Resected Glioma Research Articles

A Population of HLA-DR+ Immature Cells Accumulates in the Blood Dendritic Cell Compartment of Patients with Different Types of Cancer

Dendritic cell (DC) defects are an important component of immunosuppression in cancer. Here, we assessed whether cancer could affect circulating DC populations and its correlation with tumor progression. The blood DC compartment was evaluated in 136 patients with breast cancer, prostate cancer, and malignant glioma. Phenotypic, quantitative, and functional analyses were performed at various stages of disease. Patients had significantly fewer circulating myeloid (CD11c+) and plasmacytoid (CD123+) DC, and a concurrent accumulation of CD11c−CD123− immature cells that expressed high levels of HLA-DR+ immature cells (DR+IC). Although DR+IC exhibited a limited expression of markers ascribed to mature hematopoietic lineages, expression of HLA-DR, CD40, and CD86 suggested a role as antigenpresenting cells. Nevertheless, DR+IC had reduced capacity to capture antigens and elicited poor proliferation and interferon-γ secretion by T-lymphocytes. Importantly, increased numbers of DR+IC correlated with disease status. Patients with metastatic breast cancer showed a larger number of DR+IC in the circulation than patients with local/nodal disease. Similarly, in patients with fully resected glioma, the proportion of DR+IC in the blood increased when evaluation indicated tumor recurrence. Reduction of blood DC correlating with accumulation of a population of immature cells with poor immunologic function may be associated with increased immunodeficiency observed in cancer.

Caspase 8 is absent or low in many ex vivo gliomas

Better treatments are required urgently for patients with malignant glioma, which currently is incurable. Death ligands, such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), may offer promise for the treatment high-grade glioma if such ligands induce apoptotic signaling in vivo in glioma cells. Caspase 8 is required for death ligand signaling, and its levels may influence the sensitivity of glioma cells to death ligands. It also may act as a tumor suppressor protein. The authors analyzed caspase 8 expression levels in ex vivo glioma specimens and explored potential mechanisms of its regulation. Eleven glioblastomas, 5 anaplastic astrocytomas, and 3 low-grade astrocytomas were studied. The levels of caspase 8, caspase 10, cellular FLICE inhibitory protein (c-FLIP), and signal transducer and activator of transcription (STAT)-1 were assayed using quantitative immunoblotting. Caspase 8 mRNA was measured by Northern blot analysis. The methylation status of the caspase 8 gene was determined by bisulfate modification of genomic DNA, cloning, and sequencing. Statistical analyses were performed using nonparametric (Spearman) correlations. Some ex vivo glioma samples lacked detectable caspase 8, with many expressing barely detectable levels. No tumors expressed significant amounts of caspase 10 or c-FLIP. A strong association was found between caspase 8 mRNA and protein levels. Neither expression of the transcription factor STAT-1 nor caspase 8 gene methylation correlated with caspase 8 levels. The absence of caspase 8 protein in many resected glioma samples implied that many patients with glioma may not benefit from death ligand-based treatments, unless caspase 8 (or caspase 10) protein expression can be elevated. Demethylating agents are unlikely to boost caspase 8 levels in glioma cells, but treatments that increase caspase 8 mRNA levels may up-regulate expression of the protein.

The chemokine GRO-α (CXCL1) confers increased tumorigenicity to glioma cells

The chemokine GRO-alpha (CXCL1) has been found to mediate the proliferation of glia progenitor cells during neural development. As malignant gliomas are thought to arise from glia progenitors or their differentiated counterparts, astrocytes or oligodendrocytes, we have investigated whether GRO-alpha regulates the tumor characteristics of glioma cells. We found first that resected glioma specimens were strongly immunoreactive for GRO-alpha expression in cells with the morphology of tumor cells. In culture, the U251 glioma line transfected to overexpress GRO-alpha had elevated levels of motility and invasiveness. GRO-alpha transfectants increased their expression of several proteins associated with migratory behavior, including matrix metalloproteinase-2, beta1-integrin and SPARC. The implantation of GRO-alpha glioma clones into the brain of nude mice caused the early demise of mice and this was associated with the formation of larger intracerebral tumors when compared with mice implanted with vector control lines. These results implicate GRO-alpha in gliomas and suggest that the dysregulation of a glia proliferative factor contributes to tumorigenesis. Targeting GRO-alpha may be a useful therapeutic tool to control brain tumor biology.

Volumes-cibles anatomocliniques (GTV et CTV) des tumeurs gliales

Gliomas are the most frequent tumors of the central nervous system of the adult. These intraparenchymal tumors are infiltrative and the most important criterion for definition of GTV and CTV is the extent of infiltration. Delineation of GTV and CTV for untreated and resected glioma remains a controversial and difficult issue because of the discrepancy between real tumor invasion and that estimated by CT or MRI. Is particularly helpful a joint analysis of the four different methods as histopathological correlations with CT and MRI, use of new modality imaging, pattern of relapses after treatment and interobserver studies. The presence of isolated tumor cells in intact brain, oedema or adjacent structures requires the definition of two different options for CTV: i) a geometrical option with GTV defined as the tumor mass revealed by the contrast-enhanced zone on CT or MRI and a CTV with an expanded margin of 2 or 3 cm; ii) an anatomic option including the entire zone of oedema or isolated tumor cell infiltration extending at least as far as the limits of the hyperintense zone on T2-weighted MRI. Inclusion of adjacent structures (such as white matter, corpus callosum, subarachnoid spaces) in the CTV mainly depends on the site of the tumor and size of the volume is generally enlarged.

L-(methyl-11C) methionine positron emission tomography for target delineation in resected high-grade gliomas before radiotherapy

Using magnetic resonance imaging (MRI), residual tumor cannot be differentiated from nonspecific postoperative changes in operated patients with brain gliomas. The higher specificity and sensitivity of L-(methyl-11C)-labeled methionine positron emissions tomography (MET-PET) in gliomas has been demonstrated in previous studies and is the rationale for the integration of this investigation in gross tumor volume delineation. The goal of this trial was to quantify the affect of MET-PET vs. with MRI in gross tumor volume definition for radiotherapy planning of high-grade gliomas. The trial included 39 patients with resected malignant gliomas. MRI and MET-PET data were coregistered based on mutual information. The residual tumor volume on MET-PET and the volume of tissue abnormalities on T1-weighted MRI (gadolinium [Gd] enhancement) and T2-weighted MRI (hyperintensity areas) were compared using MET-PET/MRI fusion images. The MET-PET vs. Gd-enhanced T1-weighted MRI analysis was performed on 39 patients. In 5 patients (13%), MET uptake corresponded exactly with Gd enhancement, and in 29 (74%) of 39 patients, the region of MET uptake was larger than that of the Gd enhancement. In 27 (69%) of the 39 patients, the Gd enhancement area extended beyond the MET enhancement. MET uptake was detected up to 45 mm beyond the Gd enhancement. MET-PET vs. T2-weighted MRI was investigated in 18 patients. MET uptake did not correspond exactly with the hyperintensity areas on T2-weighted MRI in any patient. In 9 (50%) of 18 patients, MET uptake extended beyond the hyperintensity area on the T2-weighted MRI, and in 18 (100%), at least some hyperintensity on the T2-weighted MRI was located outside the MET enhancement area. MET uptake was detected up to 40 mm beyond the hyperintensity area on T2-weighted MRI. In operated patients with brain gliomas, the size and location of residual MET uptake differs considerably from abnormalities found on postoperative MRI. Because postoperative changes cannot be differentiated from residual tumor by MRI, MET-PET, with a greater specificity for tumor tissue, can help to outline the gross tumor volume with greater accuracy.

A Phase I Open-Label, Dose-Escalation, Multi-Institutional Trial of Injection with an E1B-Attenuated Adenovirus, ONYX-015, into the Peritumoral Region of Recurrent Malignant Gliomas, in the Adjuvant Setting

AbstractONYX-015 is an oncolytic virus untested as a treatment for malignant glioma. The NABTT CNS Consortium conducted a dose-escalation trial of intracerebral injections of ONYX-015. Cohorts of six patients at each dose level received doses of vector from 107 plaque-forming units (pfu) to 1010 pfu into a total of 10 sites within the resected glioma cavity. Adverse events were identified on physical exams and testing of hematologic, renal, and liver functions. Efficacy data were obtained from serial MRI scans. None of the 24 patients experienced serious adverse events related to ONYX-015. The maximum tolerated dose was not reached at 1010 pfu. The median time to progression after treatment with ONYX-015 was 46 days (range 13 to 452 + days). The median survival time was 6.2 months (range 1.3 to 28.0 + months). One patient has not progressed and 1 patient showed regression of interval-increased enhancement. With more than 19 months of follow-up, 1/6 recipients at a dose of 109 and 2/6 at a dose of 1010 pfu remain alive. In 2 patients who underwent a second resection 3 months after ONYX-015 injection, a lymphocytic and plasmacytoid cell infiltrate was observed. Injection of ONYX-015 into glioma cavities is well tolerated at doses up to 1010 pfu.

Expression of Rb2/p130 protein correlates with the degree of malignancy in gliomas

It has been reported that there is an inverse correlation between the immunohistochemical expression of Rb2/p130, a member of the retinoblastoma gene family, and the degree of malignancy in at least some histological types. In order to investigate the expression of this protein in gliomas, we evaluated 58 samples from patients with resected gliomas. We focused on the relationship between the degree of malignancy of the glioma and the immunohistochemical detection of Rb2/p130. Expression of Rb2/p130 was observed in 38 glioma specimens (65.5%), including a high expression level in low-grade glioma specimens (> 30% positive cells in 84% of tumors) and a low expression level in high-grade glioma specimens (> 30% positive cells in 12% of tumors). The most aggressive of the gliomas exhibited very low to undetectable levels of Rb2/p130. Moreover, we observed an inverse correlation between Rb2/p130 expression and the degree of malignancy. These findings suggest that the differentiation of gliomas might be partially mediated by the Rb2/p130 gene, and that Rb2/ p130 expression can additionally be an indicator of a better prognosis in patients with gliomas.

Phase I trial of ZD1839 (Iressa™) and radiation in pediatric patients newly diagnosed with brain stem tumors or incompletely resected supratentorial malignant gliomas

Phase I trial of ZD1839 (Iressa™) and radiation in pediatric patients newly diagnosed with brain stem tumors or incompletely resected supratentorial malignant gliomas

Phase I trial of ZD1839 (Iressa™) and radiation in pediatric patients newly diagnosed with brain stem tumors or incompletely resected supratentorial malignant gliomas

Phase I trial of ZD1839 (Iressa™) and radiation in pediatric patients newly diagnosed with brain stem tumors or incompletely resected supratentorial malignant gliomas

Hypermethylation of the RASSF1A gene in gliomas

Background Promoter methylation is an important pathway in transcriptional silencing of tumor suppressor genes (TSGs) in brain tumors. The identified 3p21.3 tumor suppressor gene RAS association domain family protein 1A ( RASSF1A) is highly methylated in primary lung, breast and other tumors. We investigated the promoter methylation and gene expression of RASSF1A in gliomas. Methods The methylation status of the promoter region of RASSF1A, p16 INK4A and death-associated protein kinase ( DAPK) genes was analyzed by methylation-specific PCR (MSP) in 41 surgically resected gliomas. RASSF1A expression was also detected by reverse-transcription polymerase chain reaction (RT-PCR) in 28 glioma tissues. Results The frequencies of RASSF1A, p16 INK4A and DAPK promoter methylation were 13/41 (31.7%), 3/41 (7.3%) and 6/41 (14.6%) respectively. However, the methylations of those genes were not correlated with the clinical characteristics of patients (tumor grade, tumor types and sex). Among 28 glioma tissues, 6 showed the loss of the gene (21.4%). Promoter hypermethylation of RASSF1A is associated with loss of gene expression in glioma tissues. ( p=0.022). Conclusions Our results suggested that the RASSF1A gene might play an important role in glioma carcinogenesis. It also gives us an insight for future glioma medical therapy with a demethylating agent.

3D MRSI for resected high-grade gliomas before RT: tumor extent according to metabolic activity in relation to MRI

Purpose To evaluate the presence of residual disease after surgery but before radiotherapy (RT) in patients with high-grade glioma by MRI and magnetic resonance spectroscopy imaging (MRSI) and to estimate the impact of MRSI on the definition of postoperative target volumes for RT treatment planning. Methods and materials Thirty patients (27 glioblastoma multiforme, 3 Grade III astrocytoma) underwent MRI and MRSI within 4 weeks after surgery but before the initiation of RT. The MRI data were manually contoured; the regions of interest included T 2-weighted hyperintensity (T 2), T 1-weighted contrast enhancement (T 1), and the resection cavity (RC). Levels of choline and N-acetyl-aspartate (NAA) in the three-dimensional MRSI data were analyzed on the basis of a choline-to- N-acetyl-aspartate index (CNI). The CNI and other metabolic indexes were superimposed on the MRI data as three-dimensional contours. Composite, conjoint, and disjoint volumes were defined for T 1 and T 2, with/without RC, and within the CNI contour, corresponding to a value of 2. In addition, follow-up MRI studies were examined for new onset contrast enhancement and compared with the initial spectroscopic findings obtained before RT. Results Substantial variation was found in the spatial relationship between the MRI and MRSI volumes. Ten patients had no contrast enhancement after surgery, and MRSI revealed abnormal metabolic activity in 8 of 10, averaging 20 cm 3 and extending 11–36 mm beyond the RC. In 20 patients with contrast-enhancing lesions, substantial variation was found between T 1 and CNI2; metabolic activity fell outside the contrast enhancement in 19 patients, averaging 21 cm 3 and extending 8–33 mm beyond the contrast enhancement. For all patients, the T 2 encompassed most of the metabolic volume. However, the CNI2 extended beyond the T 2 in 6 of 10 patients without contrast enhancement (mean, 8 cm 3; maximum, 15–23 mm) and in 13 of 20 patients with contrast enhancement (mean, 7 cm 3; maximum, 8–22 mm), representing an increase in the T 2 volume by as much as 180% (median 13%) and 86% (median 14%) for non–contrast-enhancing and contrast-enhancing patients, respectively. Preliminary evaluation of the MRI follow-up examinations revealed correspondence of areas of new contrast enhancement with initial MRSI abnormalities in 8 of 10 non–contrast-enhancing patients. In addition, CNI volumes correlated inversely with the time to onset of new contrast enhancement. Conclusion MRSI is a valuable diagnostic tool for the assessment of residual disease after surgical resection in high-grade glioma. The incorporation of areas of metabolic abnormality into treatment planning for postoperative patients would produce different sizes and shapes of target volumes for both primary and boost volumes. It also may encourage the use of nonuniform margins to define the extent of tumor cell infiltration, rather than the current use of uniform margins.

DAPK promotor hypermethylation correlates with reduced apoptosis in colorectal cancer

Promoter methylation is an important pathway in transcriptional silencing of tumor suppressor genes (TSGs) in brain tumors. The identified 3p21.3 tumor suppressor gene RAS association domain family protein 1A (RASSF1A) is highly methylated in primary lung, breast and other tumors. We investigated the promoter methylation and gene expression of RASSF1A in gliomas.The methylation status of the promoter region of RASSF1A, p16INK4A and death-associated protein kinase (DAPK) genes was analyzed by methylation-specific PCR (MSP) in 41 surgically resected gliomas. RASSF1A expression was also detected by reverse-transcription polymerase chain reaction (RT-PCR) in 28 glioma tissues.The frequencies of RASSF1A, p16INK4A and DAPK promoter methylation were 13/41 (31.7%), 3/41 (7.3%) and 6/41 (14.6%) respectively. However, the methylations of those genes were not correlated with the clinical characteristics of patients (tumor grade, tumor types and sex). Among 28 glioma tissues, 6 showed the loss of the gene (21.4%). Promoter hypermethylation of RASSF1A is associated with loss of gene expression in glioma tissues. (p=0.022).Our results suggested that the RASSF1A gene might play an important role in glioma carcinogenesis. It also gives us an insight for future glioma medical therapy with a demethylating agent.

Correlation between genetic alterations and growth of human malignant glioma xenografted in nude mice.

In order to develop preclinical models of malignant astrocytomas and oligodendrogliomas, a series of 54 resected gliomas (37 from oligodendroglial lineage and 17 from astrocytic lineage) were xenografted subcutaneously into nude mice. Molecular alterations commonly observed in gliomas subtypes, including LOH 1p and 1q, LOH 19q, LOH 10p and 10q, LOH 9p, TP53 and PTEN mutations, EGFR amplification, CDKN2A homozygous deletion and telomerase reactivation were systematically screened in the original and xenografted tumours. In all, 23 gliomas grew in nude mice. The most anaplastic tumours were selected as shown by pathological and molecular studies of the original tumour as well as shorter survival in patients whose tumours were successfully grafted. Comparison between the two growth profiles showed that 10q LOH and EGFR amplification gave a tumorigenic advantage. With a few exceptions, the genetic pattern was remarkably stable before and after growth in nude mice. These results suggest that subcutaneous xenografts are useful and reproducible models to analyse the molecular profile of malignant astrocytoma and oligodendroglioma. This represents the first step to improve our understanding of the correlations between molecular alterations and response to standard or experimental therapies.

PTEN protein expression correlates with PTEN gene molecular changes but not with VEGF expression in astrocytomas.

PTEN gene (10q23) is a relevant tumor suppressor gene whose protein is a phosphatase involved in the control of angiogenesis of some tumors including astrocytomas. There are no studies correlating molecular changes of PTEN and the immunohistochemical expression of its protein (pPTEN) with the expression of vascular endothelial growth factor (VEGF) in astrocytomas. Fifty-six surgically resected brain gliomas, 10 grade 2, 16 grade 3, and 30 grade 4, were studied by a combined approach, consisting of (1) PCR analysis using four microsatellite markers against the PTEN gene region (10q23), (2) the FISH technique to test chromosome 10 using a pericentromeric probe, and (3) immunohistochemical evaluation of pPTEN and VEGF. Loss of heterozygosity (LOH) of PTEN was observed in 10% of fibrillary grade 2 astrocytomas and all gemistocytic ones. In high-grade tumors, LOH was more frequent in grade 4 than in grade 3 (> or =2 loci deleted, 83% and 56%, respectively). Monosomy for chromosome 10 was observed especially in high-grade tumors (6% of grade 3 and 50% of grade 4) and in 20% of grade 2 tumors, corresponding to gemistocytic astrocytomas. Results with both antibodies against PTEN were concordant: loss of cytoplasmic immunoreactivity was frequently observed according to homogeneous or heterogeneous patterns in 70% and 50% of grades 4 and 3, respectively, but not in grade 2. Immunonegativity of pPTEN was associated with PTEN gene deletion (> or =2 loci deleted) (P = 0.04) but not with monosomy. Cytoplasmic immunoreactivity against VEGF was observed in high-grade and in gemistocytic astrocytomas, but not in conventional grade 2 tumors. Tumor expression of pPTEN was not associated with immunoreactivity against VEGF when the same areas were considered. In conclusion, loss of PTEN expression is frequent in high-grade astrocytomas, but not in grade 2 tumors, and correlates with PTEN deletion and loss of chromosome 10. PTEN immunoreactivity does not correlate with VEGF expression in astrocytomas when similar areas are considered.

Hyperfractionated radiation therapy for incompletely resected supratentorial low-grade glioma: A 10-year update of a Phase II study

Purpose To provide a 10-year update of hyperfractionated radiation therapy (Hfx RT) in adults with incompletely resected supratentorial low-grade glioma. Methods and materials A total of 37 patients were treated with 55 Gy in 50 fractions in 25 treatment days in 5 weeks to tumor plus 2 cm, and additional 17.6 Gy given in 16 fractions in 8 treatment days in 1.5 weeks to tumor plus 1 cm, (1.1 Gy twice daily). Total dose was 72.6 Gy in 66 fractions in 33 treatment days in 6.5 weeks. Results After a median follow-up time of 121 months for all patients, the median survival time (MST) for all 37 patients was 145 months, whereas 10-year survival rate was 67%. Median time to tumor progression (MTP) has not yet been attained, but 10-year progression-free survival (PFS) rate was 62%. There was no difference in survival or PFS regarding gender, age, location, site, size, CT enhancement, and histology; whereas lower KPS, higher neurologic status, and lesser extent of surgery had an adverse influence. Infield progression occurred in 15 (88%), whereas in only 2 (12%) patients, tumor progression was described as marginal. Brain necrosis has not been observed so far. Autopsy findings confirmed recurrent glioma and excluded post-RT necrosis in 14 (38%) patients. Of those, 7 (50%) patients had either Grade 3 ( n = 4) or Grade 4 ( n = 3) glioma. Conclusion High-dose HFX RT is effective with mild to moderate toxicity. Further studies are warranted with more patients before testing it against standard fractionation RT in this patient population.

CXCR4 Is a Major Chemokine Receptor on Glioma Cells and Mediates Their Survival

Chemokines were described originally in the context of providing migrational cues for leukocytes. They are now known to have broader activities, including those that favor tumor growth. We addressed whether and which chemokines may be important promoters of the growth of the incurable brain neoplasm, malignant gliomas. Analyses of 16 human glioma lines for the expression of chemokine receptors belonging to the CXCR and CCR series revealed low to negligible levels of all receptors, with the exception of CXCR4 that was expressed by 13 of 16 lines. All six resected human glioma specimens showed similarly high CXCR4 expression. The CXCR4 on glioma lines is a signaling receptor in that its agonist, stromal cell-derived factor-1 (SDF-1; CXCL12), produced rapid phosphorylation of mitogen-activated protein kinases. Furthermore, SDF-1 induced the phosphorylation of Akt (protein kinase B), a kinase associated with survival, and prevented the apoptosis of glioma cells when serum was withdrawn from the culture medium. SDF-1 also mediated glioma chemotaxis, in accordance with this better known role of chemokines. We conclude that glioma cells express a predominant chemokine receptor, CXCR4, and that this functions to regulate survival in part through activating pathways such as Akt.

Implications of IMT-SPECT for postoperative radiotherapy planning in patients with gliomas

Purpose : Using MRI, residual tumor cannot be differentiated from nonspecific postoperative changes in patients with brain gliomas after surgical resection. The goal of this study was to analyze the value of 123I-α-methyl-tyrosine-single photon emission CT (IMT-SPECT) in radiotherapy planning of patients with brain gliomas after surgical resection. Methods and Materials : In 66 patients with surgically resected brain gliomas (33 glioblastomas, 20 anaplastic astrocytomas, 7 anaplastic oligodendrogliomas, and 6 low-grade astrocytomas), IMT-SPECT and MRI were performed for radiotherapy planning. On the MRI/IMT-SPECT fusion images, the volume with IMT uptake was compared with the volume of the hyperintensity areas of T 2-weighted MRI and with the volume of contrast enhancement on T 1-weighted MRI. The regions with IMT uptake and/or MRI changes (composite Vol-MRI/IMT), regions with overlay of IMT uptake and MRI changes (common Vol-MRI/IMT), area with IMT uptake without MRI changes (increase Vol-MRI/IMT), and area with only MRI changes (Vol-MRI minus IMT) were analyzed separately. The planning target volume and boost volume defined using MRI information alone was compared with the planning target volume and boost volume defined by also using the SPECT information. Results : Focally increased IMT uptake was observed in 25 (38%) of 66 patients, contrast enhancement on MRI was outlined in 59 (89%) of 66 patients, and hyperintensity areas on T 2-weighted MRI were found in all 66 investigated patients. The mean composite Vol-T 2/IMT was 73 cm 3. The relative increase Vol-T 2/IMT, mean relative common Vol-T 2/IMT, and mean relative Vol-T 2 minus IMT was 4%, 6%, and 90% of the composite Vol-T 2/IMT, respectively. The mean composite Vol-T 1/IMT was 14 cm 3 and the mean relative increase Vol-T 1/IMT, mean relative common Vol-T 1/IMT, and mean relative Vol-T 1 minus IMT was 21%, 4%, and 64% of the mean composite Vol-T 1/IMT, respectively. In 19 (29%) of 66 patients, the focal IMT uptake was located outside the MRI changes. In this subgroup, the mean residual volume defined by focal IMT uptake in MRI/IMT-SPECT images, mean Vol-T 1, and mean Vol-T 2 was 19 cm 3, 10 cm 3, and 70 cm 3, respectively. The mean relative increase T 2/IMT was 14% and T 1/IMT was 61%. In this subgroup, the additional information of SPECT led to an increase in boost volume (mean relative increase BV-IMT) by 20%. Conclusion : In patients with surgically resected brain gliomas, the size and location of residual IMT uptake differs considerably from the abnormalities found on postoperative MRI. Because of the known high specificity of IMT uptake for tumor tissue, the findings on IMT-SPECT may significantly modify the target volumes for radiotherapy planning. This will help to focus the high irradiation dose on the tumor area and to spare normal brain tissue.

MR-spectroscopy imaging for resected high-grade gliomas prior to radiation therapy: tumor extent according to metabolic activity in relation to MRI

MR-spectroscopy imaging for resected high-grade gliomas prior to radiation therapy: tumor extent according to metabolic activity in relation to MRI

Radiation therapy for incompletely resected supratentorial low-grade glioma in adults.

In this review on current concepts in radiation therapy in the treatment of incompletely resected supratentorial low-grade glioma, a number of important issues are discussed. They include indication for radiation therapy, timing (early vs delayed), dose response issue, impact of modern neuroimaging, 'optimal' treatment fields, impact of histology, new and promising approaches as well as quality of life in this disease are also discussed. This disease remains a focus of investigations in neuro-oncology owing to the fact that a number of questions discussed in the text are still far from being optimally addressed and answers are, therefore, lacking. New studies and more patients are needed to get more insight into this disease.

Nitric oxide and glioma: a target for novel therapy?

The biological activities of nitric oxide (NO) include vasodilatation, inhibition of platelet aggregation, neurotransmission, neural plasticity, and modulation of inflammatory and immunological functions. NO synthase (NOS), which is the enzyme that produces NO, has been detected in resected human glioma specimens, and both human and rodent glioma cell lines. NO production in gliomas can alter several important pathophysiological processes, such as local host immune response, tumour cell apoptosis, tumour invasion/metastasis, free radical injury to tumour cells and adjacent normal brain tissues, tonic vasodilatation of tumour vessels, vascular permeability and neovascularization. Recently, some therapeutic strategies for gliomas using NO manipulation have been proposed, and evaluated both experimentally and indirectly in preliminary clinical trials. These include NO manipulation designed to modify tumour cell oncogenesis, tumour blood flow and disposition of anti-cancer drugs in tumour tissue. This review will discuss the biological role of NO in the central nervous system and gliomas and its current and future possibilities in neuro-oncology.