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Microstructural alterations have been reported in patients with urologic chronic pelvic pain syndrome (UCPPS). However, it isn't clear whether these alterations are reproducible within 6 months or whether long-term symptom improvement is associated with specific microstructural changes. Using data from the MAPP-II Research Network, the current study performed population-based voxel-wise DTI and probabilistic tractography in a large sample of participants from the multicenter cohort with UCPPS (N=364) and healthy controls (HCs, N=61) over 36 months. While fractional anisotropy (FA) differences between UCPPS patients and HCs were observed to be unique at baseline and 6-month follow-up visits, consistent aberrations in mean diffusivity (MD) were observed between UCPPS and HCs at baseline and repeated at 6 months. Additionally, compared to HCs, UCPPS patients showed stronger structural connectivity (SC) between the left postcentral gyrus and the left precuneus, and weaker SC from the left cuneus to the left lateral occipital cortex and the isthmus of the left cingulate cortex at baseline and 6-month. By 36 months, reduced FA and MD aberrations in these same regions were associated with symptom improvement in UCPPS. Together, results suggest changes in white matter microstructure may play a role in the persistent pain symptoms in UCPPS.

The present study describes a model-based approach for correcting off-resonance in the context of double half-echo k-space acquisitions. This technique employs center-out readouts in forward and reverse directions to reduce echo-times but is sensitive to off-resonance, which manifests as pixel shifts in both directions. Demodulating the k-space signal with a constant off-resonance term per slice removes pixel shifts and results in a marked reduction in blurring. Phantom and in vivo datasets are demonstrated from low bandwidth sodium imaging.

Correlation between mRANO-defined PFS and OS excluding patients with PFS > 120 days. (top) Correlation between radiographic PFS using the mRANO criteria applied to local measurements and OS for patients who died. (bottom) Correlation between radiographic PFS using the mRANO criteria applied to IRF-determined measurements and OS for patients who died. Open circles = patients who were censored (not used in correlation analysis, only for visualization purposes).

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Medicenna Imaging Charter for Independent Radiologic Review of MDNA55-05.

Purpose:The current study compared the standard response assessment in neuro-oncology (RANO), immunotherapy RANO (iRANO), and modified RANO (mRANO) criteria as well as quantified the association between progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM).Patients and Methods:A total of 47 patients with rGBM were enrolled in a prospective phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and centrally by an independent radiologic faculty, then standard RANO, iRANO, and mRANO criteria were applied.Results:A total of 41 of 47 patients (mean age 56 ± 11.7) were evaluable for response. PFS was significantly shorter using standard RANO compared with iRANO (log-rank, P < 0.0001; HR = 0.3) and mRANO (P < 0.0001; HR = 0.3). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (local, P = 0.47; central, P = 0.34). Using iRANO, a weak association was observed between confirmed PFS and OS via local site measurements (P = 0.017), but not central measurements (P = 0.18). A total of 24 of 41 patients (59%) were censored using iRANO and because they lacked confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local (R2 = 0.66, P < 0.0001) and centrally determined reads (R2 = 0.57, P = 0.0007).Conclusions:No correlation between radiographic PFS and OS was observed for standard RANO or iRANO, but a correlation was observed between PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients.

OBJECTIVE The aim of this study was to investigate cerebral reorganization, both structurally and functionally, occurring in patients with degenerative cervical myelopathy (DCM) after surgical decompression. METHODS In the current observational study of 19 patients, high-resolution T1-weighted structural MRI and resting-state functional MRI scans were obtained pre- and postoperatively in patients with DCM and healthy controls (HCs). The resting-state functional MRI data were utilized to perform region-of-interest (ROI)–to-ROI and ROI-to-voxel functional connectivity (FC) analysis and were similarly compared between and within cohorts. Macroscopic structural plasticity was evaluated by assessing for changes in cortical thickness within the DCM cohort after decompression surgery. RESULTS Prior to surgery, FC patterns were significantly different between DCM patients and HCs in cerebral areas responsible for postural control, motor regulation, and perception and integration of sensory information. Significantly stronger FC between the cerebellum and frontal lobes was identified in DCM patients postoperatively compared with DCM patients preoperatively. Additionally, increased FC between the cerebellum and primary sensorimotor areas was found to be positively associated with neurological improvement in patients with DCM. No macroscopic structural changes were observed in the DCM patients after surgery. CONCLUSIONS These results support the authors’ hypothesis that functional changes within the brain are associated with effective postoperative recovery, particularly in regions associated with motor regulation and with perception and integration of sensory information. In particular, increased FC between the cerebellum and the primary sensorimotor after surgery appears to be associated with neurological improvement. Macroscopic morphological changes may be too subtle to be detected within 3 months after surgery.

Background Diffusion MRI estimates of the apparent diffusion coefficient (ADC) have been shown to be useful in predicting treatment response in patients with glioblastoma (GBM), with ADC elevations indicating tumor cell death. We aimed to investigate whether the ADC values measured before and after treatment with immune checkpoint inhibitors (ICIs) and the changes in these ADC values could predict overall survival (OS) in patients with recurrent IDH wild-type GBM. Methods Forty-four patients who met the following inclusion criteria were included in this retrospective study: (i) diagnosed with recurrent IDH wild-type GBM and treated with either pembrolizumab or nivolumab and (ii) availability of diffusion data on pre- and post-ICI MRI. Tumor volume and the median relative ADC (rADC) with respect to the normal-appearing white matter within the enhancing tumor were calculated. Results Median OS among all patients was 8.1 months (range, 1.0–22.5 months). Log-rank test revealed that higher post-treatment rADC was associated with a significantly longer OS (median, 10.3 months for rADC ≥ 1.63 versus 6.1 months for rADC < 1.63; P = .02), whereas tumor volume, pretreatment rADC, and changes in rADC after treatment were not significantly associated with OS. Cox regression analysis revealed that post-treatment rADC significantly influenced OS (P = .02, univariate analysis), even after controlling for age and sex (P =.01, multivariate analysis), and additionally controlling for surgery after ICI treatment (P = .045, multivariate analysis). Conclusions Elevated post-treatment rADC may be an early imaging biomarker for OS benefits in GBM patients receiving ICI treatment.

To develop a robust amine chemical exchange saturation transfer (CEST) physical phantom, validate the temporal stability, and create a supporting software for automatic image processing and quality assurance. The phantom was designed as an assembled laser-cut acrylic rack and 18 vials of phantom solutions, prepared with different pHs, glycine concentrations, and gadolinium concentrations. We evaluated glycine concentrations using ultraviolet absorbance for 70 days and measured the pH, relaxation rates, and CEST contrast for 94 days after preparation. We used Spearman’s correlation to determine if glycine degraded over time. Linear regression and Bland–Altman analysis were performed between baseline and follow-up measurements of pH and MRI properties. No degradation of glycine was observed (p > 0.05). The pH and MRI measurements stayed stable for 3 months and showed high consistency across time points (R2 = 1.00 for pH, R1, R2, and CEST contrast), which was further validated by the Bland–Altman plots. Examples of automatically generated reports are provided. We designed a physical phantom for amine CEST-MRI, which is easy to assemble and transfer, holds 18 different solutions, and has excellent short-term chemical and MRI stability. We believe this robust phantom will facilitate the development of novel sequences and cross-scanners validations.

INTRODUCTION Sodium MRI has been recently explored in brain tumors to potentially reveal complementary information with proton MRI about the tumor microenvironment. However, there remains limited investigation combining sodium and quantitative proton MRI techniques. This pilot study explored the associations of sodium MRI with diffusion-, pH-, and hypoxia-weighted MRI biomarkers in gliomas. METHODS Eleven patients with gliomas (n=8 IDH-wild-type; n=3 IDH-mutant) who obtained sodium, anatomical, diffusion-, pH-, and hypoxia-weighted MRI were studied. All images were obtained on a 3T Siemens Prisma with a dedicated multi-nuclear head coil. Regions-of-interest were segmented on the contrast-enhancing (CE) (n=10), FLAIR (n=11), and necrotic regions (n=9). Sodium values were normalized to the mean values of the eyes. Median sodium, apparent diffusion coefficient (ADC), ADC(L) from bimodal histogram analyses, MTRasym (acidity), and R2’ (hypoxia) values were obtained. RESULTS There was increased sodium in necrosis compared to FLAIR regions (mean difference=0.24; P/i>< 0.05) and compared to CE regions (mean difference=0.17; P/i>=0.07). There were significant positive correlations between sodium and ADC in CE (R=0.94; P/i>< 0.0001) and FLAIR regions (ρ=0.77; P/i>< 0.01), but not in necrosis (R=0.44; P/i>=0.24). There was also a significant positive correlation with ADC(L) in CE regions (R=0.90; P< 0.001) but not in FLAIR regions (ρ=0.50; P/i>=0.12). Furthermore, there was a significant positive correlation between sodium and MTRasym in necrosis (R=0.74; P/i>< 0.05) and a positive trend in CE regions (R=0.55; P=0.10). There was also a negative trend between sodium and R2’ in FLAIR regions (ρ=-0.58; P/i>=0.11). CONCLUSIONS Because ADC and ADC(L) are inversely related to cell density, increased sodium in gliomas may reflect increased extracellular space stemming from lower cell density, as sodium concentration is higher extracellularly. Positive associations between sodium and acidity as well as negative associations between sodium and hypoxia may reflect alterations in coupled sodium-pH and sodium-hypoxia homeostasis in gliomas.

Amine-weighted chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is particularly valuable as an amine- and pH-sensitive imaging technique in brain tumors, targeting the intrinsically high concentration of amino acids with exchangeable amine protons and reduced extracellular pH in brain tumors. Amine-weighted CEST MRI contrast is dependent on the glioma genotype, likely related to differences in degree of malignancy and metabolic behavior. Amine-weighted CEST MRI may provide complementary value to anatomic imaging in conventional and exploratory therapies in brain tumors, including chemoradiation, antiangiogenic therapies, and immunotherapies. Continual improvement and clinical testing of amine-weighted CEST MRI has the potential to greatly impact patients with brain tumors by understanding vulnerabilities in the tumor microenvironment that may be therapeutically exploited.

Characterization of hypoxia and tissue acidosis could advance the understanding of glioma biology and improve patient management. In this study, we evaluated the ability of a pH- and oxygen-sensitive magnetic resonance imaging (MRI) technique to differentiate glioma genotypes, including isocitrate dehydrogenase (IDH) mutation, 1p/19q co-deletion, and epidermal growth factor receptor (EGFR) amplification, and investigated its prognostic value. A total of 159 adult glioma patients were scanned with pH- and oxygen-sensitive MRI at 3T. We quantified the pH-sensitive measure of magnetization transfer ratio asymmetry (MTRasym) and oxygen-sensitive measure of R2’ within the tumor region-of-interest. IDH mutant gliomas showed significantly lower MTRasym × R2’ (p < 0.001), which differentiated IDH mutation status with sensitivity and specificity of 90.0% and 71.9%. Within IDH mutants, 1p/19q codeletion was associated with lower tumor acidity (p < 0.0001, sensitivity 76.9%, specificity 91.3%), while IDH wild-type, EGFR-amplified gliomas were more hypoxic (R2’ p = 0.024, sensitivity 66.7%, specificity 76.9%). Both R2’ and MTRasym × R2’ were significantly associated with patient overall survival (R2’: p = 0.045; MTRasym × R2’: p = 0.002) and progression-free survival (R2’: p = 0.010; MTRasym × R2’: p < 0.0001), independent of patient age, treatment status, and IDH status. The pH- and oxygen-sensitive MRI is a clinically feasible and potentially valuable imaging technique for distinguishing glioma subtypes and providing additional prognostic value to clinical practice.

Purpose To evaluate the influence of phosphate on amine, amide, and hydroxyl CEST contrast using Bloch-McConnell simulations applied to physical phantom data. Methods Phantom solutions of 4 representative metabolites with exchangeable protons-glycine (α-amine protons), Cr (η-amine protons), egg white protein (amide protons), and glucose (hydroxyl protons)-were prepared at different pH levels (5.6 to 8.9) and phosphate concentrations (5 to 80 mM). CEST images of the phantom were collected with CEST-EPI sequence at 3 tesla. The CEST data were then fitted to full Bloch-McConnell equation simulations to estimate the exchange rate constants. With the fitted parameters, simulations were performed to evaluate the intracellular and extracellular contributions of CEST signals in normal brain tissue and brain tumors, as well as in dynamic glucose-enhanced experiments. Results The exchange rates of α-amine and hydroxyl protons were found to be highly dependent on both pH and phosphate concentrations, whereas the exchange rates of η-amine and amide protons were pH-dependent, albeit not catalyzed by phosphate. With phosphate being predominantly intracellular, CEST contrast of α-amine exhibited a higher sensitivity to changes in the extracellular microenvironment. Simulations of dynamic glucose-enhanced signals demonstrated that the contrast between normal and tumor tissue was mostly due to the extracellular CEST effect. Conclusion The proton exchange rates in some metabolites can be greatly catalyzed by the presence of phosphate at physiological concentrations, which substantially alters the CEST contrast. Catalytic agents should be considered as confounding factors in future CEST-MRI research. This new dimension may also benefit the development of novel phosphate-sensitive imaging methods.

IntroductionThere is growing evidence that the subventricular zone (SVZ) plays a key role in glioblastoma (GBM) tumorigenesis. However, little is known regarding how the SVZ, which is a harbor for adult neural stem cells, may be influenced by chemoradiation. The current diffusion-weighted imaging (DWI) study explored ipsilateral and contralateral alterations in the anterior SVZ in GBM patients with posterior enhancing lesions following chemoradiation.MethodsForty GBM patients with tumor involvement in the posterior SVZ (mean age = 57 ± 10; left-hemisphere N = 25; right-hemisphere N = 15) were evaluated using DWI before and after chemoradiation. Regions-of-interest were drawn on the ipsilesional and contralesional anterior SVZ on apparent diffusion coefficient (ADC) maps for both timepoints. ADC histogram analysis was performed by modeling a bimodal, double Gaussian distribution to obtain ADCL, defined as the mean of the lower Gaussian distribution.ResultsThe ipsilesional SVZ had lower ADCL values compared to the contralesional SVZ before treatment (mean difference = 0.025 μm2/ms; P = 0.007). Following chemoradiation, these changes were no longer observed (mean difference = 0.0025 μm2/ms; P > 0.5), as ADCL values of the ipsilesional SVZ increased (mean difference = 0.026 μm2/ms; P = 0.037). An increase in ipsilesional ADCL was associated with shorter progression-free (P = 0.0119) and overall survival (P = 0.0265).ConclusionsThese preliminary observations suggest baseline asymmetry as well as asymmetric changes in the SVZ proximal (ipsilesional) to the tumor with respect to contralesional SVZ regions may be present in GBM, potentially implicating this region in tumorigenesis and/or treatment resistance.

As treatments for diffuse gliomas have advanced, survival for patients with gliomas has also increased. However, there remains limited knowledge on the relationships between brain connectivity and the lasting changes to cognitive function that glioma survivors often experience long after completing treatment. This resting-state functional magnetic resonance imaging (rs-fMRI) study explored functional connectivity (FC) alterations associated with cognitive function in survivors of gliomas. In this pilot study, 22 patients (mean age 43.8 ± 11.9) with diffuse gliomas who completed treatment within the past 10 years were evaluated using rs-fMRI and neuropsychological measures. Novel rs-fMRI analysis methods were used to account for missing brain in the resection cavity. FC relationships were assessed between cognitively impaired and non-impaired glioma patients, along with self-reported cognitive impairment, non-work daily functioning, and time with surgery. In the cognitively non-impaired patients, FC was stronger in the medial prefrontal cortex, rostral prefrontal cortex, and intraparietal sulcus compared to the impaired survivors. When examining non-work daily functioning, a positive correlation with FC was observed between the accumbens and the intracalcarine cortices, while a negative correlation with FC was observed between the parietal operculum cortex and the cerebellum. Additionally, worse self-reported cognitive impairment and worse non-work daily functioning were associated with increased FC between regions involved in cognition and sensorimotor processing. These preliminary findings suggest that neural correlates for cognitive and daily functioning in glioma patients can be revealed using rs-fMRI. Resting-state network alterations may serve as a biomarker for patients’ cognition and functioning.

It remains unknown if the progressive loss of axonal conduction along sensorimotor tracts can be recovered after surgery in patients with degenerative cervical myelopathy (DCM) and if subsequent adaptive microstructural changes are associated with the neurological improvement. OBJECTIVE: To investigate the upstream recovery of microstructural integrity and reorganization of microstructural connectivity that occurs in patients with DCM after surgical decompression. METHODS: Preoperative and postoperative cerebral diffusion tensor imaging and diffusion spectrum imaging data were collected for 22 patients with DCM (age = 56.9 ± 9.1 years). Paired t-tests were used to identify significant microstructural changes within cohorts, and correlation analysis was used to identify whether those changes are associated with neurological improvement. RESULTS: Before surgery, higher structural connectivity (SC) was observed in the prefrontal/frontal lobes, anterior cingulate, the internal and external capsules, and the anterior, posterior, and superior regions of the corona radiata fibers. Following surgery, an increased modified Japanese Orthopaedic Association score was associated with increased SC from the primary sensorimotor regions to the posterior cingulate and precuneus; increased SC between the cerebellum and the bilateral lingual gyri; and decreased SC from areas of the limbic system to the basal ganglia and the frontal lobe. In addition, increased fractional anisotropy and normalized quantitative anisotropy values along white matter fibers responsible for conveying sensory information and motor coordination and planning were associated with neurological improvement of patients with DCM after surgery. CONCLUSION: Recovery of microstructural integrity along the corticospinal tract and other sensorimotor pathways, together with supraspinal reorganization of microstructural connectivity within sensory and motor-related regions, was associated with neurological improvement after surgical decompression.

Background Inhibition of the isocitrate dehydrogenase (IDH)-mutant enzyme is a novel therapeutic target in IDH-mutant gliomas. Imaging biomarkers of IDH inhibitor treatment efficacy in human IDH-mutant gliomas are largely unknown. This study investigated early volumetric, perfusion, and diffusion MRI changes in IDH1-mutant gliomas during IDH inhibitor treatment. Methods Twenty-nine IDH1-mutant glioma patients who received IDH inhibitor and obtained anatomical, perfusion, and diffusion MRI pretreatment at 3–6 weeks (n = 23) and/or 2–4 months (n = 14) of treatment were retrospectively studied. Normalized relative cerebral blood volume (nrCBV), apparent diffusion coefficient (ADC), and fluid-attenuated inversion recovery (FLAIR) hyperintensity volume were analyzed. Results After 3–6 weeks of treatment, nrCBV was significantly increased (P = .004; mean %change = 24.15%) but not FLAIR volume (P = .23; mean %change = 11.05%) or ADC (P = .52; mean %change = -1.77%). Associations between shorter progression-free survival (PFS) with posttreatment nrCBV > 1.55 (P = .05; median PFS, 240 vs 55 days) and increased FLAIR volume > 4 cm3 (P = .06; 227 vs 29 days) trended toward significance. After 2–4 months, nrCBV, FLAIR volume, and ADC were not significantly different from baseline, but an nrCBV increase > 0% (P = .002; 1121 vs 257 days), posttreatment nrCBV > 1.8 (P = .01; 1121 vs. 270 days), posttreatment ADC 0% (P = .02; 1121 vs 270 days), and FLAIR volume change > 4 cm3 (P = .03; 421 vs 226.5 days) were associated with shorter PFS. Conclusions Increased nrCBV at 3–6 weeks of treatment may reflect transient therapeutic and/or tumor growth changes, whereas nrCBV, ADC, and FLAIR volume changes occurring at 2–4 months of treatment may more accurately reflect antitumor response to IDH inhibition.

Degenerative cervical myelopathy (DCM) is a progressive condition characterized by degeneration of osseocartilaginous structures within the cervical spine resulting in compression of the spinal cord and presentation of clinical symptoms. Compared to healthy controls (HCs), studies have shown DCM patients experience structural and functional reorganization in the brain, however, sex-dependent cortical differences in DCM patients remains largely unexplored. In the present study, we investigate the role of sex differences on the structure of the cerebral cortex in DCM and determine how structural differences may relate to clinical measures of neurological function. T1-weighted structural MRI scans were acquired in 85 symptomatic and asymptomatic patients with DCM and 90 age-matched HCs. Modified Japanese Orthopedic Association (mJOA) scores were obtained for patients. A general linear model was used to determine vertex-level significant differences in gray matter volume (GMV) between the following groups (1) male HCs and female HCs, (2) male patients and female patients, (3) male patients and male HCs, and (4) female patients and female HCs. Within patients, males exhibited larger GMV in motor, language, and vision related brain regions compared to female DCM patients. Males demonstrated a significant positive correlation between GMV and mJOA score, in which patients with worsening neurological symptoms exhibited decreasing GMV primarily across somatosensory and motor related cortical regions. Females exhibited a similar association, albeit across a broader range of cortical areas including those involved in pain processing. In sensorimotor regions, female patients consistently showed smaller GMV compared with male patients, independent of mJOA score. Results from the current study suggest strong sex-related differences in cortical volume in patients with DCM, which may reflect hormonal influence or differing compensation mechanisms.

Cervical degenerative disease is a major cause of neck disability, but it has been understudied in patients with cervical spondylotic (CS), largely due to the fact that the neurological impairment associated with this condition tends to be the primary treatment focus. This observational study examined the cerebral functional alterations occurring in advanced cervical spondylosis and myelopathy using resting state functional MRI. Associations between functional connectivity (FC) and neck disability using the Neck Disability Index (NDI) were assessed. Results of the study demonstrated an increase in FC with increasing in neck disability in regions associated with sensorimotor system (both postcentral gyri and precentral gyri, bilaterally, with the SMA; bilateral precentral gyri and the left postcentral gyrus, with the left superior frontal gyrus; bilateral SMA and the left putamen, with the superior frontal gyri). Accounting for the difference in neurological function (mJOA score), strong connectivity between the precentral gyri and the SMA associated with the neck disability. Consistent with studies in chronic pain conditions, these findings suggest neck disability is associated with altered cerebral FC in cervical spondylosis patients.

Degenerative Cervical Myelopathy (DCM) is a spinal cord disorder that causes significant physical disabilities in older patients. While most DCM research focuses on the spinal cord, widespread reorganization of the brain may occur to compensate for functional impairment. This observational study used diffusion spectrum imaging (DSI) to examine reorganization of cerebral white matter associated with neurological impairment as measured by the modified Japanese Orthopedic Association (mJOA), and severity of neck disability as measured by the Neck Disability Index (NDI) score. A total of 47 patients were included in the cervical spondylosis (CS) cohort: 38 patients with DCM (mean mJOA=14.6, and mean NDI=12.0), and 9 neurologically asymptomatic patients with spinal cord compression (mJOA=18, and mean NDI=7.0). 28 healthy volunteers (HCs) served as the control group. Lower generalized fractional anisotropy (GFA) was observed throughout much of the brain in patients compared to HCs (p&nbsp

Hypoxia and tissue acidosis are two key features of the glioma microenvironment, both associated with a more aggressive phenotype through promotion of invasion, angiogenesis, and resistance to a vast number of therapies. In the current study, we demonstrate that higher levels of acidity and hypoxia in glioma are associated with worse prognosis by using simultaneous pH- and oxygen-sensitive amine chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI). A total of 159 histologically confirmed adult glioma patients (WHO grade II: N = 42; grade III: N = 38; grade IV, N = 79) were retrospectively evaluated. All patients were scanned with a custom amine CEST-SAGE-EPI MRI pulse sequence at 3T. Magnetization transfer ratio asymmetry (MTRasym) at 3ppm was used as a measure of relative acidity, R2’ was used as a surrogate of hypoxia, and their product MTRasym×R2' was used to quantify the degree of both acidity and hypoxia. Cox regression was performed to evaluate prognostic factors for OS and PFS. Univariate results suggested higher hypoxia, R2' (HR = 1.44, p = 0.0002), and higher combined measure of acidity and hypoxia, MTRasym×R2' (HR = 1.14, p = 0.0008), were associated with a shorter OS. When considering age, treatment status, and IDH mutation status as covariates, R2' and MTRasym×R2' remained significantly associated with patient OS (R2': HR = 1.27, p = 0.045; MTRasym×R2': HR = 1.17, p = 0.002). Within the treatment naïve patients, tumor acidity MTRasym, was also associated with OS (HR = 3.72, p = 0.003). R2' and MTRasym×R2' were significantly associated with PFS, both using univariate (R2': p < 0.0001; MTRasym×R2': p < 0.0001) and multivariate analyses including clinical factors (R2': p = 0.010; MTRasym×R2': p < 0.0001). In summary, tumor acidity and hypoxia measured using pH- and oxygen-sensitive metabolic MRI are significant prognostic factors in glioma.

Sodium imaging typically employs ultrashort echo time radial, density adapted and cones trajectories to capture the rapidly decaying short T2 signal. The present study considers the parameter choices involved in the use of these trajectories in terms of their impact on the resolution and signal to noise ratio. Many parameters have a strong effect on these image properties, particularly the number of spokes which impacts voxel size. The present article develops an understanding of the trade-offs involved and how to choose optimal (or at least reasonable) parameter values. This has a practical role in designing clinical protocols for imaging sodium.

Purpose: The current study compared the standard response assessment in neuro-oncology (RANO), immunotherapy RANO (iRANO), and modified RANO (mRANO) criteria as well as quantified the association between progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM). Patients and Methods: A total of 47 patients with rGBM were enrolled in a prospective phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and centrally by an independent radiologic faculty, then standard RANO, iRANO, and mRANO criteria were applied. Results: A total of 41 of 47 patients (mean age 56 ± 11.7) were evaluable for response. PFS was significantly shorter using standard RANO compared with iRANO (log-rank, P < 0.0001; HR = 0.3) and mRANO (P < 0.0001; HR = 0.3). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (local, P = 0.47; central, P = 0.34). Using iRANO, a weak association was observed between confirmed PFS and OS via local site measurements (P = 0.017), but not central measurements (P = 0.18). A total of 24 of 41 patients (59%) were censored using iRANO and because they lacked confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local (R2 = 0.66, P < 0.0001) and centrally determined reads (R2 = 0.57, P = 0.0007). Conclusions: No correlation between radiographic PFS and OS was observed for standard RANO or iRANO, but a correlation was observed between PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients.

Background Evidence from single and multicenter phase II trials have suggested diffusion MRI is a predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF therapy. The current study confirms these findings in a large, randomized phase III clinical trial. Methods Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus BV in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pretreatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 µm2/ms) or low ( Results Baseline tumor volume (P = .3460) and ADCL (P = .2143) did not differ between treatment arms. Univariate analysis showed patients with high ADCL had a significant survival advantage in all patients (P = .0006), as well as BV (P = .0159) and BV+VB-111 individually (P = .0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume, and ADCL identified continuous measures of tumor volume (P < .0001; HR = 1.0212) and ADCL phenotypes (P = .0012; HR = 0.5574) as independent predictors of OS. Conclusion Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111.

Degenerative cervical myelopathy (DCM) is the most common cause of spinal cord impairment in adults. Previous supraspinal investigations have primarily focused on cortical changes in this patient population. As the nexus between the brain and the spinal cord, the brainstem has been understudied in patients with DCM. The current study examined the structural and functional connectivity between the brainstem and cortex in DCM patients using probabilistic tractography and resting-state functional MRI. A total of 26 study patients and 32 neurologically intact, healthy volunteers (HCs) participated in this prospective analysis. The study cohort included DCM patients (n=18), as well as neurologically asymptomatic patients with evidence of cervical spine degenerative changes and spinal cord compression (n=8). Results of the study demonstrated significant differences in fiber density (FD), fiber cross-section (FDC), and the functional connectivity (FC) between the study cohort and HCs. Through seeding the brainstem, the study cohort showed reductions in FD and FDC along the corticospinal tract, including regions extending through the corona radiata and internal capsule. By correlating FD and FDC with the Neck Disability Index (NDI), and the modified Japanese Orthopaedic Association (mJOA), we identified increasing total volume of projections to the thalamus, basal ganglia, and internal capsule, and increased functional connectivity to visual network and the posterior parietal cortices. These results support our hypothesis that DCM patients tend to have long-term FC reorganization not only localized to sensorimotor regions, but also to regulatory and visual processing regions, designed to ultimately preserve neurological function.

Author(s): Tatekawa, Hiroyuki; Yao, Jingwen; Oughourlian, Talia C; Hagiwara, Akifumi; Wang, Chencai; Raymond, Catalina; Lai, Albert; Cloughesy, Timothy F; Nghiemphu, Phioanh L; Liau, Linda M; Salamon, Noriko; Ellingson, Benjamin M | Abstract: PurposeWe evaluated F-FDOPA PET and MRI characteristics in association with the molecular status and overall survival (OS) in a large number of low-grade gliomas (LGGs).MethodsEighty-six patients who underwent F-FDOPA PET and MRI and were diagnosed with new or recurrent LGGs were retrospectively evaluated with respect to their isocitrate dehydrogenase (IDH) and 1p19q status (10 IDH wild type, 57 mutant, 19 unknown; 1p19q status in IDH mutant: 20 noncodeleted, 37 codeleted). After segmentation of the hyperintense area on fluid-attenuated inversion recovery image (FLAIRROI), the following were calculated: normalized SUVmax (nSUVmax) of F-FDOPA relative to the striatum, F-FDOPA hypermetabolic volume (tumor-to-striatum ratios g1), FLAIRROI volume, relative cerebral blood volume, and apparent diffusion coefficient within FLAIRROI. Receiver operating characteristic curve and Cox regression analyses were performed.ResultsPET and MRI metrics combined with age predicted the IDH mutation and 1p19q codeletion statuses with sensitivities of 73% and 76% and specificities of 100% and 94%, respectively. Significant correlations were found between OS and the IDH mutation status (hazard ratio [HR] = 4.939), nSUVmax (HR = 2.827), F-FDOPA hypermetabolic volume (HR = 1.048), and FLAIRROI volume (HR = 1.006). The nSUVmax (HR = 151.6) for newly diagnosed LGGs and the F-FDOPA hypermetabolic volume (HR = 1.038) for recurrent LGGs demonstrated significant association with OS.ConclusionsCombining F-FDOPA PET and MRI with age proved useful for predicting the molecular status in patients with LGGs, whereas the nSUVmax and F-FDOPA hypermetabolic volume may be useful for prognostication.

BACKGROUND Evidence from independent single center as well as multicenter phase II trials have suggested diffusion MRI is a strong predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF monotherapy, but not systemic chemotherapies or combination therapies with anti-VEGF agents. The current study builds on this body of evidence by evaluating these diffusion MR phenotypes in a large randomized phase III clinical trial. METHODS Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus bevacizumab in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pre-treatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 um2/ms) or low (< 1.24 um2/ms) ADCL, the mean value of the lower peak in a double Gaussian model of the ADC histogram within the contrast enhancing tumor. RESULTS Baseline tumor volume (P=0.3460) and ADCL (P=0.2143) did not differ between treatment arms. Univariate analysis showed that patients with high ADCL had a significant survival advantage when pooling all patients (P=0.0006), as well as when examining the BV (P=0.0159) and BV+VB-111 individually (P=0.0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume and ADCL identified continuous measures of tumor volume (P< 0.0001; HR=1.0212) and ADCL phenotypes (P=0.0012; HR=0.5574) as independent predictors of OS. CONCLUSION Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111. Since ADCL was predictive of OS in combination BV+VB-111, results support the working hypothesis that co-administration of VB-111 with BV may block any VB-111 anti-tumor effect, whereas VB-111 monotherapy or priming may result in higher efficacy of VB-111.

Schizophrenia (SCZ) is a chronic cognitive and behavioral disorder associated with abnormal cortical activity during information processing. Several brain structures associated with the seven performance domains evaluated using the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) have shown cortical volume loss in first episode schizophrenia (FES) patients. However, the relationship between morphological organization and MCCB performance remains unclear. Therefore, in the current observational study, high-resolution structural MRI scans were collected from 50 FES patients, and the morphometric correlation network (MCN) using cortical volume was established to characterize the cortical pattern associated with poorer MCCB performance. We also investigated topological properties, such as the modularity, the degree and the betweenness centrality. Our findings show structural volume was directly and strongly associated with the cognitive deficits of FES patients in the precuneus, anterior cingulate, and fusiform gyrus, as well as the prefrontal, parietal, and sensorimotor cortices. The medial orbitofrontal, fusiform, and superior frontal gyri were not only identified as the predominant nodes with high degree and betweenness centrality in the MCN, but they were also found to be critical in performance in several of the MCCB domains. Together, these results suggest a widespread cortical network is altered in FES patients and that performance on the MCCB domains is associated with the core pathophysiology of SCZ.

Previous data suggest that apparent diffusion coefficient (ADC) imaging phenotypes predict survival response to anti-VEGF monotherapy in glioblastoma. However, the mechanism by which imaging may predict clinical response is unknown. We hypothesize that decorin (DCN), a proteoglycan implicated in the modulation of the extracellular microenvironment and sequestration of pro-angiogenic signaling, may connect ADC phenotypes to survival benefit to anti-VEGF therapy. Patients undergoing resection for glioblastoma as well as patients included in The Cancer Genome Atlas (TCGA) and IVY Glioblastoma Atlas Project (IVY GAP) databases had pre-operative imaging analyzed to calculate pre-operative ADCL values, the average ADC in the lower distribution using a double Gaussian mixed model. ADCL values were correlated to available RNA expression from these databases as well as from RNA sequencing from patient derived mouse orthotopic xenograft samples. Targeted biopsies were selected based on ADC values and prospectively collected during resection. Surgical specimens were used to evaluate for DCN RNA and protein expression by ADC value. The IVY Glioblastoma Atlas Project Database was used to evaluate DCN localization and relationship with VEGF pathway via in situ hybridization maps and RNA sequencing data. In a cohort of 35 patients with pre-operative ADC imaging and surgical specimens, DCN RNA expression levels were significantly larger in high ADCL tumors (41.6 vs. 1.5; P = 0.0081). In a cohort of 17 patients with prospectively targeted biopsies there was a positive linear correlation between ADCL levels and DCN protein expression between tumors (Pearson R2 = 0.3977; P = 0.0066) and when evaluating different targets within the same tumor (Pearson R2 = 0.3068; P = 0.0139). In situ hybridization data localized DCN expression to areas of microvascular proliferation and immunohistochemical studies localized DCN protein expression to the tunica adventitia of blood vessels within the tumor. DCN expression positively correlated with VEGFR1 & 2 expression and localized to similar areas of tumor. Increased ADCL on diffusion MR imaging is associated with high DCN expression as well as increased survival with anti-VEGF therapy in glioblastoma. DCN may play an important role linking the imaging features on diffusion MR and anti-VEGF treatment efficacy. DCN may serve as a target for further investigation and modulation of anti-angiogenic therapy in GBM.

PURPOSE: To assess whether hypermetabolically-defined regions of interest (ROIs) on 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (FDOPA) positron emission tomography (PET) could be used to evaluate physiological features and whether there are measurable differences between molecular subtypes and tumor grades. METHODS: Sixty-eight treatment-naïve glioma patients who underwent FDOPA PET and magnetic resonance imaging (MRI) were retrospectively included. Fluid-attenuated inversion recovery hyperintense regions (FLAIR(ROI)) were segmented. FDOPA hypermetabolic regions (FDOPA(ROI), tumor-to-striatum ratios > 1) within FLAIR(ROI) were extracted. Normalized maximum standardized uptake value (nSUV(max)), volume of each ROI, and median relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) within FLAIR(ROI) or FDOPA(ROI) were calculated. Imaging metrics were compared using Students t or Mann-Whitney U tests. Area under the curve (AUC) of receiver-operating characteristic curves were used to determine whether imaging metrics within FLAIR(ROI) or FDOPA(ROI) can discriminate different molecular statuses or grades. RESULTS: Using either FLAIR(ROI) or FDOPA(ROI), the nSUV(max) and rCBV were significantly higher and the ADC was lower in isocitrate dehydrogenase [IDH] wild-type than mutant gliomas, and in higher-grade gliomas (HGGs) than lower-grade gliomas (LGGs). The FDOPA(ROI) volume was significantly higher in 1p19q codeleted than non-codeleted gliomas, and in HGGs than LGGs. Although not significant, imaging metrics extracted by FDOPA(ROI) discriminated molecular status and tumor grade more accurately than those extracted by FLAIR(ROI) (AUC of IDH status, 0.87 vs. 0.82; 1p19q status, 0.78 vs. 0.73; grade, 0.87 vs. 0.76). CONCLUSION: FDOPA hypermetabolic ROI may extract useful imaging features of gliomas, which can illuminate biological differences between different molecular status or tumor grades.

To develop a robust amine chemical exchange saturation transfer (CEST) physical phantom, validate the temporal stability, and create a supporting software for automatic image processing and quality assurance.The phantom was designed as an assembled laser-cut acrylic rack and 18 vials of phantom solutions, prepared with different pHs, glycine concentrations, and gadolinium concentrations. We evaluated glycine concentrations using ultraviolet absorbance for 70 days and measured the pH, relaxation rates, and CEST contrast for 94 days after preparation. We used Spearman's correlation to determine if glycine degraded over time. Linear regression and Bland-Altman analysis were performed between baseline and follow-up measurements of pH and MRI properties.No degradation of glycine was observed (p 0.05). The pH and MRI measurements stayed stable for 3 months and showed high consistency across time points (RWe designed a physical phantom for amine CEST-MRI, which is easy to assemble and transfer, holds 18 different solutions, and has excellent short-term chemical and MRI stability. We believe this robust phantom will facilitate the development of novel sequences and cross-scanners validations.

The current study tested the hypotheses that (1) pH-weighted MRI measurements of tumor acidity reflect glycolytic activity in human gliomas, (2) that tumor acidity, and thus glycolytic activity, differs between human IDH mutant (mIDH) and wild type gliomas, and (3) that an increase in tumor acidity, suggestive of increased glycolytic activity, occurs after inhibition of mutant IDH enzyme activity and reduction in 2HG, an oncometabolite. To test these hypotheses, we employed a custom pH-weighted amine chemical exchange saturation transfer echoplanar (CEST-EPI) technique in 152 patients with IDH mutant or wildtype glioma prior to surgery and 11 patients before and after treatment with AG120 or AG881 enrolled at our institution in a phase 1 perioperative study in patients with recurrent, non-enhancing, IDH mutant low-grade gliomas (NCT03343197). Results from image-guided biopsies in more than 100 patients demonstrated a significant correlation between MTRasym at 3ppm, a measure of tumor acidity from pH-weighted amine CEST-EPI, and expression of key glycolytic proteins including GLUT3 (R2=0.2188,P=0.0105), HK2 (R2=0.1788,P=0.0314), LDHA (R2=0.1111,P=0.0071), and MCT1 (R2=0.1228,P=0.0039) as well as ex vivo extracellular flux analysis estimates of ATP consumption from glycolysis (R2=0.6684,P=0.0021). Data suggests a significantly lower acidity (MTRasym@3ppm) within non-enhancing tumor in IDH mutant gliomas when compared to IDH wild type gliomas (P< 0.0001). Patients in a phase 1 perioperative study showed a shift toward higher tumor acidity (i.e. higher glycolytic activity) following inhibition of IDH based on 2HG suppression in resected tumors, but at levels below that of IDH wild type gliomas. Levels of 2HG within the tumor after IDH inhibition were inversely correlated with post-treatment tumor acidity (R2=0.6342, P=0.0180). Overall, results suggest mIDH gliomas have low levels of glycolytic activity, and successful inhibition of the mutant IDH enzyme results in reduction in 2HG and a measurable metabolic shift toward elevated glycolysis as evidenced using pH-weighted molecular MRI.

Diffusion magnetic resonance imaging (MRI) estimates of the apparent diffusion coefficient (ADC) has been revealed to be useful for predicting treatment response in patients with glioblastoma (GBM), with an increase in ADC indicating tumor cell death. The aim of the current study was to investigate whether quantitative changes in diffusion MRI after treatment with immune checkpoint inhibitors (ICI) could predict OS in patients with recurrent GBM. A total of 61 patients were included in this retrospective study with the following inclusion criteria: (i) diagnosis of recurrent GBM treated either with pembrolizumab or nivolumab and (ii) availability of diffusion data in pre- and post-ICI MRI. Tumor volume and median relative apparent diffusion coefficient (rADC) within enhancing tumor with respect to normal-appearing white matter were calculated. Median OS for all patients was 7.6 months (range, 1.0–30.6 months). Results showed that higher post-treatment rADC was associated with significantly longer OS (median, 372 days for rADC ≧ 1.42 versus 211 days for rADC < 1.42; P = 0.01, log-rank test), whereas tumor volume and pre-treatment rADC were not significantly associated with OS. Cox regression analysis revealed post-treatment rADC significantly influences OS (P = 0.02, univariate analysis), even after controlling for age, sex, and IDH status (P = 0.007, multivariate analysis), and additionally controlling for whether surgery was performed after ICI treatment (P = 0.049, multivariate analysis). In conclusion, a high post-treatment rADC may be an early imaging biomarker for identifying OS benefit in recurrent GBM patients receiving ICI treatment.

Advanced multimodality treatments that have led to longer survival rates for patients with low-grade gliomas (LGGs) have also resulted in significant changes in cognition and quality of life (QoL). These changes remain poorly understood, largely due to the lack of multifactorial and in-depth studies on cognitive impairment in patients with LGG. Resting-state functional MRI (rs-fMRI) has been widely used as a reliable imaging biomarker to evaluate the treatment outcome by characterizing the cerebral networking alteration associated with a patient’s neurological status. In this preliminary report of an active study, we investigated the cognitive function and cerebral networking connectivity via rs-fMRI in survivors who had completed treatment for LGG within the past 10 years. Survivors were administered a battery of standardized neuropsychological tests. Of the 20 participants enrolled to date (mean age 43 ± 11), 10 participants were categorized as cognitively impaired based on the International Cognition and Cancer Task Force (ICCTF) guidelines, with recommended adjustments considering the number of tests in the battery. Compared to cognitively unimpaired participants, functional connectivity in cognitively impaired patients was lower between memory, visuospatial processing, and primary sensorimotor regions. These preliminary observations suggest there is a potential link between overall cognitive impairment and functional connectivity of various networks as measured using resting-state fMRI.

Advanced multimodality treatments have led to improved survival and quality of life for patients with diffuse gliomas, and widespread functional reorganization has been reported to be associated with improved cognitive function. However, investigation of morphological alterations in patients with diffuse gliomas has been problematic, largely due to the tumor resection cavities. This pilot study has overcome these challenges and aims to characterize the relationship between structural plasticity and cognitive function in survivors of diffuse gliomas. High-resolution T1 weighted images were collected from 24 patients with diffuse gliomas (mean age 44.5 ± 11.5) who had completed their treatment within the previous ten years. Interregional correlations of cortical thickness were computed to establish morphometric correlation networks (MCN) for twelve cognitively impaired and twelve non-impaired glioma patients, as well as correlated with self-reported cognitive impairment. Our findings demonstrated that both cognitively impaired (σ=1.5979) and non-impaired (σ=1.3683) glioma patients have a small world architecture in disrupted morphological networks. Although the left fusiform (p=0.0409), left inferior (p=0.0209), and temporal (p=0.0173) gyri were observed to be thicker in non-impaired patients, the robustness of their morphological network was weak and easily vulnerable to pathological attacks and neurological deterioration. Furthermore, regions such as the superior temporal gyrus (p=0.0126) and rostral middle frontal gyrus (p=0.0148) were not only identified as predominant nodes in the MCN of patients but were also found to have greater gray matter thickness, which is associated with better FACT-cognitive function. Together, these results support our hypothesis that a widespread morphological network is altered in survivors of diffuse gliomas. Predominant regions obtained by topological analysis may lead to reliable imaging biomarkers that help evaluate patients’ cognition and ability to function.