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BRAINLIFE NEWSLETTER
Volume 4, Number 16 - 5 April 2005	Volume 4 Archive

Radiosurgery with or without whole-brain radiotherapy for brain metastases: the patients' perspective regarding complications.

Kondziolka D, Niranjan A, Flickinger JC, Lunsford LD.

Department of Neurological Surgery and Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. kondziolkads@upmc.edu

INTRODUCTION: When cancer spreads to the brain, patients and their families report a much reduced quality of life. Whole-brain radiation therapy (WBRT) and/or radiosurgery (RS) are mainstays of management for patients with metastatic brain cancer. Despite the ubiquity of this problem, little is known about the patients' perspective regarding management-related complications. To assess the patients' perspective regarding current therapeutic options, we retrospectively surveyed 200 consecutive patients who underwent radiosurgery with or without WBRT. METHODS AND MATERIALS: The survey consisted of 10 questions that sought information on quality of life, employment status, side effects (hair loss, fatigue, memory, concentration, mood, or employment), activity level, and satisfaction. RESULTS: We tabulated 104 responses (52%). WBRT was used in 69% (72 of 104); all patients had radiosurgery. After WBRT, the following were noted: hair loss (88%; total regrowth in 24%), excess fatigue (95%), problems with short-term memory (72%), long-term memory (33%), concentration (61%), and depression (54%). Sixty-three percent of patients who had WBRT thought they had side effects after treatment compared with 34% who had radiosurgery only (P <0.001). Only 5% of RS patients reported fatigue. Seventy-six percent and 56% of respondents considered RS or WBRT, respectively, a good treatment of them (P = 0.25). Only 26 patients (27%) were employed at the time of treatment and 16 remained employed (62%). Eighteen percent believed that WBRT delayed other cancer treatments. CONCLUSIONS: Patients with brain metastases often report complications of their disease or its treatment. Side effects are most pronounced in those who received WBRT. Radiosurgery had fewer reported side effects and was believed by more patients or families to be effective. Further study of clinical outcomes and quality of life is important to guide our management of patients with these common brain tumors.

PMID: 15803013 [PubMed - in process] 

Meningioma presenting with transient ischaemic attacks.

Oluigbo CO, Choudhari KA, Flynn P, McConnell RS.

Department of Neurosurgery, Royal Victoria Hospital, Belfast BT12 6BA, UK.

A case of sphenoid wing meningioma mimicking the presentation of a transient ischaemic attack (TIA) is described. Based on findings from neuroimaging in this case, possible explanations of the mechanism of this uncommon presentation of meningiomas are discussed and the literature is reviewed.

PMID: 15799201 [PubMed - in process] 

High dose radiation induced meningioma.

Shenoy SN, Munish KG, Raja A.

Department of Neurosurgery, Kasturba Medical College and Hospital, Manipal, India. shenoysn@yahoo.com

Radiation therapy has played an important integral part in the management of various intracranial rumours. However, radiation has been implicated in the development of intracranial tumours. We describe three cases of radiation-induced meningiomas following high dose cranial irradiation. All these patients developed tumours within the previous radiation field and satisfied the criteria used for the definition of radiation-induced neoplasm. The interval between the irradiation and the onset of meningioma was significantly less in the younger patient. All the cases had several unique features of radiation-induced meningioma including features of atypical meningioma. Two patients developed multiple site meningiomas and one patient developed early recurrence of the tumour. This report confirms that patients exposed to cranial irradiation are at lifelong risk of developing radiation-induced tumours such as meningiomas. Hence these patients require long-term clinical and radiological surveillance to detect occurrence as early as possible.

PMID: 15799195 [PubMed - in process] 

Early prediction of infection after craniotomy for brain tumours.

Shinoura N, Yamada R, Okamoto K, Nakamura O.

Department of Neurosurgery, Komagome Metropolitan Hospital, Bunkyo-ku, Tokyo, Japan. shinoura-k@cick.jp

Reliably predicting infection soon after craniotomies would prevent infection and reduce treatment costs and hospitalization expenses. Therefore we analysed potential risk factors and blood count data after craniotomies for brain tumours in order to predict infection as soon as possible after surgery. We analysed 139 patients who underwent craniotomies for brain tumours from January 1997 to December 2001, and divided them into four categories (Types A to D) according to the following: increase in their white blood counts (WBCs) from Day 0 to Day 1, maximum WBC between Day 0 and Day 2, and maximum c-reactive protein (CRP) between Day 0 and Day 4 after surgery. We evaluated potential risk factors and the blood count data for infections via logistic regression analysis. Type D patients had a significantly higher rate of infection (p = 0.0123) than the other Types, while Type B patients had the lowest rate among the four groups (p = 0.0006). When Type A patients suffered CSF leakages, they had a significantly higher possibility of meningitis (p < 0.0001) or scalp infection (p = 0.012). In those Type A or D patients who were male, more than 70 years old, and suffered from metastases from primary lung cancer lesions, the possibility of pneumonia was significantly higher (p = 0.0178). In conclusion, we are able to predict infection within four days after craniotomies for brain tumours according to standard blood count data and certain risk factors. This possibility allows for improved care and better clinical outcomes in patients that undergo craniotomies for brain tumours.

PMID: 15799191 [PubMed - in process] 

Multiple brain metastases from malignant melanoma with long-term survival.

Hamid NA, Chandra A, Meyer CH.

Queen Elizabeth Hospital, Birmingham, UK.

We present a case of multiple malignant melanoma metastases in the brain who is leading a normal life 16 years after the brain secondaries were managed by surgical resection, stereotactic radiation and chemotherapy. The primary lesion in the left upper arm was excised 4 years prior to the brain metastases. His most recent MRI shows him to be disease free. To the best of our knowledge, this is longest survival reported of any patient with multiple brain metastases from malignant melanoma.

PMID: 15799166 [PubMed - in process] 

Complex neurobehavioural syndrome due to bilateral thalamic glioma.

Kouyialis AT, Boviatsis EJ, Prezerakos GK, Korfias S, Sakas DE.

Department of Neurosurgery, Evangelismos General Hospital, University of Athens Medical School, Greece.

We present a 65-year-old female with bilateral thalamic astrocytoma. The unusual long survival of this patient allowed the manifestation of a complex neurobehavioural syndrome due to gradual involvement of several thalamic nuclei. An attempt is made to approach the complexity of symptoms according to the anatomical areas, nuclei and thalamic connections infiltrated.

PMID: 15799161 [PubMed - in process] 

Multicystic, heterogeneously enhancing meningioma in an octogenerian.

Mangano FT, Chalif DJ, Black KS.

Departments of Neurological Surgery and Radiology, North Shore University Hospital, Long Island, Jewish Medical Center Health System, Manhasset, New York, USA.

A multicystic meningioma in an octogenerian whose tissue diagnosis was ill-defined and misleading on preoperative neuroradiologic imaging is presented. Nauta has described four cyst types that can develop in cystic meningiomas. We report the first case in which three cyst types are demonstrated concurrently, describe the histopathology and surgical management. This case represents a rare variant of a common tumour in an unusual age group, and underscores the need for definitive biopsy and resection as indicated. Furthermore, the diagnosis of multicystic meningioma does not favour an aggressive histopathology in this case.

PMID: 15799156 [PubMed - in process] 

Dramatic response of malignant craniopharyngioma to cis-platin-based chemotherapy. Should craniopharyngioma be considered as a suprasellar 'germ cell' tumour?

Plowman PN, Besser GM, Shipley J, Summersgill B, Geddes J, Afshar F.

Department of Clinical Oncology, St Bartholomew's Hospital, London, UK.

The case is described of a 21-year-old woman, who developed a malignant tumour arising from a craniopharyngioma 14 years after the original diagnosis. The remarkable response of this malignant tumour ex-craniopharyngioma to cis-platin based chemotherapy, together with other midline tumour characteristics of craniopharyngioma, raise the question as to whether craniopharyngioma should any longer be separately considered from suprasellar germ cell tumour. This subject is discussed.

PMID: 15799153 [PubMed - in process] 

Hydroxyurea chemotherapy for meningiomas: enlarged cohort with extended follow-up.

Newton HB, Scott SR, Volpi C.

Division of Neuro-Oncology, Dardinger Neuro-Oncology Center, Department of Neurology, Ohio State University Medical Center, Columbus, Ohio 43210, USA. newton.12@osu.edu

Meningiomas account for 18-20% of all intracranial tumours and often recur despite surgical resection. Hydroxyurea is under evaluation as adjuvant therapy of meningiomas. In the authors' initial report of 17 patients with meningioma, hydroxyurea demonstrated modest efficacy, with a median time to progression (TTP) of 80 weeks. In the current study, 21 patients with meningioma have been placed on hydroxyurea (20 mg/kg/day orally), with extended follow-up of the original cohort. Eighteen of 20 evaluable patients (90%) responded with stable disease ranging from 20 to 328 + weeks (median TTP 176 weeks; 11 patients censored). Five of the stabilized patients progressed after 20, 56, 36, 216 and 56 weeks, respectively. Two patients had progressive disease after 10 weeks. Toxicity was mainly haematological. Hydroxyurea has modest activity against meningiomas and should be considered for patients who are poor surgical candidates, have unresectable or large residual meningiomas, or have progressed after surgical resection or irradiation, or both.

PMID: 15799152 [PubMed - in process]

 
The treatment of primary central nervous system lymphoma in 122 immunocompetent patients: a population-based study of successively treated cohorts from the British Colombia Cancer Agency.

Shenkier TN, Voss N, Chhanabhai M, Fairey R, Gascoyne RD, Hoskins P, Klasa R, Morris J, O'Reilly SE, Pickles T, Sehn L, Connors JM.

Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. tshenkier@bccancer.bc.ca

BACKGROUND: The objective of this study was to evaluate the clinical outcome of a population-based cohort of immunocompetent patients with primary central nervous system lymphoma (PCNSL) treated with 3 different strategies over 13 years. METHODS: One hundred twenty-two consecutive patients (median age, 66 years) with PCNSL were identified. Three treatment strategies were employed: 1) whole-brain irradiation with (from January, 1990, to June, 1991) or without (from April, 1995, to December, 1999) cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-type chemotherapy (n=50 patients); 2) combined-modality therapy, including 1 g/m2 methotrexate plus whole-brain irradiation (from July, 1991, to March, 1995; n=34 patients); and 3) 8 g/m2 methotrexate alone (from January, 2000, to March, 2003) with whole-brain irradiation reserved for those with progressive disease (n=38 patients). Treatment failure was defined as progressive disease, disease recurrence, death from toxicity or lymphoma, or toxicity that necessitated a change in primary treatment. RESULTS: The median failure-free survival was 7 months, and the median overall survival (OS) was 17 months. The median OS was similar in all 3 eras. In this population-based analysis, one-third of patients did not receive the treatment strategy of the era. Therefore, the data also were analyzed by treatment received. On multivariate analysis (including era of treatment), 3 factors-age > 60 years, lactate dehydrogenase > normal, and omission of methotrexate-were associated significantly with poorer OS (hazard ratio: 2.3, 2.2, and 2.3, respectively). CONCLUSIONS: Outcomes for a general population with PCNSL remained constant despite different treatment strategies over three eras. For the two-thirds of patients who could receive potentially curative treatment, age, lactate dehydrogenase level, and receipt of > or = 1 g/m2 methotrexate appeared to be important determinants of OS. 2005 American Cancer Society.

PMID: 15651059 [PubMed - indexed for MEDLINE] 

 
Successful treatment of low-grade oligodendroglial tumors with a chemotherapy regimen of procarbazine, lomustine, and vincristine.

Stege EM, Kros JM, de Bruin HG, Enting RH, van Heuvel I, Looijenga LH, van der Rijt CD, Smitt PA, van den Bent MJ.

Department of Neurology/Neuro-Oncology, Erasmus University Medical Center/Daniel Den Hoed Cancer Center, Rotterdam, The Netherlands.

BACKGROUND: Anaplastic oligodendroglioma (OD) tumors, especially those with the combined loss of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), are sensitive to chemotherapy. Only limited data are available on the role of chemotherapy in low-grade OD. The authors retrospectively studied the outcome of the procarbazine, lomustine, and vincristine (PCV) chemotherapy regimen in a group of 16 patients with newly diagnosed OD and 5 patients with recurrent low-grade OD. METHODS: Two groups of patients were studied: newly diagnosed patients with large OD and mixed oligoastrocytomas (OA) and patients with recurrent OD and OA after radiotherapy who still showed nonenhancing tumors. Treatment consisted of standard PCV chemotherapy. In the newly diagnosed and responding patients, radiotherapy was withheld until the time of disease recurrence. Responses were assessed by T2-weighted magnetic resonance image (MRI) scans. Loss of chromosome 1p and 19q was assessed using fluorescent in situ hybridization with locus-specific probes. RESULTS: Three of five patients with recurrent tumors responded. Thirteen of the 16 newly diagnosed patients showed evidence of response. The median time to disease progression in this group was >24 months. Only one of these patients experienced disease progression while receiving chemotherapy. Several patients showed a signficant clinical improvement despite only a modest improvement of the tumor on the MRI scans. Even patients without loss of 1p or 19q showed satisfactory responses. No TP53 mutations were found. CONCLUSIONS: Newly diagnosed patients with OD tumors, with or without loss of 1p/19q, responded to PCV chemotherapy. Up-front chemotherapy may be indicated especially for patients with large tumors. MRI scans were of limited value for the assessment of response. A Phase III trial should be initiated to compare radiotherapy with chemotherapy. Copyright (c) 2005 American Cancer Society.

PMID: 15637687 [PubMed - indexed for MEDLINE] 

Rhabdoid meningioma: a new subtype of malignant meningioma also apt to occur in children.

Martinez-Lage JF, Ferri Niguez B, Sola J, Perez-Espejo MA, Ros de San Pedro J, Fernandez-Cornejo V.

Regional Service of Neurosurgery, Virgen de la Arrixaca University Hospital, 30120, El Palmar, Murcia, Spain.

CASE REPORT: The case of a 14-year-old girl who presented with a 2-week history of raised intracranial pressure is reported. A left frontal extra-axial tumor was totally removed, whose histopathologic diagnosis was rhabdoid meningioma (RM). DISCUSSION: Rhabdoid meningiomas constitute a special malignant phenotype of meningioma that has been recently included in the WHO classification of tumors of the nervous system. Usually, RMs affect middle-aged and elderly individuals. We report the fourth case of a RM occurring in a child to illustrate that the diagnosis of this tumor subtype, given its prognostic implications, must also be considered in pediatric patients.

PMID: 15800791 [PubMed - as supplied by publisher] 

 
Far lateral supracerebellar infratentorial approach for the treatment of upper brainstem gliomas: clinical experience with pediatric patients.

Vougioukas VI, Omran H, Glasker S, Van Velthoven V.

Department of Neurosurgery, Neurocenter, Albert-Ludwigs-University of Freiburg, Breisacherstrasse 64, 79106, Freiburg im Breisgau, Germany, velthov@nz.ukl.uni-freiburg.de.

OBJECTIVE: Surgical exposure of intrinsic lesions located lateral to the brainstem still represents a challenging task. The aim of this study was to assess the feasibility of the extracerebral far lateral supracerebellar infratentorial (FLSI) approach for the treatment of gliomas located in the upper brainstem in the pediatric population. METHODS AND RESULTS: Between 1992 and 2002, seven patients (mean age 8.7 years) with tumors of glial origin (WHO I-IV) located mainly in the pontomesencephalic region were operated with the FLSI approach in a sitting position. Satisfactory extent of resection without additional morbidity was achieved. CONCLUSION: In a carefully selected pediatric patient population, the FLSI approach proved to be a feasible and effective surgical route for the treatment of upper brainstem gliomas.

PMID: 15800790 [PubMed - as supplied by publisher] 

 
Positron emission tomography for the early postsurgical evaluation of pediatric brain tumors.

Pirotte B, Levivier M, Morelli D, Van Bogaert P, Detemmerman D, David P, Baleriaux D, Brotchi J, Goldman S.

Department of Neurosurgery, ERASME Hospital, Universite Libre de Bruxelles, 808 route de Lennik, 1070, Brussels, Belgium, bpirotte@ulb.ac.be.

OBJECT: The object was to study the value of postoperative positron emission tomography (PET) to assess the extension of brain tumor resection. METHODS: Twenty children operated on for total resection of a glial tumor (18 low-grade, 2 anaplastic) presented a signal on postoperative magnetic resonance (MR) images raising the question of a possible tumor residue. PET was performed early ((18)F-Fluoro-deoxyglucose in 1, (11)C-methionine in 16, both in 3) to further characterize the nature of the abnormal MR signal in order to consider second-look surgery. An increased tracer uptake found in 14 children led to reoperation on 11 of them, confirming the tumor histologically. No (11)C-methionine uptake led to a conservative attitude in 6 children in whom MR imaging follow-up showed no tumor progression. CONCLUSIONS: The early postoperative PET, especially with (11)C-methionine, appears to be a valid basis for complementary therapeutic decisions, especially second-look surgery, in glial tumors for which a radical resection is a key factor for prognosis.

PMID: 15798921 [PubMed - in process] 

Treatment of neuroblastoma meningeal carcinomatosis with intrathecal application of alpha-emitting atomic nanogenerators targeting disialo-ganglioside GD2.

Miederer M, McDevitt MR, Borchardt P, Bergman I, Kramer K, Cheung NK, Scheinberg DA.

Departments of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

Labeling of specific antibodies with bifunctional chelated Actinium-225 ((225)Ac; an alpha generator) allows the formation of new, highly potent and selective alpha-emitting anticancer drugs. We synthesized and evaluated a radioimmunoconjugate based on 3F8, an IgG(3) antibody that specifically binds to ganglioside GD2, which is overexpressed by many neuroectodermal tumors including neuroblastoma. The (225)Ac-1,4,7,10-tetra-azacylododecane (DOTA)-3F8 construct was evaluated for radiochemical purity and sterility, immunoreactivity, cytotoxicity in vitro, induction of apoptosis on GD2-positive cells, as well as for pharmacological biodistribution and metabolism of the (225)Ac generator and its daughters in a nude mouse xenograft model of neuroblastoma. The (225)Ac-3F8 showed an IC(50) of 3 Bq/ml (80 pCi/ml) on the neuroblastoma cell line, NMB7, in vitro. Apoptosis of these cells was not observed. Biodistribution in mice showed specific targeting of a subcutaneous tumor; there was redistribution of the (225)Ac daughter nuclides mainly from blood to kidneys and to small intestine. Toxicity was examined in cynomolgus monkeys. Monkeys injected with 1 to 3 doses of intrathecal (225)Ac-3F8 radioimmunoconjugate (80 to 150 kBq/kg total dose) did not show signs of toxicity based on blood chemistry, complete blood counts, or by clinical evaluations. Therapeutic efficacy of intrathecal (225)Ac-3F8 was studied in a nude rat xenograft model of meningeal carcinomatosis. The (225)Ac-3F8 treatment improved survival 2-fold from 16 to 34 days (P = 0.01). In conclusion, in vivo alpha generators targeted by 3F8 warrant additional study as a possible new approach to the treatment of carcinomatous meningitis.

PMID: 15501978 [PubMed - indexed for MEDLINE] 

Expression of hypoxia-related tissue factors correlates with diminished survival of adjuvantly treated patients with chromosome 1p aberrant oligodendroglial neoplasms and therapeutic implications.

Birner P, Preusser M, Gelpi E, Berger J, Gatterbauer B, Ambros IM, Ambros PF, Acker T, Plate KH, Harris AL, Hainfellner JA.

Institute of Neurology, Medical University Vienna, Vienna, Austria.

PURPOSE: Oligodendroglial neoplasms with chromosome 1p deletion are chemosensitive, and stratified adjuvant therapies have been proposed on the basis of 1p status. In this study, we evaluated expression of hypoxia-related factors and its influence on survival in oligodendroglial brain tumors with chromosome 1p aberrations. EXPERIMENTAL DESIGN: Forty-four primary and 16 recurrent oligodendroglial neoplasms with 1p aberrations (deletion or imbalance) were investigated immunohistochemically for expression of hypoxia-inducible factor 1alpha and carbonic anhydrase-9. We used in situ hybridization to investigate expression of vascular endothelial growth factor-mRNA. We defined as "low hypoxia score" expression of no or only one marker and as "high hypoxia score" expression of two or three markers. The predominant vascular patterns of tumors were defined as classic or bizarre vascular formations, based on anti-CD34-immunostaining. RESULTS: High hypoxia score was evident in 16 of 44 (36.4%) primary tumor specimens and in 14 of 16 (87.5%) recurrent tumors (P = 0.001). High hypoxia score was associated with the presence of bizarre vascular proliferations and WHO grade III. In the subgroup of patients who received adjuvant therapy, univariate analysis showed significantly shorter survival of patients with high hypoxia score (n = 27; P = 0.0145). For all of the primary tumors, hypoxia score was an independent prognostic factor (P = 0.045). CONCLUSIONS: A fraction of oligodendroglial neoplasms with 1p aberrations shows evidence of tissue hypoxia, which significantly influences survival of patients receiving adjuvant therapy. Evaluation of tissue hypoxia could become useful for recruitment of patients for individualized therapy strategies, e.g., selection of patients with hypoxic tumors for hyperbaric oxygenation preceding radiotherapy.

PMID: 15475445 [PubMed - indexed for MEDLINE] 

 
A phase I study of topical Tempol for the prevention of alopecia induced by whole brain radiotherapy.

Metz JM, Smith D, Mick R, Lustig R, Mitchell J, Cherakuri M, Glatstein E, Hahn SM.

Department of Radiation Oncology, University of Pennsylvania, Philadelphia 19104-4283, USA. metz@xrt.upenn.edu

PURPOSE: Complete alopecia is a universal complication of whole brain radiation therapy which contributes to patient anxiety over treatment. Tempol, a nitroxide radioprotector, has been shown to protect against radiation-induced alopecia in an animal model. This phase Ib study was designed to evaluate the safety and side effect profile of topical Tempol in patients with brain metastases being treated with whole brain radiotherapy. EXPERIMENTAL DESIGN: Twelve patients with metastatic cancer to the brain were enrolled in the study between October 2000 and February 2003. Tempol (70 mg/ml concentration solution) was applied topically to the scalp 15 minutes before and washed off immediately after the completion of each of 10 fractions of whole brain radiation. Pharmacokinetic studies to evaluate the systemic absorption of Tempol were performed. Patients were assessed for toxicity before, during, and after Tempol administration. A secondary end point of the study, hair retention, was also scored. RESULTS: Eleven patients were treated with topical Tempol. Adverse events that were considered possibly, probably, or definitely related to Tempol, included asymptomatic grade 2 (two patients) and grade 1 (one patient) hypoglycemia, grade 1 forehead skin redness (one patient), grade 1 dry scalp (one patient), and grade 1 tingling sensation on the scalp (one patient). Tempol was not detected in blood samples from more than 50% of the patients. Mean maximum Tempol levels for individual patients at any time point varied from 0.4 to 3.1 micromol/L. Hair retention was localized to the base of the scalp where the Tempol solution pooled after application in the first four patients on the study. Subsequently, full scalp hair retention was seen in three of final five evaluable patients after gauze had been wrapped around the head to hold the solution against the scalp. CONCLUSIONS: This study demonstrates that topical application of Tempol to the scalp before whole brain radiation is safe and well tolerated. Evidence of protection against radiation-induced alopecia was observed. A phase II study that uses a gel formulation to increase the exposure of scalp to Tempol has been initiated.

Publication Types: 

·        Clinical Trial 

·        Clinical Trial, Phase I 

PMID: 15475427 [PubMed - indexed for MEDLINE] 

 
Pharmaceutical-mediated inactivation of p53 sensitizes U87MG glioma cells to BCNU and temozolomide.

Xu GW, Mymryk JS, Cairncross JG.

Department of Oncology, University of Western Ontario, London, Ontario.

Pifithrin-alpha (PFTalpha) is a small molecule inhibitor of p53. By reversibly blocking apoptosis in response to DNA damage, PFTalpha protects normal cells from lethal doses of gamma-radiation (Komarov et al., Science, 1999;285:1733-7). We examined the effect of PFTalpha on the chemosensitivity of a human cancer in which cell cycle arrest, not apoptosis, is the principle cellular consequence of p53 activation. This was of interest because E6 silencing of p53 sensitizes U87MG astrocytic glioma cells to BCNU and temozolomide (TMZ), cytotoxic drugs that are modestly helpful in the treatment of aggressive astrocytic gliomas. We observed that exposure of U87MG cells to PFTalpha before cytotoxic chemotherapy attenuated p53-mediated induction of p21WAF1 protein levels, sensitizing U87MG cells to BCNU and TMZ. Sensitization of U87MG cells was associated with G1 arrest, delayed entry into S-phase and decreased repair of DNA damage by BCNU. Our findings suggest that in addition to protecting normal cells from the toxic effects of radiation and chemotherapy, small molecule inhibitors of p53, like PFTalpha, might play a role in clinical oncology by sensitizing certain resistant cancers to cytotoxic chemotherapies. (c) 2005 Wiley-Liss, Inc.

PMID: 15800902 [PubMed - as supplied by publisher] 

 
Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis.

Lefranc F, Brotchi J, Kiss R.

Laboratoire de Toxicologie, Institut de Pharmacie, Universite Libre de Bruxelles, Campus de la Plaine, Blvd du Triomphe, 1050 Brussels, Belgium; e-mail: rkiss@ulb.ac.be.

PURPOSE The present review aims to emphasize that malignant gliomas are characterized by the diffuse invasion of distant brain tissue by a myriad of single migrating cells that exhibit decreased levels of apoptosis (programmed cell death type I), thus a resistance to cytotoxic insult. METHODS The present review surveys the molecular mechanisms of migration in malignant gliomas and potential issues arising from treatments, in addition to relationships between glioma cell migration and resistance to apoptosis in terms of the molecular signaling pathways. Results Clinical and experimental data demonstrate that glioma cell migration is a complex combination of multiple molecular processes, including the alteration of tumor cell adhesion to a modified extracellular matrix, the secretion of proteases by the cells, and modifications to the actin cytoskeleton. Intracellular signaling pathways involved in the acquisition of resistance to apoptosis by migrating glioma cells concern PI3K, Akt, mTOR, NF-kappaB, and autophagy (programmed cell death type II). CONCLUSION A number of signaling pathways can be constitutively activated in migrating glioma cells, thus rendering these cells resistant to cytotoxic insults. However, these pathways are not all constitutively activated at the same time in any one glioma. Particular inhibitors should therefore only be chosen if the target is present in the tumor tissue, but this is only possible if individual patients are submitted to the molecular profiling of their tumors before undergoing any treatment to combat their migratory glioma cells. Specific antimigratory compounds should be added to conventional radio- and/or chemotherapy.

PMID: 15800333 [PubMed - in process] 

 
Randomized Phase II Study of Temozolomide and Radiotherapy Compared With Radiotherapy Alone in Newly Diagnosed Glioblastoma Multiforme.

Athanassiou H, Synodinou M, Maragoudakis E, Paraskevaidis M, Verigos C, Misailidou D, Antonadou D, Saris G, Beroukas K, Karageorgis P.

Radiation Oncology, St Savas Cancer Hospital, 79 Zimbrakaki St, 10445 Athens, Greece; e-mail: elathanasiou@yahoo.com.

PURPOSE Surgery remains the standard treatment for glioma, followed by radiotherapy (RT) with or without chemotherapy. Despite multidisciplinary approaches, the median survival time for patients with glioblastoma multiform (GBM) remains at less than 1 year from initial diagnosis. Temozolomide (TMZ), an oral alkylating agent, has shown promising activity in the treatment of malignant gliomas. We conducted a multicenter randomized phase II study comparing the efficacy and safety of TMZ administered concomitantly and sequentially to RT versus RT alone in patients with newly diagnosed GBM. PATIENTS AND METHODS One hundred thirty patients with pathologically confirmed, newly diagnosed GBM were randomly assigned (110 assessable patients) to receive either TMZ 75 mg/m(2)/d orally, concomitantly with RT (60 Gy in 30 fractions; group A, n = 57), followed by six cycles of TMZ (150 mg/m(2) on days 1 through 5 and 15 to 19 every 28 days), or RT alone (60 Gy in 30 fractions; group B, n = 53). Results Median time to progression was 10.8 months in group A and 5.2 months in group B (P = .0001). One-year progression-free survival rate was 36.6% in group A and 7.7% in group B. Median overall survival (OS) time was also significantly better in group A versus group B (13.4 v 7.7 months, respectively; P < .0001), as was the 1-year OS at 56.3% v 15.7% (P < .0001), respectively. Toxicity was mainly hematologic. One patient with grade 4 myelotoxicity died as a result of sepsis. The other side effects were mild. CONCLUSION TMZ combined with RT (concomitantly and sequentially) seems to be more effective than RT alone in patients with newly diagnosed GBM. The combined-modality treatment was well tolerated.

PMID: 15800329 [PubMed - in process] 

Analysis of target genes induced by IL-13 cytotoxin in human glioblastoma cells.

Han J, Yang L, Puri RK.

Laboratory of Molecular Tumor Biology, CBER/NCI Genomics Program, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, CBER/FDA, NIH Bldg 29B, Rm 2NN10, 29 Lincoln Dr., Bethesda, MD, USA, 20892, puri@cber.fda.gov.

IL-13 cytotoxin comprised of IL-13 and a mutated form of Pseudomonas exotoxin (fusion protein termed IL-13-PE38QQR) has been shown to inhibit protein synthesis leading to necrotic and apoptotic cell death in glioblastoma cells that express high levels of interleukin-13 receptors (IL-13R). To identify target genes of cell death and other cellular genes with IL-13 receptors in glioblastoma cells, we utilized the cDNA microarrays to analyze global gene expression profiles after IL-13 cytotoxin and IL-13 treatment. IL-13 cytotoxin mediated cytotoxicity to U251 cells in a dose-dependant manner. Hierarchical cluster analysis of differentially expressed genes in U251 glioma cells at different time points after IL-13 cytotoxin treatment showed three major groups, each representing a specific expression pattern. Randomly selected differentially expressed genes from each group were confirmed by RT-PCR analysis. Most down-regulated genes belong to cell adhesion, motility, angiogenesis, DNA repair, and metabolic pathways. While up-regulated genes belong to cell cycle arrest, apoptosis, signaling and various metabolic pathways. Unexpectedly, at early time points, both IL-13 and IL-13 cytotoxin induced several genes belonging to different pathways most notably IL-8, DIO2, END1, and ALDH1A3 indicating that these genes are early response genes and their products may be associated with IL-13R. In addition, IL-13 cytotoxin induced IL-13Ralpha2 mRNA expression during the treatment in glioma cells. Our results indicate that novel cellular genes are involved with IL-13 receptors and that IL-13 cytotoxin induced cell death involves various target genes in human glioblastoma cells. On going studies will determine the role of associated genes and their products in the IL-13R functions in glioma cells.

PMID: 15803373 [PubMed - as supplied by publisher] 

Micromolar concentrations of 2-methoxyestradiol kill glioma cells by an apoptotic mechanism, without destroying their microtubule cytoskeleton.

Chamaon K, Stojek J, Kanakis D, Braeuninger S, Kirches E, Krause G, Mawrin C, Dietzmann K.

Department of Neuropathology, University of Magdeburg, Magdeburg, Germany.

The purpose of this study was to investigate the potential effects of 2-methoxyestradiol, a natural mammalian steroid, in glioma cells, since antiproliferative effects of this compound had been shown earlier in several leukemia and carcinoma cell lines. The effects of 0.2, 2 and 20 muM concentrations of 2-methoxyestradiol were measured in three malignant human glioma cell lines (U87MG, U138MG, LN405) and one malignant rat glioma cell line (RG-2) using a microtiter-tetrazolium (MTT) assay. In all cell lines, a significant reduction of the viable cell number by more then 75% occurred ( P < 0.05) for concentrations of 2 and 20 muM 2-methoxyestradiol after 6 days. A concentration of 0.2 muM had smaller effects (10-40% cell reduction), which were significant in two of the cell lines tested. The apoptotic nature of cell death was further analyzed in U87MG and RG-2 cells. Caspase-3 activity was significantly induced to levels between 3.4- and 23-fold after 4 days for the two higher 2-methoxyestradiol concentrations (P < 0.05). In the cell line RG-2 nuclear fragmentation was visible in many nuclei, following stains with Hoechst H33258. A round cell morphology occurred in most treated cells, which was not accompanied by a complete destruction of the microtubule network, as it can be observed with other microtubule targeting drugs.

PMID: 15803369 [PubMed - in process] 

Inhibition of cell invasion by indomethacin on glioma cell lines: in vitro study.

Wang M, Yoshida D, Liu S, Teramoto A.

Department of Neurosurgery, The First Hospital, Xi'an Jiaotong University, No.1 Jiankang Road, Xi'an, China, 710061, maodewang@yahoo.com.cn.

Malignant glioma invasion into the surrounding brain tissue is still a major problem for any therapeutical methods. Matrix metalloproteinases (MMPs) have been implicated as important factors in this pathological process. In this study, one of the non-steroidal anti-inflammatory drugs (NSAIDs) indomethacin was employed to investigate the effect of inhibition of cell invasion mediated by MMP-2 and MMP-9 in human malignant glioma cell lines, A172, U87MG, U251MG, and U373MG in vitro. MTT assay was firstly examined to determine non-cytotoxic dose range, then gelatin zymography, matrigel invasion assay, migration assay and MMP-2 activity assay for 24 h exposure in indomethacin were employed to assess the inhibitory effect of indomethacin. MTT assay revealed that dose with 0, 50, and 500 muM/ml were non-cytotoxic. Zymography demonstrated: (a) expression of MMP-2 and MMP-9 activity was downregulated along with elevated dose of indomethacin. (b) MMP-2 activity that changed from pro-MMP-2 to active form of MMP-2 in supernatants of cell lines could not be inhibited by indomethacin. Invasion assay disclosed that the number of invading cells through the matrigel were significantly decreased in a dose dependent manner. Migration assay indicated indomethacin did not affect cells migration. MMP-2 activity assay showed the total and active MMP-2 secretion was suppressed by 500 muM/ml of indomethacin. Our present study is the first report on inhibitive effect of indomethacin mediated by MMP-2 and MMP-9 in invasion assay of glioma cell lines. The current study suggested that non-cytotoxic level of indomethacin was able to reduce the cell invasion of malignant gliomas mediated by MMP-2 and MMP-9, but it did not affected on cell motility. It also lowered down the activity of MMP-2 and MMP-9, and could reduce of MMP-2 secretion of cell lines. Thus, high concentration of indomethacin within non-cytotoxic dose might offer a new therapeutic strategy to impair cell invasion of gliomas.

PMID: 15803368 [PubMed - as supplied by publisher] 

Brain metastasis from an adenoid cystic carcinoma of the bartholin gland. Case report.

Hatiboglu MA, Cosar M, Iplikcioglu AC, Ozcan D.

Department of Neurosurgery, Okmeydani Social Security Training Hospital, Istanbul, Turkey. azizhatiboglu@yahoo.com

Adenoid cystic carcinoma (ACC) of the Bartholin gland is an uncommon malignant gynecological tumor. Brain metastasis from a malignant gynecological lesion is encountered rarely and the prognosis for this type of metastasis is poor. Different treatment protocols, such as resection, stereotactic radiosurgery, whole-brain radiation therapy (WBRT), and chemotherapy, are available and should be considered on an individual basis. In this article, the authors report a case of brain metastasis from an ACC of the Bartholin gland that was treated by resection and WBRT. A review of the literature did not reveal any other such case.

PMID: 15796393 [PubMed - in process] 

Glioblastoma multiforme metastasis to the axis. Case report.

Utsuki S, Tanaka S, Oka H, Iwamoto K, Sagiuchi T, Fujii K.

Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagaw, Japan. utsuki@med.kitasato-u.ac.jp

Extracranial bone metastasis from glioblastoma multiforme (GBM) has rarely been reported in the literature, and most metastatic GBMs are multiple bone metastases. The authors describe the first case of a GBM with metastasis only to the axis. This 42-year-old man presented with a 2-month history of headache, nausea, vomiting, and disorientation. Magnetic resonance imaging demonstrated a right temporal tumor, which was diagnosed as a GBM based on tumor resection. The patient was treated using radiation (6000 cGy) and the intravenous administration of nimustine hydrochloride. Eighteen months thereafter, he experienced the sudden onset of neck pain. Magnetic resonance studies revealed a tumor in the axis that was diagnosed as GBM based on biopsy procedure.

PMID: 15796392 [PubMed - in process] 

Decreased expression of heparanase in glioblastoma multiforme.

Ueno Y, Yamamoto M, Vlodavsky I, Pecker I, Ohshima K, Fukushima T.

Department of Neurosurgery, Fukuoka University School of Medicine, Fukuoka, Japan.

OBJECT: The authors investigated the presence of endoglycosidase heparanase in human glioblastoma multiforme (GBM) and metastatic brain tumors as well as in healthy brain tissue to explore the relationship between the biological characteristics of GBM and the role of heparanase. METHODS: Heparanase messenger (m)RNA was almost undetectable in GBMs in vivo, whereas it was frequently seen in metastatic brain tumors according to results of reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemical analysis of paraffin-embedded tissue sections showed that neoplastic cells in metastatic brain tumors, especially in cells that invaded blood vessels, exhibit intense heparanase immunoreactivity. Heparanase was present in two highly invasive glioma cell lines, U87MG and U251MG, in vitro. These cell lines did not have metastatic capability, which was tested in an experimental pulmonary metastases model in mice. The activity of heparanase in these cell lines was almost the same as that in the highly metastatic melanoma cell line B16-F1. After nude mice were inoculated with U87MG cells, however, heparanase was no longer detected in subcutaneous or intracerebral experimental glioma in vivo based on results of immunohistochemical analysis. According to results of real-time quantitative PCR, there was a 10-fold increase in heparanase mRNA in U87MG glioma cells in vitro compared with that in experimental U87MG glioma tissue in vivo in nude mice. CONCLUSIONS: These results indicate that the expression of heparanase was downregulated in GBM in vivo, which rarely metastasizes to distant organs outside the central nervous system. Heparanase is not implicated in the invasiveness of GBM to surrounding healthy brain tissue in vivo.

PMID: 15796387 [PubMed - in process] 

 
Lateral transsulcal approach to asymptomatic trigonal meningiomas with correlative microsurgical anatomy:technical case report.

Nagata S, Sasaki T.

Department of Neurosurgery, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

OBJECTIVE: We introduce the lateral transsulcal approach to asymptomatic trigonal meningiomas. METHODS: The approach was studied in two cadaver brains and three asymptomatic patients with trigonal meningiomas. The posterior part of the sylvian fissure, or superior temporal sulcus, is opened to the bottom. Through a small horizontal cortical incision, the trigone of the lateral ventricle is exposed in the shortest distance. The trigonal meningiomas are detached from the choroid plexus and removed. RESULTS: In patients with meningiomas on the nondominant side, the transsylvian approach was adopted. In patients with meningiomas on the dominant side, the transsylvian approach was adopted for patients with a wide sylvian cistern, and the approach through the superior temporal sulcus was adopted for patients with a narrow sylvian cistern. The transverse gyrus of Heschl was a good anatomic landmark in the operative field of the transsylvian approach. Patients with meningiomas on the dominant side exhibited transient amnestic aphasia and dyscalculia, but the symptoms disappeared in a few days or weeks. These patients were discharged without any neurological deficits. Although there are potential risks of damaging association fibers, optic radiation, the transverse gyrus of Heschl, and the parietal lobe, a thorough understanding of the topographical anatomy and careful dissection techniques can avoid morbidity. Wide opening of the sylvian fissure and debulking of the tumor are other important factors to reduce the retraction of the parietal and temporal lobes. CONCLUSION: The lateral transsulcal approach is applicable for small asymptomatic trigonal meningiomas with an acceptable risk of morbidity, even in the dominant hemisphere.

PMID: 15794842 [PubMed - in process] 

 
The microsurgical nuances of resecting tuberculum sellae meningiomas.

Benjamin V, Russell SM.

New York University School of Medicine, New York, New York.

In a recent article, our experience and knowledge of the clinical picture, microsurgical anatomy, and long-term surgical outcome of resecting tuberculum sellae meningiomas was described in detail. We now present our surgical technique in a pictorial and video format for the benefit of neurosurgeons in training, as well as for general critique. Attention is given to the details of surgery: patient positioning, surgical approaches, technique of tumor removal, and postoperative care.

PMID: 15794838 [PubMed - in process] 

 
Expression of telomeric repeat binding factor-1 in astroglial brain tumors.

La Torre D, de Divitiis O, Conti A, Angileri FF, Cardali S, Aguennouz M, Aragona M, Panetta S, d'Avella D, Vita G, La Torre F, Tomasello F.

Neurosurgical Clinic, Department of Neurosciences, Psychiatric and Anesthesiological Sciences, University of Messina School of Medicine, Messina, Italy.

OBJECTIVE: In human somatic cells, telomeres shorten with successive cell divisions, resulting in progressive genomic instability, altered gene expression, and cell death. Recently, telomere-specific deoxyribonucleic acid-binding proteins, such as telomeric repeat binding factor-1 (TRF1), have been proposed as candidates for the role of molecules regulating telomerase activity, and they have been suggested to play key roles in the maintenance of telomere function. The present study was designed to assess TRF1 expression in human astroglial brain tumors and to speculate on the clinical implications of its expression. METHODS: Twenty flash-frozen surgical specimens obtained from adult patients who underwent craniotomy for microsurgical tumor resection, histologically verified as World Health Organization Grade II to IV astrocytomas, were used. Expression of TRF1 in astrocytomas of different grades was studied by means of both immunohistochemical and Western blotting analysis. The correlation between the extent of TRF1 expression and histological grading, performance status, and length of survival of patients underwent statistical analyses. RESULTS: TRF1 was expressed in all tumor samples. The level of its expression was variable, decreasing from low-grade through high-grade astrocytomas (P = 0.0032). TRF1 expression correlated with the patient's length of survival (P < 0.001) and performance status (P < 0.001) and proved to be an independent indicator of length of survival. CONCLUSION: Our findings suggest that the loss of TRF1 expression capability, as a result of down-regulation of TRF1 expression in malignant gliomas cells, may play a role in the malignant progression of astroglial brain tumors.

PMID: 15792519 [PubMed - in process] 

 
Monitoring the Expression Profiles of Integrins and Adhesion/Growth-regulatory Galectins in Adamantinomatous Craniopharyngiomas: Their Ability to Regulate Tumor Adhesiveness to Surrounding Tissue and Their Contribution to Prognosis.

Lefranc F, Mijatovic T, Decaestecker C, Kaltner H, Andre S, Brotchi J, Salmon I, Gabius HJ, Kiss R.

Department of Neurosurgery, Erasmus University Hospital, Brussels, Belgium.

OBJECTIVE: The purpose of this study was to identify biological markers that may be involved in the adhesiveness of craniopharyngiomas to optical chiasms and/or pituitary stalks. METHODS: We determined the complete pattern of integrin expression in three craniopharyngiomas by means of a complementary deoxyribonucleic acid microarray. We quantitatively determined the levels of immunohistochemical expression of the different integrins in a series of 37 cases and the pattern of immunohistochemical expression of 10 extracellular matrix components (acting as integrin ligands) in 7 optical chiasms and 11 pituitary stalks. We also quantitatively (computer-assisted microscopy) determined the levels of immunohistochemical expression of galectin-1, -3, -4, -7, and -8 in 50 adamantinomatous craniopharyngiomas. RESULTS: The present study shows that at both the ribonucleic acid and protein levels, adamantinomatous craniopharyngiomas express the alpha(2), alpha(6), alpha(v), beta(1), beta(5), and beta(8) integrin subunits, whereas optical chiasms and pituitary stalks express vitronectin, thrombospondin, and various forms of collagens. CONCLUSION: Our data suggest that at least part of the adhesiveness of craniopharyngiomas to the surrounding tissue, such as optical chiasms and pituitary stalks, could be explained by the interactions between alpha(2beta1) integrin expressed by craniopharyngiomas and collagens on the one hand, and vitronectin expressed by the surrounding tissue on the other hand. In addition, a Cox regression analysis has revealed that the levels of galectin-4 contribute significant information toward the delay in recurrence independently of surgical status.

PMID: 15792515 [PubMed - in process]