Physiological Imaging Methods for Evaluating Response to Immunotherapies in Glioblastomas

Glioblastoma (GBM) is the most malignant brain tumor in adults, with a dismal prognosis despite aggressive multi-modal therapy. Immunotherapy is currently being evaluated as an alternate treatment modality for recurrent GBMs in clinical trials. These immunotherapeutic approaches harness the patient’s immune response to fight and eliminate tumor cells. Standard MR imaging is not adequate for response assessment to immunotherapy in GBM patients even after using refined response assessment criteria secondary to amplified immune response. Thus, there is an urgent need for the development of effective and alternative neuroimaging techniques for accurate response assessment. To this end, some groups have reported the potential of diffusion and perfusion MR imaging and amino acid-based positron emission tomography techniques in evaluating treatment response to different immunotherapeutic regimens in GBMs. The main goal of these techniques is to provide definitive metrics of treatment response at earlier time points for making informed decisions on future therapeutic interventions. This review provides an overview of available immunotherapeutic approaches used to treat GBMs. It discusses the limitations of conventional imaging and potential utilities of physiologic imaging techniques in the response assessment to immunotherapies. It also describes challenges associated with these imaging methods and potential solutions to avoid them.

Effect of Applying Leakage Correction on rCBV Measurement Derived From DSC-MRI in Enhancing and Nonenhancing Glioma

PurposeRelative cerebral blood volume (rCBV) is the most widely used parameter derived from DSC perfusion MR imaging for predicting brain tumor aggressiveness. However, accurate rCBV estimation is challenging in enhancing glioma, because of contrast agent extravasation through a disrupted blood-brain barrier (BBB), and even for nonenhancing glioma with an intact BBB, due to an elevated steady-state contrast agent concentration in the vasculature after first passage. In this study a thorough investigation of the effects of two different leakage correction algorithms on rCBV estimation for enhancing and nonenhancing tumors was conducted.MethodsTwo datasets were used retrospectively in this study: 1. A publicly available TCIA dataset (49 patients with 35 enhancing and 14 nonenhancing glioma); 2. A dataset acquired clinically at Erasmus MC (EMC, Rotterdam, NL) (47 patients with 20 enhancing and 27 nonenhancing glial brain lesions). The leakage correction algorithms investigated in this study were: a unidirectional model-based algorithm with flux of contrast agent from the intra- to the extravascular extracellular space (EES); and a bidirectional model-based algorithm additionally including flow from EES to the intravascular space.ResultsIn enhancing glioma, the estimated average contrast-enhanced tumor rCBV significantly (Bonferroni corrected Wilcoxon Signed Rank Test, p < 0.05) decreased across the patients when applying unidirectional and bidirectional correction: 4.00 ± 2.11 (uncorrected), 3.19 ± 1.65 (unidirectional), and 2.91 ± 1.55 (bidirectional) in TCIA dataset and 2.51 ± 1.3 (uncorrected), 1.72 ± 0.84 (unidirectional), and 1.59 ± 0.9 (bidirectional) in EMC dataset. In nonenhancing glioma, a significant but smaller difference in observed rCBV was found after application of both correction methods used in this study: 1.42 ± 0.60 (uncorrected), 1.28 ± 0.46 (unidirectional), and 1.24 ± 0.37 (bidirectional) in TCIA dataset and 0.91 ± 0.49 (uncorrected), 0.77 ± 0.37 (unidirectional), and 0.67 ± 0.34 (bidirectional) in EMC dataset.ConclusionBoth leakage correction algorithms were found to change rCBV estimation with BBB disruption in enhancing glioma, and to a lesser degree in nonenhancing glioma. Stronger effects were found for bidirectional leakage correction than for unidirectional leakage correction.

Magnetic Resonance Imaging with Diffusion and Perfusion in Assessment of Patients with Cerebral Infarction

Background: Diffusion-weighted MR imaging is most useful for detecting irreversibly infarcted tissue, perfusion-weighted imaging may be used to identify areas of reversible ischemia as well. This work highlights the role of MR imaging in acute ischemic infarction evaluation, with particular emphasis on the importance of diffusion and perfusion MR imaging for evaluating the penumbra. Methods: This prospective study was conducted on 30 patients who were suspected to have a cerebral infarction. All patients underwent functional MRI. Results: 25 patients (83.3%) were isointense in T1 and only 5 patients (16.6%) were low intense, in T2 there was 25 patients (83.3%) were high intense and only 5 patients (16.6%) were isointense .in FLAIR there was 24 patients (80%) were high intense and only 6 patients (20%) were isointense. In DW1 all the cases show high signal also in ADC all the cases show low signal. As regards to Ischemic area: the mean rCBV (relative cerebral blood volume) in the core was 0.33±0.30 cc while in the peripheral area was 1.24±1.35 cc. There was a highly significant difference between CT and MRI in diagnosis of acute stroke with P= 0.001. Conclusion: Only depending on a single or a few parameters may not be sufficient, instead comprehensively combining the information from each MRI sequence (i.e., DWI, FLAIR and PWI) and using various mismatch parameters (DWI-FLAIR mismatch and/or PWI-DWI mismatch) may be more helpful in establishing an indication of MRI-based thrombolysis.

Accuracy of tumor perfusion assessment in Rat C6 gliomas model with USPIO

Detailed characterization of the permeability and vascular volume of brain tumor vasculature can provide essential insights into tumor physiology. In this study, we evaluated the consistency of measurements in tumor blood volume and examined the feasibility of using ultrasmall superparamagnetic iron oxide (USPIO) versus gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) as contrast agents for MR perfusion imaging of brain gliomas in C6 Rats. Eighteen rats were intracerebrally implanted with C6 glioma cells, randomly divided into two groups and examined by 3.0T perfusion MR imaging with Gd-DTPA and USPIO. Tumor relative cerebral blood volume (rCBV) and relative maximum signal reduction ratio (rSRRmax) were created based on analysis of MR perfusion images. The mean values for rCBV were 2.09 and 1.57 in the USPIO and the Gd-DTPA groups, respectively, and rSRRmax values were 1.92 and 1.02 in the USPIO and the Gd-DTPA groups, respectively, showing signifi cant differences in both rCBV and rSRRmax between the USPIO and the Gd-DTPA groups (P < 0.05). The results showed that early vascular leakage occurred with gadolinium rather than USPIO in perfusion assessment, revealing that USPIO was useful in perfusion MR imaging for the assessment of tumor vasculature.