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1.  Isolation and Characterization of a Population of Stem-like Progenitor Cells From an Atypical Meningioma 
The majority of meningiomas are benign tumors associated with favorable outcomes; however, the less common aggressive variants with unfavorable outcomes often recur and may be due to sub-populations of less-differentiated cells residing within the tumor. These sub-populations of tumor cells have tumor-initiating properties and may be isolated from heterogeneous tumors when sorted or cultured in defined medium. We report the isolation and characterization of a population of tumor-initiating cells derived from an atypical meningioma.
We identify a tumor-initiating population from an atypical meningioma, termed meningioma-initiating cells (MICs). These MICs self-renew, differentiate, and can recapitulate the histological characteristics of the parental tumor when transplanted at 1,000 cells into the flank regions of athymic nude mice. Immunohistochemistry reveals stem-like protein expression patterns similar to neural stem and progenitor cells (NSPCs) while genomic profiling verified the isolation of cancer cells (with defined meningioma chromosomal aberrations) from the bulk tumor. Microarray and pathway analysis identifies biochemical processes and gene networks related to aberrant cell cycle progression, particularly the loss of heterozygosity of tumor suppressor genes CDKN2A (p16INK4A), p14ARF, and CDKN2B (p15INK4B). Flow cytometric analysis revealed the expression of CD44 and activated leukocyte adhesion molecule (ALCAM/CD166); these may prove to be markers able to identify this cell type. The isolation and identification of a tumor-initiating cell population capable of forming meningiomas demonstrates a useful model for understanding meningioma development. This meningioma model may be used to study the cell hierarchy of meningioma tumorogenesis and provide increased understanding of malignant progression.
PMCID: PMC3048914  PMID: 21168406
Atypical meningioma; microarray; progenitor cell; malignant progression; molecular genetics
2.  Induction Chemotherapy and Conformal Radiation Therapy for Very Young Children With Nonmetastatic Medulloblastoma: Children's Oncology Group Study P9934 
Journal of Clinical Oncology  2012;30(26):3181-3186.
P9934 was a prospective trial of systemic chemotherapy, second surgery, and conformal radiation therapy (CRT) limited to the posterior fossa and primary site for children between 8 months and 3 years old with nonmetastatic medulloblastoma. The study was open from June 2000 until June 2006.
Patients and Methods
After initial surgery, children received four cycles of induction chemotherapy, followed by age- and response-adjusted CRT to the posterior fossa (18 or 23.4 Gy) and tumor bed (cumulative 50.4 or 54 Gy) and maintenance chemotherapy. Neurodevelopmental outcomes were evaluated and event-free survival (EFS) results were directly compared with a previous study of multiagent chemotherapy without irradiation (Pediatric Oncology Group [POG] trial 9233).
Seventy-four patients met eligibility requirements. The 4-year EFS and overall survival probabilities were 50% ± 6% and 69% ± 5.5%, respectively, which compared favorably to the results from POG 9233. Analysis showed that the desmoplastic/nodular subtype was a favorable factor in predicting survival. Our 4-year EFS rate was 58% ± 8% for patients with desmoplasia. Whereas seven of 10 patients who had disease progression before CRT had primary-site failure, 15 of 19 patients who progressed after CRT had distant-site failure. Neurodevelopmental assessments did not show a decline in cognitive or motor function after protocol-directed chemotherapy and CRT.
The addition of CRT to postoperative chemotherapy in young children with nonmetastatic medulloblastoma increased event-free survival compared with the use of postoperative chemotherapy alone. Future studies will use histopathologic typing (desmoplastic/nodular versus nondesmoplastic/nodular) to stratify patients for therapy by risk of relapse.
PMCID: PMC3434977  PMID: 22851568
3.  Oncogenic Brain Metazoan Parasite Infection 
Multiple observations suggest that certain parasitic infections can be oncogenic. Among these, neurocysticercosis is associated with increased risk for gliomas and hematologic malignancies. We report the case of a 71-year-old woman with colocalization of a metazoan parasite, possibly cysticercosis, and a WHO grade IV neuroepithelial tumor with exclusively neuronal differentiation by immunohistochemical stains (immunopositive for synaptophysin, neurofilament protein, and Neu-N and not for GFAP, vimentin, or S100). The colocalization and temporal relationship of these two entities suggest a causal relationship.
PMCID: PMC3789294  PMID: 24151568
4.  Gliomas: Predicting Time to Progression or Survival with Cerebral Blood Volume Measurements at Dynamic Susceptibility-weighted Contrast-enhanced Perfusion MR Imaging1 
Radiology  2008;247(2):490-498.
To retrospectively determine whether relative cerebral blood volume (CBV) measurements can be used to predict clinical outcome in patients with high-grade gliomas (HGGs) and low-grade gliomas (LGGs) and specifically whether patients who have gliomas with a high initial relative CBV have more rapid progression than those who have gliomas with a low relative CBV.
Materials and Methods
Approval for this retrospective HIPAA-compliant study was obtained from the Institutional Board of Research Associates, with waiver of informed consent. One hundred eighty-nine patients (122 male and 67 female patients; median age, 43 years; range, 4–80 years) were examined with dynamic susceptibility-weighted contrast material–enhanced perfusion magnetic resonance (MR) imaging and were followed up clinically with MR imaging (median follow-up, 334 days). Log-rank tests were used to evaluate the association between relative CBV and time to progression by using Kaplan-Meier curves. Binary logistic regression was used to determine whether age, sex, and relative CBV were associated with an adverse event (progressive disease or death).
Values for the mean relative CBV for patients according to each clinical response were as follows: 1.41 ± 0.13 (standard deviation) for complete response (n = 4), 2.36 ± 1.78 for stable disease (n = 41), 4.84 ± 3.32 for progressive disease (n = 130), and 3.82 ± 1.93 for death (n = 14). Kaplan-Meier estimates of median time to progression in days indicated that patients with a relative CBV of less than 1.75 had a median time to progression of 3585 days, whereas patients with a relative CBV of more than 1.75 had a time to progression of 265 days. Age and relative CBV were also independent predictors for clinical outcome.
Dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging can be used to predict median time to progression in patients with gliomas, independent of pathologic findings. Patients who have HGGs and LGGs with a high relative CBV (>1.75) have a significantly more rapid time to progression than do patients who have gliomas with a low relative CBV.
PMCID: PMC3774106  PMID: 18349315
5.  Baló’s concentric sclerosis: imaging findings and pathological correlation 
Baló’s concentric sclerosis is a primary inflammatory central nervous system demyelinating disease that is considered a rare, radiographically and pathologically distinct variant of multiple sclerosis. Baló’s concentric sclerosis is characterized by alternating rings of demyelinated and myelinated axons, and it is most frequently diagnosed postmortem by autopsy or, more recently, by magnetic resonance imaging without pathologic verification. This report is of a case of Baló’s concentric sclerosis in which the patient presented with left-sided focal sensorimotor deficits. The patient’s lesion demonstrated characteristics of Baló’s concentric sclerosis by magnetic resonance imaging, but since a neoplastic process was also suspected initially, the patient underwent a surgical biopsy. This pathology sample now provides the opportunity to correlate the tissue diagnosis of demyelination with characteristic magnetic resonance imaging findings; this comparison is infrequently found in the literature.
PMCID: PMC3888114  PMID: 24421937
Baló’s concentric sclerosis; demyelinating disease; MRI; Pathology
6.  Histology predicts a favorable outcome in young children with desmoplastic medulloblastoma: A report from the Children’s Oncology Group 
Cancer  2011;117(14):3262-3267.
Contemporary therapy for medulloblastoma results in adverse neurocognitive effects on young children, particularly those under the age of three. Stratification of patients by risk group may allow toxic treatment to be avoided.
76 patients diagnosed with medulloblastoma and enrolled on CCG-9921 underwent central review of pathology, and histologic subtype was designated as desmoplastic or non-desmoplastic. Non-parametric event-free survival (EFS) and survival (OS) curves were computed using the product limit (Kaplan-Meier) estimates and the log-rank test was used to compare survival according to histologic subtype.
Patients with desmoplastic medulloblastoma experienced a favorable EFS of 77 ± 9% and OS of 85 ± 8% compared to EFS of 17 ± 5% and OS of 29 ± 6% for patients with tumors in the non-desmoplastic group (p < 0.0001 for both EFS and OS comparisons). Patients without disease progression did not receive radiation therapy.
Children less than three with desmoplastic histology of medulloblastoma represent a lower-risk group for whom reduction of therapy, including elimination of radiation therapy, is an appropriate strategy.
PMCID: PMC3119763  PMID: 21246528
Medulloblastoma; Desmoplastic; Survival; Brain Neoplasms
7.  Cerebral Edema Associated with Ventricular Reservoirs in Two Patients: A Case Report 
Placement of ventricular reservoirs is a common practice to treat various tumors of the central nervous system (CNS). Ventricular catheter-reservoir-associated edema has been noted in the literature, but a thorough review of this literature identified no articles that examine this particular complication in neurooncology patients, specifically. We report two cases of ventricular catheter-reservoir-associated edema in patients receiving treatment for CNS metastasis.
PMCID: PMC3420431  PMID: 22937353
8.  A Phase II Study (CCG 9931) of Pre-Radiotherapy Chemotherapy Followed by Hyperfractionated Radiotherapy for Newly Diagnosed High Risk Medulloblastoma/PNET: A Report from the Children’s Oncology Group 
Children with high risk medulloblastoma and non-cerebellar PNET’s were treated on a phase II study of pre-radiotherapy chemotherapy (CHT) followed by high dose, hyperfractionated craniospinal radiotherapy (CSRT). The protocol objectives were to verify feasibility and monitor progression-free (PFS) and overall survival (OS).
Methods and Materials
Eligibility criteria included age >3 years at diagnosis, medulloblastoma with either high M stage and/or >1.5 cm2 post-op residual disease and all patients with non-cerebellar PNET. Treatment was initiated with 5 alternating monthly cycles of CHT [A (cisplatin, cyclophosphamide, etoposide and vincristine, B (carboplatin and etoposide), A, B and A] followed by hyperfractionated CSRT (40 Gy) with a boost to the primary tumor (72 Gy) given in twice daily 1 Gy fractions.
The valid study group consisted of 124 patients whose median age at diagnosis was 7.8 years. Eighty-four (68%) patients completed the entire protocol within the study guidelines of 9 months and the median time to complete CSRT was 1.6 months. Major reasons for failure to complete CHT included progressive disease (17%) and toxic death (2.4%). The 5-year PFS and OS were 43 ± 5% and 52 ± 5%. No significant differences were detected in subset analysis related to response to CHT, site of primary tumor, post-op residual disease or M-stage.
The feasibility of this intensive multi-modality protocol was confirmed and response to pre-RT CHT did not impact on survival. Survival data from this protocol can not be compared to other studies, given the protocol design.
PMCID: PMC2739055  PMID: 19356859
PNET; Medulloblastoma; High risk; Hyperfractionated radiotherapy; Pre-radiation chemotherapy
9.  Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1α expression in human glioma cells by a proteasome-independent pathway: Implications for in vivo therapy1 
Neuro-Oncology  2005;7(3):225-235.
Angiogenesis is a critical step required for sustained tumor growth and tumor progression. The stimulation of endothelial cells by cytokines secreted by tumor cells such as vascular endothelial growth factor (VEGF) induces their proliferation and migration. This is a prominent feature of high-grade gliomas. The secretion of VEGF is greatly upregulated under conditions of hypoxia because of the transcription factor hypoxia-inducible factor (HIF)-1α, which controls the expression of many genes, allowing rapid adaptation of cells to their hypoxic microenvironment. Flavopiridol, a novel cyclin-dependent kinase inhibitor, has been attributed with antiangiogenic properties in some cancer cell lines by its ability to inhibit VEGF production. Here, we show that flavopiridol treatment of human U87MG and T98G glioma cell lines decreases hypoxia-mediated HIF-1α expression, VEGF secretion, and tumor cell migration. These in vitro results correlate with reduced vascularity of intracranial syngeneic GL261 gliomas from animals treated with flavopiridol. In addition, we show that flavopiridol downregulates HIF-1α expression in the presence of a proteasome inhibitor, an agent that normally results in the accumulation and overexpression of HIF-1α. The potential to downregulate HIF-1α expression with flavopiridol treatment in combination with a proteasome inhibitor makes this an extremely attractive anticancer treatment strategy for tumors with high angiogenic activity, such as gliomas.
PMCID: PMC1871916  PMID: 16053697
flavopiridol; proteasome inhibitor; hypoxia; HIF-1α; VEGF; glioma

Results 1-9 (9)