Multimodal imaging of brain tumors:treatment planning, prognostication and treatment follow-up with MRI and PET

Imaging with conventional MRI plays an essential role in the diagnosis, treatment planning and treatment follow-up of brain tumor patients. However, imaging with conventional MRI has several limitations challenging clinical decision making. This thesis explores the use of multimodal imaging with advanced methods to improve the clinical management of brain tumor patients. Part I discusses the treatment planning and prognostication of brain tumor patients. There is a special focus on the anatomical relationship of glioblastoma with the ventricles. Patients with ventricle-contacting glioblastoma have a poorer prognosis compared to patients with non-contacting tumors. This thesis finds that ventricle-contacting glioblastomas demonstrate higher peritumoral perfusion and proliferation rates as demonstrated by advanced imaging methods. These aggressive features possibly explain the survival difference between patients with ventricle contacting and non-contacting glioblastomas. Part II emphasizes on the treatment follow-up of glioblastoma patients. Due to the inevitable recurrence of glioblastomas, patients undergo frequent MRI scanning throughout treatment. However, treatment effects such as pseudoprogression can mimic tumor progression on conventional MRI. The inability to accurately differentiate pseudoprogression from tumor progression hinders reliable decision-making regarding continuation or discontinuation of treatment. This thesis demonstrates that multimodal imaging with advanced MRI and PET methods improves the treatment evaluation of glioblastoma patients. The current practice of standard scheduled MRI scans during treatment is also questioned. Pseudoprogression causes a considerable amount of uncertainty on scheduled scans and treatment decisions are often postponed. This thesis substantiates the value of multimodal imaging to aid in clinical decision making in brain tumor patients

Prognostic value of 11C-methionine volume-based PET parameters in IDH wild type glioblastoma

PURPOSE: (11)C-Methionine ((11)C-MET) PET prognostication of isocitrate dehydrogenase (IDH) wild type glioblastomas is inadequate as conventional parameters such as standardized uptake value (SUV) do not adequately reflect tumor heterogeneity. We retrospectively evaluated whether volume-based parameters such as metabolic tumor volume (MTV) and total lesion methionine metabolism (TLMM) outperformed SUV for survival correlation in patients with IDH wild type glioblastomas. METHODS: Thirteen IDH wild type glioblastoma patients underwent preoperative (11)C-MET PET. Both SUV-based parameters and volume-based parameters were calculated for each lesion. Kaplan-Meier curves with log-rank testing and Cox regression analysis were used for correlation between PET parameters and overall survival. RESULTS: Median overall survival for the entire cohort was 393 days. MTV (HR 1.136, p = 0.007) and TLMM (HR 1.022, p = 0.030) were inversely correlated with overall survival. SUV-based (11)C-MET PET parameters did not show a correlation with survival. In a paired analysis with other clinical parameters including age and radiotherapy dose, MTV and TLMM were found to be independent factors. CONCLUSIONS: MTV and TLMM, and not SUV, significantly correlate with overall survival in patients with IDH wild type glioblastomas. The incorporation of volume-based (11)C-MET PET parameters may lead to a better outcome prediction for this heterogeneous patient population

The Correlation of In Vivo MR Spectroscopy and Ex Vivo 2-Hydroxyglutarate Concentration for the Prediction of Isocitrate Dehydrogenase Mutation Status in Diffuse Glioma

Isocitrate dehydrogenase (IDH) mutation status is an important biomarker in the glioma-defining subtype and corresponding prognosis. This study proposes a straightforward method for 2-hydroxyglutarate (2-HG) quantification by MR spectroscopy for IDH mutation status detection and directly compares in vivo 2-HG MR spectroscopy with ex vivo 2-HG concentration measured in resected tumor tissue. Eleven patients with suspected lower-grade glioma (ten IDH1; one IDHwt) were prospectively included. Preoperatively, 3T point-resolved spectroscopy (PRESS) was acquired; 2-HG was measured as the percentage elevation of Glx3 (the sum of 2-HG and Glx) compared to Glx4. IDH mutation status was assessed by immunochemistry or direct sequencing. The ex vivo 2-HG concentration was determined in surgically obtained tissue specimens using gas chromatography-mass spectrometry. Pearson correlation was used for assessing the correlation between in vivo MR spectroscopy and ex vivo 2-HG concentration. MR spectroscopy was positive for 2-HG in eight patients, all of whom had IDH1 tumors. A strong correlation (r = 0.80, p = 0.003) between 2-HG MR spectroscopy and the ex vivo 2-HG concentration was found. This study shows in vivo 2-HG MR spectroscopy can non-invasively determine IDH status in glioma and demonstrates a strong correlation with ex vivo 2-HG concentration in patients with lower-grade glioma. </p

The Correlation of In Vivo MR Spectroscopy and Ex Vivo 2-Hydroxyglutarate Concentration for the Prediction of Isocitrate Dehydrogenase Mutation Status in Diffuse Glioma

Isocitrate dehydrogenase (IDH) mutation status is an important biomarker in the glioma-defining subtype and corresponding prognosis. This study proposes a straightforward method for 2-hydroxyglutarate (2-HG) quantification by MR spectroscopy for IDH mutation status detection and directly compares in vivo 2-HG MR spectroscopy with ex vivo 2-HG concentration measured in resected tumor tissue. Eleven patients with suspected lower-grade glioma (ten IDH1; one IDHwt) were prospectively included. Preoperatively, 3T point-resolved spectroscopy (PRESS) was acquired; 2-HG was measured as the percentage elevation of Glx3 (the sum of 2-HG and Glx) compared to Glx4. IDH mutation status was assessed by immunochemistry or direct sequencing. The ex vivo 2-HG concentration was determined in surgically obtained tissue specimens using gas chromatography-mass spectrometry. Pearson correlation was used for assessing the correlation between in vivo MR spectroscopy and ex vivo 2-HG concentration. MR spectroscopy was positive for 2-HG in eight patients, all of whom had IDH1 tumors. A strong correlation (r = 0.80, p = 0.003) between 2-HG MR spectroscopy and the ex vivo 2-HG concentration was found. This study shows in vivo 2-HG MR spectroscopy can non-invasively determine IDH status in glioma and demonstrates a strong correlation with ex vivo 2-HG concentration in patients with lower-grade glioma. </p

Diagnostic accuracy of magnetic resonance imaging techniques for treatment response evaluation in patients with high-grade glioma, a systematic review and meta-analysis

Treatment response assessment in high-grade gliomas uses contrast enhanced T1-weighted MRI, but is unreliable. Novel advanced MRI techniques have been studied, but the accuracy is not well known. Therefore, we performed a systematic meta-analysis to assess the diagnostic accuracy of anatomical and advanced MRI for treatment response in high-grade gliomas. Databases were searched systematically. Study selection and data extraction were done by two authors independently. Meta-analysis was performed using a bivariate random effects model when ae5 studies were included. Anatomical MRI (five studies, 166 patients) showed a pooled sensitivity and specificity of 68% (95%CI 51-81) and 77% (45-93), respectively. Pooled apparent diffusion coefficients (seven studies, 204 patients) demonstrated a sensitivity of 71% (60-80) and specificity of 87% (77-93). DSC-perfusion (18 studies, 708 patients) sensitivity was 87% (82-91) with a specificity of 86% (77-91). DCE-perfusion (five studies, 207 patients) sensitivity was 92% (73-98) and specificity was 85% (76-92). The sensitivity of spectroscopy (nine studies, 203 patients) was 91% (79-97) and specificity was 95% (65-99). Advanced techniques showed higher diagnostic accuracy than anatomical MRI, the highest for spectroscopy, supporting the use in treatment response assessment in high-grade gliomas. aEuro cent Treatment response assessment in high-grade gliomas with anatomical MRI is unreliable aEuro cent Novel advanced MRI techniques have been studied, but diagnostic accuracy is unknown aEuro cent Meta-analysis demonstrates that advanced MRI showed higher diagnostic accuracy than anatomical MRI aEuro cent Highest diagnostic accuracy for spectroscopy and perfusion MRI aEuro cent Supports the incorporation of advanced MRI in high-grade glioma treatment response assessment

Voxel based morphometry-detected white matter volume loss after multi-modality treatment in high grade glioma patients.

BackgroundRadiotherapy (RT) and chemotherapy are components of standard multi-modality treatment of high grade gliomas (HGG) aimed at achieving local tumor control. Treatment is neurotoxic and RT plays an important role in this, inducing damage even distant to the RT target volume.PurposeThis retrospective longitudinal study evaluated the effect of treatment on white matter and gray matter volume in the tumor-free hemisphere of HGG patients using voxel based morphometry (VBM).Method3D T1-weighted MR images of 12 HGG patients at multiple timepoints during standard treatment were analyzed using VBM. Segmentation of white matter and gray matter of the tumor-free hemisphere was performed. Multiple general linear models were used to asses white matter and gray matter volumetric differences between time points. A mean RT dose map was created and compared to the VBM results.ResultsDiffuse loss of white matter volume, mainly throughout the frontal and parietal lobe, was found, grossly overlapping regions that received the highest RT dose. Significant loss of white matter was first noticed after three cycles of chemotherapy and persisted after the completion of standard treatment. No significant loss of white matter volume was observed between pre-RT and the first post-RT follow-up timepoint, indicating a delayed effect.ConclusionThis study demonstrated diffuse and early-delayed decreases in white matter volume of the tumor-free hemisphere in HGG patients after standard treatment. White matter volume changes occurred mainly throughout the frontal and parietal lobe and grossly overlapped with areas that received the highest RT dose

Subventricular Zone Involvement Characterized by Diffusion Tensor Imaging in Glioblastoma.

BACKGROUND: Glioblastomas have a poor prognosis, possibly because of a subpopulation of therapy-resistant stem cells within the heterogeneous glioblastoma. Because the subventricular zone is the main source of neural stem cells, we aimed at characterizing the subventricular zone using diffusion tensor imaging (DTI) to show subventricular zone involvement in glioblastoma. METHODS: We prospectively included 93 patients with primary glioblastomas who underwent preoperative DTI. The nonenhancing high fluid-attenuated inversion recovery (FLAIR) signal was used to describe the infiltrative tumor margin. We used a 5-mm margin surrounding the lateral ventricles to define the subventricular zone. The subventricular zone with high FLAIR was compared with the subventricular zone without high FLAIR, control high FLAIR outside the subventricular zone and control contralateral normal-appearing white matter. Normalized DTI parameters were calculated and compared between the different regions. RESULTS: The subventricular zone with high FLAIR showed increased isotropic p values compared with the subventricular zone without high FLAIR (t126 = 3.9; P < 0.001) and control regions (t179 = 1.9; P = 0.046). Anisotropic q and fractional anisotropy values were lower in regions with high FLAIR compared with the subventricular zone without high FLAIR (t181 = 11.6, P < 0.001 and t184 =12.4, P < 0.001, respectively). CONCLUSION: DTI data showed that the subventricular zone is involved in glioblastoma with increased isotropic p values in the subventricular zone with high FLAIR, indicating tumor infiltration.This study was funded by a National Institute of Health Clinician Scientist Fellowship (S.P.), the Groningen University Fund (B.D.), the Marco Polo fund (B.D.), and grants from the Chang Gung Medical Foundation and Chang Gung Memorial Hospital, Keelung, Taiwan (J.Y.). The authors declare to have no conflicts of interest. This article presents independent research funded by the United Kingdom National Institute for Health Research. The views expressed are those of the author(s) and are not necessarily those of the United Kingdom National Health Service, the United Kingdom National Institute for Health Research, or the United Kingdom Department of Health