Volume 5
Archive

1: Cancer Res. 2006 Nov 17; [Epub ahead of print]

 
Marked Genomic Differences Characterize Primary and Secondary Glioblastoma Subtypes and Identify Two Distinct Molecular and Clinical Secondary Glioblastoma Entities.

Maher EA, Brennan C, Wen PY, Durso L, Ligon KL, Richardson A, Khatry D, Feng B, Sinha R, Louis DN, Quackenbush J, Black PM, Chin L, Depinho RA.

Center for Neuro-Oncology, Center for Applied Cancer Science, Belfer Institute for Innovative Cancer Science, Departments of Biostatistics and Computational Biology and Cancer Biology, Dana-Farber Cancer Institute; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; Departments of Pathology and Dermatology, Brigham and Women's Hospital and Harvard Medical School; Department of Biostatistics, Harvard School of Public Health; Department of Neurosurgery, Brigham and Women's Hospital; Department of Medicine and Genetics, Harvard Medical School, Boston, Massachusetts; Neurosurgery Service, Memorial Sloan-Kettering Cancer Center, Weill-Cornell Medical College, New York, New York; and Department of Pathology, Molecular Pathology Unit, CNY7, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.

Glioblastoma is classified into two subtypes on the basis of clinical history: "primary glioblastoma" arising de novo without detectable antecedent disease and "secondary glioblastoma" evolving from a low-grade astrocytoma. Despite their distinctive clinical courses, they arrive at an indistinguishable clinical and pathologic end point highlighted by widespread invasion and resistance to therapy and, as such, are managed clinically as if they are one disease entity. Because the life history of a cancer cell is often reflected in the pattern of genomic alterations, we sought to determine whether primary and secondary glioblastomas evolve through similar or different molecular pathogenetic routes. Clinically annotated primary and secondary glioblastoma samples were subjected to high-resolution copy number analysis using oligonucleotide-based array comparative genomic hybridization. Unsupervised classification using genomic nonnegative matrix factorization methods identified three distinct genomic subclasses. Whereas one corresponded to clinically defined primary glioblastomas, the remaining two stratified secondary glioblastoma into two genetically distinct cohorts. Thus, this global genomic analysis showed wide-scale differences between primary and secondary glioblastomas that were previously unappreciated, and has shown for the first time that secondary glioblastoma is heterogeneous in its molecular pathogenesis. Consistent with these findings, analysis of regional recurrent copy number alterations revealed many more events unique to these subclasses than shared. The pathobiological significance of these shared and subtype-specific copy number alterations is reinforced by their frequent occurrence, resident genes with clear links to cancer, recurrence in diverse cancer types, and apparent association with clinical outcome. We conclude that glioblastoma is composed of at least three distinct molecular subtypes, including novel subgroups of secondary glioblastoma, which may benefit from different therapeutic strategies. (Cancer Res 2006; 66(23): 11502-13).

PMID: 17114236 [PubMed - as supplied by publisher]

 

2: Childs Nerv Syst. 2006 Nov 22; [Epub ahead of print]

 
Outcome of children with posterior fossa medulloblastoma: a single institution experience over the decade 1994-2003.

Kombogiorgas D, Sgouros S, Walsh AR, Hockley AD, Stevens M, Grundy R, Peet A, English M, Spooner D.

Department of Neurosurgery, Birmingham Children's Hospital, Steelhouse Lane, Birmingham, B4 6NH, UK, s.sgouros@bham.ac.uk.

AIM: While the impact of radiotherapy in the management of medulloblastoma was recognised, the introduction of chemotherapy was investigated in clinical trials and shown to confer an additional advantage. We reviewed the outcome of a series of consecutive patients to assess the impact in a population-based clinical establishment. MATERIALS AND METHODS: A series of 38 children treated for medulloblastoma at Birmingham Children's Hospital between 1994 and 2003 was analysed. The effect of surgery, radiotherapy, chemotherapy and metastasis on survival was analysed. RESULTS: The overall 5-year survival rate was 61.4% for the 36 patients who had resective surgery, while 2 patients had biopsy only and died within a few months. There was no operative mortality. The incidence of hydrocephalus needing permanent shunting was higher in the first 3 years of life (p = 0.007, chi-square). The 5-year survival rate of patients with total and sub-total excision of medulloblastoma was 61.1% and 61.8%, respectively. The 5-year survival rate of patients older than 3 years was 73.4% and for patients under 3 years was 36.3% (p = 0.007, log rank). Metastases at presentation did not influence survival. All deaths occurred in the first 32 months. CONCLUSION: The contribution of chemotherapy in the improvement of the overall survival appears more evident in children younger than 3 years or presenting with metastases. The absence of significant difference in survival between patients with total or sub-total excision of medulloblastoma supports the view that total excision of medulloblastoma can be avoided when the risk for potential intra-operative damage and consequent neurological deficits is high.

PMID: 17119978 [PubMed - as supplied by publisher]

 

3: Clin Cancer Res. 2006 Nov 15;12(22):6765-71.

 
CXCR4 inhibition synergizes with cytotoxic chemotherapy in gliomas.

Redjal N, Chan JA, Segal RA, Kung AL.

Authors' Affiliations: Department of Pediatric Oncology, Dana-Farber Cancer Institute.

PURPOSE: The chemokine receptor CXCR4 is expressed in many different cancers. In malignant brain tumors, CXCR4 signaling has been implicated in tumor growth, survival, and migration, and pharmacologic inhibition of CXCR4 results in decreased tumor growth in preclinical models. To understand how CXCR4 inhibitors may be incorporated into clinical therapy, we examined determinants of responsiveness to CXCR4 inhibition. Because optimal use of CXCR4 inhibition will likely be a part of multimodality therapy, we also investigated the efficacy of CXCR4 inhibition combined with conventional cytotoxic chemotherapy. EXPERIMENTAL DESIGN: CXCR4 protein levels and responsiveness to the CXCR4 inhibitor AMD3100 were determined in a panel of glioblastoma multiforme cell lines. The effects of AMD3100, alone or in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), on cell growth were determined for several of these cell lines in vitro. We used an orthotopic model of glioblastoma multiforme to evaluate the antitumor efficacy of AMD3100 combined with BCNU in vivo. RESULTS: The level of CXCR4 protein expression in glioblastoma multiforme cells predicts the dose at which there is a response to AMD3100; cells that express higher levels of CXCR4 protein require higher doses for equivalent response. In all cell lines tested, treatment of glioblastoma multiforme cells with BCNU followed by AMD3100 results in synergistic antitumor efficacy in vitro. This synergy can also be seen in an orthotopic glioblastoma multiforme model. Treatment with subtherapeutic doses of BCNU in combination with AMD3100 results in tumor regression in vivo, and this reflects both increased apoptosis and decreased proliferation following combination therapy. CONCLUSION: These studies support testing CXCR4 inhibitors in patients with glioblastoma multiforme and establish that inhibition of CXCR4 synergizes with conventional cytotoxic therapies in a clinically relevant combinatorial strategy.

PMID: 17121897 [PubMed - in process]

 

4: Clin Cancer Res. 2006 Nov 15;12(22):6677-86.

 
Vascular targeted nanoparticles for imaging and treatment of brain tumors.

Reddy GR, Bhojani MS, McConville P, Moody J, Moffat BA, Hall DE, Kim G, Koo YE, Woolliscroft MJ, Sugai JV, Johnson TD, Philbert MA, Kopelman R, Rehemtulla A, Ross BD.

Authors' Affiliations: Molecular Therapeutics, Inc.

PURPOSE: Development of new therapeutic drug delivery systems is an area of significant research interest. The ability to directly target a therapeutic agent to a tumor site would minimize systemic drug exposure, thus providing the potential for increasing the therapeutic index. EXPERIMENTAL DESIGN: Photodynamic therapy (PDT) involves the uptake of a sensitizer by the cancer cells followed by photoirradiation to activate the sensitizer. PDT using Photofrin has certain disadvantages that include prolonged cutaneous photosensitization. Delivery of nanoparticles encapsulated with photodynamic agent specifically to a tumor site could potentially overcome the drawbacks of systemic therapy. In this study, we have developed a multifunctional polymeric nanoparticle consisting of a surface-localized tumor vasculature targeting F3 peptide and encapsulated PDT and imaging agents. RESULTS: The nanoparticles specifically bound to the surface of MDA-435 cells in vitro and were internalized conferring photosensitivity to the cells. Significant magnetic resonance imaging contrast enhancement was achieved in i.c. rat 9L gliomas following i.v. nanoparticle administration. Serial magnetic resonance imaging was used for determination of pharmacokinetics and distribution of nanoparticles within the tumor. Treatment of glioma-bearing rats with targeted nanoparticles followed by PDT showed a significant improvement in survival rate when compared with animals who received PDT after administration of nontargeted nanoparticles or systemic Photofrin. CONCLUSIONS: This study reveals the versatility and efficacy of the multifunctional nanoparticle for the targeted detection and treatment of cancer.

PMID: 17121886 [PubMed - in process]

 

5: J Clin Oncol. 2006 Nov 20;24(33):5283-90.

 
Changes in attentional performance of children and young adults with localized primary brain tumors after conformal radiation therapy.

Kiehna EN, Mulhern RK, Li C, Xiong X, Merchant TE.

Division of Radiation Oncology, Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.

PURPOSE: To prospectively assess the impact of conformal radiation therapy (CRT) and demographic and clinical variables on four measures of attention in pediatric and young adult patients with localized primary brain tumors. PATIENTS AND METHODS: We prospectively evaluated 120 patients with primary brain tumors, ages 2 to 24.4 years (median, 9.2 years). Evaluations were done using the computerized Conners' Continuous Performance Test (CCPT). We analyzed errors of omission (inattentiveness), errors of commission (impulsivity), reaction time, and an overall index of performance before CRT, weekly during CRT, and serially up to 60 months after the start of CRT. RESULTS: Before CRT, patients exhibited mild inattentiveness. During CRT, impulsivity decreased significantly (P = .002). After CRT, inattentiveness increased significantly (P = .03), and global attention disorders were associated with craniopharyngioma (P < .0001), supratentorial tumors (P = .008), optic pathway and diencephalic tumors (P = .012), and subtotal resection of the tumor (P = .010). CONCLUSION: Brain tumors and their treatment impair sustained attention and reaction time. A decline in impulsivity and relative stability of the other CCPT scores over the course of CRT demonstrated the absence of early radiation-related cognitive sequelae. Local tumor effects, initial surgical intervention, and focal irradiation of central structures contribute to long-lasting attentional problems in pediatric and young adult patients.

Publication Types:

• Research Support, N.I.H., Extramural
• Research Support, Non-U.S. Gov't

PMID: 17114662 [PubMed - in process]

 

6: J Neurooncol. 2006 Nov 22; [Epub ahead of print]

 
Fractionated stereotactic radiotherapy using gamma unit after hyperbaric oxygenation on recurrent high-grade gliomas.

Kohshi K, Yamamoto H, Nakahara A, Katoh T, Takagi M.

Division of Hyperbaric Medicine and Department of Neurosurgery, University Hospital of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, 807-8555, Kitakyushu, Japan, k-kohshi@clnc.uoeh-u.ac.jp.

BACKGROUND: To reduce this complication and to enhance the radiation effect to hypoxic cells of high-grade gliomas, the authors performed noninvasive fractionated stereotactic radiotherapy (FSRT) using a Gamma unit combined with hyperbaric oxygen (HBO) therapy for the treatment of recurrent disease. PATIENTS AND METHODS: Twenty-five consecutive patients who had previously received radiotherapy with chemotherapy for recurrent high-grade gliomas, including 14 patients with anaplastic astrocytoma (AA) and 11 with glioblastoma multiforme (GBM), underwent Gamma FSRT immediately after HBO therapy (2.5 atmospheres absolute for 60 min). The Gamma FSRT was repeatedly performed using a relocatable head cast. Median tumor volume was 8.7 cc (range, 1.7-159.3 cc), and the median total radiation dose was 22 Gy (range, 18-27 Gy) to the tumor margin in 8 fractions. RESULTS: Actuarial median survival time after FSRT was 19 months for patients with AA and 11 months for patients with GBM, which was significantly different (P = 0.012, log-rank test). Two patients underwent subsequent second FSRT for regional or remote recurrence. Seven patients (28%) underwent subsequent craniotomies and resections at a mean of 8.4 months after FSRT treatment, and 4 of them had radiation effects without viable cells and remained alive for 50-78 months. CONCLUSION: Gamma FSRT after HBO therapy appears to confer a survival benefit for patients with recurrent high-grade gliomas and warrants further investigation.

PMID: 17120158 [PubMed - as supplied by publisher]

 

7: J Neurooncol. 2006 Nov 17; [Epub ahead of print]

 
Expression of VEGFR3 in glioma endothelium correlates with tumor grade.

Grau SJ, Trillsch F, Herms J, Thon N, Nelson PJ, Tonn JC, Goldbrunner R.

Department of Neurosurgery, Klinikum Grosshadern, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81373 , Munich, Germany, stefan.grau@med.uni-muenchen.de.

Angiogenic processes are regulated by vascular endothelial growth factors (VEGFs) and their receptors VEGFR1 (Flt-1), 2 (Flk-1) and 3 (Flt-4). While VEGFR2 is thought to play a central role in tumor angiogenesis, anti-angiogenic therapies targeting VEGFR2 in glioma models can show escape phenomena with secondary onset of angiogenesis. The purpose of this study was to find explanations for these processes by searching for alternative pathways regulating glioma angiogenesis and reveal a correlation with tumor grade. Thus, VEGFR3, which is not expressed in normal brain, and its ligands VEGF-C and -D, were assessed in high grade (WHO degrees IV, glioblastomas, GBM) and low grade gliomas [WHO degrees II astrocytomas (AII)]. In all GBM, a strong protein expression of VEGFR3 was found on tumor endothelium, VEGF-C and -D expression was found on numerous cells in areas of high vascularization. On RNA level, a significant up-regulation of VEGFR3 was detected in GBM compared to AII and non-neoplastic brain. In AII, only very moderate VEGFR3, VEGF-C and -D expression was found on protein and RNA level indicating a correlation of VEGFR3 expression with tumor grade. VEGFR3 signal in both grades was found predominantly on endothelial cells, confirmed by VEGFR3 expression on isolated CD31 positive cells and the expression of various endothelial markers on VEGFR3-positive cells isolated from GBM. The demonstration of a complete angiogenic signaling system that is dependent on tumor grade may influence the traditional paradigm of glioma angiogenesis and may provide a basis for more effective anti-angiogenic treatment strategies.

PMID: 17115285 [PubMed - as supplied by publisher]

 

8: J Neurosurg. 2006 Nov;105(5):745-52.

Evaluation of particulate systems supporting tumor cell fractions in a preventive vaccination against intracranial rat glioma.

Sapin A, Clavreul A, Garcion E, Benoit JP, Menei P.

L'Institut National de la Sante et de la Recherche Medicale U 646, Angers, France.

OBJECT: Irradiated autologous tumor cells are commonly used as a source of antigens in antiglioma vaccinations to activate the immune system. As cell number is often a limiting factor in these cells' preparation, the aim of the present study was to find a means that can lower the amount of cells required. Among strategies currently developed, adjuvant particulate systems offer a promising means to improve the antitumor immune response. In this study, the authors were interested in evaluating the role of particulate systems containing biodegradable microspheres that carry tumor cell fractions on their surfaces in the induction of a protective immunity in the 9L/Fischer 344 rat glioma model. The efficiency of these particulate systems was compared to that of irradiated 9L cells. METHODS: Particulate systems composed of poly(D,L-lactide-co-glycolide) (PLGA) microspheres that support 9L cell fractions on their surfaces (cell lysates or plasma membranes) or irradiated 9L cells alone were injected subcutaneously into the flanks of syngeneic Fischer 344 rats. Eighteen days later, the rats were intracranially injected with nonirradiated 9L cells. A study of survival in these animals and an analysis of the resulting immune response were then conducted. For the same amount of protein (50 microg) injected, irradiated 9L cells provided long-term survival in 30% of animals, whereas 9L plasma membranes adsorbed onto PLGA microspheres provided long-term survival in 10% of animals and cell lysates adsorbed onto microspheres provided long-term survival in 0%. Accordingly, particulate systems induced a lower T helper cell Type 1 (Th1) peripheral immune response than irradiated 9L cells. However, greater secretion of Th1 cytokines was observed when particulate systems were used than when cell fractions separated from microspheres were used, indicating the adjuvant property of these particulate systems. CONCLUSIONS: Particulate systems have adjuvant properties but are still less efficient than irradiated whole tumor cells for vaccinations. Encapsulation of an activating molecule in the microsphere will be the next developmental step in the search for efficient antiglioma vaccinations.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 17121138 [PubMed - in process]

 

9: J Neurosurg. 2006 Nov;105(5):739-44.

Genetic profiling of a distant second glioblastoma multiforme after radiotherapy: Recurrence or second primary tumor?

van Nifterik KA, Elkhuizen PH, van Andel RJ, Stalpers LJ, Leenstra S, Lafleur MV, Vandertop WP, Slotman BJ, Hulsebos TJ, Sminia P.

Department of Radiation Oncology, Division of Radiobiology, Vrije Universiteit Medical Center, Faculty of Medicine, Amsterdam, The Netherlands. ka.vannifterik@vumc.nl

OBJECT: In nearly all patients with glioblastoma multiforme (GBM) a local recurrence develops within a short period of time. In this paper the authors describe two patients in whom a second GBM developed after a relatively long time interval at a site remote from the primary tumor. The genetic profiles of the tumors were compared to discriminate between distant recurrence and a second primary tumor. METHODS: Both patients harboring a supratentorial GBM were treated with surgery and local high-dose radiotherapy. Local control of the disease at the primary tumor site was achieved. Within 2 years, a second GBM developed in both patients, not only outside the previously irradiated target areas but infratentorially in one patient and in the opposite hemisphere in the other. The tumors were examined for the presence of several genetic alterations that are frequently found in GBMs--a loss of heterozygosity at chromosome regions 1p36, 10pl5, 19q13, and 22q13, and at the CDKN2A, PTEN, DMBT1, and TP53 gene regions; a TP53 mutation; and EGFR amplification. In the first patient, genetic profiling revealed that the primary tumor had an allelic imbalance for markers in several chromosome regions for which the second tumor displayed a complete loss. In the second patient, genetic profiling demonstrated the presence of genetic changes in the second tumor that were identical with and additional to those found in the primary tumor. CONCLUSIONS: Based on the similarities between the genetic profiles of the primary and the second tumors in these patients, the authors decided that in each case the second distant GBM was a distant recurrence rather than a second independent primary tumor.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 17121137 [PubMed - in process]

 

10: J Neurosurg. 2006 Nov;105(5):736-8.

Oncocytic meningiomas: Cases with benign histopathological features and a favorable clinical course.

Gallina P, Buccoliero AM, Mariotti F, Mennonna P, Di Lorenzo N.

Department of Neurosurgery, Careggi Hospital, Florence, Italy. pgallina@unifi.it

OBJECT: Oncocytic meningioma has recently been recognized as a distinct morphological variant of intracranial meningothelial neoplasms, and only a few cases have been reported in the literature. The first description of this lesion, which was based on data in six cases, revealed a potentially aggressive nature with a tendency to infiltrate the brain and to recur. However, the true behavior of, and the long-term follow-up data for, such lesions must still be outlined. METHODS: The authors report on five cases of intracranial oncocytic meningiomas. On neuroimaging, the lesions showed the characteristic features of common meningiomas. All patients underwent gross-total removal of the mass together with the adjacent dura mater. No additional treatments were administered. Histologically, the tumors were composed of sheets, nests, and cords of large polygonal neoplastic cells with finely granular cytoplasm. Necrosis was absent in all cases. Mitosis was also absent or exceedingly rare, and no brain cortex infiltration was observed. The follow up ranged from 6 to 54 months (mean 32.4 months). At the last follow-up evaluation, all patients were asymptomatic and magnetic resonance imaging examinations demonstrated no evidence of tumor recurrence. CONCLUSIONS: Data in the presented cases did not confirm a previously described propensity to aggressiveness in this meningioma subtype. In fact, the histological features as well as the long-term favorable clinical course may suggest benign behavior of such neoplasms, as in the common forms of meningiomas.

PMID: 17121136 [PubMed - in process]