expression of ODMs, especially MBP and PDGFR-α, may identify two clinical subsets of PA. In addition, we have shown the expression of 4 different ODMs in PAs, which may support the possibility that PAs arise from oligodendrocyte progenitor/precursor cells probably similar to the O2A progenitor cells in the mouse.

Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. After resection, patients were classified as having average-risk medulloblastoma (≤1·5 cm 2 residual tumour and no metastatic disease) or high-risk medulloblastoma (>1·5 cm 2 residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23·4 Gy for average-risk disease and 36·0–39·6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with ClinicalTrials.gov, number NCT00003211. Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75–94) in patients in the average-risk group and 70% (54–84) in those in the high-risk group (p=0·04); 5-year event-free survival was 83% (73–93) and 70% (55–85), respectively (p=0·046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0·04): 84% (74–95) for classic histology, 77% (49–100) for desmoplastic tumours, and 57% (33–80) for large-cell anaplastic tumours. Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma.