[Brainlife] Newsletter, Vol.4 No.7

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BRAINLIFE NEWSLETTER

Volume 4, Number 7 - 2 February 2005	Volume 4 Archive

1: J Neurooncol. 2004 Dec;70(3):359-69.

Phase II study of temozolomide and cisplatin as primary treatment prior to radiotherapy in newly diagnosed glioblastoma multiforme patients with measurable disease. A study of the Spanish Medical Neuro-Oncology Group (GENOM).

Balana C, Lopez-Pousa A, Berrocal A, Yaya-Tur R, Herrero A, Garcia JL, Martin-Broto J, Benavides M, Cerda-Nicolas M, Ballester R, Balart J, Capellades J.

Medical Oncology Services, Institut Catala d'Oncologia, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain. cbalana@ns.hugtip.scs.es

This phase II study evaluates the activity of temozolomide and cisplatin administered before radiation therapy in newly diagnosed glioblastoma multiforme patients, in terms of response, time to progression and survival. PATIENTS AND METHODS: Forty patients with measurable disease after surgery, a Karnofsky status > 60, and Barthel Index > 10 were included. They were treated with three cycles of temozolomide 200 mg/m2/day for 5 days and cisplatin 100 mg/m2 on day 1. Conventional focal radiation therapy to 60 Gy was administered after response evaluation. RESULTS: Three patients were not evaluable for central reviewed response but all 40 were evaluable for toxicity, time to progression and survival. Objective responses by Macdonald criteria on an intent to treat basis were 45% including complete response in three patients (7.5%), and partial response in 15 patients (37.5%). Responses were seen in biopsy-only patients (33.4%) as well as in partial surgery patients (52%). Median survival for all patients was 12.5 months. Biopsy-only patients had a median survival of 12.8 months. Grade 3 to 4 neutropenia was the most important toxicity, and occurred in 37.5% of patients. A delay in 18.2% and a dose reduction in 9.6% of cycles were necessary due to myelosuppression on day 28. Two patients had neutropenic fever resulting in one treatment-related death. Eighty-two percent of patients received radiotherapy. CONCLUSION: This regimen has significant activity, as it induces objective responses even in biopsy-only patients, appearing to improve their median survival. A better combination schedule is needed to improve the toxicity profile.

PMID: 15662978 [PubMed - in process]

2: J Neurooncol. 2004 Dec;70(3):349-57.: The relationship between peritumoral brain edema and the expression of vascular endothelial growth factor and its receptors in intracranial meningiomas.

Otsuka S, Tamiya T, Ono Y, Michiue H, Kurozumi K, Daido S, Kambara H, Date I, Ohmoto T.

Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Japan.

We examined the radiological and histological features of, and the influences of the expression of VEGF and its two major receptors, Flt-1 and Flk-1, on the development of peritumoral brain edema (PTBE) in patients with intracranial meningiomas. The expressions of VEGF and VEGF receptors in the immunohistochemical study were analyzed in relation to several factors, including tumor size, location, vascularity, and blood supply, as seen on digital subtraction angiographic studies. The edema volume (P = 0.0003) and edema index (P < 0.0001) had a significantly positive relation to VEGF expression. The positivity of Flt-1 and Flk-1 was mainly observed in tumor vessels; 44 cases (37.2%) were positive for the Flt-1 antibody and 37 cases (31.4%) for the Flk-1 antibody. The mean value of the edema index of the positive-Flt-1 group (5.220 +/- 11.586) was significantly higher than that of the negative-Flt-1 group (1.782 +/- 2.559) (P < 0.0001). The mean value of the edema index of the positive-Flk-1 group (3.925 +/- 5.870) was slightly higher than that of the negative-Flk-1 group (2.671 +/- 8.136) (P < 0.0001). Our data suggest that the expressions of VEGF and VEGF receptors positively relate to each other and to the formation of PTBE in patients with meningiomas.

PMID: 15662977 [PubMed - in process]

3: J Neurooncol. 2004 Dec;70(3):341-2.: An unusual presentation of glioblastoma multiforme.

Baehring J, Ogle E, Duncan C, Bannykh S.

Department of Neurosurgery, Yale University School of Medicine, USA.

PMID: 15662975 [PubMed - in process]

4: J Neurooncol. 2004 Dec;70(3):333-40.: Immunohistochemical study for O6-methylguanine-DNA methyltransferase in the non-neoplastic and neoplastic components of gliomas.

Nakasu S, Fukami T, Baba K, Matsuda M.

Department of Neurosurgery, Shiga University of Medical Science, Seta, Ohtsu, Shiga-ken, Japan. snakasu@belle.shiga-med.ac.jp

Although the expression O6-methylguanine-DNA methyltransferase (MGMT) is an important hallmark for decision of nitrosourea chemotherapy for glioma patients, no immunohistochemical method for analysis of MGMT has been standardized yet. Gliomas usually contain non-neoplastic cells even deep in the tumor. It is not known which of these components expresses MGMT. To clarify this point, we investigated MGMT expression in the non-neoplastic cells in autopsy and surgical specimens by immunohistochemistry. High grade gliomas were also studied to find a cut-off point for treatment decision. MGMT immunohistochemistry in the normal brain or brain with non-neoplastic disease revealed nuclear staining in some endothelial cells, inflammatory cells, ependymal cells, astrocytes and oligodendroglias. Some cells were double stained with CD68 (macrophages or microglias). The neurons were consistently MGMT-negative. High grade gliomas always contained an MGMT-positive non-neoplastic component. Although, the endothelial cells were easily distinguished from the neoplastic cells, other cells were often mistaken for tumor cells. The population of MGMT-positive non-neoplastic cells was usually less than 10%. We set a cut off-point at 10% between the positive and negative groups because the statistical difference in the overall survival was most distinct at this value. In 51 high grade glioma patients, who received both radiotherapy and chemotherapy with nimustine (ACNU), the median overall survival of the MGMT-negative group (23 months) was significantly longer than that of the MGMT-positive group (14 months) (P < 0.009). Multivariate analysis revealed that the negative MGMT expression was a significant prognostic variable next to the degree of surgical removal for the overall survival. In the MGMT-positive group, addition of platinum-based chemotherapy did not improve the survival.

PMID: 15662974 [PubMed - in process]

5: J Neurooncol. 2004 Dec;70(3):319-31.: Hyperthermia induces translocation of apoptosis-inducing factor (AIF) and apoptosis in human glioma cell lines.

Fukami T, Nakasu S, Baba K, Nakajima M, Matsuda M.

Department of Neurosurgery, Shiga University of Medical Science, Ohtsu, Shiga, Japan. tadateru@belle.shiga-med.ac.jp

In the hyperthermal treatment, the wild type (wt) p53 plays an important role in apoptosis induction in the tumor cells. In human gliomas, p53 frequently has some form of mutation. The mutant type (mt) p53 does not work properly as a tumor suppressor and this may result in poor responses during treatment. We investigated the relationship between apoptosis-inducing factor (AIF) and apoptosis under various thermal conditions (43, 45, and 47 degrees C for 1 h) using four p53-wild or -mutant human glioma cell lines (A172, T98G, U251MG, and YKG-1). AIF translocation from the mitochondria to the nucleus under hyperthermal conditions was demonstrated by confocal laser microscopy. The percentage of AIF-positive nuclei increased significantly in comparison with the control in all cell lines and in all temperature groups except for YKG-1 at 47 degrees C. Immunoblot analyses of the nuclear fraction of each cell line revealed temperature-dependent increases in AIF. A simultaneous release of cytochrome c from the mitochondria to the cytosol was noted. A flow cytometric analysis showed that apoptosis induction occurred more often in a temperature-dependent manner in the 45 and 47 degrees C groups than in the control group. These findings indicate that the hyperthermal conditions can lead to AIF translocation and apoptotic cell death in the p53-mutant human glioma cells. The present report is the first description of AIF-induced apoptosis in hyperthermia.

PMID: 15662973 [PubMed - in process]

6: J Neurooncol. 2004 Dec;70(3):309-17.: Quantification of thrombospondin-1 secretion and expression of alphavbeta3 and alpha3beta1 integrins and syndecan-1 as cell-surface receptors for thrombospondin-1 in malignant glioma cells.

Naganuma H, Satoh E, Asahara T, Amagasaki K, Watanabe A, Satoh H, Kuroda K, Zhang L, Nukui H.

Department of Neurosurgery, University of Yamanashi Faculty of Medicine, Nakakoma-gun, Yamanashi, Japan. nagahiro@yamanashi.ac.jp

Malignant glioma cells secrete thrombospondin-1 (TSP-1) which participates in the motility of glioma cells, and binds to cell surface alphavbeta3 and alpha3beta1 integrins, and syndecan-1. This study evaluated the amount of TSP-1 secretion from malignant glioma cells, and the expression of alphavbeta3 and alpha3beta1 integrins, and syndecan-1. The amounts of TSP-1 in the supernatants from 10 malignant glioma cell lines and eight non-glioma malignant tumor cell lines were measured by enzyme-linked immunosorbent assay. Expression of alphavbeta3 and alpha3beta1 integrins, and syndecan-1 were examined by flow cytometry. The amounts of TSP-1 secreted by malignant glioma cells were 43 to 2431 ng/l x 10(6) cells/24 h (mean +/- SD = 626 +/- 792). Seven of 10 glioma cell lines secreted more than 100 ng of TSP-1 and three of these cell lines secreted more than 1 microg. Seven of eight non-glioma cell lines secreted less than 100 ng of TSP-1. All glioma cell lines expressed alpha3beta1 integrin and syndecan-1, and seven of 10 glioma cell lines expressed alphavbeta3 integrin. Treatment of the glioma cell lines with TGF-beta2 did not change the expression of alphavbeta3 integrin. These results suggest that malignant glioma cells secrete high levels of TSP-1, which may be important in the migration of glioma cells via interactions with alphavbeta3 and alpha3beta1 integrins, and syndecan-1.

PMID: 15662972 [PubMed - in process]

7: J Neurooncol. 2004 Dec;70(3):301-7.: Up-regulation of CC chemokine, CCL3L1, and receptors, CCR3, CCR5 in human glioblastoma that promotes cell growth.

Kouno J, Nagai H, Nagahata T, Onda M, Yamaguchi H, Adachi K, Takahashi H, Teramoto A, Emi M.

Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, Kosugi, Kawasaki, Tokyo, Japan.

Human CC ligand 3-like protein 1 (CCL3L1), a member of the CC chemokine family, that induces MCP1 and RANTES, exhibits a variety of proinflammatory activities including chemotaxis, and functional and proliferative activation of leukocytes, lymphocytes and macrophages. Its signal is transmitted through transmembrane receptors, CC chemokine receptors, CCR1, CCR3 and CCR5. To examine gene expression of chemokine, CCL3L1, and its receptors, CCR1, CCR3 and CCR5, we analyzed tumor tissues from 21 patients with several types of primary gliomas. CCL3L1, CCR3 and CCR5 gene exhibited over-expression in 70% (7/10), 60% (6/10), and 60% (6/10) of glioblastoma, in comparison with lower frequencies seen in lower-grade gliomas. Transfection of CCL3L1-expression vector to glioblastoma cell line enhanced proliferation of the tumor cells. These data suggest that increased expression of the CCL3L1, CCR3 and CCR5 chemokine-receptors system is involved in brain tumorigenesis, especially in the progression of glioblastoma.

PMID: 15662971 [PubMed - in process]

8: J Neurooncol. 2004 Dec;70(3):289-99.: Enhanced cytotoxic effects of 5-aminolevulinic acid-mediated photodynamic therapy by concurrent hyperthermia in glioma spheroids.

Hirschberg H, Sun CH, Tromberg BJ, Yeh AT, Madsen SJ.

Department of Neurosurgery, Rikshospitalet, Oslo, Norway.

During photodynamic therapy (PDT) both normal and pathological brain tissue, in close proximity to the light source, can experience significant temperature increases. The purpose of this study was to investigate the anti-tumor effects of concurrent 5-aminolevulinic acid (ALA)-mediated PDT and hyperthermia (HT) in human and rat glioma spheroids. Human or rat glioma spheroids were subjected to PDT, HT, or a combination of the two treatments. Therapies were given concurrently to simulate the conditions that will occur during patient PDT. Predictions of diffusion theory suggest that brain tissue immediately adjacent to a spherical light applicator may experience temperature increases approaching 8 degrees C for laser input powers of 2 W. In the in vitro model employed here, HT had no effect on spheroid survival at temperatures below 49 degrees C, while sub-threshold fluence PDT results in only modest decrease in survival. HT (40-46 degrees C) and PDT interact in a synergistic manner if the two treatments are given concurrently. The degree of synergism increases with increasing temperature and light fluence. Apoptosis is the primary mode of cell death following both low-fluence rate PDT and combined HT + PDT.

PMID: 15662970 [PubMed - in process]

9: J Neurosurg. 2005 Jan;102 Suppl:293-6.: Temporary symptomatic swelling of meningiomas following gamma knife surgery. Report of two cases.

El Shehaby A, Ganz JC, Reda WA, Hafez A.

Gamma Knife Center, Cairo, Egypt.

In two patients in whom gamma knife surgery was performed for meningiomas clinically significant volume increases were observed in the first 3 months after treatment. Clinical examination and various imaging studies form the basis of the report in these patients. In each case, the volume increase was temporary.

PMID: 15662829 [PubMed - in process]

10: J Neurosurg. 2005 Jan;102 Suppl:287-8.: Tumor recurrence and survival following gamma knife surgery for brain metastases.

Mindermann T.

Gamma Knife Center Zurich, Klinik Im Park, Zurich, Switzerland. thomas.mindermann@freesurf.ch

OBJECT: The authors evaluated prognostic factors for tumor recurrence and patient survival following gamma knife surgery (GKS) for brain metastasis. METHODS: A retrospective review of 101 patient charts was undertaken for those patients treated with GKS for brain metastases from 1994 to 2001. Recurrence rates of brain metastasis following GKS depended on the duration of patient survival. Long-term survival was associated with a higher risk of tumor recurrence and shorter-term survival was associated with a lower risk. The duration of survival following GKS for brain metastases seems to be characteristic of the primary disease rather than the cerebral disease. CONCLUSIONS: Recurrence rates of brain metastasis following GKS are related to duration of survival, which is in turn mostly dependent on the nature and course of the primary tumor.

PMID: 15662827 [PubMed - in process]

11: J Neurosurg. 2005 Jan;102 Suppl:283-6.: Gamma knife surgery for atypical meningiomas.

Huffmann BC, Reinacher PC, Gilsbach JM.

Department of Neurosurgery, University Hospital Aachen, Germany. Beate.Huffmann@post.rwth-aachen.de

OBJECT: Complete resection is the optimal treatment for atypical meningiomas (AMs) but its feasibility depends on the tumor site. The object of this study was to assess the effect of gamma knife surgery (GKS) on AM. METHODS: In 15 patients 21 AMs were treated by GKS. Four patients had residual lesions and 10 patients had recurrent tumors after one or more microsurgical interventions. Three patients were treated twice with GKS because of tumor tissue outside the treatment volume, either at the margin or at a distant location. The median clinical and neuroimaging follow-up period was 35 months (range 21-67 months). Ten tumors shrank 6 to 12 months after GKS, 10 remained stable, and one grew. Between 18 and 36 months after GKS, four patients had a distant recurrence, and two had a margin recurrence. In one of these cases, an additional local recurrence was demonstrated 1 year later, and the patient underwent standard radiotherapy. No patient suffered persistent adverse effects after radiosurgery. CONCLUSIONS: After early tumor shrinkage, high recurrence rates were demonstrated both at the treatment margin and at distant locations in cases treated for AM. There was only one recurrence within the GKS radiation field. For small- and medium-sized AMs GKS may be a safe adjunct to other treatment modalities.

PMID: 15662826 [PubMed - in process]

12: J Neurosurg. 2005 Jan;102 Suppl:266-71.: Diagnostic value of thallium-201 chloride single-photon emission computerized tomography in differentiating tumor recurrence from radiation injury after gamma knife surgery for metastatic brain tumors.

Serizawa T, Saeki N, Higuchi Y, Ono J, Matsuda S, Sato M, Yanagisawa M, Iuchi T, Nagano O, Yamaura A.

Department of Neurosurgery, Chiba Cardiovascular Center, Ichihara, Japan. QWT03231@nifty.ne.jp

OBJECT: The authors assessed the diagnostic value of 201Tl Cl single-photon emission computerized tomography (SPECT), performed after gamma knife surgery (GKS) for metastatic brain tumors in differentiating tumor recurrence from radiation injury. METHODS: Of 6503 metastatic brain tumors treated with GKS, 201Tl SPECT was required in 72 to differentiate between tumor recurrence and radiation injury. When the Tl index was greater than 5, the lesion was diagnosed as a tumor recurrence. When the index was < 3.0 it was called radiation injury. In cases with a Tl index between 3 and 5, 201Tl SPECT was repeated once per month until the Tl index was greater than 5 or less than 3. If the Tl index fluctuated between 3 and 5 for 2 months, the lesion was diagnosed as radiation injury. The final diagnosis was based on histological examination or clinical course. The sensitivity of the method was 91%; thus 201Tl SPECT is effective for differentiating between tumor recurrence and radiation injury in metastatic brain tumors treated with GKS. Caution is necessary, however, for the following reasons: 1) simple interinstitutional comparisons of Tl indices are not possible because measurement methods are institute specific; 2) steroid administration decreases the Tl index to a variable degree; and 3) a severe radiation injury lesion, as is often seen after repeated GKS or very high dose GKS, may have a Tl index greater than 5. CONCLUSIONS: Used with critical insight 201Tl Cl SPECT can be useful in distinguishing between tumor regrowth and radiation necrosis in patients with cerebral metastases.

PMID: 15662823 [PubMed - in process]

13: J Neurosurg. 2005 Jan;102 Suppl:262-5.: Prolonged survival in a subgroup of patients with brain metastases treated by gamma knife surgery.

Yu CP, Cheung JY, Chan JF, Leung SC, Ho RT.

Gamma Knife Centre, Canossa Hospital, Hong Kong, China. cpyu@thebraincentre.org

OBJECT: The authors analyzed the factors involved in determining prolonged survival (> or = 24 months) in patients with brain metastases treated by gamma knife surgery (GKS). METHODS: Between 1995 and 2003, a total of 116 patients underwent 167 GKS procedures for brain metastases. There was no special case selection. Smaller and larger lesions were treated with different protocols. The mean patient age was 56.9 years, the mean number of initial lesions was 3.15, and the mean lesion volume was 10.45 cm.3 The mean follow-up time was 9.2 months. The median patient survival was 8.68 months. One-, 2-, 3-, 4-, and 5-year actuarial survival rates were 31.8%, 19.8%, 14.6%, 7.7%, and 6.9%, respectively. Patient age, number of lesions at presentation, and lesion volume had no influence on patient survival. Twenty-three (19.8%) patients survived for 24 months or more. Certain factors were associated with increased survival time. These were stable primary disease (21 of 23 patients), a long latency between diagnosis of the primary tumor and the occurrence of brain metastases (mean 28.4 months, median 16 months), absence of third-organ involvement, and repeated local procedures. Ten patients underwent repeated GKS (mean 3.4 per patient). Seven patients required open surgery for local treatment failures (recurrence or radiation necrosis). Two patients had both. Fifteen patients underwent repeated procedures. CONCLUSIONS: Aggressive local therapy with GKS, repeated GKS, and GKS plus surgery can achieve increased survival in a subgroup of patients with stable primary disease, no third-organ involvement, and long primary-brain secondary intervals.

PMID: 15662822 [PubMed - in process]

14: J Neurosurg. 2005 Jan;102 Suppl:255-8.: Gamma knife surgery of superficially located meningioma.

Kim DG, Kim ChH, Chung HT, Paek SH, Jeong SS, Han DH, Jung HW.

Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea. gknife@plaza.snu.ac.kr

OBJECT: The authors analyzed tumor control rates and complications in patients with superficially located meningiomas after gamma knife surgery (GKS). METHODS: Between 1998 and 2003, GKS was performed in 23 patients with 26 lesions in whom follow-up imaging for 1 year or more was available. The male/female ratio was 1:22. The mean age was 59 years. The median tumor volume was 4.7 cm3, and the mean margin dose was 16 Gy at the 50% isodose line. Peritumoral edema was revealed on magnetic resonance (MR) imaging in four patients before GKS. Magnetic resonance imaging and clinical examinations were performed every 6 months after GKS. The mean follow-up duration was 32 months. The tumor shrank in eight cases, was stable in 17, and enlarged in one; thus 25 (95%) of 26 tumors were controlled. A peritumoral high signal on T2-weighted MR images was found in eight lesions and preexisting edema was aggravated in three lesions after GKS. Ten of these 11 patients complained of severe headache, and three patients experienced neurological deficits at the same time after a mean latency of 3 months; however, high signal was not demonstrated on imaging before 6 months on average. Steroid agents, when required, gave relief to all patients. The complication rate was 43% (10 of 23 cases). High signal disappeared in nine patients and decreased in the remaining two. High signal was associated with a high integral dose and a large tumor volume. Tumor shrinkage at the last follow-up examination was more prominent in the patients with symptomatic high signal (p = 0.03). CONCLUSIONS: There was a good tumor control rate with a high complication rate. Longer follow up of more patients is needed. Adjusting the dose-volume relationship should be considered to reduce complications.

PMID: 15662820 [PubMed - in process]

15: J Neurosurg. 2005 Jan;102 Suppl:189-94.: Volume reduction in meningiomas after gamma knife surgery.

Feigl GC, Bundschuh O, Gharabaghi A, Samii M, Horstmann GA.

International Neuroscience Institute, Hannover, Germany. feigl@ini-hannover.de

OBJECT: The purpose of this study was to evaluate the volume-reducing effects of gamma knife surgery (GKS) of meningiomas with and without previous surgical treatment. METHODS: A group of 127 patients with a mean age of 57.1 years (range 9-81 years) with 142 meningiomas (128 World Health Organization Grade I and 14 Grade II) were included in this study. The management strategy reduces tumor volume with surgery when necessary (81 patients). Stereotactic GKS with a Gamma Knife model C was performed in all tumors of suitable size. Magnetic resonance imaging follow-up examinations with volumetric tumor analysis was performed 6 months after treatment and annually thereafter. The mean tumor volume was 5.9 cm3 (range < 5 to > 40 cm3). The mean follow-up time after GKS was 29.3 months (range 11-61 months). The mean prescription dose was 13.8 Gy (range 10-18 Gy). A reduction in volume occurred in 117 (82.4%) of all tumors, and in 20 tumors (14.1%) growth ceased. The overall tumor control rate of 96.4%. The mean volume reduction achieved with GKS was more than 46.1%. Only five tumors (3.5%) stowed a volume increase. CONCLUSIONS: Gamma knife surgery was effective in reducing meningioma volume at short-term follow up. Further studies are needed to examine the development of these findings over a longer period.

PMID: 15662808 [PubMed - in process]