Irradiated Gliomas Research Articles

An Engineered Nanoplatform with Tropism Toward Irradiated Glioblastoma Augments Its Radioimmunotherapy Efficacy.

Combining radiotherapy with immune checkpoint blockade therapy offers a promising approach to treat glioblastoma multiforme (GBM), yet challenges such as limited effectiveness and immune-related adverse events (irAEs) persist. These issues are largely due to the failure in targeting immunomodulators directly to the tumor microenvironment. To address this, a biomimetic nanoplatform that combines a genetically modified mesenchymal stem cell (MSC) membrane with a bioactive nanoparticle core for chemokine-directed radioimmunotherapy of GBM is developed. The CC chemokine receptor 2 (CCR2)-overexpressing MSC membrane acts as a tactical tentacle to achieve radiation-induced tropism toward the abundant chemokine (CC motif)ligand 2 (CCL2) in irradiated gliomas. The nanoparticle core, comprising diselenide-bridged mesoporous silica nanoparticles (MSNs) and PD-L1 antibodies (αPD-L1), enables X-ray-responsive drug release and radiosensitization. In two murine models with orthotopic GBM tumors, this nanoplatform reinvigorated immunogenic cell death, and augmented the efficacy and specificity of GBM radioimmunotherapy, with reduced occurrence of irAEs. This study suggests a promising radiation-induced tropism strategy for targeted drug delivery, and presents a potent nanoplatform that enhances the efficacy and safety of radio-immunotherapy.

The Role of PET Imaging in the Differential Diagnosis between Radiation Necrosis and Recurrent Disease in Irradiated Adult-Type Diffuse Gliomas: A Systematic Review.

Adult-type diffuse gliomas are treated with a multimodality treatment approach that includes radiotherapy both in the primary setting, and in the case of progressive or recurrent disease. Radiation necrosis represents a major complication of radiotherapy. Recurrent disease and treatment-related changes are often indistinguishable using conventional imaging methods. The present systematic review aims at assessing the diagnostic role of PET imaging using different radiopharmaceuticals in differentiating radiation necrosis and disease relapse in irradiated adult-type diffuse gliomas. We conducted a comprehensive literature search using the PubMed/MEDLINE and EMBASE databases for original research studies of interest. In total, 436 articles were assessed for eligibility. Ten original papers, published between 2014 and 2022, were selected. Four articles focused on [18F]FDG, seven on amino acid tracers ([18F]FET n = 3 and [11C]MET n = 4), one on [11C]CHO, and one on [68Ga]Ga-PSMA. Visual assessment, semi-quantitative methods, and radiomics were applied for image analysis. Furthermore, 2/10 papers were comparative studies investigating different radiopharmaceuticals. The present review, the first one on the topic in light of the new 2021 CNS WHO classification, highlighted the usefulness of PET imaging in distinguishing radiation necrosis and tumour recurrence, but revealed high heterogeneity among studies.

P14.17 Conventional MRI criteria differentiate true tumour progression from treatment-induced effects in irradiated WHO grade 3 and 4 gliomas

Abstract BACKGROUND Post-treatment radiological deterioration of patients with an irradiated high-grade (WHO grade 3 and 4) glioma (HGG) may be the result of true progressive disease (PD) or treatment-induced effects (TIE). Differentiation between these two entities is of great importance, but remains a diagnostic challenge. This study assesses the diagnostic value of conventional MRI characteristics to differentiate PD from TIE in treated HGGs. MATERIAL AND METHODS In this single-centre, retrospective cohort study, we included adult patients with a HGG, who were treated with radiotherapy and subsequently developed a new or increasing contrast-enhancing lesion on conventional follow-up MRI. TIE and PD were defined radiologically as stable/decreased for a minimum of six weeks or progressive according to the RANO criteria, and histologically as predominantly TIE without viable tumour or PD. Demographic and clinical data were retrieved. Twenty-one preselected MRI characteristics of the progressive lesions were assessed by two neuroradiologists. The statistical analysis included logistic regression to develop a) a full multivariable model b) a diagnostic model with model reduction, and a Cohen’s Kappa interrater reliability coefficient. RESULTS 210 patients (median age 61, IQR=54–68, 189 males) with 284 lesions were included, of which 141 (50%) had PD. Median time to PD was 2 (0.7–6.1) and to TIE 0.9 (0.7–3.5) months after RT. In multivariable modelling and after model reduction, the following determinants were significant diagnostic factors: Radiation dose (Odds ratio (OR)=0.68, p=0.017), longer time since radiotherapy (OR=3.56, p<0.0005), certain enhancement patterns (soap bubble enhancement: OR=2.63, p=0.003), isointense apparent diffusion coefficient-signal (OR=2.11, p=0.036), development of multiple new lesions (OR=1.68, p=0.088) and increased marginal enhancement (OR=2.04, p=0.027). ORs of >1 indicate higher odds of PD. The Hosmer & Lemeshow test showed a good calibration (p=0.947) and the area under the ROC-curve was 0.722 (95%-CI=0.66–0.78). Interrater reliability analysis between neuroradiologists revealed moderate to near-perfect agreement for the significantly predictive items, but poor agreement for others. CONCLUSION In patients with irradiated high-grade gliomas, several characteristics from conventional MRI are significant predictors for the discrimination between true progression and treatment-induced effects. Interrater reliability for these characteristics was variable. Conventional MRI characteristics from this study should be incorporated into a multimodal diagnostic model that includes advanced imaging techniques. FUNDING INFORMATION Foundation Vrienden UMC Utrecht and The StophersenkankerNU Foundation.

PET Imaging with S-[11C]Methyl-L-Cysteine and L-[Methyl-11C]Methionine in Rat Models of Glioma, Glioma Radiotherapy, and Neuroinflammation

PurposeS-[11C]-methyl-L-cysteine ([11C]MCYS) has been claimed to offer higher tumor selectivity than L-[methyl-11C]methionine ([11C]MET). We examined this claim in animal models.ProceduresRats with implanted untreated (n = 10) or irradiated (n = 7, 1 × 25 Gy, on day 8) orthotopic gliomas were scanned after 6, 9, and 12 days, using positron emission tomography. Rats with striatal injections of saline (n = 9) or bacterial lipopolysaccharide (n = 9) were scanned after 3 days.ResultsUptake of the two tracers in untreated gliomas was similar. [11C]MCYS was not accumulated in salivary glands, nasal epithelium, and healing wounds, in contrast to [11C]MET, but showed 40 % higher accumulation in the healthy brain. Both tracers showed a reduced tumor uptake 4 days after irradiation and minor accumulation in inflamed striatum. [11C]MCYS indicated higher lesion volumes than [11C]MET (untreated tumor + 47 %; irradiated tumor up to + 500 %; LPS-inflamed striatum + 240 %).Conclusions[11C]MCYS was less accumulated in some non-tumor tissues than [11C]MET, but showed lower tumor-to-brain contrast.

Ionizing radiation augments glioma tropism of mesenchymal stem cells.

OBJECTIVE Mesenchymal stem cells (MSCs) have been shown to localize to gliomas after intravascular delivery. Because these cells home to areas of tissue injury, the authors hypothesized that the administration of ionizing radiation (IR) to tumor would enhance the tropism of MSCs to gliomas. Additionally, they sought to identify which radiation-induced factors might attract MSCs. METHODS To assess the effect of IR on MSC migration in vitro, transwell assays using conditioned medium (CM) from an irradiated commercially available glioma cell line (U87) and from irradiated patient-derived glioma stem-like cells (GSCs; GSC7-2 and GSC11) were employed. For in vivo testing, green fluorescent protein (GFP)-labeled MSCs were injected into the carotid artery of nude mice harboring orthotopic U87, GSC7-2, or GSC17 xenografts that were treated with either 0 or 10 Gy of IR, and brain sections were quantitatively analyzed by immunofluorescence for GFP-positive cells. These GSCs were used because GSC7-2 is a weak attractor of MSCs at baseline, whereas GSC17 is a strong attractor. To determine the factors implicated in IR-induced tropism, CM from irradiated GSC7-2 and from GSC11 was assayed with a cytokine array and quantitative ELISA. RESULTS Transwell migration assays revealed statistically significant enhanced MSC migration to CM from irradiated U87, GSC7-2, and GSC11 compared with nonirradiated controls and in a dose-dependent manner. After their intravascular delivery into nude mice harboring orthotopic gliomas, MSCs engrafted more successfully in irradiated U87 (p = 0.036), compared with nonirradiated controls. IR also significantly increased the tropism of MSCs to GSC7-2 xenografts (p = 0.043), which are known to attract MSCs only poorly at baseline (weak-attractor GSCs). Ionizing radiation also increased the engraftment of MSCs in strong-attractor GSC17 xenografts, but these increases did not reach statistical significance. The chemokine CCL2 was released by GSC7-2 and GSC11 after irradiation in a dose-dependent manner and mediated in vitro transwell migration of MSCs. Immunohistochemistry revealed increased CCL2 in irradiated GSC7-2 gliomas near the site of MSC engraftment. CONCLUSIONS Administering IR to gliomas enhances MSC localization, particularly in GSCs that attract MSCs poorly at baseline. The chemokine CCL2 appears to play a crucial role in the IR-induced tropism of MSCs to gliomas.

The value of intraoperative ultrasonography during the resection of relapsed irradiated malignant gliomas in the brain.

PurposeThe aim of this study was to investigate whether intraoperative ultrasonography (IOUS) helped the surgeon navigate towards the tumor as seen in preoperative magnetic resonance imaging and whether IOUS was able to distinguish between tumor margins and the surrounding tissue.MethodsTwenty-five patients suffering from high-grade gliomas who were previously treated by surgery and radiotherapy were included. Intraoperatively, two histopathologic samples were obtained a sample of unequivocal tumor tissue (according to anatomical landmarks and the surgeon’s visual and tactile impressions) and a small tissue sample obtained using a navigated needle when the surgeon decided to stop the resection. This specimen was considered to be a boundary specimen, where no tumor tissue was apparent. The decision to take the second sample was not influenced by IOUS. The effect of IOUS was analyzed semi-quantitatively.ResultsAll 25 samples of unequivocal tumor tissue were histopathologically classified as tumor tissue and were hyperechoic on IOUS. Of the boundary specimens, eight were hypoechoic. Only one harbored tumor tissue (P=0.150). Seventeen boundaries were moderately hyperechoic, and these samples contained all possible histological results (i.e., tumor, infiltration, or no tumor).ConclusionDuring surgery performed on relapsed, irradiated, high-grade gliomas, IOUS provided a reliable method of navigating towards the core of the tumor. At borders, it did not reliably distinguish between remnants or tumor-free tissue, but hypoechoic areas seldom contained tumor tissue.

Irradiation of primary human gliomas triggers dynamic and aggressive survival responses involving microvesicle signaling.

Malignant gliomas are heterogeneous populations of dynamically interacting cells. Genomic and transcriptional changes define this cellular hierarchy and allow certain tumor cells to co-opt metabolic machinery and adopt gene expression profiles that promote cellular reprogramming. Resultant expansion of privileged subpopulations can then rapidly adapt to microenvironmental stress that ultimately influence tumor response to therapeutic intervention. In this study, primary gliomas were subjected to acute or chronic irradiation and analyzed for changes in survival parameters, oxidative stress, gene expression, and cell invasion before and after treatment with secreted microvesicles isolated from irradiated and nonirradiated glioma cells. We found that primary gliomas exposed to ionizing radiation undergo metabolic changes that increase oxidative stress, alter gene expression, and affect the contents of and response to cellular secreted microvesicles. Radiation-induced changes were exacerbated under chronic as compared to acute irradiation paradigms and promoted cellular reprogramming through enhanced expression of key transcription factors and regulators involved in differentiation and pluripotency (SOX2, POU3F2, SALL2, OLIG2, NANOG, POU5F1v1, MSI1). Irradiation also affected changes in paracrine signaling mediated by cellular secreted microvesicles that significantly altered target cell phenotype. Primary gliomas treated with microvesicles exhibited increased radioresistance and treatment with microvesicles from chronically irradiated gliomas promoted invasion via induction of increased matrix metalloproteinase II activity. Together, our data describe a complex radiation response of primary glioma cells involving metabolic and transcriptional changes that alter radiation sensitivity and induce invasive behavior. These important changes can contribute to tumor growth and recurrence, and confound interventions designed to forestall disease progression. Environ. Mol. Mutagen. 57:405-415, 2016. © 2015 Wiley Periodicals, Inc.

Quantitative correlational study of microbubble-enhanced ultrasound imaging and magnetic resonance imaging of glioma and early response to radiotherapy in a rat model.

Radiotherapy remains a major treatment method for malignant tumors. Magnetic resonance imaging (MRI) is the standard modality for assessing glioma treatment response in the clinic. Compared to MRI, ultrasound imaging is low-cost and portable and can be used during intraoperative procedures. The purpose of this study was to quantitatively compare contrast-enhanced ultrasound (CEUS) imaging and MRI of irradiated gliomas in rats and to determine which quantitative ultrasound imaging parameters can be used for the assessment of early response to radiation in glioma. Thirteen nude rats with U87 glioma were used. A small thinned skull window preparation was performed to facilitate ultrasound imaging and mimic intraoperative procedures. Both CEUS and MRI with structural, functional, and molecular imaging parameters were performed at preradiation and at 1 day and 4 days postradiation. Statistical analysis was performed to determine the correlations between MRI and CEUS parameters and the changes between pre- and postradiation imaging. Area under the curve (AUC) in CEUS showed significant difference between preradiation and 4 days postradiation, along with four MRI parameters, T2, apparent diffusion coefficient, cerebral blood flow, and amide proton transfer-weighted (APTw) (all p < 0.05). The APTw signal was correlated with three CEUS parameters, rise time (r = - 0.527, p < 0.05), time to peak (r = - 0.501, p < 0.05), and perfusion index (r = 458, p < 0.05). Cerebral blood flow was correlated with rise time (r = - 0.589, p < 0.01) and time to peak (r = - 0.543, p < 0.05). MRI can be used for the assessment of radiotherapy treatment response and CEUS with AUC as a new technique and can also be one of the assessment methods for early response to radiation in glioma.

Prognostic Value of MRS Metabolites in Postoperative Irradiated High Grade Gliomas.

Purpose. We studied the prognostic significance of Magnetic Resonance Spectroscopy (MRS) in operated high grade gliomas. Materials and Methods. Twelve patients were treated with radiotherapy and Temozolomide. The MRS data were taken four weeks after operation (before radiotherapy) and every six months after the completion of RT. The N-acetyl aspartate, choline, creatine, and myo-inositol parameters were quantified, analyzed, and correlated to recurrence-free survival (RFS). Results. The median RFS was 26.06 months. RFS was significantly worse in elderly patients (P = 0.001) along with the higher choline/creatine ratios at either baseline (P = 0.003) or six months post Radiotherapy (P = 0.042). Median RFS was 23 months in high choline/creatine levels ≥2 at 6 months after radiotherapy and 11 months for those with <2 choline/creatine levels. There was a significant correlation of maximum difference of choline/creatine ratio with RFS (rho = 0.64, P = 0.045). Conclusion. Age and choline/creatine ratio are strong independent prognostic factors in high grade gliomas.

Bevacizumab: radiation combination produces restricted diffusion on brain MRI.

The purpose of this paper is to investigate the effect of bevacizumab (BEV) on the diffusion properties of irradiated brain gliomas. Neuroimaging studies and medical records of 44 patients undergoing treatment for cerebral gliomas were reviewed. MRIs were analyzed for presence of restricted diffusion, time to onset, pattern/location, duration of restriction, and persistence of restriction post-treatment with BEV. Patchy confluent areas of diffusion restriction on MRI were found in 12 patients. All 12 patients received radiation therapy followed by BEV therapy. Diffusion restriction appeared 3 to 21 months after onset of radiation and 1 to 6 months after starting BEV therapy, increased in size over time, and persisted up to 23 months while on BEV. Restricted diffusion was observed in areas that received 60 Gy or more of radiation. Areas of restricted diffusion showed low T1 and increased T2 signal intensity, minimal or no contrast enhancement, and low cerebral blood volume. A thin perimeter of susceptibility outlined the restricted areas on susceptibility-weighted images in nine patients (75%). Small focal areas of tumor recurrence within larger regions of restricted diffusion were evident in only four patients (33%). In seven patients (58%) the area of restricted diffusion showed necrosis or radiation change on histology or no metabolic activity on MR spectroscopy or PET. Restricted diffusion associated with BEV-treated cerebral gliomas occurs in regions of high-dose radiation and does not indicate high-cellularity of tumor recurrence.

Partially Resected Gliomas: Diagnostic Performance of Fluid-attenuated Inversion Recovery MR Imaging for Detection of Progression

To assess whether signal intensity (SI) different from that of cerebrospinal fluid (CSF) within the resection cavity during follow-up helps predict tumor progression in partially resected gliomas. This retrospective study had local institutional review board approval, with waiver of informed consent. Seventy-five patients with partially resected and irradiated gliomas were evaluated. SI within the resection cavity on fluid-attenuated inversion recovery (FLAIR) magnetic resonance (MR) images was qualitatively and quantitatively assessed during follow-up. Qualitative analysis comprised visual comparison of SI in the resection cavity with SI of normal CSF by two readers. SI of the cavity was quantitatively assessed with region-of-interest (ROI) analysis normalized to background noise, contralateral healthy white matter, and CSF. Normalized SI during follow-up was compared with SI immediately after resection. Tumor progression was defined as increase in longest glioma diameter of at least 20% (Response Evaluation Criteria in Solid Tumors). Sensitivity and specificity of elevated SI in resection cavities for predicting or indicating tumor progression were calculated. Wilcoxon rank-sum test, Hodges-Lehman estimates, Kaplan-Meier curves, and linear mixed-effect models for repeated-measures data were used for quantitative SI measurements. Tumor progression at MR was seen in 44 patients (59%), and median progression-free survival was 4.1 years. Qualitative analysis showed that 25 of 44 patients with progression (57%) had SI increase in the resection cavity on FLAIR images. In 10 patients with progression (23%), SI increase was seen a mean of 5 months +/- 3 (standard deviation) before tumor size progression. In 15 patients with progression (34%), SI increase and tumor size progression were detected on the same MR study. In 19 patients with progressing glioma (43%), no SI increase was observed qualitatively. Among 31 patients without progression during follow-up (41%), no SI increase could be observed. Quantitative analysis showed no significant differences in ROI ratios at baseline (after surgery) between progressing and nonprogressing tumors, whereas significant differences in change of ROI ratios at the last measurement could be detected. Overall, SI increase on FLAIR images had specificity of 100% (95% confidence interval [CI]: 91%, 100%) and sensitivity of 57% (95% CI: 42%, 71%) for glioma progression. In partially resected gliomas, encapsulation of resection cavity, presumably by tumor cells, manifests as SI increase on FLAIR images and indicates tumor progression with very high specificity. (c) RSNA, 2010.

Partially Resected Gliomas: Diagnostic Performance of Fluid-attenuated Inversion Recovery MR Imaging for Detection of Progression

Purpose To assess whether signal intensity (SI) different from that of cerebrospinal fluid (CSF) within the resection cavity during follow-up helps predict tumor progression in partially resected gliomas. Materials and Methods This retrospective study had local institutional review board approval, with waiver of informed consent. Seventy-five patients with partially resected and irradiated gliomas were evaluated. SI within the resection cavity on fluid-attenuated inversion recovery (FLAIR) magnetic resonance (MR) images was qualitatively and quantitatively assessed during follow-up. Qualitative analysis comprised visual comparison of SI in the resection cavity with SI of normal CSF by two readers. SI of the cavity was quantitatively assessed with region-of-interest (ROI) analysis normalized to background noise, contralateral healthy white matter, and CSF. Normalized SI during follow-up was compared with SI immediately after resection. Tumor progression was defined as increase in longest glioma diameter of at least 20% (Response Evaluation Criteria in Solid Tumors). Sensitivity and specificity of elevated SI in resection cavities for predicting or indicating tumor progression were calculated. Wilcoxon rank-sum test, Hodges–Lehman estimates, Kaplan–Meier curves, and linear mixed-effect models for repeated-measures data were used for quantitative SI measurements. Results Tumor progression at MR was seen in 44 patients (59%), and median progression-free survival was 4.1 years. Qualitative analysis showed that 25 of 44 patients with progression (57%) had SI increase in the resection cavity on FLAIR images. In 10 patients with progression (23%), SI increase was seen a mean of 5 months ± 3 (standard deviation) before tumor size progression. In 15 patients with progression (34%), SI increase and tumor size progression were detected on the same MR study. In 19 patients with progressing glioma (43%), no SI increase was observed qualitatively. Among 31 patients without progression during follow-up (41%), no SI increase could be observed. Quantitative analysis showed no significant differences in ROI ratios at baseline (after surgery) between progressing and nonprogressing tumors, whereas significant differences in change of ROI ratios at the last measurement could be detected. Overall, SI increase on FLAIR images had specificity of 100% (95% confidence interval [CI]: 91%, 100%) and sensitivity of 57% (95% CI: 42%, 71%) for glioma progression. Conclusion In partially resected gliomas, encapsulation of resection cavity, presumably by tumor cells, manifests as SI increase on FLAIR images and indicates tumor progression with very high specificity. © RSNA, 2010

Targeted release of oncolytic measles virus by blood outgrowth endothelial cells in situ inhibits orthotopic gliomas

Malignant gliomas remain largely incurable despite intensive efforts to develop novel therapies. Replicating oncolytic viruses have shown great promise, among them attenuated measles viruses of the Edmonston B strain (MV-Edm). However, host immune response and the infiltrative nature of gliomas limit their efficacy. We show that human blood outgrowth endothelial cells (BOECs), readily expandable from peripheral blood, are easily infected by MV-Edm and allow replication of MV-Edm while surviving long enough after infection to serve as vehicles for MV-Edm (BOEC/MV-Edm). After intravenous and peritumoral injection, BOEC/MV-Edm deliver the viruses selectively to irradiated orthotopic U87 gliomas in mice. At the tumor, MV-Edm produced by the BOECs infect glioma cells. Subsequent spread from tumor cell to tumor cell leads to focal infection and cytopathic effects that decrease tumor size and, in the case of peritumoral injection, prolong survival of mice. Since MV-Edm within BOECs are not readily neutralized and because BOEC/MV-Edm search and destroy glioma cells, BOEC/MV-Edm constitute a promising novel approach for glioma therapy.

Distinction Between Recurrent Glioma and Radiation Injury Using Magnetic Resonance Spectroscopy in Combination With Diffusion-Weighted Imaging

The aim of this study was to explore the diagnostic effectiveness of magnetic resonance (MR) spectroscopy with diffusion-weighted imaging on the evaluation of the recurrent contrast-enhancing areas at the site of treated gliomas. In 55 patients who had new contrast-enhancing lesions in the vicinity of the previously resected and irradiated high-grade gliomas, two-dimensional MR spectroscopy and diffusion-weighted imaging were performed. Spectral data for N-acetylaspartate (NAA), choline (Cho), creatine (Cr), lipid (Lip), and lactate (Lac) were analyzed in conjunction with the apparent diffusion coefficient (ADC) in all patients. Diagnosis of these lesions was assigned by means of follow-up or histopathology. The Cho/NAA and Cho/Cr ratios were significantly higher in recurrent tumor than in regions of radiation injury (p < 0.01). The ADC value and ADC ratios (ADC of contrast-enhancing lesion to matching structure in the contralateral hemisphere) were significantly higher in radiation injury regions than in recurrent tumor (p < 0.01). With MR spectroscopic data, two variables (Cho/NAA and Cho/Cr ratios) were shown to differentiate recurrent glioma from radiation injury, and 85.5% of total subjects were correctly classified into groups. However, with discriminant analysis of MR spectroscopy imaging plus diffusion-weighted imaging, three variables (Cho/NAA, Cho/Cr, and ADC ratio) were identified and 96.4% of total subjects were correctly classified. There was a significant difference between the diagnostic accuracy of the two discriminant analyses (Chi-square = 3.96, p = 0.046). Using discriminant analysis, this study found that MR spectroscopy in combination with ADC ratio, rather than ADC value, can improve the ability to differentiate recurrent glioma and radiation injury.

Einsatz der 1H-MR-spektroskopischen Bildgebung in der Strahlentherapie: Cholin als Marker für die Bestimmung der relativen Wahrscheinlichkeit eines Tumorprogresses nach Bestrahlung glialer Hirntumoren

To determine the relative signal intensity ratios of choline (Cho), phosphocreatine (CR) and N-acetyl-aspartate (NAA) in MR spectroscopic imaging (proton-MRSI) for differentiating progressive tumors (PT) from non-progressive tumors (nPT) in follow-up and treatment planning of gliomas. Threshold values to indicate the probability of a progressive tumor were also calculated.Thirty-four patients with histologically proven gliomas showing a suspicious brain lesion in MRI after stereotactic radiotherapy were evaluated on a 1.5 Tesla unit (Magnetom Vision, Siemens, Erlangen, Germany) using 2D proton MRSI (repetition time/echo time = 1500/135 msec, PRESS; voxel size 9 x 9 x 15 mm (3)). A total of 274 spectra were analyzed (92 voxel were localized within the suspicious brain lesion). Relative signal intensities Cho, Cr and NAA were measured and their ability to discern between PT and nPT was assessed using the linear discrimination method, logistic regression, and the cross-validation method. PT and nPT were differentiated between on the basis of clinical course and follow-up by MRI, CT and positron emission tomography.The Cho parameter and the relative signal intensity ratios of Cr and NAA were most effective in differentiating between PT and nPT. The logistic regression method using the parameter ln(Cho/Cr) and ln(Cho/NAA) had the best predictive results in cross-validation. A sensitivity of 93.8 % and specificity of 85.7 % were achieved in the differentiation of PT from nPT by proton-MRSI.(1)H-MRSI has a high sensitivity and specificity for differentiating between therapy-related effects and the relapse of irradiated gliomas. This method allows for assessment of the probability of radiotherapy response or failure.

Follow-up gliomas after radiotherapy: 1H MR spectroscopic imaging for increasing diagnostic accuracy

We evaluated the value of magnetic resonance imaging (MRI) and the additional benefit of proton MR spectroscopic imaging (1H SI) in patients with a new suspicious lesion after fractionated stereotactic radiotherapy (FSRT) of a glioma. Thirty-four patients with histologically proven astrocytoma WHO II-IV after treatment by FSRT and a new suspect lesion in the follow-up were included in this study. Data were analysed by three independent radiologists with different experience in 1H SI: Data were verified by clinical follow-up (PT, progressive tumour; nPT, non-progressive tumour) and a kappa analysis was performed. Sensitivity and specificity of T1 weighted (w) and T2w MRI was compared (imaging at radiotherapy and follow-up) using further follow-up controls as gold standard and the additional benefit of 1H SI (imaging at follow-up) was calculated. Mean interval between last irradiation and detection of a suspicious lesion was 37 +/- 32 months. Time to clinical evaluation was 13 +/- 8 months. Interobserver agreement was significantly high in all analyses (kappa always >0.8, P < 0.05). T2w imaging proved to be superior to contrast enhanced T1w imaging in sensitivity (87.5 vs 81.25%) and specificity (85.7 vs 57.1%). Solitary 1H SI had similar results as T2w (sensitivity 87.5%, specificity 71.4%). Taking all techniques into account, all PT were correctly diagnosed. Radiologists' experience had no significant influence on correct interpretation of a suspicious lesion. We conclude that 1H SI is helpful in characterising new suspicious lesions in irradiated gliomas, particularly if pre-MRI is not available for evaluating follow-up.

Metabolic imaging to follow stereotactic radiation of gliomas -- the role of 1H MR spectroscopy in comparison to FDG-PET and IMT-SPECT

To evaluate the clinical value of 1H MR spectroscopy (1H MRSI) for follow-up of irradiated glioma compared to positron emission tomography (PET) with [18F]-2-fluoro-deoxy-D-glucose (FDG-PET) and single photon emission tomography with [123I]-a-methyl-L-tyrosine (IMT-SPECT). Twenty-four patients with irradiated gliomas were examined using 1H MRSI (2D spectroscopic imaging; PRESS; TE = 135 msec; 1.5T Magnetom Vision, Siemens; Voxel size 9 x 9 x 15 mm (3)). MR spectra (n = 233) were evaluated in areas suspicious of tumor (n = 86) as well as in healthy appearing brain tissue (n = 147). Relative signal intensity ratios of choline (Cho), creatine (Cr) and N-acetyl-aspartate (NAA) were calculated. PET scans (n = 19) were performed with 200 - 250 MBq FDG, IMT-SPECT examinations (n = 14) with 200 - 250 mBq IMT. Based on clinical and MRI/CT, follow-up lesions were classified as either neoplastic [PT] or non-neoplastic [nPT]. True positive results for the diagnosis of PT/nPT were 88/89 % (1H MRSI), 73/100 % (PET) and 100/75 % (SPECT). Cho/Cr showed highly significant changes for PT. Determinating a correlation between Cho, Cr, NAA and IMT-SPECT as well as FDG-PET was not possible because of different location of maximum tracer uptake and acquired 2D 1H MRSI. IMT-SPECT seems to be superior to detect tumor progression in irradiated gliomas. 1H MRSI was more suitable than FDG-PET to differentiate between recurrence and radiation-induced changes. FDG-PET plays a role as sensitive method for detecting high-grade tumors. PET and SPECT allowed the examination of the entire tumor including surrounding brain tissue with higher spatial resolution than the acquired 2D 1H MRSI. A main limitation of our study was that only 2D 1H MRSI was used, with only parts of the tumor evaluated. The use of 3D MR spectroscopic imaging may further increase the diagnostic accuracy.

A New Immunoperoxidase Marker for Microglia in Paraffin Section

We tested antisera against monocytic and lymphocytic lineages on 27 formalin-fixed, paraffin-embedded brains, obtained at autopsy, using the avidin-biotin-complex immunoperoxidase method. Patients ranged from one day to 69 years with 12 cases under the age of two. LN-1-positive microglia were present in 22 brains. LN-1 did not stain any other glial or neuronal cells. Five negative brains included two irradiated gliomas, two cases of multiple sclerosis and one normal case. Immunostaining was confined to cells with bipolar processes and rod-shaped nuclei recapitulating the characteristic features of microglia in silver-impregnated sections. LN-1-positive microglia were most prominent in the grey matter and in the grey-white junction with fewer positive cells seen in the white matter. Double immunostaining with LN-1 and glial fibrillary acidic protein (GFAP) clearly distinguished LN-1-positive microglia and GFAP-positive astrocytes. The expression of LN-1, a B-lymphocyte antigen, by microglia contradicts the macrophage derivation theory and supports data indicating a functional role of microglia in immune processes. LN-1, while not specific for microglia, should be considered a useful marker, more reliable than silver impregnation, for detecting microglia in paraffin section.

Delayed adverse effects after irradiation of gliomas: clinicopathological analysis.

Out of 107 pts. treated with radio- and chemotherapy for low and high grade gliomas (TD: 45-65Gy), 3 cases developed pathologically documented radionecrosis (coagulative necrosis with minimal or no persistent tumor). Clinico-therapeutic modalities were analyzed for all cases and biologically equivalent doses were calculated according to NSD, ED and btu formulas. All cases of radionecrosis fell into the group of doses close to 60Gy/30fx./42d. and NSD = 1758, ED = 1340 and btu = 1161. Isodose curve reconstruction on planes corresponding to histological sections of brains with radionecrosis demonstrated that doses received by areas of necrosis were higher than the calculated mid-plane doses in two cases. Clinical and autoptic incidence of radionecrosis were 2.8% and 10% respectively. High doses of steroids during RT seemed to offer some protection against radionecrosis, while number of chemotherapy cycles did not influence the risk of radionecrosis. A higher autoptic rate of irradiated gliomas is needed in order to obtain a better understanding of a number of unresolved problems.

HISTOPATHOLOGICAL STUDIES ON THE IRRADIATED BRAIN TUMORS

Histopathological examinations were made on the irradiated central nervous system tumors from 43 cases of autopsy, performed during 10 years period from 1970 to 1977, in order to investigate the effect of intensive radiotherapy on various histological types of intracranial and intraspinal tumors.1. Of these 43cases, 30 (70%) were found with unusual histological findings such as extensive necrosis or disappearance of the neoplasm, which were considered to be attributable to radiation treatment.2. Extensive necrosis of the tumor in areas exposed to radiation was found in 16 treated cases (37.2%) ; 11gliomas, 2 malignant lymphomas, 1 pineal teratocarcinoma and 2 metastatic brain tumors. Histopathology of the massive necrosis was that of simple coagulative necrosis sometimes with marked vascular alterations and extravasation of fibrinoid materials into the necrotic tissue. The necrosis appeared almost always incomplete and foci of residual tumor were found at the periphery of the tumor. It seems that space-taking effect of the primary tumor remained unchanged regardless of the presence of massive necrosis. The terminal picture of these cases with massive necrosis was often that of widespread intra-and extra-cranial metastases. Foci of necrosis of the brain with the histology typical of delayed radionecrosis were found in 3 other cases without residual tumor cells.3. Pineal germinoma and malignant lymphoma, both primary and secondary, appeared radiosensitive. Almost complete disappearance of the tumor was observed in some such examples with subsequent diffuse degenerative changes in the brain parenchyma exposed to radiation.4. In 5 cases of irradiated tumors autopsy findings gave the impression that the growth of the primary tumor might have been restricted. In 5 cases the tumor cytology was marked by the presence of a large number of multinucleated bizarre giant cells with evidences of degeneration both in the cytoplasm and the nucleus. In two irradiated temporal lobe gliomas fibrosarcoma developed later at the site of previous craniotomy. It is considered that these findings might be also related in some ways to radiation.5. Disseminated necrotizing lesions of the white matter of the brain have been reported in cases treated with combined radiation and chemotherapy for malignancies of the brain. Multifocal necrosis of the brain with axonal swelling and sponginess of the tissue was observed in two examined cases following combined radiation and antineoplastic chemotherapy.6. Diffuse loss and degeneration of nerve cells of the cerebral cortex in pseudolaminar fashion was observed in 7 cases with or without bilateral necrosis of the globus pallidus. The histology was that of typical anoxic encephalopathy. It is to be emphasized that the nervous system is liable to be involved by various anoxic factors during the course of therapy for brain tumors.