Corticospinal Wallerian Degeneration Before Myelination: A Case Report.

Wallerian degeneration is defined as axonal fiber and myelin sheath degeneration that affects myelinated axons within the peripheral or central nervous system. Wallerian degeneration or anterograde axonal degeneration before myelination is rarely reported. Involvement of both corticospinal tracts (CSTs) is rarely documented in the literature. We present the postmortem neuropathologic findings of a 1-week-old male neonate born at 23 weeks of gestation with bilateral CST degeneration extending from the posterior limb of the internal capsule through the brainstem into the lumbar spinal cord. Abundant CD68- and CD163-positive macrophages were the prominent histopathology in both CSTs. The cerebrum, brainstem, and spinal cord were unmyelinated, as expected. In contrast, the spinal nerve roots demonstrated early myelination. This case illustrates that Wallerian degeneration occurs in unmyelinated axis cylinders.

Hypoxia-ischemia is not an antecedent of most preterm brain damage: the illusion of validity.

Brain injury in preterm newborn infants is often attributed to hypoxia-ischemia even when neither hypoxia nor ischemia is documented, and many causative speculations are based on the same assumption. We review human and animal study contributions with their strengths and limitations, and conclude that - despite all the work done in human fetal neuropathology and developmental models in animals - the evidence remains unconvincing that hypoxemia, in the fetus or newborn infant, contributes appreciably to any encephalopathy of prematurity. Giving an inappropriate causal name to a disorder potentially limits the options for change, should our understanding of the etiologies advance. The only observationally-based title we think appropriate is 'encephalopathy of prematurity'. Future pathophysiological research should probably include appropriately designed epidemiology studies, highly active developmental processes, infection and other inflammatory stimuli, the immature immune system, long chain fatty acids and their transporters, and growth (neurotrophic) factors. WHAT THIS PAPER ADDS: Fetal hypoxemia is rarely documented in brain injury studies. Animal studies fail to consider human-animal fetal anatomical differences. Putative treatments from animal models have not found clinical use. Observational studies constitute the only approach to etiological understanding. No convincing evidence yet that hypoxemia injures preterm brain. Encephalopathy of prematurity is preferable to hypoxia-ischemia as a term for this disorder. Encephalopathy of prematurity is preferable to hypoxia-ischemia as a term for this disorder.

Impact of tumor location and pathological discordance on survival of children with midline high-grade gliomas treated on Children's Cancer Group high-grade glioma study CCG-945.

Children with high-grade glioma (HGG) have a poor prognosis compared to those with low-grade glioma (LGG). Adjuvant chemotherapy may be beneficial, but its optimal use remains undetermined. Histology and extent of resection are important prognostic factors. We tested the hypothesis that patients with midline HGG treated on Children's Cancer Group Study (CCG) CCG-945 have a worse prognosis compared to the entire group. Of 172 children eligible for analysis, 60 had midline tumors primarily localized to the thalamus, hypothalamus and basal ganglia. Time-to-progression and death were determined from the date of initial diagnosis, and survival curves were calculated. Univariate analyses were undertaken for extent of resection, chemotherapy regimen, anatomic location, histology, proliferation index, MGMT status and p53 over-expression. For the entire midline tumor group, 5-year PFS and OS were 18.3 ± 4.8 and 25 ± 5.4 %, respectively. Many patients only had a biopsy (43.3 %). The sub-groups with near/total resection and hypothalamic location appeared to have better PFS and OS. However, the effect of tumor histology on OS was significant for children with discordant diagnoses on central pathology review of LGG compared to HGG. Proliferative index (MIB-1 > 36 %), MGMT and p53 over-expression correlated with poor outcomes. Children treated on CCG-945 with midline HGG have a worse prognosis when compared to the entire group. The midline location may directly influence the extent of resection. Central pathology review and entry of patients on clinical trials continue to be priorities to improve outcomes for children with HGG.

Combined MRI and MRS improves pre-therapeutic diagnoses of pediatric brain tumors over MRI alone.

INTRODUCTION: The specific goal of this study was to determine whether the inclusion of MRS had a measureable and positive impact on the accuracy of pre-surgical MR examinations of untreated pediatric brain tumors over that of MRI alone in clinical practice. METHODS: Final imaging reports of 120 pediatric patients with newly detected brain tumors who underwent combined MRI/MRS examinations were retrospectively reviewed. Final pathology was available in all cases. Group A comprised 60 subjects studied between June 2001 and January 2005, when MRS was considered exploratory and radiologists utilized only conventional MRI to arrive at a diagnosis. For group B, comprising 60 subjects studied between January 2005 and March 2008, the radiologists utilized information from both MRI and MRS. Furthermore, radiologists revisited group A (blind review, time lapse >4 years) to determine whether the additional information from MRS would have altered their interpretation. RESULTS: Sixty-three percent of patients in group A were diagnosed correctly, whereas in 10% the report was partially correct with the final tumor type mentioned (but not mentioned as most likely tumor), while in 27% of cases the reports were wrong. For group B, the diagnoses were correct in 87%, partially correct in 5%, and incorrect in 8% of the cases, which is a significant improvement (p < 0.005). Re-review of combined MRI and MRS of group A resulted 87% correct, 7% partially correct, and 7% incorrect diagnoses, which is a significant improvement over the original diagnoses (p < 0.05). CONCLUSION: Adding MRS to conventional MRI significantly improved diagnostic accuracy in preoperative pediatric patients with untreated brain tumors.

A retrospective analysis of recurrent intracranial ependymoma.

BACKGROUND: Recurrence occurs in almost 50% of patients with intracranial ependymoma, and their outcome following recurrence is poor. METHODS: We retrospectively reviewed the medical records of 22 patients with intracranial ependymoma and subsequent relapse(s) (59 recurrences) treated at Children's Hospital Los Angeles or New York University between January 1997 and December 2012. RESULTS: Median duration of follow-up was 52 months (7-171 months). Median age at initial diagnosis was 4 years (0.3-19 years) with 8 patients younger than 3 years at presentation. Eleven patients had anaplastic and 11 cellular pathologies. Eighteen patients had infratentorial tumors at diagnosis and 3 (all infratentorial) had metastatic spinal cord involvement at presentation. Cerebrospinal fluid involvement was not identified at diagnosis or relapse. Median time to first recurrence was 16 months (1.3 to 115 months). The number of recurrences in each patient ranged from 1 to 9 (median = 2). Thirty-seven recurrences (63%) were detected asymptomatically by surveillance imaging. Fifteen recurrences (26%) arose outside the initial tumor site. Recurrences were treated by surgical resection (45), with irradiation (30), and with various oral chemotherapies (23) with (7) or without (16) conventional chemotherapy. The 5 and 10 year overall survival rates from first recurrence were 0.37 ± 0.14 and 0.25 ± 0.14. CONCLUSION: Prolonged (5-10 year) survival from first relapse was noted in over one-quarter of our patients. It remains unclear whether early radiographic diagnosis, differing treatment modalities beyond radical surgical resection or possibly unrecognized biological differences contributed towards this prolonged survival.

Long-term survival of children less than six years of age enrolled on the CCG-945 phase III trial for newly-diagnosed high-grade glioma: a report from the Children's Oncology Group.

BACKGROUND: We analyzed the long-term survival of children under 6 years of age (<6 years) enrolled upon the Children's Cancer Group (CCG)-945 high-grade glioma (HGG) study to determine the impact of intrinsic biological characteristics as well as treatment upon both survival and quality of life (QOL) in this younger age population. PROCEDURE: Analyses were undertaken on patients <6 years with institutionally diagnosed HGG enrolled on the CCG-945 trial. Comparisons of survival were performed for patients <3 years of age (<3 years) (treated with intent to avoid irradiation) versus those between 3 and 6 years of age (3-6 years) (treated with irradiation and chemotherapy) at diagnosis. Discordance between the institutional diagnoses of HGG and consensus-reviewed diagnoses led us to perform further survival analyses for both groups. We compared the two groups of patients for biological markers, and evaluated the neuropsychological and QOL outcomes of long-term survivors. RESULTS: Patients <3 years (n = 49, 19.5% of all enrolled patients) at diagnosis had a 10-year EFS and OS of 29 ± 6.5% and 37.5 ± 7%, respectively, while for patients 3-6 years (n = 34, 13.5% of all enrolled patients) 10-year EFS and OS were 35 ± 8% and 36 ± 8%, respectively. Molecular marker analysis showed that a smaller proportion of patients <3 years harbored TP53 mutations (P = 0.05). Analysis of QOL outcomes with a median length of follow-up of 15.1 years (9.5-19.2) showed comparable results. CONCLUSIONS: QOL and survival data were similar for the two groups. A larger prospective study is justified to study the efficacy of chemotherapy only regimens in younger children.

Metabolic maturation of the human brain from birth through adolescence: insights from in vivo magnetic resonance spectroscopy.

Between birth and late adolescence, the human brain undergoes exponential maturational changes. Using in vivo magnetic resonance spectroscopy, we determined the developmental profile for 6 metabolites in 5 distinct brain regions based on spectra from 309 children from 0 to 18 years of age. The concentrations of N-acetyl-aspartate (an indicator for adult-type neurons and axons), creatine (energy metabolite), and glutamate (excitatory neurotransmitter) increased rapidly between birth and 3 months, a period of rapid axonal growth and synapse formation. Myo-inositol, implicated in cell signaling and a precursor of membrane phospholipid, as well as an osmolyte and astrocyte marker, declined rapidly during this period. Choline, a membrane metabolite and indicator for de novo myelin and cell membrane synthesis, peaked from birth until approximately 3 months, and then declined gradually, reaching a plateau at early childhood. Similarly, taurine, involved in neuronal excitability, synaptic potentiation, and osmoregulation, was high until approximately 3 months and thereafter declined. These data indicate that the first 3 months of postnatal life are a critical period of rapid metabolic changes in the development of the human brain. This study of the developmental profiles of the major brain metabolites provides essential baseline information for future analyses of the pediatric health and disease.

Final report of the phase II NEXT/CNS-GCT-4 trial: GemPOx followed by marrow-ablative chemotherapy for recurrent intracranial germ cell tumors.

Background: Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx). Methods: A total of 9 patients with confirmed relapsed or refractory intracranial GCT were enrolled after signing informed consent, and received at least 2 cycles of GemPOx, of which all but 1 had relapsed or refractory NGGCTs. One patient with progressive disease was found to have pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma (without GCT elements), hence was ineligible and not included in the analysis. Patients who experienced sufficient responses proceeded to receive HDCx with AuHPCR. Treatment response was determined based on radiographic tumor assessments and tumor markers. Results: A total of 7 patients achieved sufficient response and proceeded with HDCx and AuHPCR, and 5 subsequently received additional radiotherapy. A total of 2 patients developed progressive disease while receiving GemPOx. Myelosuppression and transaminitis were the most common treatment-related adverse events. With a mean follow-up of 44 months, 4 patients (3 NGGCTs, 1 germinoma) are alive without evidence of disease. Conclusions: GemPOx demonstrates efficacy in facilitating stem cell mobilization, thus facilitating the feasibility of both HDCx and radiotherapy.

Choroid plexus tumors; management, outcome, and association with the Li-Fraumeni syndrome: the Children's Hospital Los Angeles (CHLA) experience, 1991-2010.

BACKGROUND: Choroid plexus tumors (CPT) are rare, and predominate in early childhood. An association with the Li-Fraumeni syndrome (LFS) has been reported, but the biological and clinical implications of this association remain poorly defined. We have investigated the clinical features and overall survival of all CPT patients treated at Children's Hospital Los Angeles (CHLA) over a 20-year period, with particular attention to the association of CPT with LFS. METHODS: A retrospective evaluation of the course of therapy and clinical outcome was undertaken on the 42 patients diagnosed with and treated for CPT at CHLA from January 1991 to December 2010. Any association with multiple primary tumors and family histories consistent with LFS was investigated in all patients. RESULTS: Six of the 42 patients (16.7%), demonstrated either phenotypic and/or genotypic characteristics consistent with LFS, with either a distinct family history of cancer, a synchronous diagnosis of a different type of cancer, or the subsequent development of metachronous cancers. Of 11 patients with choroid plexus carcinoma tested for TP53 germline mutations, four (36.4%) were positive. A single patient with a choroid plexus papilloma had phenotypic characteristics of LFS but tested negative for TP53. CONCLUSIONS: Children with CPC appear to have a high frequency of TP53 germline mutations in association with LFS. This raises the question whether all children with CPC should be tested for TP53 germline mutations in order to institute screening to enhance early detection and treatment of subsequent cancers.

Treatment of primary CNS germinomatous germ cell tumors with chemotherapy prior to reduced dose whole ventricular and local boost irradiation.

BACKGROUND: The purpose of this study was to evaluate a reduced irradiation dose strategy for newly diagnosed primary central nervous system (CNS) germinomas. METHODS: Twenty patients with histologically diagnosed localized pure germinoma (n = 19) or germinoma with a mature teratoma component (n = 1) received four cycles of carboplatin and etoposide at 3-week intervals. In 18 patients, chemotherapy was followed by whole ventricular irradiation to 21.6-25.5 Gy with a simultaneous integrated or sequential primary site boost to 30-30.6 Gy. Initial tumor markers for beta-human chorionic gonadotrophin (HCGbeta) and alpha-fetoprotein (AFP) were evaluated in serum and lumbar cerebrospinal fluid (CSF). Endoscopic biopsies were performed in 12 patients and partial resections in the remaining 8 patients at diagnosis. Neurocognitive function was evaluated periodically following treatment. RESULTS: Eighteen of 20 patients are without evidence of residual or recurrent tumor. Both relapsing patients were subsequently determined to harbor malignant non-germinomatous germ cell tumor (NGGCT). This retrospective study shows that the Kaplan-Meier estimates of event-free survival (EFS) and overall survival (OS) at 3 years for all 20 patients were 89.5 +/- 7.1% and 100%, respectively. Neurocognitive function was well preserved in all 19 evaluable patients. CONCLUSION: Chemotherapy followed by reduced dose whole ventricular and local boost irradiation appears to be effective in patients with localized pure CNS germinoma with evidence of preservation of neurocognitive function.

Mismatch repair deficiency is an uncommon mechanism of alkylator resistance in pediatric malignant gliomas: a report from the Children's Oncology Group.

BACKGROUND: Alkylating agents are commonly used in the treatment of childhood malignant gliomas. Overexpression of O(6)-methylguanine-DNA methyltransferase (MGMT) constitutes an important mechanism for resistance to such agents, and MGMT status has been associated with outcome in several recent trials. Deficiency in mismatch repair (MMR) function has been implicated in preclinical studies as an additional potential mechanism of resistance to methylating agents, such as temozolomide, independent of tumor MGMT status. However, the frequency of this abnormality as a clinical resistance mechanism in childhood malignant gliomas has not been well characterized. METHODS: To address this issue, we examined the frequency of microsatellite instability (MSI), a marker of defective MMR, in a series of 68 tumors, derived from newly diagnosed patients treated on the Children's Cancer Group 945 study, and the Children's Oncology Group ACNS0126 and 0423 studies. MSI was assessed using a panel of six microsatellite markers, including BAT-25, BAT-26, CAT-25, D2S123, D5S346, and D17S250. MGMT immunoreactivity was assessed in parallel to allow comparison of the relative incidence of MGMT overexpression and MSI. RESULTS: Only three tumors had high-level MSI involving three or more markers; the remainder had no MSI at any of the loci examined. These children did not have unusual features in terms of their outcome. In contrast to the infrequency of MSI, 25 tumors (37%) exhibited MGMT overexpression as assessed by immunohistochemistry. None of the tumors with MSI exhibited overexpression of MGMT. CONCLUSION: MMR deficiency is an infrequent contributor to initial alkylator resistance in children with malignant gliomas.

Excellent outcome of young children with nodular desmoplastic medulloblastoma treated on "Head Start" III: a multi-institutional, prospective clinical trial.

BACKGROUND: "Head Start" III, was a prospective clinical trial using intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) to either avoid or reduce the dose/volume of irradiation in young children with medulloblastoma. METHODS: Following surgery, patients received 5 cycles of induction followed by myeloablative chemotherapy using carboplatin, thiotepa, and etoposide with AuHCR. Irradiation was reserved for children >6 years old at diagnosis or with residual tumor post-induction. RESULTS: Between 2003 and 2009, 92 children <10 years old with medulloblastoma were enrolled. Five-year event-free survival (EFS) and overall survival (OS) rates (±SE) were 46 ±â€…5% and 62 ±â€…5% for all patients, 61 ±â€…8% and 77 ±â€…7% for localized medulloblastoma, and 35 ±â€…7% and 52 ±â€…7% for disseminated patients. Nodular/desmoplastic (ND) medulloblastoma patients had 5-year EFS and OS (±SE) rates of 89 ±â€…6% and 89 ±â€…6% compared with 26 ±â€…6% and 53 ±â€…7% for classic and 38 ±â€…13% and 46 ±â€…14% for large-cell/anaplastic (LCA) medulloblastoma, respectively. In multivariate Cox regression analysis, histology was the only significant independent predictor of EFS after adjusting for stage, extent of resection, regimen, age, and sex (P <0.0001). Five-year irradiation-free EFS was 78 ±â€…8% for ND and 21 ±â€…5% for classic/LCA medulloblastoma patients. Myelosuppression was the most common toxicity, with 2 toxic deaths. Twenty-four survivors completed neurocognitive evaluation at a mean of 4.9 years post-diagnosis. IQ and memory scores were within average range overall, whereas processing speed and adaptive functioning were low-average. CONCLUSION: We report excellent survival and preservation of mean IQ and memory for young children with ND medulloblastoma using high-dose chemotherapy, with most patients surviving without irradiation.

Metabolism of diffuse intrinsic brainstem gliomas in children.

Progress in the development of effective therapies for diffuse intrinsic brainstem gliomas (DIBSGs) is compromised by the unavailability of tissue samples and the lack of noninvasive markers that can characterize disease status. The purpose of this study was to compare the metabolic profile of DIBSGs with that of astrocytomas elsewhere in the CNS and to determine whether the measurement of metabolic features can improve the assessment of disease status. Forty in vivo MR spectroscopy (MRS) studies of 16 patients with DIBSG at baseline and after radiation therapy were retrospectively reviewed. Control data for baseline studies of DIBSGs were obtained from 14 untreated regular and anaplastic astrocytomas. All spectra were acquired with single-voxel, short echo-time (35 ms), point-resolved spectroscopy. Absolute metabolite concentrations (mmol/kg) and lipid intensities (arbitrary units) were determined. At baseline, creatine and total choline (tCho) were significantly lower in DIBSGs than in astrocytomas elsewhere in the CNS (4.3 +/- 1.1 vs. 7.5 +/- 1.9 mmol/kg, p < 0.001; 1.9 +/- 0.7 vs. 4.2 +/- 2.6, p < 0.001). Serial MRS in individual subjects revealed increasing levels of tCho (p < 0.05) and lipids (p < 0.05) and reduced ratios of N-acetylaspartate, creatine, and myoinositol relative to tCho (all p < 0.01). Metabolic progression defined by increased tCho concentration in serial MRS preceded clinical deterioration by 2.4 +/- 2.7 months (p < 0.04). Low tCho of DIBSG at baseline is consistent with low proliferative tumors. Subsequent metabolic changes that have been associated with malignant degeneration preceded clinical deterioration. MRS provides early surrogate markers for disease progression.

Evaluation of age-dependent treatment strategies for children and young adults with pineoblastoma: analysis of pooled European Society for Paediatric Oncology (SIOP-E) and US Head Start data.

Background: Pineoblastoma is a rare pineal region brain tumor. Treatment strategies have reflected those for other malignant embryonal brain tumors. Patients and Methods: Original prospective treatment and outcome data from international trial groups were pooled. Cox regression models were developed considering treatment elements as time-dependent covariates. Results: Data on 135 patients with pineoblastoma aged 0.01-20.7 (median 4.9) years were analyzed. Median observation time was 7.3 years. Favorable prognostic factors were age ≥4 years (hazard ratio [HR] for progression-free survival [PFS] 0.270, P < .001) and administration of radiotherapy (HR for PFS 0.282, P < .001). Metastatic disease (HR for PFS 2.015, P = .006), but not postoperative residual tumor, was associated with unfavorable prognosis. In 57 patients <4 years old, 5-year PFS/overall survival (OS) were 11 ± 4%/12 ± 4%. Two patients survived after chemotherapy only, while 3 of 16 treated with craniospinal irradiation (CSI) with boost, and 3 of 5 treated with high-dose chemotherapy (HDCT) and local radiotherapy survived. In 78 patients aged ≥4 years, PFS/OS were 72 ± 7%/73 ± 7% for patients without metastases, and 50 ± 10%/55 ± 10% with metastases. Seventy-three patients received radiotherapy (48 conventionally fractionated CSI, median dose 35.0 [18.0-45.0] Gy, 19 hyperfractionated CSI, 6 local radiotherapy), with (n = 68) or without (n = 6) chemotherapy. The treatment sequence had no impact; application of HDCT had weak impact on survival in older patients. Conclusion: Survival is poor in young children treated without radiotherapy. In these patients, combination of HDCT and local radiotherapy may warrant further evaluation in the absence of more specific or targeted treatments. CSI combined with chemotherapy is effective for older non-metastatic patients.

The influence of central review on outcome in malignant gliomas of the spinal cord: the CCG-945 experience.

OBJECT The impact of central pathology review on outcome has been described in pediatric patients with high-grade glioma (HGG). The objective of this report was to analyze the impact of the central pathology review on outcome in the subgroup of patients with institutional diagnosis of HGG of the spinal cord enrolled in the Children's Cancer Group 945 cooperative study. METHODS Five neuropathologists centrally reviewed the pathology of the 18 patients with HGG of the spinal cord who were enrolled in the study. These reviews were independent, and reviewers were blinded to clinical history and outcomes. A consensus diagnosis was established for each patient, based on the outcome of the review. RESULTS Of 18 patients, only 10 were confirmed to have HGG on central review. At a median follow-up of 12 years, event-free and overall survival for all 18 patients was 43.2% ± 13.3% and 50% ± 13.4%, respectively. After central review, 10-year event-free and overall survival for confirmed HGGs and discordant diagnoses was 30% ± 12.5% versus 58.3% ± 18.8% (p = 0.108) and 30% ± 12.5% versus 75% ± 14.2% (p = 0.0757), respectively. CONCLUSIONS The level of discordant diagnoses in children and adolescents with institutional diagnosis of HGG of the spinal cord was 44% in this experience. However, there was no significant difference in outcome between patients with confirmed and discordant diagnosis. This group of tumor deserves a specific attention in future trials.

Molecular subgroups of medulloblastoma identification using noninvasive magnetic resonance spectroscopy.

BACKGROUND: Medulloblastomas in children can be categorized into 4 molecular subgroups with differing clinical characteristics, such that subgroup determination aids in prognostication and risk-adaptive treatment strategies. Magnetic resonance spectroscopy (MRS) is a widely available, noninvasive tool that is used to determine the metabolic characteristics of tumors and provide diagnostic information without the need for tumor tissue. In this study, we investigated the hypothesis that metabolite concentrations measured by MRS would differ between molecular subgroups of medulloblastoma and allow accurate subgroup determination. METHODS: MRS was used to measure metabolites in medulloblastomas across molecular subgroups (SHH = 12, Groups 3/4 = 17, WNT = 1). Levels of 14 metabolites were analyzed to determine those that were the most discriminant for medulloblastoma subgroups in order to construct a multivariable classifier for distinguishing between combined Group 3/4 and SHH tumors. RESULTS: Medulloblastomas across molecular subgroups revealed distinct spectral features. Group 3 and Group 4 tumors demonstrated metabolic profiles with readily detectable taurine, lower levels of lipids, and high levels of creatine. SHH tumors showed prominent choline and lipid with low levels of creatine and little or no evidence of taurine. A 5-metabolite subgroup classifier inclusive of creatine, myo-inositol, taurine, aspartate, and lipid 13a was developed that could discriminate between Group 3/4 and SHH medulloblastomas with excellent accuracy (cross-validated area under the curve [AUC] = 0.88). CONCLUSIONS: The data show that medulloblastomas of Group 3/4 differ metabolically as measured using MRS when compared with SHH molecular subgroups. MRS is a useful and accurate tool to determine medulloblastoma molecular subgroups.

Developmental neuropathology of the second half of gestation.

In this review we focus primarily on the events taking place in the second half of gestation. At second trimester end, human brain weight gain accelerates rapidly. Germinal matrix attains maximal absolute volume, only to ablate 50% over two gestational weeks. At 10 weeks of gestation interhemispheric, choroidal, and transverse fissures exist. Germinal matrix hemorrhages peak during its devolution and some of these rupture into the lateral ventricle. By 28 weeks homologous primary sulci are present, having appeared in both hemispheres at slightly different gestational ages. Secondary sulcation, during the third trimester, is hemispherically unique. Despite emphasis on neuronal vulnerability, prevalence of lesions in white matter exceeds that of gray matter and, within white matter, diffuse white matter astrocytosis prevalence exceeds that of focal necroses. Gray matter hypotensive lesions most commonly occur in the upper brainstem and thalami followed by convexity borderzone lesions causing sclerotic microgyria. White matter hypoplasia with normal gray matter volume is sometimes associated with hypomyelination.

Differentiation of choroid plexus tumors by advanced magnetic resonance spectroscopy.

OBJECT: The management of pediatric intraventricular tumors is highly dependent on identification of the tumor type. Choroid plexus papillomas, a common intraventricular tumor in children, can be difficult to distinguish radiographically from choroid plexus carcinomas and other common pediatric central nervous system (CNS) tumors. In this study to overcome the limitations of current noninvasive imaging modalities, the authors use novel magnetic resonance (MR) spectroscopy techniques in vivo to elucidate the identifying biochemical features of choroid plexus tumors that may facilitate diagnosis and treatment. METHODS: Based on an Internal Review Board-approved protocol, six children with newly diagnosed, untreated intraventricular brain tumors were identified. On retrospective review, this series included three choroid plexus papillomas and three choroid plexus carcinomas. Single-voxel proton MR spectroscopy with a short echo time was performed, and absolute metabolite concentrations (in mmol/kg) were determined using fully automated quantitation. These results were compared with MR spectroscopy profiles obtained in 54 other untreated CNS neoplasms in children. The myo-inositol (mI) level was significantly higher in choroid plexus papillomas (> 10 mmol/kg), uniquely distinguishing these tumors from choroid plexus carcinomas and all other tumors. Choroid plexus carcinomas, on the other hand, had significantly elevated levels of choline when compared with choroid plexus papillomas. CONCLUSIONS: In this study the authors find that mI is a biochemical constituent that uniquely identifies choroid plexus papillomas and can be used as a noninvasive means of diagnosis and for follow-up evaluations in patients with this disease.

Disseminated Medulloblastoma in a Child with Germline BRCA2 6174delT Mutation and without Fanconi Anemia.

Medulloblastoma, the most common malignant brain tumor in children, occurs with increased frequency in individuals with Fanconi anemia who have biallelic germline mutations in BRCA2. We describe an 8-year-old child who had disseminated anaplastic medulloblastoma and a deleterious heterozygous BRCA2 6174delT germline mutation. Molecular profiling was consistent with Group 4 medulloblastoma. The posterior fossa mass was resected and the patient received intensive chemotherapy and craniospinal irradiation. Despite this, the patient succumbed to a second recurrence of his medulloblastoma, which presented 8 months after diagnosis as malignant pleural and peritoneal effusions. Continuous medulloblastoma cell lines were isolated from the original tumor (CHLA-01-MED) and the malignant pleural effusion (CHLA-01R-MED). Here, we provide their analyses, including in vitro and in vivo growth, drug sensitivity, comparative genomic hybridization, and next generation sequencing analysis. In addition to the BRCA2 6174delT, the medulloblastoma cells had amplification of MYC, deletion at Xp11.2, and isochromosome 17, but no structural variations or overexpression of GFI1 or GFI1B. To our knowledge, this is the first pair of diagnosis/recurrence medulloblastoma cell lines, the only medulloblastoma cell lines with BRCA2 6174delT described to date, and the first reported case of a child with medulloblastoma associated with a germline BRCA2 6174delT who did not also have Fanconi anemia.

Tumor-associated macrophages in SHH subgroup of medulloblastomas.

PURPOSE: Medulloblastoma in children can be categorized into at least four molecular subgroups, offering the potential for targeted therapeutic approaches to reduce treatment-related morbidities. Little is known about the role of tumor microenvironment in medulloblastoma or its contribution to these molecular subgroups. Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms. In this study, we investigated the hypothesis that expression of genes related to tumor-associated macrophages (TAM) correlates with the medulloblastoma molecular subgroups and contributes to a diagnostic signature. METHODS: Gene-expression profiling using human exon array (n = 168) was analyzed to identify medulloblastoma molecular subgroups and expression of inflammation-related genes. Expression of 45 tumor-related and inflammation-related genes was analyzed in 83 medulloblastoma samples to build a gene signature predictive of molecular subgroups. TAMs in medulloblastomas (n = 54) comprising the four molecular subgroups were assessed by immunohistochemistry (IHC). RESULTS: A 31-gene medulloblastoma subgroup classification score inclusive of TAM-related genes (CD163 and CSF1R) was developed with a misclassification rate of 2%. Tumors in the Sonic Hedgehog (SHH) subgroup had increased expression of inflammation-related genes and significantly higher infiltration of TAMs than tumors in the Group 3 or Group 4 subgroups (P < 0.0001 and P < 0.0001, respectively). IHC data revealed a strong association between location of TAMs and proliferating tumor cells. CONCLUSIONS: These data show that SHH tumors have a unique tumor microenvironment among medulloblastoma subgroups. The interactions of TAMs and SHH medulloblastoma cells may contribute to tumor growth revealing TAMs as a potential therapeutic target.