Comparison between MRI-derived ADC maps and 18FLT-PET in pre-operative glioblastoma.

BACKGROUND AND PURPOSE: Among principal MRI sequences used for a better pre-therapeutic characterization of glioblastoma (GBM), DWI-derived ADC is expected to be a good parameter for the evaluation of cellularity, due to restricted water diffusivity. We aimed here to compare ADC maps to 18FLT-PET, a proliferation tracer, in GBM cases. MATERIALS AND METHODS: Patients underwent 18FLT-PET, followed by multiparametric magnetic resonance imaging (MRI) just prior to surgery. We analysed in this study twenty GBM confirmed patients. The 5th percentile (5p) of the ADC values were thresholded to define the ADCmin ROI, while the 95th percentile (95p) of the SUV FLT values were used to define the FLTmax ROI. The statistical and spatial correlations between these two groups of ROIs were analyzed. RESULTS: We did not observe any significant correlations between ADCmin and FLTmax cut-off values (R2=0.0285), neither between ADCmin and FLTmax ROIs (mean Dice=0.09±0.12). Mean ADC values in the FLTmax defined ROI were significantly higher than the values in the ADCmin ROI (P<0.001). Mean FLT values in the FLTmax ROI were significantly higher than the values in the ADCmin ROI (P<0.001). CONCLUSIONS: When comparing ADC maps to 18FLT uptake, we did not observe significant anatomical overlap nor correlation, between the regions of low ADC and high FLT disabling to clearly link ADC values to cellular proliferation. The exact significance of ADC maps in GBM has yet to be elaborated.

[18F]-FMISO PET study of hypoxia in gliomas before surgery: correlation with molecular markers of hypoxia and angiogenesis.

PURPOSE: Hypoxia in gliomas is associated with tumor resistance to radio- and chemotherapy. However, positron emission tomography (PET) imaging of hypoxia remains challenging, and the validation of biological markers is, therefore, of great importance. We investigated the relationship between uptake of the PET hypoxia tracer [18F]-FMISO and other markers of hypoxia and angiogenesis and with patient survival. PATIENTS AND METHODS: In this prospective single center clinical study, 33 glioma patients (grade IV: n = 24, III: n = 3, and II: n = 6) underwent [18F]-FMISO PET and MRI including relative cerebral blood volume (rCBV) maps before surgery. Maximum standardized uptake values (SUVmax) and hypoxic volume were calculated, defining two groups of patients based on the presence or absence of [18F]-FMISO uptake. After surgery, molecular quantification of CAIX, VEGF, Ang2 (rt-qPCR), and HIF-1α (immunohistochemistry) were performed on tumor specimens. RESULTS: [18F]-FMISO PET uptake was closely linked to tumor grade, with high uptake in glioblastomas (GB, grade IV). Expression of biomarkers of hypoxia (CAIX, HIF-1α), and angiogenesis markers (VEGF, Ang2, rCBV) were significantly higher in the [18F]-FMISO uptake group. We found correlations between the degree of hypoxia (hypoxic volume and SUVmax) and expression of HIF-1α, CAIX, VEGF, Ang2, and rCBV (p < 0.01). Patients without [18F]-FMISO uptake had a longer survival time than uptake positive patients (log-rank, p < 0.005). CONCLUSIONS: Tumor hypoxia as evaluated by [18F]-FMISO PET is associated with the expression of hypoxia markers on a molecular level and is related to angiogenesis. [18F]-FMISO uptake is a mark of an aggressive tumor, almost always a glioblastoma. Our results underline that [18F]-FMISO PET could be useful to guide glioma treatment, and in particular radiotherapy, since hypoxia is a well-known factor of resistance.

Simultaneous Mapping of Vasculature, Hypoxia, and Proliferation Using Dynamic Susceptibility Contrast MRI, 18F-FMISO PET, and 18F-FLT PET in Relation to Contrast Enhancement in Newly Diagnosed Glioblastoma.

Conventional MRI plays a key role in the management of patients with high-grade glioma, but multiparametric MRI and PET tracers could provide further information to better characterize tumor metabolism and heterogeneity by identifying regions having a high risk of recurrence. In this study, we focused on proliferation, hypervascularization, and hypoxia, all factors considered indicative of poor prognosis. They were assessed by measuring uptake of 18F-3'-deoxy-3'-18F-fluorothymidine (18F-FLT), relative cerebral blood volume (rCBV) maps, and uptake of 18F-fluoromisonidazole (18F-FMISO), respectively. For each modality, the volumes and high-uptake subvolumes (hot spots) were semiautomatically segmented and compared with the contrast enhancement (CE) volume on T1-weighted gadolinium-enhanced (T1w-Gd) images, commonly used in the management of patients with glioblastoma. Methods: Dynamic susceptibility contrast-enhanced MRI (31 patients), 18F-FLT PET (20 patients), or 18F-FMISO PET (20 patients), for a total of 31 patients, was performed on preoperative glioblastoma patients. Volumes and hot spots were segmented on SUV maps for 18F-FLT PET (using the fuzzy locally adaptive bayesian algorithm) and 18F-FMISO PET (using a mean contralateral image + 3.3 SDs) and on rCBV maps (using a mean contralateral image + 1.96 SDs) for dynamic susceptibility contrast-enhanced MRI and overlaid on T1w-Gd images. For each modality, the percentages of the peripheral volumes and the peripheral hot spots outside the CE volume were calculated. Results: All tumors showed highly proliferated, hypervascularized, and hypoxic regions. The images also showed pronounced heterogeneity of both tracers regarding their uptake and rCBV maps, within each individual patient. Overlaid volumes on T1w-Gd images showed that some proliferative, hypervascularized, and hypoxic regions extended beyond the CE volume but with marked differences between patients. The ranges of peripheral volume outside the CE volume were 1.6%-155.5%, 1.5%-89.5%, and 3.1%-78.0% for 18F-FLT, rCBV, and 18F-FMISO, respectively. All patients had hyperproliferative hot spots outside the CE volume, whereas hypervascularized and hypoxic hot spots were detected mainly within the enhancing region. Conclusion: Spatial analysis of multiparametric maps with segmented volumes and hot spots provides valuable information to optimize the management and treatment of patients with glioblastoma.

Hypoxia Imaging and Adaptive Radiotherapy: A State-of-the-Art Approach in the Management of Glioma.

Severe hypoxia [oxygen partial pressure (pO2) below 5-10 mmHg] is more frequent in glioblastoma multiforme (GBM) compared to lower-grade gliomas. Seminal studies in the 1950s demonstrated that hypoxia was associated with increased resistance to low-linear energy transfer (LET) ionizing radiation. In experimental conditions, the total radiation dose has to be multiplied by a factor of 3 to achieve the same cell lethality in anoxic situations. The presence of hypoxia in human tumors is assumed to contribute to treatment failures after radiotherapy (RT) in cancer patients. Therefore, a logical way to overcome hypoxia-induced radioresistance would be to deliver substantially higher doses of RT in hypoxic volumes delineated on pre-treatment imaging as biological target volumes (BTVs). Such an approach faces various fundamental, technical, and clinical challenges. The present review addresses several technical points related to the delineation of hypoxic zones, which include: spatial accuracy, quantitative vs. relative threshold, variations of hypoxia levels during RT, and availability of hypoxia tracers. The feasibility of hypoxia imaging as an assessment tool for early tumor response to RT and for predicting long-term outcomes is discussed. Hypoxia imaging for RT dose painting is likewise examined. As for the radiation oncologist's point of view, hypoxia maps should be converted into dose-distribution objectives for RT planning. Taking into account the physics and the radiobiology of various irradiation beams, preliminary in silico studies are required to investigate the feasibility of dose escalation in terms of normal tissue tolerance before clinical trials are undertaken.

In Vivo Relationship Between Hypoxia and Angiogenesis in Human Glioblastoma: A Multimodal Imaging Study.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. This aggressiveness is in part attributed to the closely interrelated phenomena tumor hypoxia and angiogenesis, although few in vivo data exist in human brain tumors. This work aimed to study hypoxia and angiogenesis, in vivo and in situ, in patients admitted with GBM using multimodal imaging. Methods: Twenty-three GBM patients were assessed by 18F-fluoromisonidazole (18F-FMISO) PET and conventional and perfusion MRI before surgery. The level and location of hypoxia (18F-FMISO uptake, evaluated by tumor-to-blood [T/B] ratio), vascularization (cerebral blood volume [CBV]), and vascular permeability (contrast enhancement after gadolinium injection) were analyzed. The spatial relationship between tumor hypoxia and angiogenesis was assessed by an overlap analysis of the volume of 18F-FMISO uptake and the volumes of the high CBV regions and the contrast-enhancement regions. Results: A significant correlation was found between hypoxia and hypervascularization, especially for their maximum values (volume of maximal tumor hypoxia vs. relative CBV: r = 0.61, P = 0.002) and their volumes (hypoxia vs. hypervascularization: r = 0.91, P < 0.001). A large proportion of the high CBVs collocated with hypoxia (81.3%) and with contrast enhancement (46.5%). Conclusion: These results support the hypothesis of a tight association between hypoxia and angiogenesis. Our results suggest that there is insufficient tumor oxygenation in human GBM, despite increased tumor vascularization.

FMISO-PET-derived brain oxygen tension maps: application to glioblastoma and less aggressive gliomas.

Quantitative imaging modalities for the analysis of hypoxia in brain tumors are lacking. The objective of this study was to generate absolute maps of tissue ptO2 from [18F]-FMISO images in glioblastoma and less aggressive glioma patients in order to quantitatively assess tumor hypoxia. An ancillary objective was to compare estimated ptO2 values to other biomarkers: perfusion weighted imaging (PWI) and tumor metabolism obtained from 1H-MR mono-voxel spectroscopy (MRS). Ten patients with glioblastoma (GBM) and three patients with less aggressive glioma (nGBM) were enrolled. All patients had [18F]-FMISO and multiparametric MRI (anatomic, PWI, MRS) scans. A non-linear regression was performed to generate ptO2 maps based on normal appearing gray (NAGM) and white matter (NAWM) for each patient. As expected, a marked [18F]-FMISO uptake was observed in GBM patients. The ptO2 based on patient specific calculations was notably low in this group (4.8 ± 1.9 mmHg, p < 0.001) compared to all other groups (nGBM, NAGM and NAWM). The rCBV was increased in GBM (1.4 ± 0.2 when compared to nGBM tumors 0.8 ± 0.4). Lactate (and lipid) concentration increased in GBM (27.8 ± 13.8%) relative to nGBM (p < 0.01). Linear, nonlinear and ROC curve analyses between ptO2 maps, PWI-derived rCBV maps and MRS-derived lipid and lactate concentration strengthens the robustness of our approaches.

Imaging Modalities to Assess Oxygen Status in Glioblastoma.

Hypoxia, the result of an inadequacy between a disorganized and functionally impaired vasculature and the metabolic demand of tumor cells, is a feature of glioblastoma. Hypoxia promotes the aggressiveness of these tumors and, equally, negatively correlates with a decrease in outcome. Tools to characterize oxygen status are essential for the therapeutic management of patients with glioblastoma (i) to refine prognosis, (ii) to adapt the treatment regimen, and (iii) to assess the therapeutic efficacy. While methods that are focal and invasive in nature are of limited use, non-invasive imaging technologies have been developed. Each of these technologies is characterized by its singular advantages and limitations in terms of oxygenation status in glioblastoma. The aim of this short review is, first, to focus on the interest to characterize hypoxia for a better therapeutic management of patients and, second, to discuss recent and pertinent approaches for the assessment of oxygenation/hypoxia and their direct implication for patient care.