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McLendon, Roger Edwin

Overview:

Brain tumors are diagnosed in more than 20,000 Americans annually. The most malignant neoplasm, glioblastoma, is also the most common. Similarly, brain tumors constitute the most common solid neoplasm in children and include astrocytomas of the cerebellum, brain stem and cerebrum as well as medulloblastomas of the cerebellum.  My colleagues and I have endeavored to translate the bench discoveries of genetic mutations and aberrant protein expressions found in brain tumors to better understand the processes involved in the etiology, pathogenesis, and treatment of brain tumors.  Using the resources of the Preston Robert Brain Tumor Biorepository at Duke, our team, consisting of Henry Friedman, Allan Friedman, and Hai Yan and lead by Darell Bigner, have helped to identify mutations in Isocitrate Dehydrogenase (IDH1 and IDH2) as a marker of good prognosis in gliomas of adults.  This test is now offered at Duke as a clinical test.  Working with the Molecular Pathology Laboratory at Duke, we have also brought testing for TERT promoter region mutations as another major test for classifying gliomas in adults.  Our collaboration with the Toronto Sick Kids Hospital has resulted in prognostic testing for childhood medulloblastomas, primitive neuroectodermal tumors, and ependymomas at Duke.

Positions:

Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.A. 1979

B.A. — Emory University

M.D. 1982

M.D. — Medical College of Georgia School of Medicine

Resident, Pathology

Duke University

Fellow In Neuropathology, Pathology

Duke University

Assistant Clinical Professor Of Pathology, Pathology

Mercer University

Assistant Professor Of Pathology, Part Time, Pathology

Mercer University

Publications:

Histone H3.3K27M Represses p16 to Accelerate Gliomagenesis in a Murine Model of DIPG.

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor genetically distinguished from adult GBM by the high prevalence of the K27M mutation in the histone H3 variant H3.3 (H3F3A). This mutation reprograms the H3K27me3 epigenetic landscape of DIPG by inhibiting the H3K27-specific histone methyltransferase EZH2. This globally reduces H3K27me2/3, critical repressive marks responsible for cell fate decisions, and also causes focal gain of H3K27me3 throughout the epigenome. To date, the tumor-driving effects of H3.3K27M remain largely unknown. Here, it is demonstrated that H3.3K27M cooperates with PDGF-B in vivo, enhancing gliomagenesis and reducing survival of p53 wild-type (WT) and knockout murine models of DIPG. H3.3K27M expression drives increased proliferation of tumor-derived murine neurospheres, suggesting that cell-cycle deregulation contributes to increased malignancy in mutant tumors. RNA sequencing on tumor tissue from H3.3K27M-expressing mice indicated global upregulation of PRC2 target genes, and a subset of newly repressed genes enriched in regulators of development and cell proliferation. Strikingly, H3.3K27M induced targeted repression of the p16/ink4a (CDKN2A) locus, a critical regulator of the G0-G1 to S-phase transition. Increased levels of H3K27me3 were observed at the p16 promoter; however, pharmacologic reduction of methylation at this promoter did not rescue p16 expression. Although DNA methylation is also present at this promoter, it is not K27M dependent. Intriguingly, inhibition of DNA methylation restores p16 levels and is cytotoxic against murine tumor cells. Importantly, these data reveal that H3.3K27M-mediated p16 repression is an important mechanism underlying the proliferation of H3.3K27M tumor cells, as in vivo cdkn2a knockout eliminates the survival difference between H3.3K27M and H3.3WT tumor-bearing mice.Implications: This study shows that H3.3K27M mutation and PDGF signaling act in concert to accelerate gliomagenesis in a genetic mouse model and identifies repression of p16 tumor suppressor as a target of H3.3K27M, highlighting the G1-S cell-cycle transition as a promising therapeutic avenue. Mol Cancer Res; 15(9); 1243-54. ©2017 AACR.

Authors
Cordero, FJ; Huang, Z; Grenier, C; He, X; Hu, G; McLendon, RE; Murphy, SK; Hashizume, R; Becher, OJ
MLA Citation
Cordero, FJ, Huang, Z, Grenier, C, He, X, Hu, G, McLendon, RE, Murphy, SK, Hashizume, R, and Becher, OJ. "Histone H3.3K27M Represses p16 to Accelerate Gliomagenesis in a Murine Model of DIPG." Molecular cancer research : MCR 15.9 (September 2017): 1243-1254.
PMID
28522693
Source
epmc
Published In
Molecular cancer research : MCR
Volume
15
Issue
9
Publish Date
2017
Start Page
1243
End Page
1254
DOI
10.1158/1541-7786.mcr-16-0389

The whole-genome landscape of medulloblastoma subtypes.

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

Authors
Northcott, PA; Buchhalter, I; Morrissy, AS; Hovestadt, V; Weischenfeldt, J; Ehrenberger, T; Gröbner, S; Segura-Wang, M; Zichner, T; Rudneva, VA; Warnatz, H-J; Sidiropoulos, N; Phillips, AH; Schumacher, S; Kleinheinz, K; Waszak, SM; Erkek, S; Jones, DTW; Worst, BC; Kool, M; Zapatka, M; Jäger, N; Chavez, L; Hutter, B; Bieg, M; Paramasivam, N; Heinold, M; Gu, Z; Ishaque, N; Jäger-Schmidt, C; Imbusch, CD; Jugold, A; Hübschmann, D; Risch, T; Amstislavskiy, V; Gonzalez, FGR; Weber, UD; Wolf, S et al.
MLA Citation
Northcott, PA, Buchhalter, I, Morrissy, AS, Hovestadt, V, Weischenfeldt, J, Ehrenberger, T, Gröbner, S, Segura-Wang, M, Zichner, T, Rudneva, VA, Warnatz, H-J, Sidiropoulos, N, Phillips, AH, Schumacher, S, Kleinheinz, K, Waszak, SM, Erkek, S, Jones, DTW, Worst, BC, Kool, M, Zapatka, M, Jäger, N, Chavez, L, Hutter, B, Bieg, M, Paramasivam, N, Heinold, M, Gu, Z, Ishaque, N, Jäger-Schmidt, C, Imbusch, CD, Jugold, A, Hübschmann, D, Risch, T, Amstislavskiy, V, Gonzalez, FGR, Weber, UD, and Wolf, S et al. "The whole-genome landscape of medulloblastoma subtypes." Nature 547.7663 (July 2017): 311-317.
PMID
28726821
Source
epmc
Published In
Nature
Volume
547
Issue
7663
Publish Date
2017
Start Page
311
End Page
317
DOI
10.1038/nature22973

Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression.

IDH1 mutations occur in the majority of low-grade gliomas and lead to the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG). To understand the effects of tumor-associated mutant IDH1 (IDH1-R132H) on both the neural stem cell (NSC) population and brain tumorigenesis, genetically faithful cell lines and mouse model systems were generated. Here, it is reported that mouse NSCs expressing Idh1-R132H displayed reduced proliferation due to p53-mediated cell-cycle arrest as well as a decreased ability to undergo neuronal differentiation. In vivo, Idh1-R132H expression reduced proliferation of cells within the germinal zone of the subventricular zone (SVZ). The NSCs within this area were dispersed and disorganized in mutant animals, suggesting that Idh1-R132H perturbed the NSCs and the microenvironment from which gliomas arise. In addition, tumor-bearing animals expressing mutant Idh1 displayed a prolonged survival and also overexpressed Olig2, features consistent with IDH1-mutated human gliomas. These data indicate that mutant Idh1 disrupts the NSC microenvironment and the candidate cell-of-origin for glioma; thus, altering the progression of tumorigenesis. In addition, this study provides a mutant Idh1 brain tumor model that genetically recapitulates human disease, laying the foundation for future investigations on mutant IDH1-mediated brain tumorigenesis and targeted therapy.Implications: Through the use of a conditional mutant mouse model that confers a less aggressive tumor phenotype, this study reveals that mutant Idh1 impacts the candidate cell-of-origin for gliomas. Mol Cancer Res; 15(5); 507-20. ©2017 AACR.

Authors
Pirozzi, CJ; Carpenter, AB; Waitkus, MS; Wang, CY; Zhu, H; Hansen, LJ; Chen, LH; Greer, PK; Feng, J; Wang, Y; Bock, CB; Fan, P; Spasojevic, I; McLendon, RE; Bigner, DD; He, Y; Yan, H
MLA Citation
Pirozzi, CJ, Carpenter, AB, Waitkus, MS, Wang, CY, Zhu, H, Hansen, LJ, Chen, LH, Greer, PK, Feng, J, Wang, Y, Bock, CB, Fan, P, Spasojevic, I, McLendon, RE, Bigner, DD, He, Y, and Yan, H. "Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression." Molecular cancer research : MCR 15.5 (May 2017): 507-520.
PMID
28148827
Source
epmc
Published In
Molecular cancer research : MCR
Volume
15
Issue
5
Publish Date
2017
Start Page
507
End Page
520
DOI
10.1158/1541-7786.mcr-16-0485

Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination.

Purpose: Patients with glioblastoma have less than 15-month median survival despite surgical resection, high-dose radiation, and chemotherapy with temozolomide. We previously demonstrated that targeting cytomegalovirus pp65 using dendritic cells (DC) can extend survival and, in a separate study, that dose-intensified temozolomide (DI-TMZ) and adjuvant granulocyte macrophage colony-stimulating factor (GM-CSF) potentiate tumor-specific immune responses in patients with glioblastoma. Here, we evaluated pp65-specific cellular responses following DI-TMZ with pp65-DCs and determined the effects on long-term progression-free survival (PFS) and overall survival (OS).Experimental Design: Following standard-of-care, 11 patients with newly diagnosed glioblastoma received DI-TMZ (100 mg/m2/d × 21 days per cycle) with at least three vaccines of pp65 lysosome-associated membrane glycoprotein mRNA-pulsed DCs admixed with GM-CSF on day 23 ± 1 of each cycle. Thereafter, monthly DI-TMZ cycles and pp65-DCs were continued if patients had not progressed.Results: Following DI-TMZ cycle 1 and three doses of pp65-DCs, pp65 cellular responses significantly increased. After DI-TMZ, both the proportion and proliferation of regulatory T cells (Tregs) increased and remained elevated with serial DI-TMZ cycles. Median PFS and OS were 25.3 months [95% confidence interval (CI), 11.0-∞] and 41.1 months (95% CI, 21.6-∞), exceeding survival using recursive partitioning analysis and matched historical controls. Four patients remained progression-free at 59 to 64 months from diagnosis. No known prognostic factors [age, Karnofsky performance status (KPS), IDH-1/2 mutation, and MGMT promoter methylation] predicted more favorable outcomes for the patients in this cohort.Conclusions: Despite increased Treg proportions following DI-TMZ, patients receiving pp65-DCs showed long-term PFS and OS, confirming prior studies targeting cytomegalovirus in glioblastoma. Clin Cancer Res; 23(8); 1898-909. ©2017 AACR.

Authors
Batich, KA; Reap, EA; Archer, GE; Sanchez-Perez, L; Nair, SK; Schmittling, RJ; Norberg, P; Xie, W; Herndon, JE; Healy, P; McLendon, RE; Friedman, AH; Friedman, HS; Bigner, D; Vlahovic, G; Mitchell, DA; Sampson, JH
MLA Citation
Batich, KA, Reap, EA, Archer, GE, Sanchez-Perez, L, Nair, SK, Schmittling, RJ, Norberg, P, Xie, W, Herndon, JE, Healy, P, McLendon, RE, Friedman, AH, Friedman, HS, Bigner, D, Vlahovic, G, Mitchell, DA, and Sampson, JH. "Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination." Clinical cancer research : an official journal of the American Association for Cancer Research 23.8 (April 2017): 1898-1909.
PMID
28411277
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
23
Issue
8
Publish Date
2017
Start Page
1898
End Page
1909
DOI
10.1158/1078-0432.ccr-16-2057

The Utility of Expert Diagnosis in Surgical Neuropathology: Analysis of Consultations Reviewed at 5 National Comprehensive Cancer Network Institutions.

The aim of this study was to characterize the type and degree of discrepancies between non-expert and expert diagnoses of CNS tumors to identify the value of consultations in surgical neuropathology. Neuropathology experts from 5 National Comprehensive Cancer Network (NCCN) member institutions participated in the review of 1281 consultations selected based on inclusion criteria. The consultation cases were re-reviewed at the NCCN headquarters to determine concordance with the original diagnoses. Among all consultations, 249 (19.4%) were submitted for expert diagnoses without final diagnoses from the submitting institution. Within the remaining 1032 patients, the serious/major discrepancy rate was 4.8%, and less serious and minor discrepancies were seen in 19.4% of the cases. The discrepancy rate was higher among patients who were referred to NCCN institutions for consultation compared to those who were referred for treatment only. The discrepancy rates, patient demographics, type of consultations and submitting institutions varied among participating NCCN institutions. Expert consultations identified a subset of cases with significant diagnostic discrepancies, and constituted the initial diagnoses in some cases. These data indicate that expert consultations in glial tumors and all types of pediatric CNS tumors can improve accurate diagnosis and enable appropriate management.

Authors
Bruner, JM; Louis, DN; McLendon, R; Rosenblum, MK; Archambault, WT; Most, S; Tihan, T
MLA Citation
Bruner, JM, Louis, DN, McLendon, R, Rosenblum, MK, Archambault, WT, Most, S, and Tihan, T. "The Utility of Expert Diagnosis in Surgical Neuropathology: Analysis of Consultations Reviewed at 5 National Comprehensive Cancer Network Institutions." Journal of neuropathology and experimental neurology 76.3 (March 2017): 189-194.
PMID
28395084
Source
epmc
Published In
Journal of Neuropathology and Experimental Neurology
Volume
76
Issue
3
Publish Date
2017
Start Page
189
End Page
194
DOI
10.1093/jnen/nlw122

Morphological and molecular features of astroblastoma, including BRAFV600E mutations, suggest an ontological relationship to other cortical-based gliomas of children and young adults.

Astroblastomas (ABs) are rare glial tumors showing overlapping features with astrocytomas, ependymomas, and sometimes other glial neoplasms, and may be challenging to diagnose.We examined clinical, histopathological, and molecular features in 28 archival formalin-fixed, paraffin-embedded AB cases and performed survival analyses using Cox proportional hazards and Kaplan-Meier methods.Unlike ependymomas and angiocentric gliomas, ABs demonstrate abundant distinctive astroblastic pseudorosettes and are usually Olig2 immunopositive. They also frequently exhibit rhabdoid cells, multinucleated cells, and eosinophilic granular material. They retain immunoreactivity to alpha thalassemia/mental retardation syndrome X-linked, are immunonegative to isocitrate dehydrogenase-1 R132H mutation, and only occasionally show MGMT promoter hypermethylation differentiating them from many diffuse gliomas. Like pleomorphic xanthoastrocytoma, ganglioglioma, supratentorial pilocytic astrocytoma, and other predominantly cortical-based glial tumors, ABs often harbor the BRAFV600E mutation, present in 38% of cases tested (n = 21), further distinguishing those tumors from ependymomas and angiocentric gliomas. Factors correlating with longer patient survival included age less than 30 years, female gender, absent BRAFV600E , and mitotic index less than 5 mitoses/10 high-power fields; however, only the latter was significant by Cox and Kaplan-Meier analyses (n = 24; P = .024 and .012, respectively). This mitotic cutoff is therefore currently the best criterion to stratify tumors into low-grade ABs and higher-grade anaplastic ABs.In addition to their own characteristic histological features, ABs share some molecular and histological findings with other, possibly ontologically related, cortical-based gliomas of mostly children and young adults. Importantly, the presence of BRAFV600E mutations in a subset of ABs suggests potential clinical utility of targeted anti-BRAF therapy.

Authors
Lehman, NL; Hattab, EM; Mobley, BC; Usubalieva, A; Schniederjan, MJ; McLendon, RE; Paulus, W; Rushing, EJ; Georgescu, M-M; Couce, M; Dulai, MS; Cohen, ML; Pierson, CR; Raisanen, JM; Martin, SE; Lehman, TD; Lipp, ES; Bonnin, JM; Al-Abbadi, MA; Kenworthy, K; Zhao, K; Mohamed, N; Zhang, G; Zhao, W
MLA Citation
Lehman, NL, Hattab, EM, Mobley, BC, Usubalieva, A, Schniederjan, MJ, McLendon, RE, Paulus, W, Rushing, EJ, Georgescu, M-M, Couce, M, Dulai, MS, Cohen, ML, Pierson, CR, Raisanen, JM, Martin, SE, Lehman, TD, Lipp, ES, Bonnin, JM, Al-Abbadi, MA, Kenworthy, K, Zhao, K, Mohamed, N, Zhang, G, and Zhao, W. "Morphological and molecular features of astroblastoma, including BRAFV600E mutations, suggest an ontological relationship to other cortical-based gliomas of children and young adults." Neuro-oncology 19.1 (January 2017): 31-42.
PMID
27416954
Source
epmc
Published In
Neuro-Oncology
Volume
19
Issue
1
Publish Date
2017
Start Page
31
End Page
42
DOI
10.1093/neuonc/now118

Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination.

Glioblastoma is the most lethal brain tumor and harbors glioma stem cells (GSCs) with potent tumorigenic capacity. The function of GSCs in tumor propagation is maintained by several core transcriptional regulators including c-Myc. c-Myc protein is tightly regulated by posttranslational modification. However, the posttranslational regulatory mechanisms for c-Myc in GSCs have not been defined. In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation. In contrast, overexpression of the ubiquitin E3 ligase FBXL14 induced c-Myc degradation, promoted GSC differentiation, and inhibited tumor growth. Ectopic expression of the ubiquitin-insensitive mutant T58A-c-Myc rescued the effects caused by FBXL14 overexpression or USP13 disruption. These data suggest that USP13 and FBXL14 play opposing roles in the regulation of GSCs through reversible ubiquitination of c-Myc.

Authors
Fang, X; Zhou, W; Wu, Q; Huang, Z; Shi, Y; Yang, K; Chen, C; Xie, Q; Mack, SC; Wang, X; Carcaboso, AM; Sloan, AE; Ouyang, G; McLendon, RE; Bian, X-W; Rich, JN; Bao, S
MLA Citation
Fang, X, Zhou, W, Wu, Q, Huang, Z, Shi, Y, Yang, K, Chen, C, Xie, Q, Mack, SC, Wang, X, Carcaboso, AM, Sloan, AE, Ouyang, G, McLendon, RE, Bian, X-W, Rich, JN, and Bao, S. "Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination." The Journal of experimental medicine 214.1 (January 2017): 245-267.
PMID
27923907
Source
epmc
Published In
The Journal of Experimental Medicine
Volume
214
Issue
1
Publish Date
2017
Start Page
245
End Page
267
DOI
10.1084/jem.20151673

HIV-1 Envelope Mimicry of Host Enzyme Kynureninase Does Not Disrupt Tryptophan Metabolism.

The HIV-1 envelope protein (Env) has evolved to subvert the host immune system, hindering viral control by the host. The tryptophan metabolic enzyme kynureninase (KYNU) is mimicked by a portion of the HIV Env gp41 membrane proximal region (MPER) and is cross-reactive with the HIV broadly neutralizing Ab (bnAb) 2F5. Molecular mimicry of host proteins by pathogens can lead to autoimmune disease. In this article, we demonstrate that neither the 2F5 bnAb nor HIV MPER-KYNU cross-reactive Abs elicited by immunization with an MPER peptide-liposome vaccine in 2F5 bnAb VHDJH and VLJL knock-in mice and rhesus macaques modified KYNU activity or disrupted tissue tryptophan metabolism. Thus, molecular mimicry by HIV-1 Env that promotes the evasion of host anti-HIV-1 Ab responses can be directed toward nonfunctional host protein epitopes that do not impair host protein function. Therefore, the 2F5 HIV Env gp41 region is a key and safe target for HIV-1 vaccine development.

Authors
Bradley, T; Yang, G; Ilkayeva, O; Holl, TM; Zhang, R; Zhang, J; Santra, S; Fox, CB; Reed, SG; Parks, R; Bowman, CM; Bouton-Verville, H; Sutherland, LL; Scearce, RM; Vandergrift, N; Kepler, TB; Moody, MA; Liao, H-X; Alam, SM; McLendon, R; Everitt, JI; Newgard, CB; Verkoczy, L; Kelsoe, G; Haynes, BF
MLA Citation
Bradley, T, Yang, G, Ilkayeva, O, Holl, TM, Zhang, R, Zhang, J, Santra, S, Fox, CB, Reed, SG, Parks, R, Bowman, CM, Bouton-Verville, H, Sutherland, LL, Scearce, RM, Vandergrift, N, Kepler, TB, Moody, MA, Liao, H-X, Alam, SM, McLendon, R, Everitt, JI, Newgard, CB, Verkoczy, L, Kelsoe, G, and Haynes, BF. "HIV-1 Envelope Mimicry of Host Enzyme Kynureninase Does Not Disrupt Tryptophan Metabolism." Journal of immunology (Baltimore, Md. : 1950) 197.12 (December 2016): 4663-4673.
PMID
27849170
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
197
Issue
12
Publish Date
2016
Start Page
4663
End Page
4673
DOI
10.4049/jimmunol.1601484

Long-Term Outcomes for Patients With Atypical or Malignant Meningiomas Treated With Radiation Therapy: A Single-Institution Retrospective Analysis

Authors
Kent, CL; Mowery, YM; Wright, AO; Kim, GJ; Desjardins, A; Peters, KB; Vlahovic, G; Friedman, HS; Cummings, TJ; McLendon, RE; Friedman, AH; Sampson, JH; Kirkpatrick, JP
MLA Citation
Kent, CL, Mowery, YM, Wright, AO, Kim, GJ, Desjardins, A, Peters, KB, Vlahovic, G, Friedman, HS, Cummings, TJ, McLendon, RE, Friedman, AH, Sampson, JH, and Kirkpatrick, JP. "Long-Term Outcomes for Patients With Atypical or Malignant Meningiomas Treated With Radiation Therapy: A Single-Institution Retrospective Analysis." October 1, 2016.
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
96
Issue
2
Publish Date
2016
Start Page
E83
End Page
E84

Long-Term Outcomes for Patients With Atypical or Malignant Meningiomas Treated With Radiation Therapy: A Single-Institution Retrospective Analysis.

Authors
Kent, CL; Mowery, YM; Wright, AO; Kim, GJ; Desjardins, A; Peters, KB; Vlahovic, G; Friedman, HS; Cummings, TJ; McLendon, RE; Friedman, AH; Sampson, JH; Kirkpatrick, JP
MLA Citation
Kent, CL, Mowery, YM, Wright, AO, Kim, GJ, Desjardins, A, Peters, KB, Vlahovic, G, Friedman, HS, Cummings, TJ, McLendon, RE, Friedman, AH, Sampson, JH, and Kirkpatrick, JP. "Long-Term Outcomes for Patients With Atypical or Malignant Meningiomas Treated With Radiation Therapy: A Single-Institution Retrospective Analysis." International journal of radiation oncology, biology, physics 96.2S (October 2016): E83-E84.
PMID
27675478
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
96
Issue
2S
Publish Date
2016
Start Page
E83
End Page
E84
DOI
10.1016/j.ijrobp.2016.06.802

Single-Agent Carboplatin for a Rare Case of Pilomyxoid Astrocytoma of the Spinal Cord in an Adult with Neurofibromatosis Type 1.

Pilomyxoid astrocytoma (PMA) is a rare and more aggressive variant of pilocytic astrocytoma, which usually affects young children and is most often located in the hypothalamic/chiasmatic region. The association of PMA with underlying genetic disorders is not well known.We identified a 23-year-old woman with a PMA of the spinal cord who was simultaneously diagnosed with neurofibromatosis type 1. Diagnosis of neurofibromatosis type 1 was made clinically and confirmed with genetic testing that revealed a heterozygous one-amino-acid deletion (c.2970-2972 delAAT) in exon 17 of the NF1 gene, which is correlated with a milder phenotype. The patient underwent a partial surgical resection of the spinal cord tumor followed by adjuvant carboplatin 560 mg/m2 every 4 weeks. Radiation was avoided due to risks associated with neurofibromatosis type 1.At the 11-month follow-up, the patient maintained a partial radiographic response as well as complete resolution of her neurologic deficits.To our knowledge, this is the first reported case of an adult patient with neurofibromatosis type 1 and a spinal cord PMA. Single-agent carboplatin was effective and well-tolerated.

Authors
Dunn-Pirio, AM; Howell, E; McLendon, RE; Peters, KB
MLA Citation
Dunn-Pirio, AM, Howell, E, McLendon, RE, and Peters, KB. "Single-Agent Carboplatin for a Rare Case of Pilomyxoid Astrocytoma of the Spinal Cord in an Adult with Neurofibromatosis Type 1." Case reports in oncology 9.3 (September 2016): 568-573.
PMID
27920686
Source
epmc
Published In
Case Reports in Oncology
Volume
9
Issue
3
Publish Date
2016
Start Page
568
End Page
573

Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis.

Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known.Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses.Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation.The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.

Authors
Ramaswamy, V; Hielscher, T; Mack, SC; Lassaletta, A; Lin, T; Pajtler, KW; Jones, DTW; Luu, B; Cavalli, FMG; Aldape, K; Remke, M; Mynarek, M; Rutkowski, S; Gururangan, S; McLendon, RE; Lipp, ES; Dunham, C; Hukin, J; Eisenstat, DD; Fulton, D; van Landeghem, FKH; Santi, M; van Veelen, M-LC; Van Meir, EG; Osuka, S; Fan, X; Muraszko, KM; Tirapelli, DPC; Oba-Shinjo, SM; Marie, SKN; Carlotti, CG; Lee, JY; Rao, AAN; Giannini, C; Faria, CC; Nunes, S; Mora, J; Hamilton, RL; Hauser, P; Jabado, N et al.
MLA Citation
Ramaswamy, V, Hielscher, T, Mack, SC, Lassaletta, A, Lin, T, Pajtler, KW, Jones, DTW, Luu, B, Cavalli, FMG, Aldape, K, Remke, M, Mynarek, M, Rutkowski, S, Gururangan, S, McLendon, RE, Lipp, ES, Dunham, C, Hukin, J, Eisenstat, DD, Fulton, D, van Landeghem, FKH, Santi, M, van Veelen, M-LC, Van Meir, EG, Osuka, S, Fan, X, Muraszko, KM, Tirapelli, DPC, Oba-Shinjo, SM, Marie, SKN, Carlotti, CG, Lee, JY, Rao, AAN, Giannini, C, Faria, CC, Nunes, S, Mora, J, Hamilton, RL, Hauser, P, and Jabado, N et al. "Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 34.21 (July 2016): 2468-2477.
PMID
27269943
Source
epmc
Published In
Journal of Clinical Oncology
Volume
34
Issue
21
Publish Date
2016
Start Page
2468
End Page
2477
DOI
10.1200/jco.2015.65.7825

Histologically benign, clinically aggressive: Progressive non-optic pathway pilocytic astrocytomas in adults with NF1.

Although optic pathway gliomas are the most common brain tumors associated with neurofibromatosis type 1 (NF1), extra-optic gliomas occur and may behave more aggressively with outcomes that differ by age. A retrospective case-control study was designed to describe the clinical course of adult NF1 patients with progressive extra-optic pilocytic astrocytomas (PAs) and compare to a pediatric cohort. Data for patients treated at the Johns Hopkins Comprehensive Neurofibromatosis Center from 2003 to 2013 were reviewed to identify cases (adults, age >18) and controls (pediatric, age <18) with clinically or radiographically progressive extra-optic PAs. Demographic, clinical, histologic, and radiographic data were collected. Three adult NF1 cases and four pediatric NF1 controls were identified. Mean age was 32.3 ± 9.5 years, 66% male (cases); 12.8 ± 4.2 years, 100% male (controls). Symptomatic progression occurred in two-of-three adults (67%) while the majority of pediatric patients presented with isolated radiographic progression (n = 3, 75%). Onset tended to be more rapid in adults (4 ± 1 vs. 14 ± 8.3 months, P = 0.10). Subtotal resection was the treatment for all pediatric patients. Radiotherapy (n = 2), chemotherapy (n = 2), and targeted, biologic agents (n = 2) were administered in adults. Although all pediatric patients are living, outcomes were universally poor in adults with progression to death in all (median survival 17.1 months, range 6.6-30.3). In conclusion, despite grade I histology, all three adult NF1 patients with progressive extra-optic PAs suffered an aggressive clinical course which was not seen in pediatric patients. Clinicians should be aware of this clinico-histologic discrepancy when counseling and managing adult NF1 patients with progressive extra-optic PAs. © 2016 Wiley Periodicals, Inc.

Authors
Strowd, RE; Rodriguez, FJ; McLendon, RE; Vredenburgh, JJ; Chance, AB; Jallo, G; Olivi, A; Ahn, ES; Blakeley, JO
MLA Citation
Strowd, RE, Rodriguez, FJ, McLendon, RE, Vredenburgh, JJ, Chance, AB, Jallo, G, Olivi, A, Ahn, ES, and Blakeley, JO. "Histologically benign, clinically aggressive: Progressive non-optic pathway pilocytic astrocytomas in adults with NF1." American journal of medical genetics. Part A 170.6 (June 2016): 1455-1461.
PMID
26992069
Source
epmc
Published In
American Journal of Medical Genetics Part A
Volume
170
Issue
6
Publish Date
2016
Start Page
1455
End Page
1461
DOI
10.1002/ajmg.a.37622

Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats.

D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague-Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 μg (the acute cohort) and 0, 0.05, 0.1, 0.35 μg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 μg (5/10 rats) and 0.35 μg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 μg, and the no-observed-adverse-effect-level was 0.05 μg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.

Authors
Bao, X; Chandramohan, V; Reynolds, RP; Norton, JN; Wetsel, WC; Rodriguiz, RM; Aryal, DK; McLendon, RE; Levin, ED; Petry, NA; Zalutsky, MR; Burnett, BK; Kuan, C-T; Pastan, IH; Bigner, DD
MLA Citation
Bao, X, Chandramohan, V, Reynolds, RP, Norton, JN, Wetsel, WC, Rodriguiz, RM, Aryal, DK, McLendon, RE, Levin, ED, Petry, NA, Zalutsky, MR, Burnett, BK, Kuan, C-T, Pastan, IH, and Bigner, DD. "Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats." Investigational new drugs 34.2 (April 2016): 149-158.
PMID
26728879
Source
epmc
Published In
Investigational New Drugs
Volume
34
Issue
2
Publish Date
2016
Start Page
149
End Page
158
DOI
10.1007/s10637-015-0318-3

A Three-Dimensional Organoid Culture System Derived from Human Glioblastomas Recapitulates the Hypoxic Gradients and Cancer Stem Cell Heterogeneity of Tumors Found In Vivo.

Many cancers feature cellular hierarchies that are driven by tumor-initiating cancer stem cells (CSC) and rely on complex interactions with the tumor microenvironment. Standard cell culture conditions fail to recapitulate the original tumor architecture or microenvironmental gradients and are not designed to retain the cellular heterogeneity of parental tumors. Here, we describe a three-dimensional culture system that supports the long-term growth and expansion of tumor organoids derived directly from glioblastoma specimens, including patient-derived primary cultures, xenografts, genetically engineered glioma models, or patient samples. Organoids derived from multiple regions of patient tumors retain selective tumorigenic potential. Furthermore, organoids could be established directly from brain metastases not typically amenable to in vitro culture. Once formed, tumor organoids grew for months and displayed regional heterogeneity with a rapidly dividing outer region of SOX2(+), OLIG2(+), and TLX(+) cells surrounding a hypoxic core of primarily non-stem senescent cells and diffuse, quiescent CSCs. Notably, non-stem cells within organoids were sensitive to radiotherapy, whereas adjacent CSCs were radioresistant. Orthotopic transplantation of patient-derived organoids resulted in tumors displaying histologic features, including single-cell invasiveness, that were more representative of the parental tumor compared with those formed from patient-derived sphere cultures. In conclusion, we present a new ex vivo model in which phenotypically diverse stem and non-stem glioblastoma cell populations can be simultaneously cultured to explore new facets of microenvironmental influences and CSC biology. Cancer Res; 76(8); 2465-77. ©2016 AACR.

Authors
Hubert, CG; Rivera, M; Spangler, LC; Wu, Q; Mack, SC; Prager, BC; Couce, M; McLendon, RE; Sloan, AE; Rich, JN
MLA Citation
Hubert, CG, Rivera, M, Spangler, LC, Wu, Q, Mack, SC, Prager, BC, Couce, M, McLendon, RE, Sloan, AE, and Rich, JN. "A Three-Dimensional Organoid Culture System Derived from Human Glioblastomas Recapitulates the Hypoxic Gradients and Cancer Stem Cell Heterogeneity of Tumors Found In Vivo." Cancer research 76.8 (April 2016): 2465-2477.
PMID
26896279
Source
epmc
Published In
Cancer Research
Volume
76
Issue
8
Publish Date
2016
Start Page
2465
End Page
2477
DOI
10.1158/0008-5472.can-15-2402

Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis.

Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner.We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival.We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084).The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection.Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.

Authors
Thompson, EM; Hielscher, T; Bouffet, E; Remke, M; Luu, B; Gururangan, S; McLendon, RE; Bigner, DD; Lipp, ES; Perreault, S; Cho, Y-J; Grant, G; Kim, S-K; Lee, JY; Rao, AAN; Giannini, C; Li, KKW; Ng, H-K; Yao, Y; Kumabe, T; Tominaga, T; Grajkowska, WA; Perek-Polnik, M; Low, DCY; Seow, WT; Chang, KTE; Mora, J; Pollack, IF; Hamilton, RL; Leary, S; Moore, AS; Ingram, WJ; Hallahan, AR; Jouvet, A; Fèvre-Montange, M; Vasiljevic, A; Faure-Conter, C; Shofuda, T; Kagawa, N; Hashimoto, N; Jabado, N et al.
MLA Citation
Thompson, EM, Hielscher, T, Bouffet, E, Remke, M, Luu, B, Gururangan, S, McLendon, RE, Bigner, DD, Lipp, ES, Perreault, S, Cho, Y-J, Grant, G, Kim, S-K, Lee, JY, Rao, AAN, Giannini, C, Li, KKW, Ng, H-K, Yao, Y, Kumabe, T, Tominaga, T, Grajkowska, WA, Perek-Polnik, M, Low, DCY, Seow, WT, Chang, KTE, Mora, J, Pollack, IF, Hamilton, RL, Leary, S, Moore, AS, Ingram, WJ, Hallahan, AR, Jouvet, A, Fèvre-Montange, M, Vasiljevic, A, Faure-Conter, C, Shofuda, T, Kagawa, N, Hashimoto, N, and Jabado, N et al. "Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis." The Lancet. Oncology 17.4 (April 2016): 484-495.
PMID
26976201
Source
epmc
Published In
The Lancet Oncology
Volume
17
Issue
4
Publish Date
2016
Start Page
484
End Page
495
DOI
10.1016/s1470-2045(15)00581-1

Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma.

Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice.Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8(+) PD-1(+) T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1(+) peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3(+) T cells within the tumor microenvironment.This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment.

Authors
Pham, CD; Flores, C; Yang, C; Pinheiro, EM; Yearley, JH; Sayour, EJ; Pei, Y; Moore, C; McLendon, RE; Huang, J; Sampson, JH; Wechsler-Reya, R; Mitchell, DA
MLA Citation
Pham, CD, Flores, C, Yang, C, Pinheiro, EM, Yearley, JH, Sayour, EJ, Pei, Y, Moore, C, McLendon, RE, Huang, J, Sampson, JH, Wechsler-Reya, R, and Mitchell, DA. "Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma." Clinical cancer research : an official journal of the American Association for Cancer Research 22.3 (February 2016): 582-595.
PMID
26405194
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
22
Issue
3
Publish Date
2016
Start Page
582
End Page
595
DOI
10.1158/1078-0432.ccr-15-0713

MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B.

The hypoxic tumor microenvironment serves as a niche for maintaining the glioma-initiating cells (GICs) that are critical for glioblastoma (GBM) occurrence and recurrence. Here, we report that hypoxia-induced miR-215 is vital for reprograming GICs to fit the hypoxic microenvironment via suppressing the expression of an epigenetic regulator KDM1B and modulating activities of multiple pathways. Interestingly, biogenesis of miR-215 and several miRNAs is accelerated post-transcriptionally by hypoxia-inducible factors (HIFs) through HIF-Drosha interaction. Moreover, miR-215 expression correlates inversely with KDM1B while correlating positively with HIF1α and GBM progression in patients. These findings reveal a direct role of HIF in regulating miRNA biogenesis and consequently activating the miR-215-KDM1B-mediated signaling required for GIC adaptation to hypoxia.

Authors
Hu, J; Sun, T; Wang, H; Chen, Z; Wang, S; Yuan, L; Liu, T; Li, H-R; Wang, P; Feng, Y; Wang, Q; McLendon, RE; Friedman, AH; Keir, ST; Bigner, DD; Rathmell, J; Fu, X-D; Li, Q-J; Wang, H; Wang, X-F
MLA Citation
Hu, J, Sun, T, Wang, H, Chen, Z, Wang, S, Yuan, L, Liu, T, Li, H-R, Wang, P, Feng, Y, Wang, Q, McLendon, RE, Friedman, AH, Keir, ST, Bigner, DD, Rathmell, J, Fu, X-D, Li, Q-J, Wang, H, and Wang, X-F. "MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B." Cancer cell 29.1 (January 2016): 49-60.
Website
http://hdl.handle.net/10161/11667
PMID
26766590
Source
epmc
Published In
Cancer Cell
Volume
29
Issue
1
Publish Date
2016
Start Page
49
End Page
60
DOI
10.1016/j.ccell.2015.12.005

Gorlin syndrome and desmoplastic medulloblastoma: Report of 3 cases with unfavorable clinical course and novel mutations.

We present three cases of genetically confirmed Gorlin syndrome with desmoplastic medulloblastoma (DMB) in whom tumor recurred despite standard therapy. One patient was found to have a novel germline missense PTCH1 mutation. Molecular analysis of recurrent tumor using fluorescent in situ hybridization (FISH) revealed PTEN and/ or PTCH1 loss in 2 patients. Whole exome sequencing (WES) of tumor in one patient revealed loss of heterozygosity of PTCH1 and a mutation of GNAS gene in its non-coding 3' -untranslated region (UTR) with corresponding decreased protein expression. While one patient died despite high-dose chemotherapy (HDC) plus stem cell rescue (ASCR) and palliative radiotherapy, two patients are currently alive for 18+ and 120+ months respectively following retrieval therapy that did not include irradiation. Infants with DMB and GS should be treated aggressively with chemotherapy at diagnosis to prevent relapse but radiotherapy should be avoided. The use of molecular prognostic markers for DMB should be routinely used to identify the subset of tumors that might have an aggressive course.

Authors
Gururangan, S; Robinson, G; Ellison, DW; Wu, G; He, X; Lu, QR; McLendon, R; Grant, G; Driscoll, T; Neuberg, R
MLA Citation
Gururangan, S, Robinson, G, Ellison, DW, Wu, G, He, X, Lu, QR, McLendon, R, Grant, G, Driscoll, T, and Neuberg, R. "Gorlin syndrome and desmoplastic medulloblastoma: Report of 3 cases with unfavorable clinical course and novel mutations." Pediatric blood & cancer 62.10 (October 2015): 1855-1858.
PMID
25940061
Source
epmc
Published In
Pediatric Blood & Cancer
Volume
62
Issue
10
Publish Date
2015
Start Page
1855
End Page
1858
DOI
10.1002/pbc.25560

Template for Reporting Results of Biomarker Testing of Specimens From Patients With Tumors of the Central Nervous System.

Authors
Brat, DJ; Cagle, PT; Dillon, DA; Hattab, EM; McLendon, RE; Miller, MA; Buckner, JC; Members of the Cancer Biomarker Reporting Committee, College of American Pathologists,
MLA Citation
Brat, DJ, Cagle, PT, Dillon, DA, Hattab, EM, McLendon, RE, Miller, MA, Buckner, JC, Members of the Cancer Biomarker Reporting Committee, and College of American Pathologists, . "Template for Reporting Results of Biomarker Testing of Specimens From Patients With Tumors of the Central Nervous System." Archives of pathology & laboratory medicine 139.9 (September 2015): 1087-1093.
PMID
25642959
Source
epmc
Published In
Archives of Pathology and Laboratory Medicine
Volume
139
Issue
9
Publish Date
2015
Start Page
1087
End Page
1093
DOI
10.5858/arpa.2014-0588-cp

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas.We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes.Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma.The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

Authors
Cancer Genome Atlas Research Network, ; Brat, DJ; Verhaak, RGW; Aldape, KD; Yung, WKA; Salama, SR; Cooper, LAD; Rheinbay, E; Miller, CR; Vitucci, M; Morozova, O; Robertson, AG; Noushmehr, H; Laird, PW; Cherniack, AD; Akbani, R; Huse, JT; Ciriello, G; Poisson, LM; Barnholtz-Sloan, JS; Berger, MS; Brennan, C; Colen, RR; Colman, H; Flanders, AE; Giannini, C; Grifford, M; Iavarone, A; Jain, R; Joseph, I; Kim, J; Kasaian, K; Mikkelsen, T; Murray, BA; O'Neill, BP; Pachter, L; Parsons, DW; Sougnez, C et al.
MLA Citation
Cancer Genome Atlas Research Network, , Brat, DJ, Verhaak, RGW, Aldape, KD, Yung, WKA, Salama, SR, Cooper, LAD, Rheinbay, E, Miller, CR, Vitucci, M, Morozova, O, Robertson, AG, Noushmehr, H, Laird, PW, Cherniack, AD, Akbani, R, Huse, JT, Ciriello, G, Poisson, LM, Barnholtz-Sloan, JS, Berger, MS, Brennan, C, Colen, RR, Colman, H, Flanders, AE, Giannini, C, Grifford, M, Iavarone, A, Jain, R, Joseph, I, Kim, J, Kasaian, K, Mikkelsen, T, Murray, BA, O'Neill, BP, Pachter, L, Parsons, DW, and Sougnez, C et al. "Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas." The New England journal of medicine 372.26 (June 10, 2015): 2481-2498.
PMID
26061751
Source
epmc
Published In
The New England journal of medicine
Volume
372
Issue
26
Publish Date
2015
Start Page
2481
End Page
2498
DOI
10.1056/nejmoa1402121

Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development.

The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR. The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. We validated proteomic profiles using patient-derived glioblastoma xenografts (PDGX), characterizing 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. Proteins found to be associated with high EGFR activity represent potential biomarkers for GBM monitoring.

Authors
Brown, KE; Chagoya, G; Kwatra, SG; Yen, T; Keir, ST; Cooter, M; Hoadley, KA; Rasheed, A; Lipp, ES; Mclendon, R; Ali-Osman, F; Bigner, DD; Sampson, JH; Kwatra, MM
MLA Citation
Brown, KE, Chagoya, G, Kwatra, SG, Yen, T, Keir, ST, Cooter, M, Hoadley, KA, Rasheed, A, Lipp, ES, Mclendon, R, Ali-Osman, F, Bigner, DD, Sampson, JH, and Kwatra, MM. "Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development." Journal of neurochemistry 133.5 (June 2015): 730-738.
PMID
25598002
Source
epmc
Published In
Journal of Neurochemistry
Volume
133
Issue
5
Publish Date
2015
Start Page
730
End Page
738
DOI
10.1111/jnc.13032

Consultative issues in surgical neuropathology: a retrospective review of the rationale for submitting cases for expert review.

OBJECTIVES: Second opinions on neuropathology cases are sought for a variety of reasons. We investigated the rationales for seeking expert neuropathologic review. METHODS: A retrospective review was done of the correspondence accompanying neuropathology cases submitted over a 5-year period. The review used a taxonomy of referral reasons, the submitting diagnoses, and requests for ancillary tests. RESULTS: In total, 508 adult cases were submitted, including glioblastoma (n = 94), anaplastic astrocytoma (n = 49), low-grade glioma (n = 49), oligodendroglioma (n = 48), and pituitary adenoma (n = 12). Thirty-nine cases submitted requested ancillary testing. A taxonomy of four categories revealed the following: preliminary diagnosis (n = 228 cases) was the most common reason for requesting review, followed by no diagnosis rendered (n = 183 cases), second opinion (n = 53), and confirmation/quality assurance (n = 43); the remaining case was "other." Overall, 456 cases were submitted by pathologists, 40 by clinicians and 12 by patients. CONCLUSIONS: Pathologists who predominately submit cases with a preliminary diagnosis rendered seek expert consultation while clinicians seek a second opinion.

Authors
Lipp, ES; Clark, AC; McLendon, RE
MLA Citation
Lipp, ES, Clark, AC, and McLendon, RE. "Consultative issues in surgical neuropathology: a retrospective review of the rationale for submitting cases for expert review." American journal of clinical pathology 143.6 (June 2015): 807-811.
PMID
25972322
Source
epmc
Published In
American Journal of Clinical Pathology
Volume
143
Issue
6
Publish Date
2015
Start Page
807
End Page
811
DOI
10.1309/ajcpwep1hpx4edcs

Consultative Issues in Surgical Neuropathology: A Retrospective Review of the Rationale for Submitting Cases for Expert Review

Authors
Lipp, ES; Clark, AC; McLendon, RE
MLA Citation
Lipp, ES, Clark, AC, and McLendon, RE. "Consultative Issues in Surgical Neuropathology: A Retrospective Review of the Rationale for Submitting Cases for Expert Review." AMERICAN JOURNAL OF CLINICAL PATHOLOGY 143.6 (June 2015): 807-811.
Source
wos-lite
Published In
American Journal of Clinical Pathology
Volume
143
Issue
6
Publish Date
2015
Start Page
807
End Page
811
DOI
10.1309/AJ0PWEP1HPX4EDCS

Prognostic marker analysis in pediatric intracranial ependymomas.

Histologic grading methods dependent upon H&E staining review have not been shown to reliably predict survival in children with intracranial ependymomas due to the subjectivity of the analytical methods. We hypothesized that the immunohistochemical detection of MIB-1, Tenascin C, CD34, VEGF, and CA IX may represent objective markers of post-operative survival (Progression Free and Overall Survival; PFS, OS) in these patients. Intracranial ependymomas from patients aged 22 years or less were studied. The original histologic grade was recorded, H&E sections were reviewed for vascular proliferation status, and immunohistochemistry was used to determine MIB-1, Tenascin C, CD34, VEGF, and CA IX status. Based upon the World Health Organization (WHO) grading system, 3 Grade I, 18 Grade II and 9 Grade III ependymomas were studied. Median follow-up time was 9.0 years; median PFS was, 6.1 years. Original WHO grade did not correlate with PFS or OS. Peri-necrotic CA IX localization correlated with PFS (Log rank = 0.0181) and OS (Log rank p = 0.0015). All patients with a CA IX ≤ 5 % total area localization were alive at last follow-up. Perinecrotic CA IX staining was also associated with vascular proliferation (p = 0.006), though not with VEGF expression score. MIB-1 labeling index (LI) correlated with OS (HR 1.06, 95 % CI 1.01, 1.12) and PFS (HR 1.08, 95 % CI 1.02, 1.14). MIB-1 LI and perinecrotic CA IX individually correlated with PFS. The effect of perinecrotic CA IX remained when grade was added to a Cox model predicting PFS. Immunodetection of CA IX and MIB-1 expression are predictive biomarkers for survival in children with posterior fossa ependymomas. These markers represent objective indicators of survival that supplement H&E grading alone.

Authors
McLendon, RE; Lipp, E; Satterfield, D; Ehinger, M; Austin, A; Fleming, D; Perkinson, K; Lefaivre, M; Zagzag, D; Wiener, B; Gururangan, S; Fuchs, H; Friedman, HS; Herndon, JE; Healy, P
MLA Citation
McLendon, RE, Lipp, E, Satterfield, D, Ehinger, M, Austin, A, Fleming, D, Perkinson, K, Lefaivre, M, Zagzag, D, Wiener, B, Gururangan, S, Fuchs, H, Friedman, HS, Herndon, JE, and Healy, P. "Prognostic marker analysis in pediatric intracranial ependymomas." Journal of neuro-oncology 122.2 (April 2015): 255-261.
PMID
25563815
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
122
Issue
2
Publish Date
2015
Start Page
255
End Page
261
DOI
10.1007/s11060-014-1711-z

Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma.

Glioblastoma multiforme (GBM) is an aggressive malignancy associated with profound host immunosuppression mediated in part by FoxP3 expressing regulatory CD4+ T lymphocytes (Tregs) that down-regulate anti-tumor immunity. In order to assess whether FoxP3 was an independent driver differentially expressed in primary versus recurrent GBMs, we stained resected primary and recurrent GBM tumors for CD3, CD4, CD8 and FoxP3 expression using standard immunohistochemistry. Slides were scanned with a high-resolution scanner (ScanScope CS; Aperio), and image analysis software (Aperio ScanScope) was used to enumerate lymphocyte subpopulations allowing for high-throughput analysis and bypassing manual selection bias. As shown in previous studies, enumeration of individual lymphocyte populations did not correlate with clinical outcomes in patients with GBM. However, the CD4+ to regulatory FoxP3+ T cell ratio was diminished in recurrent disease, and increased CD3 and CD8+ to regulatory T cell ratios showed a positive correlation with survival outcomes in primary GBM. These results suggest that while absolute numbers of tumor infiltrating lymphocytes may not be informative for predicting clinical outcomes in patients with GBM, the effective balance of CD3, CD4 and CD8+ T cells to immunosuppressive FoxP3+ regulatory cells may influence clinical outcomes in this patient population.

Authors
Sayour, EJ; McLendon, P; McLendon, R; De Leon, G; Reynolds, R; Kresak, J; Sampson, JH; Mitchell, DA
MLA Citation
Sayour, EJ, McLendon, P, McLendon, R, De Leon, G, Reynolds, R, Kresak, J, Sampson, JH, and Mitchell, DA. "Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma." Cancer immunology, immunotherapy : CII 64.4 (April 2015): 419-427.
PMID
25555571
Source
epmc
Published In
Cancer Immunology, Immunotherapy
Volume
64
Issue
4
Publish Date
2015
Start Page
419
End Page
427
DOI
10.1007/s00262-014-1651-7

Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma

© 2014, Springer-Verlag Berlin Heidelberg. Glioblastoma multiforme (GBM) is an aggressive malignancy associated with profound host immunosuppression mediated in part by FoxP3 expressing regulatory CD4+ T lymphocytes (Tregs) that down-regulate anti-tumor immunity. In order to assess whether FoxP3 was an independent driver differentially expressed in primary versus recurrent GBMs, we stained resected primary and recurrent GBM tumors for CD3, CD4, CD8 and FoxP3 expression using standard immunohistochemistry. Slides were scanned with a high-resolution scanner (ScanScope CS; Aperio), and image analysis software (Aperio ScanScope) was used to enumerate lymphocyte subpopulations allowing for high-throughput analysis and bypassing manual selection bias. As shown in previous studies, enumeration of individual lymphocyte populations did not correlate with clinical outcomes in patients with GBM. However, the CD4+ to regulatory FoxP3+ T cell ratio was diminished in recurrent disease, and increased CD3 and CD8+ to regulatory T cell ratios showed a positive correlation with survival outcomes in primary GBM. These results suggest that while absolute numbers of tumor infiltrating lymphocytes may not be informative for predicting clinical outcomes in patients with GBM, the effective balance of CD3, CD4 and CD8+ T cells to immunosuppressive FoxP3+ regulatory cells may influence clinical outcomes in this patient population.

Authors
Sayour, EJ; McLendon, P; McLendon, R; De Leon, G; Reynolds, R; Kresak, J; Sampson, JH; Mitchell, DA
MLA Citation
Sayour, EJ, McLendon, P, McLendon, R, De Leon, G, Reynolds, R, Kresak, J, Sampson, JH, and Mitchell, DA. "Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma." Cancer Immunology, Immunotherapy 64.4 (March 22, 2015): 419-427.
Source
scopus
Published In
Cancer Immunology, Immunotherapy
Volume
64
Issue
4
Publish Date
2015
Start Page
419
End Page
427
DOI
10.1007/s00262-014-1651-7

Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.

After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.

Authors
Mitchell, DA; Batich, KA; Gunn, MD; Huang, M-N; Sanchez-Perez, L; Nair, SK; Congdon, KL; Reap, EA; Archer, GE; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; Coan, A; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, DA, Batich, KA, Gunn, MD, Huang, M-N, Sanchez-Perez, L, Nair, SK, Congdon, KL, Reap, EA, Archer, GE, Desjardins, A, Friedman, AH, Friedman, HS, Herndon, JE, Coan, A, McLendon, RE, Reardon, DA, Vredenburgh, JJ, Bigner, DD, and Sampson, JH. "Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients." Nature 519.7543 (March 11, 2015): 366-369.
PMID
25762141
Source
epmc
Published In
Nature
Volume
519
Issue
7543
Publish Date
2015
Start Page
366
End Page
369
DOI
10.1038/nature14320

Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth.

Tumour-associated macrophages (TAMs) are enriched in glioblastoma multiformes (GBMs) that contain glioma stem cells (GSCs) at the apex of their cellular hierarchy. The correlation between TAM density and glioma grade suggests a supportive role for TAMs in tumour progression. Here we interrogated the molecular link between GSCs and TAM recruitment in GBMs and demonstrated that GSCs secrete periostin (POSTN) to recruit TAMs. TAM density correlates with POSTN levels in human GBMs. Silencing POSTN in GSCs markedly reduced TAM density, inhibited tumour growth, and increased survival of mice bearing GSC-derived xenografts. We found that TAMs in GBMs are not brain-resident microglia, but mainly monocyte-derived macrophages from peripheral blood. Disrupting POSTN specifically attenuated the tumour-supportive M2 type of TAMs in xenografts. POSTN recruits TAMs through the integrin αvβ₃ as blocking this signalling by an RGD peptide inhibited TAM recruitment. Our findings highlight the possibility of improving GBM treatment by targeting POSTN-mediated TAM recruitment.

Authors
Zhou, W; Ke, SQ; Huang, Z; Flavahan, W; Fang, X; Paul, J; Wu, L; Sloan, AE; McLendon, RE; Li, X; Rich, JN; Bao, S
MLA Citation
Zhou, W, Ke, SQ, Huang, Z, Flavahan, W, Fang, X, Paul, J, Wu, L, Sloan, AE, McLendon, RE, Li, X, Rich, JN, and Bao, S. "Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth." Nature cell biology 17.2 (February 2015): 170-182.
PMID
25580734
Source
epmc
Published In
Nature Cell Biology
Volume
17
Issue
2
Publish Date
2015
Start Page
170
End Page
182
DOI
10.1038/ncb3090

Supratentorial tanycytic ependymoma in an adult male: case report and review of literature.

Ependymomas, tumors of the ependymal cells, are very rare and usually present in the pediatric population. Furthermore, there are even rarer variants of ependymomas that can include cellular, papillary, clear cell, and tanycytic subtypes. We present a case of a supratentorial tanycytic ependymoma in an adult male and review the literature in regard to this rare primary central nervous system neoplasm.

Authors
Lopez, G; McLendon, RE; Peters, KB
MLA Citation
Lopez, G, McLendon, RE, and Peters, KB. "Supratentorial tanycytic ependymoma in an adult male: case report and review of literature." Case reports in oncology 8.1 (January 2015): 159-163.
PMID
25873884
Source
epmc
Published In
Case Reports in Oncology
Volume
8
Issue
1
Publish Date
2015
Start Page
159
End Page
163
DOI
10.1159/000380906

Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: Implications for drug development

© 2015 International Society for Neurochemistry.The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR.

Authors
Brown, KE; Chagoya, G; Kwatra, SG; Yen, T; Keir, ST; Cooter, M; Hoadley, KA; Rasheed, A; Lipp, ES; McLendon, R; Ali-Osman, F; Bigner, DD; Sampson, JH; Kwatra, MM
MLA Citation
Brown, KE, Chagoya, G, Kwatra, SG, Yen, T, Keir, ST, Cooter, M, Hoadley, KA, Rasheed, A, Lipp, ES, McLendon, R, Ali-Osman, F, Bigner, DD, Sampson, JH, and Kwatra, MM. "Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: Implications for drug development." Journal of Neurochemistry 133.5 (2015): 730-738.
Source
scival
Published In
Journal of Neurochemistry
Volume
133
Issue
5
Publish Date
2015
Start Page
730
End Page
738
DOI
10.1111/jnc.13032

Abstract LB-82: MLL2 maintains neoplastic cell growth and global histone H3 lysine 4 monomethylation

Authors
Guo, C; Chen, LH; Huang, Y; Chang, C-C; Wang, P; Pirozzi, CJ; Qin, X; Bao, X; Greer, PK; McLendon, RE; Yan, H; Keir, ST; Bigner, DD; He, Y
MLA Citation
Guo, C, Chen, LH, Huang, Y, Chang, C-C, Wang, P, Pirozzi, CJ, Qin, X, Bao, X, Greer, PK, McLendon, RE, Yan, H, Keir, ST, Bigner, DD, and He, Y. "Abstract LB-82: MLL2 maintains neoplastic cell growth and global histone H3 lysine 4 monomethylation." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
LB-82
End Page
LB-82
DOI
10.1158/1538-7445.AM2014-LB-82

Abstract 63: Driving brain tumorigenesis: Generation of a mutant IDH1 mouse model of progressive glioma

Authors
Pirozzi, CJ; Wang, CY; Carpenter, AB; Zhu, H; Greer, PK; McLendon, RE; Bigner, DD; He, Y; Yan, H
MLA Citation
Pirozzi, CJ, Wang, CY, Carpenter, AB, Zhu, H, Greer, PK, McLendon, RE, Bigner, DD, He, Y, and Yan, H. "Abstract 63: Driving brain tumorigenesis: Generation of a mutant IDH1 mouse model of progressive glioma." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
63
End Page
63
DOI
10.1158/1538-7445.AM2014-63

miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways.

Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Glioma-initiating cells (GICs) are stem-like cells that have been implicated in glioblastoma progression and recurrence; however, the distinct properties of GICs and non-GICs within GBM tumors are largely uncharacterized. Here, we evaluated stem cell-associated microRNA (miR) expression in GICs from GBM patients and GICs derived from xenografted human glioma cell lines and determined that miR-33a promotes GIC growth and self-renewal. Moreover, evaluation of a GBM tissue array revealed that higher miR-33a expression was associated with poor prognosis of GBM patients. Antagonizing miR-33a function in GICs reduced self-renewal and tumor progression in immune-compromised mice, whereas overexpression of miR-33a in non-GICs promoted the display of features associated with GICs. We identified the mRNAs encoding phosphodiesterase 8A (PDE8A) and UV radiation resistance-associated gene (UVRAG) as direct miR-33a targets. PDE8A and UVRAG negatively regulated the cAMP/PKA and NOTCH pathways, respectively; therefore, miR-33a-dependent reduction of these proteins promoted growth and self-renewal of GICs by enhancing PKA and NOTCH activity. Furthermore, in GBM specimens, there was an inverse correlation between the expression levels of miR-33a and PDE8A and UVRAG expression. These findings reveal a miR-33a-centered signaling network that promotes GIC maintenance and has potential as a therapeutic target for GBM treatment.

Authors
Wang, H; Sun, T; Hu, J; Zhang, R; Rao, Y; Wang, S; Chen, R; McLendon, RE; Friedman, AH; Keir, ST; Bigner, DD; Li, Q-J; Wang, H; Wang, X-F
MLA Citation
Wang, H, Sun, T, Hu, J, Zhang, R, Rao, Y, Wang, S, Chen, R, McLendon, RE, Friedman, AH, Keir, ST, Bigner, DD, Li, Q-J, Wang, H, and Wang, X-F. "miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways." The Journal of clinical investigation 124.10 (October 2014): 4489-4502.
PMID
25202981
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
10
Publish Date
2014
Start Page
4489
End Page
4502
DOI
10.1172/jci75284

EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis.

Aberrant activation of EGFR in human cancers promotes tumorigenesis through stimulation of AKT signaling. Here, we determined that the discoidina neuropilin-like membrane protein DCBLD2 is upregulated in clinical specimens of glioblastomas and head and neck cancers (HNCs) and is required for EGFR-stimulated tumorigenesis. In multiple cancer cell lines, EGFR activated phosphorylation of tyrosine 750 (Y750) of DCBLD2, which is located within a recently identified binding motif for TNF receptor-associated factor 6 (TRAF6). Consequently, phosphorylation of DCBLD2 Y750 recruited TRAF6, leading to increased TRAF6 E3 ubiquitin ligase activity and subsequent activation of AKT, thereby enhancing EGFR-driven tumorigenesis. Moreover, evaluation of patient samples of gliomas and HNCs revealed an association among EGFR activation, DCBLD2 phosphorylation, and poor prognoses. Together, our findings uncover a pathway in which DCBLD2 functions as a signal relay for oncogenic EGFR signaling to promote tumorigenesis and suggest DCBLD2 and TRAF6 as potential therapeutic targets for human cancers that are associated with EGFR activation.

Authors
Feng, H; Lopez, GY; Kim, CK; Alvarez, A; Duncan, CG; Nishikawa, R; Nagane, M; Su, A-JA; Auron, PE; Hedberg, ML; Wang, L; Raizer, JJ; Kessler, JA; Parsa, AT; Gao, W-Q; Kim, S-H; Minata, M; Nakano, I; Grandis, JR; McLendon, RE; Bigner, DD; Lin, H-K; Furnari, FB; Cavenee, WK; Hu, B; Yan, H; Cheng, S-Y
MLA Citation
Feng, H, Lopez, GY, Kim, CK, Alvarez, A, Duncan, CG, Nishikawa, R, Nagane, M, Su, A-JA, Auron, PE, Hedberg, ML, Wang, L, Raizer, JJ, Kessler, JA, Parsa, AT, Gao, W-Q, Kim, S-H, Minata, M, Nakano, I, Grandis, JR, McLendon, RE, Bigner, DD, Lin, H-K, Furnari, FB, Cavenee, WK, Hu, B, Yan, H, and Cheng, S-Y. "EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis." The Journal of clinical investigation 124.9 (September 2014): 3741-3756.
PMID
25061874
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
9
Publish Date
2014
Start Page
3741
End Page
3756
DOI
10.1172/jci73093

EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis

Authors
Feng, H; Lopez, GY; Kim, CK; Alvarez, A; Duncan, CG; Nishikawa, R; Nagane, M; Su, A-JA; Auron, PE; Hedberg, ML; Wang, L; Raizer, JJ; Kessler, JA; Parsa, AT; Gao, W-Q; Kim, S-H; Minata, M; Nakano, I; Grandis, JR; McLendon, RE; Bigner, DD; Lin, H-K; Furnari, FB; Cavenee, WK; Hu, B; Yan, H; Cheng, S-Y
MLA Citation
Feng, H, Lopez, GY, Kim, CK, Alvarez, A, Duncan, CG, Nishikawa, R, Nagane, M, Su, A-JA, Auron, PE, Hedberg, ML, Wang, L, Raizer, JJ, Kessler, JA, Parsa, AT, Gao, W-Q, Kim, S-H, Minata, M, Nakano, I, Grandis, JR, McLendon, RE, Bigner, DD, Lin, H-K, Furnari, FB, Cavenee, WK, Hu, B, Yan, H, and Cheng, S-Y. "EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis." JOURNAL OF CLINICAL INVESTIGATION 124.9 (September 2014): 3741-3756.
Source
wos-lite
Published In
Journal of Clinical Investigation
Volume
124
Issue
9
Publish Date
2014
Start Page
3741
End Page
3756
DOI
10.1172/JC173093

Malignant brainstem gliomas in adults: clinicopathological characteristics and prognostic factors.

Adult malignant brainstem gliomas (BSGs) are poorly characterized due to their relative rarity. We have examined histopathologically confirmed cases of adult malignant BSGs to better characterize the patient and tumor features and outcomes, including the natural history, presentation, imaging, molecular characteristics, prognostic factors, and appropriate treatments. A total of 34 patients were identified, consisting of 22 anaplastic astrocytomas (AAs) and 12 glioblastomas (GBMs). The overall median survival for all patients was 25.8 months, with patients having GBMs experiencing significantly worse survival (12.1 vs. 77.0 months, p = 0.0011). The majority of tumors revealed immunoreactivity for EGFR (93.3 %) and MGMT (64.7 %). Most tumors also exhibited chromosomal abnormalities affecting the loci of epidermal growth factor receptor (92.9 %), MET (100 %), PTEN (61.5 %), and 9p21 (80 %). AAs more commonly appeared diffusely enhancing (50.0 vs. 27.3 %) or diffusely nonenhancing (25.0 vs. 0.0 %), while GBMs were more likely to exhibit focal enhancement (54.6 vs. 10.0 %). Multivariate analysis revealed confirmed histopathology for GBM to significantly affect survival (HR 4.80; 95 % CI 1.86-12.4; p = 0.0012). In conclusion, adult malignant BSGs have an overall poor prognosis, with GBM tumors faring significantly worse than AAs. As AAs and GBMs have differing imaging characteristics, tissue diagnosis may be necessary to accurately determine patient prognosis and identify molecular characteristics which may aid in the treatment of these aggressive tumors.

Authors
Babu, R; Kranz, PG; Agarwal, V; McLendon, RE; Thomas, S; Friedman, AH; Bigner, DD; Adamson, C
MLA Citation
Babu, R, Kranz, PG, Agarwal, V, McLendon, RE, Thomas, S, Friedman, AH, Bigner, DD, and Adamson, C. "Malignant brainstem gliomas in adults: clinicopathological characteristics and prognostic factors." Journal of neuro-oncology 119.1 (August 2014): 177-185.
PMID
24838419
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
119
Issue
1
Publish Date
2014
Start Page
177
End Page
185
DOI
10.1007/s11060-014-1471-9

The zinc finger transcription factor ZFX is required for maintaining the tumorigenic potential of glioblastoma stem cells.

Glioblastomas are highly lethal brain tumors containing tumor-propagating glioma stem cells (GSCs). The molecular mechanisms underlying the maintenance of the GSC phenotype are not fully defined. Here we demonstrate that the zinc finger and X-linked transcription factor (ZFX) maintains GSC self-renewal and tumorigenic potential by upregulating c-Myc expression. ZFX is differentially expressed in GSCs relative to non-stem glioma cells and neural progenitor cells. Disrupting ZFX by shRNA reduced c-Myc expression and potently inhibited GSC self-renewal and tumor growth. Ectopic expression of c-Myc to its endogenous level rescued the effects caused by ZFX disruption, supporting that ZFX controls GSC properties through c-Myc. Furthermore, ZFX binds to a specific sequence (GGGCCCCG) on the human c-Myc promoter to upregulate c-Myc expression. These data demonstrate that ZFX functions as a critical upstream regulator of c-Myc and plays essential roles in the maintenance of the GSC phenotype. This study also supports that c-Myc is a dominant driver linking self-renewal to malignancy.

Authors
Fang, X; Huang, Z; Zhou, W; Wu, Q; Sloan, AE; Ouyang, G; McLendon, RE; Yu, JS; Rich, JN; Bao, S
MLA Citation
Fang, X, Huang, Z, Zhou, W, Wu, Q, Sloan, AE, Ouyang, G, McLendon, RE, Yu, JS, Rich, JN, and Bao, S. "The zinc finger transcription factor ZFX is required for maintaining the tumorigenic potential of glioblastoma stem cells." Stem cells (Dayton, Ohio) 32.8 (August 2014): 2033-2047.
PMID
24831540
Source
epmc
Published In
Stem Cells
Volume
32
Issue
8
Publish Date
2014
Start Page
2033
End Page
2047
DOI
10.1002/stem.1730

Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas.

Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.

Authors
Zhang, L; Chen, LH; Wan, H; Yang, R; Wang, Z; Feng, J; Yang, S; Jones, S; Wang, S; Zhou, W; Zhu, H; Killela, PJ; Zhang, J; Wu, Z; Li, G; Hao, S; Wang, Y; Webb, JB; Friedman, HS; Friedman, AH; McLendon, RE; He, Y; Reitman, ZJ; Bigner, DD; Yan, H
MLA Citation
Zhang, L, Chen, LH, Wan, H, Yang, R, Wang, Z, Feng, J, Yang, S, Jones, S, Wang, S, Zhou, W, Zhu, H, Killela, PJ, Zhang, J, Wu, Z, Li, G, Hao, S, Wang, Y, Webb, JB, Friedman, HS, Friedman, AH, McLendon, RE, He, Y, Reitman, ZJ, Bigner, DD, and Yan, H. "Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas." Nature genetics 46.7 (July 2014): 726-730.
PMID
24880341
Source
epmc
Published In
Nature Genetics
Volume
46
Issue
7
Publish Date
2014
Start Page
726
End Page
730
DOI
10.1038/ng.2995

Tert promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.

Malignant cells must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas.

Authors
Yan, H; Killela, PJ; Reitman, ZJ; Jiao, Y; Bettegowda, C; Agrawal, N; Diaz, LA; Friedman, AH; Friedman, H; Gallia, GL; Giovanella, BC; Grollman, AP; He, TC; He, Y; Hruban, RH; Jallo, GI; Mandahl, N; Meeker, AK; Mertens, F; Netto, GJ; Rasheed, BA; Riggins, GJ; Rosenquist, TA; Schiffman, M; Shih, I; Theodorescu, D; Torbenson, MS; Velculescu, VE; Wang, TL; Wentzensen, N; Wood, LD; Zhang, M; Healy, P; Yang, R; Diplas, B; Wang, ZH; Greer, P; Zhu, HS; Wang, C; Carpenter, A; Herndon, JE; McLendon, RE et al.
MLA Citation
Yan, H, Killela, PJ, Reitman, ZJ, Jiao, Y, Bettegowda, C, Agrawal, N, Diaz, LA, Friedman, AH, Friedman, H, Gallia, GL, Giovanella, BC, Grollman, AP, He, TC, He, Y, Hruban, RH, Jallo, GI, Mandahl, N, Meeker, AK, Mertens, F, Netto, GJ, Rasheed, BA, Riggins, GJ, Rosenquist, TA, Schiffman, M, Shih, I, Theodorescu, D, Torbenson, MS, Velculescu, VE, Wang, TL, Wentzensen, N, Wood, LD, Zhang, M, Healy, P, Yang, R, Diplas, B, Wang, ZH, Greer, P, Zhu, HS, Wang, C, Carpenter, A, Herndon, JE, and McLendon, RE et al. "Tert promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal." Neuro Oncol 16 Suppl 3 (July 2014): iii5-iii6.
PMID
25165359
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii5
End Page
iii6
DOI
10.1093/neuonc/nou206.18

Prognostic marker analysis in pediatric posterior fossa ependymomas.

NELL2 expression has been shown to identify patients with posterior fossa ependymomas (PFEp) that exhibit prolonged survivals. We analyzed expression NELL2; KI-67; Tenascin C; CD34; VEGF; and CA IX as well as vascular density against post-operative survival (Progression Free and Overall Survival; PFS, OS) in 31 patients under the age of 22 years.

Authors
McLendon, RE; Lipp, E; Gururangan, S; Fuchs, H; Zagzag, D; Herndon, J; Healy, P
MLA Citation
McLendon, RE, Lipp, E, Gururangan, S, Fuchs, H, Zagzag, D, Herndon, J, and Healy, P. "Prognostic marker analysis in pediatric posterior fossa ependymomas." Neuro Oncol 16 Suppl 3 (July 2014): iii27-.
PMID
25165266
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii27
DOI
10.1093/neuonc/nou208.17

Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas

Authors
Zhang, L; Chen, LH; Wan, H; Yang, R; Wang, Z; Feng, J; Yang, S; Jones, S; Wang, S; Zhou, W; Zhu, H; Killela, PJ; Zhang, J; Wu, Z; Li, G; Hao, S; Wang, Y; Webb, JB; Friedman, HS; Friedman, AH; McLendon, RE; He, Y; Reitman, ZJ; Bigner, DD; Yan, H
MLA Citation
Zhang, L, Chen, LH, Wan, H, Yang, R, Wang, Z, Feng, J, Yang, S, Jones, S, Wang, S, Zhou, W, Zhu, H, Killela, PJ, Zhang, J, Wu, Z, Li, G, Hao, S, Wang, Y, Webb, JB, Friedman, HS, Friedman, AH, McLendon, RE, He, Y, Reitman, ZJ, Bigner, DD, and Yan, H. "Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas." Nature Genetics 46.7 (June 1, 2014): 726-730.
Source
crossref
Published In
Nature Genetics
Volume
46
Issue
7
Publish Date
2014
Start Page
726
End Page
730
DOI
10.1038/ng.2995

The genetic landscape of anaplastic astrocytoma.

Anaplastic astrocytoma WHO grade III (A3) is a lethal brain tumor that often occurs in middle aged patients. Clinically, it is challenging to distinguish A3 from glioblastoma multiforme (GBM) WHO grade IV. To reveal the genetic landscape of this tumor type, we sequenced the exome of a cohort of A3s (n=16). For comparison and to illuminate the genomic landscape of other glioma subtypes, we also included in our study diffuse astrocytoma WHO grade II (A2, n=7), oligoastrocytoma WHO grade II (OA2, n=2), anaplastic oligoastrocytoma WHO grade III (OA3, n=4), and GBM (n=28). Exome sequencing of A3s identified frequent mutations in IDH1 (75%, 12/16), ATRX (63%, 10/16), and TP53 (82%, 13/16). In contrast, the majority of GBMs (75%, 21/28) did not contain IDH1 or ATRX mutations, and displayed a distinct spectrum of mutations. Finally, our study also identified novel genes that were not previously linked to this tumor type. In particular, we found mutations in Notch pathway genes (NOTCH1, NOTCH2, NOTCH4, NOTCH2NL), including a recurrent NOTCH1-A465Tmutation, in 31% (5/16) of A3s. This study suggests genetic signatures will be useful for the classification of gliomas.

Authors
Killela, PJ; Pirozzi, CJ; Reitman, ZJ; Jones, S; Rasheed, BA; Lipp, E; Friedman, H; Friedman, AH; He, Y; McLendon, RE; Bigner, DD; Yan, H
MLA Citation
Killela, PJ, Pirozzi, CJ, Reitman, ZJ, Jones, S, Rasheed, BA, Lipp, E, Friedman, H, Friedman, AH, He, Y, McLendon, RE, Bigner, DD, and Yan, H. "The genetic landscape of anaplastic astrocytoma." Oncotarget 5.6 (March 30, 2014): 1452-1457.
PMID
24140581
Source
pubmed
Published In
Oncotarget
Volume
5
Issue
6
Publish Date
2014
Start Page
1452
End Page
1457
DOI
10.18632/oncotarget.1505

Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas.

Frequent mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and the promoter of telomerase reverse transcriptase (TERT) represent two significant discoveries in glioma genomics. Understanding the degree to which these two mutations co-occur or occur exclusively of one another in glioma subtypes presents a unique opportunity to guide glioma classification and prognosis. We analyzed the relationship between overall survival (OS) and the presence of IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas. We hypothesized and show that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of cases. Patients whose Grade III-IV gliomas exhibit TERT promoter mutations alone predominately have primary GBMs associated with poor median OS (11.5 months). Patients whose Grade III-IV gliomas exhibit IDH1/2 mutations alone predominately have astrocytic morphologies and exhibit a median OS of 57 months while patients whose tumors exhibit both TERT promoter and IDH1/2 mutations predominately exhibit oligodendroglial morphologies and exhibit median OS of 125 months. Analyzing gliomas based on their genetic signatures allows for the stratification of these patients into distinct cohorts, with unique prognosis and survival.

Authors
Killela, PJ; Pirozzi, CJ; Healy, P; Reitman, ZJ; Lipp, E; Rasheed, BA; Yang, R; Diplas, BH; Wang, Z; Greer, PK; Zhu, H; Wang, CY; Carpenter, AB; Friedman, H; Friedman, AH; Keir, ST; He, J; He, Y; McLendon, RE; Herndon, JE; Yan, H; Bigner, DD
MLA Citation
Killela, PJ, Pirozzi, CJ, Healy, P, Reitman, ZJ, Lipp, E, Rasheed, BA, Yang, R, Diplas, BH, Wang, Z, Greer, PK, Zhu, H, Wang, CY, Carpenter, AB, Friedman, H, Friedman, AH, Keir, ST, He, J, He, Y, McLendon, RE, Herndon, JE, Yan, H, and Bigner, DD. "Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas." Oncotarget 5.6 (March 2014): 1515-1525.
PMID
24722048
Source
epmc
Published In
Oncotarget
Volume
5
Issue
6
Publish Date
2014
Start Page
1515
End Page
1525

Clinico-pathological description of three paediatric medulloblastoma cases with MLL2/3 gene mutations

Authors
Lopez, GY; Grant, GA; Fuchs, HE; Leithe, LG; Gururangan, S; Bigner, DD; Yan, H; McLendon, RE; He, Y
MLA Citation
Lopez, GY, Grant, GA, Fuchs, HE, Leithe, LG, Gururangan, S, Bigner, DD, Yan, H, McLendon, RE, and He, Y. "Clinico-pathological description of three paediatric medulloblastoma cases with MLL2/3 gene mutations." NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY 40.2 (February 2014): 217-220.
Source
wos-lite
Published In
Neuropathology & Applied Neurobiology
Volume
40
Issue
2
Publish Date
2014
Start Page
217
End Page
220
DOI
10.1111/nan.12060

Efficacy of bevacizumab plus irinotecan in children with recurrent Low-grade gliomas-a Pediatric Brain Tumor Consortium study

Authors
Gururangan, S; Fangusaro, J; Poussaint, TY; McLendon, RE; Onar-Thomas, A; Wu, S; Packer, RJ; Banerjee, A; Gilbertson, RJ; Fahey, F; Vajapeyam, S; Jakacki, R; Gajjar, A; Goldman, S; Pollack, IF; Friedman, HS; Boyett, JM; Fouladi, M; Kun, LE
MLA Citation
Gururangan, S, Fangusaro, J, Poussaint, TY, McLendon, RE, Onar-Thomas, A, Wu, S, Packer, RJ, Banerjee, A, Gilbertson, RJ, Fahey, F, Vajapeyam, S, Jakacki, R, Gajjar, A, Goldman, S, Pollack, IF, Friedman, HS, Boyett, JM, Fouladi, M, and Kun, LE. "Efficacy of bevacizumab plus irinotecan in children with recurrent Low-grade gliomas-a Pediatric Brain Tumor Consortium study." NEURO-ONCOLOGY 16.2 (February 2014): 310-317.
Source
wos-lite
Published In
Neuro-Oncology
Volume
16
Issue
2
Publish Date
2014
Start Page
310
End Page
317
DOI
10.1093/neuonc/not154

High-throughput flow cytometry screening reveals a role for junctional adhesion molecule a as a cancer stem cell maintenance factor.

Stem cells reside in niches that regulate the balance between self-renewal and differentiation. The identity of a stem cell is linked with the ability to interact with its niche through adhesion mechanisms. To identify targets that disrupt cancer stem cell (CSC) adhesion, we performed a flow cytometry screen on patient-derived glioblastoma (GBM) cells and identified junctional adhesion molecule A (JAM-A) as a CSC adhesion mechanism essential for self-renewal and tumor growth. JAM-A was dispensable for normal neural stem/progenitor cell (NPC) function, and JAM-A expression was reduced in normal brain versus GBM. Targeting JAM-A compromised the self-renewal of CSCs. JAM-A expression negatively correlated to GBM patient prognosis. Our results demonstrate that GBM-targeting strategies can be identified through screening adhesion receptors and JAM-A represents a mechanism for niche-driven CSC maintenance.

Authors
Lathia, JD; Li, M; Sinyuk, M; Alvarado, AG; Flavahan, WA; Stoltz, K; Rosager, AM; Hale, J; Hitomi, M; Gallagher, J; Wu, Q; Martin, J; Vidal, JG; Nakano, I; Dahlrot, RH; Hansen, S; McLendon, RE; Sloan, AE; Bao, S; Hjelmeland, AB; Carson, CT; Naik, UP; Kristensen, B; Rich, JN
MLA Citation
Lathia, JD, Li, M, Sinyuk, M, Alvarado, AG, Flavahan, WA, Stoltz, K, Rosager, AM, Hale, J, Hitomi, M, Gallagher, J, Wu, Q, Martin, J, Vidal, JG, Nakano, I, Dahlrot, RH, Hansen, S, McLendon, RE, Sloan, AE, Bao, S, Hjelmeland, AB, Carson, CT, Naik, UP, Kristensen, B, and Rich, JN. "High-throughput flow cytometry screening reveals a role for junctional adhesion molecule a as a cancer stem cell maintenance factor." Cell Rep 6.1 (January 16, 2014): 117-129.
PMID
24373972
Source
pubmed
Published In
Cell Reports
Volume
6
Issue
1
Publish Date
2014
Start Page
117
End Page
129
DOI
10.1016/j.celrep.2013.11.043

High-throughput flow cytometry screening reveals a role for junctional adhesion molecule a as a cancer stem cell maintenance factor

Stem cells reside in niches that regulate the balance between self-renewal and differentiation. The identity of a stem cell is linked with the ability tointeract with its niche through adhesion mechanisms. To identify targets that disrupt cancer stemcell (CSC) adhesion, we performed a flow cytometryscreen on patient-derived glioblastoma (GBM) cells and identified junctional adhesion molecule A(JAM-A) as a CSC adhesion mechanism essentialfor self-renewal and tumor growth. JAM-A wasdispensable for normal neural stem/progenitorcell (NPC) function, and JAM-A expression was reduced in normal brain versus GBM. Targeting JAM-A compromised the self-renewal of CSCs. JAM-A expression negatively correlated to GBM patient prognosis. Our results demonstrate thatGBM-targeting strategies can be identified through screening adhesion receptors and JAM-A represents a mechanism for niche-driven CSC maintenance. © 2014 The Authors.

Authors
Lathia, JD; Li, M; Sinyuk, M; Alvarado, AG; Flavahan, WA; Stoltz, K; Rosager, AM; Hale, J; Hitomi, M; Gallagher, J; Wu, Q; Martin, J; Vidal, JG; Nakano, I; Dahlrot, RH; Hansen, S; McLendon, RE; Sloan, AE; Bao, S; Hjelmeland, AB; Carson, CT; Naik, UP; Kristensen, B; Rich, JN
MLA Citation
Lathia, JD, Li, M, Sinyuk, M, Alvarado, AG, Flavahan, WA, Stoltz, K, Rosager, AM, Hale, J, Hitomi, M, Gallagher, J, Wu, Q, Martin, J, Vidal, JG, Nakano, I, Dahlrot, RH, Hansen, S, McLendon, RE, Sloan, AE, Bao, S, Hjelmeland, AB, Carson, CT, Naik, UP, Kristensen, B, and Rich, JN. "High-throughput flow cytometry screening reveals a role for junctional adhesion molecule a as a cancer stem cell maintenance factor." Cell Reports 6.1 (January 1, 2014): 117-129.
Source
scopus
Published In
Cell Reports
Volume
6
Issue
1
Publish Date
2014
Start Page
117
End Page
129
DOI
10.1016/j.celrep.2013.11.043

Malignant brainstem gliomas in adults: Clinicopathological characteristics and prognostic factors

Adult malignant brainstem gliomas (BSGs) are poorly characterized due to their relative rarity. We have examined histopathologically confirmed cases of adult malignant BSGs to better characterize the patient and tumor features and outcomes, including the natural history, presentation, imaging, molecular characteristics, prognostic factors, and appropriate treatments. A total of 34 patients were identified, consisting of 22 anaplastic astrocytomas (AAs) and 12 glioblastomas (GBMs). The overall median survival for all patients was 25.8 months, with patients having GBMs experiencing significantly worse survival (12.1 vs. 77.0 months, p = 0.0011). The majority of tumors revealed immunoreactivity for EGFR (93.3 %) and MGMT (64.7 %). Most tumors also exhibited chromosomal abnormalities affecting the loci of epidermal growth factor receptor (92.9 %), MET (100 %), PTEN (61.5 %), and 9p21 (80 %). AAs more commonly appeared diffusely enhancing (50.0 vs. 27.3 %) or diffusely nonenhancing (25.0 vs. 0.0 %), while GBMs were more likely to exhibit focal enhancement (54.6 vs. 10.0 %). Multivariate analysis revealed confirmed histopathology for GBM to significantly affect survival (HR 4.80; 95 % CI 1.86-12.4; p = 0.0012). In conclusion, adult malignant BSGs have an overall poor prognosis, with GBM tumors faring significantly worse than AAs. As AAs and GBMs have differing imaging characteristics, tissue diagnosis may be necessary to accurately determine patient prognosis and identify molecular ch aracteristics which may aid in the treatment of these aggressive tumors. © 2014 Springer Science+Business Media.

Authors
Babu, R; Kranz, PG; Agarwal, V; McLendon, RE; Thomas, S; Friedman, AH; Bigner, DD; Adamson, C
MLA Citation
Babu, R, Kranz, PG, Agarwal, V, McLendon, RE, Thomas, S, Friedman, AH, Bigner, DD, and Adamson, C. "Malignant brainstem gliomas in adults: Clinicopathological characteristics and prognostic factors." Journal of Neuro-Oncology 119.1 (January 1, 2014): 177-185.
Source
scopus
Published In
Journal of Neuro-Oncology
Volume
119
Issue
1
Publish Date
2014
Start Page
177
End Page
185
DOI
10.1007/s11060-014-1471-9

EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is uniformly lethal. T-cell-based immunotherapy offers a promising platform for treatment given its potential to specifically target tumor tissue while sparing the normal brain. However, the diffuse and infiltrative nature of these tumors in the brain parenchyma may pose an exceptional hurdle to successful immunotherapy in patients. Areas of invasive tumor are thought to reside behind an intact blood brain barrier, isolating them from effective immunosurveillance and thereby predisposing the development of "immunologically silent" tumor peninsulas. Therefore, it remains unclear if adoptively transferred T cells can migrate to and mediate regression in areas of invasive GBM. One barrier has been the lack of a preclinical mouse model that accurately recapitulates the growth patterns of human GBM in vivo. Here, we demonstrate that D-270 MG xenografts exhibit the classical features of GBM and produce the diffuse and invasive tumors seen in patients. Using this model, we designed experiments to assess whether T cells expressing third-generation chimeric antigen receptors (CARs) targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, would localize to and treat invasive intracerebral GBM. EGFRvIII-targeted CAR (EGFRvIII+ CAR) T cells demonstrated in vitro EGFRvIII antigen-specific recognition and reactivity to the D-270 MG cell line, which naturally expresses EGFRvIII. Moreover, when administered systemically, EGFRvIII+ CAR T cells localized to areas of invasive tumor, suppressed tumor growth, and enhanced survival of mice with established intracranial D-270 MG tumors. Together, these data demonstrate that systemically administered T cells are capable of migrating to the invasive edges of GBM to mediate antitumor efficacy and tumor regression.

Authors
Miao, H; Choi, BD; Suryadevara, CM; Sanchez-Perez, L; Yang, S; De Leon, G; Sayour, EJ; McLendon, R; Herndon, JE; Healy, P; Archer, GE; Bigner, DD; Johnson, LA; Sampson, JH
MLA Citation
Miao, H, Choi, BD, Suryadevara, CM, Sanchez-Perez, L, Yang, S, De Leon, G, Sayour, EJ, McLendon, R, Herndon, JE, Healy, P, Archer, GE, Bigner, DD, Johnson, LA, and Sampson, JH. "EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma." PloS one 9.4 (January 2014): e94281-.
PMID
24722266
Source
epmc
Published In
PloS one
Volume
9
Issue
4
Publish Date
2014
Start Page
e94281
DOI
10.1371/journal.pone.0094281

Bevacizumab (BVZ)-associated toxicities in children with recurrent central nervous system tumors treated with BVZ and irinotecan (CPT-11): A Pediatric Brain Tumor Consortium Study (PBTC-022)

BACKGROUND The incidence and spectrum of acute toxicities related to the use of bevacizumab (BVZ)-containing regimens in children are largely unknown. This report describes the adverse events in a recently completed large phase 2 trial of BVZ plus irinotecan (CPT-11) in children with recurrent central nervous system tumors. METHODS Pediatric Brain T umor Consortium trial-022 evaluated the efficacy and toxicity of BVZ (10 mg/kg administered intravenously) as a single agent for 2 doses given 2 weeks apart and then combined with CPT-11 every 2 weeks (1 course = 4 weeks) in children with recurrent central nervous system tumors. Children were treated until they experienced progressive disease, unacceptable toxicity or completed up to a maximum of 2 years of therapy. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Patients who received at least 1 dose of BVZ were included for toxicity assessment. RESULTS Between October 2006 and June 2010, 92 patients evaluable for toxicity were enrolled and received 687 treatment courses. The most common toxicities attributable to BVZ included grade I-III hypertension (38% of patients), grade I-III fatigue (30%), grade I-II epistaxis (24%), and grade I-IV proteinuria (22%). Twenty-two patients (24%) stopped therapy due to toxicity. CONCLUSIONS The combination of BVZ and CPT-11 was fairly well-tolerated, and most severe BVZ-related toxicities were rare, self-limiting, and manageable. ©2013 American Cancer Society.

Authors
Fangusaro, J; Gururangan, S; Poussaint, TY; McLendon, RE; Onar-Thomas, A; Warren, KE; Wu, S; Packer, RJ; Banerjee, A; Gilbertson, RJ; Jakacki, R; Gajjar, A; Goldman, S; Pollack, IF; Friedman, HS; Boyett, JM; Kun, LE; Fouladi, M
MLA Citation
Fangusaro, J, Gururangan, S, Poussaint, TY, McLendon, RE, Onar-Thomas, A, Warren, KE, Wu, S, Packer, RJ, Banerjee, A, Gilbertson, RJ, Jakacki, R, Gajjar, A, Goldman, S, Pollack, IF, Friedman, HS, Boyett, JM, Kun, LE, and Fouladi, M. "Bevacizumab (BVZ)-associated toxicities in children with recurrent central nervous system tumors treated with BVZ and irinotecan (CPT-11): A Pediatric Brain Tumor Consortium Study (PBTC-022)." Cancer 119.23 (December 1, 2013): 4180-4187.
Source
scopus
Published In
Cancer
Volume
119
Issue
23
Publish Date
2013
Start Page
4180
End Page
4187
DOI
10.1002/cncr.28343

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma.

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.

Authors
Remke, M; Ramaswamy, V; Peacock, J; Shih, DJH; Koelsche, C; Northcott, PA; Hill, N; Cavalli, FMG; Kool, M; Wang, X; Mack, SC; Barszczyk, M; Morrissy, AS; Wu, X; Agnihotri, S; Luu, B; Jones, DTW; Garzia, L; Dubuc, AM; Zhukova, N; Vanner, R; Kros, JM; French, PJ; Van Meir, EG; Vibhakar, R; Zitterbart, K; Chan, JA; Bognár, L; Klekner, A; Lach, B; Jung, S; Saad, AG; Liau, LM; Albrecht, S; Zollo, M; Cooper, MK; Thompson, RC; Delattre, OO; Bourdeaut, F; Doz, FF; Garami, M; Hauser, P; Carlotti, CG et al.
MLA Citation
Remke, M, Ramaswamy, V, Peacock, J, Shih, DJH, Koelsche, C, Northcott, PA, Hill, N, Cavalli, FMG, Kool, M, Wang, X, Mack, SC, Barszczyk, M, Morrissy, AS, Wu, X, Agnihotri, S, Luu, B, Jones, DTW, Garzia, L, Dubuc, AM, Zhukova, N, Vanner, R, Kros, JM, French, PJ, Van Meir, EG, Vibhakar, R, Zitterbart, K, Chan, JA, Bognár, L, Klekner, A, Lach, B, Jung, S, Saad, AG, Liau, LM, Albrecht, S, Zollo, M, Cooper, MK, Thompson, RC, Delattre, OO, Bourdeaut, F, Doz, FF, Garami, M, Hauser, P, and Carlotti, CG et al. "TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma." Acta Neuropathol 126.6 (December 2013): 917-929.
PMID
24174164
Source
pubmed
Published In
Acta Neuropathologica
Volume
126
Issue
6
Publish Date
2013
Start Page
917
End Page
929
DOI
10.1007/s00401-013-1198-2

Recurrence patterns across medulloblastoma subgroups: An integrated clinical and molecular analysis

Background: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. Methods: We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. Results: Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%] ) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p < 0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). Interpretation: Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases. Funding: Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto. © 2013 Elsevier Ltd.

Authors
Ramaswamy, V; Remke, M; Bouffet, E; Faria, CC; Perreault, S; Cho, YJ; Shih, DJ; Luu, B; Dubuc, AM; Northcott, PA; Schüller, U; Gururangan, S; McLendon, R; Bigner, D; Fouladi, M; Ligon, KL; Pomeroy, SL; Dunn, S; Triscott, J; Jabado, N; Fontebasso, A; Jones, DTW; Kool, M; Karajannis, MA; Gardner, SL; Zagzag, D; Nunes, S; Pimentel, J; Mora, J; Lipp, E; Walter, AW; Ryzhova, M; Zheludkova, O; Kumirova, E; Alshami, J; Croul, SE; Rutka, JT; Hawkins, C; Tabori, U; Codispoti, KET; Packer, RJ et al.
MLA Citation
Ramaswamy, V, Remke, M, Bouffet, E, Faria, CC, Perreault, S, Cho, YJ, Shih, DJ, Luu, B, Dubuc, AM, Northcott, PA, Schüller, U, Gururangan, S, McLendon, R, Bigner, D, Fouladi, M, Ligon, KL, Pomeroy, SL, Dunn, S, Triscott, J, Jabado, N, Fontebasso, A, Jones, DTW, Kool, M, Karajannis, MA, Gardner, SL, Zagzag, D, Nunes, S, Pimentel, J, Mora, J, Lipp, E, Walter, AW, Ryzhova, M, Zheludkova, O, Kumirova, E, Alshami, J, Croul, SE, Rutka, JT, Hawkins, C, Tabori, U, Codispoti, KET, and Packer, RJ et al. "Recurrence patterns across medulloblastoma subgroups: An integrated clinical and molecular analysis." The Lancet Oncology 14.12 (November 1, 2013): 1200-1207.
Source
scopus
Published In
The Lancet Oncology
Volume
14
Issue
12
Publish Date
2013
Start Page
1200
End Page
1207
DOI
10.1016/S1470-2045(13)70449-2

KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation.

KMT2D (lysine (K)-specific methyltransferase 2D), formerly named MLL2 (myeloid/lymphoid or mixed-lineage leukemia 2, also known as ALR/MLL4), is a histone methyltransferase that plays an important role in regulating gene transcription. In particular, it targets histone H3 lysine 4 (H3K4), whose methylations serve as a gene activation mark. Recently, KMT2D has emerged as one of the most frequently mutated genes in a variety of cancers and in other human diseases, including lymphoma, medulloblastoma, gastric cancer, and Kabuki syndrome. Mutations in KMT2D identified thus far point to its loss-of-function in pathogenesis and suggest its role as a tumor suppressor in various tissues. To determine the effect of a KMT2D deficiency on neoplastic cells, we used homologous recombination- and nuclease-mediated gene editing approaches to generate a panel of isogenic colorectal and medulloblastoma cancer cell lines that differ with respect to their endogenous KMT2D status. We found that a KMT2D deficiency resulted in attenuated cancer cell proliferation and defective cell migration. Analysis of histone H3 modifications revealed that KMT2D was essential for maintaining the level of global H3K4 monomethylation and that its enzymatic SET domain was directly responsible for this function. Furthermore, we found that a majority of KMT2D binding sites are located in regions of potential enhancer elements. Together, these findings revealed the role of KMT2D in regulating enhancer elements in human cells and shed light on the tumorigenic role of its deficiency. Our study supports that KMT2D has distinct roles in neoplastic cells, as opposed to normal cells, and that inhibiting KMT2D may be a viable strategy for cancer therapeutics.

Authors
Guo, C; Chen, LH; Huang, Y; Chang, C-C; Wang, P; Pirozzi, CJ; Qin, X; Bao, X; Greer, PK; McLendon, RE; Yan, H; Keir, ST; Bigner, DD; He, Y
MLA Citation
Guo, C, Chen, LH, Huang, Y, Chang, C-C, Wang, P, Pirozzi, CJ, Qin, X, Bao, X, Greer, PK, McLendon, RE, Yan, H, Keir, ST, Bigner, DD, and He, Y. "KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation." Oncotarget 4.11 (November 2013): 2144-2153.
PMID
24240169
Source
pubmed
Published In
Oncotarget
Volume
4
Issue
11
Publish Date
2013
Start Page
2144
End Page
2153
DOI
10.18632/oncotarget.1555

Development and Validation of a Clinical Molecular Diagnostic Test for TERT Gene Promoter Mutations C250T and C228T

Authors
Gagnon, R; Yan, H; Rasheed, AB; McLendon, RE; Killella, PJ; Reitman, ZJ; Datto, MB; Sebastian, S
MLA Citation
Gagnon, R, Yan, H, Rasheed, AB, McLendon, RE, Killella, PJ, Reitman, ZJ, Datto, MB, and Sebastian, S. "Development and Validation of a Clinical Molecular Diagnostic Test for TERT Gene Promoter Mutations C250T and C228T." November 2013.
Source
wos-lite
Published In
The Journal of molecular diagnostics : JMD
Volume
15
Issue
6
Publish Date
2013
Start Page
920
End Page
920

Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis.

BACKGROUND: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. METHODS: We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. RESULTS: Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). INTERPRETATION: Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases.

Authors
Ramaswamy, V; Remke, M; Bouffet, E; Faria, CC; Perreault, S; Cho, Y-J; Shih, DJ; Luu, B; Dubuc, AM; Northcott, PA; Schüller, U; Gururangan, S; McLendon, R; Bigner, D; Fouladi, M; Ligon, KL; Pomeroy, SL; Dunn, S; Triscott, J; Jabado, N; Fontebasso, A; Jones, DTW; Kool, M; Karajannis, MA; Gardner, SL; Zagzag, D; Nunes, S; Pimentel, J; Mora, J; Lipp, E; Walter, AW; Ryzhova, M; Zheludkova, O; Kumirova, E; Alshami, J; Croul, SE; Rutka, JT; Hawkins, C; Tabori, U; Codispoti, K-ET; Packer, RJ et al.
MLA Citation
Ramaswamy, V, Remke, M, Bouffet, E, Faria, CC, Perreault, S, Cho, Y-J, Shih, DJ, Luu, B, Dubuc, AM, Northcott, PA, Schüller, U, Gururangan, S, McLendon, R, Bigner, D, Fouladi, M, Ligon, KL, Pomeroy, SL, Dunn, S, Triscott, J, Jabado, N, Fontebasso, A, Jones, DTW, Kool, M, Karajannis, MA, Gardner, SL, Zagzag, D, Nunes, S, Pimentel, J, Mora, J, Lipp, E, Walter, AW, Ryzhova, M, Zheludkova, O, Kumirova, E, Alshami, J, Croul, SE, Rutka, JT, Hawkins, C, Tabori, U, Codispoti, K-ET, and Packer, RJ et al. "Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis." Lancet Oncol 14.12 (November 2013): 1200-1207.
PMID
24140199
Source
pubmed
Published In
The Lancet Oncology
Volume
14
Issue
12
Publish Date
2013
Start Page
1200
End Page
1207
DOI
10.1016/S1470-2045(13)70449-2

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in < 5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes. © Springer-Verlag Berlin Heidelberg 2013.

Authors
Remke, M; Ramaswamy, V; Peacock, J; Shih, DJH; Koelsche, C; Northcott, PA; Hill, N; Cavalli, FMG; Kool, M; Wang, X; Mack, SC; Barszczyk, M; Morrissy, AS; Wu, X; Agnihotri, S; Luu, B; Jones, DTW; Garzia, L; Dubuc, AM; Zhukova, N; Vanner, R; Kros, JM; French, PJ; Van Meir, EG; Vibhakar, R; Zitterbart, K; Chan, JA; Bognár, L; Klekner, A; Lach, B; Jung, S; Saad, AG; Liau, LM; Albrecht, S; Zollo, M; Cooper, MK; Thompson, RC; Delattre, OO; Bourdeaut, F; Doz, FF; Garami, M; Hauser, P; Carlotti, CG et al.
MLA Citation
Remke, M, Ramaswamy, V, Peacock, J, Shih, DJH, Koelsche, C, Northcott, PA, Hill, N, Cavalli, FMG, Kool, M, Wang, X, Mack, SC, Barszczyk, M, Morrissy, AS, Wu, X, Agnihotri, S, Luu, B, Jones, DTW, Garzia, L, Dubuc, AM, Zhukova, N, Vanner, R, Kros, JM, French, PJ, Van Meir, EG, Vibhakar, R, Zitterbart, K, Chan, JA, Bognár, L, Klekner, A, Lach, B, Jung, S, Saad, AG, Liau, LM, Albrecht, S, Zollo, M, Cooper, MK, Thompson, RC, Delattre, OO, Bourdeaut, F, Doz, FF, Garami, M, Hauser, P, and Carlotti, CG et al. "TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma." Acta Neuropathologica 126.6 (October 31, 2013): 917-929.
Source
scopus
Published In
Acta Neuropathologica
Volume
126
Issue
6
Publish Date
2013
Start Page
917
End Page
929
DOI
10.1007/s00401-013-1198-2

Complete response to steroids in dural inflammatory pseudotumor associated with Still's disease.

We report a unique case of a dural-based inflammatory pseudotumor (IPT) arising in the left cavernous sinus of a patient with a history of juvenile Still's disease. The patient presented with hemi-facial paresthesias, dull, constant headaches, and transient episodes of sharp pain along the temporalis region. Treatment with oral steroid therapy resulted in complete regression of the lesion and accompanied neuralgia symptoms. Because intracranial IPT can mimic meningiomas both clinically and radiographically and can be associated with systemic arthritic diseases, neurosurgeons should be familiar with this entity in order to avoid unnecessary radical surgery and alternatively consider a tapering course of steroid therapy.

Authors
Batich, KA; William St Clair, E; McLendon, RE; Sampson, JH
MLA Citation
Batich, KA, William St Clair, E, McLendon, RE, and Sampson, JH. "Complete response to steroids in dural inflammatory pseudotumor associated with Still's disease." J Clin Neurosci 20.10 (October 2013): 1445-1448.
PMID
23768965
Source
pubmed
Published In
Journal of Clinical Neuroscience
Volume
20
Issue
10
Publish Date
2013
Start Page
1445
End Page
1448
DOI
10.1016/j.jocn.2013.01.009

The integrated landscape of driver genomic alterations in glioblastoma.

Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention.

Authors
Frattini, V; Trifonov, V; Chan, JM; Castano, A; Lia, M; Abate, F; Keir, ST; Ji, AX; Zoppoli, P; Niola, F; Danussi, C; Dolgalev, I; Porrati, P; Pellegatta, S; Heguy, A; Gupta, G; Pisapia, DJ; Canoll, P; Bruce, JN; McLendon, RE; Yan, H; Aldape, K; Finocchiaro, G; Mikkelsen, T; Privé, GG; Bigner, DD; Lasorella, A; Rabadan, R; Iavarone, A
MLA Citation
Frattini, V, Trifonov, V, Chan, JM, Castano, A, Lia, M, Abate, F, Keir, ST, Ji, AX, Zoppoli, P, Niola, F, Danussi, C, Dolgalev, I, Porrati, P, Pellegatta, S, Heguy, A, Gupta, G, Pisapia, DJ, Canoll, P, Bruce, JN, McLendon, RE, Yan, H, Aldape, K, Finocchiaro, G, Mikkelsen, T, Privé, GG, Bigner, DD, Lasorella, A, Rabadan, R, and Iavarone, A. "The integrated landscape of driver genomic alterations in glioblastoma." Nat Genet 45.10 (October 2013): 1141-1149.
PMID
23917401
Source
pubmed
Published In
Nature Genetics
Volume
45
Issue
10
Publish Date
2013
Start Page
1141
End Page
1149
DOI
10.1038/ng.2734

The somatic genomic landscape of glioblastoma.

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

Authors
Brennan, CW; Verhaak, RGW; McKenna, A; Campos, B; Noushmehr, H; Salama, SR; Zheng, S; Chakravarty, D; Sanborn, JZ; Berman, SH; Beroukhim, R; Bernard, B; Wu, C-J; Genovese, G; Shmulevich, I; Barnholtz-Sloan, J; Zou, L; Vegesna, R; Shukla, SA; Ciriello, G; Yung, WK; Zhang, W; Sougnez, C; Mikkelsen, T; Aldape, K; Bigner, DD; Van Meir, EG; Prados, M; Sloan, A; Black, KL; Eschbacher, J; Finocchiaro, G; Friedman, W; Andrews, DW; Guha, A; Iacocca, M; O'Neill, BP; Foltz, G; Myers, J; Weisenberger, DJ et al.
MLA Citation
Brennan, CW, Verhaak, RGW, McKenna, A, Campos, B, Noushmehr, H, Salama, SR, Zheng, S, Chakravarty, D, Sanborn, JZ, Berman, SH, Beroukhim, R, Bernard, B, Wu, C-J, Genovese, G, Shmulevich, I, Barnholtz-Sloan, J, Zou, L, Vegesna, R, Shukla, SA, Ciriello, G, Yung, WK, Zhang, W, Sougnez, C, Mikkelsen, T, Aldape, K, Bigner, DD, Van Meir, EG, Prados, M, Sloan, A, Black, KL, Eschbacher, J, Finocchiaro, G, Friedman, W, Andrews, DW, Guha, A, Iacocca, M, O'Neill, BP, Foltz, G, Myers, J, and Weisenberger, DJ et al. "The somatic genomic landscape of glioblastoma." Cell 155.2 (October 2013): 462-477.
PMID
24120142
Source
epmc
Published In
Cell
Volume
155
Issue
2
Publish Date
2013
Start Page
462
End Page
477
DOI
10.1016/j.cell.2013.09.034

Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and related to transcriptional class.

PURPOSE: Tumor-infiltrating lymphocytes (TIL) have prognostic significance in many cancers, yet their roles in glioblastoma have not been fully defined. We hypothesized that TILs in glioblastoma are associated with molecular alterations, histologies, and survival. EXPERIMENTAL DESIGN: We used data from The Cancer Genome Atlas (TCGA) to investigate molecular, histologic, and clinical correlates of TILs in glioblastomas. Lymphocytes were categorized as absent, present, or abundant in histopathologic images from 171 TCGA glioblastomas. Associations were examined between lymphocytes and histologic features, mutations, copy number alterations, CpG island methylator phenotype, transcriptional class, and survival. We validated histologic findings using CD3G gene expression. RESULTS: We found a positive correlation between TILs and glioblastomas with gemistocytes, sarcomatous cells, epithelioid cells, and giant cells. Lymphocytes were enriched in the mesenchymal transcriptional class and strongly associated with mutations in NF1 and RB1. These mutations are frequent in the mesenchymal class and characteristic of gemistocytic, sarcomatous, epithelioid, and giant cell histologies. Conversely, TILs were rare in glioblastomas with small cells and oligodendroglioma components. Lymphocytes were depleted in the classical transcriptional class and in EGF receptor (EGFR)-amplified and homozygous PTEN-deleted glioblastomas. These alterations are characteristic of glioblastomas with small cells and glioblastomas of the classical transcriptional class. No association with survival was shown. CONCLUSIONS: TILs were enriched in glioblastomas of the mesenchymal class, strongly associated with mutations in NF1 and RB1 and typical of histologies characterized by these mutations. Conversely, TILs were depleted in the classical class, EGFR-amplified, and homozygous PTEN-deleted tumors and rare in histologies characterized by these alterations.

Authors
Rutledge, WC; Kong, J; Gao, J; Gutman, DA; Cooper, LAD; Appin, C; Park, Y; Scarpace, L; Mikkelsen, T; Cohen, ML; Aldape, KD; McLendon, RE; Lehman, NL; Miller, CR; Schniederjan, MJ; Brennan, CW; Saltz, JH; Moreno, CS; Brat, DJ
MLA Citation
Rutledge, WC, Kong, J, Gao, J, Gutman, DA, Cooper, LAD, Appin, C, Park, Y, Scarpace, L, Mikkelsen, T, Cohen, ML, Aldape, KD, McLendon, RE, Lehman, NL, Miller, CR, Schniederjan, MJ, Brennan, CW, Saltz, JH, Moreno, CS, and Brat, DJ. "Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and related to transcriptional class." Clin Cancer Res 19.18 (September 15, 2013): 4951-4960.
PMID
23864165
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
19
Issue
18
Publish Date
2013
Start Page
4951
End Page
4960
DOI
10.1158/1078-0432.CCR-13-0551

Construction of an immunotoxin, D2C7-(scdsFv)-PE38KDEL, targeting EGFRwt and EGFRvIII for brain tumor therapy.

PURPOSE: The EGF receptor gene (EGFR) is most frequently amplified and overexpressed, along with its deletion mutant, EGFRvIII, in glioblastoma. We tested the preclinical efficacy of the recombinant immunotoxin, D2C7-(scdsFv)-PE38KDEL, which is reactive with a 55-amino acid (AA) region present in the extracellular domain of both EGFRwt (583-637 AAs) and EGFRvIII (292-346 AAs) proteins. EXPERIMENTAL DESIGN: The binding affinity and specificity of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII were measured by surface-plasmon resonance and flow cytometry. In vitro cytotoxicity of D2C7-(scdsFv)-PE38KDEL was measured by inhibition of protein synthesis in human EGFRwt-transfected NR6 (NR6W), human EGFRvIII-transfected NR6 (NR6M), EGFRwt-overexpressing A431-epidermoid-carcinoma, and glioblastoma xenograft cells (43, D08-0493MG, D2159MG, and D270MG). In vivo antitumor efficacy of D2C7-(scdsFv)-PE38KDEL was evaluated using 43, NR6M, and D270MG orthotopic tumor models. RESULTS: The KD of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII was 1.6×10(-9) mol/L and 1.3×10(-9) mol/L, respectively. Flow cytometry with NR6W and NR6M cells confirmed the specificity of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII. The D2C7-(scdsFv)-PE38KDEL IC50 was 0.18 to 2.5 ng/mL on cells expressing EGFRwt (NR6W, A431, 43, and D08-0493MG). The D2C7-(scdsFv)-PE38KDEL IC50 was approximately 0.25 ng/mL on EGFRvIII-expressing cells (NR6M) and on EGFRwt- and EGFRvIII-expressing glioblastoma xenograft cells (D2159MG and D270MG). Significantly, in intracranial tumor models of 43, NR6M, and D270MG, treatment with D2C7-(scdsFv)-PE38KDEL by convection-enhanced delivery prolonged survival by 310% (P=0.006), 28% (P=0.002), and 166% (P=0.001), respectively. CONCLUSIONS: In preclinical studies, the D2C7-(scdsFv)-PE38KDEL immunotoxin exhibited significant potential for treating brain tumors expressing EGFRwt, EGFRvIII, or both.

Authors
Chandramohan, V; Bao, X; Keir, ST; Pegram, CN; Szafranski, SE; Piao, H; Wikstrand, CJ; McLendon, RE; Kuan, C-T; Pastan, IH; Bigner, DD
MLA Citation
Chandramohan, V, Bao, X, Keir, ST, Pegram, CN, Szafranski, SE, Piao, H, Wikstrand, CJ, McLendon, RE, Kuan, C-T, Pastan, IH, and Bigner, DD. "Construction of an immunotoxin, D2C7-(scdsFv)-PE38KDEL, targeting EGFRwt and EGFRvIII for brain tumor therapy." Clin Cancer Res 19.17 (September 1, 2013): 4717-4727.
PMID
23857604
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
19
Issue
17
Publish Date
2013
Start Page
4717
End Page
4727
DOI
10.1158/1078-0432.CCR-12-3891

O6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry as a predictor of resistance to temozolomide in primary CNS lymphoma.

Temozolomide, an alkylating agent, has shown promise in treating primary central nervous system lymphoma (PCNSL). The enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) repairs alkylating damage, such as that induced by temozolomide. We hypothesized that MGMT immunohistochemistry would predict resistance to temozolomide in PCNSL. A retrospective study of newly-diagnosed and recurrent PCNSL patients treated at our institution was conducted to study the predictive value of MGMT immunohistochemistry for response to temozolomide. 20 patients who were treated with temozolomide as a single agent were identified during the study time period. 6/20 patients demonstrated a response, corresponding to an objective response rate of 30 % (95 % CI 8-52). Five patients with low MGMT level (<30 %) showed a response to temozolomide. Only one of 10 patients (10 %) with high MGMT level (≥30 %) exhibited a response to temozolomide. Small sample numbers precluded formal statistical comparisons. Two patients with complete response remain alive without progressive disease 6.7 and 7.2 years after temozolomide initiation. Immunohistochemistry can be performed on small biopsies to selectively assess MGMT status in tumor versus surrounding inflammation. MGMT analysis by immunohistochemistry may predict response to temozolomide in PCNSL and should be prospectively investigated.

Authors
Jiang, X; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Quinn, JA; Austin, AD; Herndon, JE; McLendon, RE; Friedman, HS
MLA Citation
Jiang, X, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Quinn, JA, Austin, AD, Herndon, JE, McLendon, RE, and Friedman, HS. "O6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry as a predictor of resistance to temozolomide in primary CNS lymphoma." United States. August 2013.
PMID
23686298
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
114
Issue
1
Publish Date
2013
Start Page
135
End Page
140
DOI
10.1007/s11060-013-1162-y

Clinicopathological characteristics and treatment of rhabdoid glioblastoma Clinical article

Authors
Babu, R; Hatef, J; McLendon, RE; Cummings, TJ; Sampson, JH; Friedman, AH; Adamson, C
MLA Citation
Babu, R, Hatef, J, McLendon, RE, Cummings, TJ, Sampson, JH, Friedman, AH, and Adamson, C. "Clinicopathological characteristics and treatment of rhabdoid glioblastoma Clinical article." JOURNAL OF NEUROSURGERY 119.2 (August 2013): 412-419.
PMID
23641829
Source
wos-lite
Published In
Journal of neurosurgery
Volume
119
Issue
2
Publish Date
2013
Start Page
412
End Page
419
DOI
10.3171/2013.3.JNS121773

Intraaxial dermoid cyst of the medulla

Authors
Park, JG; Babij, R; Kranz, PG; McLendon, RE; Adamson, C
MLA Citation
Park, JG, Babij, R, Kranz, PG, McLendon, RE, and Adamson, C. "Intraaxial dermoid cyst of the medulla." JOURNAL OF NEUROSURGERY 119.2 (August 2013): 442-445.
PMID
23621596
Source
wos-lite
Published In
Journal of neurosurgery
Volume
119
Issue
2
Publish Date
2013
Start Page
442
End Page
445
DOI
10.3171/2013.3.JNS122430

O6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry as a predictor of resistance to temozolomide in primary CNS lymphoma.

Temozolomide, an alkylating agent, has shown promise in treating primary central nervous system lymphoma (PCNSL). The enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) repairs alkylating damage, such as that induced by temozolomide. We hypothesized that MGMT immunohistochemistry would predict resistance to temozolomide in PCNSL. A retrospective study of newly-diagnosed and recurrent PCNSL patients treated at our institution was conducted to study the predictive value of MGMT immunohistochemistry for response to temozolomide. 20 patients who were treated with temozolomide as a single agent were identified during the study time period. 6/20 patients demonstrated a response, corresponding to an objective response rate of 30 % (95 % CI 8-52). Five patients with low MGMT level (<30 %) showed a response to temozolomide. Only one of 10 patients (10 %) with high MGMT level (≥30 %) exhibited a response to temozolomide. Small sample numbers precluded formal statistical comparisons. Two patients with complete response remain alive without progressive disease 6.7 and 7.2 years after temozolomide initiation. Immunohistochemistry can be performed on small biopsies to selectively assess MGMT status in tumor versus surrounding inflammation. MGMT analysis by immunohistochemistry may predict response to temozolomide in PCNSL and should be prospectively investigated.

Authors
Jiang, X; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Quinn, JA; Austin, AD; Herndon, JE; McLendon, RE; Friedman, HS
MLA Citation
Jiang, X, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Quinn, JA, Austin, AD, Herndon, JE, McLendon, RE, and Friedman, HS. "O6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry as a predictor of resistance to temozolomide in primary CNS lymphoma." Journal of neuro-oncology 114.1 (August 2013): 135-140.
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
114
Issue
1
Publish Date
2013
Start Page
135
End Page
140
DOI
10.1007/s11060-013-1162-y

TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.

Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low (<15%) and high (≥15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.

Authors
Killela, PJ; Reitman, ZJ; Jiao, Y; Bettegowda, C; Agrawal, N; Diaz, LA; Friedman, AH; Friedman, H; Gallia, GL; Giovanella, BC; Grollman, AP; He, T-C; He, Y; Hruban, RH; Jallo, GI; Mandahl, N; Meeker, AK; Mertens, F; Netto, GJ; Rasheed, BA; Riggins, GJ; Rosenquist, TA; Schiffman, M; Shih, I-M; Theodorescu, D; Torbenson, MS; Velculescu, VE; Wang, T-L; Wentzensen, N; Wood, LD; Zhang, M; McLendon, RE; Bigner, DD; Kinzler, KW; Vogelstein, B; Papadopoulos, N; Yan, H
MLA Citation
Killela, PJ, Reitman, ZJ, Jiao, Y, Bettegowda, C, Agrawal, N, Diaz, LA, Friedman, AH, Friedman, H, Gallia, GL, Giovanella, BC, Grollman, AP, He, T-C, He, Y, Hruban, RH, Jallo, GI, Mandahl, N, Meeker, AK, Mertens, F, Netto, GJ, Rasheed, BA, Riggins, GJ, Rosenquist, TA, Schiffman, M, Shih, I-M, Theodorescu, D, Torbenson, MS, Velculescu, VE, Wang, T-L, Wentzensen, N, Wood, LD, Zhang, M, McLendon, RE, Bigner, DD, Kinzler, KW, Vogelstein, B, Papadopoulos, N, and Yan, H. "TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal." Proc Natl Acad Sci U S A 110.15 (April 9, 2013): 6021-6026.
PMID
23530248
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
15
Publish Date
2013
Start Page
6021
End Page
6026
DOI
10.1073/pnas.1303607110

Exomic Sequencing of Four Rare Central Nervous System Tumor Types

Authors
Bettegowda, C; Agrawal, N; Jiao, Y; Wang, Y; Wood, LD; Rodriguez, FJ; Hruban, RH; Gallia, GL; Binder, ZA; Riggins, CJ; Salmasi, V; Riggins, GJ; Reitman, ZJ; Rasheed, A; Keir, S; Shinjo, S; Marie, S; McLendon, R; Jallo, G; Vogelstein, B; Bigner, D; Yan, H; Kinzler, KW; Papadopoulos, N
MLA Citation
Bettegowda, C, Agrawal, N, Jiao, Y, Wang, Y, Wood, LD, Rodriguez, FJ, Hruban, RH, Gallia, GL, Binder, ZA, Riggins, CJ, Salmasi, V, Riggins, GJ, Reitman, ZJ, Rasheed, A, Keir, S, Shinjo, S, Marie, S, McLendon, R, Jallo, G, Vogelstein, B, Bigner, D, Yan, H, Kinzler, KW, and Papadopoulos, N. "Exomic Sequencing of Four Rare Central Nervous System Tumor Types." ONCOTARGET 4.4 (April 2013): 572-583.
PMID
23592488
Source
wos-lite
Published In
Oncotarget
Volume
4
Issue
4
Publish Date
2013
Start Page
572
End Page
583

A comprehensive analysis of 41 patients with rosette-forming glioneuronal tumors of the fourth ventricle.

The rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle is a recently described, rare, and distinct tumor of the glioneuronal family. The presentation, natural history, and treatment response of these tumors has been unclear as there are no significant series of a sizeable population with long-term follow-up. We report a comprehensive analysis of 41 patients with RGNT to provide the most current understanding of this rare tumor. Treatment of these patients has consisted of resection via the transvermian and telovelar approaches, with one patient requiring radiotherapy due to tumor recurrence. Various unique imaging characteristics may allow for the preoperative identification of these tumors. Resection via the telovelar approach should be considered for symptomatic tumors and those that pose a risk of obstructive hydrocephalus. Due to their benign nature and low propensity for recurrence, subtotal resection may be appropriate for those that are adherent to the brainstem. Radiotherapy may be considered for patients with tumor recurrence.

Authors
Zhang, J; Babu, R; McLendon, RE; Friedman, AH; Adamson, C
MLA Citation
Zhang, J, Babu, R, McLendon, RE, Friedman, AH, and Adamson, C. "A comprehensive analysis of 41 patients with rosette-forming glioneuronal tumors of the fourth ventricle." J Clin Neurosci 20.3 (March 2013): 335-341. (Review)
PMID
23375398
Source
pubmed
Published In
Journal of Clinical Neuroscience
Volume
20
Issue
3
Publish Date
2013
Start Page
335
End Page
341
DOI
10.1016/j.jocn.2012.09.003

A phase I/II trial of pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma.

PURPOSE: Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGF receptor (EGFR; ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that patients with recurrent glioblastoma would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib. EXPERIMENTAL DESIGN: A phase II study evaluated the antitumor activity of pazopanib 400 mg/d plus lapatinib 1,000 mg/d in patients with grade 4 malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIAC). The phase II study used a two-stage Green-Dahlberg design for futility. An independent, parallel phase I component determined the maximum-tolerated regimen (MTR) of pazopanib and lapatinib in patients with grade 3/4 glioma receiving EIACs. RESULTS: The six-month progression-free survival (PFS) rates in phase II (n = 41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. Two patients (5%) had a partial response and 14 patients (34%) had stable disease lasting 8 or more weeks. In phase I (n = 34), the MTR was not reached. On the basis of pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1,000 mg, each twice daily, was considered safe. Concomitant EIACs reduced exposure to pazopanib and lapatinib. CONCLUSIONS: The antitumor activity of this combination at the phase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in the phase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesis-testing trials with targeted agents in malignant glioma.

Authors
Reardon, DA; Groves, MD; Wen, PY; Nabors, L; Mikkelsen, T; Rosenfeld, S; Raizer, J; Barriuso, J; McLendon, RE; Suttle, AB; Ma, B; Curtis, CM; Dar, MM; de Bono, J
MLA Citation
Reardon, DA, Groves, MD, Wen, PY, Nabors, L, Mikkelsen, T, Rosenfeld, S, Raizer, J, Barriuso, J, McLendon, RE, Suttle, AB, Ma, B, Curtis, CM, Dar, MM, and de Bono, J. "A phase I/II trial of pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma." Clin Cancer Res 19.4 (February 15, 2013): 900-908.
PMID
23363814
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
19
Issue
4
Publish Date
2013
Start Page
900
End Page
908
DOI
10.1158/1078-0432.CCR-12-1707

Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas.

Point mutations at Arg132 of the cytoplasmic NADP(+)-dependent isocitrate dehydrogenase 1 (IDH1) occur frequently in gliomas and result in a gain of function to produce the "oncometabolite" D-2-hydroxyglutarate (D-2HG). The mutated IDH1 allele is usually associated with a wild-type IDH1 allele (heterozygous) in cancer. Here, we identify 2 gliomas that underwent loss of the wild-type IDH1 allele but retained the mutant IDH1 allele following tumor progression from World Health Organization (WHO) grade III anaplastic astrocytomas to WHO grade IV glioblastomas. Intratumoral D-2HG was 14-fold lower in the glioblastomas lacking wild-type IDH1 than in glioblastomas with heterozygous IDH1 mutations. To characterize the contribution of wild-type IDH1 to cancer cell D-2HG production, we established an IDH1-mutated astrocytoma (IMA) cell line from a WHO grade III anaplastic astrocytoma. Disruption of the wild-type IDH1 allele in IMA cells by gene targeting resulted in an 87-fold decrease in cellular D-2HG levels, showing that both wild-type and mutant IDH1 alleles are required for D-2HG production in glioma cells. Expression of wild-type IDH1 was also critical for mutant IDH1-associated D-2HG production in the colorectal cancer cell line HCT116. These insights may aid in the development of therapeutic strategies to target IDH1-mutated cancers.

Authors
Jin, G; Reitman, ZJ; Duncan, CG; Spasojevic, I; Gooden, DM; Rasheed, BA; Yang, R; Lopez, GY; He, Y; McLendon, RE; Bigner, DD; Yan, H
MLA Citation
Jin, G, Reitman, ZJ, Duncan, CG, Spasojevic, I, Gooden, DM, Rasheed, BA, Yang, R, Lopez, GY, He, Y, McLendon, RE, Bigner, DD, and Yan, H. "Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas." Cancer Res 73.2 (January 15, 2013): 496-501.
PMID
23204232
Source
pubmed
Published In
Cancer Research
Volume
73
Issue
2
Publish Date
2013
Start Page
496
End Page
501
DOI
10.1158/0008-5472.CAN-12-2852

The integrated landscape of driver genomic alterations in glioblastoma

Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention. © 2013 Nature America, Inc. All rights reserved.

Authors
Frattini, V; Trifonov, V; Chan, JM; Castano, A; Lia, M; Abate, F; Keir, ST; Ji, AX; Zoppoli, P; Niola, F; al, E
MLA Citation
Frattini, V, Trifonov, V, Chan, JM, Castano, A, Lia, M, Abate, F, Keir, ST, Ji, AX, Zoppoli, P, Niola, F, and al, E. "The integrated landscape of driver genomic alterations in glioblastoma." Nature Genetics 45.10 (2013): 1141-1149.
Source
scival
Published In
Nature Genetics
Volume
45
Issue
10
Publish Date
2013
Start Page
1141
End Page
1149
DOI
10.1038/ng.2734

A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer.

Infiltration of myeloid cells in the tumor microenvironment is often associated with enhanced angiogenesis and tumor progression, resulting in poor prognosis in many types of cancer. The polypeptide chemokine PK2 (Bv8, PROK2) has been shown to regulate myeloid cell mobilization from the bone marrow, leading to activation of the angiogenic process, as well as accumulation of macrophages and neutrophils in the tumor site. Neutralizing antibodies against PK2 were shown to display potent anti-tumor efficacy, illustrating the potential of PK2-antagonists as therapeutic agents for the treatment of cancer. In this study we demonstrate the anti-tumor activity of a small molecule PK2 antagonist, PKRA7, in the context of glioblastoma and pancreatic cancer xenograft tumor models. For the highly vascularized glioblastoma, PKRA7 was associated with decreased blood vessel density and increased necrotic areas in the tumor mass. Consistent with the anti-angiogenic activity of PKRA7 in vivo, this compound effectively reduced PK2-induced microvascular endothelial cell branching in vitro. For the poorly vascularized pancreatic cancer, the primary anti-tumor effect of PKRA7 appears to be mediated by the blockage of myeloid cell migration/infiltration. At the molecular level, PKRA7 inhibits PK2-induced expression of certain pro-migratory chemokines and chemokine receptors in macrophages. Combining PKRA7 treatment with standard chemotherapeutic agents resulted in enhanced effects in xenograft models for both types of tumor. Taken together, our results indicate that the anti-tumor activity of PKRA7 can be mediated by two distinct mechanisms that are relevant to the pathological features of the specific type of cancer. This small molecule PK2 antagonist holds the promise to be further developed as an effective agent for combinational cancer therapy.

Authors
Curtis, VF; Wang, H; Yang, P; McLendon, RE; Li, X; Zhou, Q-Y; Wang, X-F
MLA Citation
Curtis, VF, Wang, H, Yang, P, McLendon, RE, Li, X, Zhou, Q-Y, and Wang, X-F. "A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer." PLoS One 8.1 (2013): e54916-.
Website
http://hdl.handle.net/10161/4982
PMID
23372791
Source
pubmed
Published In
PloS one
Volume
8
Issue
1
Publish Date
2013
Start Page
e54916
DOI
10.1371/journal.pone.0054916

Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth

Glioblastomas (GBMs) are highly vascular and lethal brain tumors that display cellular hierarchies containing self-renewing tumorigenic glioma stem cells (GSCs). Because GSCs often reside in perivascular niches and may undergo mesenchymal differentiation, we interrogated GSC potential to generate vascular pericytes. Here, we show that GSCs give rise to pericytes to support vessel function and tumor growth. In vivo cell lineage tracing with constitutive and lineage-specific fluorescent reporters demonstrated that GSCs generate the majority of vascular pericytes. Selective elimination of GSC-derived pericytes disrupts the neovasculature and potently inhibits tumor growth. Analysis of human GBM specimens showed that most pericytes are derived from neoplastic cells. GSCs are recruited toward endothelial cells via the SDF-1/CXCR4 axis and are induced to become pericytes predominantly by transforming growth factor β. Thus, GSCs contribute to vascular pericytes that may actively remodel perivascular niches. Therapeutic targeting of GSC-derived pericytes may effectively block tumor progression and improve antiangiogenic therapy. © 2013 Elsevier Inc.

Authors
Cheng, L; Huang, Z; Zhou, W; Wu, Q; Donnola, S; Liu, JK; Fang, X; Sloan, AE; Mao, Y; Lathia, JD; Min, W; McLendon, RE; Rich, JN; Bao, S
MLA Citation
Cheng, L, Huang, Z, Zhou, W, Wu, Q, Donnola, S, Liu, JK, Fang, X, Sloan, AE, Mao, Y, Lathia, JD, Min, W, McLendon, RE, Rich, JN, and Bao, S. "Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth." Cell 153.1 (2013): 139-152.
PMID
23540695
Source
scival
Published In
Cell
Volume
153
Issue
1
Publish Date
2013
Start Page
139
End Page
152
DOI
10.1016/j.cell.2013.02.021

Laminin alpha 2 enables glioblastoma stem cell growth.

OBJECTIVE: Glioblastomas (GBMs) are lethal cancers that display cellular hierarchies parallel to normal brain. At the apex are GBM stem cells (GSCs), which are relatively resistant to conventional therapy. Interactions with the adjacent perivascular niche are an important driver of malignancy and self-renewal in GSCs. Extracellular matrix (ECM) cues instruct neural stem/progenitor cell-niche interactions, and the objective of our study was to elucidate its composition and contribution to GSC maintenance in the perivascular niche. METHODS: We interrogated human tumor tissue for immunofluorescence analysis and derived GSCs from tumor tissues for functional studies. Bioinformatics analyses were conducted by mining publicly available databases. RESULTS: We find that laminin ECM proteins are localized to the perivascular GBM niche and inform negative patient prognosis. To identify the source of laminins, we characterized cellular elements within the niche and found that laminin α chains were expressed by nonstem tumor cells and tumor-associated endothelial cells (ECs). RNA interference targeting laminin α2 inhibited GSC growth and self-renewal. In co-culture studies of GSCs and ECs, laminin α2 knockdown in ECs resulted in decreased tumor growth. INTERPRETATION: Our studies highlight the contribution of nonstem tumor cell-derived laminin juxtracrine signaling. As laminin α2 has recently been identified as a molecular marker of aggressive ependymoma, we propose that the brain vascular ECM promotes tumor malignancy through maintenance of the GSC compartment, providing not only a molecular fingerprint but also a possible therapeutic target.

Authors
Lathia, JD; Li, M; Hall, PE; Gallagher, J; Hale, JS; Wu, Q; Venere, M; Levy, E; Rani, MRS; Huang, P; Bae, E; Selfridge, J; Cheng, L; Guvenc, H; McLendon, RE; Nakano, I; Sloan, AE; Phillips, HS; Lai, A; Gladson, CL; Bredel, M; Bao, S; Hjelmeland, AB; Rich, JN
MLA Citation
Lathia, JD, Li, M, Hall, PE, Gallagher, J, Hale, JS, Wu, Q, Venere, M, Levy, E, Rani, MRS, Huang, P, Bae, E, Selfridge, J, Cheng, L, Guvenc, H, McLendon, RE, Nakano, I, Sloan, AE, Phillips, HS, Lai, A, Gladson, CL, Bredel, M, Bao, S, Hjelmeland, AB, and Rich, JN. "Laminin alpha 2 enables glioblastoma stem cell growth." Ann Neurol 72.5 (November 2012): 766-778.
PMID
23280793
Source
pubmed
Published In
Annals of Neurology
Volume
72
Issue
5
Publish Date
2012
Start Page
766
End Page
778
DOI
10.1002/ana.23674

Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways.

Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. MLL genes are frequently mutated in human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 are not well-understood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in driving tumorigenesis. Here we profile the global loci targeted by MLL2. A combinatorial analysis of the MLL2 binding profile and gene expression in MLL2 wild-type versus MLL2-null isogenic cell lines identified direct transcriptional target genes and revealed the connection of MLL2 to multiple cellular signaling pathways, including the p53 pathway, cAMP-mediated signaling, and cholestasis signaling. In particular, we demonstrate that MLL2 participates in retinoic acid receptor signaling by promoting retinoic acid-responsive gene transcription. Our results present a genome-wide integrative analysis of the MLL2 target loci and suggest potential mechanisms underlying tumorigenesis driven by MLL2 alterations.

Authors
Guo, C; Chang, C-C; Wortham, M; Chen, LH; Kernagis, DN; Qin, X; Cho, Y-W; Chi, J-T; Grant, GA; McLendon, RE; Yan, H; Ge, K; Papadopoulos, N; Bigner, DD; He, Y
MLA Citation
Guo, C, Chang, C-C, Wortham, M, Chen, LH, Kernagis, DN, Qin, X, Cho, Y-W, Chi, J-T, Grant, GA, McLendon, RE, Yan, H, Ge, K, Papadopoulos, N, Bigner, DD, and He, Y. "Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways." Proc Natl Acad Sci U S A 109.43 (October 23, 2012): 17603-17608.
PMID
23045699
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
109
Issue
43
Publish Date
2012
Start Page
17603
End Page
17608
DOI
10.1073/pnas.1208807109

Phase II study of Gleevec plus hydroxyurea in adults with progressive or recurrent low-grade glioma.

BACKGROUND: We evaluated the efficacy of imatinib plus hydroxyurea in patients with progressive/recurrent low-grade glioma. METHODS: A total of 64 patients with recurrent/progressive low-grade glioma were enrolled in this single-center study that stratified patients into astrocytoma and oligodendroglioma cohorts. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg per day for patients not on enzyme-inducing antiepileptic drugs (EIAEDs) and at 500 mg twice a day if on EIAEDs. The primary endpoint was progression-free survival at 12 months (PFS-12) and secondary endpoints were safety, median progression-free survival, and radiographic response rate. RESULTS: Thirty-two patients were enrolled into each cohort. Eleven patients (17%) had before radiotherapy and 24 (38%) had received before chemotherapy. The median PFS and PFS-12 were 11 months and 39%, respectively. Outcome did not differ between the histologic cohorts. No patient achieved a radiographic response. The most common grade 3 or greater adverse events were neutropenia (11%), thrombocytopenia (3%), and diarrhea (3%). CONCLUSIONS: Imatinib plus hydroxyurea was well tolerated among recurrent/progressive LGG patients but this regimen demonstrated negligible antitumor activity.

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Herndon, JE; Coan, A; Gururangan, S; Peters, KB; McLendon, R; Sathornsumetee, S; Rich, JN; Lipp, ES; Janney, D; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Vredenburgh, JJ, Herndon, JE, Coan, A, Gururangan, S, Peters, KB, McLendon, R, Sathornsumetee, S, Rich, JN, Lipp, ES, Janney, D, and Friedman, HS. "Phase II study of Gleevec plus hydroxyurea in adults with progressive or recurrent low-grade glioma." Cancer 118.19 (October 1, 2012): 4759-4767.
PMID
22371319
Source
pubmed
Published In
Cancer
Volume
118
Issue
19
Publish Date
2012
Start Page
4759
End Page
4767
DOI
10.1002/cncr.26541

NICHE DERIVED EXTRACELLULAR MATRIX CUES ARE PIVOTAL FOR GLIOBLASTOMA STEM CELL GROWTH AND MAINTENANCE

Authors
Hall, PE; Li, M; Gallagher, J; Hale, JS; Wu, Q; Venere, M; Levy, E; Rani, MRS; Huang, P; Bae, E; Selfridge, J; Cheng, L; Guvenc, H; McLendon, RE; Nakano, I; Sloan, AE; Phillips, H; Lai, A; Gladson, C; Bredel, M; Bao, S; Hjelmeland, A; Lathia, JD; Rich, JN
MLA Citation
Hall, PE, Li, M, Gallagher, J, Hale, JS, Wu, Q, Venere, M, Levy, E, Rani, MRS, Huang, P, Bae, E, Selfridge, J, Cheng, L, Guvenc, H, McLendon, RE, Nakano, I, Sloan, AE, Phillips, H, Lai, A, Gladson, C, Bredel, M, Bao, S, Hjelmeland, A, Lathia, JD, and Rich, JN. "NICHE DERIVED EXTRACELLULAR MATRIX CUES ARE PIVOTAL FOR GLIOBLASTOMA STEM CELL GROWTH AND MAINTENANCE." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
143
End Page
143

Descriptive epidemiology of malignant and nonmalignant primary spinal cord, spinal meninges, and cauda equina tumors, United States, 2004-2007.

BACKGROUND: Primary tumors of the spinal cord, spinal meninges, and cauda equina are relatively rare, and a paucity of population-based data exist on tumors in these sites. This study intends to augment the current literature by examining incidence of these tumors on a national level. METHODS: Data from central cancer registries in the National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results (SEER) programs for 2004-2007 (covering 99.2% of US population) and 1999-2007 (covering 89.4% of US population) were analyzed. Analyses for diagnosis years 2004-2007 included cases of malignant and nonmalignant primary spinal cord, spinal meninges, and cauda equina tumors. Descriptive statistics including estimated age-adjusted incidence rates standardized to the 2000 US standard population were conducted for both malignant and nonmalignant primary spinal tumors from cases diagnosed during 2004-2007 as well as trend analyses on malignant cases of primary spinal tumors (n = 5103) for cases diagnosed during 1999-2007 using SEER Stat 6.6.2 software. RESULTS: There were 2576 cases of malignant primary spinal tumors and 9136 cases of nonmalignant primary spinal tumors in 2004-2007. The incidence of malignant and nonmalignant primary spinal tumors combined differed by age, sex, race, and ethnicity. Results of trend analyses indicated that malignant primary spinal tumors have been stable throughout the 1999-2007 period. CONCLUSIONS: This large population-based study adds new insights into the descriptive epidemiology of primary spinal cord, spinal meninges, and cauda equina tumors by providing in-depth analyses of the incidence of these tumors on a national level.

Authors
Duong, LM; McCarthy, BJ; McLendon, RE; Dolecek, TA; Kruchko, C; Douglas, LL; Ajani, UA
MLA Citation
Duong, LM, McCarthy, BJ, McLendon, RE, Dolecek, TA, Kruchko, C, Douglas, LL, and Ajani, UA. "Descriptive epidemiology of malignant and nonmalignant primary spinal cord, spinal meninges, and cauda equina tumors, United States, 2004-2007." Cancer 118.17 (September 1, 2012): 4220-4227.
PMID
22907705
Source
pubmed
Published In
Cancer
Volume
118
Issue
17
Publish Date
2012
Start Page
4220
End Page
4227
DOI
10.1002/cncr.27390

Pilot study of systemic and intrathecal mafosfamide followed by conformal radiation for infants with intracranial central nervous system tumors: a pediatric brain tumor consortium study (PBTC-001).

A pilot study to investigate the feasibility of the addition of intrathecal (IT) mafosfamide to a regimen of concomitant multi-agent systemic chemotherapy followed by conformal radiation therapy (RT) for children <3 years with newly diagnosed embryonal CNS tumors was performed. Ninety-three newly diagnosed infants and children (<3 years) with embryonal CNS tumors were enrolled. Twenty weeks of systemic multi-agent chemotherapy commenced within 35 days of surgery. Patients without CSF flow obstruction (n = 71) received IT mafosfamide (14 mg) with chemotherapy. Localized (M(0)) patients with SD or better subsequently received RT followed by 20 additional weeks of chemotherapy. Second look surgery was encouraged prior to RT if there was an incomplete surgical resection at diagnosis. 71 evaluable patients with normal CSF flow received IT Mafosfamide with systemic chemotherapy; patients with M + disease were removed from protocol therapy at 20 weeks and those with PD at the time of progression. One and 5-year progression free survival (PFS) and overall survival (OS) for the cohort of 71 evaluable patients were 52 ± 6.5 % and 33 ± 13 %, and 67 ± 6.2 % and 51 ± 11 %, respectively. The 1-year Progression Free Survival (PFS) for M0 patients with medulloblastoma (MB, n = 20), supratentorial primitive neuroectodermal tumor (PNET, n = 9), and atypical teratoid rhabdoid tumor (ATRT, n = 12) was 80 ± 7 %, 67 ± 15 % and 27 ± 13 % and 5-year PFS was 65 ± 19 %, 37 ± 29 %, and 0 ± 0 %, respectively. The addition of IT mafosfamide to systemic chemotherapy in infants with embryonal CNS tumors was feasible. The PFS for M0 patients appears comparable to or better than most prior historical comparisons and was excellent for those receiving conformal radiotherapy.

Authors
Blaney, SM; Kocak, M; Gajjar, A; Chintagumpala, M; Merchant, T; Kieran, M; Pollack, IF; Gururangan, S; Geyer, R; Phillips, P; McLendon, RE; Packer, R; Goldman, S; Banerjee, A; Heideman, R; Boyett, JM; Kun, L
MLA Citation
Blaney, SM, Kocak, M, Gajjar, A, Chintagumpala, M, Merchant, T, Kieran, M, Pollack, IF, Gururangan, S, Geyer, R, Phillips, P, McLendon, RE, Packer, R, Goldman, S, Banerjee, A, Heideman, R, Boyett, JM, and Kun, L. "Pilot study of systemic and intrathecal mafosfamide followed by conformal radiation for infants with intracranial central nervous system tumors: a pediatric brain tumor consortium study (PBTC-001)." J Neurooncol 109.3 (September 2012): 565-571.
PMID
22790443
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
109
Issue
3
Publish Date
2012
Start Page
565
End Page
571
DOI
10.1007/s11060-012-0929-x

Subgroup-specific structural variation across 1,000 medulloblastoma genomes.

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

Authors
Northcott, PA; Shih, DJH; Peacock, J; Garzia, L; Morrissy, AS; Zichner, T; Stütz, AM; Korshunov, A; Reimand, J; Schumacher, SE; Beroukhim, R; Ellison, DW; Marshall, CR; Lionel, AC; Mack, S; Dubuc, A; Yao, Y; Ramaswamy, V; Luu, B; Rolider, A; Cavalli, FMG; Wang, X; Remke, M; Wu, X; Chiu, RYB; Chu, A; Chuah, E; Corbett, RD; Hoad, GR; Jackman, SD; Li, Y; Lo, A; Mungall, KL; Nip, KM; Qian, JQ; Raymond, AGJ; Thiessen, NT; Varhol, RJ; Birol, I; Moore, RA; Mungall, AJ; Holt, R; Kawauchi, D et al.
MLA Citation
Northcott, PA, Shih, DJH, Peacock, J, Garzia, L, Morrissy, AS, Zichner, T, Stütz, AM, Korshunov, A, Reimand, J, Schumacher, SE, Beroukhim, R, Ellison, DW, Marshall, CR, Lionel, AC, Mack, S, Dubuc, A, Yao, Y, Ramaswamy, V, Luu, B, Rolider, A, Cavalli, FMG, Wang, X, Remke, M, Wu, X, Chiu, RYB, Chu, A, Chuah, E, Corbett, RD, Hoad, GR, Jackman, SD, Li, Y, Lo, A, Mungall, KL, Nip, KM, Qian, JQ, Raymond, AGJ, Thiessen, NT, Varhol, RJ, Birol, I, Moore, RA, Mungall, AJ, Holt, R, and Kawauchi, D et al. "Subgroup-specific structural variation across 1,000 medulloblastoma genomes." Nature 488.7409 (August 2, 2012): 49-56.
PMID
22832581
Source
pubmed
Published In
Nature
Volume
488
Issue
7409
Publish Date
2012
Start Page
49
End Page
56
DOI
10.1038/nature11327

Bevacizumab therapy for adults with recurrent/progressive meningioma: a retrospective series.

Intracranial meningiomas are often indolent tumors which typically grow over years to decades. Nonetheless, meningiomas that progress after maximum safe resection and radiation therapy pose a significant therapeutic challenge and effective therapies have yet to be identified. Preclinical studies implicate angiogenesis in the pathophysiology of more aggressive meningiomas, suggesting that anti-angiogenic therapies may be of utility in this setting. We performed a retrospective review of fourteen patients with recurrent meningioma treated at Duke University Medical Center with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, administered either alone or in combination with chemotherapy. Most patients were heavily pre-treated. Progression-free survival at 6 months was 86 % and was comparable regardless of meningioma grade and whether bevacizumab was administered as monotherapy or in combination with chemotherapy. Most toxicities were mild however single patients developed CNS hemorrhage (grade 1) and intestinal perforation (grade 4), respectively. Bevacizumab can be administered safely to patients with meningioma and appears to be associated with encouraging anti-tumor effect when administered as either a single agent or in combination with chemotherapy. Phase II trials investigating bevacizumab in patients with progressive/recurrent meningioma are warranted.

Authors
Lou, E; Sumrall, AL; Turner, S; Peters, KB; Desjardins, A; Vredenburgh, JJ; McLendon, RE; Herndon, JE; McSherry, F; Norfleet, J; Friedman, HS; Reardon, DA
MLA Citation
Lou, E, Sumrall, AL, Turner, S, Peters, KB, Desjardins, A, Vredenburgh, JJ, McLendon, RE, Herndon, JE, McSherry, F, Norfleet, J, Friedman, HS, and Reardon, DA. "Bevacizumab therapy for adults with recurrent/progressive meningioma: a retrospective series." J Neurooncol 109.1 (August 2012): 63-70.
PMID
22535433
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
109
Issue
1
Publish Date
2012
Start Page
63
End Page
70
DOI
10.1007/s11060-012-0861-0

Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma.

To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of dasatinib, an inhibitor of the Src family kinase proteins, with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, among recurrent malignant glioma patients. Once daily dasatinib was escalated in successive cohorts while erlotinib was administered daily at established doses based on concurrent CYP3A-inducing anticonvulsant (EIAEDS) use. Dasatinib pharmacokinetic analyzes were performed. Forty-seven patients enrolled including 37 (79 %) with grade IV and 10 (21 %) with grade III malignant glioma. Thirty patients (64 %) were at ≥second recurrence, while 27 (57 %) had received prior bevacizumab. The dasatinib MTD was 180 mg when combined with either 150 mg of erlotinib for patients not on EIAEDs, or 450 mg of erlotinib for patients on EIAEDs. The most common DLTs were diarrhea and fatigue, while most adverse events were grade 2. Pharmacokinetic data suggests that dasatinib exposure increased with increased dasatinib dose and concurrent erlotinib administration, while concurrent EIAED use diminished dasatinib exposure. No radiographic responses were observed, and only one patient (2 %) remained progression-free at 6 months. We demonstrate that dasatinib plus erlotinib can be safely co-administered on a continuous, daily dosing schedule with erlotinib, and established the recommended dose level of this combination.

Authors
Reardon, DA; Vredenburgh, JJ; Desjardins, A; Peters, KB; Sathornsumetee, S; Threatt, S; Sampson, JH; Herndon, JE; Coan, A; McSherry, F; Rich, JN; McLendon, RE; Zhang, S; Friedman, HS
MLA Citation
Reardon, DA, Vredenburgh, JJ, Desjardins, A, Peters, KB, Sathornsumetee, S, Threatt, S, Sampson, JH, Herndon, JE, Coan, A, McSherry, F, Rich, JN, McLendon, RE, Zhang, S, and Friedman, HS. "Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma." J Neurooncol 108.3 (July 2012): 499-506.
PMID
22407177
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
108
Issue
3
Publish Date
2012
Start Page
499
End Page
506
DOI
10.1007/s11060-012-0848-x

Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.

Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.

Authors
Jiao, Y; Killela, PJ; Reitman, ZJ; Rasheed, AB; Heaphy, CM; de Wilde, RF; Rodriguez, FJ; Rosemberg, S; Oba-Shinjo, SM; Nagahashi Marie, SK; Bettegowda, C; Agrawal, N; Lipp, E; Pirozzi, C; Lopez, G; He, Y; Friedman, H; Friedman, AH; Riggins, GJ; Holdhoff, M; Burger, P; McLendon, R; Bigner, DD; Vogelstein, B; Meeker, AK; Kinzler, KW; Papadopoulos, N; Diaz, LA; Yan, H
MLA Citation
Jiao, Y, Killela, PJ, Reitman, ZJ, Rasheed, AB, Heaphy, CM, de Wilde, RF, Rodriguez, FJ, Rosemberg, S, Oba-Shinjo, SM, Nagahashi Marie, SK, Bettegowda, C, Agrawal, N, Lipp, E, Pirozzi, C, Lopez, G, He, Y, Friedman, H, Friedman, AH, Riggins, GJ, Holdhoff, M, Burger, P, McLendon, R, Bigner, DD, Vogelstein, B, Meeker, AK, Kinzler, KW, Papadopoulos, N, Diaz, LA, and Yan, H. "Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas." Oncotarget 3.7 (July 2012): 709-722.
PMID
22869205
Source
pubmed
Published In
Oncotarget
Volume
3
Issue
7
Publish Date
2012
Start Page
709
End Page
722
DOI
10.18632/oncotarget.588

BEVACIZUMAB (BVZ) RELATED TOXICITIES IN CHILDREN WITH RECURRENT CENTRAL NERVOUS SYSTEM (CNS) TUMORS TREATED WITH BVZ AND IRINOTECAN (CPT-11): A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC-022)

Authors
Fangusaro, J; Gururangan, S; Onar-Thomas, A; Packer, R; Goldman, S; Kaste, S; Friedman, H; Poussaint, TY; Kun, L; Boyett, J
MLA Citation
Fangusaro, J, Gururangan, S, Onar-Thomas, A, Packer, R, Goldman, S, Kaste, S, Friedman, H, Poussaint, TY, Kun, L, and Boyett, J. "BEVACIZUMAB (BVZ) RELATED TOXICITIES IN CHILDREN WITH RECURRENT CENTRAL NERVOUS SYSTEM (CNS) TUMORS TREATED WITH BVZ AND IRINOTECAN (CPT-11): A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC-022)." June 2012.
PMID
24104527
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
17
End Page
17

MET and ALK in glioblastoma multiforme (GBM): Comparison of IHC and FISH

Authors
Kulig, K; McLendon, RE; Locke, SC; Young, DR; Zhong, X; Hudson, LL; Abernethy, AP
MLA Citation
Kulig, K, McLendon, RE, Locke, SC, Young, DR, Zhong, X, Hudson, LL, and Abernethy, AP. "MET and ALK in glioblastoma multiforme (GBM): Comparison of IHC and FISH." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Central nervous system

Several different types of tumors, benign and malignant, have been identified in the central nervous system (CNS). The prognoses for these tumors are related to several factors, such as the age of the patient and the location and histology of the tumor. In adults, about half of all CNS tumors are malignant, whereas in pediatric patients, more than 75% are malignant. For most benign CNS tumors that require treatment, neurosurgeons can offer curative resections or at least provide significant relief from mass effect. Unfortunately, we still lack effective treatments for most primary and secondary malignant CNS tumors. However, the past decade has witnessed an explosion in the understanding of the early molecular events in malignant primary CNS tumors, and for the first time in history, oncologists are seeing that a plethora of new therapies targeting these molecular events are being tested in clinical trials. There is hope on the horizon for the fight against these deadly tumors. The distribution of CNS tumors by location has remained constant for numerous years. The majority of primary CNS tumors arise in the major cortical lobes. Twenty nine percent of primary CNS tumors arise from the dural meninges that encase the CNS structures. The vast majority of these are meningiomas, of which over 90% are benign. About 10% of primary CNS tumors are found in the sella turcica region, where the pituitary gland resides. Other much less common sites of primary CNS tumors include the pineal region, ventricular system, cerebellum, brain stem, cranial nerves, and spinal cord. The distribution of CNS tumors by histology has seen a slight increase in more malignant tumors over the past decade, possibly due to increased neuroimaging practices or environmental exposures. Arising from glial cells, gliomas represent over 36% of all primary CNS tumors and consist of astrocytomas, oligodendrogliomas, ependymomas, mixed gliomas, and neuroepithelial tumors. The benign meningiomas make up 32% of primary CNS tumors, followed by nerve sheath tumors and pituitary tumors. Primary CNS lymphomas, embryonal tumors, and craniopharyngiomas are uncommon. The most common gliomas are astrocytomas, and these tumors are typically classified by the World Health Organization (WHO) as Grades I through IV. Grade IV, the most malignant grade of astrocytoma, includes glioblastoma multiforme (GBM), the most common malignant primary CNS glioma in adults, which represents 51% of all primary CNS gliomas. GBM is unfortunately the most challenging to effectively treat and has the worst patient survival. This chapter is therefore primarily devoted to the current understanding of this topic. Here we describe the molecular and cellular events associated with malignant glioma initiation and progression. We also review the importance of glioma stem cell biology and tumor immunology in early gliomagenesis. In addition, we present a brief description of the most common malignant primary CNS glioma in pediatric patients - medulloblastoma, as well as familial cancer syndromes that include gliomas as part of the syndrome. © 2012 IOS Press and the authors. All rights reserved.

Authors
Cory Adamsona, D; Rasheed, BAK; McLendon, RE; Bigner, DD
MLA Citation
Cory Adamsona, D, Rasheed, BAK, McLendon, RE, and Bigner, DD. "Central nervous system." (March 1, 2012): 193-210. (Chapter)
Source
scopus
Publish Date
2012
Start Page
193
End Page
210
DOI
10.3233/978-1-61499-024-6-193

Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naïve, recurrent glioblastoma.

We evaluated the efficacy of carboplatin, irinotecan, and bevacizumab among bevacizumab-naïve, recurrent glioblastoma (GBM) patients in a phase 2, open-label, single arm trial. Forty eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml-min) on day one, while bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) for patients on CYP3A-enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m(2) for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first two cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, non-compliance, or voluntary withdrawal. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints included safety and median overall survival (OS). All patients had progression after standard therapy. The median age was 51 years. Sixteen patients (40%) had a KPS of 90-100, while 27 (68%) were at first progression. The median time from original diagnosis was 11.4 months. The PFS-6 rate was 46.5% (95% CI: 30.4, 61.0%) and the median OS was 8.3 months [95% confidence interval (CI): 5.9, and 10.7 months]. Grade 4 events were primarily hematologic and included neutropenia and thrombocytopenia in 20 and 10%, respectively. The most common grade 3 events were neutropenia, thrombocytopenia, fatigue, and infection in 25, 20, 13, and 10%, respectively. Eleven patients (28%) discontinued study therapy due to toxicity and 17 patients (43%) required dose modification. One patient died due to treatment-related intestinal perforation. The addition of carboplatin and irinotecan to bevacizumab significantly increases toxicity but does not improve anti-tumor activity to that achieved historically with single-agent bevacizumab among bevacizumab-naïve, recurrent GBM patients. (ClinicalTrials.gov number NCT00953121).

Authors
Reardon, DA; Desjardins, A; Peters, KB; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Bulusu, A; Threatt, S; Friedman, AH; Vredenburgh, JJ; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Peters, KB, Gururangan, S, Sampson, JH, McLendon, RE, Herndon, JE, Bulusu, A, Threatt, S, Friedman, AH, Vredenburgh, JJ, and Friedman, HS. "Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naïve, recurrent glioblastoma." J Neurooncol 107.1 (March 2012): 155-164.
PMID
21986722
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
107
Issue
1
Publish Date
2012
Start Page
155
End Page
164
DOI
10.1007/s11060-011-0722-2

An animal model of MYC-driven medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients whose tumors exhibit overexpression or amplification of the MYC oncogene (c-MYC) usually have an extremely poor prognosis, but there are no animal models of this subtype of the disease. Here, we show that cerebellar stem cells expressing Myc and mutant Trp53 (p53) generate aggressive tumors following orthotopic transplantation. These tumors consist of large, pleiomorphic cells and resemble human MYC-driven MB at a molecular level. Notably, antagonists of PI3K/mTOR signaling, but not Hedgehog signaling, inhibit growth of tumor cells. These findings suggest that cerebellar stem cells can give rise to MYC-driven MB and identify a novel model that can be used to test therapies for this devastating disease.

Authors
Pei, Y; Moore, CE; Wang, J; Tewari, AK; Eroshkin, A; Cho, Y-J; Witt, H; Korshunov, A; Read, T-A; Sun, JL; Schmitt, EM; Miller, CR; Buckley, AF; McLendon, RE; Westbrook, TF; Northcott, PA; Taylor, MD; Pfister, SM; Febbo, PG; Wechsler-Reya, RJ
MLA Citation
Pei, Y, Moore, CE, Wang, J, Tewari, AK, Eroshkin, A, Cho, Y-J, Witt, H, Korshunov, A, Read, T-A, Sun, JL, Schmitt, EM, Miller, CR, Buckley, AF, McLendon, RE, Westbrook, TF, Northcott, PA, Taylor, MD, Pfister, SM, Febbo, PG, and Wechsler-Reya, RJ. "An animal model of MYC-driven medulloblastoma." Cancer Cell 21.2 (February 14, 2012): 155-167.
PMID
22340590
Source
pubmed
Published In
Cancer Cell
Volume
21
Issue
2
Publish Date
2012
Start Page
155
End Page
167
DOI
10.1016/j.ccr.2011.12.021

Clinical data simplified.

Authors
Sampson, JH; Herndon, JE; McLendon, RE; Hasselblad, V; Asher, AL; McGirt, MJ; Peterson, ED
MLA Citation
Sampson, JH, Herndon, JE, McLendon, RE, Hasselblad, V, Asher, AL, McGirt, MJ, and Peterson, ED. "Clinical data simplified." J Neurosurg 116.2 (February 2012): 346-348.
PMID
22054209
Source
pubmed
Published In
Journal of neurosurgery
Volume
116
Issue
2
Publish Date
2012
Start Page
346
End Page
348
DOI
10.3171/2011.5.JNS11279

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

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

Authors
Warren, KE; Gururangan, S; Geyer, JR; McLendon, RE; Poussaint, TY; Wallace, D; Balis, FM; Berg, SL; Packer, RJ; Goldman, S; Minturn, JE; Pollack, IF; Boyett, JM; Kun, LE
MLA Citation
Warren, KE, Gururangan, S, Geyer, JR, McLendon, RE, Poussaint, TY, Wallace, D, Balis, FM, Berg, SL, Packer, RJ, Goldman, S, Minturn, JE, Pollack, IF, Boyett, JM, and Kun, LE. "A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study." J Neurooncol 106.3 (February 2012): 643-649.
PMID
21968943
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
106
Issue
3
Publish Date
2012
Start Page
643
End Page
649
DOI
10.1007/s11060-011-0709-z

Deletion or epigenetic silencing of AJAP1 on 1p36 in glioblastoma.

Glioblastoma is universally fatal because of its propensity for rapid recurrence due to highly migratory tumor cells. Unraveling the genomic complexity that underlies this migratory characteristic could provide therapeutic targets that would greatly complement current surgical therapy. Using multiple high-resolution genomic screening methods, we identified a single locus, adherens junctional associated protein 1 (AJAP1) on chromosome 1p36 that is lost or epigenetically silenced in many glioblastomas. We found AJAP1 expression absent or reduced in 86% and 100% of primary glioblastoma tumors and cell lines, respectively, and the loss of expression correlates with AJAP1 methylation. Restoration of AJAP1 gene expression by transfection or demethylation agents results in decreased tumor cell migration in glioblastoma cell lines. This work shows the significant loss of expression of AJAP1 in glioblastoma and provides evidence of its role in the highly migratory characteristic of these tumors.

Authors
Lin, N; Di, C; Bortoff, K; Fu, J; Truszkowski, P; Killela, P; Duncan, C; McLendon, R; Bigner, D; Gregory, S; Adamson, DC
MLA Citation
Lin, N, Di, C, Bortoff, K, Fu, J, Truszkowski, P, Killela, P, Duncan, C, McLendon, R, Bigner, D, Gregory, S, and Adamson, DC. "Deletion or epigenetic silencing of AJAP1 on 1p36 in glioblastoma." Mol Cancer Res 10.2 (February 2012): 208-217.
PMID
22241217
Source
pubmed
Published In
Molecular cancer research : MCR
Volume
10
Issue
2
Publish Date
2012
Start Page
208
End Page
217
DOI
10.1158/1541-7786.MCR-10-0109

Biomarker discovery in central nervous system neoplasms: Past, present and future

© Springer Science+Business Media B.V. 2012. Brain tumor biomarkers have long been used as diagnostic tools; they are now finally being brought to bear as therapeutic elements in the fight against brain cancer. Because of the heterogeneity of glial brain tumors, it is clear that no one marker will ever define or defeat them: this has been understood since early days of the search for brain tumor biomarkers. In this chapter, therefore, we provide a context for the trajectory of current research by first discussing the history of brain tumor biomarker research. This is followed by a discussion of the immunologic, cytogenetic, biochemical, and molecular approaches that are currently being used to discover, characterize, and exploit the aberrant features of brain tumor cells. Major biomarkers that have been discovered during decades of research are covered in the earlier sections: gangliosides, tenascin, EGFR and its mutant form EGFRvIII, and GLI. Later sections describe newer, high-thoughput analyses such as gene expression analysis and integrated genome analysis, and outline their role in the discovery of more recent promising biomarkers including doublecortin, osteonectin, semaphoring3B, OTX2, and IDH1 and IDH2. A combination of old and new approaches that harnesses the power of multi-institutional and international cooperation has greatly accelerated the rate of discovery in this field, and is bringing us closer to our goal of finding cures for brain cancers.

Authors
Buckley, AF; McLendon, RE; Wikstrand, CJ; Bigner, DD
MLA Citation
Buckley, AF, McLendon, RE, Wikstrand, CJ, and Bigner, DD. "Biomarker discovery in central nervous system neoplasms: Past, present and future." Tumors of the Central Nervous System: Astrocytomas, Hemangioblastomas, and Gangliogliomas. January 1, 2012. 107-119.
Source
scopus
Volume
5
Publish Date
2012
Start Page
107
End Page
119
DOI
10.1007/978-94-007-2019-0_13

Synthesis and preliminary evaluation of n.c.a. iodoquine: a novel radiotracer with high uptake in cells with high ALDH1 expression.

PURPOSE: Chloroquine has demonstrated high affinity for aldehyde dehydrogenase 1A1 (ALDH1), an enzyme expressed in the highly tumorigenic CD133+ brain tumor initiating subpopulation. The purpose of this study is to report the novel synthesis of a chloroquine analogue, n.c.a. iodoquine, and the in vitro and in vivo uptake in cells with high ALDH1 content. METHODS AND MATERIALS: Iodoquine was synthesized in novel no-carrier-added forms (n.c.a.) for both 125I and 123I. I25I IQ and 18F FDG cell uptake assays were performed in the L1210 and L1210cpa (cyclophosphamide resistant), A549, and MG456 glioblastoma cell lines. Uptake was expressed as a percent of the administered activity. 125I IQ biodistribution studies assessed organ uptake at 1, 4, and 24 hours after IV administration (n= 15 total; 5 mice/timepoint). Radiation dosimetry estimates were calculated using standard OLINDA/EXM software. In vivo imaging of 123I IQ uptake in MG456 glioblastoma mouse model (n=10) was performed with small animal high resolution micro-SPECT. Autoradiography and histology co-localized radiotracer and tumor biodistribution. Uptake in MG456 glioblastoma tumors was quantified with gamma counting. RESULTS: L1210 cpa (high ALDH1) showed significantly higher 125I IQ uptake compared to the parental L1210 (low ALDH1) for all time points through 4 hours (20.7% ± 1.4% versus 11.0% ± 0.5%; 21.3% ± 0.9% versus 11.0% ± 0.4%; 20.6% ± 0.7% versus 9.4% ± 0.3%; and 15.7% ± 0.7% versus 7.5% + 0.4% at 30 minutes, and 1, 2 and 4 hours, respectively; p < 0.001 for all time points). In the CD133+ fraction of MG456 glioblastoma cell line, IQ uptake was significantly higher compared to FDG at all time points through 4 hours (81.5% ± 0.9% versus 1.3% ± 0.1%; 88.8% ± 0.4% versus 1.3% ± 0.1%; 87.8% ± 2.1% versus 1.7% ± 0.2%; and 87.0% ± 2.4% versus 1.8% ± 0.1 at 30 minutes, and 1, 2 and 4 hours, respectively; p > 0.001 for all time points). The A549 lung cancer cell line also showed high IQ uptake through 4 hours. IQ normal biodistribution studies showed rapid renal excretion and very low normal background brain activity after IV administration. In vivo micro-SPECT images showed mild uptake in larger MG456 glioblastomas (n=6) as verified with autoradiography and histology. Gamma well counter uptake in large tumors was 2.3% ± 0.48% ID/g (n=5). CONCLUSION: Iodoquine localizes to cells with high ALDH1 content. Cell assays show high 125I IQ uptake in the MG456 cell line, and in vivo micro-SPECT imaging showed mild 123I IQ uptake in MG456 glioblastomas. Further studies are necessary to investigate 131I IQ as a potential therapeutic agent targeting the highly tumorigenic CD133+ brain tumor stem cell subpopulation.

Authors
Chin, BB; Hjelemand, A; Rich, J; Song, H; Lascola, C; Storms, R; McLendon, R; Reiman, R; Greer, KL; Metzler, SD; McDougald, D; Dai, D; Vaidyanathan, G
MLA Citation
Chin, BB, Hjelemand, A, Rich, J, Song, H, Lascola, C, Storms, R, McLendon, R, Reiman, R, Greer, KL, Metzler, SD, McDougald, D, Dai, D, and Vaidyanathan, G. "Synthesis and preliminary evaluation of n.c.a. iodoquine: a novel radiotracer with high uptake in cells with high ALDH1 expression." Curr Radiopharm 5.1 (January 2012): 47-58.
PMID
21864242
Source
pubmed
Published In
Current Radiopharmaceuticals
Volume
5
Issue
1
Publish Date
2012
Start Page
47
End Page
58

Radioimmunotargeting of malignant glioma by monoclonal antibody D2C7 reactive against both wild-type and variant III mutant epidermal growth factor receptors.

INTRODUCTION: Malignant glioma remains a significant therapeutic challenge, and immunotherapeutics might be a beneficial approach for these patients. A monoclonal antibody (MAb) specific for multiple molecular targets could expand the treatable patient population and the fraction of tumor cells targeted, with potentially increased efficacy. This motivated the generation of MAb D2C7, which recognizes both wild-type epidermal growth factor receptor (EGFRwt) and a tumor-specific mutant, EGFRvIII. METHODS: D2C7 binding affinity was determined by surface plasmon resonance and its specificity characterized through comparison to EGFRwt-specific EGFR.1 and EGFRvIII-specific L8A4 MAbs by flow cytometry and immunohistochemical analysis. The three MAbs were labeled with (125)I or (131)I using Iodogen, and paired-label internalization assays and biodistribution experiments in athymic mice with human tumor xenografts were performed. RESULTS: The affinity of D2C7 for EGFRwt and EGFRvIII was 5.2×10(9) M(-1) and 3.6×10(9) M(-1), and cell-surface reactivity with both receptors was documented by flow cytometry. Immunohistochemical analyses revealed D2C7 reactivity with malignant glioma tissue from 90 of 101 patients. Internalization assays performed on EGFRwt-expressing WTT cells and EGFRvIII-expressing NR6M cells indicated a threefold lower degradation of (125)I-labeled D2C7 compared with (131)I-labeled EGFR.1. Uptake of (125)I-labeled D2C7 in NR6M xenografts (52.45±13.97 %ID g(-1) on Day 3) was more than twice that of (131)I-labeled L8A4; a threefold to fivefold tumor delivery advantage was seen when compared to (131)I-labeled EGFR.1 in mice with WTT xenografts. CONCLUSIONS: These results suggest that D2C7 warrants further evaluation for the development of MAb-based therapeutics against cancers expressing EGFRwt and EGFRvIII.

Authors
Zalutsky, MR; Boskovitz, A; Kuan, C-T; Pegram, CN; Ayriss, J; Wikstrand, CJ; Buckley, AF; Lipp, ES; Herndon, JE; McLendon, RE; Bigner, DD
MLA Citation
Zalutsky, MR, Boskovitz, A, Kuan, C-T, Pegram, CN, Ayriss, J, Wikstrand, CJ, Buckley, AF, Lipp, ES, Herndon, JE, McLendon, RE, and Bigner, DD. "Radioimmunotargeting of malignant glioma by monoclonal antibody D2C7 reactive against both wild-type and variant III mutant epidermal growth factor receptors." Nucl Med Biol 39.1 (January 2012): 23-34.
PMID
21958852
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
39
Issue
1
Publish Date
2012
Start Page
23
End Page
34
DOI
10.1016/j.nucmedbio.2011.06.005

Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma.

We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). PFS-6 for all patients, those with grade I tumors (n = 8) and those with grade II or III tumors (n = 13) was 61.9, 87.5 and 46.2%, respectively. Patients with grade II or III tumors had poorer PFS and OS than those with grade I tumors, (P = 0.025 and P = 0.018) respectively. The only grade 3 or greater adverse event occurring in ≥ 10% of patients was anemia (10%). Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication.

Authors
Reardon, DA; Norden, AD; Desjardins, A; Vredenburgh, JJ; Herndon, JE; Coan, A; Sampson, JH; Gururangan, S; Peters, KB; McLendon, RE; Norfleet, JA; Lipp, ES; Drappatz, J; Wen, PY; Friedman, HS
MLA Citation
Reardon, DA, Norden, AD, Desjardins, A, Vredenburgh, JJ, Herndon, JE, Coan, A, Sampson, JH, Gururangan, S, Peters, KB, McLendon, RE, Norfleet, JA, Lipp, ES, Drappatz, J, Wen, PY, and Friedman, HS. "Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma." J Neurooncol 106.2 (January 2012): 409-415.
PMID
21938530
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
106
Issue
2
Publish Date
2012
Start Page
409
End Page
415
DOI
10.1007/s11060-011-0687-1

A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma.

BACKGROUND: Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells. OBJECTIVE: To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses. METHODOLOGY: A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ). RESULTS AND CONCLUSIONS: Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00626015.

Authors
Sampson, JH; Schmittling, RJ; Archer, GE; Congdon, KL; Nair, SK; Reap, EA; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; Coan, A; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Mitchell, DA
MLA Citation
Sampson, JH, Schmittling, RJ, Archer, GE, Congdon, KL, Nair, SK, Reap, EA, Desjardins, A, Friedman, AH, Friedman, HS, Herndon, JE, Coan, A, McLendon, RE, Reardon, DA, Vredenburgh, JJ, Bigner, DD, and Mitchell, DA. "A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma." PLoS One 7.2 (2012): e31046-.
PMID
22383993
Source
pubmed
Published In
PloS one
Volume
7
Issue
2
Publish Date
2012
Start Page
e31046
DOI
10.1371/journal.pone.0031046

Central nervous system

Several different types of tumors, benign and malignant, have been identified in the central nervous system (CNS). The prognoses for these tumors are related to several factors, such as the age of the patient and the location and histology of the tumor. In adults, about half of all CNS tumors are malignant, whereas in pediatric patients, more than 75% are malignant. For most benign CNS tumors that require treatment, neurosurgeons can offer curative resections or at least provide significant relief from mass effect. Unfortunately, we still lack effective treatments for most primary and secondary malignant CNS tumors. However, the past decade has witnessed an explosion in the understanding of the early molecular events in malignant primary CNS tumors, and for the first time in history, oncologists are seeing that a plethora of new therapies targeting these molecular events are being tested in clinical trials. There is hope on the horizon for the fight against these deadly tumors. The distribution of CNS tumors by location has remained constant for numerous years. The majority of primary CNS tumors arise in the major cortical lobes. Twenty nine percent of primary CNS tumors arise from the dural meninges that encase the CNS structures. The vast majority of these are meningiomas, of which over 90% are benign. About 10% of primary CNS tumors are found in the sella turcica region, where the pituitary gland resides. Other much less common sites of primary CNS tumors include the pineal region, ventricular system, cerebellum, brain stem, cranial nerves, and spinal cord. The distribution of CNS tumors by histology has seen a slight increase in more malignant tumors over the past decade, possibly due to increased neuroimaging practices or environmental exposures. Arising from glial cells, gliomas represent over 36% of all primary CNS tumors and consist of astrocytomas, oligodendrogliomas, ependymomas, mixed gliomas, and neuroepithelial tumors. The benign meningiomas make up 32% of primary CNS tumors, followed by nerve sheath tumors and pituitary tumors. Primary CNS lymphomas, embryonal tumors, and craniopharyngiomas are uncommon. The most common gliomas are astrocytomas, and these tumors are typically classified by the World Health Organization (WHO) as Grades I through IV. Grade IV, the most malignant grade of astrocytoma, includes glioblastoma multiforme (GBM), the most common malignant primary CNS glioma in adults, which represents 51% of all primary CNS gliomas. GBM is unfortunately the most challenging to effectively treat and has the worst patient survival. This chapter is therefore primarily devoted to the current understanding of this topic. Here we describe the molecular and cellular events associated with malignant glioma initiation and progression. We also review the importance of glioma stem cell biology and tumor immunology in early gliomagenesis. In addition, we present a brief description of the most common malignant primary CNS glioma in pediatric patients - medulloblastoma, as well as familial cancer syndromes that include gliomas as part of the syndrome. © 2012 IOS Press and the authors. All rights reserved.

Authors
Adamsona, DC; Rasheed, BAK; McLendon, RE; Bigner, DD
MLA Citation
Adamsona, DC, Rasheed, BAK, McLendon, RE, and Bigner, DD. "Central nervous system." Translational Pathology of Early Cancer (2012): 193-210.
Source
scival
Published In
Translational Pathology of Early Cancer
Publish Date
2012
Start Page
193
End Page
210
DOI
10.3233/978-1-61499-024-6-193

Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy.

BACKGROUND: The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open-label, single-arm trial was evaluated. METHODS: Eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml-min) on day 1, whereas bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) for patients on CYP3A enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m(2) for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first 2 cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, noncompliance, or voluntary withdrawal. The primary end point was progression-free survival at 6 months (PFS-6), and secondary end points included safety and median overall survival (OS). RESULTS: All patients had progression on at least 1 prior bevacizumab regimen and 56% enrolled after either second or third overall progression. The median OS was 5.8 months (95% confidence interval [CI], 4.0-7.0 months) and PFS-6 rate was 16% (95% CI, 5.0%-32.5%). The most common grade 3 or 4 events were hematologic and occurred in 29% of cycles. Nine patients (38%) required dose modification. There were no treatment-related deaths. CONCLUSIONS: Carboplatin, irinotecan, and bevacizumab was associated with modest activity and adequate safety among recurrent GBM patients who progressed on bevacizumab previously.

Authors
Reardon, DA; Desjardins, A; Peters, KB; Vredenburgh, JJ; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Coan, A; Threatt, S; Friedman, AH; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Peters, KB, Vredenburgh, JJ, Gururangan, S, Sampson, JH, McLendon, RE, Herndon, JE, Coan, A, Threatt, S, Friedman, AH, and Friedman, HS. "Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy." Cancer 117.23 (December 1, 2011): 5351-5358.
PMID
21590689
Source
pubmed
Published In
Cancer
Volume
117
Issue
23
Publish Date
2011
Start Page
5351
End Page
5358
DOI
10.1002/cncr.26188

EFFICACY OF BEVACIZUMAB 1 CPT-11 IN CHILDREN WITH RECURRENT LOW- GRADE GLIOMA (LGG) - A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY

Authors
Gururangan, S; Fangusaro, J; Young-Poussaint, T; Lesh, S; Onar, A; Gilbertson, R; Packer, R; McLendon, R; Friedman, HS; Boyett, J; Kun, LE
MLA Citation
Gururangan, S, Fangusaro, J, Young-Poussaint, T, Lesh, S, Onar, A, Gilbertson, R, Packer, R, McLendon, R, Friedman, HS, Boyett, J, and Kun, LE. "EFFICACY OF BEVACIZUMAB 1 CPT-11 IN CHILDREN WITH RECURRENT LOW- GRADE GLIOMA (LGG) - A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY." NEURO-ONCOLOGY 13 (November 2011): 95-95.
PMID
24311632
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
95
End Page
95

Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans.

Lymphodepletion augments adoptive cell transfer during antitumor immunotherapy, producing dramatic clinical responses in patients with malignant melanoma. We report that the lymphopenia induced by the chemotherapeutic agent temozolomide (TMZ) enhances vaccine-driven immune responses and significantly reduces malignant growth in an established model of murine tumorigenesis. Unexpectedly, despite the improved antitumor efficacy engendered by TMZ-induced lymphopenia, there was a treatment related increase in the frequency of immunosuppressive regulatory T cells (T(Regs); P = .0006). Monoclonal antibody (mAb)-mediated inhibition of the high-affinity IL-2 receptor α (IL-2Rα/CD25) during immunotherapy in normal mice depleted T(Regs) (73% reduction; P = .0154) but also abolished vaccine-induced immune responses. However, during lymphodepletion, IL-2Rα blockade decreased T(Regs) (93% reduction; P = .0001) without impairing effector T-cell responses, to augment therapeutic antitumor efficacy (66% reduction in tumor growth; P = .0024). Of clinical relevance, we also demonstrate that anti-IL-2Rα mAb administration during recovery from lymphodepletive TMZ in patients with glioblastoma reduced T(Reg) frequency (48% reduction; P = .0061) while permitting vaccine-stimulated antitumor effector cell expansion. To our knowledge, this is the first report of systemic antibody-mediated T(Reg) depletion during lymphopenia and the consequent synergistic enhancement of vaccine-driven cellular responses, as well as the first demonstration that anti-IL-2Rα mAbs function differentially in nonlymphopenic versus lymphopenic contexts.

Authors
Mitchell, DA; Cui, X; Schmittling, RJ; Sanchez-Perez, L; Snyder, DJ; Congdon, KL; Archer, GE; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, DA, Cui, X, Schmittling, RJ, Sanchez-Perez, L, Snyder, DJ, Congdon, KL, Archer, GE, Desjardins, A, Friedman, AH, Friedman, HS, Herndon, JE, McLendon, RE, Reardon, DA, Vredenburgh, JJ, Bigner, DD, and Sampson, JH. "Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans." Blood 118.11 (September 15, 2011): 3003-3012.
PMID
21768296
Source
pubmed
Published In
Blood
Volume
118
Issue
11
Publish Date
2011
Start Page
3003
End Page
3012
DOI
10.1182/blood-2011-02-334565

Mutations in CIC and FUBP1 contribute to human oligodendroglioma.

Oligodendrogliomas are the second most common malignant brain tumor in adults and exhibit characteristic losses of chromosomes 1p and 19q. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven tumors. Among other changes, we found that the CIC gene (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six cases and that the FUBP1 gene [encoding far-upstream element (FUSE) binding protein] on chromosome 1p was somatically mutated in two tumors. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes.

Authors
Bettegowda, C; Agrawal, N; Jiao, Y; Sausen, M; Wood, LD; Hruban, RH; Rodriguez, FJ; Cahill, DP; McLendon, R; Riggins, G; Velculescu, VE; Oba-Shinjo, SM; Marie, SKN; Vogelstein, B; Bigner, D; Yan, H; Papadopoulos, N; Kinzler, KW
MLA Citation
Bettegowda, C, Agrawal, N, Jiao, Y, Sausen, M, Wood, LD, Hruban, RH, Rodriguez, FJ, Cahill, DP, McLendon, R, Riggins, G, Velculescu, VE, Oba-Shinjo, SM, Marie, SKN, Vogelstein, B, Bigner, D, Yan, H, Papadopoulos, N, and Kinzler, KW. "Mutations in CIC and FUBP1 contribute to human oligodendroglioma." Science 333.6048 (September 9, 2011): 1453-1455.
PMID
21817013
Source
pubmed
Published In
Science
Volume
333
Issue
6048
Publish Date
2011
Start Page
1453
End Page
1455
DOI
10.1126/science.1210557

Distribution of CD133 reveals glioma stem cells self-renew through symmetric and asymmetric cell divisions.

Malignant gliomas contain a population of self-renewing tumorigenic stem-like cells; however, it remains unclear how these glioma stem cells (GSCs) self-renew or generate cellular diversity at the single-cell level. Asymmetric cell division is a proposed mechanism to maintain cancer stem cells, yet the modes of cell division that GSCs utilize remain undetermined. Here, we used single-cell analyses to evaluate the cell division behavior of GSCs. Lineage-tracing analysis revealed that the majority of GSCs were generated through expansive symmetric cell division and not through asymmetric cell division. The majority of differentiated progeny was generated through symmetric pro-commitment divisions under expansion conditions and in the absence of growth factors, occurred mainly through asymmetric cell divisions. Mitotic pair analysis detected asymmetric CD133 segregation and not any other GSC marker in a fraction of mitoses, some of which were associated with Numb asymmetry. Under growth factor withdrawal conditions, the proportion of asymmetric CD133 divisions increased, congruent with the increase in asymmetric cell divisions observed in the lineage-tracing studies. Using single-cell-based observation, we provide definitive evidence that GSCs are capable of different modes of cell division and that the generation of cellular diversity occurs mainly through symmetric cell division, not through asymmetric cell division.

Authors
Lathia, JD; Hitomi, M; Gallagher, J; Gadani, SP; Adkins, J; Vasanji, A; Liu, L; Eyler, CE; Heddleston, JM; Wu, Q; Minhas, S; Soeda, A; Hoeppner, DJ; Ravin, R; McKay, RDG; McLendon, RE; Corbeil, D; Chenn, A; Hjelmeland, AB; Park, DM; Rich, JN
MLA Citation
Lathia, JD, Hitomi, M, Gallagher, J, Gadani, SP, Adkins, J, Vasanji, A, Liu, L, Eyler, CE, Heddleston, JM, Wu, Q, Minhas, S, Soeda, A, Hoeppner, DJ, Ravin, R, McKay, RDG, McLendon, RE, Corbeil, D, Chenn, A, Hjelmeland, AB, Park, DM, and Rich, JN. "Distribution of CD133 reveals glioma stem cells self-renew through symmetric and asymmetric cell divisions. (Published online)" Cell Death Dis 2 (September 1, 2011): e200-.
PMID
21881602
Source
pubmed
Published In
Cell Death and Disease
Volume
2
Publish Date
2011
Start Page
e200
DOI
10.1038/cddis.2011.80

Embryonal central nervous system neoplasms arising in infants and young children: a pediatric brain tumor consortium study.

CONTEXT: Medulloblastomas (MBs) and atypical teratoid/rhabdoid tumors (AT/RTs) arising in infants and children can be difficult to distinguish; however, histologic characterization is prognostically important. OBJECTIVE: To determine histologic and phenotypic markers associated with utility with progression-free survival (PFS) and overall survival (OS) in children younger than 3 years with MBs and AT/RTs. DESIGN: We undertook a histologic and immunophenotypic study of MBs and AT/RTs arising in infants and children younger than 3 years treated in a Pediatric Brain Tumor Consortium study. The 41 girls and 55 boys ranged in age from 2 to 36 months at enrollment. These infants and children exhibited 51 MBs, 26 AT/RTs, and 24 other tumors (not further studied). Median follow-up of the patients was 17.2 months from diagnosis (range: 1.4-93 months). RESULTS: Infants and children with AT/RT exhibited a statistically significant shorter PFS and OS when compared to infants and children with MBs (both P < .001). A lack of nuclear BAF47 immunohistochemical reactivity proved reliable in identifying AT/RTs. Among MBs, our data suggest an association of nodularity and prolonged PFS and OS, which must be independently confirmed. Anaplasia correlated with OTX2 reactivity and both OTX2 and moderate to severe anaplasia correlated with PFS but not with OS. CONCLUSION: Distinguishing AT/RT from MBs is clinically important. For expert neuropathologists, the diagnoses of AT/RT and MB can be reliably made from hematoxylin-eosin stains in the vast majority of cases. However certain rare small cell variants of AT/RT can be confused with MB. We also found that immunohistochemical reactivity for BAF47 is clinically useful in distinguishing MBs from AT/RTs and for identifying certain small cell AT/RTs. Among MBs, nodularity may be an important prognostic factor for improved PFS and OS in infants and children.

Authors
McLendon, RE; Adekunle, A; Rajaram, V; Koçak, M; Blaney, SM
MLA Citation
McLendon, RE, Adekunle, A, Rajaram, V, Koçak, M, and Blaney, SM. "Embryonal central nervous system neoplasms arising in infants and young children: a pediatric brain tumor consortium study." Arch Pathol Lab Med 135.8 (August 2011): 984-993.
PMID
21809989
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
135
Issue
8
Publish Date
2011
Start Page
984
End Page
993
DOI
10.5858/2010-0515-OAR1

Altered telomeres in tumors with ATRX and DAXX mutations.

The proteins encoded by ATRX and DAXX participate in chromatin remodeling at telomeres and other genomic sites. Because inactivating mutations of these genes are common in human pancreatic neuroendocrine tumors (PanNETs), we examined the telomere status of these tumors. We found that 61% of PanNETs displayed abnormal telomeres that are characteristic of a telomerase-independent telomere maintenance mechanism termed ALT (alternative lengthening of telomeres). All of the PanNETs exhibiting these abnormal telomeres had ATRX or DAXX mutations or loss of nuclear ATRX or DAXX protein. ATRX mutations also correlate with abnormal telomeres in tumors of the central nervous system. These data suggest that an alternative telomere maintenance function may operate in human tumors with alterations in the ATRX or DAXX genes.

Authors
Heaphy, CM; de Wilde, RF; Jiao, Y; Klein, AP; Edil, BH; Shi, C; Bettegowda, C; Rodriguez, FJ; Eberhart, CG; Hebbar, S; Offerhaus, GJ; McLendon, R; Rasheed, BA; He, Y; Yan, H; Bigner, DD; Oba-Shinjo, SM; Marie, SKN; Riggins, GJ; Kinzler, KW; Vogelstein, B; Hruban, RH; Maitra, A; Papadopoulos, N; Meeker, AK
MLA Citation
Heaphy, CM, de Wilde, RF, Jiao, Y, Klein, AP, Edil, BH, Shi, C, Bettegowda, C, Rodriguez, FJ, Eberhart, CG, Hebbar, S, Offerhaus, GJ, McLendon, R, Rasheed, BA, He, Y, Yan, H, Bigner, DD, Oba-Shinjo, SM, Marie, SKN, Riggins, GJ, Kinzler, KW, Vogelstein, B, Hruban, RH, Maitra, A, Papadopoulos, N, and Meeker, AK. "Altered telomeres in tumors with ATRX and DAXX mutations." Science 333.6041 (July 22, 2011): 425-.
PMID
21719641
Source
pubmed
Published In
Science
Volume
333
Issue
6041
Publish Date
2011
Start Page
425
DOI
10.1126/science.1207313

Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2.

Malignant gliomas are aggressive brain tumors with limited therapeutic options, and improvements in treatment require a deeper molecular understanding of this disease. As in other cancers, recent studies have identified highly tumorigenic subpopulations within malignant gliomas, known generally as cancer stem cells. Here, we demonstrate that glioma stem cells (GSCs) produce nitric oxide via elevated nitric oxide synthase-2 (NOS2) expression. GSCs depend on NOS2 activity for growth and tumorigenicity, distinguishing them from non-GSCs and normal neural progenitors. Gene expression profiling identified many NOS2-regulated genes, including the cell-cycle inhibitor cell division autoantigen-1 (CDA1). Further, high NOS2 expression correlates with decreased survival in human glioma patients, and NOS2 inhibition slows glioma growth in a murine intracranial model. These data provide insight into how GSCs are mechanistically distinct from their less tumorigenic counterparts and suggest that NOS2 inhibition may be an efficacious approach to treating this devastating disease.

Authors
Eyler, CE; Wu, Q; Yan, K; MacSwords, JM; Chandler-Militello, D; Misuraca, KL; Lathia, JD; Forrester, MT; Lee, J; Stamler, JS; Goldman, SA; Bredel, M; McLendon, RE; Sloan, AE; Hjelmeland, AB; Rich, JN
MLA Citation
Eyler, CE, Wu, Q, Yan, K, MacSwords, JM, Chandler-Militello, D, Misuraca, KL, Lathia, JD, Forrester, MT, Lee, J, Stamler, JS, Goldman, SA, Bredel, M, McLendon, RE, Sloan, AE, Hjelmeland, AB, and Rich, JN. "Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2." Cell 146.1 (July 8, 2011): 53-66.
PMID
21729780
Source
pubmed
Published In
Cell
Volume
146
Issue
1
Publish Date
2011
Start Page
53
End Page
66
DOI
10.1016/j.cell.2011.06.006

Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy.

We evaluated the efficacy of metronomic etoposide or temozolomide administered with bevacizumab among recurrent glioblastoma (GBM) patients who progressed on prior bevacizumab therapy in a phase 2, open-label, two-arm trial. Twenty-three patients received bevacizumab (10 mg/kg) every 2 weeks with either oral etoposide (50 mg/m2) daily for 21 consecutive days each month or daily temozolomide (50 mg/m2). The primary endpoint was 6-month progression-free survival (PFS-6) and secondary endpoints included safety and overall survival. Both the etoposide and temozolomide arms of the study closed at the interim analysis due to lack of adequate anti-tumor activity. No radiographic responses were observed. Although 12 patients (52%) achieved stable disease, PFS-6 was 4.4% and the median PFS was 7.3 weeks. The only grade 4 adverse event was reversible neutropenia. Grade 3 toxicities included fatigue (n = 2) and infection (n = 1). Metronomic etoposide or temozolomide is ineffective when administered with bevacizumab among recurrent GBM patients who have progressed on prior bevacizumab therapy. Alternative treatment strategies remain critically needed for this indication.

Authors
Reardon, DA; Desjardins, A; Peters, K; Gururangan, S; Sampson, J; Rich, JN; McLendon, R; Herndon, JE; Marcello, J; Threatt, S; Friedman, AH; Vredenburgh, JJ; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Peters, K, Gururangan, S, Sampson, J, Rich, JN, McLendon, R, Herndon, JE, Marcello, J, Threatt, S, Friedman, AH, Vredenburgh, JJ, and Friedman, HS. "Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy." J Neurooncol 103.2 (June 2011): 371-379.
PMID
20853132
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
103
Issue
2
Publish Date
2011
Start Page
371
End Page
379
DOI
10.1007/s11060-010-0403-6

Acidic stress promotes a glioma stem cell phenotype.

Malignant gliomas are lethal cancers that display cellular hierarchies with cancer stem cells at the apex. Glioma stem cells (GSCs) are not uniformly distributed, but rather located in specialized niches, suggesting that the cancer stem cell phenotype is regulated by the tumor microenvironment. Indeed, recent studies show that hypoxia and its molecular responses regulate cancer stem cell maintenance. We now demonstrate that acidic conditions, independent of restricted oxygen, promote the expression of GSC markers, self-renewal and tumor growth. GSCs exert paracrine effects on tumor growth through elaboration of angiogenic factors, and low pH conditions augment this expression associated with induction of hypoxia inducible factor 2α (HIF2α), a GSC-specific regulator. Induction of HIF2α and other GSC markers by acidic stress can be reverted by elevating pH in vitro, suggesting that raising intratumoral pH may be beneficial for targeting the GSC phenotype. Together, our results suggest that exposure to low pH promotes malignancy through the induction of a cancer stem cell phenotype, and that culturing cancer cells at lower pH reflective of endogenous tumor conditions may better retain the cellular heterogeneity found in tumors.

Authors
Hjelmeland, AB; Wu, Q; Heddleston, JM; Choudhary, GS; MacSwords, J; Lathia, JD; McLendon, R; Lindner, D; Sloan, A; Rich, JN
MLA Citation
Hjelmeland, AB, Wu, Q, Heddleston, JM, Choudhary, GS, MacSwords, J, Lathia, JD, McLendon, R, Lindner, D, Sloan, A, and Rich, JN. "Acidic stress promotes a glioma stem cell phenotype." Cell Death Differ 18.5 (May 2011): 829-840.
PMID
21127501
Source
pubmed
Published In
Cell Death & Differentiation
Volume
18
Issue
5
Publish Date
2011
Start Page
829
End Page
840
DOI
10.1038/cdd.2010.150

CLINICAL PATHOLOGIC DESCRIPTION OF THREE PEDIATRIC MEDULLOBLASTOMA CASES WITH MLL2/3 GENE MUTATIONS

Authors
He, Y; Lopez, G; Grant, G; Fuchs, H; Leithe, L; Gururangan, S; Bigner, D; Yan, H; Mclendon, R
MLA Citation
He, Y, Lopez, G, Grant, G, Fuchs, H, Leithe, L, Gururangan, S, Bigner, D, Yan, H, and Mclendon, R. "CLINICAL PATHOLOGIC DESCRIPTION OF THREE PEDIATRIC MEDULLOBLASTOMA CASES WITH MLL2/3 GENE MUTATIONS." May 2011.
PMID
23659599
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
I30
End Page
I30

Nonreceptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3.

Glioblastomas display cellular hierarchies containing tumor-propagating glioblastoma stem cells (GSCs). STAT3 is a critical signaling node in GSC maintenance but molecular mechanisms underlying STAT3 activation in GSCs are poorly defined. Here we demonstrate that the bone marrow X-linked (BMX) nonreceptor tyrosine kinase activates STAT3 signaling to maintain self-renewal and tumorigenic potential of GSCs. BMX is differentially expressed in GSCs relative to nonstem cancer cells and neural progenitors. BMX knockdown potently inhibited STAT3 activation, expression of GSC transcription factors, and growth of GSC-derived intracranial tumors. Constitutively active STAT3 rescued the effects of BMX downregulation, supporting that BMX signals through STAT3 in GSCs. These data demonstrate that BMX represents a GSC therapeutic target and reinforces the importance of STAT3 signaling in stem-like cancer phenotypes.

Authors
Guryanova, OA; Wu, Q; Cheng, L; Lathia, JD; Huang, Z; Yang, J; MacSwords, J; Eyler, CE; McLendon, RE; Heddleston, JM; Shou, W; Hambardzumyan, D; Lee, J; Hjelmeland, AB; Sloan, AE; Bredel, M; Stark, GR; Rich, JN; Bao, S
MLA Citation
Guryanova, OA, Wu, Q, Cheng, L, Lathia, JD, Huang, Z, Yang, J, MacSwords, J, Eyler, CE, McLendon, RE, Heddleston, JM, Shou, W, Hambardzumyan, D, Lee, J, Hjelmeland, AB, Sloan, AE, Bredel, M, Stark, GR, Rich, JN, and Bao, S. "Nonreceptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3." Cancer Cell 19.4 (April 12, 2011): 498-511.
PMID
21481791
Source
pubmed
Published In
Cancer Cell
Volume
19
Issue
4
Publish Date
2011
Start Page
498
End Page
511
DOI
10.1016/j.ccr.2011.03.004

A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma.

Glioblastoma, the most common primary malignant brain tumor among adults, is a highly angiogenic and deadly tumor. Angiogenesis in glioblastoma, driven by hypoxia-dependent and independent mechanisms, is primarily mediated by vascular endothelial growth factor (VEGF), and generates blood vessels with distinctive features. The outcome for patients with recurrent glioblastoma is poor because of ineffective therapies. However, recent encouraging rates of radiographic response and progression-free survival, and adequate safety, led the FDA to grant accelerated approval of bevacizumab, a humanized monoclonal antibody against VEGF, for the treatment of recurrent glioblastoma in May 2009. These results have triggered significant interest in additional antiangiogenic agents and therapeutic strategies for patients with both recurrent and newly diagnosed glioblastoma. Given the potent antipermeability effect of VEGF inhibitors, the Radiologic Assessment in Neuro-Oncology (RANO) criteria were recently implemented to better assess response among patients with glioblastoma. Although bevacizumab improves survival and quality of life, eventual tumor progression is the norm. Better understanding of resistance mechanisms to VEGF inhibitors and identification of effective therapy after bevacizumab progression are currently a critical need for patients with glioblastoma.

Authors
Reardon, DA; Turner, S; Peters, KB; Desjardins, A; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Jones, LW; Kirkpatrick, JP; Friedman, AH; Vredenburgh, JJ; Bigner, DD; Friedman, HS
MLA Citation
Reardon, DA, Turner, S, Peters, KB, Desjardins, A, Gururangan, S, Sampson, JH, McLendon, RE, Herndon, JE, Jones, LW, Kirkpatrick, JP, Friedman, AH, Vredenburgh, JJ, Bigner, DD, and Friedman, HS. "A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma." J Natl Compr Canc Netw 9.4 (April 2011): 414-427. (Review)
PMID
21464146
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
9
Issue
4
Publish Date
2011
Start Page
414
End Page
427

Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma.

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m(2) per 5 days) or dose-intensified (DI) TMZ (100 mg/m(2) per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3(+) T-cell (P = .005) and B-cell (P = .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (T(Reg); P = .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P = .037) and delayed-type hypersensitivity responses (P = .036) of greater magnitude. EGFRvIII-expressing tumor cells were also eradicated in nearly all patients (91.6%; CI(95): 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI(95): 11.0-18.5 months; hazard ratio [HR] = 0.35; P = .024) and overall survival (23.6 months; CI(95): 18.5-33.1 months; HR = 0.23; P = .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIII-targeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.

Authors
Sampson, JH; Aldape, KD; Archer, GE; Coan, A; Desjardins, A; Friedman, AH; Friedman, HS; Gilbert, MR; Herndon, JE; McLendon, RE; Mitchell, DA; Reardon, DA; Sawaya, R; Schmittling, R; Shi, W; Vredenburgh, JJ; Bigner, DD; Heimberger, AB
MLA Citation
Sampson, JH, Aldape, KD, Archer, GE, Coan, A, Desjardins, A, Friedman, AH, Friedman, HS, Gilbert, MR, Herndon, JE, McLendon, RE, Mitchell, DA, Reardon, DA, Sawaya, R, Schmittling, R, Shi, W, Vredenburgh, JJ, Bigner, DD, and Heimberger, AB. "Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma." Neuro Oncol 13.3 (March 2011): 324-333.
PMID
21149254
Source
pubmed
Published In
Neuro-Oncology
Volume
13
Issue
3
Publish Date
2011
Start Page
324
End Page
333
DOI
10.1093/neuonc/noq157

O6-Methylguanine-DNA Methytransferase (MGMT) Immunohistochemistry as a Predictor of Resistance to Temozolomide in Primary CNS Lymphoma

Authors
Jiang, X; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Quinn, JA; Austin, AD; Herndon, JE; McLendon, RE; Friedman, HS
MLA Citation
Jiang, X, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Quinn, JA, Austin, AD, Herndon, JE, McLendon, RE, and Friedman, HS. "O6-Methylguanine-DNA Methytransferase (MGMT) Immunohistochemistry as a Predictor of Resistance to Temozolomide in Primary CNS Lymphoma." February 2011.
Source
wos-lite
Published In
Laboratory Investigation
Volume
91
Publish Date
2011
Start Page
382A
End Page
382A

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.

Authors
Parsons, DW; Li, M; Zhang, X; Jones, S; Leary, RJ; Lin, JC-H; Boca, SM; Carter, H; Samayoa, J; Bettegowda, C; Gallia, GL; Jallo, GI; Binder, ZA; Nikolsky, Y; Hartigan, J; Smith, DR; Gerhard, DS; Fults, DW; VandenBerg, S; Berger, MS; Marie, SKN; Shinjo, SMO; Clara, C; Phillips, PC; Minturn, JE; Biegel, JA; Judkins, AR; Resnick, AC; Storm, PB; Curran, T; He, Y; Rasheed, BA; Friedman, HS; Keir, ST; McLendon, R; Northcott, PA; Taylor, MD; Burger, PC; Riggins, GJ; Karchin, R; Parmigiani, G et al.
MLA Citation
Parsons, DW, Li, M, Zhang, X, Jones, S, Leary, RJ, Lin, JC-H, Boca, SM, Carter, H, Samayoa, J, Bettegowda, C, Gallia, GL, Jallo, GI, Binder, ZA, Nikolsky, Y, Hartigan, J, Smith, DR, Gerhard, DS, Fults, DW, VandenBerg, S, Berger, MS, Marie, SKN, Shinjo, SMO, Clara, C, Phillips, PC, Minturn, JE, Biegel, JA, Judkins, AR, Resnick, AC, Storm, PB, Curran, T, He, Y, Rasheed, BA, Friedman, HS, Keir, ST, McLendon, R, Northcott, PA, Taylor, MD, Burger, PC, Riggins, GJ, Karchin, R, and Parmigiani, G et al. "The genetic landscape of the childhood cancer medulloblastoma." Science 331.6016 (January 28, 2011): 435-439.
PMID
21163964
Source
pubmed
Published In
Science
Volume
331
Issue
6016
Publish Date
2011
Start Page
435
End Page
439
DOI
10.1126/science.1198056

Treatment recommendations for primary extradural meningiomas.

Primary extradural meningiomas (PEMs) represent about 2% of all meningiomas and are often encountered by non-neurosurgeons. These lesions typically present as enlarging, painless, benign masses that can be surgically cured. Imaging is critical for defining involvement of adjacent structures; however, diagnosis depends on classic histologic patterns. Treatment for benign PEMs (WHO I) consists of resection with wide margins, whereas adjuvant therapy after resection of atypical (WHO II) or malignant (WHO III) PEMs should be considered. By using the collective experience from our comprehensive cancer center, including neuro-oncologists, neuroradiologists, and neurosurgeons, in addition to a complete literature review, the authors have established treatment guidelines not previously reported. This manuscript describes key features of these challenging tumors to aid in diagnosis, presents the largest published review of all reported PEMs (n = 163), and provides salient treatment guidelines to surgeons unfamiliar with these challenging tumors.

Authors
Mattox, A; Hughes, B; Oleson, J; Reardon, D; McLendon, R; Adamson, C
MLA Citation
Mattox, A, Hughes, B, Oleson, J, Reardon, D, McLendon, R, and Adamson, C. "Treatment recommendations for primary extradural meningiomas." Cancer 117.1 (January 1, 2011): 24-38. (Review)
PMID
20824719
Source
pubmed
Published In
Cancer
Volume
117
Issue
1
Publish Date
2011
Start Page
24
End Page
38
DOI
10.1002/cncr.25384

Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma.

Sorafenib, an oral VEGFR-2, Raf, PDGFR, c-KIT and Flt-3 inhibitor, is active against renal cell and hepatocellular carcinomas, and has recently demonstrated promising activity for lung and breast cancers. In addition, various protracted temozolomide dosing schedules have been evaluated as a strategy to further enhance its anti-tumor activity. We reasoned that sorafenib and protracted, daily temozolomide may provide complementary therapeutic benefit, and therefore performed a phase 2 trial among recurrent glioblastoma patients. Adult glioblastoma patients at any recurrence after standard temozolomide chemoradiotherapy received sorafenib (400 mg twice daily) and continuous daily temozolomide (50 mg/m²/day). Assessments were performed every eight weeks. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary end points were radiographic response, overall survival (OS), safety and sorafenib pharmacokinetics. Of 32 enrolled patients, 12 (38%) were on CYP3-A inducing anti-epileptics (EIAEDs), 17 (53%) had 2 or more prior progressions, 15 had progressed while receiving 5-day temozolomide, and 12 (38%) had failed either prior bevacizumab or VEGFR inhibitor therapy. The most common grade ≥ 3 toxicities were palmer-planter erythrodysesthesia (19%) and elevated amylase/lipase (13%). Sorafenib pharmacokinetic exposures were comparable on day 1 regardless of EIAED status, but significantly lower on day 28 for patients on EIAEDs (P = 0.0431). With a median follow-up of 93 weeks, PFS-6 was 9.4%. Only one patient (3%) achieved a partial response. In conclusion, sorafenib can be safely administered with daily temozolomide, but this regimen has limited activity for recurrent GBM. Co-administration of EIAEDs can lower sorafenib exposures in this population.

Authors
Reardon, DA; Vredenburgh, JJ; Desjardins, A; Peters, K; Gururangan, S; Sampson, JH; Marcello, J; Herndon, JE; McLendon, RE; Janney, D; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Reardon, DA, Vredenburgh, JJ, Desjardins, A, Peters, K, Gururangan, S, Sampson, JH, Marcello, J, Herndon, JE, McLendon, RE, Janney, D, Friedman, AH, Bigner, DD, and Friedman, HS. "Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma." J Neurooncol 101.1 (January 2011): 57-66.
PMID
20443129
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
101
Issue
1
Publish Date
2011
Start Page
57
End Page
66
DOI
10.1007/s11060-010-0217-6

Glioblastoma Stem Cells: A Neuropathologist's View.

Glioblastoma (WHO Grade IV) is both the most common primary brain tumor and the most malignant. Advances in the understanding of the biology of the tumor are needed in order to obtain a clearer picture of the mechanisms driving these tumors. To neuropathologists, glioblastoma is a tumor that represents a complex system of migrating pleomorphic tumor cells, proliferating blood vessels, infiltrating inflammatory cells, and necrosis. This review will highlight how the glioma stem cell concept brings these elements together into a collective whole, interacting with microenvironmental influences in complex ways. Borrowing from chaos theory a vocabulary of "self organizing systems" and "complex adaptive systems" that seem useful in describing these pathologic features, a new paradigm of glioblastoma biology will be proposed that genetic changes should be understood in a three dimensional framework as they relate not only to the tumor cells themselves but also to the multicellular hierarchical unit, not isolated from, but responsive to, its local milieu. In this way we will come to better appreciate the impact our therapeutic interventions have on the regional phenotypic heterogeneity that exists within the tumor and the intercellular communications directing adaptation and progression.

Authors
McLendon, RE; Rich, JN
MLA Citation
McLendon, RE, and Rich, JN. "Glioblastoma Stem Cells: A Neuropathologist's View." J Oncol 2011 (2011): 397195-.
PMID
21052560
Source
pubmed
Published In
Journal of Oncology
Volume
2011
Publish Date
2011
Start Page
397195
DOI
10.1155/2011/397195

Direct in vivo evidence for tumor propagation by glioblastoma cancer stem cells.

High-grade gliomas (World Health Organization grade III anaplastic astrocytoma and grade IV glioblastoma multiforme), the most prevalent primary malignant brain tumors, display a cellular hierarchy with self-renewing, tumorigenic cancer stem cells (CSCs) at the apex. While the CSC hypothesis has been an attractive model to describe many aspects of tumor behavior, it remains controversial due to unresolved issues including the use of ex vivo analyses with differential growth conditions. A CSC population has been confirmed in malignant gliomas by preferential tumor formation from cells directly isolated from patient biopsy specimens. However, direct comparison of multiple tumor cell populations with analysis of the resulting phenotypes of each population within a representative tumor environment has not been clearly described. To directly test the relative tumorigenic potential of CSCs and non-stem tumor cells in the same microenvironment, we interrogated matched tumor populations purified from a primary human tumor transplanted into a xenograft mouse model and monitored competitive in vivo tumor growth studies using serial in vivo intravital microscopy. While CSCs were a small minority of the initial transplanted cancer cell population, the CSCs, not the non-stem tumor cells, drove tumor formation and yielded tumors displaying a cellular hierarchy. In the resulting tumors, a fraction of the initial transplanted CSCs maintained expression of stem cell and proliferation markers, which were significantly higher compared to the non-stem tumor cell population and demonstrated that CSCs generated cellular heterogeneity within the tumor. These head-to-head comparisons between matched CSCs and non-stem tumor cells provide the first functional evidence using live imaging that in the same microenvironment, CSCs more than non-stem tumor cells are responsible for tumor propagation, confirming the functional definition of a CSC.

Authors
Lathia, JD; Gallagher, J; Myers, JT; Li, M; Vasanji, A; McLendon, RE; Hjelmeland, AB; Huang, AY; Rich, JN
MLA Citation
Lathia, JD, Gallagher, J, Myers, JT, Li, M, Vasanji, A, McLendon, RE, Hjelmeland, AB, Huang, AY, and Rich, JN. "Direct in vivo evidence for tumor propagation by glioblastoma cancer stem cells." PLoS One 6.9 (2011): e24807-.
PMID
21961046
Source
pubmed
Published In
PloS one
Volume
6
Issue
9
Publish Date
2011
Start Page
e24807
DOI
10.1371/journal.pone.0024807

Reply to M.S. Lesniak

Authors
Mehta, AI; Persson, O; II, JEH; Archer, GE; McLendon, R; Heimberger, AB; Mitchell, DA; Bigner, DD; Sampson, JH
MLA Citation
Mehta, AI, Persson, O, II, JEH, Archer, GE, McLendon, R, Heimberger, AB, Mitchell, DA, Bigner, DD, and Sampson, JH. "Reply to M.S. Lesniak." Journal of Clinical Oncology 29.22 (2011): 3105-3106.
Source
scival
Published In
Journal of Clinical Oncology
Volume
29
Issue
22
Publish Date
2011
Start Page
3105
End Page
3106
DOI
10.1200/JCO.2011.35.0256

Progressive multifocal leukoencephalopathy with occult Waldenström macroglobulinemia.

Authors
Chiarchiaro, J; McLendon, RE; Buckley, PJ; Laskowitz, DT
MLA Citation
Chiarchiaro, J, McLendon, RE, Buckley, PJ, and Laskowitz, DT. "Progressive multifocal leukoencephalopathy with occult Waldenström macroglobulinemia." J Clin Oncol 28.36 (December 20, 2010): e759-e761.
PMID
20855833
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
36
Publish Date
2010
Start Page
e759
End Page
e761
DOI
10.1200/JCO.2010.30.7447

Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma.

Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling are established contributors to malignant glioma (MG) biology. We, therefore, evaluated bevacizumab, a humanized anti-VEGF monoclonal antibody, in combination with the EGFR tyrosine kinase inhibitor erlotinib, in this phase 2 study for recurrent MG patients (www.ClinicalTrials.gov, NCT00671970). Fifty-seven patients (n = 25, glioblastoma [GBM]; n = 32, anaplastic glioma [AG]) were enrolled. The primary endpoint was 6-month progression-free survival (PFS-6). Overall survival (OS), radiographic response, pharmacokinetics, and correlative biomarkers were the secondary endpoints. Patients were stratified based on the concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs). Bevacizumab (10 mg/kg) was given intravenously every 2 weeks. Erlotinib was orally administered daily at 200 mg/day for patients not on EIAEDs and 500 mg/day for patients on EIAEDs. PFS-6 and median OS were 28% and 42 weeks for GBM patients and 44% and 71 weeks for AG patients, respectively. Twelve (48%) GBM patients and 10 (31%) AG patients achieved a radiographic response. Erlotinib pharmacokinetic exposures were comparable between EIAED and non-EIAED groups. Rash, mucositis, diarrhea, and fatigue were common but mostly grades 1 and 2. Among GBM patients, grade 3 rash, observed in 32%, was associated with survival benefit, whereas elevated hypoxia-inducible factor-2 alpha and VEGF receptor-2 levels were associated with poor survival. Bevacizumab plus erlotinib was adequately tolerated in recurrent MG patients. However, this regimen was associated with similar PFS benefit and radiographic response when compared with other historical bevacizumab-containing regimens.

Authors
Sathornsumetee, S; Desjardins, A; Vredenburgh, JJ; McLendon, RE; Marcello, J; Herndon, JE; Mathe, A; Hamilton, M; Rich, JN; Norfleet, JA; Gururangan, S; Friedman, HS; Reardon, DA
MLA Citation
Sathornsumetee, S, Desjardins, A, Vredenburgh, JJ, McLendon, RE, Marcello, J, Herndon, JE, Mathe, A, Hamilton, M, Rich, JN, Norfleet, JA, Gururangan, S, Friedman, HS, and Reardon, DA. "Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma." Neuro Oncol 12.12 (December 2010): 1300-1310.
PMID
20716591
Source
pubmed
Published In
Neuro-Oncology
Volume
12
Issue
12
Publish Date
2010
Start Page
1300
End Page
1310
DOI
10.1093/neuonc/noq099

Multiple phenotypic changes in mice after knockout of the B3gnt5 gene, encoding Lc3 synthase--a key enzyme in lacto-neolacto ganglioside synthesis.

BACKGROUND: Ganglioside biosynthesis occurs through a multi-enzymatic pathway which at the lactosylceramide step is branched into several biosynthetic series. Lc3 synthase utilizes a variety of galactose-terminated glycolipids as acceptors by establishing a glycosidic bond in the beta-1,3-linkage to GlcNaAc to extend the lacto- and neolacto-series gangliosides. In order to examine the lacto-series ganglioside functions in mice, we used gene knockout technology to generate Lc3 synthase gene B3gnt5-deficient mice by two different strategies and compared the phenotypes of the two null mouse groups with each other and with their wild-type counterparts. RESULTS: B3gnt5 gene knockout mutant mice appeared normal in the embryonic stage and, if they survived delivery, remained normal during early life. However, about 9% developed early-stage growth retardation, 11% died postnatally in less than 2 months, and adults tended to die in 5-15 months, demonstrating splenomegaly and notably enlarged lymph nodes. Without lacto-neolacto series gangliosides, both homozygous and heterozygous mice gradually displayed fur loss or obesity, and breeding mice demonstrated reproductive defects. Furthermore, B3gnt5 gene knockout disrupted the functional integrity of B cells, as manifested by a decrease in B-cell numbers in the spleen, germinal center disappearance, and less efficiency to proliferate in hybridoma fusion. CONCLUSIONS: These novel results demonstrate unequivocally that lacto-neolacto series gangliosides are essential to multiple physiological functions, especially the control of reproductive output, and spleen B-cell abnormality. We also report the generation of anti-IgG response against the lacto-series gangliosides 3'-isoLM1 and 3',6'-isoLD1.

Authors
Kuan, C-T; Chang, J; Mansson, J-E; Li, J; Pegram, C; Fredman, P; McLendon, RE; Bigner, DD
MLA Citation
Kuan, C-T, Chang, J, Mansson, J-E, Li, J, Pegram, C, Fredman, P, McLendon, RE, and Bigner, DD. "Multiple phenotypic changes in mice after knockout of the B3gnt5 gene, encoding Lc3 synthase--a key enzyme in lacto-neolacto ganglioside synthesis. (Published online)" BMC Dev Biol 10 (November 18, 2010): 114-.
Website
http://hdl.handle.net/10161/4341
PMID
21087515
Source
pubmed
Published In
BMC Developmental Biology
Volume
10
Publish Date
2010
Start Page
114
DOI
10.1186/1471-213X-10-114

Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma.

PURPOSE: Immunologic targeting of tumor-specific gene mutations may allow precise eradication of neoplastic cells without toxicity. Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively activated and immunogenic mutation not expressed in normal tissues but widely expressed in glioblastoma multiforme (GBM) and other neoplasms. PATIENTS AND METHODS: A phase II, multicenter trial was undertaken to assess the immunogenicity of an EGFRvIII-targeted peptide vaccine and to estimate the progression-free survival (PFS) and overall survival (OS) of vaccinated patients with newly diagnosed EGFRvIII-expressing GBM with minimal residual disease. Intradermal vaccinations were given until toxicity or tumor progression was observed. Sample size was calculated to differentiate between PFS rates of 20% and 40% 6 months after vaccination. RESULTS: There were no symptomatic autoimmune reactions. The 6-month PFS rate after vaccination was 67% (95% CI, 40% to 83%) and after diagnosis was 94% (95% CI, 67% to 99%; n = 18). The median OS was 26.0 months (95% CI, 21.0 to 47.7 months). After adjustment for age and Karnofsky performance status, the OS of vaccinated patients was greater than that observed in a control group matched for eligibility criteria, prognostic factors, and temozolomide treatment (hazard ratio, 5.3; P = .0013; n = 17). The development of specific antibody (P = .025) or delayed-type hypersensitivity (P = .03) responses to EGFRvIII had a significant effect on OS. At recurrence, 82% (95% CI, 48% to 97%) of patients had lost EGFRvIII expression (P < .001). CONCLUSION: EGFRvIII-targeted vaccination in patients with GBM warrants investigation in a phase III, randomized trial.

Authors
Sampson, JH; Heimberger, AB; Archer, GE; Aldape, KD; Friedman, AH; Friedman, HS; Gilbert, MR; Herndon, JE; McLendon, RE; Mitchell, DA; Reardon, DA; Sawaya, R; Schmittling, RJ; Shi, W; Vredenburgh, JJ; Bigner, DD
MLA Citation
Sampson, JH, Heimberger, AB, Archer, GE, Aldape, KD, Friedman, AH, Friedman, HS, Gilbert, MR, Herndon, JE, McLendon, RE, Mitchell, DA, Reardon, DA, Sawaya, R, Schmittling, RJ, Shi, W, Vredenburgh, JJ, and Bigner, DD. "Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma." J Clin Oncol 28.31 (November 1, 2010): 4722-4729.
PMID
20921459
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
31
Publish Date
2010
Start Page
4722
End Page
4729
DOI
10.1200/JCO.2010.28.6963

ADDITION OF GBM HISTOLOGICAL FEATURES AND EGFRVIII EXPRESSION TO THE CANCER GENOME ATLAS: PHENOTYPIC CORRELATES OF MOLECULAR SUBCLASSES

Authors
Brennan, CW; Brat, DJ; Aldape, KD; Cohen, M; Lehman, NL; McLendon, RE; Miller, R; Schniederjan, M; Vandenberg, SR; Working, CGACNSD
MLA Citation
Brennan, CW, Brat, DJ, Aldape, KD, Cohen, M, Lehman, NL, McLendon, RE, Miller, R, Schniederjan, M, Vandenberg, SR, and Working, CGACNSD. "ADDITION OF GBM HISTOLOGICAL FEATURES AND EGFRVIII EXPRESSION TO THE CANCER GENOME ATLAS: PHENOTYPIC CORRELATES OF MOLECULAR SUBCLASSES." November 2010.
Source
wos-lite
Published In
Neuro-Oncology
Volume
12
Publish Date
2010
Start Page
67
End Page
68

MRP3: a molecular target for human glioblastoma multiforme immunotherapy.

BACKGROUND: Glioblastoma multiforme (GBM) is refractory to conventional therapies. To overcome the problem of heterogeneity, more brain tumor markers are required for prognosis and targeted therapy. We have identified and validated a promising molecular therapeutic target that is expressed by GBM: human multidrug-resistance protein 3 (MRP3). METHODS: We investigated MRP3 by genetic and immunohistochemical (IHC) analysis of human gliomas to determine the incidence, distribution, and localization of MRP3 antigens in GBM and their potential correlation with survival. To determine MRP3 mRNA transcript and protein expression levels, we performed quantitative RT-PCR, raising MRP3-specific antibodies, and IHC analysis with biopsies of newly diagnosed GBM patients. We used univariate and multivariate analyses to assess the correlation of RNA expression and IHC of MRP3 with patient survival, with and without adjustment for age, extent of resection, and KPS. RESULTS: Real-time PCR results from 67 GBM biopsies indicated that 59/67 (88%) samples highly expressed MRP3 mRNA transcripts, in contrast with minimal expression in normal brain samples. Rabbit polyvalent and murine monoclonal antibodies generated against an extracellular span of MRP3 protein demonstrated reactivity with defined MRP3-expressing cell lines and GBM patient biopsies by Western blotting and FACS analyses, the latter establishing cell surface MRP3 protein expression. IHC evaluation of 46 GBM biopsy samples with anti-MRP3 IgG revealed MRP3 in a primarily membranous and cytoplasmic pattern in 42 (91%) of the 46 samples. Relative RNA expression was a strong predictor of survival for newly diagnosed GBM patients. Hazard of death for GBM patients with high levels of MRP3 RNA expression was 2.71 (95% CI: 1.54-4.80) times that of patients with low/moderate levels (p = 0.002). CONCLUSIONS: Human GBMs overexpress MRP3 at both mRNA and protein levels, and elevated MRP3 mRNA levels in GBM biopsy samples correlated with a higher risk of death. These data suggest that the tumor-associated antigen MRP3 has potential use for prognosis and as a target for malignant glioma immunotherapy.

Authors
Kuan, C-T; Wakiya, K; Herndon, JE; Lipp, ES; Pegram, CN; Riggins, GJ; Rasheed, A; Szafranski, SE; McLendon, RE; Wikstrand, CJ; Bigner, DD
MLA Citation
Kuan, C-T, Wakiya, K, Herndon, JE, Lipp, ES, Pegram, CN, Riggins, GJ, Rasheed, A, Szafranski, SE, McLendon, RE, Wikstrand, CJ, and Bigner, DD. "MRP3: a molecular target for human glioblastoma multiforme immunotherapy. (Published online)" BMC Cancer 10 (September 1, 2010): 468-.
Website
http://hdl.handle.net/10161/4357
PMID
20809959
Source
pubmed
Published In
BMC Cancer
Volume
10
Publish Date
2010
Start Page
468
DOI
10.1186/1471-2407-10-468

MGMT immunoexpression in silent subtype 3 pituitary adenomas: possible therapeutic implications.

The objective of the study was to assess O(6)-methylguanine-DNA methyltransferase (MGMT) immunoreactivity in pituitary adenomas of silent subtype 3 as a potential indicator of temozolomide susceptibility. The Mayo Clinic Anatomic Pathology Database was searched for all cases of silent subtype 3 pituitary adenoma. Each of the 23 cases identified had been confirmed on the basis of histology, immunohistochemical staining for pituitary hormones, as well as on diagnostic ultrastructural criteria. Unstained microscopic sections were immunostained for MGMT and were semiquantitatively assessed. Of the 23 tumors examined, 18 (78%) showed no MGMT immunoreactivity. The remaining five (22%) showed immunoreactivity in < or =50% of tumor cells. Among eight of the most clinically aggressive tumors in this study, six (75%) lacked MGMT immunoreactivity. The observed lack of or low-level expression of MGMT by this distinctive, clinically aggressive form of pituitary adenoma suggests potential efficacy of treatment with the alkylating agent temozolomide.

Authors
Fealey, ME; Scheithauer, BW; Horvath, E; Erickson, D; Kovacs, K; McLendon, R; Lloyd, RV
MLA Citation
Fealey, ME, Scheithauer, BW, Horvath, E, Erickson, D, Kovacs, K, McLendon, R, and Lloyd, RV. "MGMT immunoexpression in silent subtype 3 pituitary adenomas: possible therapeutic implications." Endocr Pathol 21.3 (September 2010): 161-165.
PMID
20480258
Source
pubmed
Published In
Endocrine Pathology
Volume
21
Issue
3
Publish Date
2010
Start Page
161
End Page
165
DOI
10.1007/s12022-010-9120-0

HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea.

Glioblastoma multiforme (GBM) is one of the deadliest tumors afflicting humans, and the mechanisms of its onset and progression remain largely undefined. Our attempts to elucidate its molecular pathogenesis through DNA copy-number analysis by genome-wide digital karyotyping and single nucleotide polymorphism arrays identified a dramatic focal amplification on chromosome 1q32 in 4 of 57 GBM tumors. Quantitative real-time PCR measurements revealed that HDMX is the most commonly amplified and overexpressed gene in the 1q32 locus. Further genetic screening of 284 low- and high-grade gliomas revealed that HDMX amplifications occur solely in pediatric and adult GBMs and that they are mutually exclusive of TP53 mutations and MDM2 amplifications. Here, we demonstrate that HDMX regulates p53 to promote GBM growth and attenuates tumor response to chemotherapy. In GBM cells, HDMX overexpression inhibits p53-mediated transcriptional activation of p21, releases cells from G0 to G1 phase, and enhances cellular proliferation. HDMX overexpression does not affect the expression of PUMA and BAX proapoptotic genes. While in GBM cells treated with the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), HDMX appears to stabilize p53 and promote phosphorylation of the DNA double-stranded break repair protein H2AX, up-regulate the DNA repair gene VPX, stimulate DNA repair, and confer resistance to BCNU. In summary, HDMX exhibits bona fide oncogenic properties and offers a promising molecular target for GBM therapeutic intervention.

Authors
Jin, G; Cook, S; Cui, B; Chen, WC; Keir, ST; Killela, P; Di, C; Payne, CA; Gregory, SG; McLendon, R; Bigner, DD; Yan, H
MLA Citation
Jin, G, Cook, S, Cui, B, Chen, WC, Keir, ST, Killela, P, Di, C, Payne, CA, Gregory, SG, McLendon, R, Bigner, DD, and Yan, H. "HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea." Neuro Oncol 12.9 (September 2010): 956-966.
PMID
20472715
Source
pubmed
Published In
Neuro-Oncology
Volume
12
Issue
9
Publish Date
2010
Start Page
956
End Page
966
DOI
10.1093/neuonc/noq045

Recombinant single-chain variable fragment antibodies against extracellular epitopes of human multidrug resistance protein MRP3 for targeting malignant gliomas.

Multidrug resistance protein 3 (MRP3), a multidrug resistance protein identified by serial analysis of gene expression as a glioblastoma multiforme (GBM)-associated molecule, is highly expressed in GBM, but not in normal brain cells. Thus, MRP3 is a candidate for GBM immunotargeting, but to date, no monoclonal antibody has been isolated that can target an extracellular MRP3 epitope. By phage display, we have isolated 3 recombinant, fully human, single-chain Fv (scFv) antibodies, M25, M58 and M89, which specifically react with the extracellular N-terminus of human MRP3. In ELISA, these scFvs reacted only with the peptide used for screening and not with other MRP3-derived peptides. Flow cytometric analysis revealed that these scFv fragments bind specifically to viable human GBM cells displaying different MRP3 expression levels, but not to MRP3-null cells. Furthermore, these scFv antibodies failed to react with tumor cells overexpressing other MRP proteins, including MRP1, MRP2, MRP4 and MRP5. M25 and M58 also bound to viable neurospheres. Iodogen-labeled scFvs demonstrated a yield of 56-76%. The immunoreactive fractions of the radiolabeled M25, M58 and M89 scFvs were 32, 52 and 69%, respectively. M25 exhibited 20% internalization into D2159MG neurospheres, M58, 33% into D54MG cells and M89, 26% into D247MG. Immunohistochemical evaluation of human gliomas to determine the localization of MRP3 antigen using scFvs M25 and M58 showed a dense cytoplasmic and membranous staining pattern. These Fv-based recombinant antibodies, which possess superior tumor penetration capabilities and selectively target tumor cells that express MRP3, may potentially be used in immunotherapy and diagnosis for brain tumors and other cancers.

Authors
Kuan, C-T; Srivastava, N; McLendon, RE; Marasco, WA; Zalutsky, MR; Bigner, DD
MLA Citation
Kuan, C-T, Srivastava, N, McLendon, RE, Marasco, WA, Zalutsky, MR, and Bigner, DD. "Recombinant single-chain variable fragment antibodies against extracellular epitopes of human multidrug resistance protein MRP3 for targeting malignant gliomas." Int J Cancer 127.3 (August 1, 2010): 598-611.
PMID
19937796
Source
pubmed
Published In
International Journal of Cancer
Volume
127
Issue
3
Publish Date
2010
Start Page
598
End Page
611
DOI
10.1002/ijc.25062

Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes.

The glioblastoma genome displays remarkable chromosomal aberrations, which harbor critical glioblastoma-specific genes contributing to several oncogenetic pathways. To identify glioblastoma-targeted genes, we completed a multifaceted genome-wide analysis to characterize the most significant aberrations of DNA content occurring in glioblastomas. We performed copy number analysis of 111 glioblastomas by Digital Karyotyping and Illumina BeadChip assays and validated our findings using data from the TCGA (The Cancer Genome Atlas) glioblastoma project. From this study, we identified recurrent focal copy number alterations in 1p36.23 and 4p16.3. Expression analyses of genes located in the two regions revealed genes which are dysregulated in glioblastomas. Specifically, we identify EGFR negative regulator, ERRFI1, within the minimal region of deletion in 1p36.23. In glioblastoma cells with a focal deletion of the ERRFI1 locus, restoration of ERRFI1 expression slowed cell migration. Furthermore, we demonstrate that TACC3, an Aurora-A kinase substrate, on 4p16.3, displays gain of copy number, is overexpressed in a glioma-grade-specific pattern, and correlates with Aurora kinase overexpression in glioblastomas. Our multifaceted genomic evaluation of glioblastoma establishes ERRFI1 as a potential candidate tumor suppressor gene and TACC3 as a potential oncogene, and provides insight on targets for oncogenic pathway-based therapy.

Authors
Duncan, CG; Killela, PJ; Payne, CA; Lampson, B; Chen, WC; Liu, J; Solomon, D; Waldman, T; Towers, AJ; Gregory, SG; McDonald, KL; McLendon, RE; Bigner, DD; Yan, H
MLA Citation
Duncan, CG, Killela, PJ, Payne, CA, Lampson, B, Chen, WC, Liu, J, Solomon, D, Waldman, T, Towers, AJ, Gregory, SG, McDonald, KL, McLendon, RE, Bigner, DD, and Yan, H. "Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes." Oncotarget 1.4 (August 2010): 265-277.
PMID
21113414
Source
pubmed
Published In
Oncotarget
Volume
1
Issue
4
Publish Date
2010
Start Page
265
End Page
277
DOI
10.18632/oncotarget.137

IDH1(R132) mutation identified in one human melanoma metastasis, but not correlated with metastases to the brain.

Isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are enzymes which convert isocitrate to alpha-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+to NADPH). IDH1/2 were recently identified as mutated in a large percentage of progressive gliomas. These mutations occur at IDH1(R132) or the homologous IDH2(R172). Melanomas share some genetic features with IDH1/2-mutated gliomas, such as frequent TP53 mutation. We sought to test whether melanoma is associated with IDH1/2 mutations. Seventy-eight human melanoma samples were analyzed for IDH1(R132) and IDH2(R172) mutation status. A somatic, heterozygous IDH1 c.C394T (p.R132C) mutation was identified in one human melanoma metastasis to the lung. Having identified this mutation in one metastasis, we sought to test the hypothesis that certain selective pressures in the brain environment may specifically favor the cell growth or survival of tumor cells with mutations in IDH1/2, regardless of primary tumor site. To address this, we analyzed IDH1(R132) and IDH2(R172) mutation status 53 metastatic brain tumors, including nine melanoma metastases. Results revealed no mutations in any samples. This lack of mutations would suggest that mutations in IDH1(R132) or IDH2(R172) may be necessary for the formation of tumors in a cell-lineage dependent manner, with a particularly strong selective pressure for mutations in progressive gliomas; this also suggests the lack of a particular selective pressure for growth in brain tissue in general. Studies on the cell-lineages of tumors with IDH1/2 mutations may help clarify the role of these mutations in the development of brain tumors.

Authors
Lopez, GY; Reitman, ZJ; Solomon, D; Waldman, T; Bigner, DD; McLendon, RE; Rosenberg, SA; Samuels, Y; Yan, H
MLA Citation
Lopez, GY, Reitman, ZJ, Solomon, D, Waldman, T, Bigner, DD, McLendon, RE, Rosenberg, SA, Samuels, Y, and Yan, H. "IDH1(R132) mutation identified in one human melanoma metastasis, but not correlated with metastases to the brain." Biochemical and biophysical research communications 398.3 (July 13, 2010): 585-587.
PMID
20603105
Source
epmc
Published In
Biochemical and Biophysical Research Communications
Volume
398
Issue
3
Publish Date
2010
Start Page
585
End Page
587
DOI
10.1016/j.bbrc.2010.06.125

IDH1 and IDH2 hotspot mutations are not found in canine glioma.

Authors
Reitman, ZJ; Olby, NJ; Mariani, CL; Thomas, R; Breen, M; Bigner, DD; McLendon, RE; Yan, H
MLA Citation
Reitman, ZJ, Olby, NJ, Mariani, CL, Thomas, R, Breen, M, Bigner, DD, McLendon, RE, and Yan, H. "IDH1 and IDH2 hotspot mutations are not found in canine glioma." Int J Cancer 127.1 (July 1, 2010): 245-246. (Letter)
PMID
19877121
Source
pubmed
Published In
International Journal of Cancer
Volume
127
Issue
1
Publish Date
2010
Start Page
245
End Page
246
DOI
10.1002/ijc.25017

Bevacizumab fails to treat temporal paraganglioma: discussion and case illustration.

Temporal paragangliomas are highly vascular tumors treated primarily by surgical resection. However, surgery to remove these tumors is associated with significant morbidity, including cranial nerve dysfunction. Interestingly, these tumors have been shown to express vascular endothelial growth factor (VEGF). A variety of tumors expressing VEGF and the VEGF receptor have been shown to reduce in size and vascularity when treated with the VEGF-specific antibody, bevacizumab (Avastin). We hypothesized that paragangliomas may be treated noninvasively with bevacizumab, either as a primary treatment or as a useful adjuvant to surgical resection or radiation. Thus, our aim was to evaluate the effects of bevacizumab on this patient's paraganglioma. A 36-year-old female presented to us with a 3 month history of positional dizziness, light-headedness, and left ear pulsatile tinnitus and hearing loss. She was found to have a temporal paraganglioma (glomus jugulare tumor) on imaging. Histopathology confirmed significant staining for VEGF. This patient was treated with bevacizumab prior to surgical treatment; radiographic imaging at 3 months, however, showed no significant response. We discuss possible reasons for treatment failure.

Authors
Aliabadi, H; Vredenburgh, JJ; Everson, RG; Desjardins, A; Friedman, HS; McLendon, RE; Tucci, DL; Sampson, JH
MLA Citation
Aliabadi, H, Vredenburgh, JJ, Everson, RG, Desjardins, A, Friedman, HS, McLendon, RE, Tucci, DL, and Sampson, JH. "Bevacizumab fails to treat temporal paraganglioma: discussion and case illustration." J Neurooncol 98.3 (July 2010): 427-430.
PMID
20020179
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
98
Issue
3
Publish Date
2010
Start Page
427
End Page
430
DOI
10.1007/s11060-009-0091-2

CYP3A-inducing antiepileptics decrease sorafenib exposures: Results of a phase II study in adults with recurrent glioblastoma.

Authors
Gururangan, S; Vredenburgh, JJ; Desjardins, A; Peters, K; Herndon, JE; McLendon, RE; Janney, D; Friedman, HS; Reardon, DA
MLA Citation
Gururangan, S, Vredenburgh, JJ, Desjardins, A, Peters, K, Herndon, JE, McLendon, RE, Janney, D, Friedman, HS, and Reardon, DA. "CYP3A-inducing antiepileptics decrease sorafenib exposures: Results of a phase II study in adults with recurrent glioblastoma." JOURNAL OF CLINICAL ONCOLOGY 28.15 (May 20, 2010).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

Phase II trial of bevacizumab plus erlotinib for patients with recurrent malignant gliomas: Final results.

Authors
Sathornsumetee, S; Desjardins, A; Vredenburgh, JJ; McLendon, RE; Marcello, J; Herndon, JE; Norfleet, J; Gururangan, S; Friedman, HS; Reardon, DA
MLA Citation
Sathornsumetee, S, Desjardins, A, Vredenburgh, JJ, McLendon, RE, Marcello, J, Herndon, JE, Norfleet, J, Gururangan, S, Friedman, HS, and Reardon, DA. "Phase II trial of bevacizumab plus erlotinib for patients with recurrent malignant gliomas: Final results." JOURNAL OF CLINICAL ONCOLOGY 28.15 (May 20, 2010).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

Integrin alpha 6 regulates glioblastoma stem cells.

Cancer stem cells (CSCs) are a subpopulation of tumor cells suggested to be critical for tumor maintenance, metastasis, and therapeutic resistance. Prospective identification and targeting of CSCs are therefore priorities for the development of novel therapeutic paradigms. Although CSC enrichment has been achieved with cell surface proteins including CD133 (Prominin-1), the roles of current CSC markers in tumor maintenance remain unclear. We examined the glioblastoma stem cell (GSC) perivascular microenvironment in patient specimens to identify enrichment markers with a functional significance and identified integrin alpha6 as a candidate. Integrin alpha6 is coexpressed with conventional GSC markers and enriches for GSCs. Targeting integrin alpha6 in GSCs inhibits self-renewal, proliferation, and tumor formation capacity. Our results provide evidence that GSCs express high levels of integrin alpha6, which can serve not only as an enrichment marker but also as a promising antiglioblastoma therapy.

Authors
Lathia, JD; Gallagher, J; Heddleston, JM; Wang, J; Eyler, CE; Macswords, J; Wu, Q; Vasanji, A; McLendon, RE; Hjelmeland, AB; Rich, JN
MLA Citation
Lathia, JD, Gallagher, J, Heddleston, JM, Wang, J, Eyler, CE, Macswords, J, Wu, Q, Vasanji, A, McLendon, RE, Hjelmeland, AB, and Rich, JN. "Integrin alpha 6 regulates glioblastoma stem cells." Cell Stem Cell 6.5 (May 7, 2010): 421-432.
PMID
20452317
Source
pubmed
Published In
Cell Stem Cell
Volume
6
Issue
5
Publish Date
2010
Start Page
421
End Page
432
DOI
10.1016/j.stem.2010.02.018

Treatment of Recurrent Intracranial Hemangiopericytoma with SRC-Related Tyrosine Kinase Targeted Therapy: A Case Report.

Hemangiopericytoma (HPC) is a rare sarcomatous tumor arising from pericytes, a support cell found in blood vessels. These tumors can occur throughout the body, particularly in the lower extremities and retroperitoneum. In rare circumstances, HPCs can arise from the meninges. In these cases, they behave similar to meningiomas, in particular angiomatous meningiomas, but tend to be more aggressive and are likely to recur. Treatment usually focuses on surgical resection and radiotherapy with possible inclusion of chemotherapy for control of recurrent disease. We describe a case of recurrent right temporal HPC that first manifested as a paraneoplastic syndrome of oncogenic osteomalacia. Despite maximum therapy, this patient experienced multiple recurrences of the tumor, and immunohistochemical analysis revealed overexpression of platelet-derived growth factor receptor, a member of the SRC-related tyrosine kinases. After multiple recurrences, the patient's tumor has been stable with treatment with monotherapy utilizing molecularly targeted therapy to SRC-related tyrosine kinases. This is the first case report of the treatment of recurrent meningeal HPC with molecularly targeted therapy to SRC-related tyrosine kinases.

Authors
Peters, KB; McLendon, R; Morse, MA; Vredenburgh, JJ
MLA Citation
Peters, KB, McLendon, R, Morse, MA, and Vredenburgh, JJ. "Treatment of Recurrent Intracranial Hemangiopericytoma with SRC-Related Tyrosine Kinase Targeted Therapy: A Case Report. (Published online)" Case Rep Oncol 3.1 (April 8, 2010): 93-97.
PMID
20740166
Source
pubmed
Published In
Case Reports in Oncology
Volume
3
Issue
1
Publish Date
2010
Start Page
93
End Page
97
DOI
10.1159/000307468

Single-stage bilateral choroid plexectomy for choroid plexus papilloma in a patient presenting with high cerebrospinal fluid output.

Cerebrospinal fluid overproduction resulting in communicating hydrocephalus is observed in patients who have choroid plexus papilloma or choroid plexus carcinoma. Less often, patients with these conditions have diffuse villous hyperplasia. Prior studies report CSF production greater than 3 L per day in these patients. These patients are treated with CSF shunting or by either unilateral choroid plexectomy or staged bilateral choroid plexectomy. The authors present a patient who had a number of congenital anomalies and a karyotype that revealed balanced translocations, 5 to 7 and 9 to 11. She presented with hydrocephalus and had CSF production of 5 L per day, greater output than ever previously reported. She was treated with a single-stage bilateral choroid plexectomy. Histopathological analysis revealed a bilateral choroid plexus papilloma. Postoperatively, the patient responded well clinically and showed radiographic improvement of her hydrocephalus. Bilateral choroid plexus papilloma has been reported in the literature as a cause for neonatal and congenital hydrocephalus. It can result in high CSF output and can be successfully treated with a single-stage bilateral choroid plexectomy. Further studies are ongoing to identify genes involved in embryogenesis of the choroid plexus.

Authors
Nimjee, SM; Powers, CJ; McLendon, RE; Grant, GA; Fuchs, HE
MLA Citation
Nimjee, SM, Powers, CJ, McLendon, RE, Grant, GA, and Fuchs, HE. "Single-stage bilateral choroid plexectomy for choroid plexus papilloma in a patient presenting with high cerebrospinal fluid output." J Neurosurg Pediatr 5.4 (April 2010): 342-345.
PMID
20367337
Source
pubmed
Published In
Journal of neurosurgery. Pediatrics
Volume
5
Issue
4
Publish Date
2010
Start Page
342
End Page
345
DOI
10.3171/2009.10.PEDS08454

Targeting A20 decreases glioma stem cell survival and tumor growth.

Glioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioblastoma stem cells (GSCs). GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutic targets. We determined that A20 (TNFAIP3), a regulator of cell survival and the NF-kappaB pathway, is overexpressed in GSCs relative to non-stem glioblastoma cells at both the mRNA and protein levels. To determine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediated delivery of short hairpin RNA (shRNA). Inhibiting A20 expression decreased GSC growth and survival through mechanisms associated with decreased cell-cycle progression and decreased phosphorylation of p65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptible to TNFalpha-induced cell death than matched non-stem glioma cells, but A20 knockdown sensitized GSCs to TNFalpha-mediated apoptosis. The decreased survival of GSCs upon A20 knockdown contributed to the reduced ability of these cells to self-renew in primary and secondary neurosphere formation assays. The tumorigenic potential of GSCs was decreased with A20 targeting, resulting in increased survival of mice bearing human glioma xenografts. In silico analysis of a glioma patient genomic database indicates that A20 overexpression and amplification is inversely correlated with survival. Together these data indicate that A20 contributes to glioma maintenance through effects on the glioma stem cell subpopulation. Although inactivating mutations in A20 in lymphoma suggest A20 can act as a tumor suppressor, similar point mutations have not been identified through glioma genomic sequencing: in fact, our data suggest A20 may function as a tumor enhancer in glioma through promotion of GSC survival. A20 anticancer therapies should therefore be viewed with caution as effects will likely differ depending on the tumor type.

Authors
Hjelmeland, AB; Wu, Q; Wickman, S; Eyler, C; Heddleston, J; Shi, Q; Lathia, JD; Macswords, J; Lee, J; McLendon, RE; Rich, JN
MLA Citation
Hjelmeland, AB, Wu, Q, Wickman, S, Eyler, C, Heddleston, J, Shi, Q, Lathia, JD, Macswords, J, Lee, J, McLendon, RE, and Rich, JN. "Targeting A20 decreases glioma stem cell survival and tumor growth. (Published online)" PLoS Biol 8.2 (February 23, 2010): e1000319-.
Website
http://hdl.handle.net/10161/4444
PMID
20186265
Source
pubmed
Published In
PLoS biology
Volume
8
Issue
2
Publish Date
2010
Start Page
e1000319
DOI
10.1371/journal.pbio.1000319

GMab-1, a high-affinity anti-3'-isoLM1/3',6'-isoLD1 IgG monoclonal antibody, raised in lacto-series ganglioside-defective knockout mice.

The lacto-series gangliosides 3'-isoLM1 and 3',6'-isoLD1 have been identified as tumor-associated antigens whose formation is initiated by the Lc3-synthase. Until now, high-affinity IgG monoclonal antibodies (mAbs) against 3'-isoLM1 and 3',6'-isoLD1, which are highly expressed in gliomas, have not been developed, although mAbs against lacto-series gangliosides are powerful tools for functional studies. We previously produced the Lc3-synthase gene beta3Gn-T5 knockout mice. In this study, we immunized beta3Gn-T5 knockout mice with 3'-isoLM1/3',6'-isoLD1 and produced the anti-3'-isoLM1/3',6'-isoLD1 mAb GMab-1, of the IgG(3) subclass, which should be useful for functional analysis of lacto-series gangliosides and for antibody-based therapy of gliomas.

Authors
Kato, Y; Kuan, C-T; Chang, J; Kaneko, MK; Ayriss, J; Piao, H; Chandramohan, V; Pegram, C; McLendon, RE; Fredman, P; Månsson, J-E; Bigner, DD
MLA Citation
Kato, Y, Kuan, C-T, Chang, J, Kaneko, MK, Ayriss, J, Piao, H, Chandramohan, V, Pegram, C, McLendon, RE, Fredman, P, Månsson, J-E, and Bigner, DD. "GMab-1, a high-affinity anti-3'-isoLM1/3',6'-isoLD1 IgG monoclonal antibody, raised in lacto-series ganglioside-defective knockout mice." Biochem Biophys Res Commun 391.1 (January 1, 2010): 750-755.
PMID
19944071
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
391
Issue
1
Publish Date
2010
Start Page
750
End Page
755
DOI
10.1016/j.bbrc.2009.11.132

Erythropoietin Receptor Signaling Through STAT3 Is Required For Glioma Stem Cell Maintenance.

Recombinant erythropoietin (EPO) is a growth factor used in the treatment of chemotherapy-induced anemia, but recent studies suggest that EPO may accelerate cancer growth. Although several cancers express EPO receptors (EPORs), the mechanism by which EPOR promotes tumor growth remains poorly understood. Glioblastomas display a cellular hierarchy of self-renewal and tumor propagation restricted to glioma stem cells (GSCs). We find that GSCs express higher levels of EPOR than matched non-stem glioma cells. Prospective enrichment for EPOR on GSCs increased neurosphere formation, suggesting that EPOR can select for a subset of GSCs with increased self-renewal capacity. Targeting EPOR expression with lentiviral mediated short hairpin RNA (shRNA) reduced GSC growth, survival, and neurosphere formation capacity, defining a crucial role for EPOR in GSC maintenance. We further find that STAT3 is an important mediator of EPOR signals in GSCs. EPOR knockdown attenuated the basal activation of STAT3 present in GSCs, and a small molecule inhibitor of STAT3 reduced GSC growth and survival. EPOR signaling was critical for survival in vivo, as targeting EPOR expression decreased GSC tumorigenic potential. Elevated EPOR expression also associated with poor patient outcome. Thus, EPOR on GSCs promotes tumor growth and may explain the poor survival of cancer patients treated with EPO.

Authors
Cao, Y; Lathia, JD; Eyler, CE; Wu, Q; Li, Z; Wang, H; McLendon, RE; Hjelmeland, AB; Rich, JN
MLA Citation
Cao, Y, Lathia, JD, Eyler, CE, Wu, Q, Li, Z, Wang, H, McLendon, RE, Hjelmeland, AB, and Rich, JN. "Erythropoietin Receptor Signaling Through STAT3 Is Required For Glioma Stem Cell Maintenance." Genes Cancer 1.1 (January 1, 2010): 50-61.
PMID
20657792
Source
pubmed
Published In
Genes and Cancer
Volume
1
Issue
1
Publish Date
2010
Start Page
50
End Page
61
DOI
10.1177/1947601909356352

OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas.

OTX2 is a developmentally regulated transcription factor involved in early morphogenesis of the central nervous system. This gene is amplified and overexpressed in medulloblastoma cell lines, but the nature and extent of its genetic alterations in primary tumors have not been evaluated. Analysis of a large cohort of primary medulloblastomas revealed frequent focal copy number gain of a region minimally containing OTX2 as a single gene. OTX2 copy number gain was restricted to tumor subtypes that did not express a molecular signature of Wnt or Shh pathway activation. FISH analysis revealed copy number gain in a subset of cells within medulloblastoma samples, suggesting a late event in tumor progression. Gain of OTX2 copy number was associated with the presence of anaplastic histologic features and shorter survival in medulloblastoma patients. In support of a functional role, ectopic OTX2 expression enhanced proliferation and tumorigenicity of immortalized primary cells, whereas OTX2 knockdown in medulloblastoma cells prolonged the survival of animals bearing xenograft tumors. Mechanistic investigations revealed upregulation of MYC as a potential mechanism whereby OTX2 promotes tumor progression. Our findings define OTX2 as an important oncogenic driver in medulloblastoma.

Authors
Adamson, DC; Shi, Q; Wortham, M; Northcott, PA; Di, C; Duncan, CG; Li, J; McLendon, RE; Bigner, DD; Taylor, MD; Yan, H
MLA Citation
Adamson, DC, Shi, Q, Wortham, M, Northcott, PA, Di, C, Duncan, CG, Li, J, McLendon, RE, Bigner, DD, Taylor, MD, and Yan, H. "OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas." Cancer Res 70.1 (January 1, 2010): 181-191.
PMID
20028867
Source
pubmed
Published In
Cancer Research
Volume
70
Issue
1
Publish Date
2010
Start Page
181
End Page
191
DOI
10.1158/0008-5472.CAN-09-2331

Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma.

We evaluated the anti-tumor activity and safety of erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent glioblastoma (GBM) in a phase 2, open-label, single-arm trial. Thirty-two patients received daily erlotinib and sirolimus. The doses of erlotinib and sirolimus were 150 mg and 5 mg for patients not on concurrent CYP3A-inducing anti-epileptics (EIAEDS), and 450 mg and 10 mg for patients on EIAEDS. Evaluations were performed every two months. The primary endpoint was 6-month progression-free survival and secondary endpoints included safety and overall survival. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and pS6. Enrolled patients were heavily pre-treated including 53% who had received three or more prior chemotherapy agents and 28% who had received prior bevacizumab therapy. The most common grade > or = 2 adverse events were rash (59%), mucositis (34%) and diarrhea (31%). Grade 3 or higher events were rare. Best radiographic response included stable disease in 15 patients (47%); no patients achieved either a CR or PR. The estimated 6-month progression-free survival was 3.1% for all patients. Progression-free survival was better for patients not on EIAEDs (P = 0.03). Tumor markers failed to show an association with PFS except for increased pAKT expression which achieved borderline significance (P = 0.045). Although neither rash nor diarrhea had an association with outcome, hyperlipidemia was associated with longer PFS (P = 0.029). Erlotinib plus sirolimus was well tolerated but had negligible activity among unselected recurrent GBM patients. (ClinicalTrials.gov number: NCT0062243).

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Friedman, AH; Herndon, JE; Marcello, J; Norfleet, JA; McLendon, RE; Sampson, JH; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Vredenburgh, JJ, Gururangan, S, Friedman, AH, Herndon, JE, Marcello, J, Norfleet, JA, McLendon, RE, Sampson, JH, and Friedman, HS. "Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma." J Neurooncol 96.2 (January 2010): 219-230.
PMID
19562254
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
96
Issue
2
Publish Date
2010
Start Page
219
End Page
230
DOI
10.1007/s11060-009-9950-0

Central nervous system.

Several different types of tumors, benign and malignant, have been identified in the central nervous system (CNS). The prognoses for these tumors are related to several factors, such as the age of the patient and the location and histology of the tumor. In adults, about half of all CNS tumors are malignant, whereas in pediatric patients, more than 75% are malignant. For most benign CNS tumors that require treatment, neurosurgeons can offer curative resections or at least provide significant relief from mass effect. Unfortunately, we still lack effective treatments for most primary and secondary malignant CNS tumors. However, the past decade has witnessed an explosion in the understanding of the early molecular events in malignant primary CNS tumors, and for the first time in history, oncologists are seeing that a plethora of new therapies targeting these molecular events are being tested in clinical trials. There is hope on the horizon for the fight against these deadly tumors. The distribution of CNS tumors by location has remained constant for numerous years. The majority of primary CNS tumors arise in the major cortical lobes. Twenty nine percent of primary CNS tumors arise from the dural meninges that encase the CNS structures. The vast majority of these are meningiomas, of which over 90% are benign. About 10% of primary CNS tumors are found in the sella turcica region, where the pituitary gland resides. Other much less common sites of primary CNS tumors include the pineal region, ventricular system, cerebellum, brain stem, cranial nerves, and spinal cord. The distribution of CNS tumors by histology has seen a slight increase in more malignant tumors over the past decade, possibly due to increased neuroimaging practices or environmental exposures. Arising from glial cells, gliomas represent over 36% of all primary CNS tumors and consist of astrocytomas, oligodendrogliomas, ependymomas, mixed gliomas, and neuroepithelial tumors. The benign meningiomas make up 32% of primary CNS tumors, followed by nerve sheath tumors and pituitary tumors. Primary CNS lymphomas, embryonal tumors, and craniopharyngiomas are uncommon. The most common gliomas are astrocytomas, and these tumors are typically classified by the World Health Organization (WHO) as Grades I through IV. Grade IV, the most malignant grade of astrocytoma, includes glioblastoma multiforme (GBM), the most common malignant primary CNS glioma in adults, which represents 51% of all CNS gliomas. GBM is unfortunately the most challenging to effectively treat and has the worst patient survival. This chapter is therefore primarily devoted to the current understanding of this topic. Here we describe the molecular and cellular events associated with malignant glioma initiation and progression. We also review the importance of glioma stem cell biology and tumor immunology in early gliomagenesis. In addition, we present a brief description of the most common malignant primary CNS glioma in pediatric patients - medulloblastoma, as well as familial cancer syndromes that include gliomas as part of the syndrome.

Authors
Adamson, DC; Rasheed, BAK; McLendon, RE; Bigner, DD
MLA Citation
Adamson, DC, Rasheed, BAK, McLendon, RE, and Bigner, DD. "Central nervous system." Cancer Biomark 9.1-6 (2010): 193-210. (Review)
PMID
22112477
Source
pubmed
Published In
Cancer biomarkers : section A of Disease markers
Volume
9
Issue
1-6
Publish Date
2010
Start Page
193
End Page
210
DOI
10.3233/CBM-2011-0177

A monoclonal antibody IMab-1 specifically recognizes IDH1R132H, the most common glioma-derived mutation.

IDH1 (isocitrate dehydrogenase 1) mutations have been identified as early and frequent genetic alterations in astrocytomas, oligodendrogliomas, and oligoastrocytomas as well as secondary glioblastomas. In contrast, primary glioblastomas very rarely contain IDH1 mutations, although primary and secondary glioblastomas are histologically indistinguishable. The IDH1 mutations are remarkably specific to a single codon in the conserved and functionally important Arg132 in IDH1. In gliomas, the most frequent IDH1 mutations (>90%) were G395A (R132H). In this study, we immunized mice with R132H-containing IDH1 (IDH1(R132H)) peptide. After cell fusion using Sendai virus envelope, the monoclonal antibodies (mAbs), which specifically reacted with IDH1(R132H), were screened in ELISA. One of the mAbs, IMab-1 reacted with the IDH1(R132H) peptide, but not with wild type IDH1 (IDH1(wt)) peptide in ELISA. In Western-blot analysis, IMab-1 reacted with only the IDH1(R132H) protein, not IDH1(wt) protein or the other IDH1 mutants, indicating that IMab-1 is IDH1(R132H)-specific. Furthermore, IMab-1 specifically stained the IDH1(R132H)-expressing cells in astrocytomas in immunohistochemistry, whereas it did not react with IDH1(R132H)-negative primary glioblastoma sections. In conclusion, we established an anti-IDH1(R132H)-specific monoclonal antibody IMab-1, which should be significantly useful for diagnosis and biological evaluation of mutation-bearing gliomas.

Authors
Kato, Y; Jin, G; Kuan, C-T; McLendon, RE; Yan, H; Bigner, DD
MLA Citation
Kato, Y, Jin, G, Kuan, C-T, McLendon, RE, Yan, H, and Bigner, DD. "A monoclonal antibody IMab-1 specifically recognizes IDH1R132H, the most common glioma-derived mutation." Biochem Biophys Res Commun 390.3 (December 18, 2009): 547-551.
PMID
19818334
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
390
Issue
3
Publish Date
2009
Start Page
547
End Page
551
DOI
10.1016/j.bbrc.2009.10.001

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study.

BACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of 59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg(-1) bevacizumab biweekly and 50 mg m(-2) etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2alpha (HIF-2alpha) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome. RESULTS: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade > or = 3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism. CONCLUSION: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Sampson, JH; Sathornsumetee, S; McLendon, RE; Herndon, JE; Marcello, JE; Norfleet, J; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Vredenburgh, JJ, Gururangan, S, Sampson, JH, Sathornsumetee, S, McLendon, RE, Herndon, JE, Marcello, JE, Norfleet, J, Friedman, AH, Bigner, DD, and Friedman, HS. "Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study." Br J Cancer 101.12 (December 15, 2009): 1986-1994.
PMID
19920819
Source
pubmed
Published In
British Journal of Cancer
Volume
101
Issue
12
Publish Date
2009
Start Page
1986
End Page
1994
DOI
10.1038/sj.bjc.6605412

Glioblastoma proto-oncogene SEC61gamma is required for tumor cell survival and response to endoplasmic reticulum stress.

Glioblastoma multiforme is the most prevalent type of adult brain tumor and one of the deadliest tumors known to mankind. The genetic understanding of glioblastoma multiforme is, however, limited, and the molecular mechanisms that facilitate glioblastoma multiforme cell survival and growth within the tumor microenvironment are largely unknown. We applied digital karyotyping and single nucleotide polymorphism arrays to screen for copy-number changes in glioblastoma multiforme samples and found that the most frequently amplified region is at chromosome 7p11.2. The high resolution of digital karyotyping and single nucleotide polymorphism arrays permits the precise delineation of amplicon boundaries and has enabled identification of the minimal region of amplification at chromosome 7p11.2, which contains two genes, EGFR and SEC61gamma. SEC61gamma encodes a subunit of a heterotrimeric protein channel located in the endoplasmic reticulum (ER). In addition to its high frequency of gene amplification in glioblastoma multiforme, SEC61gamma is also remarkably overexpressed in 77% of glioblastoma multiforme but not in lower-grade gliomas. The small interfering RNA-mediated knockdown of SEC61gamma expression in tumor cells led to growth suppression and apoptosis. Furthermore, we showed that pharmacologic ER stress agents induce SEC61gamma expression in glioblastoma multiforme cells. Together, these results indicate that aberrant expression of SEC61gamma serves significant roles in glioblastoma multiforme cell survival likely via a mechanism that is involved in the cytoprotective ER stress-adaptive response to the tumor microenvironment.

Authors
Lu, Z; Zhou, L; Killela, P; Rasheed, AB; Di, C; Poe, WE; McLendon, RE; Bigner, DD; Nicchitta, C; Yan, H
MLA Citation
Lu, Z, Zhou, L, Killela, P, Rasheed, AB, Di, C, Poe, WE, McLendon, RE, Bigner, DD, Nicchitta, C, and Yan, H. "Glioblastoma proto-oncogene SEC61gamma is required for tumor cell survival and response to endoplasmic reticulum stress." Cancer Res 69.23 (December 1, 2009): 9105-9111.
PMID
19920201
Source
pubmed
Published In
Cancer Research
Volume
69
Issue
23
Publish Date
2009
Start Page
9105
End Page
9111
DOI
10.1158/0008-5472.CAN-09-2775

Detection of amino-terminal extracellular domain of somatostatin receptor 2 by specific monoclonal antibodies and quantification of receptor density in medulloblastoma.

Somatostatin receptor 2 (SSTR2) is expressed by most medulloblastomas (MEDs). We isolated monoclonal antibodies (MAbs) to the 12-mer (33)QTEPYYDLTSNA(44), which resides in the extracellular domain of the SSTR2 amino terminus, screened the peptide-bound MAbs by fluorescence microassay on D341 and D283 MED cells, and demonstrated homogeneous cell-surface binding, indicating that all cells expressed cell surface-detectable epitopes. Five radiolabeled MAbs were tested for immunoreactive fraction (IRF), affinity (KA) (Scatchard analysis vs. D341 MED cells), and internalization by MED cells. One IgG(3) MAb exhibited a 50-100% IRF, but low KA. Four IgG(2a) MAbs had 46-94% IRFs and modest KAs versus intact cells (0.21-1.2 x 10(8) M(-1)). Following binding of radiolabeled MAbs to D341 MED at 4 degrees C, no significant internalization was observed, which is consistent with results obtained in the absence of ligand. However, all MAbs exhibited long-term association with the cells; binding at 37 degrees C after 2 h was 65-66%, and after 24 h, 52-64%. In tests with MAbs C10 and H5, the number of cell surface receptors per cell, estimated by Scatchard and quantitative FACS analyses, was 3.9 x 10(4) for the "glial" phenotype DAOY MED cell line and 0.6-8.8 x 10(5) for four neuronal phenotype MED cell lines. Our results indicate a potential immunotherapeutic application for these MAbs.

Authors
Kuan, C-T; Wikstrand, CJ; McLendon, RE; Zalutsky, MR; Kumar, U; Bigner, DD
MLA Citation
Kuan, C-T, Wikstrand, CJ, McLendon, RE, Zalutsky, MR, Kumar, U, and Bigner, DD. "Detection of amino-terminal extracellular domain of somatostatin receptor 2 by specific monoclonal antibodies and quantification of receptor density in medulloblastoma." Hybridoma (Larchmt) 28.6 (December 2009): 389-403.
Website
http://hdl.handle.net/10161/3241
PMID
20025498
Source
pubmed
Published In
Hybridoma
Volume
28
Issue
6
Publish Date
2009
Start Page
389
End Page
403
DOI
10.1089/hyb.2009.0049

Phase II trial of temozolomide (TMZ) plus irinotecan (CPT-11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy.

This phase II trial evaluated efficacy and safety of temozolomide (TMZ) in combination with irinotecan (CPT-11) before radiotherapy in patients with newly diagnosed glioblastoma multiforme (GBM). Prior to radiotherapy, patients were treated with a maximum of three 6-week cycles of TMZ and CPT-11. Patients received TMZ at a dose of 200 mg/m(2)/day on days 1-5 and CPT-11 on days 1, 8, 22, and 29, with a dose adjustment for enzyme-inducing antiepileptic drug use. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), safety, and tumor O(6)-methylguanine-DNA methyltransferase (MGMT) expression. Of the 42 patients treated, 8 (19%) patients achieved a partial response. Median PFS and median OS were 3.1 and 13.8 months, respectively. Grade 3 or 4 AEs were documented in 36% of patients, most of which were hematologic (29%). Twenty-four percent of patients had grade 3 or 4 non-hematologic AEs, with gastrointestinal AEs being the most common (12%) Two patients died, one of intracranial hemorrhage and one of treatment-related renal failure. Low MGMT expression, compared with high MGMT expression, showed no significant difference in ORR (25 vs. 8%), median PFS (14 vs. 5 months) or OS (21 vs. 15 months). Although TMZ plus CPT-11 is at least comparable in efficacy to TMZ alone, this combination appears more toxic and poorly tolerated. The lack of correlation of activity with MGMT expression is intriguing, but needs further evaluation in subsequent trials.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Friedman, AH; Sampson, JH; McLendon, RE; Herndon, JE; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Friedman, AH, Sampson, JH, McLendon, RE, Herndon, JE, and Friedman, HS. "Phase II trial of temozolomide (TMZ) plus irinotecan (CPT-11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy." J Neurooncol 95.3 (December 2009): 393-400.
PMID
19533023
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
95
Issue
3
Publish Date
2009
Start Page
393
End Page
400
DOI
10.1007/s11060-009-9937-x

The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype.

Glioblastomas are highly lethal cancers that contain cellular hierarchies with self-renewing cancer stem cells that can propagate tumors in secondary transplant assays. The potential significance of cancer stem cells in cancer biology has been demonstrated by studies showing contributions to therapeutic resistance, angiogenesis and tumor dispersal. We recently reported that physiologic oxygen levels differentially induce hypoxia inducible factor-2alpha (HIF2alpha) levels in cancer stem cells. HIF1alpha functioned in proliferation and survival of all cancer cells but also was activated in normal neural progenitors suggesting a potentially restricted therapeutic index while HIF2alpha was essential in only in cancer stem cells and was not expressed by normal neural progenitors demonstrating HIF2alpha is a cancer stem cell specific target. We now extend these studies to examine the role of hypoxia in regulating tumor cell plasticity. We find that hypoxia promotes the self-renewal capability of the stem and non-stem population as well as promoting a more stem-like phenotype in the non-stem population with increased neurosphere formation as well as upregulation of important stem cell factors, such as OCT4, NANOG and c-MYC. The importance of HIF2alpha was further supported as forced expression of non-degradable HIF2alpha induced a cancer stem cell marker and augmented the tumorigenic potential of the non-stem population. This novel finding may indicate a specific role of HIF2alpha in promoting glioma tumorigenesis. The unexpected plasticity of the non-stem glioma population and the stem-like phenotype emphasizes the importance of developing therapeutic strategies targeting the microenvironmental influence on the tumor in addition to cancer stem cells.

Authors
Heddleston, JM; Li, Z; McLendon, RE; Hjelmeland, AB; Rich, JN
MLA Citation
Heddleston, JM, Li, Z, McLendon, RE, Hjelmeland, AB, and Rich, JN. "The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype." Cell Cycle 8.20 (October 15, 2009): 3274-3284.
PMID
19770585
Source
pubmed
Published In
Cell Cycle
Volume
8
Issue
20
Publish Date
2009
Start Page
3274
End Page
3284
DOI
10.4161/cc.8.20.9701

Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth.

Glioblastomas are the most common and most lethal primary brain tumor. Recent studies implicate an important role for a restricted population of neoplastic cells (glioma stem cells (GSCs)) in glioma maintenance and recurrence. We now demonstrate that GSCs preferentially express two interleukin 6 (IL6) receptors: IL6 receptor alpha (IL6R alpha) and glycoprotein 130 (gp130). Targeting IL6R alpha or IL6 ligand expression in GSCs with the use of short hairpin RNAs (shRNAs) significantly reduces growth and neurosphere formation capacity while increasing apoptosis. Perturbation of IL6 signaling in GSCs attenuates signal transducers and activators of transcription three (STAT3) activation, and small molecule inhibitors of STAT3 potently induce GSC apoptosis. These data indicate that STAT3 is a downstream mediator of prosurvival IL6 signals in GSCs. Targeting of IL6R alpha or IL6 expression in GSCs increases the survival of mice bearing intracranial human glioma xenografts. IL6 is clinically significant because elevated IL6 ligand and receptor expression are associated with poor glioma patient survival. The potential utility of anti-IL6 therapies is demonstrated by decreased growth of subcutaneous human GSC-derived xenografts treated with IL6 antibody. Together, our data indicate that IL6 signaling contributes to glioma malignancy through the promotion of GSC growth and survival, and that targeting IL6 may offer benefit for glioma patients.

Authors
Wang, H; Lathia, JD; Wu, Q; Wang, J; Li, Z; Heddleston, JM; Eyler, CE; Elderbroom, J; Gallagher, J; Schuschu, J; MacSwords, J; Cao, Y; McLendon, RE; Wang, X-F; Hjelmeland, AB; Rich, JN
MLA Citation
Wang, H, Lathia, JD, Wu, Q, Wang, J, Li, Z, Heddleston, JM, Eyler, CE, Elderbroom, J, Gallagher, J, Schuschu, J, MacSwords, J, Cao, Y, McLendon, RE, Wang, X-F, Hjelmeland, AB, and Rich, JN. "Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth." Stem Cells 27.10 (October 2009): 2393-2404.
PMID
19658188
Source
pubmed
Published In
Stem Cells
Volume
27
Issue
10
Publish Date
2009
Start Page
2393
End Page
2404
DOI
10.1002/stem.188

EGFRvIII-targeted vaccination therapy of malignant glioma.

Given the highly infiltrative growth pattern of malignant glioma and the lack of specificity associated with currently available treatment regimens, alternative strategies designed to eradicate cancer cells while limiting collateral toxicity in normal tissues remain a high priority. To this end, the development of specific immunotherapies against targeted neoplastic cells represents a promising approach. The epidermal growth factor receptor class III variant (EGFRvIII), a constitutively activated mutant of the wild-type tyrosine kinase, is present in a substantial proportion of malignant gliomas and other human cancers, yet completely absent from normal tissues. This receptor variant consists of an in-frame deletion, the translation of which produces an extracellular junction with a novel glycine residue, flanked by amino acid sequences that are not typically adjacent in the normal protein. In this review, both preclinical and early clinical development of a peptide vaccine directed against this portion of the EGFRvIII antigenic domain are recapitulated. Following vaccination, our group has demonstrated potent, redirected cellular and humoral immunity against cancer cells expressing the mutant receptor without significant toxicity. Additionally, the corresponding therapeutic outcomes observed in these studies lend credence to the potential role of peptide-based vaccination strategies among emerging antitumor immunotherapies in patients with malignant glioma.

Authors
Choi, BD; Archer, GE; Mitchell, DA; Heimberger, AB; McLendon, RE; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Archer, GE, Mitchell, DA, Heimberger, AB, McLendon, RE, Bigner, DD, and Sampson, JH. "EGFRvIII-targeted vaccination therapy of malignant glioma." Brain Pathol 19.4 (October 2009): 713-723. (Review)
PMID
19744042
Source
pubmed
Published In
Brain Pathology
Volume
19
Issue
4
Publish Date
2009
Start Page
713
End Page
723
DOI
10.1111/j.1750-3639.2009.00318.x

Robust detection of EGFR copy number changes and EGFR variant III: technical aspects and relevance for glioma diagnostics.

Epidermal growth factor receptor (EGFR) is commonly affected in cancer, generally in the form of an increase in DNA copy number and/or as mutation variants [e.g., EGFR variant III (EGFRvIII), an in-frame deletion of exons 2-7]. While detection of EGFR aberrations can be expected to be relevant for glioma patients, such analysis has not yet been implemented in a routine setting, also because feasible and robust assays were lacking. We evaluated multiplex ligation-dependent probe amplification (MLPA) for detection of EGFR amplification and EGFRvIII in DNA of a spectrum of 216 diffuse gliomas. EGFRvIII detection was verified at the protein level by immunohistochemistry and at the RNA level using the conventionally used endpoint RT-PCR as well as a newly developed quantitative RT-PCR. Compared to these techniques, the DNA-based MLPA assay for EGFR/EGFRvIII analysis tested showed 100% sensitivity and specificity. We conclude that MLPA is a robust assay for detection of EGFR/EGFRvIII aberrations. While the exact diagnostic, prognostic and predictive value of such EGFR testing remains to be seen, MLPA has great potential as it can reliably and relatively easily be performed on routinely processed (formalin-fixed, paraffin-embedded) tumor tissue in combination with testing for other relevant glioma markers.

Authors
Jeuken, J; Sijben, A; Alenda, C; Rijntjes, J; Dekkers, M; Boots-Sprenger, S; McLendon, R; Wesseling, P
MLA Citation
Jeuken, J, Sijben, A, Alenda, C, Rijntjes, J, Dekkers, M, Boots-Sprenger, S, McLendon, R, and Wesseling, P. "Robust detection of EGFR copy number changes and EGFR variant III: technical aspects and relevance for glioma diagnostics." Brain Pathol 19.4 (October 2009): 661-671.
PMID
19744038
Source
pubmed
Published In
Brain Pathology
Volume
19
Issue
4
Publish Date
2009
Start Page
661
End Page
671
DOI
10.1111/j.1750-3639.2009.00320.x

Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma.

This phase I clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG) was designed to determine the maximum tolerated dose (MTD) and toxicity of three different 5-day dosing regimens of temozolomide (TMZ) in combination with O(6)-benzylguanine (O(6)-BG). Both TMZ and O(6)-BG were administered on days 1-5 of a 28-day treatment cycle. A bolus infusion of O(6)-BG was administered at 120 mg/m(2) over 1 h on days 1, 3, and 5, along with a continuous infusion of O(6)-BG at 30 mg/m(2)/day. TMZ was administered at the end of the first bolus infusion of O(6)-BG and then every 24 h for 5 days during the continuous infusion of O(6)-BG. Patients were accrued to one of three 5-day dosing regimens of TMZ. Twenty-nine patients were enrolled into this study. The dose-limiting toxicities (DLTs) were grade 4 neutropenia, leukopenia, and thrombocytopenia. The MTD for TMZ for the three different 5-day dosing schedules was determined as follows: schedule 1, 200 mg/m(2) on day 1 and 50 mg/m(2)/day on days 2-5; schedule 2, 50 mg/m(2)/day on days 1-5; and schedule 3, 50 mg/m(2)/day on days 1-5 while receiving pegfilgrastim. Thus, the 5-day TMZ dosing schedule that maximized the total dose of TMZ when combined with O(6)-BG was schedule 1. This study provides the foundation for a phase II trial of O(6)-BG in combination with a 5-day dosing schedule of TMZ in TMZ-resistant MG.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Walker, A; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Rich, JN, Gururangan, S, Friedman, AH, Bigner, DD, Sampson, JH, McLendon, RE, Herndon, JE, Walker, A, and Friedman, HS. "Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma." Neuro Oncol 11.5 (October 2009): 556-561.
PMID
19289491
Source
pubmed
Published In
Neuro-Oncology
Volume
11
Issue
5
Publish Date
2009
Start Page
556
End Page
561
DOI
10.1215/15228517-2009-007

Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of alpha-particle-emitting (211)At-labeled trastuzumab.

INTRODUCTION: Carcinomatous meningitis (CM) is a devastating disease characterized by the dissemination of malignant tumor cells into the subarachnoid space along the brain and spine. Systemic treatment with monoclonal antibody (mAb) trastuzumab can be effective against HER2-positive systemic breast carcinoma but, like other therapies, is ineffective against CM. The goal of this study was to evaluate the therapeutic effect of alpha-particle emitting (211)At-labeled trastuzumab following intrathecal administration in a rat model of breast carcinoma CM. METHODS: Athymic rats were injected intrathecally with MCF-7/HER2-18 breast carcinoma cells through a surgically implanted indwelling intrathecal catheter. In Experiment 1, animals received 33 or 66 muCi (211)At-labeled trastuzumab, cold trastuzumab or saline. In Experiment 2, animals were inoculated with a lower tumor burden and received 46 or 92 muCi (211)At-labeled trastuzumab or saline. In Experiment 3, animals received 28 muCi (211)At-labeled trastuzumab, 30 muCi (211)At-labeled TPS3.2 control mAb or saline. Histopathological analysis of the neuroaxis was performed at the end of the study. RESULTS: In Experiment 1, median survival increased from 21 days for the saline and cold trastuzumab groups to 45 and 48 days for 33 and 66 muCi (211)At-labeled trastuzumab, respectively. In Experiment 2, median survival increased from 23 days for saline controls to 68 and 92 days for 46 and 92 muCi (211)At-labeled trastuzumab, respectively. In Experiment 3, median survival increased from 20 days to 29 and 36 days for animals treated with (211)At-labeled TPS3.2 and (211)At-labeled trastuzumab, respectively. Long-term survivors were observed exclusively in the (211)At-trastuzumab-treated groups. CONCLUSION: Intrathecal (211)At-labeled trastuzumab shows promise as a treatment for patients with HER2-positive breast CM.

Authors
Boskovitz, A; McLendon, RE; Okamura, T; Sampson, JH; Bigner, DD; Zalutsky, MR
MLA Citation
Boskovitz, A, McLendon, RE, Okamura, T, Sampson, JH, Bigner, DD, and Zalutsky, MR. "Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of alpha-particle-emitting (211)At-labeled trastuzumab." Nucl Med Biol 36.6 (August 2009): 659-669.
PMID
19647172
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
36
Issue
6
Publish Date
2009
Start Page
659
End Page
669
DOI
10.1016/j.nucmedbio.2009.04.003

Phase 1 trial of temozolomide plus irinotecan plus O6-benzylguanine in adults with recurrent malignant glioma.

BACKGROUND: The current study was a phase 1 clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG). The trial was designed to determine the maximum tolerated dose (MTD) and toxicity of irinotecan (CPT-11) when administered with temozolomide (TMZ) and O(6)-benzylguanine (O(6)-BG). METHODS: All 3 drugs, CPT-11, TMZ, and O(6)-BG, were administered on Day 1 of a 21-day treatment. First, patients were treated with a 1-hour bolus infusion of O(6)-BG at a dose of 120 mg/m(2) followed immediately by a 48-hour continuous infusion of O(6)-BG at a dose of 30 mg/m(2)/d. Second, within 60 minutes of the end of the 1-hour bolus infusion of O(6)-BG, TMZ was administered orally at a dose of 355 mg/m(2). Third, 1 hour after administration of TMZ, CPT-11 was infused over 90 minutes. Patients were accrued to 1 of 2 strata based on CYP3A1- and CYP3A4-inducing antiepileptic drug (EIAED) use; dose escalation was conducted independently within these strata. RESULTS: Fifty-five patients were enrolled. In both strata, the dose-limiting toxicities were hematologic and included grade 4 neutropenia, febrile neutropenia, leukopenia, and/or thrombocytopenia. For Stratum 1 (EIAEDs), when TMZ was administered at a dose of 355 mg/m(2), the MTD of CPT-11 was determined to be 120 mg/m(2). In contrast, for Stratum 2 (no EIAEDs), when TMZ was administered at a dose of 200 mg/m(2), the MTD of CPT-11 was determined to be 80 mg/m(2). CONCLUSIONS: The authors believe that the results of the current study provide the foundation for a phase 2 trial of O(6)-BG in combination with CPT-11 and TMZ in patients with MG.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Gururangan, S, Sampson, JH, McLendon, RE, Herndon, JE, and Friedman, HS. "Phase 1 trial of temozolomide plus irinotecan plus O6-benzylguanine in adults with recurrent malignant glioma." Cancer 115.13 (July 1, 2009): 2964-2970.
PMID
19402172
Source
pubmed
Published In
Cancer
Volume
115
Issue
13
Publish Date
2009
Start Page
2964
End Page
2970
DOI
10.1002/cncr.24336

Chordoid glioma: a case report and molecular characterization of five cases.

Chordoid gliomas are rare, slow-growing neoplasms of the anterior third ventricle. We reported a case of chordoid glioma in a 41-year-old man with obstructive hydrocephalus. Histologically, the tumor consisted of polygonal epithelioid cells admixed with elongated cells in a myxoid stroma. A prominent lymphoplasmacytic infiltrate was present. The tumor cells expressed glial fibrillary acidic protein (GFAP), epithelial membrane antigen (EMA), vimentin, CD31, CD34, epidermal growth factor receptor (EGFR) and S100 but were negative for pankeratin and E-cadherin. The percentage of Ki67 positive cells was approximately 3%. Weak p53 immunoreactivity was seen in less than 10% of the cells. Array comparative genomic hybridization performed on this case, as well as on four other archived cases, showed losses at several loci. Fluorescence in situ hybridization (FISH) confirmed consistent genetic alterations at 9p21 and 11q13. These are the fifth through ninth reported cases of chordoid gliomas with molecular characterization suggesting a distinct genetic origin from other gliomas.

Authors
Horbinski, C; Dacic, S; McLendon, RE; Cieply, K; Datto, M; Brat, DJ; Chu, CT
MLA Citation
Horbinski, C, Dacic, S, McLendon, RE, Cieply, K, Datto, M, Brat, DJ, and Chu, CT. "Chordoid glioma: a case report and molecular characterization of five cases." Brain Pathol 19.3 (July 2009): 439-448.
PMID
18652591
Source
pubmed
Published In
Brain Pathology
Volume
19
Issue
3
Publish Date
2009
Start Page
439
End Page
448
DOI
10.1111/j.1750-3639.2008.00196.x

Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells.

Glioblastomas are lethal cancers characterized by florid angiogenesis promoted in part by glioma stem cells (GSCs). Because hypoxia regulates angiogenesis, we examined hypoxic responses in GSCs. We now demonstrate that hypoxia-inducible factor HIF2alpha and multiple HIF-regulated genes are preferentially expressed in GSCs in comparison to non-stem tumor cells and normal neural progenitors. In tumor specimens, HIF2alpha colocalizes with cancer stem cell markers. Targeting HIFs in GSCs inhibits self-renewal, proliferation, and survival in vitro, and attenuates tumor initiation potential of GSCs in vivo. Analysis of a molecular database reveals that HIF2A expression correlates with poor glioma patient survival. Our results demonstrate that GSCs differentially respond to hypoxia with distinct HIF induction patterns, and HIF2alpha might represent a promising target for antiglioblastoma therapies.

Authors
Li, Z; Bao, S; Wu, Q; Wang, H; Eyler, C; Sathornsumetee, S; Shi, Q; Cao, Y; Lathia, J; McLendon, RE; Hjelmeland, AB; Rich, JN
MLA Citation
Li, Z, Bao, S, Wu, Q, Wang, H, Eyler, C, Sathornsumetee, S, Shi, Q, Cao, Y, Lathia, J, McLendon, RE, Hjelmeland, AB, and Rich, JN. "Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells." Cancer Cell 15.6 (June 2, 2009): 501-513.
PMID
19477429
Source
pubmed
Published In
Cancer Cell
Volume
15
Issue
6
Publish Date
2009
Start Page
501
End Page
513
DOI
10.1016/j.ccr.2009.03.018

RNA Transfected Dendritic Cell Vaccines Targeting Human Cytomegalovirus Antigens in Patients with Glioblastoma

Authors
Mitchell, DA; Archer, GE; Bigner, DD; Friedman, HS; Lally-Goss, D; Perry, B; II, HJE; McGehee, S; McLendon, RE; Reardon, D; Sampson, JH
MLA Citation
Mitchell, DA, Archer, GE, Bigner, DD, Friedman, HS, Lally-Goss, D, Perry, B, II, HJE, McGehee, S, McLendon, RE, Reardon, D, and Sampson, JH. "RNA Transfected Dendritic Cell Vaccines Targeting Human Cytomegalovirus Antigens in Patients with Glioblastoma." May 2009.
Source
wos-lite
Published In
Molecular Therapy
Volume
17
Publish Date
2009
Start Page
S93
End Page
S93

INDUCTION OF IMMUNOLOGIC AND CLINICAL RESPONSES WITH EGFRVIII-TARGETED VACCINE (CDX-110) WITH CYCLES OF TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED EGFRVIII-POSITIVE GBM

Authors
Archer, GE; Heimberger, AB; Bigner, DD; Davis, T; Friedman, HS; Keler, T; McLendon, RE; Mitchell, DA; Reardon, D; Sawaya, R; Vredenberg, J; Sampson, JH
MLA Citation
Archer, GE, Heimberger, AB, Bigner, DD, Davis, T, Friedman, HS, Keler, T, McLendon, RE, Mitchell, DA, Reardon, D, Sawaya, R, Vredenberg, J, and Sampson, JH. "INDUCTION OF IMMUNOLOGIC AND CLINICAL RESPONSES WITH EGFRVIII-TARGETED VACCINE (CDX-110) WITH CYCLES OF TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED EGFRVIII-POSITIVE GBM." NEURO-ONCOLOGY 11.2 (April 2009): 224-224.
Source
wos-lite
Published In
Neuro-Oncology
Volume
11
Issue
2
Publish Date
2009
Start Page
224
End Page
224

RECOMBINANT ANTIBODY-BASED MOLECULAR THERAPEUTICS FOR BRAIN TUMOR IMMUNOTHERAPY

Authors
Kuan, C-T; Wakiya, K; II, HJE; Wikstrand, CJ; McLendon, RE; Zalutsky, MR; Pastan, IH; Bigner, DD
MLA Citation
Kuan, C-T, Wakiya, K, II, HJE, Wikstrand, CJ, McLendon, RE, Zalutsky, MR, Pastan, IH, and Bigner, DD. "RECOMBINANT ANTIBODY-BASED MOLECULAR THERAPEUTICS FOR BRAIN TUMOR IMMUNOTHERAPY." NEURO-ONCOLOGY 11.2 (April 2009): 224-224.
Source
wos-lite
Published In
Neuro-Oncology
Volume
11
Issue
2
Publish Date
2009
Start Page
224
End Page
224

Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma.

PURPOSE: This phase II trial was designed to define the role of O(6)-benzylguanine (O(6)-BG) in restoring temozolomide sensitivity in patients with recurrent or progressive, temozolomide-resistant malignant glioma and to evaluate the safety of administering O(6)-BG in combination with temozolomide. PATIENTS AND METHODS: Patients were accrued into two independent strata on the basis of histology: glioblastoma multiforme (GBM) and anaplastic glioma. Both temozolomide and O(6)-BG were administered on day 1 of a 28-day treatment cycle. Patients were administered a 1-hour O(6)-BG infusion at a dose of 120 mg/m(2) followed immediately by a 48-hour infusion at a dose of 30 mg/m(2)/d. Temozolomide was administered orally within 60 minutes of the end of the 1-hour O(6)-BG infusion at a dose of 472 mg/m(2). The primary end point was objective response rate. Secondary end points included progression-free survival, overall survival, and safety. RESULTS: Sixty-six of 67 patients who enrolled were treated with temozolomide and O(6)-BG. One of 34 patients (3%) with GBM (95% CI, 0.1% to 15%) and five of 32 assessable patients (16%) with anaplastic glioma (95% CI, 5% to 33%) were responders. The most commonly reported adverse events were grade 4 hematologic events experienced in 48% of the patients. CONCLUSION: O(6)-BG when added to a 1-day dosing regimen of temozolomide was able to restore temozolomide sensitivity in patients with temozolomide-resistant anaplastic glioma, but there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant GBM.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Walker, A; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Rich, JN, Gururangan, S, Friedman, AH, Bigner, DD, Sampson, JH, McLendon, RE, Herndon, JE, Walker, A, and Friedman, HS. "Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma." J Clin Oncol 27.8 (March 10, 2009): 1262-1267.
PMID
19204199
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
8
Publish Date
2009
Start Page
1262
End Page
1267
DOI
10.1200/JCO.2008.18.8417

IDH1 and IDH2 mutations in gliomas.

BACKGROUND: A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). METHODS: We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. RESULTS: We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wild-type IDH genes. Each of four tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein. CONCLUSIONS: Mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.

Authors
Yan, H; Parsons, DW; Jin, G; McLendon, R; Rasheed, BA; Yuan, W; Kos, I; Batinic-Haberle, I; Jones, S; Riggins, GJ; Friedman, H; Friedman, A; Reardon, D; Herndon, J; Kinzler, KW; Velculescu, VE; Vogelstein, B; Bigner, DD
MLA Citation
Yan, H, Parsons, DW, Jin, G, McLendon, R, Rasheed, BA, Yuan, W, Kos, I, Batinic-Haberle, I, Jones, S, Riggins, GJ, Friedman, H, Friedman, A, Reardon, D, Herndon, J, Kinzler, KW, Velculescu, VE, Vogelstein, B, and Bigner, DD. "IDH1 and IDH2 mutations in gliomas." N Engl J Med 360.8 (February 19, 2009): 765-773.
PMID
19228619
Source
pubmed
Published In
The New England journal of medicine
Volume
360
Issue
8
Publish Date
2009
Start Page
765
End Page
773
DOI
10.1056/NEJMoa0808710

Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma.

The growth of many cancers depends on self-renewing cells called cancer stem cells or tumor-propagating cells (TPCs). In human brain tumors, cells expressing the stem cell marker CD133 have been implicated as TPCs. Here we show that tumors from a model of medulloblastoma, the Patched mutant mouse, are propagated not by CD133(+) cells but by cells expressing the progenitor markers Math1 and CD15/SSEA-1. These cells have a distinct expression profile that suggests increased proliferative capacity and decreased tendency to undergo apoptosis and differentiation. CD15 is also found in a subset of human medulloblastomas, and tumors expressing genes similar to those found in murine CD15(+) cells have a poorer prognosis. Thus, CD15 may represent an important marker for TPCs in medulloblastoma.

Authors
Read, T-A; Fogarty, MP; Markant, SL; McLendon, RE; Wei, Z; Ellison, DW; Febbo, PG; Wechsler-Reya, RJ
MLA Citation
Read, T-A, Fogarty, MP, Markant, SL, McLendon, RE, Wei, Z, Ellison, DW, Febbo, PG, and Wechsler-Reya, RJ. "Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma." Cancer Cell 15.2 (February 3, 2009): 135-147.
PMID
19185848
Source
pubmed
Published In
Cancer Cell
Volume
15
Issue
2
Publish Date
2009
Start Page
135
End Page
147
DOI
10.1016/j.ccr.2008.12.016

Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme.

PURPOSE: This phase II trial was designed to define the efficacy of Gliadel wafers in combination with an infusion of O6-benzylguanine (O6-BG) that suppresses tumor O6-alkylguanine-DNA alkyltransferase (AGT) levels in patients with recurrent glioblastoma multiforme for 5 days and to evaluate the safety of this combination therapy. EXPERIMENTAL DESIGN: This was a phase II, open-label, single center trial. On gross total resection of the tumor, up to eight Gliadel wafers were implanted. Bolus infusion of O6-BG was administered at 120 mg/m2 over 1 hour on days 1, 3, and 5, along with a continuous infusion at 30 mg/m2/d. The primary end points were 6-month overall survival (OS) and safety, and the secondary end points were 1-year, 2-year, and median OS. RESULTS: Fifty-two patients were accrued. The 6-month OS was 82% [95% confidence interval (95% CI), 72-93%]. The 1- and 2-year OS rates were 47% (95% CI, 35-63%) and 10% (95% CI, 3-32%), respectively. The median OS was 50.3 weeks (95% CI, 36.1-69.4 weeks). Treatment-related toxicity with this drug combination included grade 3 hydrocephalus (9.6%), grade 3 cerebrospinal fluid (CSF) leak (19.2%), and grade 3 CSF/brain infection (13.4%). CONCLUSION: The efficacy of implanted Gliadel wafers may be improved with the addition of O6-BG. Although systemically administered O6-BG can be coadministered with Gliadel wafers safely, it may increase the risk of hydrocephalus, CSF leak, and CSF/brain infection. Future trials are required to verify that inhibition of tumor AGT levels by O6-BG results in increased efficacy of Gliadel wafers without added toxicity.

Authors
Quinn, JA; Jiang, SX; Carter, J; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Threatt, S; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Carter, J, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Rich, JN, Gururangan, S, Friedman, AH, Bigner, DD, Sampson, JH, McLendon, RE, Herndon, JE, Threatt, S, and Friedman, HS. "Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme." Clin Cancer Res 15.3 (February 1, 2009): 1064-1068.
PMID
19188181
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
3
Publish Date
2009
Start Page
1064
End Page
1068
DOI
10.1158/1078-0432.CCR-08-2130

Few isolated neurons in hypothalamic hamartomas may cause gelastic seizures.

Hypothalamic hamartomas (HHs) are congenital, benign masses in the hypothalamus and tuber cinereum that may cause central precocious puberty and gelastic seizures. Nodules of small neurons are thought to be a universal feature of the microarchitecture of HH lesions associated with epilepsy. Here we describe the case of a 5-year-old boy with gelastic seizures who underwent resection of a HH that contained nodules of glial cells, but only few, randomly distributed neurons. HHs that contain few or no neurons have only been reported thus far in cases associated with precocious puberty. This case demonstrates that few solitary neurons in HHs can drive the development of gelastic seizures, and nodules of small neurons may not be a universal feature of HHs associated with epilepsy. This finding is clinically important since hypothalamic hamartomas with rare neurons can easily be misdiagnosed as pilocytic astrocytomas or subependymomas if their presence is overlooked. A neuronal stain is helpful in making the correct diagnosis in these cases.

Authors
Waldau, B; McLendon, RE; Fuchs, HE; George, TM; Grant, GA
MLA Citation
Waldau, B, McLendon, RE, Fuchs, HE, George, TM, and Grant, GA. "Few isolated neurons in hypothalamic hamartomas may cause gelastic seizures." Pediatr Neurosurg 45.3 (2009): 225-229.
PMID
19521137
Source
pubmed
Published In
Pediatric neurosurgery
Volume
45
Issue
3
Publish Date
2009
Start Page
225
End Page
229
DOI
10.1159/000224620

Identification of CD15 as a Marker for Tumor-Propagating Cells in a Mouse Model of Medulloblastoma (DOI:10.1016/j.ccr.2008.12.016)

Authors
Read, T-A; Fogarty, MP; Markant, SL; McLendon, RE; Wei, Z; Ellison, DW; Febbo, PG; Wechsler-Reya, RJ
MLA Citation
Read, T-A, Fogarty, MP, Markant, SL, McLendon, RE, Wei, Z, Ellison, DW, Febbo, PG, and Wechsler-Reya, RJ. "Identification of CD15 as a Marker for Tumor-Propagating Cells in a Mouse Model of Medulloblastoma (DOI:10.1016/j.ccr.2008.12.016)." Cancer Cell 16.3 (2009): 267--.
Source
scival
Published In
Cancer Cell
Volume
16
Issue
3
Publish Date
2009
Start Page
267-
DOI
10.1016/j.ccr.2009.08.009

Brain cancer stem cells display preferential sensitivity to Akt inhibition.

Malignant brain tumors are among the most lethal cancers, and conventional therapies are largely limited to palliation. Novel therapies targeted against specific molecular pathways may offer superior efficacy and less toxicity than conventional therapies, but initial clinical trials of molecular targeted agents in brain cancer therapy have been frequently disappointing. In brain tumors and other cancers, subpopulations of tumor cells have recently been characterized by their ability to self-renew and initiate tumors. Although these cancer stem cells, or tumor initiating cells, are often only present in small numbers in human tumors, mounting evidence suggests that cancer stem cells contribute to tumor maintenance and therapeutic resistance. Thus, the development of therapies that target cancer stem cell signal transduction and biology may improve brain tumor patient survival. We now demonstrate that populations enriched for cancer stem cells are preferentially sensitive to an inhibitor of Akt, a prominent cell survival and invasion signaling node. Treatment with an Akt inhibitor more potently reduced the numbers of viable brain cancer stem cells relative to matched nonstem cancer cells associated with a preferential induction of apoptosis and a suppression of neurosphere formation. Akt inhibition also reduced the motility and invasiveness of all tumor cells but had a greater impact on cancer stem cell behaviors. Furthermore, inhibition of Akt activity in cancer stem cells increased the survival of immunocompromised mice bearing human glioma xenografts in vivo. Together, these results suggest that Akt inhibitors may function as effective anticancer stem cell therapies.

Authors
Eyler, CE; Foo, WC; LaFiura, KM; McLendon, RE; Hjelmeland, AB; Rich, JN
MLA Citation
Eyler, CE, Foo, WC, LaFiura, KM, McLendon, RE, Hjelmeland, AB, and Rich, JN. "Brain cancer stem cells display preferential sensitivity to Akt inhibition." Stem cells (Dayton, Ohio) 26.12 (December 2008): 3027-3036. (Academic Article)
PMID
18802038
Source
manual
Published In
Stem Cells
Volume
26
Issue
12
Publish Date
2008
Start Page
3027
End Page
3036
DOI
10.1634/stemcells.2007-1073

A recurrent cerebellar lesion in a young boy.

Authors
Ray, GT; Agarwal, SS; McLendon, RE
MLA Citation
Ray, GT, Agarwal, SS, and McLendon, RE. "A recurrent cerebellar lesion in a young boy." Brain Pathol 18.4 (October 2008): 623-627. (Letter)
PMID
18782180
Source
pubmed
Published In
Brain Pathology
Volume
18
Issue
4
Publish Date
2008
Start Page
623
End Page
627
DOI
10.1111/j.1750-3639.2008.00216.x

Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma.

The efficacy of high-dose chemotherapy (HDC) or standard salvage therapy was evaluated in patients with recurrent medulloblastoma (MBL) using retrospective chart review of all patients with recurrent MBL treated at Duke University Medical Center between 1995 and 2005 and who had undergone HDC with or without radiotherapy (RT) or standard salvage therapy after relapse. A total of 30 patients were diagnosed with recurrent MBL after standard RT alone or chemotherapy with RT. Nineteen patients (7 who received no RT before recurrence [group A] and 12 who received definitive RT before recurrence [group B]) underwent surgery and/or induction chemotherapy followed by HDC plus autologous stem-cell rescue. Eleven patients (group C) underwent standard salvage therapy. Six of seven group A patients also received standard RT just before or after recovery from HDC, and 5 of 12 group B patients received adjuvant palliative focal RT post-HDC. At a median follow-up of 28 months, three of seven patients in group A are alive and disease-free at >or=34, >or=110, and >or=116 months, respectively, post-HDC. All patients in groups B and C have died of tumor, at a median of 35 months and 26 months from HDC and standard salvage therapy, respectively. HDC or standard salvage therapy was ineffective in our patients with recurrent MBL who had received standard RT before recurrence. The favorable impact of HDC on disease control in the two long-term survivors cannot be clearly established due to the cofounding effect of definitive RT postrecurrence.

Authors
Gururangan, S; Krauser, J; Watral, MA; Driscoll, T; Larrier, N; Reardon, DA; Rich, JN; Quinn, JA; Vredenburgh, JJ; Desjardins, A; McLendon, RE; Fuchs, H; Kurtzberg, J; Friedman, HS
MLA Citation
Gururangan, S, Krauser, J, Watral, MA, Driscoll, T, Larrier, N, Reardon, DA, Rich, JN, Quinn, JA, Vredenburgh, JJ, Desjardins, A, McLendon, RE, Fuchs, H, Kurtzberg, J, and Friedman, HS. "Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma." Neuro Oncol 10.5 (October 2008): 745-751.
PMID
18755919
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
5
Publish Date
2008
Start Page
745
End Page
751
DOI
10.1215/15228517-2008-044

An integrated genomic analysis of human glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs.

Authors
Parsons, DW; Jones, S; Zhang, X; Lin, JC-H; Leary, RJ; Angenendt, P; Mankoo, P; Carter, H; Siu, I-M; Gallia, GL; Olivi, A; McLendon, R; Rasheed, BA; Keir, S; Nikolskaya, T; Nikolsky, Y; Busam, DA; Tekleab, H; Diaz, LA; Hartigan, J; Smith, DR; Strausberg, RL; Marie, SKN; Shinjo, SMO; Yan, H; Riggins, GJ; Bigner, DD; Karchin, R; Papadopoulos, N; Parmigiani, G; Vogelstein, B; Velculescu, VE; Kinzler, KW
MLA Citation
Parsons, DW, Jones, S, Zhang, X, Lin, JC-H, Leary, RJ, Angenendt, P, Mankoo, P, Carter, H, Siu, I-M, Gallia, GL, Olivi, A, McLendon, R, Rasheed, BA, Keir, S, Nikolskaya, T, Nikolsky, Y, Busam, DA, Tekleab, H, Diaz, LA, Hartigan, J, Smith, DR, Strausberg, RL, Marie, SKN, Shinjo, SMO, Yan, H, Riggins, GJ, Bigner, DD, Karchin, R, Papadopoulos, N, Parmigiani, G, Vogelstein, B, Velculescu, VE, and Kinzler, KW. "An integrated genomic analysis of human glioblastoma multiforme." Science 321.5897 (September 26, 2008): 1807-1812.
PMID
18772396
Source
pubmed
Published In
Science
Volume
321
Issue
5897
Publish Date
2008
Start Page
1807
End Page
1812
DOI
10.1126/science.1164382

Targeting cancer stem cells through L1CAM suppresses glioma growth.

Malignant gliomas are lethal cancers that display striking cellular heterogeneity. A highly tumorigenic glioma tumor subpopulation, termed cancer stem cells or tumor-initiating cells, promotes therapeutic resistance and tumor angiogenesis. Therefore, targeting cancer stem cells may improve patient survival. We interrogated the role of a neuronal cell adhesion molecule, L1CAM, in glioma stem cells as L1CAM regulates brain development and is expressed in gliomas. L1CAM(+) and CD133(+) cells cosegregated in gliomas, and levels of L1CAM were higher in CD133(+) glioma cells than normal neural progenitors. Targeting L1CAM using lentiviral-mediated short hairpin RNA (shRNA) interference in CD133(+) glioma cells potently disrupted neurosphere formation, induced apoptosis, and inhibited growth specifically in glioma stem cells. We identified a novel mechanism for L1CAM regulation of cell survival as L1CAM knockdown decreased expression of the basic helix-loop-helix transcription factor Olig2 and up-regulated the p21(WAF1/CIP1) tumor suppressor in CD133(+) glioma cells. To determine if targeting L1CAM was sufficient to reduce glioma stem cell tumor growth in vivo, we targeted L1CAM in glioma cells before injection into immunocompromised mice or directly in established tumors. In each glioma xenograft model, shRNA targeting of L1CAM expression in vivo suppressed tumor growth and increased the survival of tumor-bearing animals. Together, these data show that L1CAM is required for maintaining the growth and survival of CD133(+) glioma cells both in vitro and in vivo, and L1CAM may represent a cancer stem cell-specific therapeutic target for improving the treatment of malignant gliomas and other brain tumors.

Authors
Bao, S; Wu, Q; Li, Z; Sathornsumetee, S; Wang, H; McLendon, RE; Hjelmeland, AB; Rich, JN
MLA Citation
Bao, S, Wu, Q, Li, Z, Sathornsumetee, S, Wang, H, McLendon, RE, Hjelmeland, AB, and Rich, JN. "Targeting cancer stem cells through L1CAM suppresses glioma growth." Cancer Res 68.15 (August 1, 2008): 6043-6048.
PMID
18676824
Source
pubmed
Published In
Cancer Research
Volume
68
Issue
15
Publish Date
2008
Start Page
6043
End Page
6048
DOI
10.1158/0008-5472.CAN-08-1079

Mismatch repair deficiency does not mediate clinical resistance to temozolomide in malignant glioma.

PURPOSE: A major mechanism of resistance to methylating agents, including temozolomide, is the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT). Preclinical data indicates that defective DNA mismatch repair (MMR) results in tolerance to temozolomide regardless of AGT activity. The purpose of this study was to determine the role of MMR deficiency in mediating resistance in samples from patients with both newly diagnosed malignant gliomas and those who have failed temozolomide therapy. EXPERIMENTAL DESIGN: The roles of AGT and MMR deficiency in mediating resistance in glioblastoma multiforme were assessed by immunohistochemistry and microsatellite instability (MSI), respectively. The mutation status of the MSH6 gene, a proposed correlate of temozolomide resistance, was determined by direct sequencing and compared with data from immunofluorescent detection of MSH6 protein and reverse transcription-PCR amplification of MSH6 RNA. RESULTS: Seventy percent of newly diagnosed and 78% of failed-therapy glioblastoma multiforme samples expressed nuclear AGT protein in > or = 20% of cells analyzed, suggesting alternate means of resistance in 20% to 30% of cases. Single loci MSI was observed in 3% of patient samples; no sample showed the presence of high MSI. MSI was not shown to correlate with MSH6 mutation or loss of MSH6 protein expression. CONCLUSIONS: Although high AGT levels may mediate resistance in a portion of these samples, MMR deficiency does not seem to be responsible for mediating temozolomide resistance in adult malignant glioma. Accordingly, the presence of a fraction of samples exhibiting both low AGT expression and MMR proficiency suggests that additional mechanisms of temozolomide resistance are operational in the clinic.

Authors
Maxwell, JA; Johnson, SP; McLendon, RE; Lister, DW; Horne, KS; Rasheed, A; Quinn, JA; Ali-Osman, F; Friedman, AH; Modrich, PL; Bigner, DD; Friedman, HS
MLA Citation
Maxwell, JA, Johnson, SP, McLendon, RE, Lister, DW, Horne, KS, Rasheed, A, Quinn, JA, Ali-Osman, F, Friedman, AH, Modrich, PL, Bigner, DD, and Friedman, HS. "Mismatch repair deficiency does not mediate clinical resistance to temozolomide in malignant glioma." Clin Cancer Res 14.15 (August 1, 2008): 4859-4868.
PMID
18676759
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
15
Publish Date
2008
Start Page
4859
End Page
4868
DOI
10.1158/1078-0432.CCR-07-4807

Re: Axonal injury in head injuries with very short survival.

Authors
McLendon, RE
MLA Citation
McLendon, RE. "Re: Axonal injury in head injuries with very short survival." Neuropathol Appl Neurobiol 34.3 (June 2008): 371-. (Letter)
PMID
18363642
Source
pubmed
Published In
Neuropathology & Applied Neurobiology
Volume
34
Issue
3
Publish Date
2008
Start Page
371
DOI
10.1111/j.1365-2990.2008.00942.x

Surgical neuropathology update: a review of changes introduced by the WHO classification of tumours of the central nervous system, 4th edition.

CONTEXT: The World Health Organization (WHO) recently published its 4th edition of the classification of tumors of the central nervous system, incorporating a substantial number of important changes to the previous version (WHO 2000). The new WHO classification introduces 7 changes in the grading of central nervous system neoplasms, ranging in significance from minor to major, in categories of anaplastic oligoastrocytomas, meningiomas, choroid plexus tumors, pineal parenchymal tumors, ganglioglioma, cerebellar liponeurocytoma, and hemangiopericytomas. The 4th edition also introduces 10 newly codified entities, variants, and patterns, as well as 1 new genetic syndrome. A number of established brain tumors are reorganized, including medulloblastomas and primitive neuroectodermal tumors, in an attempt to more closely align classification with current understanding of central nervous system neoplasia. OBJECTIVE: To summarize and discuss the most significant updates in the 4th edition for the practicing surgical pathologist, including (1) changes in grading among established entities; (2) newly codified tumor entities, variants, patterns, and syndromes; and (3) changes in the classification of existing brain tumors. DATA SOURCES: The primary source for this review is the WHO Classification of Tumours of the Central Nervous System, 4th edition. Other important sources include the 3rd edition of this book and the primary literature that supported changes in the 4th edition. CONCLUSIONS: The new edition of the WHO blue book reflects advancements in the understanding of brain tumors in terms of classification, grading, and new entities. The changes introduced are substantial and will have an impact on the practice of general surgical pathologists and neuropathologists.

Authors
Brat, DJ; Parisi, JE; Kleinschmidt-DeMasters, BK; Yachnis, AT; Montine, TJ; Boyer, PJ; Powell, SZ; Prayson, RA; McLendon, RE; Neuropathology Committee, College of American Pathologists,
MLA Citation
Brat, DJ, Parisi, JE, Kleinschmidt-DeMasters, BK, Yachnis, AT, Montine, TJ, Boyer, PJ, Powell, SZ, Prayson, RA, McLendon, RE, Neuropathology Committee, and College of American Pathologists, . "Surgical neuropathology update: a review of changes introduced by the WHO classification of tumours of the central nervous system, 4th edition." Arch Pathol Lab Med 132.6 (June 2008): 993-1007. (Review)
PMID
18517285
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
132
Issue
6
Publish Date
2008
Start Page
993
End Page
1007
DOI
10.1043/1543-2165(2008)132[993:SNUARO]2.0.CO;2

Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors.

The purpose of this study is to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intracerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intracerebral infusion technique of convection-enhanced delivery (CED). Twenty patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last eight patients, coinfusion of (123)I-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the coinfused (123)I-albumin. Two DLTs were seen, and both were neurologic. Median survival after TP-38 was 28 weeks (95% confidence interval, 26.5-102.8). Of 15 patients treated with residual disease, two (13.3%) demonstrated radiographic responses, including one patient with glioblastoma multiforme who had a nearly complete response and remains alive >260 weeks after therapy. Coinfusion of (123)I-albumin demonstrated that high concentrations of the infusate could be delivered >4 cm from the catheter tip. However, only 3 of 16 (19%) catheters produced intraparenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intracerebral CED of TP-38 was well tolerated and produced some durable radiographic responses at doses

Authors
Sampson, JH; Akabani, G; Archer, GE; Berger, MS; Coleman, RE; Friedman, AH; Friedman, HS; Greer, K; Herndon, JE; Kunwar, S; McLendon, RE; Paolino, A; Petry, NA; Provenzale, JM; Reardon, DA; Wong, TZ; Zalutsky, MR; Pastan, I; Bigner, DD
MLA Citation
Sampson, JH, Akabani, G, Archer, GE, Berger, MS, Coleman, RE, Friedman, AH, Friedman, HS, Greer, K, Herndon, JE, Kunwar, S, McLendon, RE, Paolino, A, Petry, NA, Provenzale, JM, Reardon, DA, Wong, TZ, Zalutsky, MR, Pastan, I, and Bigner, DD. "Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors." Neuro Oncol 10.3 (June 2008): 320-329.
PMID
18403491
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
3
Publish Date
2008
Start Page
320
End Page
329
DOI
10.1215/15228517-2008-012

Protocol for the examination of specimens from patients with tumors of the brain/spinal cord.

Authors
Parisi, JE; Miller, DV; Boyer, PJ; Brat, DJ; Cochran, EJ; Cohen, ML; Demasters, BK; Dolinak, D; McComb, RD; McLendon, RE; Powell, SZ; Prayson, RA; Vinters, HV; Yachnis, AT; Members of Cancer Committee, College of American Pathologists,
MLA Citation
Parisi, JE, Miller, DV, Boyer, PJ, Brat, DJ, Cochran, EJ, Cohen, ML, Demasters, BK, Dolinak, D, McComb, RD, McLendon, RE, Powell, SZ, Prayson, RA, Vinters, HV, Yachnis, AT, Members of Cancer Committee, and College of American Pathologists, . "Protocol for the examination of specimens from patients with tumors of the brain/spinal cord." Arch Pathol Lab Med 132.6 (June 2008): 907-912.
PMID
18517271
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
132
Issue
6
Publish Date
2008
Start Page
907
End Page
912
DOI
10.1043/1543-2165(2008)132[907:PFTEOS]2.0.CO;2

Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: phase 1 trial in adults with malignant glioma.

We determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of imatinib mesylate, an inhibitor of the receptor tyrosine kinases platelet-derived growth factor receptor (PDGFR), the proto-oncogene product c-kit, and the fusion protein Bcr-Abl, when administered for 8 days in combination with temozolomide (TMZ) to malignant glioma (MG) patients. MG patients who had not failed prior TMZ were eligible to receive TMZ at a dose of 150-200 mg/m(2) per day on days 4-8 plus imatinib mesylate administered orally on days 1-8 of each 4-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing antiepileptic drugs (EIAEDs). The imatinib dose was escalated in successive cohorts of patients independently for each stratum. Imatinib, at doses ranging from 400 mg to 1,200 mg, was administered with TMZ to 65 patients: 52 (80%) with glioblastoma multiforme (GBM) and 13 (20%) with grade III MG. At enrollment, 34 patients (52%) had stable disease, and 33 (48%) had progressive disease; 30 patients (46%) were on EIAEDs. The MTD of imatinib for patients concurrently receiving or not receiving EIAEDs was 1,000 mg. DLTs were hematologic, gastrointestinal, renal, and hepatic. Pharmacokinetic analyses revealed lowered exposures and enhanced clearance among patients on EIAEDs. Among GBM patients with stable disease at enrollment (n=28), the median progression-free and overall survival times were 41.7 and 56.1 weeks, respectively. Imatinib doses up to 1,000 mg/day for 8 consecutive days are well tolerated when combined with standard TMZ dosing for MG patients. A subsequent phase 2 study is required to further evaluate the efficacy of this regimen for this patient population.

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Sathornsumetee, S; Rich, JN; Quinn, JA; Lagattuta, TF; Egorin, MJ; Gururangan, S; McLendon, R; Herndon, JE; Friedman, AH; Salvado, AJ; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Vredenburgh, JJ, Sathornsumetee, S, Rich, JN, Quinn, JA, Lagattuta, TF, Egorin, MJ, Gururangan, S, McLendon, R, Herndon, JE, Friedman, AH, Salvado, AJ, and Friedman, HS. "Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: phase 1 trial in adults with malignant glioma." Neuro Oncol 10.3 (June 2008): 330-340.
PMID
18359865
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
3
Publish Date
2008
Start Page
330
End Page
340
DOI
10.1215/15228517-2008-003

A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost.

The purpose of this study was to determine the feasibility and assess the efficacy and toxicity, among newly diagnosed malignant glioma patients, of administering (131)I-labeled murine antitenascin monoclonal antibody 81C6 ((131)I-81C6) into a surgically created resection cavity (SCRC) to achieve a patient-specific, 44-Gy boost to the 2-cm SCRC margin. A radioactivity dose of (131)I-81C6 calculated to achieve a 44-Gy boost to the SCRC was administered, followed by conventional external beam radiotherapy (XRT) and chemotherapy. Twenty-one patients were enrolled in the study: 16 with glioblastoma multiforme (GBM) and 5 with anaplastic astrocytoma. Twenty patients received the targeted 44-Gy boost (+/-10%) to the SCRC. Attributable toxicity was mild and limited to reversible grade 3 neutropenia or thrombocytopenia (n = 3; 14%), CNS wound infections (n = 3; 14%), and headache (n = 2; 10%). With a median follow-up of 151 weeks, median overall survival times for all patients and those with GBM are 96.6 and 90.6 weeks, respectively; 87% of GBM patients are alive at 1 year. It is feasible to consistently achieve a 44-Gy boost dose to the SCRC margin with patient-specific dosing of (131)I-81C6. Our study regimen ((131)I-81C6 + XRT + temozolomide) was well tolerated and had encouraging survival. To determine if selection of good-prognosis patients affects outcome associated with this approach, the U.S. Food and Drug Administration has approved a trial randomizing newly diagnosed GBM patients to either our study regimen or standard XRT plus temozolomide.

Authors
Reardon, DA; Zalutsky, MR; Akabani, G; Coleman, RE; Friedman, AH; Herndon, JE; McLendon, RE; Pegram, CN; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Guruangan, S; Boulton, S; Raynor, RH; Dowell, JM; Wong, TZ; Zhao, X-G; Friedman, HS; Bigner, DD
MLA Citation
Reardon, DA, Zalutsky, MR, Akabani, G, Coleman, RE, Friedman, AH, Herndon, JE, McLendon, RE, Pegram, CN, Quinn, JA, Rich, JN, Vredenburgh, JJ, Desjardins, A, Guruangan, S, Boulton, S, Raynor, RH, Dowell, JM, Wong, TZ, Zhao, X-G, Friedman, HS, and Bigner, DD. "A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost." Neuro Oncol 10.2 (April 2008): 182-189.
PMID
18287339
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
2
Publish Date
2008
Start Page
182
End Page
189
DOI
10.1215/15228517-2007-053

Issues of diagnostic review in brain tumor studies: from the Brain Tumor Epidemiology Consortium.

Epidemiologists routinely conduct centralized single pathology reviews to minimize interobserver diagnostic variability, but this practice does not facilitate the combination of studies across geographic regions and institutions where diagnostic practices differ. A meeting of neuropathologists and epidemiologists focused on brain tumor classification issues in the context of protocol needs for consortial studies (http://epi.grants.cancer.gov/btec/). It resulted in recommendations relevant to brain tumors and possibly other rare disease studies. Two categories of brain tumors have enough general agreement over time, across regions, and between individual pathologists that one can consider using existing diagnostic data without further review: glioblastomas and meningiomas (as long as uniform guidelines such as those provided by the WHO are used). Prospective studies of these tumors benefit from collection of pathology reports, at a minimum recording the pathology department and classification system used in the diagnosis. Other brain tumors, such as oligodendroglioma, are less distinct and require careful histopathologic review for consistent classification across study centers. Epidemiologic study protocols must consider the study specific aims, diagnostic changes that have taken place over time, and other issues unique to the type(s) of tumor being studied. As diagnostic changes are being made rapidly, there are no readily available answers on disease classification issues. It is essential that epidemiologists and neuropathologists collaborate to develop appropriate study designs and protocols for specific hypothesis and populations.

Authors
Davis, FG; Malmer, BS; Aldape, K; Barnholtz-Sloan, JS; Bondy, ML; Brännström, T; Bruner, JM; Burger, PC; Collins, VP; Inskip, PD; Kruchko, C; McCarthy, BJ; McLendon, RE; Sadetzki, S; Tihan, T; Wrensch, MR; Buffler, PA
MLA Citation
Davis, FG, Malmer, BS, Aldape, K, Barnholtz-Sloan, JS, Bondy, ML, Brännström, T, Bruner, JM, Burger, PC, Collins, VP, Inskip, PD, Kruchko, C, McCarthy, BJ, McLendon, RE, Sadetzki, S, Tihan, T, Wrensch, MR, and Buffler, PA. "Issues of diagnostic review in brain tumor studies: from the Brain Tumor Epidemiology Consortium." Cancer Epidemiol Biomarkers Prev 17.3 (March 2008): 484-489.
PMID
18349266
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
17
Issue
3
Publish Date
2008
Start Page
484
End Page
489
DOI
10.1158/1055-9965.EPI-07-0725

MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy.

Authors
Kovacs, K; Scheithauer, BW; Lombardero, M; McLendon, RE; Syro, LV; Uribe, H; Ortiz, LD; Penagos, LC
MLA Citation
Kovacs, K, Scheithauer, BW, Lombardero, M, McLendon, RE, Syro, LV, Uribe, H, Ortiz, LD, and Penagos, LC. "MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy." Acta Neuropathol 115.2 (February 2008): 261-262. (Letter)
PMID
17926052
Source
pubmed
Published In
Acta Neuropathologica
Volume
115
Issue
2
Publish Date
2008
Start Page
261
End Page
262
DOI
10.1007/s00401-007-0279-5

Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma.

Human cytomegalovirus (HCMV) has been described to be associated with several human malignancies, though the frequency of detection remains controversial. It is unclear whether HCMV plays an active role in malignant tumor progression or becomes reactivated under pathologic conditions that result in chronic inflammation or immunosuppression. In this study, we report on the investigation of detecting HCMV in the tumors and peripheral blood of patients with newly diagnosed glioblastoma multiforme (GBM). Using immunohistochemistry, in situ hybridization, and polymerase chain reaction amplification of viral DNA, the detection of HCMV was investigated in tumor and blood specimens from patients with GBM as well as in the peripheral blood of normal volunteers and patients undergoing craniotomy for diagnoses other than GBM. We found that a high percentage (>90%) of GBM tumors, not surrounding normal brain, are associated with HCMV nucleic acids and proteins. Furthermore, a significant proportion of patients (80%) with newly diagnosed GBM have detectable HCMV DNA in their peripheral blood, while sero-positive normal donors and other surgical patients did not exhibit detectable virus, suggesting either a systemic reactivation of HCMV within patients with GBM or shedding of viral DNA from infected tumor cells into the periphery. These results confirm the association of HCMV with malignant gliomas and demonstrate that subclinical HCMV viremia (presence of viral DNA in blood without clinical symptoms of infection) is a previously unrecognized disease spectrum in patients with GBM.

Authors
Mitchell, DA; Xie, W; Schmittling, R; Learn, C; Friedman, A; McLendon, RE; Sampson, JH
MLA Citation
Mitchell, DA, Xie, W, Schmittling, R, Learn, C, Friedman, A, McLendon, RE, and Sampson, JH. "Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma." Neuro Oncol 10.1 (February 2008): 10-18.
PMID
17951512
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
1
Publish Date
2008
Start Page
10
End Page
18
DOI
10.1215/15228517-2007-035

Utility of EGFR and PTEN numerical aberrations in the evaluation of diffusely infiltrating astrocytomas. Laboratory investigation.

OBJECT: Diffusely infiltrating astrocytomas are the most common primary brain tumors. As a group, they demonstrate an inherent tendency toward malignant progression. Histological grading using the guidelines of the World Health Organization (WHO) remains the gold standard for predicting the biological behavior of these tumors. Although useful, this grading system is often limited due to small sample sizes and the subjectivity in interpretation. Given the important roles for EGFR and PTEN in the malignant progression of astrocytomas, the authors hypothesized that the fraction of tumor cells with aberrations in these genetic loci would correlate with the histological grade. METHODS: The authors evaluated 217 consecutive diffusely infiltrating astrocytomas that were graded using the WHO guidelines, including 16 diffuse astrocytomas (WHO Grade II), 72 anaplastic astrocytomas ([AAs] WHO Grade III), and 129 glioblastomas multiforme ([GBMs] WHO Grade IV). Cases were evaluated quantitatively using dual-color fluorescence in situ hybridization with probes for the EGFR and PTEN loci and the centromeres of chromosomes 7 and 10. RESULTS: The population of tumor cells with polysomy of chromosome 7 and the EGFR locus and monosomy of chromosome 10 and the PTEN locus correlated significantly with histological grade. In particular, high-grade astrocytomas (that is, AAs and GBMs) had elevated fractions of tumor cells with polysomy of chromosome 7 and the EGFR locus and monosomy of chromosome 10 and the PTEN locus. Using these findings, the authors generated a mathematical model capable of subcategorizing high-grade astrocytomas. The successful model incorporated only the percentage of tumor cells with polysomy of EGFR and monosomy of PTEN, as well as patient age. The predictions of this model correlated with survival in a manner similar to histopathological grading. CONCLUSIONS: The findings presented in this study emphasize the utility of combining histological interpretation and molecular testing in the evaluation of infiltrating astrocytomas. These results underscore the utility of building a grading framework that combines histopathological and molecular analysis.

Authors
Mott, RT; Turner, KC; Bigner, DD; McLendon, RE
MLA Citation
Mott, RT, Turner, KC, Bigner, DD, and McLendon, RE. "Utility of EGFR and PTEN numerical aberrations in the evaluation of diffusely infiltrating astrocytomas. Laboratory investigation." J Neurosurg 108.2 (February 2008): 330-335.
PMID
18240930
Source
pubmed
Published In
Journal of neurosurgery
Volume
108
Issue
2
Publish Date
2008
Start Page
330
End Page
335
DOI
10.3171/JNS/2008/108/2/0330

Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan.

PURPOSE: The combination of a vascular endothelial growth factor (VEGF) -neutralizing antibody, bevacizumab, and irinotecan is associated with high radiographic response rates and improved survival outcomes in patients with recurrent malignant gliomas. The aim of these retrospective studies was to evaluate tumor vascularity and expression of components of the VEGF pathway and hypoxic responses as predictive markers for radiographic response and survival benefit from the bevacizumab and irinotecan therapy. PATIENTS AND METHODS: In a phase II trial, 60 patients with recurrent malignant astrocytomas were treated with bevacizumab and irinotecan. Tumor specimens collected at the time of diagnosis were available for further pathologic studies in 45 patients (75%). VEGF, VEGF receptor-2, CD31, hypoxia-inducible carbonic anhydrase 9 (CA9), and hypoxia-inducible factor-2alpha were semiquantitatively assessed by immunohistochemistry. Radiographic response and survival outcomes were correlated with these angiogenic and hypoxic markers. RESULTS: Of 45 patients, 27 patients had glioblastoma multiforme, and 18 patients had anaplastic astrocytoma. Twenty-six patients (58%) had at least partial radiographic response. High VEGF expression was associated with increased likelihood of radiographic response (P = .024) but not survival benefit. Survival analysis revealed that high CA9 expression was associated with poor survival outcome (P = .016). CONCLUSION: In this patient cohort, tumor expression levels of VEGF, the molecular target of bevacizumab, were associated with radiographic response, and the upstream promoter of angiogenesis, hypoxia, determined survival outcome, as measured from treatment initiation. Validation in a larger clinical trial is warranted.

Authors
Sathornsumetee, S; Cao, Y; Marcello, JE; Herndon, JE; McLendon, RE; Desjardins, A; Friedman, HS; Dewhirst, MW; Vredenburgh, JJ; Rich, JN
MLA Citation
Sathornsumetee, S, Cao, Y, Marcello, JE, Herndon, JE, McLendon, RE, Desjardins, A, Friedman, HS, Dewhirst, MW, Vredenburgh, JJ, and Rich, JN. "Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan." J Clin Oncol 26.2 (January 10, 2008): 271-278.
PMID
18182667
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
2
Publish Date
2008
Start Page
271
End Page
278
DOI
10.1200/JCO.2007.13.3652

Clinical experience with alpha-particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6.

UNLABELLED: alpha-Particle-emitting radionuclides, such as (211)At, with a 7.2-h half-life, may be optimally suited for the molecularly targeted radiotherapy of strategically sensitive tumor sites, such as those in the central nervous system. Because of the much shorter range and more potent cytotoxicity of alpha-particles than of beta-particles, (211)At-labeled agents may be ideal for the eradication of tumor cells remaining after surgical debulking of malignant brain tumors. The main goal of this study was to investigate the feasibility and safety of this approach in patients with recurrent malignant brain tumors. METHODS: Chimeric antitenascin monoclonal antibody 81C6 (ch81C6) (10 mg) was labeled with 71-347 MBq of (211)At by use of N-succinimidyl 3-[(211)At]astatobenzoate. Eighteen patients were treated with (211)At-labeled ch81C6 ((211)At-ch81C6) administered into a surgically created resection cavity (SCRC) and then with salvage chemotherapy. Serial gamma-camera imaging and blood sampling over 24 h were performed. RESULTS: A total of 96.7% +/- 3.6% (mean +/- SD) of (211)At decays occurred in the SCRC, and the mean blood-pool percentage injected dose was < or = 0.3. No patient experienced dose-limiting toxicity, and the maximum tolerated dose was not identified. Six patients experienced grade 2 neurotoxicity within 6 wk of (211)At-ch81C6 administration; this neurotoxicity resolved fully in all but 1 patient. No toxicities of grade 3 or higher were attributable to the treatment. No patient required repeat surgery for radionecrosis. The median survival times for all patients, those with glioblastoma multiforme, and those with anaplastic astrocytoma or oligodendroglioma were 54, 52, and 116 wk, respectively. CONCLUSION: This study provides proof of concept for regional targeted radiotherapy with (211)At-labeled molecules in oncology. Specifically, the regional administration of (211)At-ch81C6 is feasible, safe, and associated with a promising antitumor benefit in patients with malignant central nervous system tumors.

Authors
Zalutsky, MR; Reardon, DA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; McLendon, RE; Wong, TZ; Bigner, DD
MLA Citation
Zalutsky, MR, Reardon, DA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, McLendon, RE, Wong, TZ, and Bigner, DD. "Clinical experience with alpha-particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6." J Nucl Med 49.1 (January 2008): 30-38.
PMID
18077533
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
49
Issue
1
Publish Date
2008
Start Page
30
End Page
38
DOI
10.2967/jnumed.107.046938

Choroid plexus papilloma with neuropil-like islands.

Choroid plexus papilloma may display unusual histologic features, but the presence of neuronal differentiation at the light microscopic level has not yet been described. We thus report a choroid plexus papilloma with neuropil-like islands located within the lateral ventricle of an 11-year-old girl. The absence of atypical histologic features associated with recurrence (particularly increased mitotic activity) and recurrence-free follow-up upon gross total resection are compatible with a diagnosis of choroid plexus papilloma (WHO grade I). This case further emphasizes the capacity of choroid plexus tumor cells toward neuronal differentiation, and expands the spectrum of tumors, which may contain neuropil-like islands.

Authors
Hasselblatt, M; Jeibmann, A; Guerry, M; Senner, V; Paulus, W; McLendon, RE
MLA Citation
Hasselblatt, M, Jeibmann, A, Guerry, M, Senner, V, Paulus, W, and McLendon, RE. "Choroid plexus papilloma with neuropil-like islands." Am J Surg Pathol 32.1 (January 2008): 162-166.
PMID
18162784
Source
pubmed
Published In
American Journal of Surgical Pathology
Volume
32
Issue
1
Publish Date
2008
Start Page
162
End Page
166
DOI
10.1097/PAS.0b013e3180cc2015

Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats.

Splenda is comprised of the high-potency artificial sweetener sucralose (1.1%) and the fillers maltodextrin and glucose. Splenda was administered by oral gavage at 100, 300, 500, or 1000 mg/kg to male Sprague-Dawley rats for 12-wk, during which fecal samples were collected weekly for bacterial analysis and measurement of fecal pH. After 12-wk, half of the animals from each treatment group were sacrificed to determine the intestinal expression of the membrane efflux transporter P-glycoprotein (P-gp) and the cytochrome P-450 (CYP) metabolism system by Western blot. The remaining animals were allowed to recover for an additional 12-wk, and further assessments of fecal microflora, fecal pH, and expression of P-gp and CYP were determined. At the end of the 12-wk treatment period, the numbers of total anaerobes, bifidobacteria, lactobacilli, Bacteroides, clostridia, and total aerobic bacteria were significantly decreased; however, there was no significant treatment effect on enterobacteria. Splenda also increased fecal pH and enhanced the expression of P-gp by 2.43-fold, CYP3A4 by 2.51-fold, and CYP2D1 by 3.49-fold. Following the 12-wk recovery period, only the total anaerobes and bifidobacteria remained significantly depressed, whereas pH values, P-gp, and CYP3A4 and CYP2D1 remained elevated. These changes occurred at Splenda dosages that contained sucralose at 1.1-11 mg/kg (the US FDA Acceptable Daily Intake for sucralose is 5 mg/kg). Evidence indicates that a 12-wk administration of Splenda exerted numerous adverse effects, including (1) reduction in beneficial fecal microflora, (2) increased fecal pH, and (3) enhanced expression levels of P-gp, CYP3A4, and CYP2D1, which are known to limit the bioavailability of orally administered drugs.

Authors
Abou-Donia, MB; El-Masry, EM; Abdel-Rahman, AA; McLendon, RE; Schiffman, SS
MLA Citation
Abou-Donia, MB, El-Masry, EM, Abdel-Rahman, AA, McLendon, RE, and Schiffman, SS. "Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats." J Toxicol Environ Health A 71.21 (2008): 1415-1429.
PMID
18800291
Source
pubmed
Published In
Journal of Toxicology & Environmental Health: Part A
Volume
71
Issue
21
Publish Date
2008
Start Page
1415
End Page
1429
DOI
10.1080/15287390802328630

c-Myc is required for maintenance of glioma cancer stem cells.

BACKGROUND: Malignant gliomas rank among the most lethal cancers. Gliomas display a striking cellular heterogeneity with a hierarchy of differentiation states. Recent studies support the existence of cancer stem cells in gliomas that are functionally defined by their capacity for extensive self-renewal and formation of secondary tumors that phenocopy the original tumors. As the c-Myc oncoprotein has recognized roles in normal stem cell biology, we hypothesized that c-Myc may contribute to cancer stem cell biology as these cells share characteristics with normal stem cells. METHODOLOGY/PRINCIPAL FINDINGS: Based on previous methods that we and others have employed, tumor cell populations were enriched or depleted for cancer stem cells using the stem cell marker CD133 (Prominin-1). We characterized c-Myc expression in matched tumor cell populations using real time PCR, immunoblotting, immunofluorescence and flow cytometry. Here we report that c-Myc is highly expressed in glioma cancer stem cells relative to non-stem glioma cells. To interrogate the significance of c-Myc expression in glioma cancer stem cells, we targeted its expression using lentivirally transduced short hairpin RNA (shRNA). Knockdown of c-Myc in glioma cancer stem cells reduced proliferation with concomitant cell cycle arrest in the G(0)/G(1) phase and increased apoptosis. Non-stem glioma cells displayed limited dependence on c-Myc expression for survival and proliferation. Further, glioma cancer stem cells with decreased c-Myc levels failed to form neurospheres in vitro or tumors when xenotransplanted into the brains of immunocompromised mice. CONCLUSIONS/SIGNIFICANCE: These findings support a central role of c-Myc in regulating proliferation and survival of glioma cancer stem cells. Targeting core stem cell pathways may offer improved therapeutic approaches for advanced cancers.

Authors
Wang, J; Wang, H; Li, Z; Wu, Q; Lathia, JD; McLendon, RE; Hjelmeland, AB; Rich, JN
MLA Citation
Wang, J, Wang, H, Li, Z, Wu, Q, Lathia, JD, McLendon, RE, Hjelmeland, AB, and Rich, JN. "c-Myc is required for maintenance of glioma cancer stem cells." PLoS One 3.11 (2008): e3769-.
Website
http://hdl.handle.net/10161/4507
PMID
19020659
Source
pubmed
Published In
PloS one
Volume
3
Issue
11
Publish Date
2008
Start Page
e3769
DOI
10.1371/journal.pone.0003769

Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer. ©2008 Macmillan Publishers Limited. All rights reserved.

Authors
McLendon, R; Friedman, A; Bigner, D; Meir, EGV; Brat, DJ; Mastrogianakis, GM; Olson, JJ; Mikkelsen, T; Lehman, N; Aldape, K; Yung, WKA; Bogler, O; Weinstein, JN; VandenBerg, S; Berger, M; Prados, M; Muzny, D; Morgan, M; Scherer, S; Sabo, A; Nazareth, L; Lewis, L; Hall, O; Zhu, Y; Ren, Y; Alvi, O; Yao, J; Hawes, A; Jhangiani, S; Fowler, G; Lucas, AS; Kovar, C; Cree, A; Dinh, H; Santibanez, J; Joshi, V; Gonzalez-Garay, ML; Miller, CA; Milosavljevic, A; Donehower, L; Wheeler, DA; Gibbs, RA et al.
MLA Citation
McLendon, R, Friedman, A, Bigner, D, Meir, EGV, Brat, DJ, Mastrogianakis, GM, Olson, JJ, Mikkelsen, T, Lehman, N, Aldape, K, Yung, WKA, Bogler, O, Weinstein, JN, VandenBerg, S, Berger, M, Prados, M, Muzny, D, Morgan, M, Scherer, S, Sabo, A, Nazareth, L, Lewis, L, Hall, O, Zhu, Y, Ren, Y, Alvi, O, Yao, J, Hawes, A, Jhangiani, S, Fowler, G, Lucas, AS, Kovar, C, Cree, A, Dinh, H, Santibanez, J, Joshi, V, Gonzalez-Garay, ML, Miller, CA, Milosavljevic, A, Donehower, L, Wheeler, DA, and Gibbs, RA et al. "Comprehensive genomic characterization defines human glioblastoma genes and core pathways." Nature 455.7216 (2008): 1061-1068.
PMID
18772890
Source
scival
Published In
Nature
Volume
455
Issue
7216
Publish Date
2008
Start Page
1061
End Page
1068
DOI
10.1038/nature07385

Second messenger systems in human gliomas.

CONTEXT: Patients with glioblastoma (astrocytoma, World Health Organization grade IV) exhibit 2-year survival rates of less than 20% despite significant advances in therapeutic options available to patients. Epidermal growth factor receptor (EGFR) hyperexpression is one of the most commonly encountered abnormalities in this tumor. However, EGFR expression, amplification, and mutations are poorly predictive of patient survival. Investigators have taken to exploiting the sensitivities of activated downstream targets in the EGFR second messenger pathways to certain inhibitory drugs to downregulate their neoplastic messages promoting cell growth and inhibiting cell death. OBJECTIVE: It is important to both gain some understanding of the functional significance of these pathways and to understand the role the pathologist might play in characterizing the activation status of certain downstream messenger proteins that are targeted in these brain tumor therapies. We have reviewed the literature regarding histologic assays that have been incorporated into trials of these new drugs and report on the methods used to study these proteins and the conclusions of these studies. DATA SOURCES: Literature review and primary material from Duke University (Durham, NC) Department of Pathology archives. CONCLUSIONS: To date, drug trial reports indicate that identification of the presence of the EGFR variant, EGFRvIII, and measurement of the activated downstream targets, phospho-Akt, phospho-S6, and phospho-MAPK, may be useful in predicting sensitivity to some of the EGFR kinase inhibitors. No studies to date have identified prognostic significance related to immunoreactivity status among any of these markers that is independent of histologic grade.

Authors
McLendon, RE; Turner, K; Perkinson, K; Rich, J
MLA Citation
McLendon, RE, Turner, K, Perkinson, K, and Rich, J. "Second messenger systems in human gliomas." Arch Pathol Lab Med 131.10 (October 2007): 1585-1590. (Review)
PMID
17922598
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
131
Issue
10
Publish Date
2007
Start Page
1585
End Page
1590
DOI
10.1043/1543-2165(2007)131[1585:SMSIHG]2.0.CO;2

Targeting methylguanine-DNA methyltransferase in the treatment of neuroblastoma.

PURPOSE: The combination of temozolomide and irinotecan has preclinical schedule-dependent synergy against neuroblastoma but is not curative for relapsed high-risk patients. We hypothesized that the DNA repair protein methylguanine-DNA methyltransferase (MGMT) is an important resistance factor, and that inactivation of MGMT would sensitize neuroblastoma cells to these agents. EXPERIMENTAL DESIGN: MGMT protein expression was assessed in 74 primary neuroblastoma tumors. Growth inhibition assays were done to determine the IC(50) and the extent of synergy observed with various concentrations of temozolomide, irinotecan, and the MGMT-inactivating agent O(6)-benzylguanine, using cultured syngeneic neuroblastoma cells with either low or high levels of MGMT expression. We then assessed efficacy in a mouse xenograft model of metastatic neuroblastoma. RESULTS: MGMT was expressed by all 74 tumors evaluated. Pretreatment of neuroblastoma cells with O(6)-benzylguanine reduced the IC(50) of temozolomide by 10-fold regardless of level of MGMT expression, and pretreatment with BG followed by temozolomide + irinotecan further reduced the IC(50) in cells with high MGMT expression another 10-fold, to well below clinically achievable concentrations. The combination index was 0.27 to 0.30 for all three drugs in both cell lines, indicating strong synergy. Survival at 100 days for mice with metastatic neuroblastoma was 56% with three-drug treatment, compared with untreated controls (0%, P < 0.001) or temozolomide + irinotecan (10%, P = 0.081). CONCLUSIONS: MGMT is widely expressed in primary neuroblastoma tumors, and is a relevant therapeutic target. Both in vitro and in vivo studies suggest inactivation of MGMT with O(6)-benzylguanine may increase the activity of temozolomide and irinotecan against neuroblastoma.

Authors
Wagner, LM; McLendon, RE; Yoon, KJ; Weiss, BD; Billups, CA; Danks, MK
MLA Citation
Wagner, LM, McLendon, RE, Yoon, KJ, Weiss, BD, Billups, CA, and Danks, MK. "Targeting methylguanine-DNA methyltransferase in the treatment of neuroblastoma." Clin Cancer Res 13.18 Pt 1 (September 15, 2007): 5418-5425.
PMID
17875772
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
18 Pt 1
Publish Date
2007
Start Page
5418
End Page
5425
DOI
10.1158/1078-0432.CCR-07-0418

Tumor resection cavity administered iodine-131-labeled antitenascin 81C6 radioimmunotherapy in patients with malignant glioma: neuropathology aspects.

INTRODUCTION: The neurohistological findings in patients treated with targeted beta emitters such as (131)I are poorly described. We report a histopathologic analysis from patients treated with combined external beam therapy and a brachytherapy consisting of a (131)I-labeled monoclonal antibody (mAb) injected into surgically created resection cavities during brain tumor resections. METHODS: Directed tissue samples of the cavity walls were obtained because of suspected tumor recurrence from 28 patients. Samples and clinical follow-up were evaluated on all patients (Group A) based on total radiation dose received and a subset of these (n=18; Group B, proximal therapy subset) who had received external beam therapy within

Authors
McLendon, RE; Akabani, G; Friedman, HS; Reardon, DA; Cleveland, L; Cokgor, I; Herndon, JE; Wikstrand, C; Boulton, ST; Friedman, AH; Bigner, DD; Zalutsky, MR
MLA Citation
McLendon, RE, Akabani, G, Friedman, HS, Reardon, DA, Cleveland, L, Cokgor, I, Herndon, JE, Wikstrand, C, Boulton, ST, Friedman, AH, Bigner, DD, and Zalutsky, MR. "Tumor resection cavity administered iodine-131-labeled antitenascin 81C6 radioimmunotherapy in patients with malignant glioma: neuropathology aspects." Nucl Med Biol 34.4 (May 2007): 405-413.
PMID
17499730
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
34
Issue
4
Publish Date
2007
Start Page
405
End Page
413
DOI
10.1016/j.nucmedbio.2007.01.009

Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas.

PURPOSE: Recent reports demonstrate the activity of imatinib mesylate, an ATP-mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme. We performed the current phase 2 study to evaluate this regimen among patients with recurrent WHO grade III malignant glioma (MG). PATIENTS AND METHOD: Patients with grade III MG at any recurrence, received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Clinical assessments were performed monthly and radiographic assessments were obtained at least every 2 months. The primary endpoint was 6-month progression-free survival (PFS) rate. RESULTS: Thirty-nine patients were enrolled. All patients had progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. The median number of episodes of prior progression was 2 (range, 1-7) and the median number of prior treatment regimens was 3 (range, 1-8). With a median follow-up of 82.9 weeks, 24% of patients were progression-free at 6 months. The radiographic response rate was 10%, while 33% achieved stable disease. Among patients who achieved at least stable disease at first evaluation, the 6-month and 12-month PFS rates were 53% and 29%, respectively. The most common grade 3 or greater toxicities were hematologic and complicated less than 4% of administered courses. CONCLUSION: Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG.

Authors
Desjardins, A; Quinn, JA; Vredenburgh, JJ; Sathornsumetee, S; Friedman, AH; Herndon, JE; McLendon, RE; Provenzale, JM; Rich, JN; Sampson, JH; Gururangan, S; Dowell, JM; Salvado, A; Friedman, HS; Reardon, DA
MLA Citation
Desjardins, A, Quinn, JA, Vredenburgh, JJ, Sathornsumetee, S, Friedman, AH, Herndon, JE, McLendon, RE, Provenzale, JM, Rich, JN, Sampson, JH, Gururangan, S, Dowell, JM, Salvado, A, Friedman, HS, and Reardon, DA. "Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas." J Neurooncol 83.1 (May 2007): 53-60.
PMID
17245623
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
83
Issue
1
Publish Date
2007
Start Page
53
End Page
60
DOI
10.1007/s11060-006-9302-2

Recurrent glioblastoma diagnosed by fluorescence in situ hybridization for EGFR.

Authors
Grunkemeier, MN; Turner, K; McLendon, RE
MLA Citation
Grunkemeier, MN, Turner, K, and McLendon, RE. "Recurrent glioblastoma diagnosed by fluorescence in situ hybridization for EGFR." Acta Neuropathol 113.2 (February 2007): 217-219. (Letter)
PMID
17151838
Source
pubmed
Published In
Acta Neuropathologica
Volume
113
Issue
2
Publish Date
2007
Start Page
217
End Page
219
DOI
10.1007/s00401-006-0175-4

Cerebellopontine angle craniopharyngioma: case report and literature review.

The authors report an unusual case of adamantinomatous craniopharyngioma occurring in isolation in the cerebellopontine angle of a 12-year-old female. The patient presented with a 1-year history of nausea, vomiting, and headache. MRI revealed a left cerebellopontine angle tumor without connection to the suprasellar space. Following near-total resection, histological review confirmed the lesion as an adamantinomatous craniopharyngioma. This is only the third published report of craniopharyngioma occurring in isolation in the cerebellopontine angle. The case report and a brief review of the literature are presented.

Authors
Powers, CJ; New, KC; McLendon, RE; Friedman, AH; Fuchs, HE
MLA Citation
Powers, CJ, New, KC, McLendon, RE, Friedman, AH, and Fuchs, HE. "Cerebellopontine angle craniopharyngioma: case report and literature review." Pediatr Neurosurg 43.2 (2007): 158-163. (Review)
PMID
17337933
Source
pubmed
Published In
Pediatric neurosurgery
Volume
43
Issue
2
Publish Date
2007
Start Page
158
End Page
163
DOI
10.1159/000098394

Glioma stem cells promote radioresistance by preferential activation of the DNA damage response.

Ionizing radiation represents the most effective therapy for glioblastoma (World Health Organization grade IV glioma), one of the most lethal human malignancies, but radiotherapy remains only palliative because of radioresistance. The mechanisms underlying tumour radioresistance have remained elusive. Here we show that cancer stem cells contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. The fraction of tumour cells expressing CD133 (Prominin-1), a marker for both neural stem cells and brain cancer stem cells, is enriched after radiation in gliomas. In both cell culture and the brains of immunocompromised mice, CD133-expressing glioma cells survive ionizing radiation in increased proportions relative to most tumour cells, which lack CD133. CD133-expressing tumour cells isolated from both human glioma xenografts and primary patient glioblastoma specimens preferentially activate the DNA damage checkpoint in response to radiation, and repair radiation-induced DNA damage more effectively than CD133-negative tumour cells. In addition, the radioresistance of CD133-positive glioma stem cells can be reversed with a specific inhibitor of the Chk1 and Chk2 checkpoint kinases. Our results suggest that CD133-positive tumour cells represent the cellular population that confers glioma radioresistance and could be the source of tumour recurrence after radiation. Targeting DNA damage checkpoint response in cancer stem cells may overcome this radioresistance and provide a therapeutic model for malignant brain cancers.

Authors
Bao, S; Wu, Q; McLendon, RE; Hao, Y; Shi, Q; Hjelmeland, AB; Dewhirst, MW; Bigner, DD; Rich, JN
MLA Citation
Bao, S, Wu, Q, McLendon, RE, Hao, Y, Shi, Q, Hjelmeland, AB, Dewhirst, MW, Bigner, DD, and Rich, JN. "Glioma stem cells promote radioresistance by preferential activation of the DNA damage response." Nature 444.7120 (December 7, 2006): 756-760.
PMID
17051156
Source
pubmed
Published In
Nature
Volume
444
Issue
7120
Publish Date
2006
Start Page
756
End Page
760
DOI
10.1038/nature05236

Phase II study of oxaliplatin in children with recurrent or refractory medulloblastoma, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors: a pediatric brain tumor consortium study.

BACKGROUND: An open-label Phase II study of oxaliplatin was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB), supratentorial primitive neuroectodermal tumors (SPNET), and atypical teratoid rhabdoid tumor (ATRT). METHODS: Patients were stratified as follows: stratum IA, first recurrence MB with measurable disease; IB, recurrent MB with only cerebral spinal fluid (CSF) positivity or linear leptomeningeal disease (LLD); IC, MB > or =second recurrence; stratum II, recurrent SPNET; stratum III, recurrent ATRT. Patients received oxaliplatin, 130 mg/m(2) intravenously over 2 hours every 3 weeks. The primary objective was to estimate the sustained response rate in stratum 1A. Plasma ultrafiltrate platinum pharmacokinetics were evaluated. RESULTS: A total of 43 patients with a median age of 8.5 years (range, 0.6-18.9 years) were enrolled. In stratum 1A, 2 of 15 had partial responses (PRs, 1 sustained PR). No responses were observed in other strata. The most frequent Grade 3 and 4 toxicities included thrombocytopenia (25.6%), neutropenia (16.3%), leukopenia (12%), increase in serum alanine transaminase (ALT) (7%), vomiting (4.7%), and sensory neuropathy (4.7%). No severe ototoxicity or nephrotoxicity was reported. Plasma ultrafiltrate platinum pharmacokinetic parameters were similar to adults, with a median clearance of 12.2 L/hr (range, 4.4-30 L/hr) and median area under the curve (AUC(0-infinity)) of 9.4 microg/mL/hr (range, 6.2-13.9 microg/mL/hr). CONCLUSIONS: Oxaliplatin was well tolerated in children but has limited activity in children with recurrent CNS embryonal tumors previously treated with platinum compounds.

Authors
Fouladi, M; Blaney, SM; Poussaint, TY; Freeman, BB; McLendon, R; Fuller, C; Adesina, AM; Hancock, ML; Danks, MK; Stewart, C; Boyett, JM; Gajjar, A
MLA Citation
Fouladi, M, Blaney, SM, Poussaint, TY, Freeman, BB, McLendon, R, Fuller, C, Adesina, AM, Hancock, ML, Danks, MK, Stewart, C, Boyett, JM, and Gajjar, A. "Phase II study of oxaliplatin in children with recurrent or refractory medulloblastoma, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors: a pediatric brain tumor consortium study." Cancer 107.9 (November 1, 2006): 2291-2297.
PMID
17019740
Source
pubmed
Published In
Cancer
Volume
107
Issue
9
Publish Date
2006
Start Page
2291
End Page
2297
DOI
10.1002/cncr.22241

A phase II trial of O6-benzylguanine and carmustine in patients with advanced soft tissue sarcoma.

PURPOSE: Tumor resistance to alkylating agents such as carmustine (BCNU) has been found to be associated with intracellular expression of O6-methylguanine-DNA methyltransferase (MGMT). Administration of O6-benzylguanine (O6-BG), a substrate that inactivates MGMT, may help overcome chemotherapy resistance. We performed a phase II study to explore the activity of O6-BG in combination with BCNU in patients with advanced soft tissue sarcoma. EXPERIMENTAL DESIGN: Informed consent was obtained from patients with metastatic soft tissue sarcoma naïve to systemic chemotherapy (adjuvant chemotherapy allowed). Patients received O6-BG 120 mg/m2 I.V. followed by BCNU 40 mg/m2 I.V. Treatment was repeated every 6 weeks until disease progression or development of unacceptable toxicity. RESULTS: No objective responses were observed in 12 enrolled patients. Four patients exhibited stable disease lasting 11-25+ weeks. The median overall survival was 16.9 months (95% CI, 2.9-NR). The most common grade 3-4 toxicities were neutropenia, thrombocytopenia, and anemia. Depletion of MGMT activity was demonstrated in peripheral blood mononuclear cells. Immunohistochemical estimation of MGMT expression from archival tissue ranged from 20 to 99% positive staining cells. CONCLUSIONS: Observed toxicities were consistent with previous studies of O6-BG plus BCNU. The degree of MGMT expression was variable in this small sample of heterogeneous sarcomas. Further development of this regimen and dose for the treatment of soft tissue sarcoma is not warranted due to the lack of objective responses.

Authors
Ryan, CW; Dolan, ME; Brockstein, BB; McLendon, R; Delaney, SM; Samuels, BL; Agamah, ES; Vokes, EE
MLA Citation
Ryan, CW, Dolan, ME, Brockstein, BB, McLendon, R, Delaney, SM, Samuels, BL, Agamah, ES, and Vokes, EE. "A phase II trial of O6-benzylguanine and carmustine in patients with advanced soft tissue sarcoma." Cancer Chemother Pharmacol 58.5 (November 2006): 634-639.
PMID
16520986
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
58
Issue
5
Publish Date
2006
Start Page
634
End Page
639
DOI
10.1007/s00280-006-0210-0

Treatment of neoplastic meningitis with intrathecal 9-nitro-camptothecin.

The topoisomerase I inhibitor, 9-nitro-camptothecin (9NC), is highly tumoricidal against glioblastoma multiforme (GBM) in vitro. However, systemic administration of 9NC has not shown the expected efficacy in clinical trials. This failure may be due to the rapid hydrolysis of 9NC in plasma from the active form to the inactive and myelosuppressive form in the presence of human albumin at physiologic pH. Concurrent treatment with anticonvulsants and dexamethasone, drugs indispensable for the supportive therapy of patients with GBM, has also been shown to decrease plasma concentrations of these drugs. Intrathecal drug delivery circumvents the blood-brain barrier and minimizes systemic toxicity. Intrathecal delivery of 9NC may also have the more specific advantage of significantly reducing the hydrolysis of 9NC that occurs after systemic delivery due to the more favorable pH and reduced albumin content in cerebrospinal fluid. The present study evaluated the toxicity and efficacy of intrathecal delivery of 9NC in an athymic rat model of neoplastic meningitis. Toxicity tests showed that 0.3 micromol (5000 microM), 0.03 micromol (500 microM), 0.003 micromol (50 microM), or 0.0003 micromol (5 microM) of 9NC administered intrathecally to the athymic rats caused no evidence of clinical or histological toxicity. Intrathecal administration of 0.3 micromol (5000 microM) of 9NC twice a week for three doses to athymic rats with neoplastic meningitis induced by the GBM cell line, U87MGDeltaEGFR, resulted in a 26% increase of median survival compared to the control group (p < 0.005). These results suggest that intrathecal treatment with 9NC may be useful for patients with GBM neoplastic meningitis.

Authors
Ochiai, H; Pernell, CT; Archer, GE; Chewning, TA; McLendon, RE; Friedman, HS; Sampson, JH
MLA Citation
Ochiai, H, Pernell, CT, Archer, GE, Chewning, TA, McLendon, RE, Friedman, HS, and Sampson, JH. "Treatment of neoplastic meningitis with intrathecal 9-nitro-camptothecin." Neurol Med Chir (Tokyo) 46.10 (October 2006): 485-489.
PMID
17062987
Source
pubmed
Published In
Neurologia medico-chirurgica
Volume
46
Issue
10
Publish Date
2006
Start Page
485
End Page
489

Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma.

Promoter hypermethylation of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) has been associated with an enhanced response to chloroethylating and methylating agents in patients with malignant glioma. The purpose of this study was to compare three distinct yet related indices for measuring AGT to determine if these assays could be used interchangeably when AGT status is to be used to guide chemotherapeutic decisions. Real-time methylation-specific PCR (MSP), assessed as the ratio of methylated AGT copies to internal beta-actin control, was used to quantitate AGT hypermethylation in 32 glioma samples. Data were compared with AGT enzyme activity as well as immunohistochemical detection of AGT protein from the same samples. Hypermethylation of the AGT promoter was detected in 19 of 31 (61%) samples evaluable by MSP. Low-level AGT, defined as <20% nuclear AGT staining by immunohistochemistry, was found in 10 of 32 samples (31%), whereas 12 of 32 (38%) had low levels of AGT activity. Correlation of immunohistochemistry to AGT activity was statistically significant (P = 0.014) as was the correlation of immunohistochemistry to MSP (P = 0.043), whereas MSP compared with AGT activity (P = 0.246) was not significant. Cross-tabulation of immunohistochemistry and MSP data based on prognostic groups, where good prognosis was represented by an immunohistochemistry of <20% and an MSP ratio >12, showed no significant relationship (P = 0.214), suggesting that one assay cannot be used interchangeably for another. The observed discordance between respective measures of AGT based on prognosis supports further standardization of AGT assays designed to guide therapeutic practice. The data also suggest that consideration be given to the large population of AGT-expressing cells within samples when therapeutic strategies based on tumor methylation are used.

Authors
Maxwell, JA; Johnson, SP; Quinn, JA; McLendon, RE; Ali-Osman, F; Friedman, AH; Herndon, JE; Bierau, K; Bigley, J; Bigner, DD; Friedman, HS
MLA Citation
Maxwell, JA, Johnson, SP, Quinn, JA, McLendon, RE, Ali-Osman, F, Friedman, AH, Herndon, JE, Bierau, K, Bigley, J, Bigner, DD, and Friedman, HS. "Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma." Mol Cancer Ther 5.10 (October 2006): 2531-2539.
PMID
17041097
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
5
Issue
10
Publish Date
2006
Start Page
2531
End Page
2539
DOI
10.1158/1535-7163.MCT-06-0106

AAL881, a novel small molecule inhibitor of RAF and VEGFR activities, blocks growth of malignant glioma

Authors
Sathornsumetee, S; Hjelmeland, AB; Keir, ST; McLendon, RE; Batt, D; Ramsey, T; Yusuff, N; Ahmed Rasheed, BK; Kieran, MW; Laforme, A; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Sathornsumetee, S, Hjelmeland, AB, Keir, ST, McLendon, RE, Batt, D, Ramsey, T, Yusuff, N, Ahmed Rasheed, BK, Kieran, MW, Laforme, A, Bigner, DD, Friedman, HS, and Rich, JN. "AAL881, a novel small molecule inhibitor of RAF and VEGFR activities, blocks growth of malignant glioma." October 2006.
Source
wos-lite
Published In
Neuro-Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
417
End Page
417

Glioma cancer stem cells promote tumor angiogenesis through vascular endothelial growth factor

Authors
Bao, S; Wu, Q; Sathornsumetee, S; Hao, Y; Li, Z; Hjelmeland, AB; Shi, Q; McLendon, RE; Bigner, DD; Rich, JN
MLA Citation
Bao, S, Wu, Q, Sathornsumetee, S, Hao, Y, Li, Z, Hjelmeland, AB, Shi, Q, McLendon, RE, Bigner, DD, and Rich, JN. "Glioma cancer stem cells promote tumor angiogenesis through vascular endothelial growth factor." October 2006.
Source
wos-lite
Published In
Neuro-Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
392
End Page
392

Characterizing genomic rearrangements in oligodendroglioma using whole genome tilepath hrCGH arrays

Authors
Gregory, SG; Johnson, NV; Connelly, JJ; Virgadamo, J; McLendon, RE; Vance, JM; Bigner, DD
MLA Citation
Gregory, SG, Johnson, NV, Connelly, JJ, Virgadamo, J, McLendon, RE, Vance, JM, and Bigner, DD. "Characterizing genomic rearrangements in oligodendroglioma using whole genome tilepath hrCGH arrays." October 2006.
Source
wos-lite
Published In
Neuro-Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
421
End Page
421

AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma.

Malignant gliomas are highly proliferative and angiogenic cancers resistant to conventional therapies. Although RAS and RAF mutations are uncommon in gliomas, RAS activity is increased in gliomas. Additionally, vascular endothelial growth factor and its cognate receptors are highly expressed in gliomas. We now report that AAL881, a novel low-molecular weight inhibitor of the kinase activities associated with B-RAF, C-RAF (RAF-1), and VEGF receptor-2 (VEGFR2), showed activity against glioma cell lines and xenografts. In culture, AAL881 inhibited the downstream effectors of RAF in a concentration-dependent manner, with inhibition of proliferation associated with a G(1) cell cycle arrest, induction of apoptosis, and decreased colony formation. AAL881 decreased the proliferation of bovine aortic endothelial cells as well as the tumor cell secretion of vascular endothelial growth factor and inhibited the invasion of glioma cells through an artificial extracellular matrix. Orally administered AAL881 was well tolerated with minimal weight loss in non-tumor-bearing mice. Established s.c. human malignant glioma xenografts grown in immunocompromised mice treated with a 10-day course of oral AAL881 exhibited growth delays relative to control tumors, frequently resulting in long-term complete regressions. AAL881 treatment extended the survival of immunocompromised mice bearing orthotopic glioma xenografts compared with placebo controls. The intraparenchymal portions of orthotopic AAL881-treated tumors underwent widespread necrosis consistent with vascular disruption compared with the subarachnoid elements. These effects are distinct from our prior experience with VEGFR2 inhibitors, suggesting that targeting RAF itself or in combination with VEGFR2 induces profound tumor responses in gliomas and may serve as a novel therapeutic approach in patients with malignant gliomas.

Authors
Sathornsumetee, S; Hjelmeland, AB; Keir, ST; McLendon, RE; Batt, D; Ramsey, T; Yusuff, N; Rasheed, BKA; Kieran, MW; Laforme, A; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Sathornsumetee, S, Hjelmeland, AB, Keir, ST, McLendon, RE, Batt, D, Ramsey, T, Yusuff, N, Rasheed, BKA, Kieran, MW, Laforme, A, Bigner, DD, Friedman, HS, and Rich, JN. "AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma." Cancer Res 66.17 (September 1, 2006): 8722-8730.
PMID
16951188
Source
pubmed
Published In
Cancer Research
Volume
66
Issue
17
Publish Date
2006
Start Page
8722
End Page
8730
DOI
10.1158/0008-5472.CAN-06-0284

Chimeric murine/human IgG(2) anti-tenascin 81C6 monoclonal antibody: phase I trial in patients with malignant glioma of a construct with improved stability

Authors
Zalutsky, MR; Reardon, DA; Quinn, JA; Coleman, RE; Akabani, G; Friedman, AH; Friedman, HS; II, HJE; McLendon, RE; Wong, TZ; Bigner, DD
MLA Citation
Zalutsky, MR, Reardon, DA, Quinn, JA, Coleman, RE, Akabani, G, Friedman, AH, Friedman, HS, II, HJE, McLendon, RE, Wong, TZ, and Bigner, DD. "Chimeric murine/human IgG(2) anti-tenascin 81C6 monoclonal antibody: phase I trial in patients with malignant glioma of a construct with improved stability." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 (September 2006): S194-S194.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
33
Publish Date
2006
Start Page
S194
End Page
S194

Radioimmunotherapy of patients with malignant brain tumors: patient-specific dosing of I-131-labeled anti-tenacin antibody to achieve 44 Gy boost dose to resection cavity margins

Authors
Reardon, DA; Zalutsky, MR; Akabani, G; Coleman, RE; Friedman, AH; McLendon, RE; Friedman, HS; II, HJE; Kirkpatrick, J; Bigner, DD
MLA Citation
Reardon, DA, Zalutsky, MR, Akabani, G, Coleman, RE, Friedman, AH, McLendon, RE, Friedman, HS, II, HJE, Kirkpatrick, J, and Bigner, DD. "Radioimmunotherapy of patients with malignant brain tumors: patient-specific dosing of I-131-labeled anti-tenacin antibody to achieve 44 Gy boost dose to resection cavity margins." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 (September 2006): S194-S194.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
33
Publish Date
2006
Start Page
S194
End Page
S194

Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor.

Malignant gliomas are highly lethal cancers dependent on angiogenesis. Critical tumor subpopulations within gliomas share characteristics with neural stem cells. We examined the potential of stem cell-like glioma cells (SCLGC) to support tumor angiogenesis. SCLGC isolated from human glioblastoma biopsy specimens and xenografts potently generated tumors when implanted into the brains of immunocompromised mice, whereas non-SCLGC tumor cells isolated from only a few tumors formed secondary tumors when xenotransplanted. Tumors derived from SCLGC were morphologically distinguishable from non-SCLGC tumor populations by widespread tumor angiogenesis, necrosis, and hemorrhage. To determine a potential molecular mechanism for SCLGC in angiogenesis, we measured the expression of a panel of angiogenic factors secreted by SCLGC. In comparison with matched non-SCLGC populations, SCLGC consistently secreted markedly elevated levels of vascular endothelial growth factor (VEGF), which were further induced by hypoxia. In an in vitro model of angiogenesis, SCLGC-conditioned medium significantly increased endothelial cell migration and tube formation compared with non-SCLGC tumor cell-conditioned medium. The proangiogenic effects of glioma SCLGC on endothelial cells were specifically abolished by the anti-VEGF neutralizing antibody bevacizumab, which is in clinical use for cancer therapy. Furthermore, bevacizumab displayed potent antiangiogenic efficacy in vivo and suppressed growth of xenografts derived from SCLGC but limited efficacy against xenografts derived from a matched non-SCLGC population. Together these data indicate that stem cell-like tumor cells can be a crucial source of key angiogenic factors in cancers and that targeting proangiogenic factors from stem cell-like tumor populations may be critical for patient therapy.

Authors
Bao, S; Wu, Q; Sathornsumetee, S; Hao, Y; Li, Z; Hjelmeland, AB; Shi, Q; McLendon, RE; Bigner, DD; Rich, JN
MLA Citation
Bao, S, Wu, Q, Sathornsumetee, S, Hao, Y, Li, Z, Hjelmeland, AB, Shi, Q, McLendon, RE, Bigner, DD, and Rich, JN. "Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor." Cancer Res 66.16 (August 15, 2006): 7843-7848.
PMID
16912155
Source
pubmed
Published In
Cancer Research
Volume
66
Issue
16
Publish Date
2006
Start Page
7843
End Page
7848
DOI
10.1158/0008-5472.CAN-06-1010

Russell & Rubinstein's Pathology of Tumors of the Nervous System 7Ed

This is the leading international professional reference text that also serves as a bench book, describing all aspects of the pathology of brain tumours - genetics, molecular biology, epidemiology, morphology, immunohistochemistry, ...

Authors
McLendon, RE; Rosenblum, MK; Bigner, DD
MLA Citation
McLendon, RE, Rosenblum, MK, and Bigner, DD. Russell & Rubinstein's Pathology of Tumors of the Nervous System 7Ed. CRC Press, July 28, 2006. (Edited Book)
Source
manual
Publish Date
2006

Russell & Rubinstein's Pathology of Tumors of the Nervous System 7Ed

This is the leading international professional reference text that also serves as a bench book, describing all aspects of the pathology of brain tumours - genetics, molecular biology, epidemiology, morphology, immunohistochemistry, ...

Authors
McLendon, RE; Rosenblum, MK; Bigner, DD
MLA Citation
McLendon, RE, Rosenblum, MK, and Bigner, DD. Russell & Rubinstein's Pathology of Tumors of the Nervous System 7Ed. CRC Press, July 28, 2006. (Edited Book)
Source
manual
Publish Date
2006

Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results.

UNLABELLED: Results from animal experiments have shown that human IgG2/mouse chimeric antitenascin 81C6 (ch81C6) monoclonal antibody exhibited higher tumor accumulation and enhanced stability compared with its murine parent. Our objective was to determine the effect of these differences on the maximum tolerated dose (MTD), pharmacokinetics, dosimetry, and antitumor activity of (131)I-ch81C6 administered into the surgically created resection cavity (SCRC) of malignant glioma patients. METHODS: In this phase I trial, eligible patients received a single injection of (131)I-ch81C6 administered through a Rickham catheter into the SCRC. Patients were stratified as newly diagnosed and untreated (stratum A), newly diagnosed after external beam radiotherapy (XRT) (stratum B), and recurrent (stratum C). (131)I-ch81C6 was administered either before (stratum A) or after (stratum B) conventional XRT for newly diagnosed patients. In addition, chemotherapy was prescribed for all patients after (131)I-ch81C6 administration. Dose escalation was performed independently for each stratum. Patients were observed for toxicity and response until death or progressive disease. RESULTS: We treated 47 patients with (131)I-ch81C6 doses up to 4.44 GBq (120 mCi), including 35 with newly diagnosed tumors (strata A and B) and 12 with recurrent disease (stratum C). Dose-limiting hematologic toxicity defined the MTD to be 2.96 GBq (80 mCi) for all patients, regardless of treatment strata. Neurologic dose-limiting toxicity developed in 3 patients; however, none required further surgery to debulk radiation necrosis. Median survival was 88.6 wk and 65.0 wk for newly diagnosed and recurrent patients, respectively. CONCLUSION: The MTD of (131)I-ch81C6 is 2.96 GBq (80 mCi) because of dose-limiting hematologic toxicity. Although encouraging survival was observed, (131)I-ch81C6 was associated with greater hematologic toxicity, probably due to the enhanced stability of the IgG2 construct, than previously observed with (131)I-murine 81C6.

Authors
Reardon, DA; Quinn, JA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Pegram, CN; Provenzale, JM; Dowell, JM; Rich, JN; Vredenburgh, JJ; Desjardins, A; Sampson, JH; Gururangan, S; Wong, TZ; Badruddoja, MA; Zhao, X-G; Bigner, DD; Zalutsky, MR
MLA Citation
Reardon, DA, Quinn, JA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, Herndon, JE, McLendon, RE, Pegram, CN, Provenzale, JM, Dowell, JM, Rich, JN, Vredenburgh, JJ, Desjardins, A, Sampson, JH, Gururangan, S, Wong, TZ, Badruddoja, MA, Zhao, X-G, Bigner, DD, and Zalutsky, MR. "Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results." J Nucl Med 47.6 (June 2006): 912-918.
PMID
16741299
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
47
Issue
6
Publish Date
2006
Start Page
912
End Page
918

Errors in surgical neuropathology and the influence of cognitive biases: the psychology of intelligence analysis.

CONTEXT: A significant difficulty that pathologists encounter in arriving at a correct diagnosis is related to the way information from various sources is processed and assimilated in context. OBJECTIVE: These issues are addressed by the science of cognitive psychology. Although cognitive biases are the focus of a number of studies on medical decision making, few if any focus on the visual sciences. DATA SOURCES: A recent publication authored by Richards Heuer, Jr, The Psychology of Intelligence Analysis, directly addresses many of the cognitive biases faced by neuropathologists and anatomic pathologists in general. These biases include visual anticipation, first impression, and established mindsets and subconsciously influence our critical decision-making processes. CONCLUSIONS: The book points out that while biases are an inherent property of cognition, the influence of such biases can be recognized and the effects blunted.

Authors
McLendon, RE
MLA Citation
McLendon, RE. "Errors in surgical neuropathology and the influence of cognitive biases: the psychology of intelligence analysis." Arch Pathol Lab Med 130.5 (May 2006): 613-616.
PMID
16683873
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
130
Issue
5
Publish Date
2006
Start Page
613
End Page
616
DOI
10.1043/1543-2165(2006)130[613:EISNAT]2.0.CO;2

A phase II window trial of procarbazine and topotecan in children with high-grade glioma: a report from the children's oncology group.

The role of chemotherapy in the treatment of high-grade gliomas in children is unclear. Early reports were suggestive of improved outcome in children with high-grade glioma with the addition of chemotherapy after surgery and radiation therapy. Subsequent studies did not show similar favorable contribution of chemotherapy to the outcome of these children. Further efforts to identify active chemotherapy agents in children include use of agents that have shown efficacy in adult patients with high-grade glioma and agents that have shown promise in mice bearing human xenografts of brain tumors. A Pediatric Oncology Group (POG 9431) trial tested the activity of two such agents, procarbazine and topotecan in newly diagnosed patients with high-grade glioma who had measurable disease after diagnostic surgery. Neither agent showed efficacy within the confines of the statistical design of the study. This study showed that children with high-grade glioma have an innate resistance to alkylating agents based on mismatch repair deficiency and high levels of alkyguanine transferase (AGT). Future trials should consider strategies to overcome the resistance mechanisms in children with high-grade glioma.

Authors
Chintagumpala, MM; Friedman, HS; Stewart, CF; Kepner, J; McLendon, RE; Modrich, PL; McCluggage, C; Burger, P; Holmes, E; Thompson, S; Rutka, J; Michalski, J; Woo, S; Blaney, SM; Kun, LE; Horowitz, ME; Pediatric Oncology Group Study,
MLA Citation
Chintagumpala, MM, Friedman, HS, Stewart, CF, Kepner, J, McLendon, RE, Modrich, PL, McCluggage, C, Burger, P, Holmes, E, Thompson, S, Rutka, J, Michalski, J, Woo, S, Blaney, SM, Kun, LE, Horowitz, ME, and Pediatric Oncology Group Study, . "A phase II window trial of procarbazine and topotecan in children with high-grade glioma: a report from the children's oncology group." J Neurooncol 77.2 (April 2006): 193-198.
PMID
16314955
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
77
Issue
2
Publish Date
2006
Start Page
193
End Page
198
DOI
10.1007/s11060-005-9024-x

Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma.

PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of gefitinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent malignant glioma. PATIENTS AND METHODS: Gefitinib and sirolimus were administered on a continuous daily dosing schedule at dose levels that were escalated in successive cohorts of malignant glioma patients at any recurrence who were stratified based on concurrent use of CYP3A-inducing anticonvulsants [enzyme-inducing antiepileptic drugs, (EIAED)]. Pharmacokinetic and archival tumor biomarker data were also assessed. RESULTS: Thirty-four patients with progressive disease after prior radiation therapy and chemotherapy were enrolled, including 29 (85%) with glioblastoma multiforme and 5 (15%) with anaplastic glioma. The MTD was 500 mg of gefitinib plus 5 mg of sirolimus for patients not on EIAEDs and 1,000 mg of gefitinib plus 10 mg of sirolimus for patients on EIAEDs. DLTs included mucositis, diarrhea, rash, thrombocytopenia, and hypertriglyceridemia. Gefitinib exposure was not affected by sirolimus administration but was significantly lowered by concurrent EIAED use. Two patients (6%) achieved a partial radiographic response, and 13 patients (38%) achieved stable disease. CONCLUSION: We show that gefitinib plus sirolimus can be safely coadministered on a continuous, daily dosing schedule, and established the recommended dose level of these agents in combination for future phase 2 clinical trials.

Authors
Reardon, DA; Quinn, JA; Vredenburgh, JJ; Gururangan, S; Friedman, AH; Desjardins, A; Sathornsumetee, S; Herndon, JE; Dowell, JM; McLendon, RE; Provenzale, JM; Sampson, JH; Smith, RP; Swaisland, AJ; Ochs, JS; Lyons, P; Tourt-Uhlig, S; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Reardon, DA, Quinn, JA, Vredenburgh, JJ, Gururangan, S, Friedman, AH, Desjardins, A, Sathornsumetee, S, Herndon, JE, Dowell, JM, McLendon, RE, Provenzale, JM, Sampson, JH, Smith, RP, Swaisland, AJ, Ochs, JS, Lyons, P, Tourt-Uhlig, S, Bigner, DD, Friedman, HS, and Rich, JN. "Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma." Clin Cancer Res 12.3 Pt 1 (February 1, 2006): 860-868.
PMID
16467100
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
3 Pt 1
Publish Date
2006
Start Page
860
End Page
868
DOI
10.1158/1078-0432.CCR-05-2215

Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results.

PURPOSE: To assess the efficacy and toxicity of intraresection cavity iodine-131-labeled murine antitenascin monoclonal antibody 81C6 (131I-m81C6) among recurrent malignant brain tumor patients. PATIENTS AND METHODS: In this phase II trial, 100 mCi of 131I-m81C6 was injected directly into the surgically created resection cavity (SCRC) of 43 patients with recurrent malignant glioma (glioblastoma multiforme [GBM], n = 33; anaplastic astrocytoma [AA], n = 6; anaplastic oligodendroglioma [AO], n = 2; gliosarcoma [GS], n = 1; and metastatic adenocarcinoma, n = 1) followed by chemotherapy. RESULTS: With a median follow-up of 172 weeks, 63% and 59% of patients with GBM/GS and AA/AO tumors were alive at 1 year. Median overall survival for patients with GBM/GS and AA/AO tumors was 64 and 99 weeks, respectively. Ten patients (23%) developed acute hematologic toxicity. Five patients (12%) developed acute reversible neurotoxicity. One patient (2%) developed irreversible neurotoxicity. No patients required reoperation for radionecrosis. CONCLUSION: In this single-institution phase II study, administration of 100 mCi of 131I-m81C6 to recurrent malignant glioma patients followed by chemotherapy is associated with a median survival that is greater than that of historical controls treated with surgery plus iodine-125 brachytherapy. Furthermore, toxicity was acceptable. Administration of a fixed millicurie dose resulted in a wide range of absorbed radiation doses to the SCRC. We are now conducting a phase II trial, approved by the US Food and Drug Administration, using patient-specific 131I-m81C6 dosing, to deliver 44 Gy to the SCRC followed by standardized chemotherapy. A phase III multicenter trial with patient-specific dosing is planned.

Authors
Reardon, DA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Pegram, CN; Provenzale, JM; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Gururangan, S; Badruddoja, M; Dowell, JM; Wong, TZ; Zhao, X-G; Zalutsky, MR; Bigner, DD
MLA Citation
Reardon, DA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, Herndon, JE, McLendon, RE, Pegram, CN, Provenzale, JM, Quinn, JA, Rich, JN, Vredenburgh, JJ, Desjardins, A, Gururangan, S, Badruddoja, M, Dowell, JM, Wong, TZ, Zhao, X-G, Zalutsky, MR, and Bigner, DD. "Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results." J Clin Oncol 24.1 (January 1, 2006): 115-122.
PMID
16382120
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
1
Publish Date
2006
Start Page
115
End Page
122
DOI
10.1200/JCO.2005.03.4082

Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.

PURPOSE: We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS: Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). RESULTS: Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. CONCLUSION: Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.

Authors
Reardon, DA; Egorin, MJ; Quinn, JA; Rich, JN; Gururangan, S; Vredenburgh, JJ; Desjardins, A; Sathornsumetee, S; Provenzale, JM; Herndon, JE; Dowell, JM; Badruddoja, MA; McLendon, RE; Lagattuta, TF; Kicielinski, KP; Dresemann, G; Sampson, JH; Friedman, AH; Salvado, AJ; Friedman, HS
MLA Citation
Reardon, DA, Egorin, MJ, Quinn, JA, Rich, JN, Gururangan, S, Vredenburgh, JJ, Desjardins, A, Sathornsumetee, S, Provenzale, JM, Herndon, JE, Dowell, JM, Badruddoja, MA, McLendon, RE, Lagattuta, TF, Kicielinski, KP, Dresemann, G, Sampson, JH, Friedman, AH, Salvado, AJ, and Friedman, HS. "Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme." J Clin Oncol 23.36 (December 20, 2005): 9359-9368.
PMID
16361636
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
36
Publish Date
2005
Start Page
9359
End Page
9368
DOI
10.1200/JCO.2005.03.2185

ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors.

PURPOSE: Primary central nervous system (CNS) tumors represent a diverse group of tumor types with heterogeneous molecular mechanisms that underlie their formation and maintenance. CNS tumors depend on angiogenesis and often display increased activity of ErbB-associated pathways. Current nonspecific therapies frequently have poor efficacy in many of these tumor types, so there is a pressing need for the development of novel targeted therapies. EXPERIMENTAL DESIGN: ZD6474 is a novel, orally available low molecular weight inhibitor of the kinase activities associated with vascular endothelial growth factor receptor-2 and epidermal growth factor receptor. We hypothesized that ZD6474 may provide benefit in the treatment of several CNS tumor types. RESULTS: In mice bearing established s.c. tumor xenografts of CNS tumors (malignant glioma and ependymoma) or rhabdomyosarcoma, a limited course of ZD6474 treatment produced significant tumor growth delays and a high rate of partial tumor regression in most models examined. Mice with i.c. malignant glioma xenografts treated with ZD6474 experienced a significant prolongation of survival. Tumors from mice treated with ZD6474 displayed a lower proliferative index and disrupted tumor vascularity. Notably, some of these models are insensitive to low molecular weight kinase inhibitors targeting only vascular endothelial growth factor receptor-2 or epidermal growth factor receptor functions, suggesting that the combined disruption of both epidermal growth factor receptor and vascular endothelial growth factor receptor-2 activities may significantly increase tumor control. CONCLUSIONS: In conclusion, ZD6474 shows significant activity against xenograft models of several primary human CNS tumor types. Consideration for clinical development in this disease setting seems warranted.

Authors
Rich, JN; Sathornsumetee, S; Keir, ST; Kieran, MW; Laforme, A; Kaipainen, A; McLendon, RE; Graner, MW; Rasheed, BKA; Wang, L; Reardon, DA; Ryan, AJ; Wheeler, C; Dimery, I; Bigner, DD; Friedman, HS
MLA Citation
Rich, JN, Sathornsumetee, S, Keir, ST, Kieran, MW, Laforme, A, Kaipainen, A, McLendon, RE, Graner, MW, Rasheed, BKA, Wang, L, Reardon, DA, Ryan, AJ, Wheeler, C, Dimery, I, Bigner, DD, and Friedman, HS. "ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors." Clin Cancer Res 11.22 (November 15, 2005): 8145-8157.
PMID
16299247
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
22
Publish Date
2005
Start Page
8145
End Page
8157
DOI
10.1158/1078-0432.CCR-05-0319

Survival analysis of presumptive prognostic markers among oligodendrogliomas.

BACKGROUND: Allelic losses of 1p and 19q arms correlate with the oligodendroglial phenotype as well as with sensitivity to radiotherapy and chemotherapy. Furthermore, the DNA repair gene, methylguanine methyltransferase (MGMT), is diminished in 80% of oligodendroglial tumors and represents a possible mechanism for this therapeutic sensitivity. However, the authors questioned the relevance of genetic testing and measuring MGMT levels in tumors that were diagnostic of oligodendroglioma. METHODS: The authors performed a retrospective analysis of 1p, 19q, 9p21, TP53, and MGMT status in 46 patients with oligodendrogliomas to address any relations that may exist among these markers with regard to progression-free survival (PFS) and total survival. Methodologies included comparative genomic hybridization; loss of heterozygosity (LOH) on 1p, 19q, and 9p21; TP53 mutational analysis; and immunohistochemistry for MGMT. RESULTS: The authors found that survival among patients with light microscopically diagnosed oligodendroglial tumors demonstrating LOH of 1p and 19q trended toward statistical significance (P = 0.102 and P = 0.058, respectively). 9p21 LOH was significant as a predictor of PFS only among anaplastic oligodendrogliomas in this cohort (P = 0.033). TP53 mutation was found to be significantly predictive of a shorter survival (P = 0.027) among all patients and exhibited a strong trend toward a shorter PFS (P = 0.060). Low-level MGMT labeling index (LI) (< 20%) was noted in 86% of all oligodendroglial tumors. MGMT LI was not found to correlate with an improved PFS or total survival in this cohort, recognizing that median survival was not reached after a median follow-up of 104 months. CONCLUSIONS: 9p21 and TP53 mutational status assisted in developing a stricter subclassification of these tumors with prognostic significance. MGMT levels were decreased in a majority of oligodendrogliomas.

Authors
McLendon, RE; Herndon, JE; West, B; Reardon, D; Wiltshire, R; Rasheed, BKA; Quinn, J; Friedman, HS; Friedman, AH; Bigner, DD
MLA Citation
McLendon, RE, Herndon, JE, West, B, Reardon, D, Wiltshire, R, Rasheed, BKA, Quinn, J, Friedman, HS, Friedman, AH, and Bigner, DD. "Survival analysis of presumptive prognostic markers among oligodendrogliomas." Cancer 104.8 (October 15, 2005): 1693-1699.
PMID
16116609
Source
pubmed
Published In
Cancer
Volume
104
Issue
8
Publish Date
2005
Start Page
1693
End Page
1699
DOI
10.1002/cncr.21362

Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma.

BACKGROUND: The authors determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan (CPT-11), a topoisomerase I inhibitor, when administered with temozolomide among patients with recurrent malignant glioma (MG). METHODS: Patients with MG at any recurrence received temozolomide (TMZ) at a dose of 200 mg/m(2)/day on Days 1-5 plus CPT-11 administered as a 90-minute intravenous infusion during Weeks 1, 2, 4, and 5 of each 6-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing anticonvulsants (enzyme-inducing antiepileptic drugs [EIAEDs]). The CPT-11 dose was escalated in successive cohorts of patients independently for each stratum. RESULTS: CPT-11, at doses ranging from 40 mg/m(2) to 375 mg/m(2), was administered with TMZ to 107 patients. Ninety-one patients (85%) had recurrent glioblastoma multiforme (GBM) and 16 (15%) had recurrent anaplastic glioma. Sixty-eight patients (64%) were given EIAEDs. The MTD of CPT-11 for patients concurrently receiving and not receiving EIAEDs was 325 mg/m(2) and 125 mg/m(2), respectively. The DLTs were hematologic, gastrointestinal, and hepatic. Fifteen patients (14%) achieved either a radiographic complete (n = 5) or partial (n = 10) response across a wide range of CPT-11 dose levels. Patients with recurrent GBM who achieved radiographic response had a median time to disease progression of 54.9 weeks. CONCLUSIONS: The current study built on preclinical observations designed to increase the clinical activity of topoisomerase I inhibitors. CPT-11, administered at full dose levels, was well tolerated in combination with TMZ. Furthermore, durable responses were observed in this recurrent population. Ongoing Phase II studies will evaluate the efficacy of this regimen and its application to other malignancies.

Authors
Reardon, DA; Quinn, JA; Rich, JN; Desjardins, A; Vredenburgh, J; Gururangan, S; Sathornsumetee, S; Badruddoja, M; McLendon, R; Provenzale, J; Herndon, JE; Dowell, JM; Burkart, JL; Newton, HB; Friedman, AH; Friedman, HS
MLA Citation
Reardon, DA, Quinn, JA, Rich, JN, Desjardins, A, Vredenburgh, J, Gururangan, S, Sathornsumetee, S, Badruddoja, M, McLendon, R, Provenzale, J, Herndon, JE, Dowell, JM, Burkart, JL, Newton, HB, Friedman, AH, and Friedman, HS. "Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma." Cancer 104.7 (October 1, 2005): 1478-1486.
PMID
16088964
Source
pubmed
Published In
Cancer
Volume
104
Issue
7
Publish Date
2005
Start Page
1478
End Page
1486
DOI
10.1002/cncr.21316

Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG. PATIENTS AND METHODS: For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined. RESULTS: The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression. CONCLUSION: This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.

Authors
Quinn, JA; Desjardins, A; Weingart, J; Brem, H; Dolan, ME; Delaney, SM; Vredenburgh, J; Rich, J; Friedman, AH; Reardon, DA; Sampson, JH; Pegg, AE; Moschel, RC; Birch, R; McLendon, RE; Provenzale, JM; Gururangan, S; Dancey, JE; Maxwell, J; Tourt-Uhlig, S; Herndon, JE; Bigner, DD; Friedman, HS
MLA Citation
Quinn, JA, Desjardins, A, Weingart, J, Brem, H, Dolan, ME, Delaney, SM, Vredenburgh, J, Rich, J, Friedman, AH, Reardon, DA, Sampson, JH, Pegg, AE, Moschel, RC, Birch, R, McLendon, RE, Provenzale, JM, Gururangan, S, Dancey, JE, Maxwell, J, Tourt-Uhlig, S, Herndon, JE, Bigner, DD, and Friedman, HS. "Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma." J Clin Oncol 23.28 (October 1, 2005): 7178-7187.
PMID
16192602
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
28
Publish Date
2005
Start Page
7178
End Page
7187
DOI
10.1200/JCO.2005.06.502

PIK3CA is mutated in oligodendrogliomas, astrocytomas, and medulloblastomas and associated with chromosome 1p, 19q LOH in oligodendrogliomas

Authors
Adamson, DC; Broderick, DK; Di, C; Samuels, YR; McLendon, RE; Fults, DW; Velculescu, VE; Rasheed, A; Bigner, DD; Yan, H
MLA Citation
Adamson, DC, Broderick, DK, Di, C, Samuels, YR, McLendon, RE, Fults, DW, Velculescu, VE, Rasheed, A, Bigner, DD, and Yan, H. "PIK3CA is mutated in oligodendrogliomas, astrocytomas, and medulloblastomas and associated with chromosome 1p, 19q LOH in oligodendrogliomas." July 2005.
Source
wos-lite
Published In
Neuro-Oncology
Volume
7
Issue
3
Publish Date
2005
Start Page
345
End Page
345

Dosimetry and radiographic analysis of 131I-labeled anti-tenascin 81C6 murine monoclonal antibody in newly diagnosed patients with malignant gliomas: a phase II study.

UNLABELLED: The objective was to perform dosimetry and evaluate dose-response relationships in newly diagnosed patients with malignant brain tumors treated with direct injections of (131)I-labeled anti-tenascin murine 81C6 monoclonal antibody (mAb) into surgically created resection cavities (SCRCs) followed by conventional external-beam radiotherapy and chemotherapy. METHODS: Absorbed doses to the 2-cm-thick shell, measured from the margins of the resection cavity interface, were estimated for 33 patients with primary brain tumors. MRI/SPECT registrations were used to assess the distribution of the radiolabeled mAb in brain parenchyma. Results from biopsies obtained from 15 patients were classified as tumor, radionecrosis, or tumor and radionecrosis, and these were correlated with absorbed dose and dose rate. Also, MRI/PET registrations were used to assess radiographic progression among patients. RESULTS: This therapeutic strategy yielded a median survival of 86 and 79 wk for all patients and glioblastoma multiforme (GBM) patients, respectively. The average SCRC residence time of (131)I-mu81C6 mAb was 76 h (range, 34-169 h). The average absorbed dose to the 2-cm cavity margins was 48 Gy (range, 25-116 Gy) for all patients and 51 Gy (range, 27-116 Gy) for GBM patients. In MRI/SPECT registrations, we observed a preferential distribution of (131)I-mu81C6 mAb through regions of vasogenic edema. An analysis of the relationship between the absorbed dose and dose rate and the first biopsy results yielded a most favorable absorbed dose of 44 Gy. A correlation between decreased survival and irreversible neurotoxicity was noted. A comparative analysis, in terms of median survival, was performed with previous brachytherapy clinical studies, which showed a proportional relationship between the average boost absorbed dose and the median survival. CONCLUSION: This study shows that (131)I-mu81C6 mAb increases the median survival of GBM patients. An optimal absorbed dose of 44 Gy to the 2-cm cavity margins is suggested to reduce the incidence of neurologic toxicity. Further clinical studies are warranted to determine the effectiveness of (131)I-mu81C6 mAb based on a target dose of 44 Gy rather than a fixed administered activity.

Authors
Akabani, G; Reardon, DA; Coleman, RE; Wong, TZ; Metzler, SD; Bowsher, JE; Barboriak, DP; Provenzale, JM; Greer, KL; DeLong, D; Friedman, HS; Friedman, AH; Zhao, X-G; Pegram, CN; McLendon, RE; Bigner, DD; Zalutsky, MR
MLA Citation
Akabani, G, Reardon, DA, Coleman, RE, Wong, TZ, Metzler, SD, Bowsher, JE, Barboriak, DP, Provenzale, JM, Greer, KL, DeLong, D, Friedman, HS, Friedman, AH, Zhao, X-G, Pegram, CN, McLendon, RE, Bigner, DD, and Zalutsky, MR. "Dosimetry and radiographic analysis of 131I-labeled anti-tenascin 81C6 murine monoclonal antibody in newly diagnosed patients with malignant gliomas: a phase II study." J Nucl Med 46.6 (June 2005): 1042-1051.
PMID
15937318
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
46
Issue
6
Publish Date
2005
Start Page
1042
End Page
1051

Gene expression profiling and genetic markers in glioblastoma survival.

Despite the strikingly grave prognosis for older patients with glioblastomas, significant variability in patient outcome is experienced. To explore the potential for developing improved prognostic capabilities based on the elucidation of potential biological relationships, we did analyses of genes commonly mutated, amplified, or deleted in glioblastomas and DNA microarray gene expression data from tumors of glioblastoma patients of age >50 for whom survival is known. No prognostic significance was associated with genetic changes in epidermal growth factor receptor (amplified in 17 of 41 patients), TP53 (mutated in 11 of 41 patients), p16INK4A (deleted in 15 of 33 patients), or phosphatase and tensin homologue (mutated in 15 of 41 patients). Statistical analysis of the gene expression data in connection with survival involved exploration of regression models on small subsets of genes, based on computational search over multiple regression models with cross-validation to assess predictive validity. The analysis generated a set of regression models that, when weighted and combined according to posterior probabilities implied by the statistical analysis, identify patterns in expression of a small subset of genes that are associated with survival and have value in assessing survival risks. The dominant genes across such multiple regression models involve three key genes-SPARC (Osteonectin), Doublecortex, and Semaphorin3B-which play key roles in cellular migration processes. Additional analysis, based on statistical graphical association models constructed using similar computational analysis methods, reveals other genes which support the view that multiple mediators of tumor invasion may be important prognostic factor in glioblastomas in older patients.

Authors
Rich, JN; Hans, C; Jones, B; Iversen, ES; McLendon, RE; Rasheed, BKA; Dobra, A; Dressman, HK; Bigner, DD; Nevins, JR; West, M
MLA Citation
Rich, JN, Hans, C, Jones, B, Iversen, ES, McLendon, RE, Rasheed, BKA, Dobra, A, Dressman, HK, Bigner, DD, Nevins, JR, and West, M. "Gene expression profiling and genetic markers in glioblastoma survival." Cancer Res 65.10 (May 15, 2005): 4051-4058.
PMID
15899794
Source
pubmed
Published In
Cancer Research
Volume
65
Issue
10
Publish Date
2005
Start Page
4051
End Page
4058
DOI
10.1158/0008-5472.CAN-04-3936

Accreditation council for graduate medical education (ACGME) competencies in neuropathology training.

The Accreditation Council for Graduate Medical Education (ACGME) has defined 6 core competencies for all physicians: patient care; medical knowledge; practice-based learning and improvement; interpersonal and communication skills; professionalism; and systems-based practice. However, the specific wording of the descriptions often assumes that the physician is a clinician rather than a pathologist. Therefore, the American Association of Neuropathologists, Inc. asked its Professional Affairs Committee to examine the core competencies and determine how they relate to training in neuropathology. The Committee's report is presented here in 6 sections, corresponding to the 6 competencies. In each section, the ACGME definition of that particular competency is either quoted directly or, more often, modified slightly to clarify how the competency applies to neuropathology. Each of the defined competencies is then followed by possible assessment tools, selected from those recommended in the ACGME's "toolbox." Specific suggestions are given for designing tools that apply to neuropathology. Many of the suggested activities and documentation methods can be combined into efficient, carefully formulated training/evaluation exercises. Different tools may be more applicable in some training programs.

Authors
Crain, BJ; Alston, SR; Bruch, LA; Hamilton, RL; McLendon, RE; Rhodes, CH; Tihan, T; Weidenheim, KM
MLA Citation
Crain, BJ, Alston, SR, Bruch, LA, Hamilton, RL, McLendon, RE, Rhodes, CH, Tihan, T, and Weidenheim, KM. "Accreditation council for graduate medical education (ACGME) competencies in neuropathology training." J Neuropathol Exp Neurol 64.4 (April 2005): 273-279.
PMID
15835263
Source
pubmed
Published In
Journal of Neuropathology and Experimental Neurology
Volume
64
Issue
4
Publish Date
2005
Start Page
273
End Page
279

Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid.

Through digital karyotyping of permanent medulloblastoma cell lines, we found that the homeobox gene OTX2 was amplified more than 10-fold in three cell lines. Gene expression analyses showed that OTX2 transcripts were present at high levels in 14 of 15 (93%) medulloblastomas with anaplastic histopathologic features. Knockdown of OTX2 expression by siRNAs inhibited medulloblastoma cell growth in vitro, whereas pharmacologic doses of all-trans retinoic acid repressed OTX2 expression and induced apoptosis only in medulloblastoma cell lines that expressed OTX2. These observations suggest that OTX2 is essential for the pathogenesis of anaplastic medulloblastomas and that these tumors may be amenable to therapy with all-trans-retinoic acid.

Authors
Di, C; Liao, S; Adamson, DC; Parrett, TJ; Broderick, DK; Shi, Q; Lengauer, C; Cummins, JM; Velculescu, VE; Fults, DW; McLendon, RE; Bigner, DD; Yan, H
MLA Citation
Di, C, Liao, S, Adamson, DC, Parrett, TJ, Broderick, DK, Shi, Q, Lengauer, C, Cummins, JM, Velculescu, VE, Fults, DW, McLendon, RE, Bigner, DD, and Yan, H. "Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid." Cancer Res 65.3 (February 1, 2005): 919-924.
PMID
15705891
Source
pubmed
Published In
Cancer Research
Volume
65
Issue
3
Publish Date
2005
Start Page
919
End Page
924

Sustained radiographic and clinical response in patient with bifrontal recurrent glioblastoma multiforme with intracerebral infusion of the recombinant targeted toxin TP-38: case study.

Glioblastoma multiforme remains refractory to conventional therapy, and novel therapeutic modalities are desperately needed. TP-38 is a recombinant chimeric protein containing a genetically engineered form of the cytotoxic Pseudomonas exotoxin fused to transforming growth factor (TGF)-alpha. TGF-alpha binds with high affinity to the epidermal growth factor receptor, which is uniformly overexpressed in malignant gliomas, often because of gene amplification. Prior to therapy with TP-38, the patient described here was completely refractory to multiple other therapies, with radiographic and pathologic evidence of tumor progression. After therapy, she improved clinically, was weaned off steroids and anti-convulsants, and experienced a progressive decrease in enhancing tumor volume. Despite multiple prior recurrences, she has not progressed for >43 months after TP-38 therapy. Small remaining areas of enhancement demonstrate no evidence of tumor histologically and are hypometabolic on positron emission tomography. This report describes a dramatic and sustained clinical and radiographic response in a patient with a bifrontal glioblastoma multiforme treated with intratumoral infusion of a novel targeted toxin, TP-38.

Authors
Sampson, JH; Reardon, DA; Friedman, AH; Friedman, HS; Coleman, RE; McLendon, RE; Pastan, I; Bigner, DD
MLA Citation
Sampson, JH, Reardon, DA, Friedman, AH, Friedman, HS, Coleman, RE, McLendon, RE, Pastan, I, and Bigner, DD. "Sustained radiographic and clinical response in patient with bifrontal recurrent glioblastoma multiforme with intracerebral infusion of the recombinant targeted toxin TP-38: case study." Neuro Oncol 7.1 (January 2005): 90-96.
PMID
15701286
Source
pubmed
Published In
Neuro-Oncology
Volume
7
Issue
1
Publish Date
2005
Start Page
90
End Page
96
DOI
10.1215/S1152851703000589

Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition.

Malignant gliomas are highly lethal tumors that display striking genetic heterogeneity. Novel therapies that inhibit a single molecular target may slow tumor progression, but tumors are likely not dependent on a signal transduction pathway. Rather, malignant gliomas exhibit sustained mitogenesis and cell growth mediated in part through the effects of receptor tyrosine kinases and the mammalian target of rapamycin (mTOR). AEE788 is a novel orally active tyrosine kinase inhibitor that decreases the kinase activity associated with the epidermal growth factor receptor and, at higher concentrations, the vascular endothelial growth factor receptor 2 (kinase domain region). RAD001 (everolimus) is an orally available mTOR inhibitor structurally related to rapamycin. We hypothesized that combined inhibition of upstream epidermal growth factor receptor and kinase domain region receptors with AEE788 and inhibition of the downstream mTOR pathway with RAD001 would result in increased efficacy against gliomas compared with single-agent therapy. In vitro experiments showed that the combination of AEE788 and RAD001 resulted in increased rates of cell cycle arrest and apoptosis and reduced proliferation more than either agent alone. Combined AEE788 and RAD001 given orally to athymic mice bearing established human malignant glioma tumor xenografts resulted in greater tumor growth inhibition and greater increases in median survival than monotherapy. These studies suggest that simultaneous inhibition of growth factor receptor and mTOR pathways offer increased benefit in glioma therapy.

Authors
Goudar, RK; Shi, Q; Hjelmeland, MD; Keir, ST; McLendon, RE; Wikstrand, CJ; Reese, ED; Conrad, CA; Traxler, P; Lane, HA; Reardon, DA; Cavenee, WK; Wang, X-F; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Goudar, RK, Shi, Q, Hjelmeland, MD, Keir, ST, McLendon, RE, Wikstrand, CJ, Reese, ED, Conrad, CA, Traxler, P, Lane, HA, Reardon, DA, Cavenee, WK, Wang, X-F, Bigner, DD, Friedman, HS, and Rich, JN. "Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition." Mol Cancer Ther 4.1 (January 2005): 101-112.
PMID
15657358
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
4
Issue
1
Publish Date
2005
Start Page
101
End Page
112

Ependymoma

Authors
Friedman, AH; McLendon, RE; Provenzale, JN; Friedman, HS
MLA Citation
Friedman, AH, McLendon, RE, Provenzale, JN, and Friedman, HS. "Ependymoma." Textbook of Neuro-Oncology (2005): 190-198.
Source
scival
Published In
Textbook of Neuro-Oncology
Publish Date
2005
Start Page
190
End Page
198
DOI
10.1016/B978-0-7216-8148-1.50028-0

Meningioma with eosinophilic granular inclusions.

Rare meningiomas have been described that contain eosinophilic inclusions that have a granular or granulofilamentous ultrastructure. We describe a 66-year-old woman who developed a planum sphenoidale meningioma. Histologically, the tumor was composed of meningothelial cells arranged in fascicles and whorls, typical of a well-differentiated meningioma. Many tumor cells contained round intracytoplasmic eosinophilic inclusions that were periodic acid Schiff-negative and red on Masson trichrome. The inclusions were immunopositive for vimentin, and were immunonegative for epithelial membrane antigen, smooth muscle actin, desmin and type IV collagen. Ultrastructural examination showed the inclusions were composed of round to oval, well-demarcated, non-membrane-bound, osmiophilic granular material. The inclusions within this tumor had histochemical, immunohistochemical and ultrastructural properties not described in other reported meningiomas with eosinophilic granular or granulofilamentous inclusions.

Authors
Alexander, RT; McLendon, RE; Cummings, TJ
MLA Citation
Alexander, RT, McLendon, RE, and Cummings, TJ. "Meningioma with eosinophilic granular inclusions." Clin Neuropathol 23.6 (November 2004): 292-297.
PMID
15584214
Source
pubmed
Published In
Clinical neuropathology
Volume
23
Issue
6
Publish Date
2004
Start Page
292
End Page
297

Detection and immunologic recognition of cytomegalovirus antigens expressed within malignant gliomas

Authors
Mitchell, DA; Learn, C; Schmittling, R; Friedman, A; McLendon, RE; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, DA, Learn, C, Schmittling, R, Friedman, A, McLendon, RE, Bigner, DD, and Sampson, JH. "Detection and immunologic recognition of cytomegalovirus antigens expressed within malignant gliomas." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
343
End Page
343

Inhibition of receptor tyrosine kinases and mammalian target of rapamycin offers combinatorial benefit in tumor control

Authors
Gondar, RK; Hjelmeland, MD; Keir, ST; Conrad, CA; McLendon, RE; Wikstrand, CJ; Traxler, P; Lane, HA; Reardon, DA; Cavenee, WK; Wang, XF; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Gondar, RK, Hjelmeland, MD, Keir, ST, Conrad, CA, McLendon, RE, Wikstrand, CJ, Traxler, P, Lane, HA, Reardon, DA, Cavenee, WK, Wang, XF, Bigner, DD, Friedman, HS, and Rich, JN. "Inhibition of receptor tyrosine kinases and mammalian target of rapamycin offers combinatorial benefit in tumor control." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
407
End Page
407

Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas.

The phosphatidylinositol 3'-kinase pathway is activated in multiple advanced cancers, including glioblastomas, through inactivation of the PTEN tumor suppressor gene. Recently, mutations in PIK3CA, a member of the family of phosphatidylinositol 3'-kinase catalytic subunits, were identified in a significant fraction (25-30%) of colorectal cancers, gastric cancers, and glioblastomas and in a smaller fraction of breast and lung cancers. These mutations were found to cluster into two major "hot spots" located in the helical and catalytic domains. To determine whether PIK3CA is genetically altered in brain tumors, we performed a large-scale mutational analysis of the helical and catalytic domains. A total of 13 mutations of PIK3CA within these specific domains were identified in anaplastic oligodendrogliomas, anaplastic astrocytomas, glioblastoma multiforme, and medulloblastomas, whereas no mutations were identified in ependymomas or low-grade astrocytomas. These observations implicate PIK3CA as an oncogene in a wider spectrum of adult and pediatric brain tumors and suggest that PIK3CA may be a useful diagnostic marker or a therapeutic target in these cancers.

Authors
Broderick, DK; Di, C; Parrett, TJ; Samuels, YR; Cummins, JM; McLendon, RE; Fults, DW; Velculescu, VE; Bigner, DD; Yan, H
MLA Citation
Broderick, DK, Di, C, Parrett, TJ, Samuels, YR, Cummins, JM, McLendon, RE, Fults, DW, Velculescu, VE, Bigner, DD, and Yan, H. "Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas." Cancer Res 64.15 (August 1, 2004): 5048-5050.
PMID
15289301
Source
pubmed
Published In
Cancer Research
Volume
64
Issue
15
Publish Date
2004
Start Page
5048
End Page
5050
DOI
10.1158/0008-5472.CAN-04-1170

Comparative genomic hybridization analysis of astrocytomas: prognostic and diagnostic implications.

Astrocytoma is comprised of a group of common intracranial neoplasms that are classified into four grades based on the World Health Organization histological criteria and patient survival. To date, histological grade, patient age, and clinical performance, as reflected in the Karnofsky score, are the most reliable prognostic predictors. Recently, there has been a significant effort to identify additional prognostic markers using objective molecular genetic techniques. We believe that the identification of such markers will characterize new chromosomal loci important in astrocytoma progression and aid clinical diagnosis and prognosis. To this end, our laboratory used comparative genomic hybridization to identify DNA sequence copy number changes in 102 astrocytomas. Novel losses of 19p loci were detected in low-grade pilocytic astrocytomas and losses of loci on 9p, 10, and 22 along with gains on 7, 19, and 20 were detected in a significant proportion of high-grade astrocytomas. The Cox proportional hazards statistical modeling showed that the presence of +7q and -10q comparative genomic hybridization alterations significantly increased a patient's risk of dying, independent of histological grade. This investigation demonstrates the efficacy of comparative genomic hybridization for identifying tumor suppressor and oncogene loci in different astrocytic grades. The cumulative effect of these loci is an important consideration in their diagnostic and prognostic implications.

Authors
Wiltshire, RN; Herndon, JE; Lloyd, A; Friedman, HS; Bigner, DD; Bigner, SH; McLendon, RE
MLA Citation
Wiltshire, RN, Herndon, JE, Lloyd, A, Friedman, HS, Bigner, DD, Bigner, SH, and McLendon, RE. "Comparative genomic hybridization analysis of astrocytomas: prognostic and diagnostic implications." J Mol Diagn 6.3 (August 2004): 166-179.
PMID
15269292
Source
pubmed
Published In
The Journal of molecular diagnostics : JMD
Volume
6
Issue
3
Publish Date
2004
Start Page
166
End Page
179
DOI
10.1016/S1525-1578(10)60507-7

Correlation of 1p-19q-defects in human gliomas with the light microscopic appearance of oligodendroglioma.

Authors
McLendon, RE; Rasheed, A; Wiltshire, R; Herndon, J
MLA Citation
McLendon, RE, Rasheed, A, Wiltshire, R, and Herndon, J. "Correlation of 1p-19q-defects in human gliomas with the light microscopic appearance of oligodendroglioma." Mod Pathol 17.5 (May 2004): 604-605. (Letter)
PMID
15105803
Source
pubmed
Published In
Modern Pathology
Volume
17
Issue
5
Publish Date
2004
Start Page
604
End Page
605
DOI
10.1038/modpathol.3800077

Fish markers in diffuse astrocytomas.

Authors
Mott, RT; Turner, KC; McLendon, RE
MLA Citation
Mott, RT, Turner, KC, and McLendon, RE. "Fish markers in diffuse astrocytomas." May 2004.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
63
Issue
5
Publish Date
2004
Start Page
538
End Page
538

Phase II trial of gefitinib in recurrent glioblastoma.

PURPOSE: To evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. PATIENTS AND METHODS: This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. RESULTS: Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-week cycles, and the 6-month event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 weeks, and the median overall survival (OS) time from treatment initiation was 39.4 weeks. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea positively predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. CONCLUSION: Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.

Authors
Rich, JN; Reardon, DA; Peery, T; Dowell, JM; Quinn, JA; Penne, KL; Wikstrand, CJ; Van Duyn, LB; Dancey, JE; McLendon, RE; Kao, JC; Stenzel, TT; Ahmed Rasheed, BK; Tourt-Uhlig, SE; Herndon, JE; Vredenburgh, JJ; Sampson, JH; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Rich, JN, Reardon, DA, Peery, T, Dowell, JM, Quinn, JA, Penne, KL, Wikstrand, CJ, Van Duyn, LB, Dancey, JE, McLendon, RE, Kao, JC, Stenzel, TT, Ahmed Rasheed, BK, Tourt-Uhlig, SE, Herndon, JE, Vredenburgh, JJ, Sampson, JH, Friedman, AH, Bigner, DD, and Friedman, HS. "Phase II trial of gefitinib in recurrent glioblastoma." J Clin Oncol 22.1 (January 1, 2004): 133-142.
PMID
14638850
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
22
Issue
1
Publish Date
2004
Start Page
133
End Page
142
DOI
10.1200/JCO.2004.08.110

The pathology of extracranial scalp and skull masses in young children.

OBJECTIVE: Extracranial subcutaneous masses involving the scalp and/or skull in young children are uncommon lesions that get excised by the neurosurgeon. Although the most common reported lesion is the dermoid cyst, our experience suggests that the spectrum of pathology in these lesions can present diagnostic challenges to the pathologist. MATERIAL: We reviewed 30 consecutive extracranial masses from 29 patients between July 1998 and June 2003. METHOD: Hematoxylin and eosin-stained sections were reviewed in all cases, and immunohistochemistry was performed in select cases. RESULTS: Twenty-three were within the scalp, 5 involved the scalp and skull and 2 were within the limits of the inner and outer tables of the skull. There were 8 dermoid cysts, 2 epidermoid cysts, 6 post-traumatic lesions including 3 calcified cephalhematomas and 3 pseudocysts, 5 vascular lesions including 3 capillary hemangiomas, 1 venous angioma and 1 lymphangioma, 2 cases of cranial fasciitis and 1 case each of benign teratoma, deep granuloma annulare, benign fibrous histiocytoma, congenital melanocytic nevus, hamartoma with ectopic meningothelial elements, cutaneous hyalinised ectopic meningioma and a meningocele with a fibrohistiocytic reaction. No lesions have recurred or exhibited malignant features. CONCLUSIONS: Surgical pathologists and neuropathologists should be aware that the differential diagnosis of "lumps and bumps on babie's heads" is quite varied and can be histologically challenging.

Authors
Cummings, TJ; George, TM; Fuchs, HE; McLendon, RE
MLA Citation
Cummings, TJ, George, TM, Fuchs, HE, and McLendon, RE. "The pathology of extracranial scalp and skull masses in young children." Clin Neuropathol 23.1 (January 2004): 34-43.
PMID
14986932
Source
pubmed
Published In
Clinical neuropathology
Volume
23
Issue
1
Publish Date
2004
Start Page
34
End Page
43

The double-stranded RNA-activated protein kinase mediates viral-induced encephalitis.

The double-stranded (ds) RNA-activated protein kinase (PKR) plays an important role in control of viral infections and cell growth. We have studied the role of PKR in viral infection in mice that are defective in the PKR signaling pathway. Transgenic mice were derived that constitutively express a trans-dominant-negative kinase-defective mutant PKR under control of the beta-actin promoter. The trans-dominant-negative PKR mutant expressing transgenic mice do not have a detectable phenotype, similar to observations with PKR knock-out mice. The requirement for PKR in viral pathogenesis was studied by intracerebral infection of mice with a mouse-adapted poliovirus. Histopathological analysis revealed diffuse encephalomyelitis with severe inflammatory lesions throughout the central nervous system (CNS) in infected wild-type mice. In contrast, histopathological evaluation of virus-injected trans-dominant-negative PKR transgenic mice as well as PKR knock-out mice yielded no signs of tissue damage associated with inflammatory host responses. However, the virus did replicate in both models of PKR-deficient mice at a level equal to that observed in wild-type infected mice. Although the results indicate a clear difference in susceptibility to poliovirus-induced encephalitis, this difference manifests clinically as a slight delay in fatal neuropathy in trans-dominant-negative PKR transgenic and PKR knock-out animals. Our observations support the finding that viral-induced PKR activation may play a significant role in pathogenesis by mediating the host response to viral CNS infection. They support PKR to be an effective target to control tissue damage due to deleterious host responses to viral infection.

Authors
Scheuner, D; Gromeier, M; Davies, MV; Dorner, AJ; Song, B; Patel, RV; Wimmer, EJ; McLendon, RE; Kaufman, RJ
MLA Citation
Scheuner, D, Gromeier, M, Davies, MV, Dorner, AJ, Song, B, Patel, RV, Wimmer, EJ, McLendon, RE, and Kaufman, RJ. "The double-stranded RNA-activated protein kinase mediates viral-induced encephalitis." Virology 317.2 (December 20, 2003): 263-274.
PMID
14698665
Source
pubmed
Published In
Virology
Volume
317
Issue
2
Publish Date
2003
Start Page
263
End Page
274

Efficacy of intracerebral microinfusion of trastuzumab in an athymic rat model of intracerebral metastatic breast cancer.

PURPOSE: The monoclonal antibody (MAb) trastuzumab (Herceptin) effectively treats HER2-overexpressing extracerebral breast neoplasms. Delivery of such macromolecule therapeutic agents to intracerebral metastases, however, is limited by the tight junctions characteristic of the cerebral vasculature. Direct intracerebral microinfusion (ICM) is a technique that bypasses this blood-brain barrier and allows for a greater delivery of drugs directly into intracerebral tumors. EXPERIMENTAL DESIGN: A human breast cancer cell line transfected to overexpress HER2, MCF-7/HER2-18, was transplanted into the cerebrum of athymic rats. Saline, trastuzumab, or an isotype-matched control MAb was delivered systemically or by ICM to assess toxicity and efficacy. RESULTS: No clinical or histological toxicity related to trastuzumab was evident under any of the conditions studied. Delivery of trastuzumab (2 mg/kg) i.p. led to a median survival of 26.5 days, whereas treatment with trastuzumab (2 mg/kg) by ICM increased the median survival by 96% to 52 days, with two of nine rats surviving >120 days (P = 0.009). Treatment with an isotype-matched control MAb (16 mg/kg) resulted in a median survival of 21 days, which did not differ significantly from the survival of rats treated by ICM with saline (16 days; P = 0.42). Treatment by ICM with trastuzumab (16 mg/kg) led to a median survival of 45 days, with 2 of 10 rats surviving >120 days. These results represent 181% and 114% increases in median survival over the saline and MAb controls, respectively (P < 0.001). CONCLUSION: ICM of trastuzumab is safe and superior to systemic delivery as therapy for HER2-overexpressing intracerebral neoplasms in an athymic rat model.

Authors
Grossi, PM; Ochiai, H; Archer, GE; McLendon, RE; Zalutsky, MR; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Grossi, PM, Ochiai, H, Archer, GE, McLendon, RE, Zalutsky, MR, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Efficacy of intracerebral microinfusion of trastuzumab in an athymic rat model of intracerebral metastatic breast cancer." Clin Cancer Res 9.15 (November 15, 2003): 5514-5520.
PMID
14654531
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
15
Publish Date
2003
Start Page
5514
End Page
5520

Is the long-term survival of patients with intracranial glioblastoma multiforme overstated?

BACKGROUND: The 5-year survival rate for intracranial glioblastoma multiforme (GBM) has remained at 4-5% for the last 30 years, in spite of multiple randomized prospective trials. The authors hypothesized, based on the literature, that even this remarkably poor survival rate is an overstatement. They investigated this hypothesis using the the Duke University Medical Center Tumor Registry. METHODS: The authors reviewed all patients with the diagnosis of intracranial GBM recorded in the Duke University Medical Center Tumor Registry from the registry's inception in 1976 through 1996. This search identified a population of patients with a minimum of 5 years of follow-up. Each of the long-term survivors was assigned a code number for clinical information. The pathology slides were provided to a neuropathologist in a coded fashion so that the patients could not be identified. The neuropathologist reviewed the slides to analyze the presence or absence of nine histologic factors. A match technique was used to identify a control population of patients with GBM who were not 5-year survivors and were all deceased. The control population was compared with the study population to ascertain if there are histologic correlates associated with long-term survivorship. RESULTS: The authors identified 766 patients recorded by the tumor registry as having an intracranial GBM with a minimum of 5 years of follow up. Of the total population, 32 patients initially appeared to be 5-year survivors (4%). Upon review of the medical records for these 32 patients, however, the authors found only 17 patients who were truly 5-year survivors. The most common reason for miscoding was the presence of a low-grade astrocytoma that subsequently dedifferentiated into GBM. The 17 long-term survivors included 11 males and 6 females. Their mean age at diagnosis was 40.2 years. Therapy consisted of a macroscopic total resection in 4 patients (22%), a biopsy in 1 patient (6%), a subtotal resection in 10 patients (56%), and unknown extent of resection in 2 patients (11%). All patients received partial brain irradiation (mean dose, 62.6 Gy) and chemotherapy. Thirteen different single-agent or combination chemotherapy programs were used. Two patients also received I-131 monoclonal antibody therapy. Analysis of the nine histopathologic factors studied showed that intermediate fibrillary elements were more common and small anaplastic elements were less common in the long-term survivors than in the control population. CONCLUSIONS: Survival data on intracranial GBM, based on tumor registry data, should be interpreted cautiously. Reliable conclusions can only be drawn when such data are supplemented with clinical information and the histopathology is reviewed carefully. The group of long-term survivors in the current study were younger than the typical GBM population. Conventionally treated patients with GBM, chosen from an unselected population from a tumor registry, have a smaller chance of long-term survival than is generally believed.

Authors
McLendon, RE; Halperin, EC
MLA Citation
McLendon, RE, and Halperin, EC. "Is the long-term survival of patients with intracranial glioblastoma multiforme overstated?." Cancer 98.8 (October 15, 2003): 1745-1748.
PMID
14534892
Source
pubmed
Published In
Cancer
Volume
98
Issue
8
Publish Date
2003
Start Page
1745
End Page
1748
DOI
10.1002/cncr.11666

Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors.

TP-38 is a recombinant chimeric targeted toxin composed of the EGFR binding ligand TGF-alpha and a genetically engineered form of the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum tolerated dose (MTD), we investigated this agent in a Phase I trial. The primary objective of this study was to define the MTD and dose limiting toxicity of TP-38 delivered by convection-enhanced delivery in patients with recurrent malignant brain tumors. Twenty patients were enrolled in the study and doses were escalated from 25 ng/mL to 100 with a 40 mL infusion volume delivered by two catheters. One patient developed Grade IV fatigue at the 100 ng/mL dose, but the MTD has not been established. The overall median survival after TP-38 for all patients was 23 weeks whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients, with residual disease at the time of therapy, have demonstrated radiographic responses and one patient with a complete response and has survived greater than 83 weeks.

Authors
Sampson, JH; Akabani, G; Archer, GE; Bigner, DD; Berger, MS; Friedman, AH; Friedman, HS; Herndon, JE; Kunwar, S; Marcus, S; McLendon, RE; Paolino, A; Penne, K; Provenzale, J; Quinn, J; Reardon, DA; Rich, J; Stenzel, T; Tourt-Uhlig, S; Wikstrand, C; Wong, T; Williams, R; Yuan, F; Zalutsky, MR; Pastan, I
MLA Citation
Sampson, JH, Akabani, G, Archer, GE, Bigner, DD, Berger, MS, Friedman, AH, Friedman, HS, Herndon, JE, Kunwar, S, Marcus, S, McLendon, RE, Paolino, A, Penne, K, Provenzale, J, Quinn, J, Reardon, DA, Rich, J, Stenzel, T, Tourt-Uhlig, S, Wikstrand, C, Wong, T, Williams, R, Yuan, F, Zalutsky, MR, and Pastan, I. "Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors." J Neurooncol 65.1 (October 2003): 27-35.
PMID
14649883
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
65
Issue
1
Publish Date
2003
Start Page
27
End Page
35

High-dose chemotherapy with autologous stem-cell rescue in children and adults with newly diagnosed pineoblastomas.

PURPOSE: We evaluated the usefulness of a treatment regimen that included high-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) in patients with newly diagnosed pineoblastoma (PBL). PATIENTS AND METHODS: Twelve patients with PBL were initially treated with surgery and induction chemotherapy. All but two patients underwent radiotherapy. Subsequently, all patients received HDC using cyclophosphamide (CTX) + melphalan (MEL) or busulfan (Bu) + MEL regimens and ASCR. RESULTS: A total of six children and six adults with median ages of 4.2 (range, 0.3 to 19.8 years) and 23 years (range, 23 to 43.7 years), respectively, were treated according to this strategy. Four patients had metastatic disease confined to the neuraxis. Five of 12 patients (42%) had a complete tumor resection at diagnosis. Ten patients received radiotherapy at median doses of 36.0 and 59.4 Gy to the neuraxis and pineal region, respectively. Eleven patients received HDC with CTX + MEL, and one patient received BU + MEL followed by ASCR. Nine patients are alive with no evidence of disease recurrence at a median of 62 months from diagnosis (range, 28 to 125 months), including three patients with metastatic disease and two infants who did not receive any radiotherapy. Three patients have died of progressive disease at 19, 32, and 37 months from diagnosis, respectively. The actuarial 4-year progression-free and overall survivals are 69% (95% confidence interval [CI], 39% to 99%) and 71% (95% CI, 43% to 99%), respectively. CONCLUSION: The use of HDC in addition to radiotherapy seems to be an effective treatment for patients with newly diagnosed pineoblastoma.

Authors
Gururangan, S; McLaughlin, C; Quinn, J; Rich, J; Reardon, D; Halperin, EC; Herndon, J; Fuchs, H; George, T; Provenzale, J; Watral, M; McLendon, RE; Friedman, A; Friedman, HS; Kurtzberg, J; Vredenbergh, J; Martin, PL
MLA Citation
Gururangan, S, McLaughlin, C, Quinn, J, Rich, J, Reardon, D, Halperin, EC, Herndon, J, Fuchs, H, George, T, Provenzale, J, Watral, M, McLendon, RE, Friedman, A, Friedman, HS, Kurtzberg, J, Vredenbergh, J, and Martin, PL. "High-dose chemotherapy with autologous stem-cell rescue in children and adults with newly diagnosed pineoblastomas." J Clin Oncol 21.11 (June 1, 2003): 2187-2191.
PMID
12775745
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
21
Issue
11
Publish Date
2003
Start Page
2187
End Page
2191
DOI
10.1200/JCO.2003.10.096

Sub-classification of glioblastoma defined by comparative genomic hybridization alterations.

Authors
McLendon, RE; Wiltshire, RN; Herndon, JE; Lloyd, A; Friedman, HS; Bigner, DD; Bigner, SH
MLA Citation
McLendon, RE, Wiltshire, RN, Herndon, JE, Lloyd, A, Friedman, HS, Bigner, DD, and Bigner, SH. "Sub-classification of glioblastoma defined by comparative genomic hybridization alterations." May 2003.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
62
Issue
5
Publish Date
2003
Start Page
542
End Page
542

Primary anaplastic large cell lymphoma of the central nervous system: prognostic effect of ALK-1 expression.

Anaplastic large cell lymphoma (ALCL) rarely occurs in the central nervous system. Although defined by its composition of large, pleomorphic, CD30-positive lymphocytes, ALCL is heterogeneous. Most are T cell but some are null cell. Most but not all have a characteristic 2:5 translocation producing the fusion protein ALK-1, which is reliably detected by immunohistochemistry. In systemic ALCL, ALK-1 expression correlates with young patient age and a favorable prognosis. Herein we report four new cases of primary central nervous system ALCL from the Mayo Clinic and incorporate additional data from five previously published cases. ALK-1 expression was determined in all nine tumors. Patient age was 4-66 years (mean 29 years) with a bimodal distribution: 6 < or = 22 years, 3 > or = 50 years. Six were female. Tumors were mostly supratentorial, five were multifocal, and seven had involvement of dura or leptomeninges. Seven tumors were T cell, two were null cell, and five of nine were ALK-1 immunopositive. Total mortality was six of nine. Three patients, 4-18 years of age (mean 13 years), were alive at 4.8-6.1 years postdiagnosis; these tumors were all ALK positive. Five patients, 13-66 years of age (mean 43 years), died of tumor 4 days to 11 weeks postdiagnosis; four of five of these tumors were ALK negative. One 10-year-old child with an ALK-positive tumor died of sepsis, but in remission. Central nervous system ALCL is aggressive. Our study suggests that a better outcome may be associated with young age and ALK-1 positivity, prognostic parameters similar to systemic ALCL.

Authors
George, DH; Scheithauer, BW; Aker, FV; Kurtin, PJ; Burger, PC; Cameselle-Teijeiro, J; McLendon, RE; Parisi, JE; Paulus, W; Roggendorf, W; Sotelo, C
MLA Citation
George, DH, Scheithauer, BW, Aker, FV, Kurtin, PJ, Burger, PC, Cameselle-Teijeiro, J, McLendon, RE, Parisi, JE, Paulus, W, Roggendorf, W, and Sotelo, C. "Primary anaplastic large cell lymphoma of the central nervous system: prognostic effect of ALK-1 expression." Am J Surg Pathol 27.4 (April 2003): 487-493. (Review)
PMID
12657933
Source
pubmed
Published In
American Journal of Surgical Pathology
Volume
27
Issue
4
Publish Date
2003
Start Page
487
End Page
493

Phase II trial of temozolomide in patients with progressive low-grade glioma.

PURPOSE: Temozolomide (Temodar; Schering-Plough Corp, Kenilworth, NJ) is an imidazole tetrazinone that undergoes chemical conversion to the active methylating agent 5-(3-methyltriazen-1yl)imidazole-4-carboximide under physiologic conditions. Previous studies have confirmed activity of Temodar in the treatment of progressive and newly diagnosed malignant gliomas. We have extended these results, and now we report results of a phase II trial of Temodar for patients with progressive, low-grade glioma. PATIENTS AND METHODS: Temodar was administered orally once a day for five consecutive days (in a fasting state) at a starting dose of 200 mg/m(2)/d. Treatment cycles were repeated every 28 days following the first daily dose of Temodar. Response criteria used a combination of magnetic resonance imaging and physical examination to evaluate activity. RESULTS: Forty-six patients with low-grade glioma have been treated to date. The objective response rate was 61% (24% complete response and 37% partial response), with an additional 35% of patients having stable disease. Median progression-free survival (PFS) was 22 months (95% confidence interval [CI], 15 to infinity months) with a 6-month PFS of 98% (95% CI, 94% to 100%) and a 12-month PFS of 76% (95% CI, 63% to 92%). Toxicity observed during the study was limited to only six patients. Three patients experienced grade 3 neutropenia, with a duration greater than 3 weeks in one patient, and two patients experienced grade 3 thrombocytopenia. One patient experienced > or = grade 4 toxicity, with intracerebral hemorrhage, neutropenia, thrombocytopenia, sepsis, and death. CONCLUSION: Initial results indicate that Temodar may be active in the treatment of low-grade glioma, and thus, further evaluation of this agent in the treatment of these tumors is warranted.

Authors
Quinn, JA; Reardon, DA; Friedman, AH; Rich, JN; Sampson, JH; Provenzale, JM; McLendon, RE; Gururangan, S; Bigner, DD; Herndon, JE; Avgeropoulos, N; Finlay, J; Tourt-Uhlig, S; Affronti, ML; Evans, B; Stafford-Fox, V; Zaknoen, S; Friedman, HS
MLA Citation
Quinn, JA, Reardon, DA, Friedman, AH, Rich, JN, Sampson, JH, Provenzale, JM, McLendon, RE, Gururangan, S, Bigner, DD, Herndon, JE, Avgeropoulos, N, Finlay, J, Tourt-Uhlig, S, Affronti, ML, Evans, B, Stafford-Fox, V, Zaknoen, S, and Friedman, HS. "Phase II trial of temozolomide in patients with progressive low-grade glioma." J Clin Oncol 21.4 (February 15, 2003): 646-651.
PMID
12586801
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
21
Issue
4
Publish Date
2003
Start Page
646
End Page
651
DOI
10.1200/JCO.2003.01.009

Vascular targeted endoradiotherapy of tumors using alpha-particle-emitting compounds: theoretical analysis.

PURPOSE: To establish the theoretical framework and study the feasibility of (211)At-labeled anti-tenascin chimeric 81C6 monoclonal antibody (mAb) as anti-vascular endoradiotherapy for the treatment of glioblastoma multiforme (GBM) tumors. METHODS AND MATERIALS: The morphology of blood vessels from histologic images was analyzed and used along with reaction-diffusion equations to assess the activity concentration of (211)At-labeled chimeric 81C6 mAb in GBM tumor and normal-brain tissue. Alpha particle microdosimetry was then used to assess the survival probability and average absorbed dose for tumor and normal tissue endothelial cells (ECs) per unit vascular cumulated activity concentration q(source) (MBq-s g(-1)). In turn, these survival probabilities were used to assess the probability of failure Phi for a single vessel. Furthermore, using the vessel density, the specific tumor control probability per unit mass of tumor tissue (tcp) and the specific normal-tissue complication probability per unit mass of normal-brain tissue (ntcp) were estimated. The specific tumor control probability, tcp, was used to assess the overall tumor control probability (TCP) as a function of tumor mass. RESULTS: The levels of (211)At-labeled ch81C6 mAb cumulated activity concentration in GBM tumor tissue were approximately five times higher than that in normal-brain tissue. Thus, the average absorbed dose to tumor ECs was higher than that of normal tissue ECs, and the survival probability for GBM ECs was lower than for normal-brain tissue ECs. Consequently, the resulting vessel-failure probability, Phi, for GBM tumor and for normal-brain tissue differ considerably, yielding a q(source) range between 10(3) and 10(4) MBq-s g(-1). CONCLUSIONS: This theoretical analysis demonstrated that (211)At-labeled chimeric 81C6 is an effective anti-vascular therapy for the treatment of GBM tumors, yielding a tcp higher than 0.999 for vascular cumulated activity concentrations q(source) higher than 1 x 10(4) MBq-s g(-1), while yielding a low probability for normal-brain tissue damage.

Authors
Akabani, G; McLendon, RE; Bigner, DD; Zalutsky, MR
MLA Citation
Akabani, G, McLendon, RE, Bigner, DD, and Zalutsky, MR. "Vascular targeted endoradiotherapy of tumors using alpha-particle-emitting compounds: theoretical analysis." Int J Radiat Oncol Biol Phys 54.4 (November 15, 2002): 1259-1275.
PMID
12419456
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
54
Issue
4
Publish Date
2002
Start Page
1259
End Page
1275

Biphasic malignant meningioma: a comparative genomic hybridization study.

To ascertain if a carcinoma-like component within a fibroblastic meningioma represented a metastatic carcinoma to a meningioma or malignant progression, we employed traditional immunohistochemical methods as well as comparative genomic hybridization (CGH) which compares chromosomal alterations. Vimentin and epithelial membrane antigen were strongly immunoreactive in both the fibroblastic and carcinoma-like components. The CGH profile in both components had similar chromosomal alterations, including losses of 1p, 14, 16p13-->p10 and 22. However, the CGH profiles from the fibroblastic component showed losses of 4p, 10q23-->q24 and 18, along with gains of 1q, 6q25-->qter and 13q32-->qter. The profile of the carcinoma-like component showed losses of chromosome 4, in addition to gains of 3p12-->q13.11, 5q14.3-->q23.2, 6pter-->p23, and 13q14.2-->qter. CGH analysis of a biphasic malignant meningioma confirmed that the disparate histologic components were genetically related and likely derivative from a common precursor, demonstrating genetic instability and clonal expansion. Furthermore, CGH showed that the histologically appearing low-grade fibroblastic component had not solely the characteristic alterations of a benign meningioma but had already progressed to an atypical meningioma.

Authors
Heimberger, AB; Wiltshire, RN; Bronec, R; McLendon, RE; Cummings, TJ
MLA Citation
Heimberger, AB, Wiltshire, RN, Bronec, R, McLendon, RE, and Cummings, TJ. "Biphasic malignant meningioma: a comparative genomic hybridization study." Clin Neuropathol 21.6 (November 2002): 258-264.
PMID
12489674
Source
pubmed
Published In
Clinical neuropathology
Volume
21
Issue
6
Publish Date
2002
Start Page
258
End Page
264

Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (iressa).

Iressa (ZD1839) is a p.o.-active, selective, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that blocks signal transduction pathways implicated in cancer cell proliferation, survival, and host-dependent processes promoting cancer growth. EGFR is up-regulated in primary malignant tumors of the central nervous system (CNS) and in many systemic tumors that metastasize to the CNS. The purpose of our study was to evaluate the efficacy and toxicity of p.o.-administered ZD1839 for the treatment of established intracerebral (i.c.) tumors expressing EGFR or the tumorigenic mutated variant EGFRvIII, which is constitutively phosphorylated. Oral administration of ZD1839 at 50 or 100 mg/kg/day for 3 weeks in athymic mice with established i.c. A431 human epidermoid carcinoma expressing EGFR increased median survival by 88% (P = 0.009) and 105% (P < 0.001), respectively. Additionally, there was no evidence of systemic or CNS toxicity. However, ZD1839 failed to inhibit either s.c. or i.c. in vivo tumor growth when tumorigenicity was conferred by EGFRvIII. Western blotting revealed that treatment with ZD1839 virtually ablated phosphorylation of EGFR Tyr-1173 in A431 tumors. However, treatment of NR6M tumors with ZD1839 only partially decreased phosphorylation of EGFRvIII Tyr-1173 while up-regulating overall expression, suggesting that EGFRvIII may not be susceptible to the same molecular mechanisms of tyrosine kinase inhibition as EGFR. In conclusion, ZD1839 is active in a brain tumor model expressing EGFR, but not EGFRvIII, as EGFR mutations may lead to relative therapeutic resistance. On the basis of these observations, we believe that clinical trials of ZD1839 against brain tumors expressing EGFR are warranted, but that special consideration should be given to tumors that coexpress EGFRvIII.

Authors
Heimberger, AB; Learn, CA; Archer, GE; McLendon, RE; Chewning, TA; Tuck, FL; Pracyk, JB; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Heimberger, AB, Learn, CA, Archer, GE, McLendon, RE, Chewning, TA, Tuck, FL, Pracyk, JB, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (iressa)." Clin Cancer Res 8.11 (November 2002): 3496-3502.
PMID
12429640
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
8
Issue
11
Publish Date
2002
Start Page
3496
End Page
3502

Targeted delivery in primary and metastatic brain tumors: summary report of the seventh annual meeting of the Blood-Brain Barrier Disruption Consortium.

The November 2000 NIH report of the Brain Tumor Progress Review Group identified delivering and targeting therapeutic agents as a priority in the treatment of malignant brain tumors. For this reason, the seventh annual Blood-Brain Barrier Disruption Consortium meeting, partially funded by an NIH R13 Grant, focused on recent advances in targeted delivery to the central nervous system, clinical trials for primary and metastatic brain tumors using enhanced chemotherapy delivery, and strategies to lessen the toxicities associated with dose intensive treatments, using thiols.

Authors
Doolittle, ND; Abrey, LE; Ferrari, N; Hall, WA; Laws, ER; McLendon, RE; Muldoon, LL; Peereboom, D; Peterson, DR; Reynolds, CP; Senter, P; Neuwelt, EA
MLA Citation
Doolittle, ND, Abrey, LE, Ferrari, N, Hall, WA, Laws, ER, McLendon, RE, Muldoon, LL, Peereboom, D, Peterson, DR, Reynolds, CP, Senter, P, and Neuwelt, EA. "Targeted delivery in primary and metastatic brain tumors: summary report of the seventh annual meeting of the Blood-Brain Barrier Disruption Consortium." Clin Cancer Res 8.6 (June 2002): 1702-1709.
PMID
12060607
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
8
Issue
6
Publish Date
2002
Start Page
1702
End Page
1709

Molecular markers of prognosis in astrocytic tumors.

BACKGROUND: Astrocytoma is a primary brain tumor that affects 20,000 Americans each year. To date, only age and histologic grade stand out as independent predictors of survival. There is now increased interest in the use of molecular markers as objective standards against which to establish diagnosis and grade. METHODS: The study evaluated human glioma tumor suppressor genes and associated loci in fresh snap-frozen gliomas from 63 males and 37 females, with a median age of 42 years, including 19 low-grade astrocytomas. The tumor samples were selected so that about equal numbers of glioblastomas from younger and older patients were represented in the series. Methods for suppressor gene and genetic loci evaluation included loss of heterozygosity (LOH) analysis, multiplex polymerase chain reaction analysis, and gene sequencing. RESULTS: Low-grade astrocytomas had the least number of molecular abnormalities. LOH on 9p and/or CDKN2A deletion occurred more often in glioblastomas (P < 0.001), LOH on 17p/TP53 mutations occurred more frequently in anaplastic astrocytomas (AAs; P = 0.112), and LOH on 10q/PTEN mutation frequency was similar in glioblastomas and AAs (P < 0.001). Poorer survival was associated significantly with the occurrence of either deletion of p16 (P = 0.031), LOH on 9p (P = 0.016), or LOH on 10q (P = 0.0007). The absence of LOH on 17p and the presence of PTEN mutation were associated marginally with survival. Even though TP53 mutations were more frequent among younger patients with glioblastoma, they had no statistically significant effect on survival after adjustment for age (P = 0.62). In all multivariate models, age and grade were the only significant predictors of survival or were nearly significant predictors of survival. CONCLUSIONS: The results suggest that LOH on 9p and p16 deletions may prove to be objective standards for the diagnosis of patients with high-grade gliomas, although the absence of these abnormalities is nonprognostic.

Authors
Rasheed, A; Herndon, JE; Stenzel, TT; Raetz, JGM; Kendelhardt, J; Friedman, HS; Friedman, AH; Bigner, DD; Bigner, SH; McLendon, RE
MLA Citation
Rasheed, A, Herndon, JE, Stenzel, TT, Raetz, JGM, Kendelhardt, J, Friedman, HS, Friedman, AH, Bigner, DD, Bigner, SH, and McLendon, RE. "Molecular markers of prognosis in astrocytic tumors." Cancer 94.10 (May 15, 2002): 2688-2697.
PMID
12173338
Source
pubmed
Published In
Cancer
Volume
94
Issue
10
Publish Date
2002
Start Page
2688
End Page
2697

Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma.

PURPOSE: We conducted a phase II trial of carmustine (BCNU) plus the O(6)-alkylguanine-DNA alkyltransferase inhibitor O(6)-benzylguanine (O(6)-BG) to define the activity and toxicity of this regimen in the treatment of adults with progressive or recurrent malignant glioma resistant to nitrosoureas. PATIENTS AND METHODS: Patients were treated with O(6)-BG at an intravenous dose of 120 mg/m(2) followed 1 hour later by 40 mg/m(2) of BCNU, with cycles repeated at 6-week intervals. RESULTS: Eighteen patients were treated (15 with glioblastoma multiforme, two with anaplastic astrocytoma, and one with malignant glioma). None of the 18 patients demonstrated a partial or complete response. Two patients exhibited stable disease for 12 weeks before their tumors progressed. Three patients demonstrated stable disease for 6, 12, and 18 weeks before discontinuing therapy because of hematopoietic toxicity. Twelve patients experienced reversible > or = grade 3 hematopoietic toxicity. There was no difference in half-lives (0.56 +/- 0.21 hour v 0.54 +/- 0.20 hour) or area under the curve values (4.8 +/- 1.7 microg/mL/h v 5.0 +/- 1.3 microg/mL/h) of O(6)-BG for patients receiving phenytoin and those not treated with this drug. CONCLUSION: These results indicate that O(6)-BG plus BCNU at the dose schedule used in this trial is unsuccessful in producing tumor regression in patients with nitrosourea-resistant malignant glioma, although stable disease was seen in five patients for 6, 12, 12, 12, and 18 weeks. Future use of this approach will require strategies to minimize dose-limiting toxicity of BCNU such as regional delivery or hematopoietic stem-cell protection.

Authors
Quinn, JA; Pluda, J; Dolan, ME; Delaney, S; Kaplan, R; Rich, JN; Friedman, AH; Reardon, DA; Sampson, JH; Colvin, OM; Haglund, MM; Pegg, AE; Moschel, RC; McLendon, RE; Provenzale, JM; Gururangan, S; Tourt-Uhlig, S; Herndon, JE; Bigner, DD; Friedman, HS
MLA Citation
Quinn, JA, Pluda, J, Dolan, ME, Delaney, S, Kaplan, R, Rich, JN, Friedman, AH, Reardon, DA, Sampson, JH, Colvin, OM, Haglund, MM, Pegg, AE, Moschel, RC, McLendon, RE, Provenzale, JM, Gururangan, S, Tourt-Uhlig, S, Herndon, JE, Bigner, DD, and Friedman, HS. "Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma." J Clin Oncol 20.9 (May 1, 2002): 2277-2283.
PMID
11980998
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
20
Issue
9
Publish Date
2002
Start Page
2277
End Page
2283
DOI
10.1200/JCO.2002.09.084

MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children's Oncology Group.

CONTEXT: Brain tumors are the most common solid tumor in childhood, and medulloblastoma is the most common malignant brain tumor in this age group. Cytogenetic abnormalities that have been described in childhood medulloblastoma include loss of 17p, amplification of MYCC (c-myc), amplification of MYCN (N-myc), and isochromosome 17q. Data on these tumors indicate that the frequency of MYCC amplification is 5% to 10%. Fluorescence in situ hybridization is a powerful tool for investigating these features on archival material. OBJECTIVES: To determine if intratumoral heterogeneity exists for MYCC and MYCN in medulloblastomas and if tumors with amplified MYCC or MYCN exhibit consistent histologic patterns. DESIGN: In this fluorescence in situ hybridization study, we investigated the frequency and prognostic significance of MYCC and MYCN amplification in 77 medulloblastomas derived from the Children's Oncology Group. RESULTS: MYCC amplification occurred in only 4 (5.2%) of 77 tumors. The 4 patients died of clinically aggressive neoplasms within 7 months of diagnosis. Similarly, 4 of 77 patients' tumors were found to exhibit MYCN amplification, but survival data are incomplete at present, therefore prognostic significance cannot be characterized. CONCLUSIONS: These data establish the frequency of MYCC amplification in a large cohort of children with medulloblastoma and further suggest that MYCC amplification may be a marker of poor prognosis. Intratumoral heterogeneity was identified for these oncogenes in that 1 patient's tumor exhibited evidence of both MYCN and MYCC amplification, and this patient experienced a shortened survival time.

Authors
Aldosari, N; Bigner, SH; Burger, PC; Becker, L; Kepner, JL; Friedman, HS; McLendon, RE
MLA Citation
Aldosari, N, Bigner, SH, Burger, PC, Becker, L, Kepner, JL, Friedman, HS, and McLendon, RE. "MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children's Oncology Group." Arch Pathol Lab Med 126.5 (May 2002): 540-544.
PMID
11958658
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
126
Issue
5
Publish Date
2002
Start Page
540
End Page
544
DOI
10.1043/0003-9985(2002)126<0540:MAMOAI>2.0.CO;2

Comparative genomic hybridization of a biphasic malignant meningioma.

Authors
Cummings, TJ; Wiltshire, RN; McLendon, RE; Heimberger, AB
MLA Citation
Cummings, TJ, Wiltshire, RN, McLendon, RE, and Heimberger, AB. "Comparative genomic hybridization of a biphasic malignant meningioma." JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 61.5 (May 2002): 480-480.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
61
Issue
5
Publish Date
2002
Start Page
480
End Page
480

Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: the Duke experience.

A phase II study of irinotecan (CPT-11) was conducted at Duke University Medical Center, Durham, NC, to evaluate the activity of this agent in children with high-risk malignant brain tumors. A total of 22 children were enrolled in this study, including 13 with histologically verified recurrent malignant brain tumors (glioblastoma multiforme [GBM] 4, anaplastic astrocytoma 1, ependymoma 5, and medulloblastoma/primitive neuroectodermal tumor 3), 5 with recurrent diffuse pontine glioma, and 4 with newly diagnosed GBM. All patients with recurrent tumor had prior chemotherapy and/or irradiation. Each course of CPT-11 consisted of 125 mg/m ( 2 ) per week given i.v. for 4 weeks followed by a 2-week rest period. Patients with recurrent tumors received therapy until disease progression or unacceptable toxicity. Patients with newly diagnosed tumors initially received 3 cycles of treatment to assess tumor response and then were allowed radiotherapy at physician's choice; patients who demonstrated a response to CPT-11 prior to radiotherapy were allowed to continue the drug after radiation until disease progression or unacceptable toxicity. A 25% to 50% dose reduction was made for grade III-IV toxicity. Responses were assessed after every course by gadolinium-enhanced MRI of the brain and spine. Twenty-two patients received a median of 2 courses of CPT-11 (range, 1-16). Responses were seen in 4 of 9 patients with GBM or anaplastic astrocytoma (44%; 95% confidence interval, 11%-82%) (complete response in 2 patients with recurrent GBM lasting 9 months and 48+ months; partial response in one patient with a newly diagnosed midbrain GBM lasting 18 months prior to radiotherapy; and partial response lasting 11 months in 1 patient with recurrent anaplastic astrocytoma), 1 of 5 patients with recurrent ependymoma (partial response initially followed by stable disease lasting 11 months), and none of 5 patients with recurrent diffuse pontine glioma. Two of 3 patients with medulloblastoma/primitive neuroectodermal tumor had stable disease for 9 and 13 months. Toxicity was mainly myelosuppression, with 12 of 22 patients (50%) suffering grade II-IV neutropenia. Seven patients required dose reduction secondary to neutropenia. CPT-11, given in this schedule, appears to be active in children with malignant glioma, medulloblastoma, and ependymoma with acceptable toxicity. Ongoing studies will demonstrate if activity of CPT-11 can be enhanced when combined with alkylating agents, including carmustine and temozolomide.

Authors
Turner, CD; Gururangan, S; Eastwood, J; Bottom, K; Watral, M; Beason, R; McLendon, RE; Friedman, AH; Tourt-Uhlig, S; Miller, LL; Friedman, HS
MLA Citation
Turner, CD, Gururangan, S, Eastwood, J, Bottom, K, Watral, M, Beason, R, McLendon, RE, Friedman, AH, Tourt-Uhlig, S, Miller, LL, and Friedman, HS. "Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: the Duke experience." Neuro Oncol 4.2 (April 2002): 102-108.
PMID
11916501
Source
pubmed
Published In
Neuro-Oncology
Volume
4
Issue
2
Publish Date
2002
Start Page
102
End Page
108

Comprehensive molecular cytogenetic investigation of chromosomal abnormalities in human medulloblastoma cell lines and xenograft.

Cell lines and xenografts derived from medulloblastomas are useful tools to investigate the chromosomal changes in these tumors. Here we used G-banding, fluorescence in situ hybridization (FISH), spectral karyotyping (SKY), and comparative genomic hybridization to study 4 medulloblastoma cell lines and 1 xenograft. Cell line D-425 Med had a relatively simple karyotype, with a terminal deletion of 10q and amplification of MYC in double-minutes (dmins). FISH demonstrated that an apparent isochromosome (17q) by routine karyotyping was actually an unbalanced translocation between 2 copies of chromosome 17. Cell line D-556 Med also had a simple near-diploid stemline with an unbalanced 1;13 translocation resulting in a gain of 1q, an isochromosome (17q), and dmins. These findings were initially described using routine G-banded preparations, and FISH showed that the dmins were an amplification of MYC and the i(17q) was an isodicentric 17q chromosome. The other finding was confirmed by FISH, SKY, and comparative genomic hybridization. Cell lines D-721 Med and D-581 Med had complex karyotypic patterns that could be completely characterized only when FISH and SKY were used. Xenograft D-690 Med also had a complex pattern that FISH and SKY were helpful in completely elucidating. Interestingly, balanced reciprocal translocations were seen as well as complicated unbalanced translocations and marker chromosomes. Comparative genomic hybridization demonstrated only a deletion of 10q22-10q24, supporting the idea that despite the complexity of the chromosomal rearrangements, minimal alterations in the overall chromosomal content had occurred. This study demonstrates that routine cytogenetic preparations are adequate to describe chromosomal abnormalities in occasional medulloblastoma samples, but a broader spectrum of molecular cytogenetic methods is required to completely analyze most of these tumor samples.

Authors
Aldosari, N; Wiltshire, RN; Dutra, A; Schrock, E; McLendon, RE; Friedman, HS; Bigner, DD; Bigner, SH
MLA Citation
Aldosari, N, Wiltshire, RN, Dutra, A, Schrock, E, McLendon, RE, Friedman, HS, Bigner, DD, and Bigner, SH. "Comprehensive molecular cytogenetic investigation of chromosomal abnormalities in human medulloblastoma cell lines and xenograft." Neuro Oncol 4.2 (April 2002): 75-85.
PMID
11916498
Source
pubmed
Published In
Neuro-Oncology
Volume
4
Issue
2
Publish Date
2002
Start Page
75
End Page
85

Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas.

PURPOSE: To assess the efficacy and toxicity of intraresection cavity (131)I-labeled murine antitenascin monoclonal antibody 81C6 and determine its true response rate among patients with newly diagnosed malignant glioma. PATIENTS AND METHODS: In this phase II trial, 120 mCi of (131)I-labeled murine 81C6 was injected directly into the surgically created resection cavity of 33 patients with previously untreated malignant glioma (glioblastoma multiforme [GBM], n = 27; anaplastic astrocytoma, n = 4; anaplastic oligodendroglioma, n = 2). Patients then received conventional external-beam radiotherapy followed by a year of alkylator-based chemotherapy. RESULTS: Median survival for all patients and those with GBM was 86.7 and 79.4 weeks, respectively. Eleven patients remain alive at a median follow-up of 93 weeks (range, 49 to 220 weeks). Nine patients (27%) developed reversible hematologic toxicity, and histologically confirmed, treatment-related neurologic toxicity occurred in five patients (15%). One patient (3%) required reoperation for radionecrosis. CONCLUSION: Median survival achieved with (131)I-labeled 81C6 exceeds that of historical controls treated with conventional radiotherapy and chemotherapy, even after accounting for established prognostic factors including age and Karnofsky performance status. The median survival achieved with (131)I-labeled 81C6 compares favorably with either (125)I interstitial brachy-therapy or stereotactic radiosurgery and is associated with a significantly lower rate of reoperation for radionecrosis. Our results confirm the efficacy of (131)I-labeled 81C6 for patients with newly diagnosed malignant glioma and suggest that a randomized phase III study is indicated.

Authors
Reardon, DA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; Cokgor, I; McLendon, RE; Pegram, CN; Provenzale, JM; Quinn, JA; Rich, JN; Regalado, LV; Sampson, JH; Shafman, TD; Wikstrand, CJ; Wong, TZ; Zhao, X-G; Zalutsky, MR; Bigner, DD
MLA Citation
Reardon, DA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, Herndon, JE, Cokgor, I, McLendon, RE, Pegram, CN, Provenzale, JM, Quinn, JA, Rich, JN, Regalado, LV, Sampson, JH, Shafman, TD, Wikstrand, CJ, Wong, TZ, Zhao, X-G, Zalutsky, MR, and Bigner, DD. "Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas." J Clin Oncol 20.5 (March 1, 2002): 1389-1397.
PMID
11870184
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
20
Issue
5
Publish Date
2002
Start Page
1389
End Page
1397
DOI
10.1200/JCO.2002.20.5.1389

Dendritic cells pulsed with a tumor-specific peptide induce long-lasting immunity and are effective against murine intracerebral melanoma.

OBJECTIVE: Dendritic cells (DCs) are specialized cells of the immune system that are capable of generating potent immune responses that are active even within the "immunologically privileged" central nervous system. However, immune responses generated by DCs have also been demonstrated to produce clinically significant autoimmunity. Targeting the epidermal growth factor receptor variant III (EGFRvIII), which is a mutation specific to tumor tissue, could eliminate this risk. The purpose of this study was to demonstrate that DC-based immunizations directed solely against this tumor-specific antigen, which is commonly found on tumors that originate within or metastasize to the brain, could be efficacious. METHODS: C3H mice were vaccinated with DCs mixed with a keyhole limpet hemocyanin conjugate of the tumor-specific peptide, PEP-3, which spans the EGFRvIII mutation, or the random-sequence peptide, PEP-1, and were intracerebrally challenged with a syngeneic melanoma expressing a murine homologue of EGFRvIII. RESULTS: Systemic immunization with DCs mixed with PEP-3-keyhole limpet hemocyanin generated antigen-specific immunity. Among mice challenged with intracerebral tumors, this resulted in an approximately 600% increase in the median survival time (>300 d, P < 0.0016), relative to control values. Sixty-three percent of mice treated with DCs mixed with the tumor-specific peptide survived in the long term and 100% survived rechallenge with tumor, indicating that antitumor immunological memory was also induced. CONCLUSION: In a murine melanoma model, immunization with DCs mixed with tumor-specific peptide results in an antigen-specific immunological response that recognizes the EGFRvIII mutation, has potent antitumor efficacy against intracerebral tumors that express EGFRvIII, and results in long-lasting antitumor immunity.

Authors
Heimberger, AB; Archer, GE; Crotty, LE; McLendon, RE; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Heimberger, AB, Archer, GE, Crotty, LE, McLendon, RE, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Dendritic cells pulsed with a tumor-specific peptide induce long-lasting immunity and are effective against murine intracerebral melanoma." Neurosurgery 50.1 (January 2002): 158-164.
PMID
11844246
Source
pubmed
Published In
Neurosurgery
Volume
50
Issue
1
Publish Date
2002
Start Page
158
End Page
164

Primary anaplastic large cell lymphoma of the central nervous system: ALK-1 and other prognostic factors

Authors
George, DH; Scheithauer, BW; Aker, FV; Kurtin, PC; Burger, PC; McLendon, RE; Parisi, JE; Paulus, W; Reed, LE; Roggendorf, W; Sotelo, C; Cameselle-Teijero, J; Robson, DK
MLA Citation
George, DH, Scheithauer, BW, Aker, FV, Kurtin, PC, Burger, PC, McLendon, RE, Parisi, JE, Paulus, W, Reed, LE, Roggendorf, W, Sotelo, C, Cameselle-Teijero, J, and Robson, DK. "Primary anaplastic large cell lymphoma of the central nervous system: ALK-1 and other prognostic factors." MODERN PATHOLOGY 15.1 (January 2002): 299A-300A.
Source
wos-lite
Published In
Modern Pathology
Volume
15
Issue
1
Publish Date
2002
Start Page
299A
End Page
300A

Primary anaplastic large cell lymphoma of the central nervous system: ALK-1 and other prognostic factors

Authors
George, DH; Scheithauer, BW; Aker, FV; Kurtin, PC; Burger, PC; McLendon, RE; Parisi, JE; Paulus, W; Reed, LE; Roggendorf, W; Sotelo, C; Cameselle-Teijero, J; Robson, DK
MLA Citation
George, DH, Scheithauer, BW, Aker, FV, Kurtin, PC, Burger, PC, McLendon, RE, Parisi, JE, Paulus, W, Reed, LE, Roggendorf, W, Sotelo, C, Cameselle-Teijero, J, and Robson, DK. "Primary anaplastic large cell lymphoma of the central nervous system: ALK-1 and other prognostic factors." LABORATORY INVESTIGATION 82.1 (January 2002): 299A-300A.
Source
wos-lite
Published In
Laboratory Investigation
Volume
82
Issue
1
Publish Date
2002
Start Page
299A
End Page
300A

Glioneuronal tumors of the central nervous system.

Advances in the immunohistochemical detection of neuron-specific and neuronal-associated antigens have resulted in the discovery of neuronal elements in certain primary human brain tumors. The results have been not only to expand what neuropathologists commonly recognize as gangliogliomas, including the tumors now known as glioneurocytic tumor with neuropil rosettes and papillary ganglioneuroma, but also to expand the spectrum of tumor types to now include tumors such as central neurocytoma, dysembryoplastic neuroepithelial tumor, and desmoplastic infantile ganglioglioma. These discoveries have helped us to better understand the biology of these tumors and to refine our classification of them. Distinctions among these tumors include sites of predilection, such as the temporal lobe with the dysembryoplastic neuroepithelial tumors, and a spectrum of clinical aggressiveness that spans indolent "quasi-hamartomatous" lesions, such as the dysembryoplastic neuroepithelial tumor, to high-grade, highly aggressive tumors, such as the supratentorial primitive neuroectodermal tumor (World Health Organization Grade IV). Many of these tumors also commonly exhibit a glial component, as determined by both their histologic appearance and their immunoreactivity for glial fibrillary acidic protein. This review covers these recently described lesions, including the desmoplastic infantile ganglioglioma, the dysembryoplastic neuroepithelial tumor, the papillary glioneuronal tumor, the glioneuronal tumor with neuropil rosettes, and the mixed glioblastoma-cerebral neuroblastoma (supratentorial primitive neuroectodermal tumor), as well as the known tumors, ganglioglioma, medulloepithelioma, and medulloblastoma. For pathologists confronted by this growing array of tumors and subtypes, it is appropriate to focus on them and understand the differential diagnosis to be considered when confronted by them.

Authors
McLendon, RE; Provenzale, J
MLA Citation
McLendon, RE, and Provenzale, J. "Glioneuronal tumors of the central nervous system." Brain Tumor Pathol 19.2 (2002): 51-58. (Review)
PMID
12622133
Source
pubmed
Published In
Brain Tumor Pathology
Volume
19
Issue
2
Publish Date
2002
Start Page
51
End Page
58

Endodermal cyst of the oculomotor nerve.

Endodermal cysts are rare congenital intracranial lesions. Although histologically benign, they can become symptomatic as a result of mass effect and cause neurological deficits. We report a 30-year-old woman who presented with paresis of her right oculomotor nerve. Magnetic resonance imaging showed a 13 x 8-mm cystic lesion originating from the right oculomotor nerve at its exit from the mesencephalon. She underwent craniotomy, biopsy, slit resection, and drainage of the cyst. To our knowledge, endodermal cysts have not been previously described in relation to the oculomotor nerve.

Authors
Morgan, MA; Enterline, DS; Fukushima, T; McLendon, RE; Cummings, TJ
MLA Citation
Morgan, MA, Enterline, DS, Fukushima, T, McLendon, RE, and Cummings, TJ. "Endodermal cyst of the oculomotor nerve." Neuroradiology 43.12 (December 2001): 1063-1066.
PMID
11792045
Source
pubmed
Published In
Neuroradiology
Volume
43
Issue
12
Publish Date
2001
Start Page
1063
End Page
1066

Diffusion-weighted MR imaging in a patient with spinal meningioma.

Authors
Eastwood, JD; Turner, DA; McLendon, RE; Provenzale, JM
MLA Citation
Eastwood, JD, Turner, DA, McLendon, RE, and Provenzale, JM. "Diffusion-weighted MR imaging in a patient with spinal meningioma." AJR Am J Roentgenol 177.6 (December 2001): 1479-1481. (Review)
PMID
11717111
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
177
Issue
6
Publish Date
2001
Start Page
1479
End Page
1481
DOI
10.2214/ajr.177.6.1771479

CD34 and dural fibroblasts: the relationship to solitary fibrous tumor and meningioma.

Intracranial solitary fibrous tumors (SFTs) are typically dural-based, CD34-positive neoplasms of uncertain histogenesis. We examined ten cases of meninges obtained at autopsy from patients with no history of neurological illness, head trauma, or neurosurgical intervention, and ten cases of typical meningiomas with attached dural margins not involved by tumor. All cases were immunostained with CD34. CD34 reactivity was noted in the long, thin delicate processes of dural fibroblasts preferentially located in the meningeal portion of the dura rather than the periosteal portion. No CD34 reactivity was identified in the arachnoid or pia mater, except in some endothelial cells. One supratentorial dural-based fibrous nodule and one SFT within the confines of the fourth ventricle showed strong and diffuse reactivity to CD34, bcl-2, and vimentin, and were negative for epithelial membrane antigen (EMA), S-100 protein, glial fibrillary acidic protein, smooth muscle actin, and desmin. We also describe a meningothelial meningioma within which a well circumscribed SFT-like nodule was embedded. The SFT-like nodule was strongly CD34 positive and EMA negative, and the meningioma was strongly EMA positive and CD34 negative. Fibroblasts of the dural border cell layer are attached to the underlying arachnoid, and their inclusion with arachnoidal stromal elements and pial-based tela choroidea during formation of choroid plexus interstitium may account for intraventricular SFTs. Our results suggest that SFTs and dural-based fibrous nodules derive from CD34-positive dural-based fibroblasts, and that CD34 reactivity in meningiomas may result from inclusion of dural fibroblasts within the neoplasm.

Authors
Cummings, TJ; Burchette, JL; McLendon, RE
MLA Citation
Cummings, TJ, Burchette, JL, and McLendon, RE. "CD34 and dural fibroblasts: the relationship to solitary fibrous tumor and meningioma." Acta Neuropathol 102.4 (October 2001): 349-354.
PMID
11603810
Source
pubmed
Published In
Acta Neuropathologica
Volume
102
Issue
4
Publish Date
2001
Start Page
349
End Page
354

Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas.

Both Gliadel wafers [1,3-bis(2-chloroethyl)-1-nitrosourea] and temozolomide (TEMO) have been shown in independent studies to prolong survival of patients with recurrent malignant glioma following surgery and radiotherapy. On the basis of preclinical evidence of synergism between Gliadel wafers and TEMO, a phase I study was designed to evaluate the toxicity of combining these 2 agents in the treatment of patients with recurrent supratentorial malignant glioma. All patients had surgical resection of the tumor at relapse, and up to 8 Gliadel (3.85%) wafers were placed in the surgical cavity following resection. Two weeks after surgery, TEMO was given orally daily for 5 days. Cohorts of 3 patients received TEMO at daily doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2, respectively. Patients were assessed for toxicity 4 weeks after start of the first course of TEMO. Contrast-enhanced MRI of the brain was used to assesstumor response after the first cycle of TEMO. Patients with stable disease or response after the first cycle of TEMO were allowed to continue treatment at the same dose every 4 weeks for 12 cycles or until disease progression or unacceptable toxicity. Ten patients with a median age of 47 years (range, 22-66 years) were enrolled in this study. There were 7 patients with glioblastoma multiforme and 3 patients with anaplastic astrocytoma. Three patients were treated with TEMO at the first dose level of 100 mg/m2, 4 at the second dose level of 150 mg/m2, and 3 at the third dose level of 200 mg/m2. The 10 patients received a median of 3 cycles (range, 1-12 cycles) of TEMO following placement of Gliadel wafers. The treatment was well tolerated, with only 1 patient suffering grade III thrombocytopenia at the highest dose level. Two patients at each dose level had no evidence of disease progression after treatment. Four patients suffered progressive disease on therapy. Our study demonstrates that TEMO can be given safely after placement of Gliadel (3.85%) wafers. The recommended dosage for TEMO for a phase II study of this combination is 200 mg/m2 per day for 5 days.

Authors
Gururangan, S; Cokgor, L; Rich, JN; Edwards, S; Affronti, ML; Quinn, JA; Herndon, JE; Provenzale, JM; McLendon, RE; Tourt-Uhlig, S; Sampson, JH; Stafford-Fox, V; Zaknoen, S; Early, M; Friedman, AH; Friedman, HS
MLA Citation
Gururangan, S, Cokgor, L, Rich, JN, Edwards, S, Affronti, ML, Quinn, JA, Herndon, JE, Provenzale, JM, McLendon, RE, Tourt-Uhlig, S, Sampson, JH, Stafford-Fox, V, Zaknoen, S, Early, M, Friedman, AH, and Friedman, HS. "Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas." Neuro Oncol 3.4 (October 2001): 246-250.
PMID
11584894
Source
pubmed
Published In
Neuro-Oncology
Volume
3
Issue
4
Publish Date
2001
Start Page
246
End Page
250

Biological model for assessing the role in glioma formation of genes differentially expressed in human gliomas

Authors
Rich, JN; Guo, CH; McLendon, RE; Bigner, DD; Wang, XF; Counter, CM
MLA Citation
Rich, JN, Guo, CH, McLendon, RE, Bigner, DD, Wang, XF, and Counter, CM. "Biological model for assessing the role in glioma formation of genes differentially expressed in human gliomas." September 2001.
Source
wos-lite
Published In
Annals of Neurology
Volume
50
Issue
3
Publish Date
2001
Start Page
S31
End Page
S31

March 2000: A 16 year old female with a cerebellar mass.

The March COM: A 16 year old female presented with headaches and cerebellar dysfunction. MR images showed a mass lesion of the right cerebellar hemisphere with mass effect on the medulla. The mass exhibited a striated pattern of alternating isointense and hypointense zones on T1-weighted images that did not contrast enhance. The lesion was hyperintense on T2-weighted images, and also showed a striated appearance. A suboccipital craniotomy and resection of the lesion was performed. Microscopically, the specimen consisted of widened folia and a disorganized cerebellar architectonic pattern in which the internal granular cell layer was occupied by a population of large dysmorphic nerve cell bodies. Patient's diagnosed with Lhermitte-Duclos disease must be adequately evaluated for Cowden's syndrome.

Authors
Cummings, TJ; Ebert, RH; Provenzale, J; McLendon, RE
MLA Citation
Cummings, TJ, Ebert, RH, Provenzale, J, and McLendon, RE. "March 2000: A 16 year old female with a cerebellar mass." Brain Pathol 11.3 (July 2001): 391-393.
PMID
11414481
Source
pubmed
Published In
Brain Pathology
Volume
11
Issue
3
Publish Date
2001
Start Page
391
End Page
393

A genetically tractable model of human glioma formation.

Gliomas remain one of the deadliest forms of cancer. Improved therapeutics will require a better understanding of the molecular nature of these tumors. We, therefore, mimicked the most common genetic changes found in grade III-IV gliomas, disruption of the p53 and RB pathways and activation of telomere maintenance and independence from growth factors, through the ectopic expression of the SV40 T/t-Ag oncogene, an oncogenic form of H-ras (H-ras(V12G)), and the human telomerase catalytic subunit hTERT in normal human astrocytes. The resulting cells displayed many of the hallmarks of grade III-IV gliomas, including greatly expanded life span and growth in soft agar and, most importantly, were tumorigenic with pathology consistent with grade III-IV neuroectodermal tumors in mice. This model system will, for the first time, allow the biological significance of selected genetic alterations to be studied in human gliomas.

Authors
Rich, JN; Guo, C; McLendon, RE; Bigner, DD; Wang, XF; Counter, CM
MLA Citation
Rich, JN, Guo, C, McLendon, RE, Bigner, DD, Wang, XF, and Counter, CM. "A genetically tractable model of human glioma formation." Cancer Res 61.9 (May 1, 2001): 3556-3560.
PMID
11325817
Source
pubmed
Published In
Cancer Research
Volume
61
Issue
9
Publish Date
2001
Start Page
3556
End Page
3560

Ham56-immunoreactive macrophages in untreated infiltrating gliomas.

CONTEXT: Classic diagnostic neuropathologic teachings have cautioned against making the diagnosis of neoplasia in the presence of a macrophage population. The knowledge of macrophage distribution should prove useful when confronted with an infiltrating glioma containing macrophages. OBJECTIVE: To identify macrophages in untreated, infiltrating gliomas using the monoclonal antibody HAM56, and to confirm their presence in an untreated glioblastoma multiforme (GBM) with the serial analysis of gene expression (SAGE) method. METHODS: We evaluated the presence of macrophages in 16 cases of untreated, supratentorial infiltrating gliomas with the macrophage monoclonal antibody HAM56. We performed SAGE for one case of GBM and for normal brain tissue. RESULTS: In World Health Organization (WHO) grade II well-differentiated astrocytoma and oligodendroglioma, HAM56 reactivity was noted only in endothelial cells, and unequivocal macrophages were not identified. In WHO grade III anaplastic astrocytoma and anaplastic oligodendroglioma, rare HAM56-positive macrophages were noted in solid areas of tumor. In WHO grade IV GBM, HAM56-positive macrophages were identified in areas of solid tumor (mean labeling index, 8.6%). In all cases of GBM, nonquantitated HAM56-positive macrophages were identified in foci of pseudopalisading cells abutting necrosis and in foci of microvascular proliferations. In none of the cases were granulomas or microglial nodules found, and there was no prior history of surgical intervention, radiation therapy, chemotherapy, or head trauma in these cases. By SAGE, the macrophage-related proteins osteopontin and macrophage-capping protein were overexpressed 12-fold and eightfold, respectively, in one untreated GBM compared with normal brain tissue. In this case, numerous HAM56-positive macrophages (labeling index, 24.5%) were present in the solid portion of tumor, and abundant nonquantified macrophages were identified in foci of pseudopalisading cells abutting necrosis and in foci of microvascular proliferations. CONCLUSIONS: This study confirms the utility of the monoclonal antibody HAM56 in identifying macrophages within untreated infiltrating gliomas. The overexpression of macrophage-related proteins in one case of GBM as detected by SAGE signifies that macrophages may be present in untreated GBMs.

Authors
Cummings, TJ; Hulette, CM; Bigner, SH; Riggins, GJ; McLendon, RE
MLA Citation
Cummings, TJ, Hulette, CM, Bigner, SH, Riggins, GJ, and McLendon, RE. "Ham56-immunoreactive macrophages in untreated infiltrating gliomas." Arch Pathol Lab Med 125.5 (May 2001): 637-641.
PMID
11300934
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
125
Issue
5
Publish Date
2001
Start Page
637
End Page
641
DOI
10.1043/0003-9985(2001)125<0637:HIMIUI>2.0.CO;2

Radioimmunotherapy of recurrent glioma patients using alpha-particle emitting astatine-211 labeled chimeric anti-tenascin monoclonal antibody.

Authors
Zalutsky, MR; Akabani, G; Friedman, HS; Cokgor, I; Coleman, RE; Friedman, AH; McLendon, RE; Zhao, XG; Alston, KL; Bigner, DD
MLA Citation
Zalutsky, MR, Akabani, G, Friedman, HS, Cokgor, I, Coleman, RE, Friedman, AH, McLendon, RE, Zhao, XG, Alston, KL, and Bigner, DD. "Radioimmunotherapy of recurrent glioma patients using alpha-particle emitting astatine-211 labeled chimeric anti-tenascin monoclonal antibody." JOURNAL OF NUCLEAR MEDICINE 42.5 (May 2001): 121P-122P.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
42
Issue
5
Publish Date
2001
Start Page
121P
End Page
122P

Pathology of the normal versus the tethered filum terminale.

Authors
Cummings, TJ; Bulsara, KR; McLendon, RE; Fuchs, HE; George, TM
MLA Citation
Cummings, TJ, Bulsara, KR, McLendon, RE, Fuchs, HE, and George, TM. "Pathology of the normal versus the tethered filum terminale." May 2001.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
60
Issue
5
Publish Date
2001
Start Page
553
End Page
553

Molecular profiling of astrocytomas.

Authors
McLendon, RE; Rasheed, A; Wiltshire, R; Herndon, J; Friedman, H; Friedman, A; Bigner, D; Bigner, S
MLA Citation
McLendon, RE, Rasheed, A, Wiltshire, R, Herndon, J, Friedman, H, Friedman, A, Bigner, D, and Bigner, S. "Molecular profiling of astrocytomas." JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 60.5 (May 2001): 535-535.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
60
Issue
5
Publish Date
2001
Start Page
535
End Page
535

Comparative genomic hybridization analysis of primitive neuroectodermal tumors.

Authors
Wiltshire, RN; Lloyd, A; Powers, J; Kepner, J; Friedman, H; Bigner, S; McLendon, RE
MLA Citation
Wiltshire, RN, Lloyd, A, Powers, J, Kepner, J, Friedman, H, Bigner, S, and McLendon, RE. "Comparative genomic hybridization analysis of primitive neuroectodermal tumors." JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 60.5 (May 2001): 541-541.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
60
Issue
5
Publish Date
2001
Start Page
541
End Page
541

An anatomical investigation of the human cervical facet capsule, quantifying muscle insertion area.

Facet capsule injury has been hypothesised as a mechanism for neck pain. While qualitative studies have demonstrated the proximity of neck muscles to the cervical facet capsule, the magnitude of their forces remains unknown owing to a lack of quantitative muscle geometry. In this study, histological techniques were employed to quantify muscle insertions on the human cervical facet capsule. Computerised image analysis of slides stained with Masson's trichrome was performed to characterise the geometry of the cervical facet capsule and determine the total insertion area of muscle fibres into the facet capsule for the C4-C5 and C5-C6 joints. Muscle insertions were found to cover 22.4+/-9.6% of the capsule area for these cervical levels, corresponding to a mean muscle insertion area of 47.6+/-21.8 mm2. The magnitude of loading to the cervical facet capsule due to eccentric muscle contraction is estimated to be as high as 51 N. When taken in conjunction with the forces acting on the capsular ligament due to vertebral motions, these forces can be as high as 66 N. In that regard, these anatomical data provide quantitative evidence of substantial muscle insertions into the cervical facet capsular ligament and provide a possible mechanism for injury to this ligament and the facet joint as a whole.

Authors
Winkelstein, BA; McLendon, RE; Barbir, A; Myers, BS
MLA Citation
Winkelstein, BA, McLendon, RE, Barbir, A, and Myers, BS. "An anatomical investigation of the human cervical facet capsule, quantifying muscle insertion area." J Anat 198.Pt 4 (April 2001): 455-461.
PMID
11327207
Source
pubmed
Published In
Journal of Anatomy
Volume
198
Issue
Pt 4
Publish Date
2001
Start Page
455
End Page
461

Pathologic quiz case: pituitary mass in a 48-year-old woman.

Authors
Cummings, TJ; Bentley, RC; McLendon, RE
MLA Citation
Cummings, TJ, Bentley, RC, and McLendon, RE. "Pathologic quiz case: pituitary mass in a 48-year-old woman." Arch Pathol Lab Med 125.2 (February 2001): 299-300.
PMID
11175658
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
125
Issue
2
Publish Date
2001
Start Page
299
End Page
300
DOI
10.1043/0003-9985(2001)125<0299:PQCPMI>2.0.CO;2

Pathologic quiz case - Pituitary mass in a 48-year-old woman - Pathologic diagnosis: Granular cell tumor of the infundibulum

Authors
Cummings, TJ; Bentley, RC; McLendon, RE
MLA Citation
Cummings, TJ, Bentley, RC, and McLendon, RE. "Pathologic quiz case - Pituitary mass in a 48-year-old woman - Pathologic diagnosis: Granular cell tumor of the infundibulum." ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE 125.2 (February 2001): 299-300.
Source
wos-lite
Published In
Archives of Pathology and Laboratory Medicine
Volume
125
Issue
2
Publish Date
2001
Start Page
299
End Page
300

An anatomical investigation of the human cervical facet capsule, quantifying muscle insertion area

Facet capsule injury has been hypothesised as a mechanism for neck pain. While qualitative studies have demonstrated the proximity of neck muscles to the cervical facet capsule, the magnitude of their forces remains unknown owing to a lack of quantitative muscle geometry. In this study, histological techniques were employed to quantify muscle insertions on the human cervical facet capsule. Computerised image analysis of slides stained with Masson's trichrome was performed to characterise the geometry of the cervical facet capsule and determine the total insertion area of muscle fibres into the facet capsule for the C4-C5 and C5-C6 joints. Muscle insertions were found to cover 22.4±9.6% of the capsule area for these cervical levels, corresponding to a mean muscle insertion area of 47.6±21.8 mm2. The magnitude of loading to the cervical facet capsule due to eccentric muscle contraction is estimated to be as high as 51 N. When taken in conjunction with the forces acting on the capsular ligament due to vertebral motions, these forces can be as high as 66 N. In that regard, these anatomical data provide quantitative evidence of substantial muscle insertions into the cervical facet capsular ligament and provide a possible mechanism for injury to this ligament and the facet joint as a whole.

Authors
Winkelstein, BA; McLendon, RE; Barbir, ANA; Myers, BS
MLA Citation
Winkelstein, BA, McLendon, RE, Barbir, ANA, and Myers, BS. "An anatomical investigation of the human cervical facet capsule, quantifying muscle insertion area." Journal of Anatomy 198.4 (2001): 455-461.
Source
scival
Published In
Journal of Anatomy
Volume
198
Issue
4
Publish Date
2001
Start Page
455
End Page
461
DOI
10.1017/S0021878201007518

Phase I trial results of iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with newly diagnosed malignant gliomas.

PURPOSE: To determine the maximum-tolerated dose (MTD) of iodine-131 ((131)I)-labeled 81C6 antitenascin monoclonal antibody (mAb) administered clinically into surgically created resection cavities (SCRCs) in malignant glioma patients and to identify any objective responses with this treatment. PATIENTS AND METHODS: In this phase I trial, newly diagnosed patients with malignant gliomas with no prior external-beam therapy or chemotherapy were treated with a single injection of (131)I-labeled 81C6 through a Rickham reservoir into the resection cavity. The initial dose was 20 mCi and escalation was in 20-mCi increments. Patients were observed for toxicity and response until death or for a minimum of 1 year after treatment. RESULTS: We treated 42 patients with (131)I-labeled 81C6 mAb in administered doses up to 180 mCi. Dose-limiting toxicity was observed at doses greater than 120 mCi and consisted of delayed neurotoxicity. None of the patients developed major hematologic toxicity. Median survival for patients with glioblastoma multiforme and for all patients was 69 and 79 weeks, respectively. CONCLUSION: The MTD for administration of (131)I-labeled 81C6 into the SCRC of newly diagnosed patients with no prior radiation therapy or chemotherapy was 120 mCi. Dose-limiting toxicity was delayed neurologic toxicity. We are encouraged by the survival and toxicity and by the low 2.5% prevalence of debulking surgery for symptomatic radiation necrosis.

Authors
Cokgor, I; Akabani, G; Kuan, CT; Friedman, HS; Friedman, AH; Coleman, RE; McLendon, RE; Bigner, SH; Zhao, XG; Garcia-Turner, AM; Pegram, CN; Wikstrand, CJ; Shafman, TD; Herndon, JE; Provenzale, JM; Zalutsky, MR; Bigner, DD
MLA Citation
Cokgor, I, Akabani, G, Kuan, CT, Friedman, HS, Friedman, AH, Coleman, RE, McLendon, RE, Bigner, SH, Zhao, XG, Garcia-Turner, AM, Pegram, CN, Wikstrand, CJ, Shafman, TD, Herndon, JE, Provenzale, JM, Zalutsky, MR, and Bigner, DD. "Phase I trial results of iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with newly diagnosed malignant gliomas." J Clin Oncol 18.22 (November 15, 2000): 3862-3872.
PMID
11078500
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
18
Issue
22
Publish Date
2000
Start Page
3862
End Page
3872
DOI
10.1200/JCO.2000.18.22.3862

Oral administration of the specific EGFR tyrosine kinase inhibitor, ZD1839 (Iressa (TM)), is active against EGFR-overexpressing intracranial tumors.

Authors
Heimberger, AB; Archer, GE; McLendon, RE; Price, D; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Heimberger, AB, Archer, GE, McLendon, RE, Price, D, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Oral administration of the specific EGFR tyrosine kinase inhibitor, ZD1839 (Iressa (TM)), is active against EGFR-overexpressing intracranial tumors." CLINICAL CANCER RESEARCH 6 (November 2000): 4542S-4543S.
Source
wos-lite
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
6
Publish Date
2000
Start Page
4542S
End Page
4543S

Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O(6) position of guanine. O(6)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS: Patients were treated with O(6)-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O(6)-BG, 8-oxo-O(6)-BG, and 8-oxoguanine concentration. RESULTS: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O(6)-BG rapidly disappeared from plasma (elimination half-life = 0. 54 +/- 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O(6)-BG (elimination half-life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O(6)-BG 5 hours after the start of the O(6)-BG infusion; however, 8-oxo-O(6)-BG and 8-oxoguanine concentrations were detected 25 hours after O(6)-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O(6)-BG was 17.5 times greater than the mean AUC for O(6)-BG. CONCLUSION: These results indicate that the MTD of BCNU when given in combination with O(6)-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O(6)-BG plus BCNU in nitrosourea-resistant malignant glioma.

Authors
Friedman, HS; Pluda, J; Quinn, JA; Ewesuedo, RB; Long, L; Friedman, AH; Cokgor, I; Colvin, OM; Haglund, MM; Ashley, DM; Rich, JN; Sampson, J; Pegg, AE; Moschel, RC; McLendon, RE; Provenzale, JM; Stewart, ES; Tourt-Uhlig, S; Garcia-Turner, AM; Herndon, JE; Bigner, DD; Dolan, ME
MLA Citation
Friedman, HS, Pluda, J, Quinn, JA, Ewesuedo, RB, Long, L, Friedman, AH, Cokgor, I, Colvin, OM, Haglund, MM, Ashley, DM, Rich, JN, Sampson, J, Pegg, AE, Moschel, RC, McLendon, RE, Provenzale, JM, Stewart, ES, Tourt-Uhlig, S, Garcia-Turner, AM, Herndon, JE, Bigner, DD, and Dolan, ME. "Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma." J Clin Oncol 18.20 (October 15, 2000): 3522-3528.
PMID
11032594
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
18
Issue
20
Publish Date
2000
Start Page
3522
End Page
3528
DOI
10.1200/JCO.2000.18.20.3522

Temozolomide delivered by intracerebral microinfusion is safe and efficacious against malignant gliomas in rats.

Intracerebral microinfusion (ICM) is an innovative technique of delivering therapeutic agents throughout large portions of the brain that circumvents the blood-brain barrier, minimizes systemic toxicity, and provides a homogeneous distribution of the infused agent. Temozolomide is a novel methylating agent with proven efficacy against malignant gliomas (MGs) after systemic administration but with dose-limiting myelotoxicity. Because MGs rarely metastasize, systemic drug delivery is unnecessary. Therefore, we evaluated the efficacy and toxicity of ICM with temozolomide in an athymic rat model of human MGs. Treatment of rats by ICM with temozolomide 3 days after intracerebral challenge with D54 human MG xenograft increased median survival by 128% compared with rats treated by ICM with saline, by 113% compared with rats treated with i.p. saline, and by 100% compared with rats treated with i.p. temozolomide (P < 0.001). Delay of treatment until 9 days after tumor challenge still resulted in a 23% increase in median survival in rats treated by ICM of temozolomide compared with rats treated with i.p. temozolomide. In addition, overall, 21.7% of rats treated by ICM with temozolomide survived for > 100 days without clinical or histological evidence of tumor. The dose of temozolomide delivered by ICM in this study was limited only by drug solubility, and no neurological or systemic toxicity could be attributed to ICM with temozolomide. Therefore, ICM of temozolomide may offer significant advantages in the treatment of MGs.

Authors
Heimberger, AB; Archer, GE; McLendon, RE; Hulette, C; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Heimberger, AB, Archer, GE, McLendon, RE, Hulette, C, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Temozolomide delivered by intracerebral microinfusion is safe and efficacious against malignant gliomas in rats." Clin Cancer Res 6.10 (October 2000): 4148-4153.
PMID
11051269
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
6
Issue
10
Publish Date
2000
Start Page
4148
End Page
4153

Human chorionic gonadotropin beta subunit protein immunoreactivity in pituitary adenomas: Pathologic features

Authors
Cummings, TJ; McLendon, RE; Villavicencio, AT; Friedman, AH; Burchette, JL; Bentley, RC
MLA Citation
Cummings, TJ, McLendon, RE, Villavicencio, AT, Friedman, AH, Burchette, JL, and Bentley, RC. "Human chorionic gonadotropin beta subunit protein immunoreactivity in pituitary adenomas: Pathologic features." BRAIN PATHOLOGY 10.4 (September 2000): 746-747.
Source
wos-lite
Published In
Brain Pathology
Volume
10
Issue
4
Publish Date
2000
Start Page
746
End Page
747

Glioma-associated antigen expression in oligodendroglial neoplasms. Tenascin and epidermal growth factor receptor.

Epidermal growth factor receptor (EGFR), its variant, EGFRvIII, and tenascin are glioma-associated antigens that are hyperexpressed by neoplastic glial cells relative to normal brain, making them attractive antigenic targets for immunotherapy. Preliminary surveys indicate that oligodendroglial tumors also produce these proteins, although the exact patterns and degrees of reactivity are not known. In this study we examined the immunoreactivity of tenascin among 50 oligodendroglial tumors, including 25 well-differentiated oligodendrogliomas (WDOs) and 12 glioblastomas (GBMs) exhibiting high proportions of oligodendroglia-like cells. We used well-characterized immunoreagents with defined specificities against the target antigens on formalin-fixed, paraffin-embedded archival tissue. The tumors were graded according to WHO guidelines. Immunoreactivity was reported on a 1-3 scale according to staining intensity multiplied by a 1-3 distribution scale distribution within tumor as focal (1), multifocal (2), and diffuse (3) for both the parenchymal and the perivascular components. Although there is considerable overlap in antigen production among the grades of tumor, this study establishes the production of tenascin and wild-type EGFR (but not EGFR vIII) in oligodendroglial neoplasms and supports the concept that antigen production increases with tumor grade.

Authors
McLendon, RE; Wikstrand, CJ; Matthews, MR; Al-Baradei, R; Bigner, SH; Bigner, DD
MLA Citation
McLendon, RE, Wikstrand, CJ, Matthews, MR, Al-Baradei, R, Bigner, SH, and Bigner, DD. "Glioma-associated antigen expression in oligodendroglial neoplasms. Tenascin and epidermal growth factor receptor." J Histochem Cytochem 48.8 (August 2000): 1103-1110.
PMID
10898803
Source
pubmed
Published In
Journal of Histochemistry and Cytochemistry
Volume
48
Issue
8
Publish Date
2000
Start Page
1103
End Page
1110
DOI
10.1177/002215540004800807

Castleman's disease confined to the leptomeninges.

We report a rare case of the plasma cell variant of Castleman's disease confined to the leptomeninges in a 42-year-old female. Flow cytometry demonstrated a minor monoclonal kappa light chain population, and conventional Southern blotting confirmed clonal rearrangement of the J(H) immunoglobulin heavy-chain gene. Polymerase chain reaction for Epstein-Barr virus and Kaposi's sarcoma-associated herpes virus was negative. The patient is disease-free five years after surgical resection. To our knowledge, clonal gene rearrangement has not been previously reported in the plasma cell variant of localized intracranial Castleman's disease.

Authors
Cummings, TJ; Gong, JZ; Friedman, AH; McLendon, RE
MLA Citation
Cummings, TJ, Gong, JZ, Friedman, AH, and McLendon, RE. "Castleman's disease confined to the leptomeninges." Ann Clin Lab Sci 30.3 (July 2000): 278-282. (Review)
PMID
10945568
Source
pubmed
Published In
Annals of Clinical and Laboratory Science
Volume
30
Issue
3
Publish Date
2000
Start Page
278
End Page
282

Pineal epidermoid cysts.

Authors
Cummings, TJ; McLendon, RE
MLA Citation
Cummings, TJ, and McLendon, RE. "Pineal epidermoid cysts." J Neurosurg 92.5 (May 2000): 909-910. (Letter)
PMID
10794322
Source
pubmed
Published In
Journal of neurosurgery
Volume
92
Issue
5
Publish Date
2000
Start Page
909
End Page
910

Gliomas of the optic nerve: histological, immunohistochemical (MIB-1 and p53), and MRI analysis.

Gliomas of the optic nerve, although typically of pilocytic (WHO grade I) histology, can present within the spectrum of astrocytic neoplasia including glioblastoma (WHO grade IV). In certain cases, histologic features alone make the distinction between pilocytic and diffuse astrocytomas difficult. We reviewed 22 cases of optic nerve gliomas, 19 of which were pilocytic astrocytomas (PA), and 3 of which were diffuse, non-pilocytic astrocytomas. The cases were evaluated for their clinical course, radiographic appearance, histologic grade, and proliferation indices as detected by MIB-1 (Ki-67) and p53 antibodies. Of the 19 PA, 14 showed no tumor growth by magnetic resonance imaging, and had Ki-67 and p53 labeling indices (LI) of < 1%. The other 5 PA exhibited aggressive behavior manifest by marked diffuse infiltrative tumor growth causing death in 2 patients, 1 of whom was diagnosed with neurofibromatosis type 1 (immunoperoxidase and radiographs not available), and marked local growth with an average time to growth of 39.3 months, a Ki-67 LI of 2-3%, and a p53 LI of < 1% in three others. Three of the five aggressive PA histologically demonstrated a finely reticulated pattern, a pattern that appears as an exaggeration or expansion of the normal neuroglia of the optic nerve, and may simulate a diffuse low-grade astrocytoma. Two demonstrated the coarsely reticulated pattern, with the biphasic and microcystic pattern typical of PA. Three diffuse astrocytomas (2 anaplastic astrocytomas and 1 glioblastoma) originated clinically and radiographically from the optic nerve, and revealed a Ki-67 LI of 2-12%, a p53 LI of 2-8%, and an average time to growth of 8 months. We conclude that the majority of PA of the optic nerve are non-aggressive, stabilize radiographically, and have Ki-67 and p53 LI < 1%. However, a subpopulation of PA has a propensity for aggressive behavior, and are identified by a Ki-67 LI of 2-3% and a p53 LI of < 1%. Diffuse astrocytomas have both Ki-67 and p53 LI > 2%. Thus, in cases of aggressive optic nerve tumors in which the histologic review of biopsy material cannot confidently confirm the diagnosis of pilocytic or diffuse fibrillary glioma, a p53 LI of > 1% appears to favor the diagnosis of diffuse astrocytoma.

Authors
Cummings, TJ; Provenzale, JM; Hunter, SB; Friedman, AH; Klintworth, GK; Bigner, SH; McLendon, RE
MLA Citation
Cummings, TJ, Provenzale, JM, Hunter, SB, Friedman, AH, Klintworth, GK, Bigner, SH, and McLendon, RE. "Gliomas of the optic nerve: histological, immunohistochemical (MIB-1 and p53), and MRI analysis." Acta Neuropathol 99.5 (May 2000): 563-570.
PMID
10805102
Source
pubmed
Published In
Acta Neuropathologica
Volume
99
Issue
5
Publish Date
2000
Start Page
563
End Page
570

Microdosimetry of alpha-particle-emitting At-211-labelled monoclonal antibody (MAb) using histological images of malignant brain tumors.

Authors
Akabani, G; McLendon, RE; Bigner, DD; Zalutsky, MR
MLA Citation
Akabani, G, McLendon, RE, Bigner, DD, and Zalutsky, MR. "Microdosimetry of alpha-particle-emitting At-211-labelled monoclonal antibody (MAb) using histological images of malignant brain tumors." JOURNAL OF NUCLEAR MEDICINE 41.5 (May 2000): 84P-84P.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
41
Issue
5
Publish Date
2000
Start Page
84P
End Page
84P

HAM56 immunoreactivity in infiltrating glial neoplasms.

Authors
Cummings, TJ; Hulette, CM; Bigner, S; Lal, A; Riggins, GJ; Burchette, JL; McLendon, RE
MLA Citation
Cummings, TJ, Hulette, CM, Bigner, S, Lal, A, Riggins, GJ, Burchette, JL, and McLendon, RE. "HAM56 immunoreactivity in infiltrating glial neoplasms." JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 59.5 (May 2000): 437-437.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
59
Issue
5
Publish Date
2000
Start Page
437
End Page
437

Characterization of chromosome 17 abnormalities in medulloblastomas.

Loss of portions of chromosome 17p, usually through the formation of i(17qp) is a well-known finding in medulloblastomas. Loss of heterozygosity (LOH) studies, however, occasionally demonstrate loss of the more distal portions of 17p, a pattern which is more consistent with a terminal deletion. Here we use a combination of routine karyotyping, fluorescence in situ hybridization (FISH) and LOH studies on four medulloblastoma cell lines and one xenograft to demonstrate the spectrum of chromosome 17 abnormalities which occur in these tumors. Cell line D-556 Med showed a typical dicentric i(17q) and cell line D-721 Med showed two normal copies of chromosome 17 by all methods. Cell line D-425 Med showed loss of terminal 17p by LOH, while the karyotype showed what appeared to be an i(17q). FISH and chromosome 17 painting, however, demonstrated that the abnormal chromosome 17 was actually formed through an unbalanced translocation involving two copies of chromosome 17, with breakpoints at p12 and q11-1, an explanation which reconciled the cytogenetic and LOH findings. Cell line D 581 Med had a terminal deletion at 17p11.2. The finding of two cells with i(17q) in this case by interphase FISH suggests that the terminal deletion arose from breakage of an i(17q). Finally, xenograft D 690 Med showed LOH for regions distal to 17p12, whereas karyotyping, FISH using probes on 17p, and chromosome 17 painting showed two intact copies of chromosome 17. This pattern can be explained by homologous recombination. These data support the concept that the critical deletion of 17p can occur through a variety of mechanisms in the medulloblastoma. The losses may occur through typical i(17q), as well as other mechanisms such as terminal deletions, possibly through breakage of i(17q), unbalanced translocations and homologous recombination.

Authors
Aldosari, N; Rasheed, BK; McLendon, RE; Friedman, HS; Bigner, DD; Bigner, SH
MLA Citation
Aldosari, N, Rasheed, BK, McLendon, RE, Friedman, HS, Bigner, DD, and Bigner, SH. "Characterization of chromosome 17 abnormalities in medulloblastomas." Acta Neuropathol 99.4 (April 2000): 345-351.
PMID
10787031
Source
pubmed
Published In
Acta Neuropathologica
Volume
99
Issue
4
Publish Date
2000
Start Page
345
End Page
351

Dosimetry and dose-response relationships in newly diagnosed patients with malignant gliomas treated with iodine-131-labeled anti-tenascin monoclonal antibody 81C6 therapy.

PURPOSE: The objective of this study was to perform the dosimetry and evaluate the dose-response relationships in newly diagnosed patients with malignant brain tumors treated by direct injections of (131)I-labeled 81C6 monoclonal antibody (MAb) into surgically created resection cavities (SCRCs). METHODS AND MATERIALS: Absorbed doses to the 2-cm-thick shell as measured from the margins of the resection cavity interface were estimated for 42 patients with primary brain tumors. MR images were used to assess the enhanced-rim volume as a function of time after radiolabeled MAb therapy. Biopsy samples were obtained from 15 patients and 1 autopsy. RESULTS: The average absorbed dose [range] to the 2-cm shell region was 32 [3-59] Gy. For the endpoint of minimal time to MR contrast enhancement, the optimal absorbed dose and initial dose-rate were 43 +/- 16 Gy and 0. 41 +/- 0.10 Gy/h, respectively. There was a correlation between the absorbed dose and dose rate to the shell region and biopsy outcome (tumor recurrence, radionecrosis, and tumor recurrence and/or radionecrosis). In this Phase I study, the maximum tolerated dose (MTD) was 120 mCi. At this MTD, the estimated average absorbed dose and initial dose rate to the 2-cm shell were 41 [9-89] Gy and 0.51 [0.24-1.13] Gy/h, respectively. These values are in agreement with the optimal values based on the time to MR lesion rim enhancement. CONCLUSIONS: The average absorbed dose to the 2-cm shell region varied considerably and mainly depended on cavity volume. In future clinical trials, the administered activity of (131)I-labeled 81C6 MAb may be adjusted based on cavity volume in order to deliver the optimal absorbed dose of 43 Gy rather than giving a fixed administered activity.

Authors
Akabani, G; Cokgor, I; Coleman, RE; González Trotter, D; Wong, TZ; Friedman, HS; Friedman, AH; Garcia-Turner, A; Herndon, JE; DeLong, D; McLendon, RE; Zhao, XG; Pegram, CN; Provenzale, JM; Bigner, DD; Zalutsky, MR
MLA Citation
Akabani, G, Cokgor, I, Coleman, RE, González Trotter, D, Wong, TZ, Friedman, HS, Friedman, AH, Garcia-Turner, A, Herndon, JE, DeLong, D, McLendon, RE, Zhao, XG, Pegram, CN, Provenzale, JM, Bigner, DD, and Zalutsky, MR. "Dosimetry and dose-response relationships in newly diagnosed patients with malignant gliomas treated with iodine-131-labeled anti-tenascin monoclonal antibody 81C6 therapy." Int J Radiat Oncol Biol Phys 46.4 (March 1, 2000): 947-958.
PMID
10705017
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
46
Issue
4
Publish Date
2000
Start Page
947
End Page
958

Comparison of patient age with MR imaging features of gangliogliomas.

OBJECTIVE: The purpose of this study was to compare MR imaging features of gangliogliomas in children less than 10 years old with those seen in patients at least 10 years old. MATERIALS AND METHODS: Our study population consisted of 15 female patients and 10 male patients with a mean age of 20 years. The early childhood group was composed of six children with a mean age of 5.5 years. The older group was composed of 19 patients with a mean age of 25.6 years. We assessed tumor volume, tumor location, percentage of tumor that was cystic, pattern of contrast enhancement, and degree of edema. RESULTS: The temporal lobe was the most common tumor location in both groups. Mean tumor volume in the early childhood group was 83 cm3, which was significantly larger than the mean tumor volume (9.78 cm3) for the older group (p = 0.001). Cystic tumors were more common in the early childhood group (83%) than in the older group (63%), and the average percentage of cysts in the cystic tumors was much higher in the early childhood group (67%) than in the older group (30%). Contrast enhancement was seen in five of six early childhood tumors and 13 of 16 tumors in older patients. Four of six tumors in the early childhood group and five of 19 tumors in the older patient group had associated edema. CONCLUSION: The mean tumor volume of gangliogliomas in the early childhood group was significantly larger than that of the older patient group. This finding may be indicative of differences in tumor growth patterns in the two groups, ability of the hemicranium to adjust to mass effect in childhood, or sampling error as a result of a relatively small sample size.

Authors
Provenzale, JM; Ali, U; Barboriak, DP; Kallmes, DF; Delong, DM; McLendon, RE
MLA Citation
Provenzale, JM, Ali, U, Barboriak, DP, Kallmes, DF, Delong, DM, and McLendon, RE. "Comparison of patient age with MR imaging features of gangliogliomas." AJR Am J Roentgenol 174.3 (March 2000): 859-862.
PMID
10701639
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
174
Issue
3
Publish Date
2000
Start Page
859
End Page
862
DOI
10.2214/ajr.174.3.1740859

Parasitic lesion of the insula suggesting cerebral sparganosis: case report.

Cerebral sparganosis, a parasitic disease, rarely produces a chronic active inflammatory response in the brain. Clinically and radiographically the process may mimic a neoplasm. We report a 30-year-old man who underwent surgical exploration for a mass in the insular cortex. Histology revealed a densely fibrotic mass heavily infiltrated with plasma cells and lymphocytes, in which were embedded parasitic forms consistent with sparganosis. We describe the MRI appearances and pathologic features. Intracranial mass lesions secondary to sparganosis must be considered in patients with a history of travel to endemic areas, especially Asia.

Authors
Cummings, TJ; Madden, JF; Gray, L; Friedman, AH; McLendon, RE
MLA Citation
Cummings, TJ, Madden, JF, Gray, L, Friedman, AH, and McLendon, RE. "Parasitic lesion of the insula suggesting cerebral sparganosis: case report." Neuroradiology 42.3 (March 2000): 206-208.
PMID
10772144
Source
pubmed
Published In
Neuroradiology
Volume
42
Issue
3
Publish Date
2000
Start Page
206
End Page
208

Bone marrow-derived dendritic cells pulsed with tumor homogenate induce immunity against syngeneic intracerebral glioma.

To evaluate the efficacy and toxicity of dendritic cell (DC) based therapy for intracerebral gliomas, we utilized a cell line derived from an astrocytoma that arose spontaneously in a VM/Dk mouse. This astrocytoma mirrors human gliomas phenotypically, morphologically and secretes transforming growth factor (TGF)-betas, immunosuppressive cytokines secreted by human gliomas. Systemic vaccination of mice with DCs pulsed with tumor homogenate followed by intracranial tumor challenge produced a > 160% increase in median survival (p = 0.016) compared with mice vaccinated with PBS or unpulsed DCs (p = 0.083). Fifty percent of mice treated with pulsed DCs survived long-term. Immunologic memory was demonstrated by survival of mice rechallenged with tumor. Both cell-mediated and humoral immunity was induced. On histological examination only focal areas of demyelination at the tumor implantation site were present. There was no evidence that autoimmune encephalomyelitis was induced by DC vaccination. Therefore, in a murine model, vaccination with DCs pulsed with glioma tumor homogenate is a safe and effective therapy against a syngeneic glioma located in the immunologically privileged central nervous system (CNS).

Authors
Heimberger, AB; Crotty, LE; Archer, GE; McLendon, RE; Friedman, A; Dranoff, G; Bigner, DD; Sampson, JH
MLA Citation
Heimberger, AB, Crotty, LE, Archer, GE, McLendon, RE, Friedman, A, Dranoff, G, Bigner, DD, and Sampson, JH. "Bone marrow-derived dendritic cells pulsed with tumor homogenate induce immunity against syngeneic intracerebral glioma." J Neuroimmunol 103.1 (February 1, 2000): 16-25.
PMID
10674985
Source
pubmed
Published In
Journal of Neuroimmunology
Volume
103
Issue
1
Publish Date
2000
Start Page
16
End Page
25

Pineal epidermoid cysts [9] (multiple letters)

Authors
Cummings, TJ; McLendon, RE; Spallone, A
MLA Citation
Cummings, TJ, McLendon, RE, and Spallone, A. "Pineal epidermoid cysts [9] (multiple letters)." Journal of Neurosurgery 92.5 (2000): 909-910.
Source
scival
Published In
Journal of Neurosurgery
Volume
92
Issue
5
Publish Date
2000
Start Page
909
End Page
910

Primary central nervous system lymphomas: a 30-year experience at a single institution.

Primary central nervous system lymphoma (PCNSL) is a rare disease that has been increasing in frequency. Clinical, histologic, and immunohistochemical data from 64 cases of PCNSL seen at Duke University Medical Center since 1968 were reviewed and tumors were classified using the REAL classification system. Thirty-two patients were male and 32 were female, with a mean age of 57.1 years, ranging from 16 to 82 years. Large B-cell lymphoma represented overwhelming the majority of PCNSL, accounting for 81% of all cases. Phenotypic T-cell lymphomas were rare with only two cases over the course of the study. Epstein-Barr virus was detected only in the immunocompromised patients and was identified in 75% of those immunocompromised patients who were tested. Overall survival was poor with a mean survival of 357 days and median survival of 158 days. One- and three-year survival rates were 29.6% and 7.8%, respectively. Type of treatment, duration of symptoms, site of lesion, and histologic subtype were not significant prognostic indicators, whereas concurrent immunosuppression was the strongest predictor of poor outcome. In AIDS patients (which accounted for 21.9% of the study group), the median survival was 65 days, which was significantly different than that seen in the immunocompetent group of 217 days (P = .001).

Authors
Nuckols, JD; Liu, K; Burchette, JL; McLendon, RE; Traweek, ST
MLA Citation
Nuckols, JD, Liu, K, Burchette, JL, McLendon, RE, and Traweek, ST. "Primary central nervous system lymphomas: a 30-year experience at a single institution." Mod Pathol 12.12 (December 1999): 1167-1173.
PMID
10619271
Source
pubmed
Published In
Modern Pathology
Volume
12
Issue
12
Publish Date
1999
Start Page
1167
End Page
1173

A public database for gene expression in human cancers.

A public database, SAGEmap, was created as a component of the Cancer Genome Anatomy Project to provide a central location for depositing, retrieving, and analyzing human gene expression data. This database uses serial analysis of gene expression to quantify transcript levels in both malignant and normal human tissues. By accessing SAGEmap (http://www.ncbi.nlm.nih.gov/SAGE) the user can compare transcript populations between any of the posted libraries. As an initial demonstration of the database's utility, gene expression in human glioblastomas was compared with that of normal brain white matter. Of the 47,174 unique transcripts expressed in these two tissues, 471 (1.0%) were differentially expressed by more than 5-fold (P<0.001). Classification of these genes revealed functions consistent with the biological properties of glioblastomas, in particular: angiogenesis, transcription, and cell cycle related genes.

Authors
Lal, A; Lash, AE; Altschul, SF; Velculescu, V; Zhang, L; McLendon, RE; Marra, MA; Prange, C; Morin, PJ; Polyak, K; Papadopoulos, N; Vogelstein, B; Kinzler, KW; Strausberg, RL; Riggins, GJ
MLA Citation
Lal, A, Lash, AE, Altschul, SF, Velculescu, V, Zhang, L, McLendon, RE, Marra, MA, Prange, C, Morin, PJ, Polyak, K, Papadopoulos, N, Vogelstein, B, Kinzler, KW, Strausberg, RL, and Riggins, GJ. "A public database for gene expression in human cancers." Cancer Res 59.21 (November 1, 1999): 5403-5407.
PMID
10554005
Source
pubmed
Published In
Cancer Research
Volume
59
Issue
21
Publish Date
1999
Start Page
5403
End Page
5407

Electron microscopic diagnosis of human flavivirus encephalitis: use of confocal microscopy as an aid.

The distinction between intracranial viral infections and inflammatory conditions requiring immunosuppression is important. Although specific laboratory reagents are readily available for some viruses, diagnosis of arbovirus infection is more difficult. Transmission electron microscopy (TEM) theoretically allows identification of viral particles independent of reagent availability, but it has limited sensitivity. We report two cases of human flavivirus encephalitis diagnosed by TEM. Laser scanning confocal microscopy (LSCM) was used in one case to survey unembedded tissue slices for focal abnormalities, from which fragments smaller than 1 mm2 were excised for epoxy embedding. This facilitated TEM identification of intracytoplasmic, budding, 35-40 nm spherical virus particles, confirmed by serology as St. Louis encephalitis. In contrast to mosquitoes and newborn mice, in which high viral loads are associated with minimal tissue responses, these biopsies showed florid angiodestructive inflammation and microgliosis, with rare virions in necrotic perivascular cells and astrocytes. To our knowledge, this represents the first ultrastructural study of St. Louis encephalitis in humans, indicating the potential value of LSCM-aided TEM.

Authors
Chu, CT; Howell, DN; Morgenlander, JC; Hulette, CM; McLendon, RE; Miller, SE
MLA Citation
Chu, CT, Howell, DN, Morgenlander, JC, Hulette, CM, McLendon, RE, and Miller, SE. "Electron microscopic diagnosis of human flavivirus encephalitis: use of confocal microscopy as an aid." Am J Surg Pathol 23.10 (October 1999): 1217-1226.
PMID
10524522
Source
pubmed
Published In
American Journal of Surgical Pathology
Volume
23
Issue
10
Publish Date
1999
Start Page
1217
End Page
1226

Radiotoxicity of systemically administered 211At-labeled human/mouse chimeric monoclonal antibody: a long-term survival study with histologic analysis.

PURPOSE: The antitenascin human/mouse chimeric monoclonal antibody labeled with the alpha-particle-emitting radionuclide 211At is of interest as an endoradiotherapeutic agent for the treatment of brain tumors. To facilitate the investigation of 211At-labeled chimeric 81C6 in patients, the long-term radiotoxicity of this radiopharmaceutical has been evaluated. METHODS AND MATERIALS: Antibody labeling was performed using N-succinimidyl 3-[211At]astato-benzoate. After an initial dose-finding experiment, a second toxicity study was carried out at 4 dose levels in groups of 30 nonthyroid blocked B6C3F1 mice per group (15 males, 15 females). Male mice received either saline or 15-81 kBq/g and females received either saline or 16-83 kBq/g of 211At-labeled antibody. Ten animals (5 males, 5 females) were followed for 6 months and the remainder for 1 year. RESULTS: The lethal dose in 10% of animals (LD10) for 211At-labeled chimeric 81C6 was 46 kBq/g in females and 102 kBq/g in males. Toxic effects--perivascular fibrosis of the intraventricular septum of the heart, bone marrow suppression, splenic white pulp atrophy, and spermatic maturational delay--generally were confined to a few animals receiving the highest doses of labeled antibody. CONCLUSIONS: The LD10 of 211At-labeled chimeric 81C6 in this mouse strain was about half that of [211At]astatide. These results establish the preclinical maximum tolerated dose of 211At-labeled chimeric 81C6 and define in the mouse the target organs for toxicity. These studies will be useful for determining starting doses for clinical studies with 211At-labeled chimeric 81C6.

Authors
McLendon, RE; Archer, GE; Larsen, RH; Akabani, G; Bigner, DD; Zalutsky, MR
MLA Citation
McLendon, RE, Archer, GE, Larsen, RH, Akabani, G, Bigner, DD, and Zalutsky, MR. "Radiotoxicity of systemically administered 211At-labeled human/mouse chimeric monoclonal antibody: a long-term survival study with histologic analysis." Int J Radiat Oncol Biol Phys 45.2 (September 1, 1999): 491-499.
PMID
10487576
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
45
Issue
2
Publish Date
1999
Start Page
491
End Page
499

Meningioma of the fourth ventricle.

Meningiomas are primary meningeal based tumors of the central nervous system that rarely are located strictly within the fourth ventricle. We report a 72-year-old man operated upon for such a tumor. The pre-operative magnetic resonance images revealed a well circumscribed mass in the fourth ventricle that exhibited a low signal on T1-weighted magnetic resonance images and homogenously enhanced with gadolinium. By light microscopy the tumor was composed of tightly packed spindle cells separated by collagen. Immunohistochemistry showed the tumor cells to be positive for vimentin and epithelial membrane antigen, and negative for glial fibrillary acidic protein. Electron microscopy revealed typical findings of meningioma, including interdigitating cell processes, desmosomes, and intermediate filaments. Although rare, fibroblastic meningioma must be included in the differential diagnosis of a fourth ventricular spindle cell tumor in elderly patients.

Authors
Cummings, TJ; Bentley, RC; Gray, L; Check, WE; Lanier, TE; McLendon, RE
MLA Citation
Cummings, TJ, Bentley, RC, Gray, L, Check, WE, Lanier, TE, and McLendon, RE. "Meningioma of the fourth ventricle." Clin Neuropathol 18.5 (September 1999): 265-269.
PMID
10505436
Source
pubmed
Published In
Clinical neuropathology
Volume
18
Issue
5
Publish Date
1999
Start Page
265
End Page
269

Regional treatment of epidermal growth factor receptor vIII-expressing neoplastic meningitis with a single-chain immunotoxin, MR-1.

The incidence of neoplastic meningitis is on the rise. Neoplastic meningitis can result from a direct seeding of the neuraxis by primary brain tumors or by hematogeneous spread of systemic solid tumors. A frequent genetic alteration in primary brain tumors such as gliomas is an in-frame deletion in the epidermal growth factor receptor (EGFR) gene EGFRvIII, which brings together what were normally distant polypeptide sequences in the intact receptor. A novel glycine is formed at the fusion junction, resulting in a unique and tumor-specific target. By using phage display, we have isolated a single-chain antibody specific for the EGFRvIII mutation and expressed it with a modified form of the Pseudomonas exotoxin to form the immunotoxin MR1scFvPE38KDEL (MR-1). The multiple dose toxicity and therapeutic efficacy of MR-1 immunotoxin were tested in an athymic rat model of neoplastic meningitis. The maximally tolerated doses in non-tumor-bearing rats were three doses of 3 microg each. For therapeutic studies, the target was a neoplastic meningitis induced by intrathecal inoculation of the EGFRvIII-expressing human glioma U87MG.deltaEGFR. A dose escalation study compared the survival of three equal doses of 1, 2, and 3 microg of MR-1 immunotoxin with saline or 3 microg of the control immunotoxin specific for the interleukin 2 receptor, anti-Tac. All animals treated with three doses of saline or 3 microg of anti-Tac died, with median survival of 7 and 10 days, respectively. There were 75% (six of eight) long-term survivors in the group treated with three doses of 1 microg and 57% (four of seven) long-term survivors in the groups treated with three doses of either 2 or 3 microg of MR-1 immunotoxin. None of the MR-1 immunotoxin-treated groups reached median survival by the termination of the study at 53 days. Therefore, median survival was estimated to be >53 days, resulting in an estimated increase in median survival of >657% compared with saline and 430% versus anti-Tac. Compartmental therapy with three doses of 2 microg of MR-1 immunotoxin is effective in the treatment of EGFRvIII-expressing neoplastic meningitis. This dose was found to have no clinical or histopathological effects on non-tumor-bearing animals. MR-1 immunotoxin is, therefore, considered specific and safe within its therapeutic window. Phase I clinical trials for tumors invading the intrathecal space that express the EGFRvIII target should be initiated.

Authors
Archer, GE; Sampson, JH; Lorimer, IA; McLendon, RE; Kuan, CT; Friedman, AH; Friedman, HS; Pastan, IH; Bigner, DD
MLA Citation
Archer, GE, Sampson, JH, Lorimer, IA, McLendon, RE, Kuan, CT, Friedman, AH, Friedman, HS, Pastan, IH, and Bigner, DD. "Regional treatment of epidermal growth factor receptor vIII-expressing neoplastic meningitis with a single-chain immunotoxin, MR-1." Clin Cancer Res 5.9 (September 1999): 2646-2652.
PMID
10499644
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
5
Issue
9
Publish Date
1999
Start Page
2646
End Page
2652

Astatine-211 labeled chimeric anti-tenascin antibody: Phase I trial in brain tumor resection cavity patients

Authors
Zalutsky, MR; Akabani, G; Cokgor, I; Friedman, HS; Coleman, RE; Friedman, AH; McLendon, RE; Bigner, DD
MLA Citation
Zalutsky, MR, Akabani, G, Cokgor, I, Friedman, HS, Coleman, RE, Friedman, AH, McLendon, RE, and Bigner, DD. "Astatine-211 labeled chimeric anti-tenascin antibody: Phase I trial in brain tumor resection cavity patients." EUROPEAN JOURNAL OF NUCLEAR MEDICINE 26.9 (September 1999): 1215-1215.
Source
wos-lite
Published In
European journal of nuclear medicine
Volume
26
Issue
9
Publish Date
1999
Start Page
1215
End Page
1215

Molecular genetic aspects of oligodendrogliomas including analysis by comparative genomic hybridization.

Oligodendroglial neoplasms are a subgroup of gliomas with distinctive morphological characteristics. In the present study we have evaluated a series of these tumors to define their molecular profiles and to determine whether there is a relationship between molecular genetic parameters and histological pattern in this tumor type. Loss of heterozygosity (LOH) for 1p and 19q was seen in 17/23 (74%) well-differentiated oligodendrogliomas, in 18/23 (83%) anaplastic oligodendrogliomas, and in 3/8 (38%) oligoastrocytomas grades II and III. LOH for 17p and/or mutations of the TP53 gene occurred in 14 of these 55 tumors. Only one of the 14 cases with 17p LOH/TP53 gene mutation also had LOH for 1p and 19q, and significant astrocytic elements were seen histologically in the majority of these 14 tumors. LOH for 9p and/or deletion of the CDKN2A gene occurred in 15 of these 55 tumors, and 11 of these cases were among the 24 (42%) anaplastic oligodendrogliomas. Comparative genomic hybridization (CGH) identified the majority of cases with 1p and 19q loss and, in addition, showed frequent loss of chromosomes 4, 14, 15, and 18. These findings demonstrate that oligodendroglial neoplasms usually have loss of 1p and 19q whereas astrocytomas of the progressive type frequently contain mutations of the TP53 gene, and that 9p loss and CDKN2A deletions are associated with progression from well-differentiated to anaplastic oligodendrogliomas.

Authors
Bigner, SH; Matthews, MR; Rasheed, BK; Wiltshire, RN; Friedman, HS; Friedman, AH; Stenzel, TT; Dawes, DM; McLendon, RE; Bigner, DD
MLA Citation
Bigner, SH, Matthews, MR, Rasheed, BK, Wiltshire, RN, Friedman, HS, Friedman, AH, Stenzel, TT, Dawes, DM, McLendon, RE, and Bigner, DD. "Molecular genetic aspects of oligodendrogliomas including analysis by comparative genomic hybridization." Am J Pathol 155.2 (August 1999): 375-386.
PMID
10433931
Source
pubmed
Published In
The American journal of pathology
Volume
155
Issue
2
Publish Date
1999
Start Page
375
End Page
386
DOI
10.1016/S0002-9440(10)65134-6

Gliomatosis cerebri: cytologic and autopsy findings in a case involving the entire neuraxis.

We describe the case of a 7-year-old girl who was clinically diagnosed as having a pontine glioma based on magnetic resonance imaging studies. Neoplastic cells were identified upon cytologic examination of cerebrospinal fluid. Autopsy studies revealed an anaplastic astrocytoma (WHO grade III) diffusely infiltrating the cerebral hemispheres, brain stem, cerebellum, leptomeninges, and spinal cord to the level of the conus medullaris. The Ki-67 labeling index focally approached 30%. Although many of the neoplastic cells displayed elongated twisted nuclei reminiscent of microglia, these cells stained intensely for glial fibrillary acidic protein, supporting an astrocytic origin. Unusual features of this case of gliomatosis cerebri include involvement of the entire central neuraxis, correlation with pre-mortem lumbar puncture cytology, and a markedly elevated Ki-67 labeling index.

Authors
Cummings, TJ; Hulette, CM; Longee, DC; Bottom, KS; McLendon, RE; Chu, CT
MLA Citation
Cummings, TJ, Hulette, CM, Longee, DC, Bottom, KS, McLendon, RE, and Chu, CT. "Gliomatosis cerebri: cytologic and autopsy findings in a case involving the entire neuraxis." Clin Neuropathol 18.4 (July 1999): 190-197.
PMID
10442461
Source
pubmed
Published In
Clinical neuropathology
Volume
18
Issue
4
Publish Date
1999
Start Page
190
End Page
197

Treatment of neoplastic meningitis with intrathecal temozolomide.

Neoplastic meningitis (NM) results from leptomeningeal dissemination of cancers arising within the central nervous system or metastasizing to the leptomeninges from systemic neoplasms. The inability to produce therapeutic drug levels intrathecally (i.t.) with systemic administration and the minimal efficacy of chemotherapeutic agents currently available for direct i.t. use limit therapy. Temozolomide [8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4([3H])-one] is a novel methylating agent with proven activity against intraparenchymal malignant gliomas (MGs). Insolubility of the standard formulation prevents its efficacious use as an i.t. agent, however. To overcome this obstacle, we have developed a unique microcrystalline formulation of temozolomide with greatly enhanced solubility. Treatment of athymic rats bearing subarachnoid MER- human MG xenografts with four doses of i.t. microcrystalline temozolomide over a 2-week period produced a 142% increase in median survival at individual doses of 2.2 micromol (P = 0.0073) and a >367% increase in median survival at individual doses of 6.8 micromol (P = 0.0015). At the higher dose tested, three of eight rats treated developed no neurological symptoms and had no evidence of residual tumor on histological examination after treatment. Use of this microcrystalline formulation in athymic rats bearing subarachnoid MER+ human MG xenografts increased median survival >132% (P < 0.0058) at both dose levels tested. Toxicity directly attributable to the i.t. administration of microcrystalline temozolomide was exhibited in the highest dose groups only and was limited to small patchy areas of focal demyelination involving <5% of spinal cord long tracks.

Authors
Sampson, JH; Archer, GE; Villavicencio, AT; McLendon, RE; Friedman, AH; Bishop, WR; Bigner, DD; Friedman, HS
MLA Citation
Sampson, JH, Archer, GE, Villavicencio, AT, McLendon, RE, Friedman, AH, Bishop, WR, Bigner, DD, and Friedman, HS. "Treatment of neoplastic meningitis with intrathecal temozolomide." Clin Cancer Res 5.5 (May 1999): 1183-1188.
PMID
10353755
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
5
Issue
5
Publish Date
1999
Start Page
1183
End Page
1188

Fine-needle aspiration cytology of "ancient" schwannoma.

The term "ancient" schwannoma was proposed for a group of neural tumors showing degenerative changes and marked nuclear atypia. Prior to the realization that the observed atypia was a regressive phenomenon, many of these lesions were erroneously diagnosed as sarcomas. Fine-needle aspiration (FNA) cytologic material from five patients is included in this study. Tissue examined histologically included four resected tumors and 18 gauge core biopsies of one tumor. Aspirates of ancient schwannoma showed many of the same features as FNA of regular schwannoma: aggregates of spindled cells with indistinct cytoplasm and elongate nuclei with blunt point ends. The feature unique to these lesions was nuclear pleomorphism, which was identified in all aspirates. Nuclear inclusions were identified in all but one case. Cystic degeneration, xanthomatous changes, and perivascular sclerosis were identified in excised lesions. Ancient schwannomas show most of the FNA features of benign schwannomas but can demonstrate marked nuclear atypia. The FNA features of ancient schwannoma are important to note because of the potential to confuse this lesion with a more serious one such as sarcoma on FNA.

Authors
Dodd, LG; Marom, EM; Dash, RC; Matthews, MR; McLendon, RE
MLA Citation
Dodd, LG, Marom, EM, Dash, RC, Matthews, MR, and McLendon, RE. "Fine-needle aspiration cytology of "ancient" schwannoma." Diagn Cytopathol 20.5 (May 1999): 307-311.
PMID
10319234
Source
pubmed
Published In
Diagnostic Cytopathology
Volume
20
Issue
5
Publish Date
1999
Start Page
307
End Page
311

Irinotecan therapy in adults with recurrent or progressive malignant glioma.

PURPOSE: To determine the activity, toxicity, and pharmacokinetics of irinotecan (CPT-11, Camptosar; Pharmacia & Upjohn, Kalamazoo, MI) in the treatment of adults with progressive, persistent, or recurrent malignant glioma. PATIENTS AND METHODS: Patients with progressive or recurrent malignant gliomas were enrolled onto this study between October 1996 and August 1997. CPT-11 was given as a 90-minute intravenous (i.v.) infusion at a dose of 125 mg/m2 once weekly for 4 weeks followed by a 2-week rest, which comprised one course. Plasma concentrations of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were determined in a subset of patients. RESULTS: All 60 patients who enrolled (36 males and 24 females) were treated with CPT-11 and all were assessable for toxicity, response, and survival. Pharmacokinetic data were available in 32 patients. Nine patients (15%; 95% confidence interval, 6% to 24%) had a confirmed partial response, and 33 patients (55%) achieved stable disease lasting more than two courses (12 weeks). Toxicity observed during the study was limited to infrequent neutropenia, nausea, vomiting, and diarrhea. CPT-11, SN-38, and SN-38G area under the plasma concentration-time curves through infinite time values in these patients were approximately 40%, 25%, and 25%, respectively, of those determined previously in patients with metastatic colorectal cancer not receiving antiepileptics or chronic dexamethasone treatment. CONCLUSION: Response results document that CPT-11, given with a standard starting dose and treatment schedule, has activity in patients with recurrent malignant glioma. However, the low incidence of severe toxicity and low plasma concentrations of CPT-11 and SN-38 achieved in this patient population suggest that concurrent treatment with anticonvulsants and dexamethasone enhances drug clearance.

Authors
Friedman, HS; Petros, WP; Friedman, AH; Schaaf, LJ; Kerby, T; Lawyer, J; Parry, M; Houghton, PJ; Lovell, S; Rasheed, K; Cloughsey, T; Stewart, ES; Colvin, OM; Provenzale, JM; McLendon, RE; Bigner, DD; Cokgor, I; Haglund, M; Rich, J; Ashley, D; Malczyn, J; Elfring, GL; Miller, LL
MLA Citation
Friedman, HS, Petros, WP, Friedman, AH, Schaaf, LJ, Kerby, T, Lawyer, J, Parry, M, Houghton, PJ, Lovell, S, Rasheed, K, Cloughsey, T, Stewart, ES, Colvin, OM, Provenzale, JM, McLendon, RE, Bigner, DD, Cokgor, I, Haglund, M, Rich, J, Ashley, D, Malczyn, J, Elfring, GL, and Miller, LL. "Irinotecan therapy in adults with recurrent or progressive malignant glioma." J Clin Oncol 17.5 (May 1999): 1516-1525.
PMID
10334539
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
17
Issue
5
Publish Date
1999
Start Page
1516
End Page
1525
DOI
10.1200/JCO.1999.17.5.1516

Long term recurrent juvenile pilocytic astrocytomas of the cerebellum: Histologic and pathologic studies.

Authors
Cummings, TJ; Chu, CT; McLendon, RE
MLA Citation
Cummings, TJ, Chu, CT, and McLendon, RE. "Long term recurrent juvenile pilocytic astrocytomas of the cerebellum: Histologic and pathologic studies." JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 58.5 (May 1999): 538-538.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
58
Issue
5
Publish Date
1999
Start Page
538
End Page
538
DOI
10.1097/00005072-199905000-00126

Malignant supratentorial ganglioglioma (ganglion cell-giant cell glioblastoma): a case report and review of the literature.

BACKGROUND: From both epidemiologic and pathologic viewpoints, gangliogliomas exhibiting components of giant cell glioblastomas are extraordinary neoplasms. We report herein the case of a 6-year-old girl who presented initially with a World Health Organization grade IV anaplastic ganglioglioma (a mixed ganglion cell tumor-giant cell glioblastoma). Despite aggressive management, the patient died of disease in a relatively short period. METHODS: Formalin-fixed, paraffin-embedded tissue blocks were sectioned at 5 microm for histochemical and immunohistochemical analyses. Hematoxylin-eosin-stained sections and immunohistochemically stained sections from the primary and secondary resections were reviewed. Reactivity for glial fibrillary acidic protein, neurofilament protein, synaptophysin, and Ki67 nuclear antigen was evaluated. RESULTS: Histologically, 2 distinct cell populations were noted on both the primary and secondary resections. The primary resection revealed a neoplasm having a predominant glial component consistent with a glioblastoma. Interspersed were dysmorphic ganglion cells supporting a diagnosis of ganglioglioma. The second resection (following therapy) demonstrated a much more prominent dysmorphic ganglion cell component and a subdued glial component. CONCLUSION: Although immunohistochemical analysis clearly distinguished the 2 tumor cell populations, the identification of Nissl substance in neurons proved to be equally helpful. Although other cases of grade III gangliogliomas and rare cases of grade IV gangliogliomas have been reported, the present case is exceptional in that, to our knowledge, it is the only report of a patient who presented initially with a composite grade IV ganglioglioma and who was clinically followed up to the time of death. This case allows direct comparison between the histologic findings in a giant cell glioblastoma and a ganglioglioma and documents the aggressive biologic behavior of this complex neoplasm.

Authors
Dash, RC; Provenzale, JM; McComb, RD; Perry, DA; Longee, DC; McLendon, RE
MLA Citation
Dash, RC, Provenzale, JM, McComb, RD, Perry, DA, Longee, DC, and McLendon, RE. "Malignant supratentorial ganglioglioma (ganglion cell-giant cell glioblastoma): a case report and review of the literature." Arch Pathol Lab Med 123.4 (April 1999): 342-345.
PMID
10320149
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
123
Issue
4
Publish Date
1999
Start Page
342
End Page
345
DOI
10.1043/0003-9985(1999)123<0342:MSGGCG>2.0.CO;2

Gangliogliomas: characterization by registered positron emission tomography-MR images.

OBJECTIVE: The purpose of this study was to correlate 18F-fluorodeoxyglucose positron emission tomography (PET) and MR imaging features of cerebral gangliogliomas before and after PET-MR image registration. CONCLUSION: After registration of PET and MR images, all six gangliogliomas in our series were shown to have heterogeneous metabolic activity. Areas of hypermetabolic activity were seen in all lesions. In five of the six cases, PET-MR image registration provided information regarding tumor metabolism that was not available on nonregistered hard-copy examinations.

Authors
Provenzale, JM; Arata, MA; Turkington, TG; McLendon, RE; Coleman, RE
MLA Citation
Provenzale, JM, Arata, MA, Turkington, TG, McLendon, RE, and Coleman, RE. "Gangliogliomas: characterization by registered positron emission tomography-MR images." AJR Am J Roentgenol 172.4 (April 1999): 1103-1107.
PMID
10587156
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
172
Issue
4
Publish Date
1999
Start Page
1103
End Page
1107
DOI
10.2214/ajr.172.4.10587156

Topotecan treatment of adults with primary malignant glioma. The Brain Tumor Center at Duke.

BACKGROUND: Topotecan activity was evaluated for the treatment of malignant glioma. METHODS: Sixty-three patients with newly diagnosed (n = 25) or recurrent (n = 38) malignant glioma were treated with topotecan [AU: Please verify all dosages here and throughout text.]at a dose of 2.6 mg/m2 over a 72-hour period weekly. Recurrent tumors included glioblastoma multiforme (GBM) (n = 28) and anaplastic astrocytoma (AA) (n = 10). Newly diagnosed tumors included GBM (n = 14), AA (n = 8), and anaplastic oligodendroglioma (n = 3). RESULTS: Partial responses were observed in 2 of 14 evaluable patients with newly diagnosed GBM, 1 of 8 patients with newly diagnosed AA, 3 of 10 patients with recurrent AA, and none of 28 patients with recurrent GBM. Four patients with recurrent AA and 7 patients with recurrent GBM demonstrated stable disease (range, 8-52 weeks; median, 21 weeks). Toxicity was limited to infrequent National Cancer Institute Common Toxicity Criteria Grade 3 myelosuppression. CONCLUSIONS: These results suggest that topotecan has modest activity against malignant glioma and continued evaluation of its effectiveness may be warranted when alternative schedules or combination regimens are used.

Authors
Friedman, HS; Kerby, T; Fields, S; Zilisch, JE; Graden, D; McLendon, RE; Houghton, PJ; Arbuck, S; Cokgor, I; Friedman, AH
MLA Citation
Friedman, HS, Kerby, T, Fields, S, Zilisch, JE, Graden, D, McLendon, RE, Houghton, PJ, Arbuck, S, Cokgor, I, and Friedman, AH. "Topotecan treatment of adults with primary malignant glioma. The Brain Tumor Center at Duke." Cancer 85.5 (March 1, 1999): 1160-1165.
PMID
10091802
Source
pubmed
Published In
Cancer
Volume
85
Issue
5
Publish Date
1999
Start Page
1160
End Page
1165

Diagnostic markers in paediatric medulloblastoma: a Paediatric Oncology Group Study.

AIMS: We have reviewed immunohistochemically 17 paediatric medulloblastomas in order to determine if correlations exist that might be useful in subclassifying these tumours. METHODS AND RESULTS: The patient group included 11 children who had died (mean survival 13 months) and six still alive (followed for up to 10 years). Ten tumours were diffuse and six were nodular (one biopsy had only perivascular tumour). Of the 10 diffuse tumours, three were desmoplastic: of the six nodular tumours, all six were desmoplastic. All 17 tumours were synaptophysin-reactive: three nodular tumours were glial fibrillary acidic protein (GFAP)-reactive in the nodules (two of three S 100-reactive tumours were also GFAP-reactive). MIB-1 labelling indices (LI) ranged from 5 to 80%. Six tumours exhibited at least 1% LI against Tp53 (Mab D07 and/or Mab 1801). Eight cases were 100% bcl2-reactive with nine cases having an LI <80% ('low labelling'). All nine 'low labelling' bcl2 cases were TP53 non-reactive; all six Tp53-reactive cases were bcl2 100% reactive. Six of 10 patients with diffuse medulloblastomas survived 18 months or less while four of 10 are alive up to 10 years. In contrast, five of six patients with nodular neoplasms died within 48 months of diagnosis with one patient followed up for less than 1 year. CONCLUSIONS: Immunohistochemistry is a useful adjunct in characterizing subsets of paediatric medulloblastomas and confirms that larger co-operative studies may be fruitful in identifying a prognostic utility of a combined histochemical/immunohistochemical analysis on these tumours.

Authors
McLendon, RE; Friedman, HS; Fuchs, HE; Kun, LE; Bigner, SH
MLA Citation
McLendon, RE, Friedman, HS, Fuchs, HE, Kun, LE, and Bigner, SH. "Diagnostic markers in paediatric medulloblastoma: a Paediatric Oncology Group Study." Histopathology 34.2 (February 1999): 154-162.
PMID
10064395
Source
pubmed
Published In
Histopathology
Volume
34
Issue
2
Publish Date
1999
Start Page
154
End Page
162

Morphologic and molecular genetic aspects of oligodendroglial neoplasms.

Morphologic criteria for diagnosing oligodendrogliomas and for classifying them as well-differentiated (World Health Organization grade II) and anaplastic (World Health Organization grade III) are well recognized. Nevertheless, applying these guidelines to specific cases often reveals discrepancies among different observers. In addition, whether a given tumor also contains an astrocytic component may be debatable. Loss of heterozygosity studies have demonstrated that oligodendroglial neoplasms have a high incidence of loss of the 1p and 19q chromosomal arms. Although loss of heterozygosity for portions of 19q are sometimes seen in astrocytic neoplasms, these tumors seldom show complete loss of 19q accompanied by loss of 1p. Loss of 9p or homozygous deletion of the CDKN2 gene or both are associated with anaplastic oligodendrogliomas, whereas loss of 17p or TP53 gene mutations or both are frequent in astrocytomas, but rare in oligodendrogliomas. These observations suggest that molecular genetic parameters could provide an objective, reproducible framework for classifying oligodendroglial neoplasms.

Authors
Bigner, SH; Rasheed, BK; Wiltshire, R; McLendon, RE
MLA Citation
Bigner, SH, Rasheed, BK, Wiltshire, R, and McLendon, RE. "Morphologic and molecular genetic aspects of oligodendroglial neoplasms." Neuro Oncol 1.1 (January 1999): 52-60. (Review)
PMID
11550302
Source
pubmed
Published In
Neuro-Oncology
Volume
1
Issue
1
Publish Date
1999
Start Page
52
End Page
60

Gliomas of the optic nerve in children and adults.

Authors
Cummings, TJ; Provenzale, J; Hunter, S; Friedman, HS; Klintworth, G; Bigner, SH; McLendon, RE
MLA Citation
Cummings, TJ, Provenzale, J, Hunter, S, Friedman, HS, Klintworth, G, Bigner, SH, and McLendon, RE. "Gliomas of the optic nerve in children and adults." LABORATORY INVESTIGATION 79.1 (January 1999): 170A-170A.
Source
wos-lite
Published In
Laboratory Investigation
Volume
79
Issue
1
Publish Date
1999
Start Page
170A
End Page
170A

Intrathecal busulfan treatment of human neoplastic meningitis in athymic nude rats.

The current study was designed to evaluate the toxicity and activity of Spartaject Busulfan, a microcrystalline preparation of busulfan, following its intrathecal administration into a nude rat model of human neoplastic meningitis. Animals were treated through permanent indwelling subarachnoid catheters. Human glioma D-456 MG growing in the subarachnoid space was treated with 8.1 micromol of intrathecal Spartaject Busulfan. Single-dose therapy was also subsequently compared with 4 doses of 8.1 and 2.0 micromol busulfan, respectively, against D-456 MG neoplastic meningitis. Additional experiments evaluated a saline control versus 8.1 micromol x 1, 6.2 micromol x 4 and 4.1 micromol x 4, respectively, against D-456 MG. A single dose of 8.1 micromol of intrathecal Spartaject Busulfan resulted in an increase in median survival of 61.7% compared with the saline control. In experiment 2, all busulfan treatments showed increases in median survival of 142.8% (8.1 micromol x 1), 52.3% (2.0 micromol x 4), and 23% (8.1 micromol x 4) (p < 0.001 for all groups) compared with the saline control. These results suggest that a narrow therapeutic dose range for both toxicity and activity has been defined for intrathecal busulfan in the treatment of human neoplastic meningitis in athymic nude rats. Although busulfan has only limited activity against solid tumors, the high doses achievable in the CSF following intrathecal administration coupled with the steep dose-response relationships of alkylating agents, provide rationale for further evaluation of this agent.

Authors
Archer, GE; Sampson, JH; McLendon, RE; Friedman, AH; Colvin, OM; Rose, M; Sands, H; McCullough, W; Fuchs, HE; Bigner, DD; Friedman, HS
MLA Citation
Archer, GE, Sampson, JH, McLendon, RE, Friedman, AH, Colvin, OM, Rose, M, Sands, H, McCullough, W, Fuchs, HE, Bigner, DD, and Friedman, HS. "Intrathecal busulfan treatment of human neoplastic meningitis in athymic nude rats." J Neurooncol 44.3 (1999): 233-241.
PMID
10720203
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
44
Issue
3
Publish Date
1999
Start Page
233
End Page
241

Topotecan treatment of adults with primary malignant glioma

BACKGROUND. Topotecan activity was evaluated for the treatment of malignant glioma. METHODS. Sixty-three patients with newly diagnosed (n = 25) or recurrent (n = 38) malignant glioma were treated with topotecan {AU: Please verify all dosages here and throughout text.}at a dose of 2.6 mg/m2 over a 72-hour period weekly. Recurrent tumors included glioblastoma multiforme (GBM) (n = 28) and anaplastic astrocytoma (AA) (n = 10). Newly diagnosed tumors included GBM (n = 14), AA (n = 8), and anaplastic oligodendroglioma (n = 3). RESULTS. Partial responses were observed in 2 of 14 evaluable patients with newly diagnosed GBM, 1 of 8 patients with newly diagnosed AA, 3 of 10 patients with recurrent AA, and none of 28 patients with recurrent GBM. Four patients with recurrent AA and 7 patients with recurrent GBM demonstrated stable disease (range, 8-52 weeks; median, 21 weeks). Toxicity was limited to infrequent National Cancer Institute Common Toxicity Criteria Grade 3 myelosuppression. CONCLUSIONS. These results suggest that topotecan has modest activity against malignant glioma and continued evaluation of its effectiveness may be warranted when alternative schedules or combination regimens are used.

Authors
Friedman, HS; Kerby, T; Fields, S; Zilisch, JE; Graden, D; McLendon, RE; Houghton, PJ; Arbuck, S; Cokgor, I; Friedman, AH
MLA Citation
Friedman, HS, Kerby, T, Fields, S, Zilisch, JE, Graden, D, McLendon, RE, Houghton, PJ, Arbuck, S, Cokgor, I, and Friedman, AH. "Topotecan treatment of adults with primary malignant glioma." Cancer 85.5 (1999): 1160-1165.
Source
scival
Published In
Cancer
Volume
85
Issue
5
Publish Date
1999
Start Page
1160
End Page
1165
DOI
10.1002/(SICI)1097-0142(19990301)85:5<1160::AID-CNCR21>3.0.CO;2-F

DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma.

PURPOSE: We evaluated the response to Temodal (Schering-Plough Research Institute, Kenilworth, NJ) of patients with newly diagnosed malignant glioma, as well as the predictive value of quantifying tumor DNA mismatch repair activity and O6-alkylguanine-DNA alkyltransferase (AGT). PATIENTS AND METHODS: Thirty-three patients with newly diagnosed glioblastoma multiforme (GBM) and five patients with newly diagnosed anaplastic astrocytoma (AA) were treated with Temodal at a starting dose of 200 mg/m2 daily for 5 consecutive days with repeat dosing every 28 days after the first daily dose. Immunochemistry for the detection of the human DNA mismatch repair proteins MSH2 and MLH1 and the DNA repair protein AGT was performed with monoclonal antibodies and characterized with respect to percent positive staining. RESULTS: Of the 33 patients with GBM, complete responses (CRs) occurred in three patients, partial responses (PRs) occurred in 14 patients, stable disease (SD) was seen in four patients, and 12 patients developed progressive disease (PD). Toxicity included infrequent grades 3 and 4 myelosuppression, constipation, nausea, and headache. Thirty tumors showed greater than 60% cells that stained for MSH2 and MLH1, with three CRs, 12 PRs, three SDs, and 12 PDs. Eight tumors showed 60% or less cells that stained with antibodies to MSH2 and/or MLH1, with 3 PRs, 3 SDs, and 2 PDs. Eleven tumors showed 20% or greater cells that stained with an antibody to AGT, with 1 PR, 2 SDs, and 8 PDs. Twenty-five tumors showed less than 20% cells that stained for AGT, with 3 CRs, 12 PRs, 4 SDs, and 6 PDs. CONCLUSION: These results suggest that Temodal has activity against newly diagnosed GBM and AA and warrants continued evaluation of this agent. Furthermore, pretherapy analysis of tumor DNA mismatch repair and, particularly, AGT protein expression may identify patients in whom tumors are resistant to Temodal.

Authors
Friedman, HS; McLendon, RE; Kerby, T; Dugan, M; Bigner, SH; Henry, AJ; Ashley, DM; Krischer, J; Lovell, S; Rasheed, K; Marchev, F; Seman, AJ; Cokgor, I; Rich, J; Stewart, E; Colvin, OM; Provenzale, JM; Bigner, DD; Haglund, MM; Friedman, AH; Modrich, PL
MLA Citation
Friedman, HS, McLendon, RE, Kerby, T, Dugan, M, Bigner, SH, Henry, AJ, Ashley, DM, Krischer, J, Lovell, S, Rasheed, K, Marchev, F, Seman, AJ, Cokgor, I, Rich, J, Stewart, E, Colvin, OM, Provenzale, JM, Bigner, DD, Haglund, MM, Friedman, AH, and Modrich, PL. "DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma." J Clin Oncol 16.12 (December 1998): 3851-3857.
PMID
9850030
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
16
Issue
12
Publish Date
1998
Start Page
3851
End Page
3857
DOI
10.1200/JCO.1998.16.12.3851

Intradural spinal teratoma: evidence for a dysembryogenic origin. Report of four cases.

Intradural spinal teratoma is a rare tumor that can be associated with dysraphic defects. Although the origin of these tumors is traditionally thought to be secondary to primordial germ cells misplaced early in embryogenesis, the pathogenesis of intraspinal teratoma remains unclear. The authors present a series of patients in whom an intradural teratoma arose at the same site as a developmental spinal cord abnormality, including a split cord malformation, myelomeningocele, and lipomyelomeningocele. It is postulated that these lesions were the result of a dysembryogenic mechanism and were not neoplastic.

Authors
Koen, JL; McLendon, RE; George, TM
MLA Citation
Koen, JL, McLendon, RE, and George, TM. "Intradural spinal teratoma: evidence for a dysembryogenic origin. Report of four cases." J Neurosurg 89.5 (November 1998): 844-851.
PMID
9817426
Source
pubmed
Published In
Journal of neurosurgery
Volume
89
Issue
5
Publish Date
1998
Start Page
844
End Page
851
DOI
10.3171/jns.1998.89.5.0844

Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma.

PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy is the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which removes chlorethylation or methylation damage from the O6-position of guanine. O6-benzylguanine (O6-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial to define the presurgical dose required for depletion of tumor AGT activity in patients with malignant glioma. MATERIALS AND METHODS: Patients were to be treated 18 hours before craniotomy with intravenous doses that ranged between 40 and 100 mg/m2 given over 1 hour. Resected tumor was snap-frozen in liquid nitrogen and AGT activity analyzed by high-pressure liquid chromatography (HPLC). Up to 13 patients were treated at a specific dose of O6-BG, with a target end point of > or = 11 of 13 patients with undetectable tumor AGT levels (< 10 fmol/mg protein). RESULTS: Thirty patients with malignant gliomas were enrolled, with 11 of 11 patients treated at 100 mg/m2 O6-BG demonstrating tumor AGT levels less than 10 fmol/mg protein. No toxicity was noted in any patient treated. CONCLUSION: These results indicate that 100 mg/m2 of O6-BG can maintain tumor AGT levels less than 10 fmol/mg protein for at least 18 hours after treatment, a time interval in which bis(2-chloroethyl)nitrosourea (BCNU)-induced chloroethyl adducts are fully converted into interstrand cross-links. A 100-mg/m2 dose of O6-BG will be used in combination with BCNU in another phase I trial designed to determine the maximal-tolerated dose of BCNU.

Authors
Friedman, HS; Kokkinakis, DM; Pluda, J; Friedman, AH; Cokgor, I; Haglund, MM; Ashley, DM; Rich, J; Dolan, ME; Pegg, AE; Moschel, RC; McLendon, RE; Kerby, T; Herndon, JE; Bigner, DD; Schold, SC
MLA Citation
Friedman, HS, Kokkinakis, DM, Pluda, J, Friedman, AH, Cokgor, I, Haglund, MM, Ashley, DM, Rich, J, Dolan, ME, Pegg, AE, Moschel, RC, McLendon, RE, Kerby, T, Herndon, JE, Bigner, DD, and Schold, SC. "Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma." J Clin Oncol 16.11 (November 1998): 3570-3575.
PMID
9817277
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
16
Issue
11
Publish Date
1998
Start Page
3570
End Page
3575
DOI
10.1200/JCO.1998.16.11.3570

Papillary glioneuronal tumor: a new variant of mixed neuronal-glial neoplasm.

We describe the clinicopathologic features of nine cases of a unique papillary glioneuronal tumor (PGNT) exhibiting astrocytic as well as extensive and varied neuronal differentiation. The four male and five female patients studied ranged in age from 11 to 52 years (mean 27.7 years). They either presented with mild neurologic symptoms or were asymptomatic. Magnetic resonance imaging showed demarcated cystic, 1.5-cm to 7-cm contrast-enhancing masses; five involved the temporal lobe, two the parietal, and two the frontal. All but one were totally resected. No recurrence was noted despite a follow-up period of 3 years. Two microscopic components were evident: 1) compact pseudopapillae composed of hyalinized vessels covered by a single layer of glial fibrillary acid protein (GFAP)-positive astrocytes and 2) synaptophysin-positive neuronal cells of varying size, including neurocytes, ganglioid cells, and ganglion cells within neuropil. Immunostains for chromogranin-A were negative, as was in situ hybridization for chromogranin-A mRNA. Ultrastructurally, neuronal cells featured microtubule-containing processes and aberrant synaptic terminals, but dense core granules were rare. Overall, cellularity was moderate and atypia was minimal. No mitotic activity or necrosis was noted. The proportions of the two components varied, but essential morphologic findings were identical in all cases. In that the clinical, radiographic, and morphologic characteristics of PGNT are distinctive, it appears to represent a previously undescribed form of mixed neuronal-glial tumor of the central nervous system.

Authors
Komori, T; Scheithauer, BW; Anthony, DC; Rosenblum, MK; McLendon, RE; Scott, RM; Okazaki, H; Kobayashi, M
MLA Citation
Komori, T, Scheithauer, BW, Anthony, DC, Rosenblum, MK, McLendon, RE, Scott, RM, Okazaki, H, and Kobayashi, M. "Papillary glioneuronal tumor: a new variant of mixed neuronal-glial neoplasm." Am J Surg Pathol 22.10 (October 1998): 1171-1183.
PMID
9777979
Source
pubmed
Published In
American Journal of Surgical Pathology
Volume
22
Issue
10
Publish Date
1998
Start Page
1171
End Page
1183

Ependymomas: MIB-1 proliferation index and survival.

The biologic behavior of ependymomas is highly variable, and its correlation with histologic features is at best imprecise. This retrospective study attempted to correlate the malignant histologic characteristics of ependymomas with MIB-1 proliferation index and survival. Biopsy and resection specimens taken from 34 patients who received treatment 1972 to 1996 were histologically examined. The patients' ages range was 1 to 59 years. The histologic specimens were assessed for anaplastic features (necrosis, mitosis, vascular proliferation, cellular pleomorphism, and overlapping of nuclei) and an MIB-1 (Ki-67 antigen) proliferation index was also determined. The overall median MIB-1 proliferation index was 7.8% (range 0.1 - 62.5%). An MIB-1 of 20% was significant for a decrease in survival (RR = 5.7) (p = 0.0013). The median MIB-1 for patients < 20 years old was 20.6% with range (0.1, 43%), while that for patients > 20 years was 5.1% (range 0.2, 9.4%) (KW p = 0.055). Three of 5 histological features evaluated were significantly associated with outcome: > 5 mitotic figures per high-power field, necrosis, and vascular proliferation, but not nuclear overlap or pleomorphism. All pathologic factors except pleomorphism were significantly related to the MIB-1 proliferation index. In brief, our data support the association of poor prognoses in ependymomas with young age, the presence of three to four anaplastic histologic features, and an MIB-1 proliferation index > 20%.

Authors
Ritter, AM; Hess, KR; McLendon, RE; Langford, LA
MLA Citation
Ritter, AM, Hess, KR, McLendon, RE, and Langford, LA. "Ependymomas: MIB-1 proliferation index and survival." J Neurooncol 40.1 (October 1998): 51-57.
PMID
9874186
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
40
Issue
1
Publish Date
1998
Start Page
51
End Page
57

Locally increased uptake of fluorine-18-fluorodeoxyglucose after intracavitary administration of iodine-131-labeled antibody for primary brain tumors.

UNLABELLED: After the intracavitary administration of 131I-labeled monoclonal antibody for treatment of primary brain tumors after surgical resection, a persistent rim of 18F-fluorodeoxyglucose (FDG) accumulation surrounding the cavity can be observed on PET. This rim, although it accumulates more FDG than adjacent normal brain tissue, is not necessarily associated with tumor. In our study, we examine the characteristics of the rim that indicate persistent tumor and tumor progression. METHODS: Sequential PET studies obtained after treatment in 10 patients were reviewed and the results correlated with dosimetry and post-treatment histologic diagnoses. RESULTS: The rim of FDG accumulation was seen on the first post-treatment scan obtained 1-3 mo after therapy and persisted unchanged over the 2-26 mo follow-up period. Pathologically, the nonmalignant rim was associated with marked increase of macrophage infiltrates. Nodularity of the rim was associated with tumor. CONCLUSION: Our study demonstrates that a rim of FDG accumulation is seen after intracavitary administration of 131I-labeled monoclonal antibody therapy independent of the presence of malignant disease. Malignant recurrence is suggested by the development of new nodularity in the rim of FDG accumulation.

Authors
Marriott, CJ; Thorstad, W; Akabani, G; Brown, MT; McLendon, RE; Hanson, MW; Coleman, RE
MLA Citation
Marriott, CJ, Thorstad, W, Akabani, G, Brown, MT, McLendon, RE, Hanson, MW, and Coleman, RE. "Locally increased uptake of fluorine-18-fluorodeoxyglucose after intracavitary administration of iodine-131-labeled antibody for primary brain tumors." J Nucl Med 39.8 (August 1998): 1376-1380.
PMID
9708511
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
39
Issue
8
Publish Date
1998
Start Page
1376
End Page
1380

Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results.

PURPOSE: To determine the maximum-tolerated dose (MTD) of iodine 131 (131I)-labeled 81C6 monoclonal antibody (mAb) in brain tumor patients with surgically created resection cavities (SCRCs) and to identify any objective responses to this treatment. METHODS: In this phase I trial, eligible patients were treated with a single injection of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating dosages of 131I (starting dose of 20 mCi with a 20-mCi escalation in subsequent cohorts) administered through an Ommaya reservoir in the SCRC. Patients were followed up for toxicity and response until death or for a minimum of 1 year after treatment. The SCRC patients, who were previously irradiated, were followed up without additional treatment unless progressive disease was identified. RESULTS: We administered 36 treatments of 131I doses up to 120 mCi to 34 previously irradiated patients with recurrent or metastatic brain tumors. Dose-limiting toxicity was reached at 120 mCi and was limited to neurologic or hematologic toxicity. None of the patients treated with less than 120 mCi developed significant neurologic toxicity; one patient developed major hematologic toxicity (MHT). The estimated median survival for patients with glioblastoma multiforme (GBM) and for all patients was 56 and 60 weeks, respectively. CONCLUSION: The MTD for administration of 131I-labeled 81C6 into the SCRCs of previously irradiated patients with recurrent primary or metastatic brain tumors was 100 mCi. The dose-limiting toxicity was neurologic toxicity. We are encouraged by the minimal toxicity and survival in this phase I trial. Radiolabeled mAbs may improve the current therapy for brain tumor patients.

Authors
Bigner, DD; Brown, MT; Friedman, AH; Coleman, RE; Akabani, G; Friedman, HS; Thorstad, WL; McLendon, RE; Bigner, SH; Zhao, XG; Pegram, CN; Wikstrand, CJ; Herndon, JE; Vick, NA; Paleologos, N; Cokgor, I; Provenzale, JM; Zalutsky, MR
MLA Citation
Bigner, DD, Brown, MT, Friedman, AH, Coleman, RE, Akabani, G, Friedman, HS, Thorstad, WL, McLendon, RE, Bigner, SH, Zhao, XG, Pegram, CN, Wikstrand, CJ, Herndon, JE, Vick, NA, Paleologos, N, Cokgor, I, Provenzale, JM, and Zalutsky, MR. "Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results." J Clin Oncol 16.6 (June 1998): 2202-2212.
PMID
9626222
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
16
Issue
6
Publish Date
1998
Start Page
2202
End Page
2212
DOI
10.1200/JCO.1998.16.6.2202

Analysis of DNA mismatch repair proteins in human medulloblastoma.

During replication, the primary function of the eukaryotic DNA mismatch repair (MMR) system is to recognize and correct mismatched base pairs within the DNA helix. Deficiencies in MMR have been reported previously in cases of hereditary nonpolyposis colorectal cancer and sporadic tumors occurring in a variety of tissues including gliomas. Furthermore, recent evidence indicates that the MMR system may be involved in mediating therapeutic sensitivity to alkylating agents. In this study, 22 neoplastic tissue samples from 22 patients who underwent surgical resection for medulloblastoma, a common cerebellar tumor of childhood, were assayed for the presence or absence of MMR polypeptides using Western blot and immunohistochemical techniques. Results from these experiments indicate that the MMR system is not commonly deficient in medulloblastoma.

Authors
Lee, SE; Johnson, SP; Hale, LP; Li, J; Bullock, N; Fuchs, H; Friedman, A; McLendon, R; Bigner, DD; Modrich, P; Friedman, HS
MLA Citation
Lee, SE, Johnson, SP, Hale, LP, Li, J, Bullock, N, Fuchs, H, Friedman, A, McLendon, R, Bigner, DD, Modrich, P, and Friedman, HS. "Analysis of DNA mismatch repair proteins in human medulloblastoma." Clin Cancer Res 4.6 (June 1998): 1415-1419.
PMID
9626457
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
4
Issue
6
Publish Date
1998
Start Page
1415
End Page
1419

Immunohistochemical detection of the DNA repair enzyme O6-methylguanine-DNA methyltransferase in formalin-fixed, paraffin-embedded astrocytomas.

Authors
McLendon, RE; Cleveland, L; Pegram, C; Bigner, SH; Bigner, DD; Friedman, HS
MLA Citation
McLendon, RE, Cleveland, L, Pegram, C, Bigner, SH, Bigner, DD, and Friedman, HS. "Immunohistochemical detection of the DNA repair enzyme O6-methylguanine-DNA methyltransferase in formalin-fixed, paraffin-embedded astrocytomas." Lab Invest 78.5 (May 1998): 643-644.
PMID
9605190
Source
pubmed
Published In
Laboratory Investigation
Volume
78
Issue
5
Publish Date
1998
Start Page
643
End Page
644

Molecular and immunohistologic (IHC) studies on oligodendroglial (O) tumors

Authors
Matthews, MR; Rasheed, BKA; McLendon, RE; Wikstrand, CJ; Bigner, DD; Bigner, SH
MLA Citation
Matthews, MR, Rasheed, BKA, McLendon, RE, Wikstrand, CJ, Bigner, DD, and Bigner, SH. "Molecular and immunohistologic (IHC) studies on oligodendroglial (O) tumors." JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 57.5 (May 1998): 473-473.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
57
Issue
5
Publish Date
1998
Start Page
473
End Page
473

Electron microscopic diagnosis of arboviral meningoencephalitis.

Authors
Chu, CT; Howell, DN; Morgenlander, JC; McLendon, RE; Miller, SE
MLA Citation
Chu, CT, Howell, DN, Morgenlander, JC, McLendon, RE, and Miller, SE. "Electron microscopic diagnosis of arboviral meningoencephalitis." JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 57.5 (May 1998): 505-505.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
57
Issue
5
Publish Date
1998
Start Page
505
End Page
505
DOI
10.1097/00005072-199805000-00161

Phase II study of carboplatin (CBDCA) in progressive low-grade gliomas.

In this study, the authors sought to investigate the response rate and toxicity of carboplatin in patients with progressive low-grade glioma (LGG). Thirty-two patients with progressive LGG were treated with carboplatin at a dosage of 560 mg/m(2). Treatment was given at 4-week intervals and continued until the disease progressed, unacceptable toxicity supervened, or for 12 additional courses after achieving maximal response. Patients with stable disease were treated with a total of 12 cycles. All patients were treated as outpatients. Patients were evaluated for response to treatment and toxicity. All patients received a minimum of two cycles of carboplatin, and were examined for response. A partial response was achieved in nine patients (28%) and a minimal response in two (6%), for an overall response rate of 34% (11 of 32 patients). Eighteen patients (56%) had stable disease. A partial response was achieved in the nine patients after a median of six cycles (range 4-11 cycles), a minimal response was achieved in the two patients after five cycles. Glioma progression was noted in three patients after three, five, and five cycles, respectively. The 11 patients in whom some response was achieved had either an optic pathway tumor or a juvenile pilocytic astrocytoma. Twenty-six of the 32 patients had those characteristics, making the response rate in that group 42% (11 of 26 patients). Thirty-two patients received a total of 387 cycles of chemotherapy. Hematological toxicity was moderate. Twenty-one patients developed thrombocytopenia (platelet count < 50,000/microl); three patients required one platelet transfusion each. Nine patients developed neutropenia (absolute neutrophil count < 500/microl); one developed fever and required administration of antibiotic agents. One dose adjustment in each of the patients prevented further thrombocytopenia and neutropenia. Two patients with stable disease died of respiratory complications. One patient developed Grade III ototoxicity after receiving five cycles, one patient developed hypersensitivity to carboplatin, and none developed nephrotoxicity. Carboplatin given at a dosage of 560 mg/m(2) every 4 weeks has activity in patients with progressive LGG. This drug regimen is relatively simple and well tolerated. Further investigation and longer follow-up study are warranted.

Authors
Moghrabi, A; Friedman, HS; Ashley, DM; Bottom, KS; Kerby, T; Stewart, E; Bruggers, C; Provenzale, JM; Champagne, M; Hershon, L; Watral, M; Ryan, J; Rasheed, K; Lovell, S; Korones, D; Fuchs, H; George, T; McLendon, RE; Friedman, AH; Buckley, E; Longee, DC
MLA Citation
Moghrabi, A, Friedman, HS, Ashley, DM, Bottom, KS, Kerby, T, Stewart, E, Bruggers, C, Provenzale, JM, Champagne, M, Hershon, L, Watral, M, Ryan, J, Rasheed, K, Lovell, S, Korones, D, Fuchs, H, George, T, McLendon, RE, Friedman, AH, Buckley, E, and Longee, DC. "Phase II study of carboplatin (CBDCA) in progressive low-grade gliomas." Neurosurg Focus 4.4 (April 15, 1998): e3-.
PMID
17168503
Source
pubmed
Published In
Neurosurgical focus
Volume
4
Issue
4
Publish Date
1998
Start Page
e3

Activity of high-dose cyclophosphamide in the treatment of childhood malignant gliomas.

Seventeen patients less than or equal to 20 years of age with newly diagnosed (n = 10) or recurrent (n = 7) malignant gliomas (anaplastic astrocytoma and glioblastoma multiforme) were treated with cyclophosphamide in association with hematopoietic cytokines (GM-CSF or G-CSF). Cyclophosphamide was given at a dose of 2 g/m2 daily for 2 days at 4-week intervals. Toxicity consisted of grade IV neutropenia and thrombocytopenia in 95% and 48% of cycles, respectively. There were no cyclophosphamide-related cardiac, pulmonary, or urothelial toxicities observed. Four of 10 patients with newly diagnosed disease demonstrated responses (three complete and one partial responses; one CR was only of 2 months duration). None of the seven patients with recurrent tumors demonstrated a response. We conclude that high-dose cyclophosphamide warrants further evaluation in children with newly diagnosed malignant glioma.

Authors
McCowage, GB; Friedman, HS; Moghrabi, A; Kerby, T; Ferrell, L; Stewart, E; Duncan-Brown, M; Fuchs, HE; Tien, R; McLendon, RE; Meier, L; Kurtzberg, J; Ashley, D; Colvin, OM; Longee, DC
MLA Citation
McCowage, GB, Friedman, HS, Moghrabi, A, Kerby, T, Ferrell, L, Stewart, E, Duncan-Brown, M, Fuchs, HE, Tien, R, McLendon, RE, Meier, L, Kurtzberg, J, Ashley, D, Colvin, OM, and Longee, DC. "Activity of high-dose cyclophosphamide in the treatment of childhood malignant gliomas." Med Pediatr Oncol 30.2 (February 1998): 75-80.
PMID
9403013
Source
pubmed
Published In
Pediatric Blood and Cancer
Volume
30
Issue
2
Publish Date
1998
Start Page
75
End Page
80

Solitary fibrous tumor of the meninges occurring after irradiation of a mixed germ cell tumor of the pineal gland.

Twenty-nine months after surgery, irradiation, and systemic chemotherapy for a pineal mixed germ cell tumor, an 11-year-old Caucasian male developed a 3 cm dural based nodule in the occipital lobe that proved to be a solitary fibrous tumor by immunohistochemical and ultrastructural examination. Differential diagnosis included fibrous meningioma, neurofibroma, Schwannoma, cranial fasciitis of infancy, and solitary fibrous tumor. A Masson trichrome stain revealed a prominent collagenous stroma and reticulin staining exhibited strong pericellular positivity. Immunohistochemical staining demonstrated diffuse vimentin and focal CD34 positivity of tumor cells. Ultrastructural examination revealed fibroblastic differentiation. These features are consistent with solitary fibrous tumor. Although we favor a radiation-induced origin for the neoplasm, alternative explanations for the tumor's origin include cerebrospinal fluid spread from the original germ cell tumor or a de novo neoplasm.

Authors
Slavik, T; Bentley, RC; Gray, L; Fuchs, HE; McLendon, RE
MLA Citation
Slavik, T, Bentley, RC, Gray, L, Fuchs, HE, and McLendon, RE. "Solitary fibrous tumor of the meninges occurring after irradiation of a mixed germ cell tumor of the pineal gland." Clin Neuropathol 17.1 (January 1998): 55-60.
PMID
9496542
Source
pubmed
Published In
Clinical neuropathology
Volume
17
Issue
1
Publish Date
1998
Start Page
55
End Page
60

DNA mismatch repair enzyme detection in adult glioblastoma (GBM) by immunohistochemistry.

Authors
McLendon, RE; Friedman, HS; Bigner, SH; Modrich, PL
MLA Citation
McLendon, RE, Friedman, HS, Bigner, SH, and Modrich, PL. "DNA mismatch repair enzyme detection in adult glioblastoma (GBM) by immunohistochemistry." MODERN PATHOLOGY 11.1 (January 1998): 160A-160A.
Source
wos-lite
Published In
Modern Pathology
Volume
11
Issue
1
Publish Date
1998
Start Page
160A
End Page
160A

Locally increased uptake of fluorine-18-fluorodeoxyglucose after intracavitary administration of iodine-131-labeled antibody for primary brain tumors

After the intracavitary administration of 131I-labeled monoclonal antibody for treatment of primary brain tumors after surgical resection, a persistent rim of 18F-fluorodeoxyglucose (FDG) accumulation surrounding the cavity can be observed on PET. This rim, although it accumulates more FDG than adjacent normal brain tissue, is not necessarily associated with tumor. In our study, we examine the characteristics of the rim that indicate persistent tumor and tumor progression. Methods: Sequential PET studies obtained after treatment in 10 patients were reviewed and the results correlated with dosimetry and post-treatment histologic diagnoses. Results: The rim of FDG accumulation was seen on the first post-treatment scan obtained 1-3 mo after therapy and persisted unchanged over the 2-26 mo follow-up period. Pathologically, the nonmalignant rim was associated with marked increase of macrophage infiltrates. Nodularity of the nm was associated with tumor. Conclusion: Our study demonstrates that a rim of FDG accumulation is seen after intracavitary administration of 131I-labeled monoclonal antibody therapy independent of the presence of malignant disease. Malignant recurrence is suggested by the development of new nodularity in the rim of FDG accumulation.

Authors
Marriott, CJC; Thorstad, W; Akabani, G; Brown, MT; McLendon, RE; Hanson, MW; Coleman, RE
MLA Citation
Marriott, CJC, Thorstad, W, Akabani, G, Brown, MT, McLendon, RE, Hanson, MW, and Coleman, RE. "Locally increased uptake of fluorine-18-fluorodeoxyglucose after intracavitary administration of iodine-131-labeled antibody for primary brain tumors." Journal of Nuclear Medicine 39.8 SUPPL. (1998): 1376-1380.
Source
scival
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
39
Issue
8 SUPPL.
Publish Date
1998
Start Page
1376
End Page
1380

Pten gene mutations are seen in high grade, but not in low grade gliomas.

Authors
Stenzel, TT; Rasheed, BKA; McLendon, RE; Parsons, R; Friedman, AH; Friedman, HS; Bigner, SH
MLA Citation
Stenzel, TT, Rasheed, BKA, McLendon, RE, Parsons, R, Friedman, AH, Friedman, HS, and Bigner, SH. "Pten gene mutations are seen in high grade, but not in low grade gliomas." CLINICAL CHEMISTRY 43.11 (November 1997): 25-25.
Source
wos-lite
Published In
Clinical chemistry
Volume
43
Issue
11
Publish Date
1997
Start Page
25
End Page
25

PTEN gene mutations are seen in high-grade but not in low-grade gliomas.

The PTEN gene, located on 10q23, has recently been implicated as a candidate tumor suppressor gene in brain, breast and prostate tumors. In the present study, 123 brain tumors, including various grades and histological types of gliomas occurring in children and adults, were analyzed for PTEN mutations by SSCP assay and sequencing. Mutations in the PTEN gene were found in 13 of 42 adult glioblastomas and 3 of 13 adult anaplastic astrocytomas, whereas none of the 21 low-grade adult gliomas or the 22 childhood gliomas of all grades showed mutations. The single medulloblastoma with a mutation was a recurrent tumor that also possessed a p53 mutation. High-grade adult gliomas with PTEN mutations included cases that also contained gene amplification or p53 gene mutations, as well as cases that did not contain either of these abnormalities. There was no obvious relationship between presence of PTEN mutation and survival; however, there was a tendency for PTEN mutations to occur in older age group patients. This analysis suggest that PTEN gene mutations are restricted to high-grade adult gliomas and that this abnormality is independent of the presence or absence of gene amplification or p53 gene mutation in these tumors.

Authors
Rasheed, BK; Stenzel, TT; McLendon, RE; Parsons, R; Friedman, AH; Friedman, HS; Bigner, DD; Bigner, SH
MLA Citation
Rasheed, BK, Stenzel, TT, McLendon, RE, Parsons, R, Friedman, AH, Friedman, HS, Bigner, DD, and Bigner, SH. "PTEN gene mutations are seen in high-grade but not in low-grade gliomas." Cancer Res 57.19 (October 1, 1997): 4187-4190.
PMID
9331072
Source
pubmed
Published In
Cancer Research
Volume
57
Issue
19
Publish Date
1997
Start Page
4187
End Page
4190

Cell surface localization and density of the tumor-associated variant of the epidermal growth factor receptor, EGFRvIII.

The potential of therapeutic targeting of tumor cell surface epidermal growth factor receptors (EGFRs) by modified ligands or specific antibodies has been limited by the normal tissue distribution of the receptor. The identification and characterization of a variant of this receptor, EGFRvIII, which is not expressed in normal tissues but has been described in gliomas, non-small cell lung carcinomas, and breast carcinomas, has provided a highly specific, internalizing target for antibody-mediated approaches. To determine the feasibility of immunotargeting EGFRvIII, we have assessed the qualitative distribution and quantitative expression at both the population and cellular levels of EGFRvIII in 21 biopsy samples of human gliomas by indirect analytical and quantitative flow cytometry and by immunohistochemical assay of frozen and formalin-fixed tissue. Consistent with previous reports, 50% of gliomas tested (1 of 2 anaplastic astrocytomas, 7 of 12 glioblastoma multiforme, and 2 of 6 oligodendrogliomas) expressed EGFRvIII, as determined by a minimum of 2 separate assays. Minimum estimates of the proportion of positive tumor cells in these populations ranged from 37-86%; in four of five cases in which quantitation of the EGFRvIII density/cell was performed, values of 2.7-6.8 x 10(5) were obtained with monoclonal antibody (mAb) L8A4 (EGFRvIII specific), levels consistent with successful in vivo immunotargeting. Confocal microscopic analysis confirmed that the subcellular localization of EGFRvIII was identical to that described for EGFR: predominant cell membrane expression, with some perinuclear distribution suggestive of localization to the Golgi region. Neither EGFR nor EGFRvIII was found within the nucleus. This study establishes for the first time that approximately 50% of human glioma biopsies contain cell populations expressing a sufficient number of membrane-expressed EGFRvIIIs to mediate specific anti-EGFRvIII mAb localization. Coupled with previous demonstrations of the rapid internalization of specific mAb-EGFRvIII complexes and the susceptibility of the targeted cells to isotope or toxin-mediated cytotoxicity, this study establishes the validity of targeting EGFRvIII for therapy of mutant receptor-positive gliomas, breast carcinomas, and non-small cell lung carcinomas.

Authors
Wikstrand, CJ; McLendon, RE; Friedman, AH; Bigner, DD
MLA Citation
Wikstrand, CJ, McLendon, RE, Friedman, AH, and Bigner, DD. "Cell surface localization and density of the tumor-associated variant of the epidermal growth factor receptor, EGFRvIII." Cancer Res 57.18 (September 15, 1997): 4130-4140.
PMID
9307304
Source
pubmed
Published In
Cancer Research
Volume
57
Issue
18
Publish Date
1997
Start Page
4130
End Page
4140

Chromosomal characteristics of childhood brain tumors.

In the present cytogenetic analysis of 116 pediatric brain tumors, chromosomal abnormalities were demonstrated in 44 cases, 48 cases revealed only 46,XX or 46,XY cells, and 24 cases were nonproductive. In contrast to studies of adult brain tumors in which isolated loss of one X or the Y chromosome is often encountered, 45,X,-X and 45,X-Y stemlines or sidelines were not observed in this series of childhood tumors. Among the 17 medulloblastomas with cytogenetic abnormalities, chromosome 1 was most frequently affected by structural deviations; the most prevalent specific alteration (7 of 17 tumors) was loss of 17p, through i(17)(q10) or unbalanced translocation. The majority of low grade astrocytomas had normal stemlines, although one pilocytic astrocytoma and one cerebellar astrocytoma had frequent telomeric associations and a second pilocytic astrocytoma had a clone with trisomy 11. Thirteen of 19 high-grade and recurrent astrocytic tumors had abnormal stemlines that were approximately equally divided among cases with chromosomal counts in the near-diploid, hyperdiploid, and near-triploid-tetraploid ranges. Although no consistent abnormalities were observed, subsets of cases had structural abnormalities of chromosome 3, 7q, 9q, or 17p. The cases of childhood brain tumors described here demonstrate that 45,X,-X, and 45,X,-Y stemlines or sidelines are rare in these tumors and confirm frequent loss of 17p in medulloblastomas. High-grade astrocytic tumors in children frequently have abnormal stemlines, often in the hyperdiploid and polyploid ranges, and they differ from high-grade gliomas in the adult by lacking consistent numerical and structural deviations.

Authors
Bigner, SH; McLendon, RE; Fuchs, H; McKeever, PE; Friedman, HS
MLA Citation
Bigner, SH, McLendon, RE, Fuchs, H, McKeever, PE, and Friedman, HS. "Chromosomal characteristics of childhood brain tumors." Cancer Genet Cytogenet 97.2 (September 1997): 125-134.
PMID
9283596
Source
pubmed
Published In
Cancer Genetics and Cytogenetics
Volume
97
Issue
2
Publish Date
1997
Start Page
125
End Page
134

Pseudopapillary glioneuronal tumor (PGNT)

Authors
Komori, T; Scheithauer, BW; Anthony, DC; Rosenblum, MK; McLendon, RE
MLA Citation
Komori, T, Scheithauer, BW, Anthony, DC, Rosenblum, MK, and McLendon, RE. "Pseudopapillary glioneuronal tumor (PGNT)." BRAIN PATHOLOGY 7.4 (September 1997): 1189-1189.
Source
wos-lite
Published In
Brain Pathology
Volume
7
Issue
4
Publish Date
1997
Start Page
1189
End Page
1189

Malignant supratentorial glial-neuronal neoplasms: report of two cases and review of the literature.

OBJECTIVE: Malignant neoplasms exhibiting mixed populations of neuronal and glial cells occurring in the cerebral hemispheres of young adults and children are well recognized, but rare. A confusing array of diagnostic terms has arisen. We describe two patients with such tumors and review the literature concerning these interesting cases. PATIENTS: A 21-year-old man and a 5-year-old girl presented with large, cystic, intracerebral lesions on magnetic resonance images, which proved to be composite neoplasms exhibiting malignant neurons and astrocytes. RESULTS: The 21-year-old man had a frontal lobe mass with enhancing and nonenhancing regions, which corresponded to cerebral neuroblastoma and anaplastic astrocytoma, respectively. The presence of occasional microtubules and rare primitive presynaptic processes, accompanied by antisynaptophysin immunoreactivity, established the neuronal nature of the cells in the enhancing region. The nonenhancing region was composed of a moderately cellular neoplasm of fibrillar astrocytes that were mitotically active. The 5-year-old girl presented with a left parietal lobe neoplasm, which histologically was composed of lobular proliferations of neuroblasts and glia. The neuroblastic populations exhibited evidence of maturation with small anaplastic cells, spindle-shaped cells, and large dysmorphic ganglion cells. The glial tumor showed both well-differentiated fibrillary astrocytes with microcysts and anaplastic populations with central necrosis and pseudopalisading. CONCLUSIONS: Present classification systems devised to describe mixed neuronal and glial tumors do not adequately encompass the diversity of morphologies presented by these two cases. We conclude that the terms cerebral neuroblastoma-anaplastic astrocytoma for case 1 and cerebral ganglioneuroblastoma-glioblastoma for case 2 are preferred because they convey useful clinical information by reflecting concepts already encompassed by the World Health Organization's classification system of tumors of the central nervous system.

Authors
McLendon, RE; Bentley, RC; Parisi, JE; Tien, RD; Harrison, JC; Tarbell, NJ; Billitt, AL; Gualtieri, RJ; Friedman, HS
MLA Citation
McLendon, RE, Bentley, RC, Parisi, JE, Tien, RD, Harrison, JC, Tarbell, NJ, Billitt, AL, Gualtieri, RJ, and Friedman, HS. "Malignant supratentorial glial-neuronal neoplasms: report of two cases and review of the literature." Arch Pathol Lab Med 121.5 (May 1997): 485-492. (Review)
PMID
9167602
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
121
Issue
5
Publish Date
1997
Start Page
485
End Page
492

Implantation metastasis of primary malignant rhabdoid tumor of the brain in an adult (one case report).

Primary malignant rhabdoid tumor (PMRT) of the brain is a rare and recently described neoplasm of youth. We report magnetic resonance imaging (MRI), computed tomography (CT), and pathology of one case of PMRT in an adult which seeded along the needle track for stereotactic biopsy.

Authors
Ashraf, R; Bentley, RC; Awan, AN; McLendon, RE; Ragozzino, MW
MLA Citation
Ashraf, R, Bentley, RC, Awan, AN, McLendon, RE, and Ragozzino, MW. "Implantation metastasis of primary malignant rhabdoid tumor of the brain in an adult (one case report)." Med Pediatr Oncol 28.3 (March 1997): 223-227.
PMID
9024522
Source
pubmed
Published In
Pediatric Blood and Cancer
Volume
28
Issue
3
Publish Date
1997
Start Page
223
End Page
227

Implantation metastasis of primary malignant rhabdoid tumor of the brain in an adult (one case report)

Primary malignant rhabdoid tumor (PMRT) of the brain is a rare and recently described neoplasm of youth. We report magnetic resoonance imaging (MRI), computed tomography (C↑), and pathology of one case of PMRT in an adult which seeded along the needle track for stereotactic biopsy.

Authors
Ashraf, R; Bentley, RC; Awan, AN; McLendon, RE; Ragozzino, MW
MLA Citation
Ashraf, R, Bentley, RC, Awan, AN, McLendon, RE, and Ragozzino, MW. "Implantation metastasis of primary malignant rhabdoid tumor of the brain in an adult (one case report)." Medical and Pediatric Oncology 28.3 (February 25, 1997): 223-227.
Source
scopus
Published In
Pediatric Blood and Cancer
Volume
28
Issue
3
Publish Date
1997
Start Page
223
End Page
227
DOI
10.1002/(SICI)1096-911X(199703)28:3<223::AID-MPO14>3.0.CO;2-F

False positive images in the follow-up of patients with brain tumors.

In recent years, major advances in the diagnosis and treatment of patients with brain tumors have been seen. Today, evaluation of the central nervous system almost always includes magnetic resonance imaging (MRI). The appearance of a new lesion on the MRI scan of a patient previously treated for a central nervous system (CNS) tumor raises concern for recurrent disease with the need for selection of new, potentially toxic therapy. However, the sensitivity of MRI may allow demonstration of new lesions which are not due to tumor. We now report three patients with medulloblastoma who demonstrated new enhancing lesions on MRI following treatment of their tumors with surgery (3 patients), chemotherapy (2 patients), and radiotherapy (2 patients). Two patients underwent resection of the lesion revealing gliosis. One patient had serial imaging that showed disappearance of the lesions. This suggests that not all new enhancing lesions in previously treated brain tumor patients represent tumor. Histologic proof of a suspicious lesion should be demonstrated prior to initiation of new therapy.

Authors
Moghrabi, A; Tien, R; Fuchs, H; Longee, D; McLendon, R; Friedman, HS
MLA Citation
Moghrabi, A, Tien, R, Fuchs, H, Longee, D, McLendon, R, and Friedman, HS. "False positive images in the follow-up of patients with brain tumors." Med Pediatr Oncol 28.2 (February 1997): 127-131.
PMID
8986148
Source
pubmed
Published In
Pediatric Blood and Cancer
Volume
28
Issue
2
Publish Date
1997
Start Page
127
End Page
131

Craniocerebral plasmacytoma: MR features.

We report the MR imaging findings in two patients with solitary craniocerebral plasmacytoma, a benign plasma cell tumor that can arise from the skull, the dura, or, rarely, the brain. In both patients, the lesion was extraaxial and nearly isointense with gray matter on T2-weighted MR images, and diffusely enhanced after administration of contrast material, bearing some similarities to meningioma. A diagnosis of solitary craniocerebral plasmacytoma should be considered when a mass with these imaging features is seen, because total excision may not be necessary for this radiosensitive tumor.

Authors
Provenzale, JM; Schaefer, P; Traweek, ST; Ferry, J; Moore, JO; Friedman, AH; McLendon, RE
MLA Citation
Provenzale, JM, Schaefer, P, Traweek, ST, Ferry, J, Moore, JO, Friedman, AH, and McLendon, RE. "Craniocerebral plasmacytoma: MR features." AJNR Am J Neuroradiol 18.2 (February 1997): 389-392.
PMID
9111682
Source
pubmed
Published In
American Journal of Neuroradiology
Volume
18
Issue
2
Publish Date
1997
Start Page
389
End Page
392

Intraarterial O6-benzylguanine enables the specific therapy of nitrosourea-resistant intracranial human glioma xenografts in athymic rats with 1,3-bis(2-chloroethyl)-1-nitrosourea.

The prognosis for patients with malignant gliomas continues to be dismal. The high degree of resistance of gliomas to nitrosourea-based chemotherapy is one major factor in poor treatment outcome. The identification of O6-alkylguanine-DNA alkyltransferase (AGAT) as a major determinant of nitrosourea resistance has resulted in the development of several agents to inactivate this repair protein and counteract tumor cell resistance. However, a major problem in preclinical trials has been the marked nitrosourea dose limitations imposed by the prior administration of AGAT-depleting agents. We investigated the AGAT depletion and selective enhancement of BCNU activity of intraarterial (i.a.) O6-benzylguanine (O6BG) in the human malignant glioma xenograft D-456 MG growing intracranially (i.e.) in athymic rats. Whereas i.a. O6BG at 2.5 mg/kg produced 100% inhibition of D-456 MG AGAT i.e. activity 8 h after administration, intraperitoneal (i.p.) O6BG at this dose produced only 40% inhibition, requiring dose escalation to 10 mg/kg to produce 100% AGAT depletion. Prior administration of i.p. O6BG (10 mg/kg) and i.a. O6BG (2.5 mg/kg) limited maximum tolerated intravenous (i.v.) BCNU doses (37.5 mg/kg when given alone) to 6.25 and 25 mg/kg, respectively. Higher doses of BCNU alone or in combination with O6BG produced histopathologic evidence of cerebral and hepatic toxicity. Therapy experiments revealed a significantly improved median survival for rats treated with O6BG i.a. (2.5 mg/kg) plus BCNU i.v. (25 mg/kg, days 61 and 59 in duplicate experiments) compared with saline (day 21. P = 0.001). O6BG i.a. or i.p. (days 22 and 23, P = 0.001), BCNU i.v. (37.5 mg/kg, day 29, P = 0.001), and O6BG i.p. (10 mg/kg), plus BCNU i.v. (6.25 mg/kg, day 37, P < 0.001). Therefore, O6BG i.a., by virtue of rapid AGAT depletion and selective uptake into i.c. tumors, offers significant potential for regional chemomodulation of AGAT-mediated nitrosourea resistance in malignant human gliomas with concomitant reduction of systemic toxicity.

Authors
Kurpad, SN; Dolan, ME; McLendon, RE; Archer, GE; Moschel, RC; Pegg, AE; Bigner, DD; Friedman, HS
MLA Citation
Kurpad, SN, Dolan, ME, McLendon, RE, Archer, GE, Moschel, RC, Pegg, AE, Bigner, DD, and Friedman, HS. "Intraarterial O6-benzylguanine enables the specific therapy of nitrosourea-resistant intracranial human glioma xenografts in athymic rats with 1,3-bis(2-chloroethyl)-1-nitrosourea." Cancer Chemother Pharmacol 39.4 (1997): 307-316.
PMID
9025771
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
39
Issue
4
Publish Date
1997
Start Page
307
End Page
316
DOI
10.1007/s002800050577

The impact of hypoxia and oxygenation modification on the radiation response of an intracranial rat glioma

Authors
Bean, JM; Archer, GE; Munley, MT; Ong, E; Snyder, SA; Haroon, ZA; McLendon, RE; Marks, LB; Stratford, MRL; Chaplin, DJ; Brizel, DM; Bigner, DD; Dewhirst, MW
MLA Citation
Bean, JM, Archer, GE, Munley, MT, Ong, E, Snyder, SA, Haroon, ZA, McLendon, RE, Marks, LB, Stratford, MRL, Chaplin, DJ, Brizel, DM, Bigner, DD, and Dewhirst, MW. "The impact of hypoxia and oxygenation modification on the radiation response of an intracranial rat glioma." INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 39.2 (1997): 247-247.
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
39
Issue
2
Publish Date
1997
Start Page
247
End Page
247
DOI
10.1016/S0360-3016(97)80782-1

Gliomatosis cerebri presenting with optic nerve involvement: MRI.

Gliomatosis cerebri is a rare form of astrocytoma characterized by extreme infiltration of the brain structure in conjunction with a relative paucity of clinical findings. We describe the MRI findings in a patient with gliomatosis cerebri widely infiltrating the brain who presented with symptoms related to involvement of the optic nerves and chiasm. Contrast-enhanced MRI showed enlargement of the optic nerves and chiasm with pathological enhancement; T2-weighted images showed extensive infiltration of the brain by tumor. Histopathologic examination of the biopsy specimen showed anaplastic astrocytoma with gemistocytic predominance and a diagnosis of gliomatosis cerebri was reached.

Authors
Felsberg, GJ; Glass, JP; Tien, RD; McLendon, R
MLA Citation
Felsberg, GJ, Glass, JP, Tien, RD, and McLendon, R. "Gliomatosis cerebri presenting with optic nerve involvement: MRI." Neuroradiology 38.8 (November 1996): 774-777.
PMID
8957803
Source
pubmed
Published In
Neuroradiology
Volume
38
Issue
8
Publish Date
1996
Start Page
774
End Page
777

Successful treatment of childhood pilocytic astrocytomas metastatic to the leptomeninges with high-dose cyclophosphamide.

Leptomeningeal dissemination of childhood pilocytic astrocytoma (PA) is a rare event with little information available regarding therapy. We report here four children with disseminated PA whom we treated with high doses of cyclophosphamide with clinical benefit. The patients were aged 2.5 to 8 years. Three patients presented with PA localized in the posterior fossa, initially treated with surgical resection (n = 3) and radiotherapy (n = 1). Leptomeningeal dissemination occurred at 32, 44, and 8 months from diagnosis, respectively. The fourth patient presented with an optic pathway tumor with leptomeningeal dissemination at diagnosis. At commencement of cyclophosphamide therapy, disease was present in the subarachnoid space (intracranial, n = 2; spinal, n = 4), cerebral ventricles (n = 2), and primary site (n = 3). Histology was identical at diagnosis and recurrence in the two biopsied cases and cerebrospinal fluid was negative in all cases. Treatment was with cyclophosphamide 4-5 g/m2/cycle given every 4 weeks for a total of two cycles (n = 1) and four cycles (n = 3). One patient achieved disease stabilization (duration 27 months at the time of publication) and three patients experienced significant reductions in tumor burden. Subsequent intrathecal therapy was administered to two patients. Two patients developed disease progression at 10 and 9 months from cessation of chemotherapy. The one re-treated patient responded to further, lower dose, cyclophosphamide. This is the first report of the use of high dose cyclophosphamide for disseminated PA. The recurrence of disease in two cases with a further response to lower dose cyclophosphamide has implications for the optimal duration of therapy for these low grade, aggressive tumors.

Authors
McCowage, G; Tien, R; McLendon, R; Felsberg, G; Fuchs, H; Graham, ML; Kurtzberg, J; Moghrabi, A; Ferrell, L; Kerby, T; Duncan-Brown, M; Stewart, E; Robertson, PL; Colvin, OM; Golembe, B; Bigner, DD; Friedman, HS
MLA Citation
McCowage, G, Tien, R, McLendon, R, Felsberg, G, Fuchs, H, Graham, ML, Kurtzberg, J, Moghrabi, A, Ferrell, L, Kerby, T, Duncan-Brown, M, Stewart, E, Robertson, PL, Colvin, OM, Golembe, B, Bigner, DD, and Friedman, HS. "Successful treatment of childhood pilocytic astrocytomas metastatic to the leptomeninges with high-dose cyclophosphamide." Med Pediatr Oncol 27.1 (July 1996): 32-39.
PMID
8614389
Source
pubmed
Published In
Pediatric Blood and Cancer
Volume
27
Issue
1
Publish Date
1996
Start Page
32
End Page
39
DOI
10.1002/(SICI)1096-911X(199607)27:1<32::AID-MPO7>3.0.CO;2-V

Intrathecal 131I-labeled antitenascin monoclonal antibody 81C6 treatment of patients with leptomeningeal neoplasms or primary brain tumor resection cavities with subarachnoid communication: phase I trial results.

We aimed to determine the maximum tolerated dose (MTD) of 131I-labeled 81C6 in patients with leptomeningeal neoplasms or brain tumor resection cavities with subarachnoid communication and to identify any objective responses. 81C6 is a murine IgG monoclonal antibody that reacts with tenascin in gliomas/carcinomas but does not react with normal adult brain. 131I-labeled 81C6 delivers intrathecal (IT) radiation to these neoplasms. This study was a Phase I trial in which patients were treated with a single IT dose of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating doses of 131I (starting dose, 40 mCi; 20 mCi escalations) on 10 mg 81C6. MTD is defined as the highest dose resulting in serious toxicity in no more than two of six patients. Serious toxicity is defined as grade III/IV nonhematological toxicity or major hematological toxicity. We treated 31 patients (8 pediatric and 23 adult). Eighteen had glioblastoma multiforme. Patients were treated with 131I doses from 40 to 100 mCi. Hematological toxicity was dose limiting and correlated with the administered 131I dose. No grade III/IV nonhematological toxicities were encountered. A partial response occurred in 1 patient and disease stabilization occurred in 13 (42%) of 31 patients. Twelve patients are alive (median follow-up, > 320 days); five are progression free >409 days median posttreatment. The MTD of a single IT administration of 131I-labeled 81C6 in adults is 80 mCi 131I-labeled 81C6. The MTD in pediatric patients was not reached at 131I doses up to 40 mCi normalized for body surface area.

Authors
Brown, MT; Coleman, RE; Friedman, AH; Friedman, HS; McLendon, RE; Reiman, R; Felsberg, GJ; Tien, RD; Bigner, SH; Zalutsky, MR; Zhao, XG; Wikstrand, CJ; Pegram, CN; Herndon, JE; Vick, NA; Paleologos, N; Fredericks, RK; Schold, SC; Bigner, DD
MLA Citation
Brown, MT, Coleman, RE, Friedman, AH, Friedman, HS, McLendon, RE, Reiman, R, Felsberg, GJ, Tien, RD, Bigner, SH, Zalutsky, MR, Zhao, XG, Wikstrand, CJ, Pegram, CN, Herndon, JE, Vick, NA, Paleologos, N, Fredericks, RK, Schold, SC, and Bigner, DD. "Intrathecal 131I-labeled antitenascin monoclonal antibody 81C6 treatment of patients with leptomeningeal neoplasms or primary brain tumor resection cavities with subarachnoid communication: phase I trial results." Clin Cancer Res 2.6 (June 1996): 963-972.
PMID
9816257
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
2
Issue
6
Publish Date
1996
Start Page
963
End Page
972

Treatment of patients with pineoblastoma with high dose cyclophosphamide.

The outcome for patients with pineoblastoma has historically been very poor, with most patients dying of disseminated disease despite irradiation. Furthermore, the low incidence of this tumor has hindered progress toward defining better treatment strategies. Here we report the activity and toxicity of cyclophosphamide administered as a single agent at a dose schedule of 2 g/m2/day for 2 successive days at monthly intervals for a maximum of four courses. Eight patients were evaluated, six newly diagnosed and two recurrent. Amongst the six newly diagnosed patients, there were three patients demonstrating partial responses, and three had stable disease throughout the cyclophosphamide treatment period. All six patients are alive and disease free after further therapy. One patient with recurrent disease demonstrated tumor progression on cyclophosphamide, and the other had stable disease throughout the cyclophosphamide treatment period. Both patients subsequently died of progressive disease. The major toxicity of high dose cyclophosphamide was hematopoietic, with one patient requiring a dose reduction after three courses due to prolonged thrombocytopenia. One patient was also withdrawn from treatment with cyclophosphamide due to impaired pulmonary function. This study demonstrates the activity of high dose cyclophosphamide in the treatment of pineoblastoma and may serve as basis for the design of future studies of this tumor.

Authors
Ashley, DM; Longee, D; Tien, R; Fuchs, H; Graham, ML; Kurtzberg, J; Casey, J; Olson, J; Meier, L; Ferrell, L; Kerby, T; Duncan-Brown, M; Stewart, E; Colvin, OM; Pipas, JM; McCowage, G; McLendon, R; Bigner, DD; Friedman, HS
MLA Citation
Ashley, DM, Longee, D, Tien, R, Fuchs, H, Graham, ML, Kurtzberg, J, Casey, J, Olson, J, Meier, L, Ferrell, L, Kerby, T, Duncan-Brown, M, Stewart, E, Colvin, OM, Pipas, JM, McCowage, G, McLendon, R, Bigner, DD, and Friedman, HS. "Treatment of patients with pineoblastoma with high dose cyclophosphamide." Med Pediatr Oncol 26.6 (June 1996): 387-392.
PMID
8614374
Source
pubmed
Published In
Pediatric Blood and Cancer
Volume
26
Issue
6
Publish Date
1996
Start Page
387
End Page
392
DOI
10.1002/(SICI)1096-911X(199606)26:6<387::AID-MPO3>3.0.CO;2-D

Production and characterization of two ependymoma xenografts.

Childhood ependymomas exhibit epidemiologic, anatomic, histologic, and biologic features and distinguish them from other gliomas. Because of their propensity to grow in functionally sensitive regions of the brain, adequate tumor sampling for basic and therapeutic research is limited. We have established xenografts in both subcutaneous and intracranial nude mouse systems (D528 EP-X, D612 EP-X) from the ependymomas of two nonrelated children. Median subcutaneous growth rates (reported in days to grow from 200 mm3 to 1000 mm3) are 82 days for D528 EP-X (n = 10) and 50 days for D612 EP-X (n = 10). D528 EP-X grows intracranially with a median postimplantation survival of 85 days (n = 10); D612 EP produces a median postimplantation survival of 72.5 days (n = 10). Both xenografts grow as well-formed masses with no evidence of infiltration into either brain or subcutaneous tissues. While perivascular pseudopalisading is found in both xenografts, true ependymal rosette formation is absent. Ultrastructurally, neither xenograft exhibits cilia, but both produce abundant intermediate filaments. By light microscopy, the neoplastic cells are immunoreactive for the intermediate filaments glial fibrillary acidic protein, vimentin, and nestin. Karyotypically D528 EP exhibits 46,XX,del(6)(q22q26)/46,XX while D612 EP exhibits 50,XX, +X,t(1;8)(p11;q11),t(1;8)(p11;q11), +1,-4, der(5)t(4;5)(q12;q35), +der(5)t(4;5)(q12;q35),-6, +9, +9,-16, +der(17)t(6;17)(p11;p11), +mar. Restriction fragment length polymorphism studies comparing the primary brain tumor tissue from each patient against multiple passages of the resulting xenografts confirm the origin of both xenografts. These xenografts represent models on which future studies into the oncogenesis, progression and therapy of ependymomas can be performed.

Authors
McLendon, RE; Fung, KM; Bentley, RC; Ahmed Rasheed, BK; Trojanowski, JQ; Bigner, SH; Bigner, DD; Friedman, HS
MLA Citation
McLendon, RE, Fung, KM, Bentley, RC, Ahmed Rasheed, BK, Trojanowski, JQ, Bigner, SH, Bigner, DD, and Friedman, HS. "Production and characterization of two ependymoma xenografts." J Neuropathol Exp Neurol 55.5 (May 1996): 540-548.
PMID
8627345
Source
pubmed
Published In
Journal of Neuropathology and Experimental Neurology
Volume
55
Issue
5
Publish Date
1996
Start Page
540
End Page
548

Castleman's disease (plasma cell variant) confined to the leptomeninges.

Authors
McLendon, RE; Friedman, AH; Provenzale, JM; Brown, MT; Mann, KP
MLA Citation
McLendon, RE, Friedman, AH, Provenzale, JM, Brown, MT, and Mann, KP. "Castleman's disease (plasma cell variant) confined to the leptomeninges." JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 55.5 (May 1996): 76-76.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
55
Issue
5
Publish Date
1996
Start Page
76
End Page
76

Radiotoxicity of systematically administered [211At]astatide in B6C3F1 and BALB/c (nu/nu) mice: a long-term survival study with histologic analysis.

PURPOSE: The present study undertook to establish the dose (LD) of systematically administered (via tail vein) sodium [211At]astatide that would kill 10% (LD10) of exposed animals in two mouse models and to evaluate the resulting histologic lesions. METHODS AND MATERIALS: Three dose escalation experiments were carried out using groups of 10 3- to 4-week-old, 20 +/- 2 g B6C3F1 mice, and one dose escalation experiment was carried out with groups of 10 4- to 6-week-old, 22 +/- 2 g BALB/c (nu/nu) mice. All animals were weighed daily and checked twice daily for general health; autopsies were performed within 12 h of death. RESULTS: The LD10 (95% confidence interval) level of free [211At]astatide at 360 days was 15.1 microCi (5.2-19.1 microCi) in B6C3F1 mice and was associated with a 37.8% weight difference from saline controls (p < 0.001). In the BALB/c (nu/nu) mice, the LD10 at 360 days was 7.7 microCi (0-14.2 microCi), while a dose of 10 microCi (0.42 microCi g(-1)) was associated with a 9.44% weight difference vs. saline controls (p < 0.05). Exclusive of the well-known effects on thyroid, [211At]astatide activity levels were associated with severe bone marrow depression, testicular atrophy, focal alopecia, and nuclear atypia of the epidermoid mucosa of the fore-stomach in the B6C3F1 mice; at activity levels approximating LD10 at 360 days, mild changes in the heart, liver, stomach, and spleen were observed. For BALB/c (nu/nu) mice, administration of 10 microCi was associated at autopsy with mild histologic lesions in the heart, stomach, liver, and spleen. CONCLUSIONS: These studies provide a basis for the design of further investigations of [211At]-labeled compounds as therapeutic agents.

Authors
McLendon, RE; Archer, GE; Garg, PK; Bigner, DD; Zalutsky, MR
MLA Citation
McLendon, RE, Archer, GE, Garg, PK, Bigner, DD, and Zalutsky, MR. "Radiotoxicity of systematically administered [211At]astatide in B6C3F1 and BALB/c (nu/nu) mice: a long-term survival study with histologic analysis." Int J Radiat Oncol Biol Phys 35.1 (April 1, 1996): 69-80.
PMID
8641929
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
35
Issue
1
Publish Date
1996
Start Page
69
End Page
80

Spinal angiolipomas: MR features.

PURPOSE: To determine the MR features of spinal angiolipomas and to compare these findings with their histologic appearance. METHODS: The MR examinations of three patients with surgically proved angiolipomas were reviewed for tumor location and extent, signal characteristics, and pattern of contrast enhancement, and were then compared with the histologic findings. RESULTS: Four tumors were found in the three patients, all located in the posterior epidural compartment, averaging about 2.5 vertebral bodies in length. On noncontrast T1-weighted images, all lesions were inhomogeneous and hypointense relative to epidural fat. Inhomogeneous enhancement was seen in three lesions on postcontrast T1-weighted images obtained with fat-saturation techniques. Angiolipomas were least conspicuous on T2-weighted images. A high vascular content correlated with the presence of large hypointense regions on T1-weighted images. CONCLUSION: Spinal angiolipomas are typically hyperintense on noncontrast T-1-weighted images relative to other tumors. Angiolipomas that contain large hypointense foci on noncontrast T1-weighted images can be expected to have a high degree of vascularity.

Authors
Provenzale, JM; McLendon, RE
MLA Citation
Provenzale, JM, and McLendon, RE. "Spinal angiolipomas: MR features." AJNR Am J Neuroradiol 17.4 (April 1996): 713-719.
PMID
8730192
Source
pubmed
Published In
American Journal of Neuroradiology
Volume
17
Issue
4
Publish Date
1996
Start Page
713
End Page
719

Ganglion cell-containing tumors of the pituitary gland.

The ganglion cell-containing tumors of the pituitary are rare lesions of undetermined histogenesis and nosology. A review of the literature revealed 42 such tumors, including the 3 cases described below. On the basis of this review, the tumors were divided into two histologic groups, one consisting of both adenomatous and gangliocytic elements (32 cases), and the other of the gangliocytic component only (10 cases). The first group of tumors were more common in females (23 of 32 cases) and were often active endocrinologically (28 of 32 cases), and acromegaly was the most common manifestation (19 cases). The second group was also more common in females (7 of 10 cases) but was less frequently active endocrinologically (3 of 19 cases). We review histologic and immunocytochemical findings in these tumors and discuss their histogenesis. We propose that the term mixed pituitary adenoma-gangliocytoma be used for the first group and gangliocytoma for the second. The two groups should be kept separate until their histogenesis is better understood.

Authors
Towfighi, J; Salam, MM; McLendon, RE; Powers, S; Page, RB
MLA Citation
Towfighi, J, Salam, MM, McLendon, RE, Powers, S, and Page, RB. "Ganglion cell-containing tumors of the pituitary gland." Arch Pathol Lab Med 120.4 (April 1996): 369-377. (Review)
PMID
8619749
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
120
Issue
4
Publish Date
1996
Start Page
369
End Page
377

Microsatellite analysis of childhood brain tumors.

Loss of heterozygosity at specific chromosomal locations has been taken as evidence of a tumor suppressor gene located in that area. We performed a genomic allelotyping study on 46 childhood brain tumors of different histopathological types in order to identify and confirm common areas of deletion in different tumor types. Two hundred microsatellite DNA probes equally distributed over the 22 autosomes were applied, covering the genome in steps of approximately 25 cM. Our results confirm frequent loss of heterozygosity of chromosome arms 9q, 10q, 11p, 11q, 16q, and 22q in high-grade gliomas, medulloblastomas, and ependymomas. In addition, we found a new region of loss on chromosome segment 2p21-23 affected predominantly in high-grade gliomas and medulloblastomas.

Authors
Blaeker, H; Rasheed, BK; McLendon, RE; Friedman, HS; Batra, SK; Fuchs, HE; Bigner, SH
MLA Citation
Blaeker, H, Rasheed, BK, McLendon, RE, Friedman, HS, Batra, SK, Fuchs, HE, and Bigner, SH. "Microsatellite analysis of childhood brain tumors." Genes Chromosomes Cancer 15.1 (January 1996): 54-63.
PMID
8824726
Source
pubmed
Published In
Genes, Chromosomes and Cancer
Volume
15
Issue
1
Publish Date
1996
Start Page
54
End Page
63
DOI
10.1002/(SICI)1098-2264(199601)15:1<54::AID-GCC8>3.0.CO;2-3

Efficacy of compartmental administration of immunotoxin LMB-1 (B3-LysPE38) in a rat model of carcinomatous meningitis.

LMB-1 (B3-LysPE38) is an immunotoxin composed of the tumor-reactive monoclonal antibody B3 and a genetically engineered form of Pseudomonas exotoxin. Monoclonal antibody B3 reacts with a carbohydrate epitope that is found on a number of solid tumors (e.g., breast, ovarian, and lung carcinomas) that frequently invade the intrathecal space, causing neoplastic meningitis. The Pseudomonas exotoxin has been engineered to remove the binding domain to eliminate nonspecific binding. A model of human neoplastic meningitis using rats bearing the human epidermoid carcinoma A431 was used for therapeutic studies of immunotoxin LMB-1. Therapy was initiated 3 days after injection of the tumor cells, which was one third of the median survival time of untreated rats. A single intrathecal injection of 40 microgram increased median survival from 9 days with saline injection to 16 days (78%, P < 0.001), and a single dose of 200 microgram increased median survival to 25 days (188%, P < 0. 001). Three doses of 40 or 200 microgram given on days 3, 6, and 8 significantly increased the median survival of 9.5 days associated with saline injection to 40.5 days (326% increase) and 33.0 days (247% increase), respectively, with two long-term survivors (191-day survival) in each treatment group. LMB-1 had no therapeutic effect on the treatment of two B3 antigen-negative neoplastic meningitis models. Treatment of the antigen-positive A431 neoplastic meningitis with B3 alone or a nonspecific monoclonal, MOPC, coupled to the engineered Pseudomonas exotoxin produced no survival effects. Nontumor-bearing athymic rats showed no toxicity with a single dose of either 40 microgram or 200 microgram, or 3 doses of 40 microgram. However, when they were given three doses of 200 microgram, these rats showed weight loss and loss of neurological function, and two of eight animals died. These studies indicate that, in the range of the most therapeutically effective dosage, the immunotoxin LMB-1 is tolerated in the intrathecal space and should be considered for human intrathecal trials.

Authors
Bigner, DD; Archer, GE; McLendon, RE; Friedman, HS; Fuchs, HE; Pai, LH; Herndon, JE; Pastan, IH
MLA Citation
Bigner, DD, Archer, GE, McLendon, RE, Friedman, HS, Fuchs, HE, Pai, LH, Herndon, JE, and Pastan, IH. "Efficacy of compartmental administration of immunotoxin LMB-1 (B3-LysPE38) in a rat model of carcinomatous meningitis." Clin Cancer Res 1.12 (December 1995): 1545-1555.
PMID
9815955
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
1
Issue
12
Publish Date
1995
Start Page
1545
End Page
1555

Tumor antigens in astrocytic gliomas.

Gliomas affect 15,000 to 17,000 Americans every year and carry a dismal prognosis. The potential of immunologically mediated diagnosis and therapy, although greatly enhanced since the advent of monoclonal antibodies, has not been fully realized due to significant problems, most especially the challenge of identifying antigenic molecules specific to glial tumors. Other problematic issues include antigen-associated factors such as heterogeneity, modulation, shedding, and cross-reactivity with normal cells, and factors associated with therapeutic agent delivery, typically variable tumor perfusion and unfavorable diffusional forces in tumor microenvironment. An understanding of these problems called for the delineation of operationally specific antigens (tumor-associated antigens not expressed by the normal central nervous system) combined with the use of compartmental therapeutic approaches to increase the specificity of therapy. Numerous antigens have been identified and are classified as extracellular/matrix-associated, membrane-associated, and intracellular antigens. Nevertheless, only a few have been demonstrated to be of significant therapeutic and diagnostic utility. These few include the extracellular matrix-associated antigens tenascin and GP 240, defined by the monoclonal antibodies 81C6 and Mel-14, both of which are now in Phase I clinical trials, and membrane-associated ganglioside molecules, primarily 3', 6'-isoLD1, defined by the antibody DMAb-22. Recent identification of the overexpression of a deletion variant of the epidermal growth factor receptor (EGFRvIII) in up to 50% of the more malignant glial tumors and the subsequent creation of monoclonal antibodies that are specific to this molecule and do not recognize the wild-type EGFR provide the most exciting development yet in the design of specific antiglioma immunoconjugates. In addition, the tumor-specific nature of EGFRvIII combined with improved knowledge of immune mechanisms, especially in the context of the central nervous system, will facilitate the design of highly selective cell-mediated therapeutic approaches with a view toward obtaining tumor-specific immunity.

Authors
Kurpad, SN; Zhao, XG; Wikstrand, CJ; Batra, SK; McLendon, RE; Bigner, DD
MLA Citation
Kurpad, SN, Zhao, XG, Wikstrand, CJ, Batra, SK, McLendon, RE, and Bigner, DD. "Tumor antigens in astrocytic gliomas." Glia 15.3 (November 1995): 244-256. (Review)
PMID
8586461
Source
pubmed
Published In
Glia
Volume
15
Issue
3
Publish Date
1995
Start Page
244
End Page
256
DOI
10.1002/glia.440150306

MRI of papillary meningiomas in children.

We report two cases of papillary meningioma in children. The MRI appearance of this special type of meningioma is described for the first time. Both lesions were dura based and associated with cystic components. We review the literature pertaining to this type of meningioma and discuss the differential diagnosis of the MRI appearance. Because this is a malignant type of meningioma, early diagnosis and surgical intervention are important in the management of patients.

Authors
Lirng, JF; Enterline, DS; Tien, RD; Fuchs, H; Friedman, HS; Ellington, KS; McLendon, RP
MLA Citation
Lirng, JF, Enterline, DS, Tien, RD, Fuchs, H, Friedman, HS, Ellington, KS, and McLendon, RP. "MRI of papillary meningiomas in children." Pediatr Radiol 25 Suppl 1 (November 1995): S9-13.
PMID
8577564
Source
pubmed
Published In
Pediatric Radiology
Volume
25 Suppl 1
Publish Date
1995
Start Page
S9
End Page
13

Intraarterial administration of melphalan for treatment of intracranial human glioma xenografts in athymic rats.

Malignant gliomas will affect 15,000-17,000 Americans each year and carry a dismal prognosis. Adjuvant chemotherapy is hampered by inadequate drug delivery, systemic toxicity, and a markedly variable biological sensitivity. Intraarterial (i.a.) therapy may enhance selectivity by improving tumor drug delivery and reducing systemic toxicity. Using melphalan given i.a., we studied the therapy of intracranial human glioma xenografts in male athymic nude rats (mean weight, 300 g) which were inoculated intracerebrally with D-54 MG and D-456 MG. On Days 6 and 7 (D-54 MG) or Days 9 and 10 (D-456 MG), rats randomized by body weight and treated with single-dose melphalan given i.a. at 0.5 or 0.75 mg produced significantly higher median survival (D-54 MG, Days 33 and 32; D-456 MG, Days 52 and 54, respectively) compared with i.a. saline (D-54 MG, Day 14, P < 0.001; D-456 MG, Day 24, P = 0.000) or melphalan given i.v. at 0.75 mg and 0.9 mg (D-54 MG only; Day 19, P < 0.001; Day 23, P < 0.001, respectively) and at 0.5 and 0.75 mg (D-456 MG only; Day 26 for both doses, P = 0.00). Although a dose-dependent increase in median survival (D-54 MG, 0.25 mg, Day 18; 0.5 mg, Day 28.5; 0.75 mg, Day 32.5) was observed with i.a. administered melphalan, no significant difference was apparent between 0.5 and 0.75 mg in either tumor model (D-54 MG, P = 0.15; D-456 MG, P = 0.37). Toxicity studies in nontumor-bearing athymic rats yielded a maximum tolerated dose of 0.8 mg for i.a. administered melphalan. This dosage was superior in spite of different xenograft permeabilities (apparent mean blood-to-tissue transport [K] values for alpha-aminoisobutyric acid, 5.8 for D-54 MG and 1.3 for D-456 MG). Pharmacokinetic experiments demonstrated a significant first pass advantage for i.a. (versus i.v.) melphalan. The short plasma half-life, marked antiglioma activity, and lack of requirement for metabolic activation indicate that i.a. melphalan holds considerable promise for human glioma therapy.

Authors
Kurpad, SN; Friedman, HS; Archer, GE; McLendon, RE; Petros, WM; Fuchs, HE; Guaspari, A; Bigner, DD
MLA Citation
Kurpad, SN, Friedman, HS, Archer, GE, McLendon, RE, Petros, WM, Fuchs, HE, Guaspari, A, and Bigner, DD. "Intraarterial administration of melphalan for treatment of intracranial human glioma xenografts in athymic rats." Cancer Res 55.17 (September 1, 1995): 3803-3809.
PMID
7641197
Source
pubmed
Published In
Cancer Research
Volume
55
Issue
17
Publish Date
1995
Start Page
3803
End Page
3809

Frontoethmoidal giant cell reparative granuloma.

We present a case of a giant cell reparative granuloma of the frontoethmoidal region that had a large intracranial extraaxial component and was studied with MR. Although rare, giant cell reparative granuloma can be suggested in the correct clinical setting and when MR features suggest a fibrous lesion.

Authors
Felsberg, GJ; Tien, RD; McLendon, RE
MLA Citation
Felsberg, GJ, Tien, RD, and McLendon, RE. "Frontoethmoidal giant cell reparative granuloma." AJNR Am J Neuroradiol 16.7 (August 1995): 1551-1554.
PMID
7484655
Source
pubmed
Published In
American Journal of Neuroradiology
Volume
16
Issue
7
Publish Date
1995
Start Page
1551
End Page
1554

Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas.

Despite molecular biological advances in understanding human cancers, translation into therapy has been less forthcoming; targeting neoplastic cells still requires that tumor-specific markers, preferably those on the cell surface, be identified. The epidermal growth factor receptor (EGFR) exists in a deletion-mutant form, EGFRvIII, which has been identified by genetic and immunological means in a subset of gliomas and non-small cell lung carcinomas. Specific polyvalent antisera to the extracellular portion of the variant were readily induced, but immunization using a synthetic linear peptide representing the unique EGFRvIII primary sequence has been unsuccessful in mice or macaques. We report here five specific monoclonal antibodies (mAbs) developed through long-term immunization protocols using the EGFRvIII-specific synthetic peptide and the intact variant in different formats that maintained secondary and tertiary conformation. These mAbs identify the EGFRvIII on the cell surface with relatively high affinity (KA range, 0.13 to 2.5 x 10(9) M-1) by live cell Scatchard analysis. These mAbs are specific for EGFRvIII as determined by RIA, ELISA, Western blot, analytical flow cytometry, autophosphorylation, and immunohistochemistry. Isolating specific mAbs enabled us to analyze normal and neoplastic human tissue and establish that EGFRvIII is truly tumor specific for subsets of breast carcinomas and for previously reported non-small cell lung carcinomas and gliomas. Also, this receptor is not expressed by any normal human tissues thus far examined, including elements of the peripheral, central nervous, and lymphoid systems. With mAbs, we identified a higher incidence of EGFRvIII positivity in gliomas than previously described and identified an EGFRvIII-positive subset of breast tumors; also, we observed that the EGFRvIII epitope is not expressed in normal tissues, and we demonstrated the localizing and therapeutic potential of the mAbs for tumors expressing this epitope. Our observations strongly warrant development of this mAb-antigen system as therapy for breast, lung, and central nervous system tumors.

Authors
Wikstrand, CJ; Hale, LP; Batra, SK; Hill, ML; Humphrey, PA; Kurpad, SN; McLendon, RE; Moscatello, D; Pegram, CN; Reist, CJ
MLA Citation
Wikstrand, CJ, Hale, LP, Batra, SK, Hill, ML, Humphrey, PA, Kurpad, SN, McLendon, RE, Moscatello, D, Pegram, CN, and Reist, CJ. "Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas." Cancer Res 55.14 (July 15, 1995): 3140-3148.
PMID
7606735
Source
pubmed
Published In
Cancer Research
Volume
55
Issue
14
Publish Date
1995
Start Page
3140
End Page
3148

Chromosome 10 deletion mapping in human gliomas: a common deletion region in 10q25.

The high incidence of loss of chromosome 10 alleles in glioblastoma multiforme suggests the presence on this chromosome of a tumor suppressor gene that is important in glioma tumorigenesis and progression. Our initial deletion mapping studies using restriction fragment length polymorphism markers indicated a common deletion region in 10q24-qter. In an attempt to localize the deleted region further, we screened a panel of 117 gliomas for loss of heterozygosity for chromosome 10 loci using 10 microsatellite markers. Seventeen tumors showed partial loss of a copy of chromosome 10 and were further analysed using 28 additional microsatellite markers. Of these, 10 had terminal deletion in the q arm, three had deletions in both p and q arms, two contained interstitial deletion in 10q and two carried deletions in 10p. In the 15 tumors with deletions in 10q, the minimal overlapping deletion region was in distal 10q between markers D10S587 and D10S216. Loci D10S587 and D10S216 are approximately mapped to a 5 cM region in 10q25.1.

Authors
Rasheed, BK; McLendon, RE; Friedman, HS; Friedman, AH; Fuchs, HE; Bigner, DD; Bigner, SH
MLA Citation
Rasheed, BK, McLendon, RE, Friedman, HS, Friedman, AH, Fuchs, HE, Bigner, DD, and Bigner, SH. "Chromosome 10 deletion mapping in human gliomas: a common deletion region in 10q25." Oncogene 10.11 (June 1, 1995): 2243-2246.
PMID
7784070
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
10
Issue
11
Publish Date
1995
Start Page
2243
End Page
2246

A pial window model for the intracranial study of human glioma microvascular function.

A new model for human brain tumor uses the intracranial placement of tumor xenografts under transparent glass cranial windows in nude rats, which require no immunosuppression for tumor engraftment. Adult male nude rats underwent implantation of human anaplastic astrocytomas (D-54 MG in 10 rats, D-317 MG in 11 rats). The tumors were placed on the pial surface of the left cerebral hemisphere under a glass cranial window overlying the cranium. Six control animals underwent cranial window placement alone. Tumor volumes were estimated from direct measurements of tumor dimensions, revealing a mean doubling time of 1.58 days for the D-54 MG tumors and 2.62 days for the D-317 MG tumors. When tumor volume estimates reached 35 mm3, photomicrographs revealed tumor vasculature in each tumor cell line that was distinct from both the other xenograft and the normal brain parenchyma. Qualitative differences in vascular appearance were supported by length/density coefficient calculations in each study group, with D-317 MG demonstrating the highest vascular density. Vessel caliber tended to be smaller in D-54 MG tumors than in D-317 MG tumors. Laser-Doppler measurements of local blood flow in tumors and normal parenchyma revealed significantly lower blood flow in both tumor cell lines than in control brain. Evaluation of leukocyte/endothelial cell interactions indicated more leukocyte rolling in D-54 MG tumors than in D-317 MG tumors; no evidence of this cell interaction was found in normal pial vasculature. This model allows direct serial inspection of human brain tumor growth and vascular function in an experimental animal and could be used to study tumor vascular and inflammatory responses to a variety of therapeutic manipulations.

Authors
Foltz, RM; McLendon, RE; Friedman, HS; Dodge, RK; Bigner, DD; Dewhirst, MW
MLA Citation
Foltz, RM, McLendon, RE, Friedman, HS, Dodge, RK, Bigner, DD, and Dewhirst, MW. "A pial window model for the intracranial study of human glioma microvascular function." Neurosurgery 36.5 (May 1995): 976-984.
PMID
7791991
Source
pubmed
Published In
Neurosurgery
Volume
36
Issue
5
Publish Date
1995
Start Page
976
End Page
984

SYNCHRONOUS EPENDYMO-GLIOMAS

Authors
MCLENDON, RE; FRIEDMAN, HS; LONGEE, DC; FUCHS, HE; HESSLER, RB
MLA Citation
MCLENDON, RE, FRIEDMAN, HS, LONGEE, DC, FUCHS, HE, and HESSLER, RB. "SYNCHRONOUS EPENDYMO-GLIOMAS." May 1995.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
54
Issue
3
Publish Date
1995
Start Page
422
End Page
422
DOI
10.1097/00005072-199505000-00062

MIB-1 (KI-67 ANTIGEN) LABELING INDEXES IN NONNEOPLASTIC GLIAL-CELL PROLIFERATIONS

Authors
KOCHI, M; MCLENDON, RE; LANGFORD, LA
MLA Citation
KOCHI, M, MCLENDON, RE, and LANGFORD, LA. "MIB-1 (KI-67 ANTIGEN) LABELING INDEXES IN NONNEOPLASTIC GLIAL-CELL PROLIFERATIONS." JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 54.3 (May 1995): 461-461.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
54
Issue
3
Publish Date
1995
Start Page
461
End Page
461
DOI
10.1097/00005072-199505000-00215

Shadow cells in an intracranial dermoid cyst.

A case of an intracranial dermoid cyst containing shadow cells is presented. This case expands the group of lesions in which shadow cells, indicative of hair matrical differentiation, have been described.

Authors
Hitchcock, MG; Ellington, KS; Friedman, AH; Provenzaie, JM; McLendon, RE
MLA Citation
Hitchcock, MG, Ellington, KS, Friedman, AH, Provenzaie, JM, and McLendon, RE. "Shadow cells in an intracranial dermoid cyst." Arch Pathol Lab Med 119.4 (April 1995): 371-373.
PMID
7726731
Source
pubmed
Published In
Archives of Pathology and Laboratory Medicine
Volume
119
Issue
4
Publish Date
1995
Start Page
371
End Page
373

Intrathecal administration of single-chain immunotoxin, LMB-7 [B3(Fv)-PE38], produces cures of carcinomatous meningitis in a rat model.

LMB-7 [B3(Fv)-PE38] is a single-chain immunotoxin constructed from the murine monoclonal antibody B3 and a truncated from of Pseudomonas exotoxin PE38. Antibody B3 recognizes a carbohydrate epitope found on solid tumors that frequently invade the intrathecal space and cause neoplastic meningitis. We tested the therapeutic value of intrathecally administered LMB-7 by using a model of human neoplastic meningitis in athymic rats. This model is representative of a clinical situation in that antibody B3 cross-reacts with a number of normal tissues that can be used to monitor potential systemic toxicity. Treatment was begun 3 days after A431 tumor implantation. Without treatment, the animals median survival was 10 days. Intrathecal administration of 10 micrograms of LMB-7 in 40 microliters on days 3, 5, and 7 produced 4 of 10 and 8 of 10 long-term survivors (> 170 days) in two experiments. Of the long-term survivors, 2 of 4 and 7 of 8 survivors had no microscopic evidence of tumor and were considered histologic cures. Lack of significant toxicity in the effective dose range and specificity make LMB-7 an excellent candidate for intrathecal treatment of neoplastic meningitis in humans.

Authors
Pastan, IH; Archer, GE; McLendon, RE; Friedman, HS; Fuchs, HE; Wang, QC; Pai, LH; Herndon, J; Bigner, DD
MLA Citation
Pastan, IH, Archer, GE, McLendon, RE, Friedman, HS, Fuchs, HE, Wang, QC, Pai, LH, Herndon, J, and Bigner, DD. "Intrathecal administration of single-chain immunotoxin, LMB-7 [B3(Fv)-PE38], produces cures of carcinomatous meningitis in a rat model." Proc Natl Acad Sci U S A 92.7 (March 28, 1995): 2765-2769.
PMID
7708720
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
92
Issue
7
Publish Date
1995
Start Page
2765
End Page
2769

Inhibition of epidural scar formation after lumbar laminectomy in the rat.

STUDY DESIGN: An animal model of laminectomy in rats was used to study scar tissue formation around the spinal cord. Dexamethasone, in controlled-release form, was tested in this system for its ability to decrease fibrous tissue formation. OBJECTIVES: The results were evaluated to determine whether dexamethasone in a biodegradable controlled-release vehicle could be used to limit scar tissue formation around the spinal cord after laminectomy. SUMMARY OF BACKGROUND DATA: Steroids can delay the formation of scar tissue. Continued treatment with dexamethasone results in various unacceptable side effects. Use of biodegradable controlled-release vehicles to deliver drugs may allow for prolonged low-dose treatment, concentrated at the surgical site, thereby avoiding side effects. METHODS: Forty-four Sprague Dawley rats underwent laminectomies and were treated with dexamethasone in one of two controlled-release vehicles or with vehicle alone. After 4 weeks, the rats were killed and histologic sections prepared from the spines were examined and graded by a pathologist. In addition, the dexamethasone preparations were introduced into Hunt-Schilling wound chambers, which were implanted in rats. Four weeks after implantation, the wound chambers were removed and the tissue inside was assayed for DNA and protein content. RESULTS: Dexamethasone acetate (Decadron, MSD, West Point, PA) significantly reduced the density of the scar tissue undermining the laminas. Steroids embedded in polymer did not change the scar formation in the back, but did decrease protein and DNA values in wound chamber tissues. CONCLUSIONS: Long-term release of small amounts of steroid from the polymer poly-carboxy-phenoxypropane does not appear to reduce scar at laminectomy sites but does decrease the protein:DNA ratio in wound chambers. In contrast, Decadron does not significantly alter the biochemistry of wound chamber tissue but does reduce scar in the back.

Authors
Hinton, JL; Warejcka, DJ; Mei, Y; McLendon, RE; Laurencin, C; Lucas, PA; Robinson, JS
MLA Citation
Hinton, JL, Warejcka, DJ, Mei, Y, McLendon, RE, Laurencin, C, Lucas, PA, and Robinson, JS. "Inhibition of epidural scar formation after lumbar laminectomy in the rat." Spine (Phila Pa 1976) 20.5 (March 1, 1995): 564-570.
PMID
7604326
Source
pubmed
Published In
Spine
Volume
20
Issue
5
Publish Date
1995
Start Page
564
End Page
570

Post-traumatic epidermoid cyst: CT appearance.

We report development of an intracranial epidermoid cyst 2 years after a depressed skull fracture. The epidermoid cyst is presumed to be the result of introduction of epidermal elements at the time of trauma. Post-traumatic intracranial epidermoid cysts are rare and appear to be less common than those occurring in the spine.

Authors
Lee, VS; Provenzale, JM; Fuchs, HE; Osumi, A; McLendon, RE
MLA Citation
Lee, VS, Provenzale, JM, Fuchs, HE, Osumi, A, and McLendon, RE. "Post-traumatic epidermoid cyst: CT appearance." J Comput Assist Tomogr 19.1 (January 1995): 153-155.
PMID
7822537
Source
pubmed
Published In
Journal of Computer Assisted Tomography
Volume
19
Issue
1
Publish Date
1995
Start Page
153
End Page
155

Radiologic-pathologic correlation. Bilateral retinoblastoma with coexistent pinealoblastoma (trilateral retinoblastoma).

Authors
Provenzale, JM; Weber, AL; Klintworth, GK; McLendon, RE
MLA Citation
Provenzale, JM, Weber, AL, Klintworth, GK, and McLendon, RE. "Radiologic-pathologic correlation. Bilateral retinoblastoma with coexistent pinealoblastoma (trilateral retinoblastoma)." AJNR Am J Neuroradiol 16.1 (January 1995): 157-165. (Review)
PMID
7900586
Source
pubmed
Published In
American Journal of Neuroradiology
Volume
16
Issue
1
Publish Date
1995
Start Page
157
End Page
165

Prognostic implications of chromosome 17p deletions in human medulloblastomas.

DNA derived from medulloblastoma biopsies was analyzed to determine if deletions of the 17p region, mutations of the TP53 gene, or amplification of the c-myc, N-myc, EGFR (epidermal growth factor receptor), or MDM2 (murine double-minute-2) genes was indicative of a poor prognosis. Loss of heterozygosity for 17p, observed in 8/28 (29%) paired samples, was associated with a shortened survival period (p = 0.045 by the logrank test). TP53 mutations occurred in 2/46 (4.3%) tumor samples. c-myc Amplification was seen in 3/43 (6.9%) cases, while none of the tumors contained amplified N-myc, EGFR, or MDM2 genes. These results demonstrate that, while only rare medulloblastomas contain TP53 gene mutations or amplification of the c-myc gene, loss of heterozygosity on chromosome 17p is indicative of a significantly worse prognosis among patients with these tumors. Further, these results provide a strong impetus for a prospective analysis of loss of heterozygosity in a cooperative group setting, which would include tumor staging, a selection of treatment modalities, and multivariate analyses.

Authors
Batra, SK; McLendon, RE; Koo, JS; Castelino-Prabhu, S; Fuchs, HE; Krischer, JP; Friedman, HS; Bigner, DD; Bigner, SH
MLA Citation
Batra, SK, McLendon, RE, Koo, JS, Castelino-Prabhu, S, Fuchs, HE, Krischer, JP, Friedman, HS, Bigner, DD, and Bigner, SH. "Prognostic implications of chromosome 17p deletions in human medulloblastomas." J Neurooncol 24.1 (1995): 39-45.
PMID
8523074
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
24
Issue
1
Publish Date
1995
Start Page
39
End Page
45

Phase I studies of treatment of malignant gliomas and neoplastic meningitis with 131I-radiolabeled monoclonal antibodies anti-tenascin 81C6 and anti-chondroitin proteoglycan sulfate Me1-14 F (ab')2--a preliminary report.

The advent of monoclonal antibody (MAb) technology has made Ehrlich's postulate of the 'magic bullet' an attainable goal. Although specific localization of polyvalent antibodies to human gliomas was demonstrated in the 1960s, the lack of specific, high affinity antibody populations and of defined target antigens of sufficient density precluded therapeutic applications. Not until the identification of operationally specific tumor-associated antigens (present in tumor tissue but not normal central nervous system tissue); production of homogeneous, high affinity MAbs to such antigens; and the use of compartmental administration (intrathecal or intracystic), has the promise of passive immunotherapy of primary and metastatic central nervous system neoplasms been recognized. We report here preliminary data from Phase I studies of the compartmental administration of the anti-tenascin MAb 81C6 and F(ab2)2 fragments of MAb Me1-14, which recognizes the proteoglycan chondroitin sulfate-associated protein of gliomas and melanomas, to patients with primary central nervous system tumors or tumors metastatic to the central nervous system. Phase I dose escalation studies of intracystically administered 131I-labeled anti-tenascin MAb 81C6 to either spontaneous cysts of recurrent gliomas or surgically created cystic resection cavities have resulted in striking responses. Of five patients with recurrent cystic gliomas treated, four had partial responses, clinically or radiographically. Similarly, in patients with surgically created resection cavities, a partial response at the treatment site and extended stable disease status has been obtained following intracystic administration of 131I-labeled 81C6. No evidence of hematologic or neurologic toxicity has been observed in either patient population, with the exception of transient exacerbation of a pre-existing seizure disorder in a single patient. Dosimetry calculations indicated high intracystic retention for four to six weeks with little or no systemic dissemination; estimated total doses intracystically ranged from 12,700-70,290 rad. Intrathecal administration of labeled MAbs to patients with neoplastic meningitis is more difficult to assess in terms of clinical responsiveness. Of patients so treated with either 131I-labeled 81C6 or 131I-labeled Me1-14 (F(ab)2, cerebrospinal fluid and radiographic responses have been achieved, and survival prolongation through maintenance of stable disease has been observed in several cases. Initial results from pHase I dose escalation trials are encouraging in terms of the proportion of cases of disease stabilization and partial and complete responses obtained. Importantly, neurotoxicity has been virtually nonexistent, and hematologic toxicity rare and rapidly responsive to treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Authors
Bigner, DD; Brown, M; Coleman, RE; Friedman, AH; Friedman, HS; McLendon, RE; Bigner, SH; Zhao, XG; Wikstrand, CJ; Pegram, CN
MLA Citation
Bigner, DD, Brown, M, Coleman, RE, Friedman, AH, Friedman, HS, McLendon, RE, Bigner, SH, Zhao, XG, Wikstrand, CJ, and Pegram, CN. "Phase I studies of treatment of malignant gliomas and neoplastic meningitis with 131I-radiolabeled monoclonal antibodies anti-tenascin 81C6 and anti-chondroitin proteoglycan sulfate Me1-14 F (ab')2--a preliminary report." J Neurooncol 24.1 (1995): 109-122.
PMID
8523067
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
24
Issue
1
Publish Date
1995
Start Page
109
End Page
122

Cerebral phaeohyphomycosis complicated with brain abscess: A case report

Cerebral phaeohyphomycosis is used to describe the rare clinical syndrome of cerebral infection caused by dematiaceous (i.e. pigmented olivaceous-brown) fungi. It usually presents as brain abscess. In view of the rarity of this fungal infection and its clinical importance, we report a case of cerebral phaeohypomycosis caused by Xylohypha bantiana. The patient presented with a seizure attack. The MRI study revealed a ring-enhancing lesion with marked perifocal edema in right high frontoparietal junction of the brain. He underwent an initial craniotomy for removal of the lesion and a second craniotomy for recurrence of the lesion 3 months later. The diagnosis was based on successful cultivation of X. bantiana from the surgical specimen and on histopathology. The patient received antifungal drug therapy of 5-flucytosine and itraconazole. He has done well without any symptoms. We think complete surgical removal of the brain abscess combined with antifungal drug therapy is the best management for this rare fungal disease.

Authors
Lirng, J-F; Tien, RD; Osumi, AK; Madden, JF; McLendon, RP; Sexton, D
MLA Citation
Lirng, J-F, Tien, RD, Osumi, AK, Madden, JF, McLendon, RP, and Sexton, D. "Cerebral phaeohyphomycosis complicated with brain abscess: A case report." Chinese Medical Journal (Taipei) 55.6 (1995): 491-495.
PMID
7634190
Source
scival
Published In
Chinese Medical Journal (Taipei)
Volume
55
Issue
6
Publish Date
1995
Start Page
491
End Page
495

Intrathecal melphalan therapy of human neoplastic meningitis in athymic nude rats.

We report the activity and toxicity of intrathecal melphalan in the treatment of human neoplastic meningitis in the subarachnoid space of athymic nude rats. Animals received injections via chronic indwelling subarachnoid catheters with 5 x 10(5) or 5 x 10(6) TE-671 human rhabdomyosarcoma cells or 5 x 10(6) D-54 MG human glioma cells and were treated with melphalan on days 8, 5, or 5, respectively. Melphalan toxicity in nontumor-bearing rats was assessed at single doses of a 2.0, 3.0, 4.0, or 5.0 mM solution, with clinical and histological evidence of neurotoxicity observed at the 4.0 and 5.0 mM levels. Multiple-dose toxicity studies using a dosing schedule of twice a week for two weeks with a 0.25, 0.5, 0.75, 1.0, 1.5, or 2 mM solution revealed dose-dependent clinical and histological evidence for toxicity at all dosages. Treatment of TE-671 with a single dose of 2.0 mM intrathecal melphalan produced an increase in median survival of 442% compared with saline controls (P < 0.003). Comparison of a single dose of 1.0 or 2.0 mM melphalan with a multiple dose regimen at 0.25 or 0.5 mM melphalan in the treatment of TE-671 revealed increases in median survival of 50% for 1.0 mM, 57% for 2.0 mM, 79% for 0.5 mM, and 111% for 0.25 mM concentrations. Comparison of a single dose of 1 mM melphalan with multiple doses of 0.25 mM melphalan in the treatment of D-54 MG revealed an increase in median survival of 475+% for each of the regimens. Intrathecal melphalan may be an important new addition in the treatment of neoplastic meningitis and is currently being evaluated clinically in a Phase 1 trial.

Authors
Friedman, HS; Archer, GE; McLendon, RE; Schuster, JM; Colvin, OM; Guaspari, A; Blum, R; Savina, PA; Fuchs, HE; Bigner, DD
MLA Citation
Friedman, HS, Archer, GE, McLendon, RE, Schuster, JM, Colvin, OM, Guaspari, A, Blum, R, Savina, PA, Fuchs, HE, and Bigner, DD. "Intrathecal melphalan therapy of human neoplastic meningitis in athymic nude rats." Cancer Res 54.17 (September 1, 1994): 4710-4714.
PMID
8062269
Source
pubmed
Published In
Cancer Research
Volume
54
Issue
17
Publish Date
1994
Start Page
4710
End Page
4714

Radioimmunotherapy of neoplastic meningitis in rats using an alpha-particle-emitting immunoconjugate.

Because of their short range and high linear energy transfer, alpha-particles may be particularly effective in the treatment of neoplastic meningitis. Monoclonal antibody 81C6 was labeled with alpha-particle-emitting 211At using N-succinimidyl3-[211At]astatobenzoate, and the efficacy and toxicity of this immunoconjugate were evaluated in an athymic rat model. Animals were given injections via a chronic indwelling catheter with 5 x 10(5) TE-671 human rhabdomyosarcoma cells and treated 8 days later with single intrathecal doses of either saline or 4-18 microCi of 211At-labeled specific 81C6 antibody or isotype-matched control 211At-labeled 45.6 antibody. In the first experiment, 4, 7, and 13 microCi 211At-labeled 81C6 produced statistically significant (P = 0.004-0.02) increases in median survival of 33, 29, and 51%, respectively, as compared with saline. Two of 10 animals receiving the 13-microCi dose lived for 6 months before being killed for histological analysis. In the second experiment, 12 microCi of 211At-labeled 45.6 did not increase median survival significantly relative to saline control, while 12 microCi of 211At-labeled 81C6 increased median survival by 113% (P < 0.005) and resulted in 33% apparent cures. Five of 10 animals receiving 18 microCi of 211At-labeled 81C6 survived until they were killed at 295 days. An additional study was performed in animals given intrathecal injections of 5 x 10(6) TE-671 cells and given a single dose of 18 microCi of 211At-labeled 81C6 or 211At-labeled 45.6. At this higher cell number, significantly prolonged survival was still seen for specific antibody as compared with saline (P < 0.001) and control antibody (P < 0.05). These results suggest that treatment with 211At-labeled monoclonal antibodies may be a valuable approach for neoplastic meningitis.

Authors
Zalutsky, MR; McLendon, RE; Garg, PK; Archer, GE; Schuster, JM; Bigner, DD
MLA Citation
Zalutsky, MR, McLendon, RE, Garg, PK, Archer, GE, Schuster, JM, and Bigner, DD. "Radioimmunotherapy of neoplastic meningitis in rats using an alpha-particle-emitting immunoconjugate." Cancer Res 54.17 (September 1, 1994): 4719-4725.
PMID
8062270
Source
pubmed
Published In
Cancer Research
Volume
54
Issue
17
Publish Date
1994
Start Page
4719
End Page
4725

Well differentiated astrocytoma occurring nine years after radiation therapy for medulloblastoma.

Conventional treatment for medulloblastoma includes surgical resection followed by craniospinal irradiation, with the potential risk of subsequent radiotherapy-induced secondary neoplasms. We report a 23-year-old woman previously irradiated nine years earlier for a cerebellar medulloblastoma who developed a new enhancing lesion in the primary radiation field four weeks following completion of high dose chemotherapy with bone marrow transplantation for recurrent disease. Resection of this lesion revealed a low grade glioma with no evidence of recurrent medulloblastoma.

Authors
Osumi, AK; Mclendon, RE; Tien, RD; Friedman, HS; Graham, M; Hockenberger, B; Halperin, EC; Oakes, WJ
MLA Citation
Osumi, AK, Mclendon, RE, Tien, RD, Friedman, HS, Graham, M, Hockenberger, B, Halperin, EC, and Oakes, WJ. "Well differentiated astrocytoma occurring nine years after radiation therapy for medulloblastoma." Clin Neuropathol 13.5 (September 1994): 281-285. (Review)
PMID
7805312
Source
pubmed
Published In
Clinical neuropathology
Volume
13
Issue
5
Publish Date
1994
Start Page
281
End Page
285

Immunohistochemistry of the glial fibrillary acidic protein: basic and applied considerations.

The immunohistochemical localization of glial fibrillary acidic protein has proven its utility in the histologic identification of benign astrocytes and neoplastic cells of glial lineage in the central nervous system. Its application in the developing nervous system has contributed significantly to following the histogenesis of neural tissue. Its identification in various forms of injury and neoplasia has helped in discovering the function of astrocytes in these processes. In diagnostic neuropathology, its greatest contribution has been in the elucidation of the cellular constituencies of neoplasms previously considered of enigmatic origin.

Authors
McLendon, RE; Bigner, DD
MLA Citation
McLendon, RE, and Bigner, DD. "Immunohistochemistry of the glial fibrillary acidic protein: basic and applied considerations." Brain Pathol 4.3 (July 1994): 221-228. (Review)
PMID
7952263
Source
pubmed
Published In
Brain Pathology
Volume
4
Issue
3
Publish Date
1994
Start Page
221
End Page
228

QUANTITATIVE MORPHOLOGY OF RAT CARCINOMA WITH RELEVANCE TO OXYGENATION

Authors
KLITZMAN, B; SCHRADER, N; MCLENDON, RE; DEWHIRST, MW
MLA Citation
KLITZMAN, B, SCHRADER, N, MCLENDON, RE, and DEWHIRST, MW. "QUANTITATIVE MORPHOLOGY OF RAT CARCINOMA WITH RELEVANCE TO OXYGENATION." March 18, 1994.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
8
Issue
5
Publish Date
1994
Start Page
A1046
End Page
A1046

Alterations of the TP53 gene in human gliomas.

Glial tumors of all grades and histological types from 72 adults and 48 children were analyzed for mutations of the TP53 gene, loss of heterozygosity (LOH) for 17p, and accumulation of TP53 protein to determine whether the incidence and type of TP53 alterations differ among tumors of different histological type and between tumors from adults and children. These tumors were also evaluated for LOH for chromosome 10 and for amplification of the epidermal growth factor receptor, C-MYC, N-MYC, GLI, platelet-derived growth factor receptor-alpha, and murine double minute 2 genes to determine the patterns of molecular alterations involved in the progression of these neoplasms. Seventeen of the 120 tumors contained mutations of the TP53 gene. One of the tumors with TP53 gene mutation was from one of the 48 patients less than 18 years of age. Twelve of the 17 tumors with mutations occurred among the 27 patients in the 18-45-year age group, while 4 tumors with mutations were among the 45 patients more than 45 years old. There was also an increased incidence of TP53 mutation in patients with anaplastic astrocytoma histology. However, no significant association between presence of TP53 mutation and patient survival was observed. These studies demonstrate that TP53 gene mutations are a common mechanism for glial cell neoplasms in the 18-45-year age group but are unrelated to progression and advanced histological grade. LOH for chromosome 10 and gene amplification, however, occurring in 82 and 40%, respectively, of glioblastoma multiforme, whether seen alone or along with TP53 gene alterations, are related to advanced histological grade of the tumor. In childhood gliomas, in contrast, TP53 gene alterations, LOH for 17p and 10q, and gene amplification are uncommon in tumors of all grades, suggesting that presently unknown mechanisms are responsible for the genesis and progression of these tumors.

Authors
Rasheed, BK; McLendon, RE; Herndon, JE; Friedman, HS; Friedman, AH; Bigner, DD; Bigner, SH
MLA Citation
Rasheed, BK, McLendon, RE, Herndon, JE, Friedman, HS, Friedman, AH, Bigner, DD, and Bigner, SH. "Alterations of the TP53 gene in human gliomas." Cancer Res 54.5 (March 1, 1994): 1324-1330.
PMID
8118823
Source
pubmed
Published In
Cancer Research
Volume
54
Issue
5
Publish Date
1994
Start Page
1324
End Page
1330

Altered expression of ganglioside phenotypes of human gliomas in vivo and in vitro.

A library of epitope-defined antiganglioside monoclonal antibodies has been used to analyze the ganglioside phenotype of human glioma cell lines, rodent xenografts derived from them, and a separate panel of human glioma biopsies by multiple quantitative and qualitative assays. We have shown that the ganglioside phenotypes of cultured cell lines differ from the ganglioside phenotypes in the xenografts grown from the parent lines. The lacto series gangliosides 3'-isoLM1 and 3',6'-isoLD1 are expressed in the majority of primary human central nervous system neoplasms and xenografts derived from glioma cell lines, whereas glioma cell lines themselves express 3'-isoLM1 and 3',6'-isoLD1 in only 2/15 and 0/15 cases, respectively. Examination of the ganglioside profiles of serially passaged xenografts established from the glioma cell line D-54 MG, which does not express the lacto series, revealed the appearance of these gangliosides within one to two passages in vivo. The presence of these defined gangliosides in the majority of human gliomas and their absence in normal brain supports their application in compartmental therapy of primary central nervous system tumors.

Authors
Wikstrand, CJ; Fredman, P; McLendon, RR; Svennerholm, L; Bigner, DD
MLA Citation
Wikstrand, CJ, Fredman, P, McLendon, RR, Svennerholm, L, and Bigner, DD. "Altered expression of ganglioside phenotypes of human gliomas in vivo and in vitro." Mol Chem Neuropathol 21.2-3 (February 1994): 129-138.
PMID
7522005
Source
pubmed
Published In
Molecular and chemical neuropathology / sponsored by the International Society for Neurochemistry and the World Federation of Neurology and research groups on neurochemistry and cerebrospinal fluid
Volume
21
Issue
2-3
Publish Date
1994
Start Page
129
End Page
138
DOI
10.1007/BF02815347

COMPOSITE NEUROBLASTOMA MALIGNANT GLIOMA

Authors
MCLENDON, RE; BRADLEY, A; PARISI, JE; SCHEITHAUER, BW; FELSBERG, G; FRIEDMAN, HS
MLA Citation
MCLENDON, RE, BRADLEY, A, PARISI, JE, SCHEITHAUER, BW, FELSBERG, G, and FRIEDMAN, HS. "COMPOSITE NEUROBLASTOMA MALIGNANT GLIOMA." LABORATORY INVESTIGATION 70.1 (January 1994): A139-A139.
Source
wos-lite
Published In
Laboratory Investigation
Volume
70
Issue
1
Publish Date
1994
Start Page
A139
End Page
A139

Arteriovenous malformation mimicking recurrent medulloblastoma.

Magnetic resonance imaging (MRI) is becoming the method of choice for evaluation of central nervous system tumors. However, the sensitivity of this modality raises concern that new lesions in patients previously diagnosed with a brain tumor may not necessarily represent recurrent disease. We report a patient previously treated with surgery, radiotherapy, and chemotherapy for a medulloblastoma who developed a new lesion in the floor of the fourth ventricle. Histologic review following excision revealed an arteriovenous malformation.

Authors
Moghrabi, A; Friedman, HS; McLendon, R; Hockenberger, B; Tien, RD; Halperin, EC; Oakes, WJ
MLA Citation
Moghrabi, A, Friedman, HS, McLendon, R, Hockenberger, B, Tien, RD, Halperin, EC, and Oakes, WJ. "Arteriovenous malformation mimicking recurrent medulloblastoma." Med Pediatr Oncol 22.2 (1994): 140-143.
PMID
8259101
Source
pubmed
Published In
Pediatric Blood and Cancer
Volume
22
Issue
2
Publish Date
1994
Start Page
140
End Page
143

Intraarterial therapy of human glioma xenografts in athymic rats using 4-hydroperoxycyclophosphamide.

The addition of chemotherapy, notably using nitrosoureas, in the treatment of patients with glioblastoma multiforme has resulted in only modest improvements in long-term patient survival over the use of surgical intervention and irradiation alone. Intraarterial (i.a.) chemotherapy offers the potential benefit of increasing tumor drug delivery because of first-pass drug uptake, while minimizing systemic drug levels and toxicity. We have now investigated the i.a. therapy of intracerebral human glioma xenografts in athymic rats with 4-hydroperoxycyclophosphamide (4-HC), a preactivated derivative of cyclophosphamide. Athymic male rats were given intracerebral injections of the human glioma line D-54 MG. On Day 5 after injection, the rats were randomized (n = 8-10) by body weight (mean weight, approximately 300 g). In one set of experiments, each group received either i.v. saline, i.a. saline, 6 mg i.a. 4-HC, 6 mg i.v. 4-HC (6 mg), or 12 mg i.v. 4-HC. Intraarterial 4-HC produced significant increases in median survival (Day 24) compared with i.a. saline controls (140% increase), equivalent doses given i.v. (71% increase), and twice the equivalent dose given i.v. (50% increase) (by Wilcoxon rank sum analysis, P < 0.05 is statistically significant). The i.a. maximum tolerated dose was subsequently determined to be approximately 12.5 mg in non-tumor-bearing rats. Further experiments demonstrated a dose-response increase in survival for i.a. dosages of 6, 9, and 12.5 mg with significant improvement when compared with saline controls and 12.5 mg i.v. Pharmacokinetic experiments also demonstrated a significant first-pass uptake advantage for i.a. (versus i.v.) administered 4-HC. The short plasma half-life and marked antiglioma activity of 4-HC, without the need for hepatic activation, suggest a therapeutic application of this drug in the i.a. treatment of brain tumors.

Authors
Schuster, JM; Friedman, HS; Archer, GE; Fuchs, HE; McLendon, RE; Colvin, OM; Bigner, DD
MLA Citation
Schuster, JM, Friedman, HS, Archer, GE, Fuchs, HE, McLendon, RE, Colvin, OM, and Bigner, DD. "Intraarterial therapy of human glioma xenografts in athymic rats using 4-hydroperoxycyclophosphamide." Cancer Res 53.10 Suppl (May 15, 1993): 2338-2343.
PMID
8485721
Source
pubmed
Published In
Cancer Research
Volume
53
Issue
10 Suppl
Publish Date
1993
Start Page
2338
End Page
2343

MRI of gangliocytoma of cerebellum and spinal cord.

Gangliocytomas are rare CNS tumors that occur in children and young adults. We present a case of a cerebellar gangliocytoma with invasion of the cervical spinal cord demonstrated on MR. Radiographic differentiation of gangliocytomas from other ganglion cell tumors--ganglioglioma, dysplastic gangliocytoma of Lhermitte-Duclos, and desmoplastic infantile ganglioglioma--is discussed.

Authors
Furie, DM; Felsberg, GJ; Tien, RD; Friedman, HS; Fuchs, H; McLendon, R
MLA Citation
Furie, DM, Felsberg, GJ, Tien, RD, Friedman, HS, Fuchs, H, and McLendon, R. "MRI of gangliocytoma of cerebellum and spinal cord." J Comput Assist Tomogr 17.3 (May 1993): 488-491.
PMID
8491919
Source
pubmed
Published In
Journal of Computer Assisted Tomography
Volume
17
Issue
3
Publish Date
1993
Start Page
488
End Page
491

NEUROPATHOLOGY OF MULTIPLE VERSUS SINGLE-DOSE INTRATHECAL MELPHALAN IN RATS

Authors
ARCHER, GE; SCHUSTER, JM; FUCHS, HE; GUASPARI, A; BIGNER, DD; FRIEDMAN, HS; MCLENDON, RE
MLA Citation
ARCHER, GE, SCHUSTER, JM, FUCHS, HE, GUASPARI, A, BIGNER, DD, FRIEDMAN, HS, and MCLENDON, RE. "NEUROPATHOLOGY OF MULTIPLE VERSUS SINGLE-DOSE INTRATHECAL MELPHALAN IN RATS." May 1993.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
52
Issue
3
Publish Date
1993
Start Page
298
End Page
298

EXPRESSION OF C-MYC IN MEDULLOBLASTOMA XENOGRAFTS

Authors
MCLENDON, RE; BATRA, SK; FRIEDMAN, HS; RASHEED, BKA; BIGNER, DD; BIGNER, SH
MLA Citation
MCLENDON, RE, BATRA, SK, FRIEDMAN, HS, RASHEED, BKA, BIGNER, DD, and BIGNER, SH. "EXPRESSION OF C-MYC IN MEDULLOBLASTOMA XENOGRAFTS." JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 52.3 (May 1993): 267-267.
Source
wos-lite
Published In
Journal of Neuropathology and Experimental Neurology
Volume
52
Issue
3
Publish Date
1993
Start Page
267
End Page
267

Lactotetraose series ganglioside 3',6'-isoLD1 in tumors of central nervous and other systems in vitro and in vivo.

Two monoclonal antibodies, DMAb-21 and DMAb-22, directed against the lactotetraose series ganglioside-associated epitope IV3NeuAc,III6-NeuAcLcOse4Cer (3',6'-isoLD1), were found to define the minimum binding epitope NeuAc(or NeuGc)alpha 2-3Gal beta 1-3(NeuAc or NeuGc)alpha 2-6GlcNAc. The distribution of 3',6'-isoLD1 in cultured cell lines and derived xenografts of primary tumors of the human central nervous system and of embryonal or neuroectodermal tumor derivation was determined. Only 4 of 26 cell lines, 3 teratomas and 1 pancreatic adenocarcinoma, expressed detectable 3',6'-isoLD1 when cultured in vitro; none of 14 tested glioma lines, including 2 that expressed the monosialo-precursor IV3NeuAcLcOse4Cer in vitro, expressed