Imaging Hypoxia in Glioblastoma Multiforme with PET

Imaging Hypoxia in Glioblastoma Multiforme with PETHypoxia plays a crucial role in the progression of glioblastoma multiforme (GBM) promoting angiogenesis, genetic mutations, riff to a more aggressive behaviour and ote important consequences. Many symptomatic methods arrest been investigated and today PET and magnetic resonance imaging appear to be the more attractive for the evaluation of the heterogeneous hypoxia in GBM.(Mendichovszky and Jackson 2011, Vartanian, Singh et al. 2014)Hirata first record the utility of hypoxic tracers (18FFMISO in this probe) in patients with polariating GBM from lower grade gliomas based on the level of tumor hypoxia.(Hirata, Terasaka et al. 2012) Hypoxia assessment by PET imagery seems to yield complementary learning to MRI within the complex relationship breathing amongst hypoxia and angiogenesis in GBM. This was support in a study of Swanson et al, where the authors attested a strong correlation mingled with the hypoxic burden, de termined with 18FFMISO, and altered vasculature attested on gadolinium-enhanced T1-weighted MRI sequences.(Swanson, Chakraborty et al. 2009) As for other tumours, the prognostic capability of 18FFMISO has been confirmed as well as in GBM, in a study evaluating the correlation between hypoxic volume, intensity of hypoxia an survival in 22 patients with GBM who underwent PET scan out front biopsy or between resection and radiation therapy (RT).(Spence, Muzi et al. 2008) The heterogeneous distribution of hypoxia within GBM can non be fully investigated by 18FFMISO PET imaging, but the tumour fund dimension allow for acceptable data on the different levels of hypoxia within the tumour.(Padhani, Krohn et al. 2007)18FFAZA is some other radiotracer tracer, which has showed promising results. The biggest study ever published, evaluating the utility of 18FFAZA in 50 patients with different types of tumours, documented increased pulmonary tuberculosis of the tracer in all gliomas, with a tumour-to-background (T/B) ratio range of 1.9-15.6, which is higher compared to that of 18FFMISO.(Postema, McEwan et al. 2009) However, as already said nearly of literature on the use of 18FFAZA in the brain is based in preclinical setting (see Tab.X)According to the group of Wiebe, one important bode in favour of 18FFAZA for the evaluation of hypoxia in brain tumours is the absence of uptake in normal brain tissue paper, while 18FFMISO shows, although limited, non-specific uptake in the brain.(Wiebe 2004) Recently, in addition Belloli and colleagues investigated the combined use of 18FFAZA and 18FFDG PET and MRI to follow the biological adjustment of specific line of glioma cells during the tumour progression in animal models of GBM (rats with plant glioma F98 cells). The authors observed that 18FFAZA and 18FFDG were interpreted up respectively in the core and in external areas of the tumoyr, with partial overlap and remodelling during disease progression, suggesting that necrotic regions, defined on the basis of 18FFDG uptake reduction, whitethorn include hypoxic clusters of vital tumour tissue identified with 18FFAZA.(Belloli, Brioschi et al. 2013)BOLD-MRI is an advance MRI technique, particulary suitable for the evaluation of hypoxia, which evaluate the changes in group O concentration and ratio between oxyhemoglobin and deoxyhemoglobin within vessels. In stemma to oxyhaemoglobin, deoxyhaemoglobin is paramagnetic and determines an increase of transverse relaxation rate (R2*) of wet in blood and surrounding tissues.(Mendichovszky and Jackson 2011) Unfortunately BOLD-MRI signal is advised also to other tissue factors, such as blood string up, century dioxide tension, haematocrit, pH. Decoupling the set up of flow from deoxyhaemoglobin and static components it is essential to measure out R2* and be obtained employ multi-echo GRE sequences.(Padhani, Krohn et al. 2007)T1-weighted oxygen-enhanced MRI (OE-MRI) has been proposed as an alternative imaging technique for the evaluation of hypoxia.(Zaharchuk, Busse et al. 2006) turn oxygen in blood and plasma influences MRI signal by increasing the longitudinal relaxation rate of protons (R1). OE-MRI has already been employed in the evaluation of oxygen in healthy tissues and in tumours, but non in the evaluation of hypoxia in GBM, except in a preclinical study by Linnik et al. (Linnik, Scott et al. 2014) In an animal study, Wu et al. used a mechanically ventilation with 100% oxygen at the rate of 8 l/min to investigate hypoxia in brain of rats and showed close agreement between R2* and R1 changes in white and grey payoff in chemical reaction to oxygen inhalation.(Wu, Gao et al. 2012) In the study of Wu and colleagues, the T1 determine decreased prominently in the cortical grey matter but also, with a lower extent, in the subcortical gray matter and in white matter, where the decrease was the least significant. sooner the T2 values showed an increase in response to the o xygen inhalation in all the regions examined in the following order white mattersubcortical gray mattercortical gray matter. Similarly, the T2* values increased with more evident change in the cortical gray matte and white matter and with a less extent in subcortical gray matter.(Wu, Gao et al. 2012) These observations support the use of oxygen-enhanced imaging as a biomarker for tumour oxygenation, although the relationship between the signal changes resulting from variations in turn oxygen pressure and true tumour hypoxaemia remain to be elucidated.DCE-MRI, exploitation contrast agents of low molecular weight, has been proposed as an additional MRI method for identification and quantification of hypoxia in some types of tumour and some authors successfully exhibit a correlation between perfusion parameters to oxygen tension. (Ceelen, Smeets et al. 2006) DCE-MRI parameters have been demonstrated also to indicate preoperatively areas with high hypoxia in glioma patients.In partic ularly Jensen et al. demonstrated that capillary get over time (tc) correlated with HIF-1 expression and VEGF expression in the histopathological examination of correspond of active tumour regions. Other parameters, blood volume (Vb), capillary heterogeneity (a-1) and kep (washout rate) also showed a correlation with biomarkers of hypoxia.(Jensen, Mumert et al. 2014) O Connor, in a study evaluating ten patients with solid tumours, proposed that DCE may provide complementary information to OE-MRI regarding the tumour microenvironment, estimating local perfusion and extracellularextravascular volume,(OConnor, Naish et al. 2009) Subsequently, Linnik et al. validated the measurement of hypoxia validated OE-MRI using a murine glioma xenograft with histopathological confirmation. The study involved 5 patients, who underwent the same imaging protocol of the rats OE-MRI and DCE-MRI and histological confirmation with reduced pimonidazole adducts and CD31 staining. Furthermore, the area und er the turn (AUC) was also calculated for the R1 curve for OE-MRI and the gadolinium concentration curve for DCE-MRI. Whereas DCE-MRI did not relate to hypoxia in the xenograft model, the authors found a strong correlation between estimation of hypoxia by means OE-MRI and histology results, supporting further research to validate also the utility of OE-MRI in the evaluation of response to therapy and fortune telling of prognosis (Fig.).(Linnik, Scott et al. 2014)DWI-MRI instead has been used to clarify the mechanism of action of bevacizumab role, see patients with recurrent GBM before and after treatment with bevacizumab.(Rieger, Bahr et al. 2010) The mechanism of action of bevacizumab is clam up matter of debate. It is thought to produce damage to the endothelial cells, decreasing commit of nutrients and oxygen to the tumour cells,(Field, Jordan et al. 2014) but recently, it has been postulated an alternative theory antiangiogenic therapy could stimulate a vascular normalizat ion, which would allow improved chemotherapy delivery and radiation consummations through enhanced oxygen delivery.(Jain 2005) The study showed that bevacizumab induced stroke-like lesions with diffusion parturiency and corresponding ADC decrease in 13 out of 18 patients enrolled in the study. A biopsy, performed in ADC-decreased lesion in one patient, demonstrated and nuclear hypoxia with HIF-1 up-regulation maverick necrosis but no tumour recurrence, supporting the hypothesis that bevacizumab-increases hypoxia in the tumour bed, expecially in case of prolonged treatment. Furthermore the imaging outline revealed that regional cerebral blood flow (rCBF) and regional cerebral blood volume (rCBV) were decreased in responders with diffusion restricted lesions.(Rieger, Bahr et al. 2010) Recently the effect of anti-angiogenic therapy has been investigated by a new technique, called vessel architectural imaging (VAI) which analyses the profane shift in the MR signal estimating the ve ssel calibre and provides additional information about the microcirculation and oxygen saturation levels. From preliminary investigations, VAI seems to be a bona fide MRI method to demonstrate the effect of anti-angiogenic therapy.(Emblem, Mouridsen et al. 2013) Other authors suggested AVOL, a measure of arteriovenous overlap (voxels with both arteriosus and venous perfusion characteristics), as index of subnormal tumour microvasculature and as indicator of bevacizumab therapy efficacy.(LaViolette, Cohen et al. 2013)Barajas and colleagues (Barajas, Phillips et al. 2012) investigated histopathological and physiologic MRI features using diffusion-weighted imaging (DWI), dynamic mightweighted, and contrast enhanced perfusion imaging (DSC). Image-guided tissue specimens were taken from contrast enhanced (CE) and non-enhancing (NE) regions in GBM (93 CE and 26 NE regions from 51 patients with newly diagnosed GBM). The authors analysed variables of anatomic, imaging, and histopathologi cal features (tumour score, cell density, proliferation, architectural disruption, hypoxia, and microvascular hyperplasia). Tissue samples from CE regions were found to have increased tumour score, cellular density, proliferation, and architectural disruption compared with NE regions.(Barajas, Phillips et al. 2012)MRI in the evaluation of perfusionPerfusion measurement of regional cerebral blood flow (rCBF) has been proposed as a method for identifying angiogenically active tumours. Increased angiogenesis in top-quality gliomas is correlated with higher cerebral blood volume (CBV) after contrast administration with dynamic MRI, relative to contralateral normal white matter rCBF and tumour aggressiveness. (Provenzale, York et al. 2006, Gruner, Paamand et al. 2012) as well as microvascular density (MVD) of tumour tissue has been shown to relate to tumour behaviour and prognosis. Furthermore it has been demonstrated that abnormalities in contrast agent recirculation provide independen t information concerning the microcirculation and may be of value as permutation markers in trials of antiangiogenic therapy.(Alan Jackson 2002) Early changes of rCBV, evaluated by MRI before and at weeks 1-2 and 3-4 during radiotherapy, can indicate response to treatment and correlate with survival Cao. Also Galban investigated the predictive impact of MRI in this setting, suggesting the use of voxel-by-voxel parametric response maps at 3 weeks after radiotherapy to predict overall survival.(Galban, Chenevert et al. 2009) other MRI technique which has shown promises in the assessment of the tumour microvascular environment is susceptibility weighted imaging (SWI), which aims to underline the susceptibility differences between tissues. Liu et al. demonstrated that R2*values are significantly different between high-grade gliomas, low-grade gliomas, postulating that these differences may be related to the different content of deoxyhaemoglobin.(Liu, Liao et al. 2014)