The potential for strategies using micronutrients and heterocyclic drugs to treat invasive gliomas

Summary ¶Local invasion of neoplastic cells into the surrounding brain is perhaps the most important aspect of the biology of gliomas that precludes successful therapy. Despite significant advances in neuro-imaging, neurosurgery and radiotherapy, the median survival for patients with a malignant glioma is still less than one year. With the increasing knowledge of the biology of brain tumours, derived from cellular and molecular studies, new methods of treatment are being developed with some success. Approaches studied already include anti-invasive, pro-apoptotic and anti-angiogenesis strategies and clinical trials are imminent.In this article we review two new approaches to the management of gliomas: nutraceutical intervention and heterocyclic drugs. The first approach uses a combination of naturally occurring agents, including citrus flavonoids, chokeberry extract, red grape seed extract, lycopene, selenium and red clover extract. These agents can either trigger apoptosis or affect the pathways underlying diffuse invasion. The second approach involves the use of a heterocyclic drug, clomipramine, which selectively triggers apoptosis in neoplastic cells but not in normal glia. The article refers to the results of recent studies performed in our laboratory which suggest that these new approaches can be translated into benefit to patients.Published online July 31, 2003     

Molecular Targeting with Recombinant Cytotoxins of Interleukin-13 Receptor α 2-expressing Glioma

A restricted receptor for interleukin 13 (IL-13R2) is over-expressed in high-grade astrocytoma (HGA), but not in normal organs. In order to design and examine new anti-HGA therapies, which are molecularly directed against IL-13R2, we established an IL-13R2-expressing syngeneic immunocompetent murine model of HGA. The model was obtained by transfecting G-26 murine glioma cells with IL-13R2. G-26-IL-13R2(+) cells, but not mock-transfected cells, became susceptible to IL-13 mutant-based cytotoxic proteins that kill human HGA cells. G-26-IL-13R2(+) cells maintained their tumorigenicity in immunocompetent C57BL/J6 mice and preserved their expression of IL-13R2 in vivo. These characteristics of the G-26-IL-13R2(+) tumors allowed us to test molecularly defined anti-glioma passive immunotherapy. A targeted recombinant chimera cytotoxin composed of multiply mutated IL-13 (IL-13.E13Y/R66D/S69D) and a derivative of Pseudomonas exotoxin (PE), PE1E, IL-13.E13Y/R66D/S69D-PE1E, was used in anti-tumor experiments. G-26-IL-13R2(+) cells were killed by IL-13.E13Y/R66D/S69D-PE1E in an IL-4-independent fashion. To test the cytotoxin in vivo, G-26-IL-13R2(+) tumors were established in C57BL/J6 mice and when the tumors reached a size of at least 50mm³, the mice were treated with IL-13.E13Y/R66D/S69D-PE1E. In the mice treated with the targeted fusion cytotoxin, the tumors regressed and 80% of the animals were cured. This study documents the establishment of an IL-13R2-positive model of HGA in immunocompetent rodents. Furthermore, the effectiveness and safety of the targeted IL-13-based cytotoxin against IL-13R2-expressing tumors in a more clinically relevant in vivo HGA model is promising with regard to the future clinical utility of the cytotoxin.     

Prediction of Pathology and Survival by FDG PET in Gliomas

Objectives: Despite being in use for nearly two decades, the utility of [18F]2-fluoro-2deoxy-d-glucose positron emission tomography (FDG PET) in the evaluation and treatment of brain tumors remains controversial. We retrospectively analyzed all patients with histologically proven gliomas, between the years 1990 and 2000, who underwent FDG PET studies at various stages of their treatment and who were followed till either death or for a minimum period of 1 year in an attempt to bring resolution to this controversy. Methods: All PET scans prior to 1997 were acquired on an ECAT 951/31 scanner in 2D. Scans since 1997 were obtained on a Siemens HR+ scanner in 3D mode. The majority of FDG PET scans were co-registered with the magnetic resonance imaging (MRI) scans to aid in diagnosis and therapy. Based on independent visual inspection, two board certified nuclear medicine physicians graded the highest activity level of the tumor using the metabolic grading: 0 = no uptake; 1 = uptake less or equal to normal white matter; 2 = uptake greater than normal white matter and less than gray matter; 3 = uptake equal to or greater than gray mater. The measure of association of lambda was used to measure the strength of predictive ability of FDG PET for pathological grading of the gliomas. The Cox proportional hazards regression model was used to assess the significance of grade of uptake on survival. Results: A total of 331 patients were analyzed of which 137 had a PET scan prior to histological diagnosis and therapeutic intervention (mean age = 46.5years; M:F = 1.7:1). Eighty six percent (143/166) of the patients with low uptake (metabolic scores 0,1) had low-grade gliomas (grade I,II) and 14% (23/166) high-grade gliomas (grade III,IV) on histologic examination. Ninety four percent (154/165) of the patients with high uptake (metabolic scores 2,3) on PET had high-grade gliomas and 7% (11/165) had low-grade gliomas on histologic examination. The grade of uptake had increasing significance on survival as the level increased from 'low' to 'high' (P = 0.0009). Ninety four percent (156/166) of the patients with low uptake survived for >1 year (median survival of 28 months) and 19% survived for >5 years. Only 29% (48/165) of patients with high uptake survived for >1 year, (median survival of 11 months) and none survived for >5 years. Irrespective of when the scan showed a high uptake of FDG, before or after intervention, the prognosis following that scan was poor. Conclusions: Our observations confirm the utility of FDG PET as a prognostic tool for the histological grading and survival in patients with gliomas and appears to more than complement pathological grading.     

Tolerance of Nitrosurea-Based Multiagent Chemotherapy Regime for Low-Grade Pediatric Gliomas

The aim of this study was to compare tolerance of a nitrosurea-based regime with 'standard' therapy of vincristine (VCR) and carboplatin for low-grade gliomas. Ten children with low-grade gliomas received second line therapy consisting of thioguanine, procarbazine, CCNU and vincristine (TPCV). Two groups were identified, i.e. patients who had either experienced significant toxicity with carboplatin (reaction group) or had re-growth of their tumor (re-growth group) following first line therapy. Patients were evaluated for toxicity. Data was available on nine patients. Patients in the reaction group completed a mean of 3 cycles of TPCV (range 2–4). One patient stopped after 2 cycles of TPCV due to tumor progression and died 3 months later and one remained on therapy at the time of analysis. Patients in the re-growth group received a mean of 5.5 cycles of TPCV (range 4–8). Treatment was discontinued in one patient after 4 cycles due to hematological toxicity, one experienced tumor progression after 4 cycles and one stopped after 6 cycles because of neurological toxicity. There was no difference in the incidence of grade 3/4 neutropenia or thrombocytopenia, transfusion requirements or delays in chemotherapy between TPCV and VCR/carboplatin in either group. There were no serious infections or toxic deaths. Seven of nine patients had stable disease at a mean of 13 months of follow up. TPCV therapy is a well-tolerated regime with comparable bone marrow toxicity to VCR/carboplatin. Significant disease stabilization was observed with TPCV and hence this regime may be used as second line therapy.     

Dose-intensive,Time-compressed Procarbazine,CCNU, Vincristine (PCV) with Peripheral Blood Stem Cell Support and Concurrent Radiation in Patients with Newly Diagnosed High-grade Gliomas

The dose intensity of the PCV regimen can be doubled using peripheral blood stem cell (PBSC) support. This study sought to determine the feasibility of giving dose-intensive PCV concurrently with radiation therapy. Twelve patients, age 3.2–22.7 years, median 7.5 years, with newly diagnosed high grade gliomas were enrolled. Diagnoses included diffuse intrinsic brainstem gliomas (BSG) (n=6), glioblastoma (n=4), anaplastic astrocytoma (n=2). PBSCs were harvested prior to chemotherapy with G-CSF priming. Chemotherapy consisted of CCNU 130 mg/m² and vincristine 1.5 mg/m² on day 0, and procarbazine 150 mg/m² on days 1–7. PBSCs were reinfused on day 9 of each course. Four courses of chemotherapy were administered every 28 days or when blood counts recovered. The first course was administered the week prior to RT, the second course began on week 3 of RT and the third and fourth course were given after RT. Hematologic toxicity was mild and the majority of courses were given on schedule. Five of six patients with diffuse BSG showed clinical improvement and three showed a radiographic response; however, only one remains alive 12+ months from diagnosis. All four patients with non-brainstem large-volume tumors showed clinical deterioration and radiographic progression during or shortly after RT. MRI scans showed massive edema and enhancement. Median time to radiographic progression was five months. Median overall survival was 11 months. We conclude that dose-intensive, time-compressed PCV given concurrently with large-volume RT appears to result in unacceptable toxicity in patients with large residual tumors.     

脑胶质瘤中cyclin D1／p16—pRB路径的异常及意义

目的 研究ｃｙｃｌｉｎＤ１／ｐ１６－ｐＲＢ路径在脑胶质瘤中的异常情况，并对其意义进行分析。方法 用免疫且化对２３例脑胶质瘤（包括１４例星形细胞瘤和９例胶质母细胞瘤）及６例正常脑组织中３种因子的表达进行检测，并分析了实验结果与肿瘤分型的关系以及各个因子在此路径中的作用。结果 ２３例肿瘤中有１７例ｃｙｃｌｉｎ Ｄ１过度表达（７３．９％），１３ｐ１６和８例ｐＲＢ缺失（５６．５％和３４．８％），３种因子的     

Serial stereotactic biopsies and CT scan in gliomas: correlative study in 100 astrocytomas,oligo-astrocytomas and oligodendrocytomas

Histologic features of 100 supra-tentorial astrocytomas, oligodendrogliomas and oligo-astrocytomas obtained from serial stereotactic biopsies were compared with the corresponding CT scans. Topographic comparisons provided by visualization of the biopsy trajectories on post-biopsy CT scans were available in 24 cases. Areas of contrast enhancement and low attenuation were compared with the histologic grade of malignancy, tumor delimitation and structural type. The latter was determined as follows: Type I-solid tumor tissue without significant peripheral isolated tumor cells; Type II-solid tumor tissue associated with peripheral isolated tumor cells; Type III-isolated tumor cells only.There was a strong correlation between areas of contrast enhancement and tumor microvascularity. In addition, contrast enhancement occurred only in the solid tumor tissue component of the neoplasm. This correlation accounted for the relationship observed between CT images and the structural type of glioma. Contrast enhancement was constant in structural type I gliomas, inconstant in structural type II, and absent in structural type III. No correlation was found between malignancy and contrast enhancement. Contrast enhancement occurred in all grades of malignancy but was a constant feature of grade 4 gliomas. The volume of the tumors could not be reliably determined from CT images alone. Areas of low attenuation on contrast CT scans could correspond to either peritumoral edema or to edematous parenchyma infiltrated by isolated tumor cells.Serial stereotactic biopsies combined with calculations based on the CT scan provided a more precise definition of the tumor volume and identification of structural type. Such classification may prove useful in prospective analysis of various modes of therapy.     

Multicentric Gliomas Misdiagnosed as Metastatic Tumors: One Case Report and Literature Review

Introduction Multicentric gliomas are considered to be well recognized but uncommon; often scatter widely in different lobes or hemispheres; and cannot be attributed to a definite pathway[1]. A patient diagnosed as multicentric gliomas is presented in this paper. He was fi rstly misdiagnosed as cerebral metastatic tumors, but later the histopathological examination revealed them to be glioblastoma (WHO grade IV). Additionally, the aim of the paper was to describe the case history of the patient and the problems encountered in the pathogenesis, pathophysiology, diagnosis and treatment.     

Short echo time MR spectroscopy of brain tumors: Grading of cerebral gliomas by correlation analysis of normalized spectral amplitudes

Purpose:

To process single voxel spectra of low‐ and high‐grade gliomas. To propose correlation analysis of the scatter plots of normalized spectral amplitudes as a pattern recognition tool for the classification (grading) of brain tumors. To propose a spectrum processing approach that improves the differentiation of proton spectra with dominating macromolecule and lipid peaks.

Materials and Methods:

LCModel was used to process spectra. Mean metabolite concentrations and mean normalized spectra were obtained for normal white matter and for gliomas. The mean spectra of macromolecules and lipids (ML) in the range 1.4–0.9 ppm, and mean difference spectra (DS) without ML and lactate were computed. Correlation analysis of the scatter plot of the patient and mean normalized spectral amplitudes and dispersion of the scatter plot points were used for classification and grading of tumors.

Results:

It was found advantageous to perform the classifications using DS spectra. The shape of ML spectrum and concentration of tCr seem to be a good markers for glioma grade.

Conclusion:

Combining a qualitative comparison of the patient and mean DS spectra of the tumors using correlation analysis of normalized spectra amplitudes with a quantitative comparison of metabolite concentrations is a powerful tool in studying brain lesions. J. Magn. Reson. Imaging 2010;31:39–45. © 2009 Wiley‐Liss, Inc.     

Fast neutron therapy for malignant astrocytomas

The treatment of supratentorial malignant gliomas has continued to be a major problem for neurosurgeons and oncologists. Post-operative conventional radiotherapy is known to prolong survival and to enhance the quality of life. Local persistence of tumor kills the majority of patients. Fast neutron irradiation is being utilized to treat malignant gliomas based on its reputed radiobiological advantages for treatment of large tumors and the encouraging preliminary reports showing tumor eradication in post-radiation biopsy and autopsy specimens. This paper reviews the results of fast neutron irradiation alone and in combination with photons and hypoxic cell sensitizers. Survival comparisons do not show any superiority for neutrons compared to conventional radiation. However, post-neutron radiation tissue samples have shown less agressive and minimal residual tumor in many instances. At the same time radiation necrosis has emerged as a significant problem. In summary, even though neutron irradiation can eradicate malignant gliomas a therapeutic window has yet to be identified. Address for offprints: Neutron Therapy Facility, MS-301, P.O. Box 500, Batavia, IL 60510, USA