Non-Invasive Assessment of Isocitrate Dehydrogenase-Mutant Gliomas Using Optimized Proton Magnetic Resonance Spectroscopy on a Routine Clinical 3-Tesla MRI.

PURPOSE: The isocitrate dehydrogenase (IDH) mutation has become one of the most important prognostic biomarkers in glioma management, indicating better treatment response and prognosis. IDH mutations confer neomorphic activity leading to the conversion of alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2HG). The purpose of this study was to investigate the clinical potential of proton MR spectroscopy (1H-MRS) in identifying IDH-mutant gliomas by detecting characteristic resonances of 2HG and its complex interplay with other clinically relevant metabolites. MATERIALS AND METHODS: Thirty-two patients with suspected infiltrative glioma underwent a single-voxel (SVS, n = 17) and/or single-slice-multivoxel (1H-MRSI, n = 15) proton MR spectroscopy (1H-MRS) sequence with an optimized echo-time (97 ms) on 3T-MRI. Spectroscopy data were analyzed using the linear combination (LC) model. Cramér-Rao lower bound (CRLB) values of <40% were considered acceptable for detecting 2HG and <20% for other metabolites. Immunohistochemical analyses for determining IDH mutational status were subsequently performed from resected tumor specimens and findings were compared with the results from spectral data. Mann-Whitney and chi-squared tests were performed to ascertain differences in metabolite levels between IDH-mutant and IDH-wild-type gliomas. Receiver operating characteristic (ROC) curve analyses were also performed. RESULTS: Data from eight cases were excluded due to poor spectral quality or non-tumor-related etiology, and final data analyses were performed from 24 cases. Of these cases, 9/12 (75%) were correctly identified as IDH-mutant or IDH-wildtype gliomas through SVS and 10/12 (83%) through 1H-MRSI with an overall concordance rate of 79% (19/24). The sensitivity, specificity, positive predictive value, and negative predictive value were 80%, 77%, 86%, and 70%, respectively. The metabolite 2HG was found to be significant in predicting IDH-mutant gliomas through the chi-squared test (p < 0.01). The IDH-mutant gliomas also had a significantly higher NAA/Cr ratio (1.20 ± 0.09 vs. 0.75 ± 0.12 p = 0.016) and lower Glx/Cr ratio (0.86 ± 0.078 vs. 1.88 ± 0.66; p = 0.029) than those with IDH wild-type gliomas. The areas under the ROC curves for NAA/Cr and Glx/Cr were 0.808 and 0.786, respectively. CONCLUSIONS: Noninvasive optimized 1H-MRS may be useful in predicting IDH mutational status and 2HG may serve as a valuable diagnostic and prognostic biomarker in patients with gliomas.

Assessment of treatment response to dendritic cell vaccine in patients with glioblastoma using a multiparametric MRI-based prediction model.

PURPOSE: Autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) is a promising treatment modality for glioblastomas. The purpose of this study was to investigate the potential utility of multiparametric MRI-based prediction model in evaluating treatment response in glioblastoma patients treated with DCVax-L. METHODS: Seventeen glioblastoma patients treated with standard-of-care therapy + DCVax-L were included. When tumor progression (TP) was suspected and repeat surgery was being contemplated, we sought to ascertain the number of cases correctly classified as TP + mixed response or pseudoprogression (PsP) from multiparametric MRI-based prediction model using histopathology/mRANO criteria as ground truth. Multiparametric MRI model consisted of predictive probabilities (PP) of tumor progression computed from diffusion and perfusion MRI-derived parameters. A comparison of overall survival (OS) was performed between patients treated with standard-of-care therapy + DCVax-L and standard-of-care therapy alone (external controls). Additionally, Kaplan-Meier analyses were performed to compare OS between two groups of patients using PsP, Ki-67, and MGMT promoter methylation status as stratification variables. RESULTS: Multiparametric MRI model correctly predicted TP + mixed response in 72.7% of cases (8/11) and PsP in 83.3% (5/6) with an overall concordance rate of 76.5% with final diagnosis as determined by histopathology/mRANO criteria. There was a significant concordant correlation coefficient between PP values and histopathology/mRANO criteria (r = 0.54; p = 0.026). DCVax-L-treated patients had significantly prolonged OS than those treated with standard-of-care therapy (22.38 ± 12.8 vs. 13.8 ± 9.5 months, p = 0.040). Additionally, glioblastomas with PsP, MGMT promoter methylation status, and Ki-67 values below median had longer OS than their counterparts. CONCLUSION: Multiparametric MRI-based prediction model can assess treatment response to DCVax-L in patients with glioblastoma.

Taming Glioblastoma in "Real Time": Integrating Multimodal Advanced Neuroimaging/AI Tools Towards Creating a Robust and Therapy Agnostic Model for Response Assessment in Neuro-Oncology.

The highly aggressive nature of glioblastoma carries a dismal prognosis despite aggressive multimodal therapy. Alternative treatment regimens, such as immunotherapies, are known to intensify the inflammatory response in the treatment field. Follow-up imaging in these scenarios often mimics disease progression on conventional MRI, making accurate evaluation extremely challenging. To this end, revised criteria for assessment of treatment response in high-grade gliomas were successfully proposed by the RANO Working Group to distinguish pseudoprogression from true progression, with intrinsic constraints related to the postcontrast T1-weighted MRI sequence. To address these existing limitations, our group proposes a more objective and quantifiable "treatment agnostic" model, integrating into the RANO criteria advanced multimodal neuroimaging techniques, such as diffusion tensor imaging (DTI), dynamic susceptibility contrast-perfusion weighted imaging (DSC-PWI), dynamic contrast enhanced (DCE)-MRI, MR spectroscopy, and amino acid-based positron emission tomography (PET) imaging tracers, along with artificial intelligence (AI) tools (radiomics, radiogenomics, and radiopathomics) and molecular information to address this complex issue of treatment-related changes versus tumor progression in "real-time", particularly in the early posttreatment window. Our perspective delineates the potential of incorporating multimodal neuroimaging techniques to improve consistency and automation for the assessment of early treatment response in neuro-oncology.

Multiparametric MRI assessment of response to convection-enhanced intratumoral delivery of MDNA55, an interleukin-4 receptor targeted immunotherapy, for recurrent glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common malignant brain tumor and carries a dismal prognosis. Attempts to develop biologically targeted therapies are challenging as the blood-brain barrier can limit drugs from reaching their target when administered through conventional (intravenous or oral) routes. Furthermore, systemic toxicity of drugs often limits their therapeutic potential. To circumvent these problems, convection-enhanced delivery (CED) provides direct, targeted, intralesional therapy with a secondary objective to alter the tumor microenvironment from an immunologically "cold" (nonresponsive) to an "inflamed" (immunoresponsive) tumor. CASE DESCRIPTION: We report a patient with right occipital recurrent GBM harboring poor prognostic genotypes who was treated with MRI-guided CED of a fusion protein MDNA55 (a targeted toxin directed toward the interleukin-4 receptor). The patient underwent serial anatomical, diffusion, and perfusion MRI scans before initiation of targeted therapy and at 1, 3-month posttherapy. Increased mean diffusivity along with decreased fractional anisotropy and maximum relative cerebral blood volume was noted at follow-up periods relative to baseline. CONCLUSION: Our findings suggest that diffusion and perfusion MRI techniques may be useful in evaluating early response to CED of MDNA55 in recurrent GBM patients.

Advanced MRI assessment of non-enhancing peritumoral signal abnormality in brain lesions.

Evaluation of Central Nervous System (CNS) focal lesions has been classically made focusing on the assessment solid or enhancing component. However, the assessment of solitary peripherally enhancing lesions where the differential diagnosis includes High-Grade Gliomas (HGG) and metastasis, is usually challenging. Several studies have tried to address the characteristics of peritumoral non-enhancing areas, for better characterization of these lesions. Peritumoral hyperintense T2/FLAIR signal abnormality predominantly contains infiltrating tumor cells in HGG whereas CNS metastasis induce pure vasogenic edema. In addition, the accurate determination of the real extension of HGG is critical for treatment selection and outcome. Conventional MRI sequences are limited in distinguishing infiltrating neoplasm from vasogenic edema. Advanced MRI sequences like Diffusion Weighted Imaging (DWI), Diffusion Tensor Imaging (DTI), Perfusion Weighted Imaging (PWI) and MR spectroscopy (MRS) have all been utilized for this aim with acceptable results. Other advanced MRI approaches, less explored for this task such as Arterial Spin Labelling (ASL), Diffusion Kurtosis Imaging (DKI), T2 relaxometry or Amide Proton Transfer (APT) are also showning promising results in this scenario. In this article, we will discuss the physiopathological basis of peritumoral T2/FLAIR signal abnormality and review potential applications of advanced MRI sequences for its evaluation.

Multiparametric magnetic resonance imaging in the assessment of anti-EGFRvIII chimeric antigen receptor T cell therapy in patients with recurrent glioblastoma.

EGFRvIII targeted chimeric antigen receptor T (CAR-T) cell therapy has recently been reported for treating glioblastomas (GBMs); however, physiology-based MRI parameters have not been evaluated in this setting. Ten patients underwent multiparametric MRI at baseline, 1, 2 and 3 months after CAR-T therapy. Logistic regression model derived progression probabilities (PP) using imaging parameters were used to assess treatment response. Four lesions from "early surgery" group demonstrated high PP at baseline suggestive of progression, which was confirmed histologically. Out of eight lesions from remaining six patients, three lesions with low PP at baseline remained stable. Two lesions with high PP at baseline were associated with large decreases in PP reflecting treatment response, whereas other two lesions with high PP at baseline continued to demonstrate progression. One patient didn't have baseline data but demonstrated progression on follow-up. Our findings indicate that multiparametric MRI may be helpful in monitoring CAR-T related early therapeutic changes in GBM patients.

It is About "Time": Academic Neuroradiologist Time Distribution for Interpreting Brain MRIs.

RATIONALE AND OBJECTIVES: Efficiency is central to current radiology practice. Knowledge of report generation timing is essential for workload optimization and departmental staffing decisions. Yet little research evaluates the distribution of activities performed by neuroradiologists in daily work. MATERIALS AND METHODS: This observational study tracked radiologists interpreting 358 brain magnetic resonance imaging (MRI) in an academic practice over 9 months. We measured the total duration from study opening to report signing and times for five activities performed during this period: image viewing, report transcription, obtaining clinical data, education, and other. Attendings, fellows, and residents reading studies independently and attendings over-reading trainee-previewed studies were observed. RESULTS: Ten attendings, 12 fellows, and 13 residents spent a mean of 11, 18, and 16 minutes reading brain MRIs independently. Mean duration was significantly different comparing attendings in all assignments to fellows (18.36 ± 1.05 minutes, p = 0.0001) or residents (16.31 ± 1.11 minutes, p = 0.001) but not between fellows/residents. Mean duration among attendings reading independently versus over-reading trainees was not statistically different. Attendings spent the same time on image viewing (4.07-5.33 minutes) with or without trainees. Attending transcription time was shortest when over-reading trainees (2.24 minutes) and longest when reading independently (4.20 minutes), demonstrating benefit of the draft report. Fellows and Residents spent longer on image viewing (7.14 minutes and 8.06 minutes, respectively) and transcription (7.02 minutes and 5.40 minutes, respectively) than attendings reading independently. CONCLUSION: Neuroradiologist time/activity distributions for reading brain MRI studies were measured, setting the stage to establish a benchmark for future reference and suggesting opportunities for greater efficiency. Furthermore, report production time can be decreased when a draft report is available.

Chapter 8 On the Horizon: Advanced Imaging Techniques to Improve Noninvasive Assessment of Cervical Lymph Nodes.

Conventional imaging modalities are limited in the evaluation of lymph nodes as they predominantly rely on size and morphology, which have suboptimal sensitivity and specificity for malignancy. In this review we will explore the role of "on the horizon" advanced imaging modalities that can look beyond the size and morphologic features of a cervical lymph node and explore its molecular nature and can aid in personalizing therapy rather than use the "one-size-fits-all" approach.

Trends in Fluoroscopy Time in Fluoroscopy-Guided Lumbar Punctures Performed by Trainees Over an Academic Year.

RATIONALE AND OBJECTIVES: Fluoroscopy-guided lumbar puncture (FGLP) is an operator-dependent procedure that can contribute to lifetime cumulative radiation dose. Benchmark fluoroscopic times (FTs) have been published for ranges of body mass index (BMI), but trends in FT in FGLPs performed by neuroradiology trainees during their training have not been studied. The purpose of this study was to investigate the trends in FTs in FGLPs performed by neuroradiology fellows in an academic year. MATERIALS AND METHODS: We retrospectively reviewed FGLPs performed at our institution from July 2013 to June 2015 and determined the FT average and standard deviation of residents and non-neuroradiology fellows, neuroradiology fellows, and neuroradiology attendings. We used the Kruskal-Wallis test to evaluate group differences in FT in operator groups and academic quarters and by patient age, BMI, and needle length. Linear and Poisson regression analyses were performed to directly examine the relationship between the number of FGLPs performed and FTs. RESULTS: A total of 776 patients had successful FGLPs; 594 cases (77%) were performed by neuroradiology fellows (n = 14). The average FT and variance for neuroradiology fellows significantly decreased over the year (P = 0.004 and P < 0.001) with an estimated decrease of 0.01 minute of FT per FGLP. BMI, long needle length, and age ≥65 years old significantly affected the average FT (P = 0.03, P < 0.001, and P < 0.001) and FT decreased in all of these subgroups in the academic year. CONCLUSIONS: FT in FGLP cases performed by neuroradiology fellows decreases during the year. Our data can be utilized by radiology training programs and practices as a benchmark to monitor individual operator FT.

Assessment of early response to tumor-treating fields in newly diagnosed glioblastoma using physiologic and metabolic MRI: initial experience.

Tumor-treating fields (TTFields) is a novel antimitotic treatment modality for patients with glioblastoma. To assess response to TTFields, a newly diagnosed patient with glioblastoma underwent diffusion, perfusion and 3D echo-planar spectroscopic imaging prior to initiation of TTFields plus temozolamide (baseline) and at 1- and 2-month follow-up periods. Increased mean diffusivity along with decreased fractional anisotropy and maximum relative cerebral blood volume were noted at 2 months relative to baseline suggesting inhibition of tumor growth and angiogenesis. Additionally, a reduction in choline/creatine was also noted during this period. These preliminary data indicate the potential of physiologic and metabolic MRI in assessing early treatment response to TTFields in combination with temozolamide.

Multi-detector computer tomography angiography in the initial assessment of patients acutely suspected of having intracranial aneurysm rupture.

INTRODUCTION: Multi-detector computer tomography angiography (CTA) provides a fast non-invasive assessment of the cerebral vessels, is readily available in an acute setting and can potentially replace invasive digital subtraction angiography (DSA) for the diagnosis of intracranial vascular lesions in an emergency setting. We report our experience in the use of emergent cerebral CTA versus DSA in the assessment of patients presenting acutely with symptoms suspicious of brain aneurysm rupture. MATERIALS AND METHODS: Thirty-seven consecutive patients presenting acutely with clinical suspicion of brain aneurysm rupture were evaluated over a 4-month period from January to April 2008. CTA with peripheral intravenous contrast injection was performed on a 32 slice helical scanner. DSA was performed within 48 hours for all cases when CTA was the initial assessment. Studies were assessed via radiology reports using DSA or surgery as the gold standard. RESULTS: All except for 3 patients had CTA as the initial study. There were 26 cerebral aneurysms detected by CTA in these 37 patients, with 9 negative studies. There were 2 patients with arteriovenous malformations (AVM), 1 with AV fistula (AVF), 1 tumoral bleed, 2 vertebral dissections, and 1 missed sagittal sinus thrombosis (CVT) on CTA. Based solely on CTA assessment, 3 patients had direct surgical clipping of the aneurysm, while 4 proceeded to direct endovascular coiling. CONCLUSION: Emergent CTA is a non-invasive, reliable and viable alternative to emergent DSA for the assessment of the cerebral vessels in the acute assessment of patients presenting with symptoms suspicious of brain aneurysm rupture. Where positive, it can serve as a guide to therapeutic decisions. Review of CTA source data is essential, especially for small lesions and for post-clipping assessment.