[Brainlife] Newsletter, Vol.4 No.25

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BRAINLIFE NEWSLETTER

Volume 4, Number 25 - 12 June 2005	Volume 4 Archive

1: Cancer. 2005 May 1;103(9):1939-48.

Congenital abnormalities and childhood cancer.

Agha MM, Williams JI, Marrett L, To T, Zipursky A, Dodds L.

Pediatric Oncology Group of Ontario, Toronto, Ontario, Canada. mohammad@ices.on.ca

BACKGROUND: The examination of specific characteristics of neoplasms diagnosed in children have suggested that a significant proportion can be attributed to a genetic mutation or genetic predisposition. Although the study of a genetic predisposition to cancer in children remains in the early stages, congenital abnormalities could provide essential information for mapping predisposing lesions in children with cancer. METHODS: In the current study, 2 large cohorts of children with and without congenital abnormalities were followed for the occurrence of cancer and death up to 18 years. Through this study, the risk of developing cancer by age at diagnosis, effects of birth characteristics on cancer risk, and possible associations between specific anomalies and tumor types were examined. RESULTS: Based on the follow-up of 90,400 children, the risk of developing cancer during the first year of life was found to be nearly 6 times higher in children with anomalies (rate ratio [RR] of 5.8; 95% confidence interval [95% CI], 3.7-9.1). Children with birth defects were found to be at a higher risk for developing leukemia (RR of 2.7; 95% CI, 2.1-3.6), tumors of the central nervous system (RR of 2.5; 95% CI, 1.8-3.4), sympathetic nervous system tumors (RR of 2.2; 95% CI, 1.4-3.4), and soft tissue sarcomas (RR of 1.9; 95% CI, 1.0-3.5). Among children with birth defects, children with Down syndrome, nervous system anomalies, and anomalies of the urinary system had the highest incidence rates of cancer. In the presence of birth defects, other factors such as birth weight, gestational age, age of the mother, and birth order were not found to be associated significantly with the risk of cancer. CONCLUSIONS: The significant relative risks found in the current study provided evidence of links between the presence of abnormalities and the development of cancer. Some "cancer-prone" abnormalities were identified in the current study. Such anomalies may be markers of other exposures or processes that increase the risk of developing cancer. (c) 2005 American Cancer Society.

PMID: 15770693 [PubMed - indexed for MEDLINE]

2: Childs Nerv Syst. 2005 Jan;21(1):77-80. Epub 2004 Apr 17.

Split-cord malformation and tethered cord associated with immature teratoma.

Uzum N, Dursun A, Baykaner K, Kurt G.

Department of Pathology, Gazi Universitesi School of Medicine, Ankara, Turkey. nuketuzum@yahoo.com

CASE REPORT: We report a case of a 12-month-old boy with split-cord malformation, tethered cord, and intradural immature teratoma containing immature nephroblastic tissue. He also had a horseshoe kidney. OUTCOME: Surgical removal of the teratoma and tethered cord resulted in functional improvement of the existing bladder dysfunction. DISCUSSION: To our knowledge, such a case has not been reported before.

Publication Types:

Case Reports

PMID: 15095105 [PubMed - indexed for MEDLINE]

3: Int J Radiat Oncol Biol Phys. 2005 Jul 1;62(3):814-9.: Fractionated stereotactic radiotherapy of optic pathway gliomas: Tolerance and long-term outcome.

Combs SE, Schulz-Ertner D, Moschos D, Thilmann C, Huber PE, Debus J.

Department of Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany.

Purpose: To evaluate the effectiveness and toxicity of fractionated stereotactically guided radiotherapy (FSRT) in the management of optic glioma. Methods and Materials: Fifteen patients with optic pathway gliomas were treated with FSRT at our institution between 1990 and 2003. A median target dose of 52.2 Gy (range, 45.2-57.6 Gy) was applied using a median fractionation of 5 fractions of 1.8 Gy weekly using a linear accelerator. Results: The median follow-up time was 97 months (range, 8-151 months). Of the 15 patients, 1 died of tumor progression during the follow-up period. The progression-free survival rate at 3 and 5 years was 92% and 72%, respectively. The median overall survival after FSRT was 90 months (range, 8-151 months). The 5-year survival rate after FSRT was 90%. We did not observe secondary malignancies. Conclusion: Fractionated stereotactic radiotherapy was safe and well tolerated in all patients. The good tumor control and the potential of sparing normal brain tissue, especially the pituitary gland in lesions involving the optic chiasm, permit effective treatment of patients with optic nerve gliomas. Longer follow-up is needed to assess the incidence of late effects fully.

PMID: 15936565 [PubMed - in process]

4: Int J Radiat Oncol Biol Phys. 2005 Jun 1; [Epub ahead of print]: Epidermal growth factor receptor amplification does not have prognostic significance in patients with glioblastoma multiforme.

Quan AL, Barnett GH, Lee SY, Vogelbaum MA, Toms SA, Staugaitis SM, Prayson RA, Peereboom DM, Stevens GH, Cohen BH, Suh JH.

Department of Radiation Oncology.

PURPOSE: There have been conflicting reports in the literature regarding the prognostic significance of epidermal growth factor receptor (EGFR) amplification in patients with glioblastoma multiforme (GBM). The purpose of this study is to determine the prognostic significance of EGFR amplification in patients with GBM treated at the Cleveland Clinic Foundation. METHODS AND MATERIALS: A retrospective review of GBM patients treated with surgery at the Cleveland Clinic Foundation was performed. Amplification of EGFR was evaluated with fluorescence in situ hybridization in a total of 107 patients diagnosed between December 1995 and May 2003. In addition to EGFR status, various prognostic factors were evaluated to determine the factors that influenced survival and radiographic response rate. The median follow-up was 9 months. RESULTS: The overall median survival was 9.8 months, with a 1-year survival of 40%. Of the 107 patients in whom EGFR status was evaluated, 36 (33.6%) were found to have EGFR amplification. On multivariate analysis, median survival was found to be significantly improved for patients with age <60 (12.6 months vs. 8 months, p = 0.0061), patients with Karnofsky Performance Status >/=70 (12.1 months vs. 4.4 months, p < 0.0001), patients who had undergone subtotal resection or gross total resection (11.1 months vs. 4.1 months, p = 0.002), and patients who received a radiation dose >/=60 Gy compared with no radiation (12.7 months vs. 3 months, p < 0.0001). There was no association of EGFR amplification with survival. When stratified by age (<60 vs. >/=60), EGFR status still did not reach statistical significance in predicting for survival. For the 81 patients who had radiographic follow-up, the 1-year overall local control was 14%. On univariate analysis, only treatment with radiation (<60 Gy vs. >/=60 Gy vs. no radiation, p = 0.03) was found to predict for improved local control. Treatment with radiation did not remain statistically significant on multivariate analysis. CONCLUSION: Epidermal growth factor receptor amplification was not found to be a significant prognostic indicator of overall survival or radiographic local control in patients with GBM treated with surgery at the Cleveland Clinic Foundation. Further studies are needed to fully delineate the significance of this molecular marker in patients with GBM.

PMID: 15936158 [PubMed - as supplied by publisher]

5: Int J Radiat Oncol Biol Phys. 2005 May 1;62(1):32-7.: Gamma knife radiosurgery of radiation-induced intracranial tumors: local control, outcomes, and complications.

Jensen AW, Brown PD, Pollock BE, Stafford SL, Link MJ, Garces YI, Foote RL, Gorman DA, Schomberg PJ.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA.

PURPOSE: To determine local control (LC) and complication rates for patients who underwent radiosurgery for radiation-induced intracranial tumors. METHODS AND MATERIALS: Review of a prospectively maintained database (2,714 patients) identified 16 patients (20 tumors) with radiation-induced tumors treated with radiosurgery between 1990 and 2004. Tumor types included typical meningioma (n=17), atypical meningioma (n=2), and schwannoma (n=1). Median patient age at radiosurgery was 47.5 years (range, 27-70 years). The median tumor margin dose was 16 Gy (range, 12-20 Gy). Median follow-up was 40.2 months (range, 10.8-146.2 months). Time-to-event outcomes were calculated with Kaplan-Meier estimates. RESULTS: Three-year and 5-year LC rates were 100%. Three-year and 5-year overall survival rates were 92% and 80%, respectively. Cause-specific survival rates at 3 and 5 years were 100%. Three patients died: 1 had in-field progression 65.1 months after radiosurgery and later died of the tumor, 1 died of progression of a preexisting brain malignancy, and 1 died of an unrelated cause. One patient had increased seizure activity that correlated with development of edema seen on neuroimaging. CONCLUSIONS: LC, survival, and complication rates in our series are comparable to those in previous reports of radiosurgery for intracranial meningiomas. Also, LC rates with radiosurgery are at least comparable to those of surgical series for radiation-induced meningiomas. Radiosurgery is a safe and effective treatment option for radiation-induced intracranial tumors, most of which are typical meningiomas.

PMID: 15850899 [PubMed - indexed for MEDLINE]

6: J Neurochem. 2005 Jun;93(5):1293-303.: Enhanced expression and shedding of the transmembrane chemokine CXCL16 by reactive astrocytes and glioma cells.

Ludwig A, Schulte A, Schnack C, Hundhausen C, Reiss K, Brodway N, Held-Feindt J, Mentlein R.

Institute of Biochemistry, Christian-Albrechts-University, Kiel, Olshausenstrasse, Germany.

The transmembrane chemokine CXCL16 is expressed by dendritic and vascular cells and mediates chemotaxis and adhesion of activated T cells via the chemokine receptor CXCR6/Bonzo. Here we describe the expression and shedding of this chemokine by glioma cells in situ and in vitro. By quantitative RT-PCR and immunohistochemistry, we show that CXCL16 is highly expressed in human gliomas, while expression in normal brain is low and mainly restricted to brain vascular endothelial cells. In cultivated human glioma cells as well as in activated mouse astroglial cells, CXCL16 mRNA and protein is constitutively expressed and further up-regulated by tumour necrosis factor alpha (TNFalpha) and interferon-gamma (IFNgamma). CXCL16 is continuously released from glial cells by proteolytic cleavage which is rapidly enhanced by stimulation with phorbol-12-myristate-13-acetate (PMA). As shown by inhibitor studies, two distinct members of the disintegrin-like metalloproteinase family ADAM10 and 17 are involved in the constitutive and PMA-induced shedding of glial CXCL16. In addition to the chemokine, its receptor CXCR6 could be detected by quantitative RT-PCR in human glioma tissue, cultivated murine astrocytes and at a lower level in microglial cells. Functionally, recombinant soluble CXCL16 enhanced proliferation of CXCR6-positive murine astroglial and microglial cells. Thus, the transmembrane chemokine CXCL16 is expressed in the brain by malignant and inflamed astroglial cells, shed to a soluble form and targets not only activated T cells but also glial cells themselves.

PMID: 15934948 [PubMed - in process]

7: J Neurooncol. 2005 May;72(3):273-80.: Characterization of brain tumors by MRS, DWI and Ki-67 labeling index.

Calvar JA, Meli FJ, Romero C, Yanez ML, Martinez AR, Lambre H, Taratuto AL, Sevlever G.

Institute for Neurological Research (FLENI), Instituto de Investigaciones Neurologicas Raul Carrea, Montaneses 2325, CP1428CQK, Buenos Aires, Argentina, jcalvar@fleni.org.ar.

With the advent of fast imaging hardware and specialized software, additional non-invasive magnetic resonance characterization of tumors has become available through proton magnetic resonance spectroscopy (MRS), hemodynamic imaging and diffusion-weighted imaging (DWI). Thus, patterns could be discerned to discriminate different types of tumors and even to infer their possible evolution in time. The purpose of this study was to investigate the correlation between MRS, DWI, histopathology and Ki-67 labeling index in a large number of brain tumors. Localized proton spectra were obtained in 47 patients with brain tumors who subsequently underwent surgery (biopsy or tumor removal). We performed MRS with short echo-time (30 ms) and metabolic values in spectra were measured using an external software with 25 peaks. In all patients who had DWI, we measured apparent diffusion coefficients (ADC) in the same region of interest (ROI) where the voxel in MRS was located. In most tumors the histological diagnosis and Ki-67 labeling index had been determined on our original surgical specimen. Cho/Cr, (Lip+Mm)/Cr, NAA/(Cho+Cr) and Glx/Cr indexes in MRS allowed discriminating between low- and high-grade gliomas and metastases (MTs). Likewise, absolute ADC values differentiated low- from high-grade gliomas expressed by Ki-67 labeling index. A novel finding was that high Glx/Cr in vivo MRS index (similar to other known indexes) was a good predictor of tumor grading.

PMID: 15937653 [PubMed - in process]

8: J Neurooncol. 2005 May;72(3):261-5.: The contribution of Magnetic Resonance Spectroscopy and echoplanar perfusion-weighted MRI in the initial assessment of brain tumours.

Fayed N, Modrego PJ.

Magnetic Resonance Unit, Clinica Quiron, Zaragoza, Spain.

Conventional Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are the cornerstone in the initial evaluation of brain tumours. The purpose of this study is to evaluate the contribution of Magnetic Resonance Spectroscopy (MRS) and Perfusion-weighted MRI to distinguish malignant from benign tumours.We included 55 patients diagnosed with single brain tumour by CT and MRI, and final histopathological verification of the tumour type: 25 were low-grade gliomas, 8 anaplastic gliomas, 11 glioblastomas, and 11 solitary metastases. We carried out brain MRS and dynamic perfusion-weighted echoplanar MRI in all cases. Perfusion was assessed in the centre of the lesion and in the area of maximum contrast-enhancement.In MRS, we found significant differences in Choline/Creatine ratios in relation to the tumour type with the highest values in high-grade gliomas and metastases. A Ch/Cr ratio equal or higher than 1.78 predicted malignancy at 80% sensitivity and 73% specificity. We found no significant differences in the relative cerebral blood volume (rCBV) for every type of tumour. The mean rCBV was 1.24 for benign tumours and 1.5 for the malignant ones(1.24 for low-grade gliomas, 1.91 for anaplastic gliomas, 1.03 for glioblastomas, and 1.57 for metastases).We conclude that, individually considered, MRS is superior to Perfusion-weighted MRI in the initial assessment of brain tumours. Perfsion MRI has not demonstrated predictive power to distinguish malignant from benign tumours.

PMID: 15937650 [PubMed - in process]

9: J Neurooncol. 2005 May;72(3):255-60.: P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy.

Oberndorfer S, Piribauer M, Marosi C, Lahrmann H, Hitzenberger P, Grisold W.

Department of Neurology and LBI for Neurooncology, Kaiser Franz Josef Hospital, SMZ-Sud, Kundratstr. 3, 1100, Vienna, Austria, stefan.oberndorfer@wienkav.at.

The co-administration of antiepileptic drugs (AED) and chemotherapeutic agents in patients with glioblastoma multiforme (GBM) is common. Interactions of chemotherapeutic agents and AED have not been investigated sufficiently. The purpose of this study is to evaluate the effects of enzyme inducing (EI-AED) and non-EI-AED in patients with GBM treated with standard chemotherapeutic agents on survival and haematotoxicity. One hundred and sixty eight glioblastoma patients with standard treatment including surgery, radiotherapy and chemotherapy were retrospectively analysed. Patients were separated into three groups: Group A patients without AED (n=88), Group B patients with EI-AED (n=43), and Group C patients with non-EI-AED (n=37). CCNU was the most frequently used first-line drug in all three groups (Group A: 77%; Group B: 81%; Group C: 78%). Second line treatment, mainly temozolomide, was applicated in 58 of patients and third-line treatment in 9. Carbamazepine was the most frequently administered AED in Group B (81%) and valproic acid in Group C (85%). For statistical analysis, only patients with CCNU first line treatment were calculated. A significant difference regarding survival was detected between Group B (10.8 month) and Group C (13.9 month), as well as increased haematotoxicity for Group C. These results indicate that AED influence the pharmacokinetics of chemotherapeutic drugs in patients with GBM. Valproic acid might be responsible for increasing haematotoxicity. Whether the difference regarding survival between Group B and Group C is due to a decrease of efficacy of chemotherapeutic agents by EI-AED, or due to increased efficacy of chemotherapeutic agents caused by the enzyme inhibiting properties of valproic acid, has to be evaluated in future studies.

PMID: 15937649 [PubMed - in process]

10: J Neurooncol. 2005 May;72(3):245-53.: Neuropsychological performance and quality of life of 10 year survivors of childhood medulloblastoma.

Maddrey AM, Bergeron JA, Lombardo ER, McDonald NK, Mulne AF, Barenberg PD, Bowers DC.

Division of Consult Liaison & Behavioral Medicine, Department of Psychiatry, U.T. Southwestern Medical Center, The Annette Strauss Center for Neuro-Oncology, 5323 Harry Hines Blvd, Dallas, TX, 75390-8898, USA.

Purpose: Survivors of medulloblastoma, the most frequently occurring malignant brain tumor of childhood, suffer neuropsychological damage in the first decade after diagnosis. Cognitive performance, psychosocial functioning and quality of life were assessed in medulloblastoma survivors in the second decade after diagnosis. Methods: Ten year survivors were evaluated with a battery of neuropsychological tests, and self-report questionnaires regarding quality of life and emotional functioning. Clinical variables examined included the patient's age at diagnosis, duration since diagnosis, treatment, and complications. Results: Sixteen medulloblastoma survivors [mean age at diagnosis: 7.2 years, range: 1-15 years; 6 males] were tested at a mean age of 22.2 years [range: 13.6-27.9 years]. All survivors had been treated with craniospinal radiation therapy; nine were treated with chemotherapy. Significant impairments were identified in more than 50 of survivors on tests within all neuropsychological domains, including attention, memory, visuospatial abilities, motor functioning, language, and executive functioning. Significant impairments were also identified in all psychosocial domains examined, including employment, ability to drive an automobile, participation in normal education, independent living, and dating history. Most importantly, quality of life scores, reported by both survivors and their caretakers, were in the normal range. Conclusion: Survivors of childhood medulloblastoma frequently suffer severe persistent deficits in a wide-range of neuropsychological functional domains. Nevertheless, survivors and their families do not report impaired quality of life. These severe neuropsychological and psychosocial deficiencies justify further attempts to reduce or delay the use of craniospinal radiation therapy for childhood medulloblastoma.

PMID: 15937648 [PubMed - in process]

11: J Neurooncol. 2005 May;72(3):241-4.: A phase I trial of surgery, Gliadel wafer implantation, and immediate postoperative carboplatin in combination with radiation therapy for primary anaplastic astrocytoma or glioblastoma multiforme.

Limentani SA, Asher A, Heafner M, Kim JW, Fraser R.

Carolinas Hematology-Oncology Associates, 1100 South Tryon Street, Charlotte, North Carolina, 28203, USA, steven.limentani@carolinashealthcare.org.

Two types of chemotherapy used in the treatment of patients with malignant glioma are carboplatin and Gliadel((R)) wafer [(3.85% 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU)]. To date there have been no published data examining their concurrent use in this disease. The purpose of this study was to evaluate combination chemotherapy with Gliadel wafer and carboplatin in patients with high-grade, malignant glioma. In this prospective phase I study, 16 patients underwent surgery, Gliadel wafer implantation (up to 8 wafers), intravenous carboplatin given postoperatively (day 3 or 4) at a dose escalation range of area under the curve (AUC)=2-6, and external beam radiation. Median age was 55 years (range 27-66 years). Fourteen (88%) patients had glioblastoma multiforme and 2 (12%) had anaplastic astrocytoma. Performance status was as follows: Eastern Cooperative Oncology Group (ECOG)=0 (2 patients), ECOG=1 (13 patients), and ECOG=2 (2 patients). Three patients were treated at each dosing level (AUC=2-6), and 4 patients were treated at an AUC=5. Carboplatin was administered to all patients by postoperative day 4. Radiation was begun on day 14-36. No grade 3 or 4 toxicities were noted in this study. Median progression-free and overall survival was 266 and 679 days, respectively. We conclude that administering systemic carboplatin is safe and well tolerated in the postoperative period immediately following resection and implantation of Gliadel wafer for the treatment of malignant glioma. Further evaluation in a phase II setting, at maximal carboplatin dose to establish potential efficacy, with this combination is warranted.

PMID: 15937647 [PubMed - in process]

12: J Neurooncol. 2005 May;72(3):231-8.: Prognostic significance of the immunohistochemical index of survivin in glioma: a comparative study with the MIB-1 index.

Uematsu M, Ohsawa I, Aokage T, Nishimaki K, Matsumoto K, Takahashi H, Asoh S, Teramoto A, Ohta S.

Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki, Kanagawa, Japan, 211-8533, ohta@nms.ac.jp.

Objective: Survivin has been identified as a protein expressed in cancer cells and a member of the inhibitor-of-apoptosis protein family. Recent studies suggest that the expression of survivin increases during the G2/M phase of the cell cycle, and may be used in clinical prognosis. We examined whether survivin expression in human gliomas would be a correlative of prognosis. Methods: We prepared polyclonal anti-survivin serum to establish a survivin index for stained sections, using an immunohistochemical procedure, according to the method used for scoring MIB-1 index, and then stained 29 paraffin-embedded sections from surgical specimens of 29 patients who were classified into three grades of World Health Organization with the mean age of low grade astocytoma (grade II) being 34.7; anaplastic astrocytoma (grade III), 48.8; and glioblastoma multiform (grade IV), 58.4. Results: On staining with the anti-survivin antiserum, all specimens contained positive cells, but the survivin index was heterogeneous among grades. The mean percentage of immunoreactive cells in each specimen was 70.0 (SD 18.2) in grade II, 81.3 (16.5) in grade III, and 85.0 (13.6) in grade IV. Then we compared the survivin index to the MIB-1 index and found that in low-grade gliomas (grade II and III), the difference in survival times between the high and low survivin indexes was significant (P=0.007), whereas that between the high and low MIB-1 indexes was not significant (P=0.092).Conclusion: Survivin is more sensitive marker than MIB-1 for the evaluation of low-grade gliomas in that it helps to predict patient survival. Much larger glioma patient series are needed to validate the findings of our limited study.

PMID: 15937645 [PubMed - in process]

13: J Neurooncol. 2005 May;72(3):217-23.: Interferons upregulate thymidine phosphorylase expression via JAK-STAT-dependent transcriptional activation and mRNA stabilization in human glioblastoma cells.

Yao Y, Kubota T, Sato K, Takeuchi H, Kitai R, Matsukawa S.

Department of Neurosurgery Department of Microbiology and Immunology, Indiana University School of Medicine and Walther Oncology Center, Indianapolis, IN, 46202, USA.

Overexpression of the angiogenic enzyme thymidine phosphorylase (TP) in tumor cells and/or infiltrating macrophages correlates with increased microvessel density and poor prognosis in various tumor types including glioma. The present study examined how the TP gene expression is regulated by different types of interferons (IFNs) in human T98G and A172 glioblastoma cells. Both type I (alpha, beta) and type II (gamma) IFNs upregulated TP mRNA and protein expression while inhibiting cell proliferation. IFN-induced TP mRNA accumulation was not inhibited by the protein synthesis inhibitor cycloheximide, but was strongly blocked by the transcription inhibitor actinomycin D, as well as by transcription factor decoy oligodeoxynucleotides containing the putative IFN response element or the gamma-activated sequence in the TP promoter. The Janus kinase (JAK) inhibitor AG-490 blocked both IFN-induced STAT1 (signal transducers and activators of transcription 1) phosphorylation and TP expression. All IFNs increased the stability of TP mRNA as well. In addition, IFN-evoked TP enzyme activity enhanced the cytotoxicity of 5-fluorouracil (5-FU). These findings indicate that TP expression may be upregulated by IFNs via the JAK-STAT signaling pathway and both transcriptional and posttranscriptional mechanisms. Combined treatment with IFN and 5-fluorouracil may be a useful therapeutic strategy for malignant gliomas.

PMID: 15937643 [PubMed - in process]

14: J Neurooncol. 2005 May;72(3):209-15.: Local chemotherapy of F98 rat glioblastoma with paclitaxel and carboplatin embedded in liquid crystalline cubic phases.

Eckardstein KL, Patt S, Kratzel C, Kiwit JC, Reszka R.

Department of Neurosurgery, HELIOS Klinikum Berlin, Klinikum Buch, Berlin, Hobrechtsfelder Chaussee 96, 13125, Germany, keckardstein@berlin.helios-kliniken.de.

Implanted drug carrier systems for retarded chemotherapy against gliomas are mainly based upon polymers containing nitrosoureas. The authors have developed an intracavitary carrier system of biodegradable liquid crystalline cubic phases encapsulating carboplatin and paclitaxel and studied it for release kinetics, antitumor activity, and survival prolongation. A total of 61 Fisher rats with F98 tumors were divided into six treatment groups at day 12 post-inoculation, receiving either no treatment, surgery with partial tumor resection, or partial resection with implantation of cubic phases containing either paclitaxel and carboplatin, paclitaxel alone, carboplatin alone, or no drug. Animals were killed for tumor size analysis at day 21 post-inoculation (n=28) or were included in survival studies (n=33). Additional 12 animals received a paclitaxel/carboplatin application and were killed at different time intervals (6 h, 24 h, 48 h, 5 d, 7 d, 10 d post-agent application) for in vivo diffusion studies. Animals from the paclitaxel/carboplatin group showed a significantly smaller tumor (mean 3.25 mm(2) +/- SD 1.79 mm(2)) than animals from the control group (15.30 +/- 5.86 mm(2); P=0.0031), animals having received the empty matrix (11.62 +/- 6.66 mm(2); P=0.0241), and animals after tumor resection without implantation (20.87 +/- 3.56 mm(2); P </= 0.0001). There was no significant difference in survival. Carboplatin was found in brain tissue at 6 h, paclitaxel was found at up to 48 h after implantation at 3 mm distance. Biodegradable crystalline cubic phases embedding cytotoxic drugs as paclitaxel and carboplatin might play an important role in local glioblastoma treatment.

PMID: 15937642 [PubMed - in process]

15: J Nucl Med. 2005 Jun;46(6):1042-51.: Dosimetry and Radiographic Analysis of 131I-Labeled Anti-Tenascin 81C6 Murine Monoclonal Antibody in Newly Diagnosed Patients with Malignant Gliomas: A Phase II Study.

Akabani G, Reardon DA, Coleman RE, Wong TZ, Metzler SD, Bowsher JE, Barboriak DP, Provenzale JM, Greer KL, Delong D, Friedman HS, Friedman AH, Zhao XG, Pegram CN, McLendon RE, Bigner DD, Zalutsky MR.

Department of Radiology, Duke University Medical Center, Durham, North Carolina.

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

PMID: 15937318 [PubMed - in process]

16: J Nucl Med. 2005 Jun;46(6):945-52.: Imaging Proliferation in Brain Tumors with 18F-FLT PET: Comparison with 18F-FDG.

Chen W, Cloughesy T, Kamdar N, Satyamurthy N, Bergsneider M, Liau L, Mischel P, Czernin J, Phelps ME, Silverman DH.

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California.

3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) is a recently developed PET tracer to image tumor cell proliferation. We characterized (18)F-FLT PET of brain gliomas and compared (18)F-FLT with (18)F-FDG PET in side-by-side studies of the same patients. METHODS: Twenty-five patients with newly diagnosed or previously treated glioma underwent PET with (18)F-FLT and (18)F-FDG on consecutive days. Three stable patients in long-term remission were included as negative control subjects. Tracer kinetics in normal brain and tumor were measured. Uptake of (18)F-FLT and (18)F-FDG was quantified by the standardized uptake value (SUV) and the tumor-to-normal tissue (T/N) ratio. The accuracy of (18)F-FLT and (18)F-FDG PET in evaluating newly diagnosed and recurrent gliomas was compared. More than half of the patients underwent resection after the PET study and correlations between PET uptake and the Ki-67 proliferation index were examined. Patients were monitored for a mean of 15.4 mo (range, 12-20 mo). The predictive power of PET for tumor progression and survival was analyzed using Kaplan-Meier statistics. RESULTS: (18)F-FLT uptake in tumors was rapid, peaking at 5-10 min after injection and remaining stable up to 75 min. Hence, a 30-min scan beginning at 5 min after injection was sufficient for imaging. (18)F-FLT visualized all high-grade (grade III or IV) tumors. Grade II tumor did not show appreciable (18)F-FLT uptake and neither did the stable lesions. The absolute uptake of (18)F-FLT was low (maximum-pixel SUV [SUV(max)], 1.33) but image contrast was better than with (18)F-FDG (T/N ratio, 3.85 vs. 1.49). (18)F-FDG PET studies were negative in 5 patients with recurrent high-grade glioma who subsequently suffered tumor progression within 1-3 mo. (18)F-FLT SUV(max) correlated more strongly with Ki-67 index (r = 0.84; P < 0.0001) than (18)F-FDG SUV(max) (r = 0.51; P = 0.07). (18)F-FLT uptake also had more significant predictive power with respect to tumor progression and survival (P = 0.0005 and P = 0.001, respectively). CONCLUSION: Thirty-minute (18)F-FLT PET 5 min after injection was more sensitive than (18)F-FDG to image recurrent high-grade tumors, correlated better with Ki-67 values, and was a more powerful predictor of tumor progression and survival. Thus, (18)F-FLT appears to be a promising tracer as a surrogate marker of proliferation in high-grade gliomas.

PMID: 15937304 [PubMed - in process]

17: J Nucl Med. 2005 Apr;46(4):574-9.

Timing of examination affects reliability of 99mTc-methoxyisobutylisonitrile SPECT in distinguishing neoplastic from nonneoplastic brain hematomas.

Minutoli F, Angileri FF, Conti A, Herberg A, Arico D, Baldari S, Cardali S, de Divitiis O, Germano A, Baldari S.

Department of Radiological Sciences, University of Messina, Messina, Italy.

99mTc-methoxyisobutylisonitrile (MIBI) SPECT has been reported to be 100% sensitive and specific in the early differential diagnosis between neoplastic and nonneoplastic intraparenchymal cerebral hemorrhage (ICH), because nonneoplastic ICH does not show 99mTc-MIBI accumulation on SPECT examinations performed within 48 h from the onset of clinical symptoms. The aims of this study were to investigate the behavior of nonneoplastic ICH on more delayed 99mTc-MIBI SPECT examinations and to determine how the timing of examination affects the reliability of 99mTc-MIBI SPECT in differentiating neoplastic from nonneoplastic ICH. METHODS: We prospectively enrolled 32 patients with acute neurologic deterioration caused by nontraumatic ICH. Patients were randomly allocated to 4 groups of 8 patients each. Patients in the first, second, third, and fourth groups underwent 99mTc-MIBI SPECT 2, 5, 10, and 30 d, respectively, after the onset of clinical deterioration. Furthermore, patients in the first group underwent a second (99m)Tc-MIBI SPECT examination at 30 d. 99mTc-MIBI SPECT studies were visually and semiquantitatively evaluated. Patients were followed up to confirm the nonneoplastic etiology of the ICH. RESULTS: Two of the 32 studied patients, 1 in the second and 1 in the fourth group, were excluded because the ICH turned out to be related to a neoplastic lesion. Visual analysis showed no 99mTc-MIBI uptake in any patient studied at 2 d, whereas increased radiotracer uptake was found in 1 (14%) of 7, 5 (62.5%) of 8, and 5 (71%) of 7 patients studied 5, 10, and 30 d, respectively, after clinical deterioration. Moreover, with the semiquantitative analysis, a statistically significant difference was found among 99mTc-MIBI indices in the 4 groups (P = 0.0011). All patients in group 1 showed a significant 99mTc-MIBI accumulation when studied at 30 d. CONCLUSION: Nonneoplastic ICH, showing no 99mTc-MIBI uptake within 2 d, can show 99mTc-MIBI accumulation on more delayed imaging. 99mTc-MIBI SPECT can clearly differentiate between neoplastic and nonneoplastic ICH only during the acute phase. Our findings suggest that examination be performed early after the onset of symptoms and certainly within 5 d.

Publication Types:

Clinical Trial
Randomized Controlled Trial

PMID: 15809478 [PubMed - indexed for MEDLINE]

18: Neurology. 2004 Oct 12;63(7):1299-301.

Polyomaviruses and primary central nervous system lymphomas.

Murray JM, Morgello S.

Department of Pathology, Box 1143, Mount Sinai School of Medicine, New York, NY 11377, USA. jacinta.murray@mssm.edu

The authors investigated the potential association of human primary CNS non-Hodgkin lymphoma (PCNSL) with polyomavirus in HIV-1 infected and uninfected individuals. Immunohistochemical analysis of CNS biopsies from 19 HIV-negative and 17 HIV-positive patients and PCR analysis of 12 HIV-negative and 14 HIV-positive patients revealed that the lymphomas were uniformly negative for polyomaviruses. The authors conclude that polyomaviruses are unlikely to be related to the pathogenesis of most PCNSL.

PMID: 15477558 [PubMed - indexed for MEDLINE]

19: Surg Neurol. 2005 Jun;63(6):584-5.: Meningioma associated with abscess formation-a case report.

Young JP, Young PH.

Department of Surgery-Section of Neurosurgery, St. Louis University School of Medicine, MO 63109, USA.

A rare case of meningioma associated with both intratumoral and peritumoral abscess formation occurred in a 38-year-old man presenting with signs and symptoms of elevated intracranial pressure, intracranial infection, and right temporal pole mass lesion. The mass lesion was totally removed, revealing a meningioma. Group B streptococcus and peptostreptococcus were cultured from both the tumor and peritumoral white matter. Hematogenous spread of the organisms related to recent dental work was the likely mechanism.

PMID: 15936397 [PubMed - in process]

20: Surg Neurol. 2005 Jun;63(6):576-82.: Extremely rare glioblastoma multiforme of the conus medullaris with holocord and brain stem metastases, leading to cranial nerve deficit and respiratory failure: a case report and review of the literature.

Medhkour A, Chan M.

Division of Neurological Surgery, The Medical College of Ohio, Toledo, OH 43614-5807, USA; Division of Neurological Oncology, The Medical College of Ohio, Toledo, OH 43614-5807, USA.

BACKGROUND: Spinal glioblastoma multiforme (GBM) is an uncommon entity and metastases are extremely rare. Glioblastoma multiforme of the conus medullaris is a rare and highly aggressive entity that can quickly progress to a dismal state. Proper diagnosis via histopathologic and immunochemical staining with close clinical and radiological follow-up is important for the management of this very aggressive tumor. CASE DESCRIPTION: The authors report the clinical features, histopathologic and immunochemical staining characteristics, as well as the radiographic evidence of a case of primary GBM of the conus medullaris with metastases to the whole spinal cord and brain in a 20-year-old man who presented with low back pain and bilateral lower extremity weakness and numbness. Review of the pathology slides using histopathologic and immunochemical staining showed GBM. Serial magnetic resonance scans, performed after the initial surgery, demonstrated enlargement of the primary GBM in the conus medullaris with metastases to the thoracic and cervical spinal cord as well as to the brain. CONCLUSIONS: Glioblastoma multiforme of the conus medullaris with such clinical findings is extremely rare. We analyze similar cases in the literature and discuss the importance of monitoring the progression of such an entity as well as the need for aggressive management of the different complications as they arise to maintain a good quality of life.

PMID: 15936395 [PubMed - in process]

21: Surg Neurol. 2005 Jun;63(6):542-8.: Correlation of factors predicting intraoperative brain shift with successful resection of malignant brain tumors using image-guided techniques.

Benveniste RJ, Germano IM.

Department of Neurosurgery, Mt Sinai School of Medicine, New York, NY 10029, USA.

BACKGROUND: Intraoperative brain shift may cause inaccuracy of stereotactic image guidance on the basis of preoperatively acquired imaging data. The purpose of our study was to determine whether factors predicting brain shift affect the success of image-guided resection of malignant brain tumors. METHODS: We retrospectively studied 54 patients who underwent image-guided resections of histopathologically confirmed malignant brain tumors (9 metastases, 45 high-grade gliomas). Precautions were taken during surgery to minimize brain shift, but intraoperative imaging was not performed. The following factors predictive of intraoperative brain shift were assessed: tumor size, periventricular location, patient age, prior surgery or radiation therapy, patient positioning, use of mannitol, and length of operative time. Postoperative magnetic resonance imaging was obtained in all cases within 48 hours of surgery to assess extent of resection. RESULTS: Perioperative mortality was 0% in our series; perioperative morbidity was 3 of 54 patients (5.5%); 1 patient required reoperation for a hematoma, and 2 had transient neurological deficits. Successful resection was accomplished in 93% of tumors less than 30 cm(3) compared with 63.6% of tumors greater than 30 cm(3) (P = .026, Fisher exact test). This difference was more pronounced for patients with malignant gliomas. However, other factors predictive of intraoperative brain shift were not associated with unsuccessful resection. CONCLUSIONS: Intraoperative brain shift does not significantly affect the likelihood of successful resection of malignant brain tumors smaller than 30 cm(3). Larger tumors are less likely to be successfully resected, although factors other than brain shift can contribute to unsuccessful resection.

PMID: 15936381 [PubMed - in process]

22: Surg Neurol. 2005 Jun;63(6):520-5.: Immunohistochemical detection of female sex hormone receptors in craniopharyngiomas: correlation with clinical and histologic features.

Izumoto S, Suzuki T, Kinoshita M, Hashiba T, Kagawa N, Wada K, Fujimoto Y, Hashimoto N, Saitoh Y, Maruno M, Yoshimine T.

Department of Neurosurgery, Osaka University Medical School, Osaka 565-0871, Japan.

BACKGROUND: Although craniopharyngiomas have a histologically benign nature, their treatment can be difficult. The correlation among clinical, proliferative, and immunohistologic features of female sex hormone receptors was determined in craniopharyngiomas to analyze whether they influence the growth of the tumor. METHODS: The study subjects were 43 patients with previously untreated craniopharyngioma who underwent surgery at our department over the past 15 years. Serial tissue sections were immunostained with the antibodies against estrogen receptor (ER), progesterone receptor (PR), and Ki-67. RESULTS: The Ki-67 labeling index was significantly higher in patients with regrowth (7.8%) than without regrowth (3.9%). ER and PR were detected in 9 of 30 (30%) craniopharyngiomas, and the incidence of postoperative tumor regrowth was significantly higher in patients negative for ER and PR (29%) than in those positive for both receptors (11%). CONCLUSIONS: A high Ki-67 labeling index suggests a high possibility of tumor regrowth, and the presence of ER and PR is suggestive of a high tissue differentiating potential. ER and PR assay may be useful for determining the indication for additional radiation therapy in craniopharyngioma patients treated by incomplete resection.

PMID: 15936368 [PubMed - in process]

23: Surg Neurol. 2005 Jun;63(6):511-9.: Why are systemic glioblastoma metastases rare? Systemic and cerebral growth of mouse glioblastoma.

Mourad PD, Farrell L, Stamps LD, Chicoine MR, Silbergeld DL.

Department of Neurological Surgery, University of Washington, Seattle, WA 98195-6470, USA; Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, WA 98195-6470, USA.

BACKGROUND: Systemic metastasis of glioblastoma multiforme (GBM) in the form of bulk tumor is rare. This could be because of patient death before clinically detectable systemic metastasis, impediments to systemic egress, or the inability of GBM to grow outside the central nervous system (CNS). In the present paper, we tested this last hypothesis. METHODS: The delayed brain tumor (DBT) cell was characterized with respect to in vitro and in vivo morphology, growth rate, anchorage-independent growth, glial fibrillary acidic protein expression and cytogenetic analysis, and major histocompatibility complex (MHC) typing. We then assayed implantation-induced intracerebral and systemic GBM growth using 3 rodent models with increasing relative immunologic differences between implanted DBT cells and hosts (Balb/c mice, an isograft, MHC I H2, class type D; C3H mice, an allograft; Wistar rats, a xenograft). RESULTS: After implantation in the brain, DBT cells generated tumors that were similar to human GBM. Intracerebral DBT implantation as an isograft or allograft produced only intracranial tumors, whereas intracerebral and systemic implantation as a xenograft produced no tumors. Systemic isograft implantation yielded only systemic tumors. Systemic implantation as allografts produced only transient subcutaneous masses. CONCLUSIONS: Delayed brain tumor cells implanted outside the CNS formed tumors unless there was a significant difference between the immunotype of the implanted cells and host. These results support the hypothesis that the rarity of systemic GBM tumors lies in the presence of physical barriers and/or systemic hurdles that prevent their timely growth. These results also demonstrate that GBMs are antigenic, although not immunogenic, with their syngeneic host. Therefore, GBM may be amenable to targeted immunotherapy given successful artificial priming of the immune system.

PMID: 15936366 [PubMed - in process]