FMISO-PET-derived brain oxygen tension maps: application to glioblastoma and less aggressive gliomas.
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ABSTRACT:
SUBMITTER: Chakhoyan A
PROVIDER: S-EPMC5579277 | biostudies-literature | 2017 Aug
REPOSITORIES: biostudies-literature
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FMISO-PET-derived brain oxygen tension maps: application to glioblastoma and less aggressive gliomas.
Chakhoyan Ararat A Guillamo Jean-Sebastien JS Collet Solène S Kauffmann François F Delcroix Nicolas N Lechapt-Zalcman Emmanuèle E Constans Jean-Marc JM Petit Edwige E MacKenzie Eric T ET Barré Louisa L Bernaudin Myriam M Touzani Omar O Valable Samuel S
Scientific reports 20170831 1
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 p<sub>t</sub>O<sub>2</sub> from [<sup>18</sup>F]-FMISO images in glioblastoma and less aggressive glioma patients in order to quantitatively assess tumor hypoxia. An ancillary objective was to compare estimated p<sub>t</sub>O<sub>2</sub> values to other biomarkers: perfusion weighted imaging (PWI) and tumor metabolism obtained from <sup>1</s ...[more]
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Project description:PurposeStructural and functional alterations in tumor vasculature are thought to contribute to tumor hypoxia which is a primary driver of malignancy through its negative impact on the efficacy of radiation, immune surveillance, apoptosis, genomic stability, and accelerated angiogenesis. We performed a prospective, multicenter study to test the hypothesis that abnormal tumor vasculature and hypoxia, as measured with MRI and PET, will negatively impact survival in patients with newly diagnosed glioblastoma.Experimental designPrior to the start of chemoradiation, patients with glioblastoma underwent MRI scans that included dynamic contrast enhanced and dynamic susceptibility contrast perfusion sequences to quantitate tumor cerebral blood volume/flow (CBV/CBF) and vascular permeability (ktrans) as well as 18F-Fluoromisonidazole (18F-FMISO) PET to quantitate tumor hypoxia. ROC analysis and Cox regression models were used to determine the association of imaging variables with progression-free and overall survival.ResultsFifty patients were enrolled of which 42 had evaluable imaging data. Higher pretreatment 18F-FMISO SUVpeak (P = 0.048), mean ktrans (P = 0.024), and median ktrans (P = 0.045) were significantly associated with shorter overall survival. Higher pretreatment median ktrans (P = 0.021), normalized RCBV (P = 0.0096), and nCBF (P = 0.038) were significantly associated with shorter progression-free survival. SUVpeak [AUC = 0.75; 95% confidence interval (CI), 0.59-0.91], nRCBV (AUC = 0.72; 95% CI, 0.56-0.89), and nCBF (AUC = 0.72; 95% CI, 0.56-0.89) were predictive of survival at 1 year.ConclusionsIncreased tumor perfusion, vascular volume, vascular permeability, and hypoxia are negative prognostic markers in newly diagnosed patients with gioblastoma, and these important physiologic markers can be measured safely and reliably using MRI and 18F-FMISO PET. Clin Cancer Res; 22(20); 5079-86. ©2016 AACR.
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Project description:Hypoxia is regarded as a potential prognostic biomarker for tumor aggressiveness, progression, and response to therapy. The radiotracer 18F-fluoromisonidazole ([18F]FMISO) has been used with positron emission tomography (PET) to reveal tumor hypoxia. Meanwhile, blood oxygen level dependent (BOLD) MRI and tissue oxygen level dependent (TOLD) MRI offer insight into oxygenation based on endogenous signals without the need for radiolabels. Here, we compared BOLD and TOLD MRI with [18F]FMISO uptake using Dunning prostate R3327-AT1 tumor bearing rats. BOLD and TOLD MRI were acquired with respect to an oxygen gas breathing challenge. The following day, dynamic PET was performed up to 90 minutes following IV injection of [18F]FMISO. Tumors showed distinct heterogeneity based on each technique. Correlations were observed between magnitude of mean BOLD or TOLD MRI signal responses to oxygen-breathing challenge and initial distribution of [18F]FMISO. Correlations were observed for whole tumor as well on a regional basis with stronger correlations in the well perfused tumor periphery indicating the strong influence of perfused vasculature. After 90 minutes most correlations with signal intensity became quite weak, but correlations were observed between hypoxic fraction based on FMISO and fractions of tumor showing BOLD or TOLD response in a subset of tumors. This emphasizes the importance of considering regional heterogeneity and responsive fractions, as opposed to simple magnitudes of responses. Although the data represent a small cohort of tumors they present direct correlations between oxygen sensitive MRI and PET hypoxia reporter agents in the same tumors, indicating the potential utility of further investigations.
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Project description:Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide is a hypoxia-targeting prodrug being tested for recurrent GBM. To characterize resistance to bevacizumab and identify those with recurrent GBM who may benefit from evofosfamide, we ascertained MRI features and hypoxia in patients with GBM progression receiving both agents. Thirty-three patients with recurrent GBM refractory to bevacizumab were enrolled. Patients underwent MR and 18F-FMISO PET imaging at baseline and 28 days. Tumor volumes were determined, MRI and 18F-FMISO PET-derived parameters calculated, and Spearman correlations between parameters assessed. Progression-free survival decreased significantly with hypoxic volume [hazard ratio (HR) = 1.67, 95% confidence interval (CI) 1.14 to 2.46, P = 0.009] and increased significantly with time to the maximum value of the residue (Tmax) (HR = 0.54, 95% CI 0.34 to 0.88, P = 0.01). Overall survival decreased significantly with hypoxic volume (HR = 1.71, 95% CI 1.12 to 12.61, p = 0.01), standardized relative cerebral blood volume (srCBV) (HR = 1.61, 95% CI 1.09 to 2.38, p = 0.02), and increased significantly with Tmax (HR = 0.31, 95% CI 0.15 to 0.62, p < 0.001). Decreases in hypoxic volume correlated with longer overall and progression-free survival, and increases correlated with shorter overall and progression-free survival. Hypoxic volume and volume ratio were positively correlated (rs = 0.77, P < 0.0001), as were hypoxia volume and T1 enhancing tumor volume (rs = 0.75, P < 0.0001). Hypoxia is a key biomarker in patients with bevacizumab-refractory GBM. Hypoxia and srCBV were inversely correlated with patient outcomes. These radiographic features may be useful in evaluating treatment and guiding treatment considerations.
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Project description:Structural MR images concomitantly acquired with PET images can provide crucial anatomic information for precise quantitative analysis. However, in the clinical setting, not all the subjects have corresponding MR images. Here, we developed a model to generate structural MR images from amyloid PET using deep generative networks. We applied our model to quantification of cortical amyloid load without structural MR. Methods: We used florbetapir PET and structural MR data from the Alzheimer Disease Neuroimaging Initiative database. The generative network was trained to generate realistic structural MR images from florbetapir PET images. After the training, the model was applied to the quantification of cortical amyloid load. PET images were spatially normalized to the template space using the generated MR, and then SUV ratio (SUVR) of the target regions was measured by predefined regions of interest. A real MR-based quantification was used as the gold standard to measure the accuracy of our approach. Other MR-less methods-a normal PET template-based, a multiatlas PET template-based, and a PET segmentation-based normalization/quantification-were also tested. We compared the performance of quantification methods using generated MR with that of MR-based and MR-less quantification methods. Results: Generated MR images from florbetapir PET showed signal patterns that were visually similar to the real MR. The structural similarity index between real and generated MR was 0.91 ± 0.04. The mean absolute error of SUVR of cortical composite regions estimated by the generated MR-based method was 0.04 ± 0.03, which was significantly smaller than other MR-less methods (0.29 ± 0.12 for the normal PET template, 0.12 ± 0.07 for the multiatlas PET template, and 0.08 ± 0.06 for the PET segmentation-based methods). Bland-Altman plots revealed that the generated MR-based SUVR quantification was the closest to the SUVRs estimated by the real MR-based method. Conclusion: Structural MR images were successfully generated from amyloid PET images using deep generative networks. Generated MR images could be used as templates for accurate and precise amyloid quantification. This generative method might be used to generate multimodal images of various organs for further quantitative analyses.
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Project description:BackgroundGlioblastoma multiforme (GBM) is one of most common and still poorly treated primary brain tumors. In search for new therapeutic approaches, Bone Morphogenetic Proteins (BMPs) induce astroglial commitment in GBM-derived cells in vitro. However, we recently suggested that hypoxia, which is characteristic of the brain niche where GBM reside, strongly counter-acts BMP effects. It seems apparent that a more complete understanding of the biology of GBM cells is needed, in particular considering the role played by hypoxia as a signaling pathways regulator. HIF-1alpha is controlled at the transcriptional and translational level by mTOR and, alike BMP, also mTOR pathway modulates glial differentiation in central nervous system (CNS) stem cells.Methodology/principal findingsHere, we investigate the role of mTOR signaling in the regulation of HIF-1alpha stability in primary GBM-derived cells maintained under hypoxia (2% oxygen). We found that GBM cells, when acutely exposed to high oxygen tension, undergo Akt/mTOR pathway activation and that BMP2 acts in an analogous way. Importantly, repression of Akt/mTOR signaling is maintained by HIF-1alpha through REDD1 upregulation. On the other hand, BMP2 counter-acts HIF-1alpha stability by modulating intracellular succinate and by controlling proline hydroxylase 2 (PHD2) protein through inhibition of FKBP38, a PHD2 protein regulator.Conclusions/significanceIn this study we elucidate the molecular mechanisms by which two pro-differentiating stimuli, BMP2 and acute high oxygen exposure, control HIF-1alpha stability. We previously reported that both these stimuli, by inducing astroglial differentiation, affect GBM cells growth. We also found differences in high oxygen and BMP2 sensitivity between GBM cells and normal cells that should be further investigated to better define tumor cell biology.
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Project description:Despite numerous efforts aiming to characterise glioblastoma pathology (GBM) and discover new therapeutic strategies, GBM remains one of the most challenging tumours to treat. Here we propose the optimisation of in vitro culturing of GBM patient-derived cells, namely the establishment of GBM-derived cultures and their maintenance at oxygen tension mimicking oxygenation conditions occurring within the tumour. To globally analyse cell states, we performed the transcriptome analysis of GBM patient-derived cells kept as spheroids in serum-free conditions at the reduced oxygen tension (5% O2), cells cultured at atmospheric oxygen (20% O2), and parental tumour. Immune cells present in the tumour were depleted, resulting in the decreased expression of the immune system and inflammation-related genes. The expression of genes promoting cell proliferation and DNA repair was higher in GBM cell cultures when compared to the relevant tumour sample. However, lowering oxygen tension to 5% did not affect the proliferation rate and expression of cell cycle and DNA repair genes in GBM cell cultures. Culturing GBM cells at 5% oxygen was sufficient to increase the expression of specific stemness markers, particularly the PROM1 gene, without affecting neural cell differentiation markers. GBM spheroids cultured at 5% oxygen expressed higher levels of hypoxia-inducible genes, including those encoding glycolytic enzymes and pro-angiogenic factors. The genes up-regulated in cells cultured at 5% oxygen had higher expression in parental GBMs compared to that observed in 20% cell cultures, suggesting the preservation of the hypoxic component of GBM transcriptome at 5% oxygen and its loss in standard culture conditions. Evaluation of expression of those genes in The Cancer Genome Atlas dataset comprising samples of normal brain tissue, lower-grade gliomas and GBMs indicated the expression pattern of the indicated genes was specific for GBM. Moreover, GBM cells cultured at 5% oxygen were more resistant to temozolomide, the chemotherapeutic used in GBM therapy. The presented comparison of GBM cultures maintained at high and low oxygen tension together with analysis of tumour transcriptome indicates that lowering oxygen tension during cell culture may more allegedly reproduce tumour cell behaviour within GBM than standard culture conditions (e.g., atmospheric oxygen tension). Low oxygen culture conditions should be considered as a more appropriate model for further studies on glioblastoma pathology and therapy.
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Project description:BackgroundTo assess the effect of radiochemotherapy (RCT) on proposed tumour hypoxia marker transverse relaxation time (T2*) and to analyse the relation between T2* and 18F-misonidazole PET/CT (FMISO-PET) and 18F-fluorodeoxyglucose PET/CT (FDG-PET).MethodsTen patients undergoing definitive RCT for squamous cell head-and-neck cancer (HNSCC) received repeat FMISO- and 3 Tesla T2*-weighted MRI at weeks 0, 2 and 5 during treatment and FDG-PET at baseline. Gross tumour volumes (GTV) of tumour (T), lymph nodes (LN) and hypoxic subvolumes (HSV, based on FMISO-PET) and complementary non-hypoxic subvolumes (nonHSV) were generated. Mean values for T2* and SUVmean FDG were determined.ResultsDuring RCT, marked reduction of tumour hypoxia on FMISO-PET was observed (T, LN), while mean T2* did not change significantly. At baseline, mean T2* values within HSV-T (15 ± 5 ms) were smaller compared to nonHSV-T (18 ± 3 ms; p = 0.051), whereas FDG SUVmean (12 ± 6) was significantly higher for HSV-T (12 ± 6) than for nonHSV-T (6 ± 3; p = 0.026) and higher for HSV-LN (10 ± 4) than for nonHSV-LN (5 ± 2; p ≤ 0.011). Correlation between FMISO PET and FDG PET was higher than between FMSIO PET and T2* (R2 for GTV-T (FMISO/FDG) = 0.81, R2 for GTV-T (FMISO/T2*) = 0.32).ConclusionsMarked reduction of tumour hypoxia between week 0, 2 and 5 found on FMISO PET was not accompanied by a significant T2*change within GTVs over time. These results suggest a relation between tumour oxygenation status and T2* at baseline, but no simple correlation over time. Therefore, caution is warranted when using T2* as a substitute for FMISO-PET to monitor tumour hypoxia during RCT in HNSCC patients.Trial registrationDRKS, DRKS00003830 . Registered 23.04.2012.
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Project description:BACKGROUND:Concomitant chemo-radiotherapy is the reference treatment for non-resectable locally-advanced Non-Small Cell Lung Cancer (NSCLC). Increasing radiotherapy total dose in the whole tumour volume has been shown to be deleterious. Functional imaging with positron emission tomography (PET/CT) offers the potential to identify smaller and biologically meaningful target volumes that could be irradiated with larger doses without compromising Organs At Risk (OAR) tolerance. This study investigated four scenarios, based on 18FDG and 18F-miso PET/CT, to delineate the target volumes and derive radiotherapy plans delivering up to 74Gy. METHOD:Twenty-one NSCLC patients, selected from a prospective phase II trial, had 18FDG- and 18F-miso PET/CT before the start of radiotherapy and 18FDG PET/CT during the radiotherapy (42Gy). The plans were based planned on a standard plan delivering 66 Gy (plan 1) and on three different boost strategies to deliver 74Gy total dose in pre-treatment 18FDG hotspot (70% of SUVmax) (plan 2), pre-treatment 18F-miso target (SUVmax?>?1.4) (plan 3) and per-treatment 18FDG residual (40% of SUVmax). (plan 4). RESULTS:The mean target volumes were 4.8 cc (± 1.1) for 18FDG hotspot, 38.9 cc (± 14.5) for 18F-miso and 36.0 cc (± 10.1) for per-treatment 18FDG. In standard plan (66 Gy), the mean dose covering 95% of the PTV (D95%) were 66.5 (± 0.33), 66.1 (± 0.32) and 66.1 (± 0.32) Gy for 18FDG hotspot, 18F-miso and per-treatment 18FDG. In scenario 2, the mean D95% was 72.5 (± 0.25) Gy in 18FDG hotspot versus 67.9 (± 0.49) and 67.9 Gy (± 0.52) in 18F-miso and per-treatment 18FDG, respectively. In scenario 3, the mean D95% was 72.2 (± 0.27) Gy to 18F-miso versus 70.4 (± 0.74) and 69.5Gy (± 0.74) for 18FDG hotspot and per-treatment 18FDG, respectively. In scenario 4, the mean D95% was 73.1 (± 0.3) Gy to 18FDG per-treatment versus 71.9 (± 0.61) and 69.8 (± 0.61) Gy for 18FDG hotspot and 18F-miso, respectively. The dose/volume constraints to OARs were matched in all scenarios. CONCLUSION:Escalated doses can be selectively planned in NSCLC target volumes delineated on 18FDG and 18F-miso PET/CT functional images. The most relevant strategy should be investigated in clinical trials. TRIAL REGISTRATION:(RTEP5, NCT01576796 , registered 15 june 2012).
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