[Brainlife] Newsletter, Vol.4 No.13

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BRAINLIFE NEWSLETTER

Volume 4, Number 13 - 14 March 2005	Volume 4 Archive

1: AJNR Am J Neuroradiol. 2005 Mar;26(3):650-3.

Neuro-behcet disease mimicking brain tumor.

Matsuo K, Yamada K, Nakajima K, Nakagawa M.

Department of Neurology, Saiseikai Shiga Hospital, Ritto, Shiga, Japan.

Neuro-Behcet disease is one of the clinical forms of Behcet disease. We report a case of neuro-Behcet disease mimicked a brain tumor. This case was initially considered as a brain tumor from mass lesion with edema at left basal ganglia on radiologic images. The lesion, however, was not neoplasia by pathologic diagnosis. By using steroid therapy, the size had been markedly shrunken on the follow-up images. The clinical symptoms were also improved.

PMID: 15760881 [PubMed - in process]

2: Cancer Res. 2005 Mar 1;65(5):1934-40.: The excitatory amino acid transporter-2 induces apoptosis and decreases glioma growth in vitro and in vivo.

de Groot JF, Liu TJ, Fuller G, Yung WK.

The Brain Tumor Center, Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. jdegroot@mdanderson.org

Accumulating evidence suggests that glutamate plays a key role in the proliferation and invasion of glioblastoma tumors. Astrocytic tumors have been shown to release glutamate at high levels, which may stimulate tumor cell proliferation and motility via activation of glutamate receptors. Excess glutamate has also been found to facilitate tumor invasion by causing excitotoxic damage to normal brain thereby paving a pathway for tumor migration. Results from tissue microarray analyses showed decreased excitatory amino acid transporter-2 (EAAT-2) expression in high-grade glial tumors compared with low-grade astrocytomas and normal brain. EAAT-2 expression was inversely correlated with tumor grade, implicating its potential role in glial tumor progression, which was reflected by an undetectable level of EAAT-2 protein in glioma cell lines. In this study, we sought to investigate the effect of reconstituted EAAT-2 on glioma cell growth in vitro and in vivo by adenoviral-mediated gene transfer. Infection of glioma cells with Ad-EAAT-2 resulted in a physiologic level of functional EAAT-2, and a subsequent dose-dependent reduction in cell proliferation in all glioma cell lines tested compared with controls. Interestingly, results from analyses of Annexin V staining, detection of poly(ADP-ribose)polymerase cleavage and caspase-3 activation all indicated that Ad-EAAT-2 infection elicited apoptosis in glioma cells. Ex vivo experiments in nude mice showed a total suppression of tumor growth at sites that received Ad-EAAT-2-infected cells. Collectively, our results uncovered a new function of EAAT-2 in controlling glioma proliferation. Further studies will improve our knowledge of the role of glutamate in glioma growth and may provide useful prognostic information and alternative therapeutic targets for the treatment of glioma.

PMID: 15753393 [PubMed - in process]

3: Cancer Res. 2005 Mar 1;65(5):1678-86.: Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma.

Nigro JM, Misra A, Zhang L, Smirnov I, Colman H, Griffin C, Ozburn N, Chen M, Pan E, Koul D, Yung WK, Feuerstein BG, Aldape KD.

Department of Neurological Surgery (Brain Tumor Research Center), University of California, School of Medicine, San Francisco, California, USA.

Glioblastoma, the most aggressive primary brain tumor in humans, exhibits a large degree of molecular heterogeneity. Understanding the molecular pathology of a tumor and its linkage to behavior is an important foundation for developing and evaluating approaches to clinical management. Here we integrate array-comparative genomic hybridization and array-based gene expression profiles to identify relationships between DNA copy number aberrations, gene expression alterations, and survival in 34 patients with glioblastoma. Unsupervised clustering on either profile resulted in similar groups of patients, and groups defined by either method were associated with survival. The high concordance between these separate molecular classifications suggested a strong association between alterations on the DNA and RNA levels. We therefore investigated relationships between DNA copy number and gene expression changes. Loss of chromosome 10, a predominant genetic change, was associated not only with changes in the expression of genes located on chromosome 10 but also with genome-wide differences in gene expression. We found that CHI3L1/YKL-40 was significantly associated with both chromosome 10 copy number loss and poorer survival. Immortalized human astrocytes stably transfected with CHI3L1/YKL-40 exhibited changes in gene expression similar to patterns observed in human tumors and conferred radioresistance and increased invasion in vitro. Taken together, the results indicate that integrating DNA and mRNA-based tumor profiles offers the potential for a clinically relevant classification more robust than either method alone and provides a basis for identifying genes important in glioma pathogenesis.

PMID: 15753362 [PubMed - in process]

4: Childs Nerv Syst. 2005 Mar 10; [Epub ahead of print]: Monstrous craniopharyngioma.

Zuccaro GN.

, Cavia 3063, 1425, Buenos Aires, Argentina, gnzuccaro@fibertel.com.ar.

PMID: 15761694 [PubMed - as supplied by publisher]

5: Childs Nerv Syst. 2005 Mar 10; [Epub ahead of print]: Monstrous craniopharyngioma Case presentations and term proposal.

Trejos H, Caceres A, Segura JL.

National Children's Hospital, P.O. Box 225-6151, Santa Ana 2000, Costa Rica, htrejos@hospitalcima.com.

INTRODUCTION: Craniopharyngiomas (CF) are benign tumors, which can be cured by total resection; however, this is not always possible to achieve, thus leading to tumor recurrence. When these tumors achieve disproportionate growth, the treatment is even more difficult, fortunately grotesque CF are not frequent, making experience and data collection more arduous to obtain. CASE REPORTS: Four patients are presented here to illustrate the need for the use of a new term, "monstrous craniopharyngioma," which is proposed with the aim of making the evaluation of the different kinds of treatment available more accurate. CONCLUSIONS: Craniopharyngiomas that have grown into more than one cranial fossa with mixed solid and cystic components pose a special challenge for resection, and therefore a systematic classification and approach are required in order to obtain the best surgical results.

PMID: 15759158 [PubMed - as supplied by publisher]

6: Clin Cancer Res. 2004 Aug 1;10(15):5072-5.

Pharmacokinetics of O(6)-benzylguanine in pediatric patients with central nervous system tumors: a pediatric oncology group study.

Neville K, Blaney S, Bernstein M, Thompson P, Adams D, Aleksic A, Berg S.

Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

PURPOSE: To report the results of the first pharmacokinetic study in pediatric patients of O(6)-benzylguanine (O(6)BG), which irreversibly inactivates the DNA repair protein alkylguanine-alkyltransferase, thus enhancing the cytotoxicity of nitrosoureas. EXPERIMENTAL DESIGN: As part of a Pediatric Oncology Group Phase I study, 120 mg/m(2) of O(6)BG was administered i.v. over 1 h, before 1,3-bis(2-chloroethyl)-1-nitrosourea administration in children with recurrent or refractory brain tumors. Serial blood samples for plasma pharmacokinetic studies were obtained. Concentrations of O(6)BG and its active metabolite O(6)-benzyl-8-oxoguanine (8-oxo-O(6)BG) were measured by high-performance liquid chromatography. A pharmacokinetic model and additional first-order elimination rate constants for each compound were developed. RESULTS: O(6)BG concentration versus time data were evaluated for 25 patients. The peak concentration of O(6)BG (mean +/- SD) was 11 +/- 4 microm, and the peak concentration of its active metabolite, 8-oxo-O(6)BG, was 35 +/- 10 microm. O(6)BG was rapidly eliminated with a half-life of 85 +/- 140 min, area under the curve of 795 +/- 320 microm. min and clearance of 760 +/- 400 ml/min/m(2). The area under the curve of 8-oxo-O(6)BG when extrapolated to infinity was 22,700 +/- 11,800 microm. min. The clearance and terminal half-life of 8-oxo-O(6)BG were 30 +/- 15 ml/min/m(2) and 360 +/- 220 min, respectively. CONCLUSIONS: There is rapid elimination of O(6)BG after i.v. administration over 1 h. In contrast, the terminal half-life for the active metabolite, 8-oxo-O(6)BG, is 4-fold longer. The pharmacokinetic parameters for O(6)BG and 8-oxo-O(6)BG are similar to those reported previously in adults.

Publication Types:

Clinical Trial

PMID: 15297409 [PubMed - indexed for MEDLINE]

7: Int J Cancer. 2005 Mar 8; [Epub ahead of print]: Reply to: Occupational risk factors for low grade and high grade glioma by B. Hocking.

Schlehofer B, Hettinger I, Blettner M, Preston-Martin S, Arslan A, Ahlbom A, Choi WN, Giles GG, Howe GR, Little J, Menegoz F, Rodvall Y, Ryan P, Wahrendorf J.

Unit of Environmental Epidemiology, German Cancer Research Centre, Heidelberg, Germany.

No abstract.

PMID: 15756688 [PubMed - as supplied by publisher]

8: Int J Cancer. 2005 Mar 8; [Epub ahead of print]: Bystander signaling between glioma cells and fibroblasts targeted with counted particles.

Shao C, Folkard M, Michael BD, Prise KM.

Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom.

Radiation-induced bystander effects may play an important role in cancer risks associated with environmental, occupational and medical exposures and they may also present a therapeutic opportunity to modulate the efficacy of radiotherapy. However, the mechanisms underpinning these responses between tumor and normal cells are poorly understood. Using a microbeam, we investigated interactions between T98G malignant glioma cells and AG01522 normal fibroblasts by targeting cells through their nuclei in one population, then detecting cellular responses in the other co-cultured non-irradiated population. It was found that when a fraction of cells was individually irradiated with exactly 1 or 5 helium particles ((3)He(2+)), the yield of micronuclei (MN) in the non-irradiated population was significantly increased. This increase was not related to the fraction of cells targeted or the number of particles delivered to those cells. Even when one cell was targeted with a single (3)He(2+), the induction of MN in the bystander non-irradiated population could be increased by 79% for AG01522 and 28% for T98G. Furthermore, studies showed that nitric oxide (NO) and reactive oxygen species (ROS) were involved in these bystander responses. Following nuclear irradiation in only 1% of cells, the NO level in the T98G population was increased by 31% and the ROS level in the AG0 population was increased by 18%. Treatment of cultures with 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (c-PTIO), an NO scavenger, abolished the bystander MN induction in non-irradiated AG01522 cells but only partially in non-irradiated T98G cells, and this could be eliminated by treatment with either DMSO or antioxidants. Our findings indicate that differential mechanisms involving NO and ROS signaling factors play a role in bystander responses generated from targeted T98G glioma and AG0 fibroblasts, respectively. These bystander interactions suggest that a mechanistic control of the bystander effect could be of benefit to radiotherapy. (c) 2005 Wiley-Liss, Inc.

PMID: 15756683 [PubMed - as supplied by publisher]

9: Int J Cancer. 2005 Mar 8; [Epub ahead of print]: Occupational risk factors for low grade and high grade glioma.

Hocking B.

Camberwell, Victoria, Australia.

No abstract.

PMID: 15756682 [PubMed - as supplied by publisher]

10: Int J Cancer. 2005 Mar 1;113(6):866-9.: Parathyroid adenoma and primary CNS tumors.

Backlund LM, Grander D, Brandt L, Hall P, Ekbom A.

Department of Oncology-Pathology, Karolinska University Hospital, Stockholm, Sweden. magnus.backlund@onkpat.ki.se

Hyperparathyroidism onset at a young age is one feature in multiple endocrine neoplasia (MEN) type 1 and MEN type 2A cancer syndromes. There are several case reports of MEN Type 1-associated central nervous system (CNS) tumors. To determine if there is an association between parathyroid adenomas and CNS tumors, we used Swedish registry data to identify all individuals operated on for parathyroid adenomas between 1958-99 (n = 12,468). Follow-up for the occurrence of CNS tumors in these individuals was through linkage with the Swedish Cancer Registry. There were 70 observed cases of a CNS tumor diagnosed after a parathyroid adenoma, to be compared to 35 expected (standard incidence ratio [SIR] = 2.0; 95% confidence interval [CI] = 1.5-2.5). This increased risk was independent of duration of follow-up and was confined to meningiomas (SIR = 2.4, 95% CI = 1.7-3.4) and neurinomas (SIR = 3.4, 95% CI = 1.5-6.8). These results strongly indicate an association between these tumor forms that may be genetic, environmental (such as radiation) or a combination of both. (c) 2004 Wiley-Liss, Inc.

PMID: 15515018 [PubMed - indexed for MEDLINE]

11: Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):387-91.: Postoperative radiation therapy for grade II and III intracranial ependymoma.

Mansur DB, Perry A, Rajaram V, Michalski JM, Park TS, Leonard JR, Luchtman-Jones L, Rich KM, Grigsby PW, Lockett MA, Wahab SH, Simpson JR.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA. mansur@radonc.wustl.edu

PURPOSE: To retrospectively determine the long-term outcome of intracranial ependymoma patients treated with surgery and postoperative radiation therapy. METHODS AND MATERIALS: Sixty patients were treated at our institution between 1964 and 2000. Forty patients had World Health Organization Grade II ependymoma, and 20 patients had Grade III ependymoma. The median patient age was 10.7 years. The majority of patients were male (55%), had infratentorial tumors (80%), and had subtotal resections (72%). Postoperative radiation therapy was delivered to all patients to a median total dose of 50.4 Gy. Craniospinal radiation therapy was used in the earlier era in only 12 patients (20%). RESULTS: The median follow-up of surviving patients was 12.5 years. The 5-year and 10-year disease-free survival rates for all patients were 58.4% and 49.5%, respectively. The 5-year and 10-year overall survival rates for all patients were 71.2% and 55.0%, respectively. Supratentorial tumor location was independently associated with a worse disease-free survival. Subtotal resection and supratentorial location predicted a worse overall survival, but this failed to reach statistical significance. No statistically significant effect on prognosis was observed with tumor grade, patient age, or radiation dose or volume. CONCLUSION: Our long-term follow-up indicates that half of ependymoma patients will have disease recurrences, indicating the need for more effective treatments.

PMID: 15667957 [PubMed - indexed for MEDLINE]

12: Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):380-6.

Phase II trial of carmustine, cisplatin, and oral etoposide chemotherapy before radiotherapy for grade 3 astrocytoma (anaplastic astrocytoma): results of North Central Cancer Treatment Group trial 98-72-51.

Rao RD, Krishnan S, Fitch TR, Schomberg PJ, Dinapoli RP, Nordstrom K, Scheithauer B, O'Fallon JR, Maurer MJ, Buckner JC.

Division of Medical Oncology, Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905 USA.

PURPOSE: To evaluate the efficacy of preradiotherapy (RT) chemotherapy with carmustine, cisplatin, and oral etoposide combined with RT in the treatment of newly diagnosed anaplastic astrocytoma. METHODS AND MATERIALS: Therapy consisted of carmustine (40 mg/m(2)/d) on Days 1-3, oral etoposide (50 mg/d) on Days 1-21 and 29-49, and cisplatin (20 mg/m(2)/d i.v.) on Days 1-3 and 29-31. The regimen was repeated every 8 weeks for three cycles, with conventionally fractionated RT (5000 cGy with a 1000-cGy boost) delivered concurrently with the third cycle. RESULTS: A total of 29 patients were enrolled between December 1999 and March 2001. For varying reasons (e.g., progression, refusal, death, or toxicity), only 48% completed the chemotherapy regimen and 76% completed RT. Grade 3-4 toxicities were observed in 14 patients (48%). The primary study endpoint was the 23-month (700-day) survival, the median survival of patients with anaplastic astrocytoma in a previous North Central Cancer Treatment Group trial. To be considered an active treatment, a maximum of 9 patient deaths (of the first 25) were allowed before 700 days. However, 14 patients had died by 700 days after therapy. CONCLUSION: Our results have demonstrated that pre-RT chemotherapy with this regimen is insufficiently active in patients with anaplastic astrocytoma.

Publication Types:

Clinical Trial
Clinical Trial, Phase II

PMID: 15667956 [PubMed - indexed for MEDLINE]

13: J Clin Oncol. 2005 Jan 20;23(3):541-7.

Advanced-stage large-cell lymphoma in children and adolescents: results of a randomized trial incorporating intermediate-dose methotrexate and high-dose cytarabine in the maintenance phase of the APO regimen: a Pediatric Oncology Group phase III trial.

Laver JH, Kraveka JM, Hutchison RE, Chang M, Kepner J, Schwenn M, Tarbell N, Desai S, Weitzman S, Weinstein HJ, Murphy SB.

Department of Pediatrics, Medical College of Virginia, PO Box 980646, Richmond, VA 23298-0646, USA. jhlaver@hsc.vcu.edu

PURPOSE: The Pediatric Oncology Group adopted a histology-based approach to non-Hodgkin's lymphoma and treated patients with advanced large-cell lymphoma on a separate protocol (doxorubicin, vincristine, prednisone, 6-mercaptopurin, and methotrexate; APO regimen). In this study, we assessed the effects of an intense antimetabolite therapy alternating with APO on overall survival (OS) and event-free survival (EFS) and looked into biologic correlates. PATIENTS AND METHODS: From December 1994 to April 2000, we enrolled 180 eligible pediatric patients with stage III/IV large-cell lymphoma (LCL); 90 patients were randomly assigned to the intermediate-dose methotrexate (IDM) and high-dose cytarabine (HiDAC) arm, 85 patients to the APO arm, and five patients directly to the APO arm by study design due to CNS involvement. Planned therapy duration was 12 months. RESULTS: The 4-year EFS for all patients was 67.4% (SE, 4.2%), and OS was 80.1% (SE, 3.6%) without any significant difference between the two arms. The 4-year EFS and OS were 71.8% (SE, 6.1%) and 88.1% (SE, 4.4%), respectively, for patients with anaplastic large-cell lymphoma, and 63.8% (SE, 10.3%) and 70.3% (SE, 9.0%), respectively, for patients with diffuse large B-cell lymphoma. Only 11 patients required radiation (due to unresponsive bulky disease or CNS involvement). The IDM/HiDAC arm was associated with more toxicity. CONCLUSION: The efficacy of incorporating IDM/HiDAC in the treatment plan of pediatric and adolescent patients with advanced-stage LCL was inconclusive as to its effect on EFS, regardless of the lymphoma phenotype. It cannot be excluded that with a higher number of patients, one treatment could prove superior and future studies will build on these data.

Publication Types:

Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial

PMID: 15659500 [PubMed - indexed for MEDLINE]

14: J Neurochem. 2005 Mar;92(6):1340-9.: Hypoxia sensitizes human malignant glioma cells towards CD95L-induced cell death.

Steinbach JP, Wolburg H, Klumpp A, Weller M.

Laboratory of Molecular Neuro-Oncology, Department of Neurology, Hertie Institute for Clinical Brain Research, University of Tubingen, Tubingen, Germany.

Death ligands such as CD95 ligand (CD95L) have limited activity against glioma cells under normoxic conditions. Hypoxia is a critical aspect of the microenvironment of gliomas in vivo. We investigated the effect of co-exposure to acute hypoxia and CD95 ligand in three human malignant glioma cell lines with different susceptibility to CD95L under normoxic conditions. Hypoxia sensitized all three cell lines towards CD95L-induced cell death. Co-exposure resulted in apoptotic changes in the early phase, with gradual conversion to secondary necrosis with increasing length of hypoxia. The mitochondrial injury induced by hypoxia was enhanced by co-treatment, and caspase cleavage became prominent. Inhibition of the epidermal growth factor receptor (EGFR), although sensitizing glioma cells to CD95L under normoxia, protects glioma cells from hypoxia by reducing energy consumption. However, the opposing effects of EGFR signalling on death induced by CD95L or hypoxia were neutralized by co-exposure to hypoxia and CD95L. Furthermore, inhibition of protein synthesis by cycloheximide also reduced glucose consumption and conferred protection from hypoxia, but did not modulate CD95L-induced cell death under hypoxic conditions. These results suggest that death ligands may be useful to target hypoxic tumour cells resistant to conventional therapies or to complement strategies aiming at the induction of tumour hypoxia.

PMID: 15748153 [PubMed - in process]

15: J Nucl Med. 2005 Mar;46(3):450-4.: 18F-CPFPX PET Identifies Changes in Cerebral A1 Adenosine Receptor Density Caused by Glioma Invasion.

Bauer A, Langen KJ, Bidmon H, Holschbach MH, Weber S, Olsson RA, Coenen HH, Zilles K.

Institute of Medicine, Research Center Julich, Julich, Germany.

Adenosine plays a critical role in both tumor proliferation and the cerebral response to tumor invasion. We used 8-cyclopentyl-3-(3-(18)F-fluoropropyl)-1-propylxanthine ((18)F-CPFPX) PET to investigate A(1) adenosine receptor (A(1)AR) density as a potential indicator of the local cerebral response to glioma invasion. METHODS: A(1)AR density in F98 glioma-bearing rats was examined by (18)F-CPFPX and (3)H-CPFPX using PET, quantitative in vitro and ex vivo double-label receptor autoradiography, and immunohistochemical analyses. RESULTS: For all imaging modalities, A(1)AR signal intensity was increased in a zone surrounding experimental tumors (136%-146% that in control tissue) (P < 0.01). Immunostaining identified activated astrocytes as the main origin of peritumoral A(1)AR upregulation. The results of a pilot (18)F-CPFPX PET study on a patient with recurrent glioblastoma multiforme confirmed increases in A(1)AR density in the immediate vicinity of the tumor. CONCLUSION: (18)F-CPFPX PET is suitable for the detection of peritumoral changes in A(1)AR density. Molecular imaging with (18)F-CPFPX PET may open novel possibilities for gaining experimental and clinical insights into the cerebral response to tumor invasion.

PMID: 15750158 [PubMed - in process]

16: Neuroradiology. 2004 Nov;46(11):888-95. Epub 2004 Oct 29.: Central neurocytoma: a clinicopathological and neuroradiological study.

Zhang B, Luo B, Zhang Z, Sun G, Wen J.

Department of Radiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. zhangbo0616@sohu.com

Central neurocytoma (CNC) is an uncommon benign tumor of the central nervous system (CNS) occurring in adults and is more likely to be located in the region of the foramina of Monra. Few studies have described the neuroradiological features of CNC, and most are single case reports. Our aim was to analyze the clinicopathological and neuroradiological characteristics of CNC. We retrospectively studied the preoperative CT (n=2) and MRI (n=5) of three men and two women (mean age 45 years, ranging from 30 to 63 years) with pathologically proven CNC. The tumors were primarily located in the region of the foramina of Monra. Two of them occupied the lateral ventricle, appearing to be attached to the septum pellucidum, and the other three tumors arose from the septum pellucidum and extended into the lateral ventricles. The tumors were of mixed density with cystic features and patchy or fine calcification on noncontrast CT scans, and they were of low or isointense signal on T1- and heterogeneously hyperintense signal on T2- and FLAIR weighted images. Contrast enhancement varied greatly from very slight to intense. Immunohistochemical staining showed a positive reaction for synaptophysin (Syn), neuro-specific enclase (NSE), neurofilament protein (NF) in the tumor cells and glial fibrillary acid protein (GFAP) in the fibrillar zones. CNC should be taken into consideration first if a tumor arises from the region of the foramina of Monra with CNC neuroradiological characteristics and the patient is an adult.

PMID: 15517228 [PubMed - indexed for MEDLINE]

17: Oncogene. 2005 Mar 7; [Epub ahead of print]: Expression analysis of genes involved in brain tumor progression driven by retroviral insertional mutagenesis in mice.

Johansson FK, Goransson H, Westermark B.

1The Rudbeck Laboratory, Department of Genetics and Pathology, University Hospital, SE-751 85 Uppsala, Sweden.

Retroviral tagging previously identified putative cancer-causing genes in a mouse brain tumor model where a recombinant Moloney murine leukemia virus encoding the platelet-derived growth factor B-chain (MMLV/PDGFB) was intracerebrally injected in newborn mice. In the present study, expression analysis using cDNA arrays revealed several similarities of virus-induced mouse gliomas with human brain tumors. Brain tumors with short latency contained on average 8.0 retroviral insertions and resembled human glioblastoma multiforme (GBM) whereas long-latency gliomas were of lower grade, similar to human oligodendroglioma (OD) and had 2.3 insertions per tumor. Several known and novel genes of tumor progression or cell markers were differentially expressed between OD- and GBM-like tumors. Array and quantitative real-time PCR analysis demonstrated elevated expression similar to Pdgfralpha of retrovirally tagged genes Abhd2, Ddr1, Fos, Ng2, Ppfibp1, Rad51b and Sulf2 in both glioma types compared to neonatal and adult normal brain. The retrovirally tagged genes Plekhb1, Prex1, Prkg2, Sox10 and 1200004M23Rik were upregulated in the tumors but had a different expression profile than Pdgfralpha whereas Rap1gap, Gli1, Neurl and Camk2b were downregulated in the tumors. The present study accentuates the proposed role of the retrovirally tagged genes in PDGF-driven gliomagenesis and indicates that insertional mutagenesis can promote glioma progression.Oncogene advance online publication, 7 March 2005; doi:10.1038/sj.onc.1208553.

PMID: 15750623 [PubMed - as supplied by publisher]

18: Pediatr Hematol Oncol. 2004 Oct-Nov;21(7):647-60.: Epidemiology of central nervous system tumors in children and young adults (0-29 years), Yorkshire, United Kingdom.

Feltbower RG, Picton S, Bridges LR, Crooks DA, Glaser AW, McKinney PA.

Paediatric Epidemiology Group, Centre for Epidemiology and Biostatistics, University of Leeds, Leeds LS2 9LN, UK.

The authors describe the incidence and survival of 480 patients diagnosed under 30 years with a CNS tumor in Yorkshire, UK, between 1990 and 2001. The effect on survival from deprivation and other prognostic factors was examined. Young adults (aged 15-29) were significantly less likely to develop CNS tumors than children (p = .001), largely because of an excess of medulloblastoma and ependymoma in the pediatric age range. No significant temporal trends in incidence were present apart from young adults with "other CNS" tumors showing an average annual increase of 10.7% (95% CI 1.3-21.0%; p = .03). Young adults had significantly lower survival rates than children (hazard ratio = 1.52, 95% CI 1.10-2.10). The highest risk of death was observed for patients from the most affluent areas. The overall burden of CNS tumors appears to be relatively constant, but the significantly poorer survival for young people needs further rapid investigation.

PMID: 15626021 [PubMed - indexed for MEDLINE]

19: Pediatr Hematol Oncol. 2004 Oct-Nov;21(7):635-45.: A pilot trial of tandem autologous peripheral blood progenitor cell transplantation following high-dose thiotepa and carboplatin in children with poor-risk central nervous system tumors.

Ozkaynak MF, Sandoval C, Levendoglu-Tugal O, Jayabose S.

New York Medical College, Department of Pediatrics, Section of Hematology/Oncology and Blood and Marrow Transplantation, Valhalla, NY 10595, USA. mehmet_ozkaynak@nymc.edu

This is a pilot study performed to determine the maximum tolerated number of courses of high-dose thiotepa and carboplatin with autologous peripheral blood progenitor cell (PBPC) transplantation in poor-risk pediatric central nervous system (CNS) tumor patients. Twelve patients were enrolled and a total of 24 PBPC transplants were performed. The median age was 7.7 years. All patients had CNS tumors: 4 relapsed CNS PNET, 2 high-risk PNET in first remission, 2 relapsed/progressive brainstem tumor, 2 relapsed/progressive anaplastic astrocytoma, 1 relapsed GBM, and 1 recurrent ependymoma. The regimen consisted of thiotepa 250 mg/m2/day x 3 days and carboplatin 400 mg/m2/day x 3 days. No toxic deaths occurred. All patients were hospitalized for a median duration of 17 days. The median number of CD34 cells infused was 5.4 x 10(6)/kg (2.1-29.7 x 10(6)/kg) per course. Median time to ANC > 0.5 x 10(9)/L was 9 days, and platelets > 20 x 10(9)/L was 13.5 days. Four patients came off protocol after only one course of PBPC (2 had tumor progression, 2 parental choice); 4 patients underwent two, and 4 patients three courses of PBPC. Major nonhematologic complications were mucositis that necessitated infusion of narcotics (11/24 courses), fever of unknown origin (12/24), documented infection (9/24), and hemorrhagic cystitis (3/24). TPN was administered during 22 of 24 courses with a median duration of 15 days. It isfeasible to administer 2-3 courses of tandem high-dose thiotepa and carboplatin with PBPC transplant with prompt engraftment and manageable toxicities in pediatric CNS tumor patients.

PMID: 15626020 [PubMed - indexed for MEDLINE]

20: Surg Neurol. 2005 Feb;63(2):182-4; discussion 184.

Plexiform neurofibroma of the cauda equina: case report.

Joseffer SS, Babu RP, Kleinman G.

Department of Neurosurgery, New York University, NY 10016, USA. seth.joseffer@med.nyu.edu

BACKGROUND: Plexiform neurofibromas are rarely found in the cauda equina. The most recent report of a plexiform neurofibroma of the cauda equina noted only 2 previously described cases. CASE DESCRIPTION: To these we add the current case, as well as 2 additional previously published cases. We report the case of a 44-year-old man with a sudden exacerbation of his long-standing lower-back and bilateral leg pain. An intradural lesion was seen on magnetic resonance imaging and he underwent surgery. Intraoperatively, there were swollen nerve roots and tumor insinuating itself between the roots. A biopsy was performed, and pathology findings were consistent with plexiform neurofibroma. CONCLUSIONS: Plexiform neurofibroma of the cauda equina is a rare tumor, with variable manifestations. These tumors are not amenable to complete resection. Surgical treatment consists of either partial resection or biopsy, possibly with dural grafting for decompression.

Publication Types:

Case Reports

PMID: 15680670 [PubMed - indexed for MEDLINE]

21: Surg Neurol. 2005 Feb;63(2):178-81; discussion 181.

Dural cavernous angioma of the posterior sagittal sinus: case report.

Boockvar JA, Stiefel M, Malhotra N, Dolinskas C, Dwyer-Joyce C, LeRoux PD.

Weill Cornell Medical College, New York, NY 10021, USA. boockvaj@uphs.upenn.edu

BACKGROUND: Extraaxial cavernous hemangiomas (cavernomas) are very rare lesions, and less than 20 descriptions of these lesions outside the middle fossa have been reported. In this report, we describe a dural cavernous angioma involving the posterior sagittal sinus and discuss the clinical, radiological, operative, and histological features of this very uncommon lesion. CASE DESCRIPTION: A 31-year-old right-handed male presented with headache and decreasing visual acuity. Severe bilateral papilledema was found on fundoscopic examination. Neurological examination demonstrated a minor right temporal field cut. Brain magnetic resonance imaging with contrast demonstrated a 2.5 x 2.5 cm hyperintense enhancing mass in the midline, which was contiguous with the posterior margin of the falx cerebri. The patient underwent a bilateral occipital craniotomy centered on the lesion. The histological features were consistent with cavernous angioma. CONCLUSION: This report demonstrates that although extra axial cavernomas are quite rare, they must be included in the differential diagnosis of enhancing lesions along the posterior sagittal sinus. The operative removal of these lesions can be quite treacherous and usually requires a careful reapproximation of the patent sinus after lesion excision.

Publication Types:

Case Reports

PMID: 15680668 [PubMed - indexed for MEDLINE]

22: Surg Neurol. 2005 Feb;63(2):174-6; discussion 176-7.

Gamma knife radiosurgery for cavernous sinus plasmacytoma in a patient with breast cancer history.

Peker S, Abacioglu U, Bayrakli F, Kilic T, Pamir MN.

Department of Neurosurgery, Marmara University Neurological Sciences Institute, Istanbul, Turkey. peker@atlas.net.tr

BACKGROUND: Multiple myeloma (MM) presentation with cerebral mass lesion is unusual. Gamma knife radiosurgery for plasmacytoma has not been reported so far. CASE REPORT: We report a 70-year-old female with a medical history of infiltrative ductal carcinoma of the breast. She developed cavernous sinus syndrome (CSS) 5 months before admission to the hospital. The magnetic resonance imaging revealed an isointense solitary mass in the left cavernous sinus in noncontrast T1-weighted images. The lesion was highly enhancing with gadolinium-diethylenetriaminopentaacetic acid. She was operated by using Dolenc technique, and the tumor was partially resected. The pathological examination of the tumor tissue revealed a plasmacytoma. Systemic evaluation was positive for the diagnosis of MM. She underwent gamma knife radiosurgery for the residual cavernous sinus tumor. Chemotherapy with prednisolone and melphalan was given. Follow-up magnetic resonance images 6 months after the treatment demonstrated complete tumor disappearance. However, she died of sepsis 26 months after the diagnosis. CONCLUSION: This is an unusual MM case with a history of breast cancer, which had CSS and which demonstrated an excellent response to gamma knife radiosurgery.

Publication Types:

Case Reports

PMID: 15680666 [PubMed - indexed for MEDLINE]

23: Surg Neurol. 2005 Feb;63(2):170-3; discussion 173.

A brainstem cavernoma demonstrating a dramatic, spontaneous decrease in size during follow-up: case report and review of the literature.

Yasui T, Komiyama M, Iwai Y, Yamanaka K, Matsusaka Y, Morikawa T, Ishiguro T.

Department of Neurosurgery, Osaka City General Hospital, Osaka 534, Japan. yasui@msic.med.osaka-cu.ac.jp

BACKGROUND: Many reports have demonstrated a worse prognosis for patients whose cavernomas were subtotally removed than for those whose cavernomas were not surgically treated. Therefore, it is better not to touch the cavernoma if a surgeon is not prepared to totally remove it. This report describes a large brainstem cavernoma showing a spontaneous, dramatic reduction in size after removal of only the biopsy specimen of the lesion. CASE DESCRIPTION: A 42-year-old woman experienced facial numbness, diplopia, and ataxia. A magnetic resonance (MR) study revealed a pontine cavernoma with hemorrhage. Two weeks later, recurrence of the patient's symptoms and consciousness disturbance were noted. An MR study revealed massive hemorrhage from the cavernoma with a ventricle dilatation. An operation on the lesion was conducted 3 months after the initial hemorrhage. However, the operation was aborted when an exploration of the lesion showed a tight adhesion between the lesion and the pons. Removal of only a biopsy specimen and evacuation of the suckable hematoma were done. No neurologic recovery and no decrease in the size of the cavernoma were detected postoperatively. Her family did not wish for further treatments. She was in a bedridden state with severe brainstem dysfunction when she was transferred to a local hospital. Sixteen months after the surgery, her consciousness was clear, and MR imaging confirmed a marked reduction in the size of the cavernoma. CONCLUSION: A dramatic, spontaneous decrease in size does occur even in the case of a large brainstem cavernoma showing hemorrhages. Conservative therapy may be one of the treatment options for the symptomatic brainstem cavernoma.

Publication Types:

Case Reports
Review

PMID: 15680664 [PubMed - indexed for MEDLINE]

24: Surg Neurol. 2005 Feb;63(2):143-8.

The falcine trigeminocardiac reflex: case report and review of the literature.

Bauer DF, Youkilis A, Schenck C, Turner CR, Thompson BG.

University of Michigan Medical School, Ann Arbor, MI 48109, USA.

BACKGROUND: Trigeminocardiac reflex (TCR), the reproducible hypotension and bradycardia upon stimulation of the trigeminal nerve, has been reported during craniofacial surgery and during surgery within the cerebellopontine angle, petrosal sinus, orbit, and trigeminal ganglion. Whereas the falx cerebri is known to be innervated by the nervus tentorii, a recurrent branch of V1, there have been no reports to date of this response upon mechanical stimulation of the falx. CASE DESCRIPTION: We report a case of immediate, reproducible, and reflexive response of asystole upon stimulation of the falx cerebri during operative resection of a parafalcine meningioma in a 53-year-old woman. Upon recognition of the reproducible relationship between falcine stimulation and increased vagal tone, the patient was given glycopyrrolate in an effort to block cholinergic hyperactivity. After glycopyrrolate was given, no further dysrhythmias occurred. CONCLUSION: In this patient, mechanical stimulation of the falx likely resulted in the hyperactivity of the trigeminal ganglion, thereby triggering TCR. The dorsal region of the spinal trigeminal tract includes neurons from hypoglossal and vagus nerves, and projections have been seen between the vagus and trigeminal nuclei. The vagus provides parasympathetic innervation to the heart, vascular smooth muscle, and abdominal viscera. Vagal stimulation via these connections after trigeminal nerve activation likely accounts for the reflexive response of asystole seen in this patient. This is confirmed by the observation that the reflex was inhibited by the anticholinergic effects of glycopyrrolate. Awareness of TCR allows for early detection and appropriate treatment.

Publication Types:

Case Reports
Review

PMID: 15680656 [PubMed - indexed for MEDLINE]

25: Surg Neurol. 2005 Jan;63(1):52-5; discussion 55.: Intrathecal chemotherapy for patients with meningeal carcinomatosis.

Yoshida S, Morii K.

Department of Neurosurgery, Niigata Cancer Hospital, Kawagishi-chou 2-15-3, Niigata 951, Japan. bain@niigata-cc.niigata.niigata.jp

BACKGROUND: Meningeal carcinomatosis (MC) is increasing, and these patients have a poor prognosis. We analyzed the effects of intrathecal (IT) chemotherapy for these patients. METHODS: Patients received both methotrexate (MTX) (15 mg/m(2)) and prednisolone (10 mg/m(2)) 6 times in 2 weeks by Ommaya reservoir, along with cytosine arabinoside (10 mg/m(2)) for 4 doses of MTX. A cycle consisted of a 2-week period during which patients received these drugs and then 2 weeks off. Treatments were repeated 3 to 6 cycles depending on the clinical status. Cerebrospinal fluid (CSF) samples were also analyzed for cytology and a few markers. RESULTS: Of the 58 patients treated the most common tumor was lymphoma (30 patients), followed by lung and breast. Elevated soluble IL-2 receptor levels were observed in 23 of 30 patients with lymphomatous meningitis. Median survival of MC patients with malignant lymphoma, lung cancer, and breast cancer was 32.8 +/- 9.8, 13.0 +/- 4.1, and 18.4 +/- 7.4 months, respectively. Thus, the patients with lymphoma responded best, both by clearing the CSF and clinically. CONCLUSIONS: Our treatment regimen can improve the neurologic status of patients with MC. In particular, early IT chemotherapy can be effective for patients with lymphoma.

PMID: 15639526 [PubMed - indexed for MEDLINE]

26: Surg Neurol. 2005 Jan;63(1):42-6; discussion 46.: Visual outcome of blind eyes in pituitary apoplexy after transsphenoidal surgery: a series of 14 eyes.

Agrawal D, Mahapatra AK.

Department of Neurosurgery, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.

BACKGROUND: To study the visual outcome of patients who became blind after an episode of pituitary apoplexy and who subsequently underwent emergency transsphenoidal decompression of the optic apparatus, and to identify factors that may have a bearing on the visual outcome in such patients. METHODS: Twenty-three patients underwent transsphenoidal surgery for pituitary apoplexy over a 5-year period at the All India Institute of Medical Sciences. Among them, 8 (35%) presented with visual deterioration to monocular (n = 2) or binocular (n = 6) blindness after the apoplectic episode. There were 7 males and 1 female with the average age of patients being 43 years. The mean delay between the apoplexy and neurosurgical consultation was 10 days, with a range of 4 to 30 days. The adenoma was classified as "giant" in 4 and multicompartmental in 2 patients. After surgery, all patients had a minimum follow-up of 3 months. RESULTS: Four patients (50%) had improvement in vision to greater than 2/60 (Snellen's), including 2 patients whose vision improved to 6/6. All patients in whom there was improvement in vision had been operated on within a week of the apoplectic episode. CONCLUSIONS: This study shows that even completely blind eyes may have remarkable improvement in vision if surgical decompression of the optic apparatus is undertaken early. Awareness regarding pituitary apoplexy and reversibility of vision loss needs to be increased among the medical community, especially ophthalmologists and physicians, so that timely neurosurgical intervention can occur.

PMID: 15639521 [PubMed - indexed for MEDLINE]

27: Surg Neurol. 2005 Jan;63(1):3-4.

Research news and notes.

Roitberg B.

Department of Neurosurgery, University of Illinois at Chicago, IL 60612, USA. roitberg@uic.edu

Publication Types:

Review
Review, Tutorial

PMID: 15639508 [PubMed - indexed for MEDLINE]

28: Surg Neurol. 2005;63 Suppl 1:S13-21; discussion S21.: Central nervous system paracoccidioidomycosis: diagnosis and treatment.

Elias J Jr, dos Santos AC, Carlotti CG Jr, Colli BO, Canheu A, Matias C, Furlanetti L, Martinez R, Takayanagui OM, Sakamoto AC, Serafini LN, Chimelli L.

Division of Imaging, Department of Internal Medicine, Hospital das Clinicas, Ribeirao Preto Medical School, University of Sao Paulo, 14048-900 Ribeirao Preto, SP, Brazil.

BACKGROUND: Paracoccidioidomycosis (PCM) is a systemic mycosis caused by Paracoccidioides brasiliensis. The involvement of the central nervous system (CNS) in paracoccidioidomycosis is higher than previously thought and 2 clinical presentations have been reported, meningitis and pseudotumoral. METHODS: Twenty medical records of patients with CNS paracoccidioidomycosis treated from 1986 to 2003 were analyzed. The follow-up ranged from 1 to 18 years (mean = 8.9 +/- 4.2). RESULTS: Besides CNS paracoccidioidomycosis, all patients but one had the chronic systemic form and the pseudotumoral clinical presentation was the most frequent. Based on computed tomography scan findings, 4 image patterns were identified: low-density lesion with ring enhancement, lesion with calcification and ring enhancement, multiloculated low-density lesion with ring enhancement, and diffuse subarachnoid enhancement. The magnetic resonance imaging was performed in 3 patients and showed subarachnoid enhancement in 1 patient and heterogeneous lesion with ring enhancement in 2 patients. Eleven patients were submitted to medical treatment and 9 needed neurosurgical treatment; ventriculoperitoneal shunts in 4 patients, brain lesions resection in 3 patients, and partial resection of spinal cord lesions in 2 patients. Eleven patients had excellent outcome, 4 patients died, 3 are in good clinical condition with residual pulmonary dysfunction, and 1 patient was lost to follow-up. CONCLUSIONS: The diagnosis of paracoccidioidomycosis with involvement of the CNS is difficult and clinical suspicion is a key point to achieve the correct diagnosis. Patients with early diagnosis have a favorable outcome with clinical or surgical treatment.

PMID: 15629337 [PubMed - indexed for MEDLINE]

29: N Engl J Med. 2005 Mar 10;352(10):987-96.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group.

Multidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. roger.stupp@chuv.hospvd.ch

BACKGROUND: Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. METHODS: Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. RESULTS: A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. CONCLUSIONS: The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Copyright 2005 Massachusetts Medical Society.

PMID: 15758009 [PubMed - in process]

30: N Engl J Med. 2005 Mar 10;352(10):997-1003.: MGMT gene silencing and benefit from temozolomide in glioblastoma.

Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R.

Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, University Hospital Lausanne, Lausanne, Switzerland. monika.hegi@chuv.hospvd.ch

BACKGROUND: Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. METHODS: We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. RESULTS: The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. CONCLUSIONS: Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit. Copyright 2005 Massachusetts Medical Society.

PMID: 15758010 [PubMed - in process]