Changes in brain white matter structure are associated with urine proteins in urologic chronic pelvic pain syndrome (UCPPS): A MAPP Network study.

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network has yielded neuroimaging and urinary biomarker findings that highlight unique alterations in brain structure and in urinary proteins related to tissue remodeling and vascular structure in patients with Urological Chronic Pelvic Pain Syndrome (UCPPS). We hypothesized that localized changes in diffusion tensor imaging (DTI) measurements might be associated with corresponding changes in urinary protein levels in UCPPS. To test this hypothesis, we created statistical parameter maps depicting the linear correlation between DTI measurements (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)) and urinary protein quantification (MMP2, MMP9, NGAL, MMP9/NGAL complex, and VEGF) in 30 UCPPS patients from the MAPP Research Network, after accounting for clinical covariates. Results identified a brainstem region that showed a strong correlation between both ADC (R2 = 0.49, P<0.0001) and FA (R2 = 0.39, P = 0.0002) with urinary MMP9 levels as well as a correlation between both ADC (R2 = 0.42, P = 0.0001) and FA (R2 = 0.29, P = 0.0020) and urinary MMP9/NGAL complex. Results also identified significant correlations between FA and urinary MMP9 in white matter adjacent to sensorimotor regions (R2 = 0.30, P = 0.002; R2 = 0.36, P = 0.0005, respectively), as well as a correlation in similar sensorimotor regions when examining ADC and urinary MMP2 levels (R2 = 0.42, P<0.0001) as well as FA and urinary MMP9/NGAL complex (R2 = 0.33, P = 0.0008). A large, diffuse cluster of white matter was identified as having a strong correlation between both ADC (R2 = 0.35, P = 0.0006) and FA (R2 = 0.43, P<0.0001) with urinary NGAL levels. In contrast, no significant association between DTI measurements and VEGF was observed. Results suggest that elevated MMP9 or MMP9/NGAL in UCPPS may be related to degenerative neuronal changes in brainstem nuclei through excitotoxicity, while also facilitating synaptic plasticity in sensorimotor regions.

Mono-exponential, diffusion kurtosis and stretched exponential diffusion MR imaging response to chemoradiation in newly diagnosed glioblastoma.

PURPOSE: To quantify changes and prognostic value of diffusion MRI measurements obtained using mono-exponential, diffusion kurtosis imaging (DKI) and stretched exponential (SE) models prior and after chemoradiation in newly diagnosed glioblastoma (GBM). METHODS: Diffusion-weighted images (DWIs) were acquired in twenty-three patients following surgery, prior chemoradiation and within 7 days following completion of treatment, using b-values ranging from 0 to 5000s/mm2. Mono-exponential diffusion (apparent diffusion coefficient: ADC), isotropic (non-directional) DKI model with apparent diffusivity (Dapp) and kurtosis (Kapp) estimates as well as SE model with distributed-diffusion coefficient (DDC) and mean intra-voxel heterogeneity (α) were computed for all patients prior and after chemoradiation. Median values were calculated for normal appearing white matter (NAWM) and contrast-enhancing tumor (CET). The magnitudes of diffusion change prior and after chemoradiation were used to predict overall survival (OS). RESULTS: Diffusivity in NAWM was consistent for all diffusion measures during chemoradiation, while diffusivity measurements (ADC, Dapp and DDC) within CET changed significantly. A strong positive correlation existed between ADC, Dapp, and DDC measurements prior to chemoradiation; however, this association was weak following chemoradiation, suggesting a more complex microstructural environment after cytotoxic therapy. When combined with baseline tumor volume and MGMT status, age and ADC changes added significant prognostic values, whereas more complex diffusion models did not show significant value in predicting OS. CONCLUSIONS: Despite increased tissue complexity following chemoradiation, advanced diffusion models have longer acquisition times, provide largely comparable measures of diffusivity, and do not appear to provide additional prognostic value compared to mono-exponential ADC maps.

Post-chemoradiation volumetric response predicts survival in newly diagnosed glioblastoma treated with radiation, temozolomide, and bevacizumab or placebo.

Background: In the current study we used contrast-enhanced T1 subtraction maps to test whether early changes in enhancing tumor volume are prognostic for overall survival (OS) in newly diagnosed glioblastoma (GBM) patients treated with chemoradiation with or without bevacizumab (BV). Methods: Seven hundred ninety-eight patients (404 BV and 394 placebo) with newly diagnosed GBM in the AVAglio trial (NCT00943826) had baseline MRI scans available, while 337 BV-treated and 269 placebo-treated patients had >4 MRI scans for response evaluation. The volume of contrast-enhancing tumor was quantified and used for subsequent analyses. Results: A decrease in tumor volume during chemoradiation was associated with a longer OS in the placebo group (hazard ratio [HR] = 1.578, P < 0.0001) but not BV-treated group (HR = 1.135, P = 0.4889). Results showed a higher OS in patients on the placebo arm with a sustained decrease in tumor volume using a post-chemoradiation baseline (HR = 1.692, P = 0.0005), and a trend toward longer OS was seen in BV-treated patients (HR = 1.264, P = 0.0724). Multivariable Cox regression confirmed that sustained response or stable disease was prognostic for OS (HR = 0.7509, P = 0.0127) when accounting for age (P = 0.0002), KPS (P = 0.1516), postsurgical tumor volume (P < 0.0001), O6-methylguanine-DNA methyltransferase status (P < 0.0001), and treatment type (P = 0.7637) using the post-chemoradiation baseline. Conclusions: The post-chemoradiation timepoint is a better baseline for evaluating efficacy in newly diagnosed GBM. Early progression during the maintenance phase is consequential in predicting OS, supporting the use of progression-free survival rates as a meaningful surrogate for GBM.

Volumetric response quantified using T1 subtraction predicts long-term survival benefit from cabozantinib monotherapy in recurrent glioblastoma.

Background: To overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288). Methods: A total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (>65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS). Results: Volumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P < 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P < 0.0001) and volumetric response (HR = 0.2240, P < 0.0001) were independent predictors of OS. Conclusions: T1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.

Diffusion MRI Phenotypes Predict Overall Survival Benefit from Anti-VEGF Monotherapy in Recurrent Glioblastoma: Converging Evidence from Phase II Trials.

Purpose: Anti-VEGF therapies remain controversial in the treatment of recurrent glioblastoma (GBM). In the current study, we demonstrate that recurrent GBM patients with a specific diffusion MR imaging signature have an overall survival (OS) advantage when treated with cediranib, bevacizumab, cabozantinib, or aflibercept monotherapy at first or second recurrence. These findings were validated using a separate trial comparing bevacizumab with lomustine.Experimental Design: Patients with recurrent GBM and diffusion MRI from the monotherapy arms of 5 separate phase II clinical trials were included: (i) cediranib (NCT00035656); (ii) bevacizumab (BRAIN Trial, AVF3708g; NCT00345163); (iii) cabozantinib (XL184-201; NCT00704288); (iv) aflibercept (VEGF Trap; NCT00369590); and (v) bevacizumab or lomustine (BELOB; NTR1929). Apparent diffusion coefficient (ADC) histogram analysis was performed prior to therapy to estimate "ADCL," the mean of the lower ADC distribution. Pretreatment ADCL, enhancing volume, and clinical variables were tested as independent prognostic factors for OS.Results: The coefficient of variance (COV) in double baseline ADCL measurements was 2.5% and did not significantly differ (P = 0.4537). An ADCL threshold of 1.24 µm2/ms produced the largest OS differences between patients (HR ∼ 0.5), and patients with an ADCL > 1.24 µm2/ms had close to double the OS in all anti-VEGF therapeutic scenarios tested. Training and validation data confirmed that baseline ADCL was an independent predictive biomarker for OS in anti-VEGF therapies, but not in lomustine, after accounting for age and baseline enhancing tumor volume.Conclusions: Pretreatment diffusion MRI is a predictive imaging biomarker for OS in patients with recurrent GBM treated with anti-VEGF monotherapy at first or second relapse. Clin Cancer Res; 23(19); 5745-56. ©2017 AACR.

Baseline pretreatment contrast enhancing tumor volume including central necrosis is a prognostic factor in recurrent glioblastoma: evidence from single and multicenter trials.

BACKGROUND: The prognostic significance of baseline contrast enhancing tumor prior to second- or third-line therapy in recurrent glioblastoma (GBM) for overall survival (OS) remains controversial, particularly in the context of repeated surgical resection and/or use of anti-angiogenic therapy. In the current study, we examined recurrent GBM patients from both single and multicenter clinical trials to test whether baseline enhancing tumor volume, including central necrosis, is a significant prognostic factor for OS in recurrent GBM. METHODS: Included were 497 patients with recurrent GBM from 4 data sources: 2 single-center sites (University of Toronto, University of California Los Angeles) and 2 phase II multicenter trials (AVF3708G, Bevacizumab ± Irinotecan, NCT00345163; XL184-201, Cabozantinib, NCT00704288). T1 subtraction maps were used to define volume of contrast enhancing tumor, including central necrosis. Cox multivariable and univariate analyses were used to evaluate the relationship between tumor volume prior to second- or third-line therapy and OS. RESULTS: Both continuous measures of baseline tumor volume and tumors dichotomized into large (≥15cc) and small (<15cc) tumors were significant predictors of OS (P<.0001), independently of age and treatment. Univariate analysis demonstrated significant OS differences (P<.05) between large (≥15cc) and small (<15cc) tumors in patients under all therapeutic scenarios. Only patients treated with cabozantinib who previously failed anti-angiogenic therapy did not show an OS dependence on baseline tumor volume. CONCLUSIONS: Baseline tumor volume is a significant prognostic factor in recurrent GBM. Clinical trial treatment arms must have a balanced distribution of tumor size, and tumor size should be considered when interpreting therapeutic efficacy.

Topographical Distribution of Epileptogenic Tubers in Patients With Tuberous Sclerosis Complex.

Tuberous sclerosis complex is a multisystem genetic syndrome often affecting the central nervous system. The purpose of the current study was to identify topographical patterns in the distribution specific to epileptogenic (n = 37) and nonepileptogenic (n = 544) tubers throughout the brain for a cohort of 23 tuberous sclerosis complex patients with a history of seizures. Tubers localized to the inferior parietal lobes, middle frontal lobes, middle temporal lobes, or central sulcus regions were associated with a high frequency of epileptogenic tubers. Epileptogenic tubers occurred statistically more frequently within the inferior parietal lobe and within the central sulcus region in children younger than 1 or between 1 and 3 years old, respectively. Results imply seizure activity in tuberous sclerosis complex patients can be associated with the location of cortical tubers.

Diffusion MRI quality control and functional diffusion map results in ACRIN 6677/RTOG 0625: a multicenter, randomized, phase II trial of bevacizumab and chemotherapy in recurrent glioblastoma.

Functional diffusion mapping (fDM) is a cancer imaging technique that quantifies voxelwise changes in apparent diffusion coefficient (ADC). Previous studies have shown value of fDMs in bevacizumab therapy for recurrent glioblastoma multiforme (GBM). The aim of the present study was to implement explicit criteria for diffusion MRI quality control and independently evaluate fDM performance in a multicenter clinical trial (RTOG 0625/ACRIN 6677). A total of 123 patients were enrolled in the current multicenter trial and signed institutional review board-approved informed consent at their respective institutions. MRI was acquired prior to and 8 weeks following therapy. A 5-point QC scoring system was used to evaluate DWI quality. fDM performance was evaluated according to the correlation of these metrics with PFS and OS at the first follow-up time-point. Results showed ADC variability of 7.3% in NAWM and 10.5% in CSF. A total of 68% of patients had usable DWI data and 47% of patients had high quality DWI data when also excluding patients that progressed before the first follow-up. fDM performance was improved by using only the highest quality DWI. High pre-treatment contrast enhancing tumor volume was associated with shorter PFS and OS. A high volume fraction of increasing ADC after therapy was associated with shorter PFS, while a high volume fraction of decreasing ADC was associated with shorter OS. In summary, DWI in multicenter trials are currently of limited value due to image quality. Improvements in consistency of image quality in multicenter trials are necessary for further advancement of DWI biomarkers.

Recurrent glioblastoma treated with bevacizumab: contrast-enhanced T1-weighted subtraction maps improve tumor delineation and aid prediction of survival in a multicenter clinical trial.

PURPOSE: To compare the capability to aid prediction of clinical outcome measures, including progression-free survival (PFS) and overall survival (OS), between volumetric estimates from contrast material-enhanced (CE) T1-weighted subtraction maps and traditional segmentation in a randomized multicenter clinical trial of recurrent glioblastoma (GBM) patients treated with bevacizumab. MATERIALS AND METHODS: All patients participating in this study signed institutional review board-approved informed consent at their respective institutions prior to enrolling in the multicenter clinical trial. One-hundred sixty patients with recurrent GBM enrolled as part of a HIPAA-compliant, multicenter clinical trial (AVF3708 g, BRAIN trial). Contrast-enhancing tumor volumes and change in volumes as a response to therapy were quantified by using either conventional segmentation or CE T1-weighted subtraction maps created by voxel-by-voxel subtraction of intensity-normalized nonenhanced T1-weighted images from CE T1-weighted images. These volumes were then tested as predictors of PFS and OS by using log-rank univariate analysis, the multivariate Cox proportional hazards regression model, and receiver operating characteristic analysis. RESULTS: Use of CE T1-weighted subtraction maps qualitatively improved visualization and improved quantification of tumor volume after bevacizumab treatment. Significant trends between the volume of tumor and change in tumor volume after therapy on CE T1-weighted subtraction maps were found for both PFS and OS (pretreatment volume < 15 cm(3), P < .003; posttreatment volume < 7.5 cm(3), P < .05; percentage change in volume > 25%, P = .004 for PFS and P = .053 for OS). CE T1-weighted subtraction maps were significantly better at aiding prediction of 6-month PFS and 12-month OS compared with conventional segmentation by using receiver operating characteristic analysis (P < .05). CONCLUSION: Use of CE T1-weighted subtraction maps improved visualization and aided better prediction of patient survival in recurrent GBM treated with bevacizumab compared with conventional segmentation of CE T1-weighted images. Clinical trial registration no. NCT00345163. Online supplemental material is available for this article.

Nonlinear distortion correction of diffusion MR images improves quantitative DTI measurements in glioblastoma.

The purpose of this study was to use a retrospective nonlinear distortion correction technique and evaluate the changes in DTI metrics in areas of interest in and around GBM tumors. A total of 24 histologically confirmed GBM patients with pre-operative 20-direction DTI scans were examined. Variability in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in normal tissue before and after distortion correction were examined. Changes in mean, median and variance of ADC and FA in contrast enhancing and T2/FLAIR ROIs were also examined with and without distortion correction. Results suggest the intra-subject SDs of ADC and FA decreased in normal tissue after the application of distortion correction (P < 0.0001). FA mean and median values decreased after distortion correction in both T1+C and T2 ROIs (P < 0.017), while ADC mean and median values did not significantly change except for the median ADC in T1+C ROIs (P = 0.0054). The intra-subject SD of ADC and FA values in tumor ROIs changed significantly with distortion correction, and Bland-Altman analysis indicated that the bias and the SD of the bias of these intra-subject SDs were larger than those of the mean and median terms. Additionally, the means of the two curves of a double Gaussian fit to the histogram of ADC values from T1+C ROIs, ADCL (mean of lower Gaussian) as well as ADCH (mean of the higher Gaussian) were found to change significantly with distortion correction (P = 0.0045 for ADCL and P = 0.0370 for ADCH). Nonlinear distortion correction better aligns neuro-anatomical structures between DTI and anatomical scans, and significantly alters the measurement of values within tumor ROIs for GBM patients.

Hypervascular tumor volume estimated by comparison to a large-scale cerebral blood volume radiographic atlas predicts survival in recurrent glioblastoma treated with bevacizumab.

BACKGROUND: Dynamic susceptibility contrast (DSC)-MRI is a well-established perfusion MR imaging technique for estimating relative cerebral blood volume (CBV) in primary brain tumors; however, tumors localized to regions with naturally elevated perfusion, including cortical tissue and common vascular territories, make evaluation of tumor vascularity difficult to assess. In the current study, we have constructed a large-scale radiographic atlas of CBV to assess treatment response to bevacizumab in individual patients with recurrent glioblastoma. METHODS: Z-score normalized CBV maps were registered to stereotactic atlas space in 450 patients with brain tumors. A CBV atlas was created by calculating the voxel-wise mean and variability in CBV. MRI and CBV maps from 32 recurrent glioblastoma patients were then obtained prior to and following treatment with bevacizumab, registered to and compared with the CBV atlas. The volume of tumor tissue with elevated CBV, percentage of enhancing tumor with elevated CBV, and the mean and maximum change in normalized CBV intensity relative to the atlas were computed. RESULTS: Voxel-wise comparison of individual patient CBV maps to the atlas allowed delineation of elevated tumor perfusion from artery and normal cortical tissue. An atlas-defined hypervascular tumor blood volume greater than 2.35 cc prior to treatment, 0.14 cc after treatment, and a decrease in atlas-defined hypervascular tumor volume less than 80% following treatment were characteristic of a shorter PFS and OS. Traditional measures of CBV were not predictive of PFS or OS. CONCLUSIONS: This study highlights the advantages of large-scale population maps to identify abnormal biological tissues.

Increased sensitivity to radiochemotherapy in IDH1 mutant glioblastoma as demonstrated by serial quantitative MR volumetry.

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations have been linked to favorable outcomes in patients with glioblastoma multiforme (GBM). Recent in vitro experiments suggest that IDH1 mutation sensitizes tumors to radiation damage. We hypothesized that radiographic treatment response would be significantly different between IDH1 mutant versus wild-type GBMs after radiotherapy (RT) and concurrent temozolomide (TMZ). METHODS: A total of 39 newly diagnosed GBM patients with known IDH1 mutational status (10 IDH1 mutants), who followed standard therapy and had regular post-contrast T1W (T1+C) and T2W/ fluid-attenuated inversion recovery (FLAIR) images in the 6-month period after starting RT, were enrolled. The volume of contrast-enhancing and FLAIR hyperintensity were calculated from each scan. Linear and polynomial regression techniques were used to estimate the rate of change and temporal patterns in tumor volumes. RESULTS: IDH1 mutant GBMs demonstrated a favorable response to RT/TMZ in the study period, as demonstrated by 10 of 10 mutants showing radiographic response (decreasing V(T1+C)), compared with 13 of 29 wild-types (P < .001). During the study period, V(T1+C) and V(FLAIR) changed at -3.6% per week and +0.6% per week in IDH1 mutant tumors, respectively, as compared with +0.8% per week and +5.2% per week in IDH1 wild-type tumors (P = .0076 and P = .0118, respectively). Amongst the radiographic responders, IDH1 mutant GBMs still demonstrated significant progression-free and overall survival benefit. Aggregated tumor kinetics by group showed significant lower rate in IDH1 mutant GBMs in specific periods: >105 days for V(FLAIR) and 95-120 and >150 days for V(T1+C) from starting RT/TMZ. CONCLUSIONS: The current study supports the hypothesis that IDH1 mutant GBMs are more sensitive to radiochemotherapy than IDH1 wild-type GBMs.