Search

This study explores the predictive utility of multi-time point, multi-modality quantitative imaging biomarkers (QIBs) and clinical factors in patients with poor-prognosis head and neck cancers (HNCs) using interpretable machine learning. We examined 93 patients with p16 + oropharyngeal squamous cell carcinoma or locally advanced p16- HNCs enrolled in a phase II adaptive radiation dose escalation trial. FDG-PET and multiparametric MRI scans were conducted before radiation therapy and at the 10th fraction (2 weeks). A survival network analyzed MRI and PET-derived biomarkers such as gross tumor volume (GTV), blood volume (BV), and metabolic tumor volume (MTV 50 ), along with clinical factors to predict local (LF) and distant failures (DF). Feature attributions and interactions were assessed using Expected Gradients (EG) and Expected Hessian (EH). Through rigorous cross-validation, the model for predicting LF, incorporating biomarkers like p16 status and radiation boost, achieved a c-index of 0.758. Similarly, the DF prediction model showed a c-index of 0.695. The analysis of feature attributions and interactions enhanced understanding of important features and complex factor interplays, potentially guiding more personalized and intensified treatment approaches for HNC patients., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Functional liver parenchyma can be damaged from treatment of liver malignancies with 90 Y selective internal radiation therapy (SIRT). Evaluating functional parenchymal changes and developing an absorbed dose (AD)-toxicity model can assist the clinical management of patients receiving SIRT. We aimed to determine whether there is a correlation between 90 Y PET AD voxel maps and spatial changes in the nontumoral liver (NTL) function derived from dynamic gadoxetic acid-enhanced MRI before and after SIRT. Methods: Dynamic gadoxetic acid-enhanced MRI scans were acquired before and after treatment for 11 patients undergoing 90 Y SIRT. Gadoxetic acid uptake rate (k 1 ) maps that directly quantify spatial liver parenchymal function were generated from MRI data. Voxel-based AD maps, derived from the 90 Y PET/CT scans, were binned according to AD. Pre- and post-SIRT k 1 maps were coregistered to the AD map. Absolute and percentage k 1 loss in each bin was calculated as a measure of loss of liver function, and Spearman correlation coefficients between k 1 loss and AD were evaluated for each patient. Average k 1 loss over the patients was fit to a 3-parameter logistic function based on AD. Patients were further stratified into subgroups based on lesion type, baseline albumin-bilirubin scores and alanine transaminase levels, dose-volume effect, and number of SIRT treatments. Results: Significant positive correlations (ρ = 0.53-0.99, P < 0.001) between both absolute and percentage k 1 loss and AD were observed in most patients (8/11). The average k 1 loss over 9 patients also exhibited a significant strong correlation with AD (ρ ≥ 0.92, P < 0.001). The average percentage k 1 loss of patients across AD bins was 28%, with a logistic function model demonstrating about a 25% k 1 loss at about 100 Gy. Analysis between patient subgroups demonstrated that k 1 loss was greater among patients with hepatocellular carcinoma, higher alanine transaminase levels, larger fractional volumes of NTL receiving an AD of 70 Gy or more, and sequential SIRT treatments. Conclusion: Novel application of multimodality imaging demonstrated a correlation between 90 Y SIRT AD and spatial functional liver parenchymal degradation, indicating that a higher AD is associated with a larger loss of local hepatocyte function. With the developed response models, PET-derived AD maps can potentially be used prospectively to identify localized damage in liver and to enhance treatment strategies., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Advances in diagnostic and treatment technology along with rapid developments in translational research may now allow the realization of precision radiotherapy. Integration of biologically informed multimodality imaging to address the spatial and temporal heterogeneity underlying treatment resistance in glioblastoma is now possible for patient care, with evidence of safety and potential benefit. Beyond their diagnostic utility, several candidate imaging biomarkers have emerged in recent early-phase clinical trials of biologically based radiotherapy, and their definitive assessment in multicenter prospective trials is already in development. In this review, the rationale for clinical implementation of candidate advanced magnetic resonance imaging and positron emission tomography imaging biomarkers to guide personalized radiotherapy, the current landscape, and future directions for integrating imaging biomarkers into radiotherapy for glioblastoma are summarized. Moving forward, response-adaptive radiotherapy using biologically informed imaging biomarkers to address emerging treatment resistance in rational combination with novel systemic therapies may ultimately permit improvements in glioblastoma outcomes and true individualization of patient care., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

There is debate about why stereotactic body radiation therapy (SBRT) produces superior control of hepatocellular cancer (HCC) compared to fractionated treatment. Both preclinical and clinical evidence has been presented to support a "classic" biological explanation: the greater BED of SBRT produces more DNA damage and tumor cell kill. More recently, preclinical evidence has supported the concept of a "new biology", particularly radiation-induced vascular collapse, which increases hypoxia and free radical activation. This is hypothesized to cause much greater tumor cell death than was produced by the initial radiation-induced DNA damage to the tumor. We decided to investigate if vascular collapse occurs after standard SBRT for patients with HCC. Eight patients with 10 lesions underwent dynamic contrast enhanced MRI at the time of simulation and either 48 or 96 hours after the first fraction. Only three of 10 tumors showed a decrease in blood flow. These findings suggest that vascular collapse does not typically occur after SBRT for HCC., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Stereotactic body radiation therapy (SBRT) produces excellent local control for patients with hepatocellular carcinoma (HCC). However, the risk of toxicity for normal liver tissue is still a limiting factor. Normal tissue complication probability (NTCP) models have been proposed to estimate the toxicity with the assumption of uniform liver function distribution, which is not optimal. With more accurate regional liver functional imaging available for individual patient, we can improve the estimation and be more patient-specific., Purpose: To develop normal tissue complication probability (NTCP) models using pre-/during-treatment (RT) dynamic Gadoxetic Acid-enhanced (DGAE) MRI for adaptation of RT in a patient-specific manner in hepatocellular cancer (HCC) patients who receive SBRT., Methods: 24 of 146 HCC patients who received SBRT underwent DGAE MRI. Physical doses were converted into EQD2 for analysis. Voxel-by-voxel quantification of the contrast uptake rate (k1) from DGAE-MRI was used to quantify liver function. A logistic dose-response model was used to estimate the fraction of liver functional loss, and NTCP was estimated using the cumulative functional reserve model for changes in Child-Pugh (C-P) scores. Model parameters were calculated using maximum-likelihood estimations. During-RT liver functional maps were predicted from dose distributions and pre-RT k1 maps with a conditional Wasserstein generative adversarial network (cWGAN). Imaging prediction quality was assessed using root-mean-square error (RMSE) and structural similarity (SSIM) metrics. The dose-response and NTCP were fit on both original and cWGAN predicted images and compared using a Wilcoxon signed-rank test., Results: Logistic dose response models for changes in k1 yielded D50 of 35.2 (95% CI: 26.7-47.5) Gy and k of 0.62 (0.49-0.75) for the whole population. The high baseline ALBI (poor liver function) subgroup showed a significantly smaller D50 of 11.7 (CI: 9.06-15.4) Gy and larger k of 0.96 (CI: 0.74-1.22) compared to a low baseline ALBI (good liver function) subgroup of 54.8 (CI: 38.3-79.1) Gy and 0.59 (CI: 0.48-0.74), with p-values of < 0.001 and = 0.008, respectively, which indicates higher radiosensitivity for the worse baseline liver function cohort. Subset analyses were also performed for high/low baseline CP subgroups. The corresponding NTCP models showed good agreement for the fit parameters between cWGAN predicted and the ground-truth during-RT images with no statistical differences for low ALBI subgroup., Conclusions: NTCP models which incorporate voxel-wise functional information from DGAE-MRI k1 maps were successfully developed and feasibility was demonstrated in a small patient cohort. cWGAN predicted functional maps show promise for estimating localized patient-specific response to RT and warrant further validation in a larger patient cohort., (© 2023 American Association of Physicists in Medicine.)

Purpose: To investigate direct radiation dose-related and inflammation-mediated regional hepatic function losses after stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC) and poor liver function., Methods and Materials: Twenty-four patients with HCC enrolled on an IRB-approved adaptive SBRT trial had liver dynamic gadoxetic acid-enhanced magnetic resonance imaging and blood sample collections before and 1 month after SBRT. Gadoxetic acid uptake rate (k1) maps were quantified for regional hepatic function and coregistered to both 2-Gy equivalent dose and physical dose distributions. Regional k1 loss patterns from before to after SBRT were analyzed for effects of dose and patient using a mixed-effects model and logistic function and were associated with pretherapy liver-function albumin-bilirubin scores. Plasma levels of tumor necrosis factor α receptor 1 (TNFR1), an inflammation marker, were correlated with mean k1 losses in the lowest dose regions by Spearman rank correlation., Results: The whole group had a k1 loss rate of 0.4%/Gy (2-Gy equivalent dose); however, there was a significant random effect of patient in the mixed-effect model (P < .05). Patients with poor and good liver functions lost 50% of k1 values at 12.5 and 57.2 Gy and 33% and 16% of k1 values at the lowest dose regions (<5 Gy), respectively. The k1 losses at the lowest dose regions of individual patients were significantly correlated with their TNFR1 levels after SBRT (P < .02)., Conclusions: The findings suggest that regional hepatic function losses after SBRT in patients with HCC include both direct radiation dose-dependent and inflammation-mediated effects, which could influence how to manage these patients to preserve their liver function after SBRT., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Adversely prognostic hypercellular and hyperperfused regions of glioblastoma (GBM) predict progression-free survival, and are a novel target for dose-intensified chemoradiation (chemoRT) recently implemented in a phase II clinical trial. As a secondary aim, we hypothesized that dose-intensified chemoRT would induce greater mid-treatment response of hypercellular/hyperperfused tumor regions vs standard chemoradiation, and that early response would improve overall survival (OS)., Methods: Forty-nine patients with newly diagnosed GBM underwent prospective, multiparametric high b value diffusion-weighted MRI (DW-MRI) and perfusion dynamic contrast-enhanced MRI (DCE-MRI) pre-RT and 3-4 weeks into RT. The hypercellular tumor volume (TVHCV, mean contralateral normal brain + 2SD) and hyperperfused tumor volume (TVCBV, contralateral normal frontal gray matter + 1SD) were generated using automated thresholding. Twenty-six patients were enrolled on a dose-escalation trial targeting TVHCV/TVCBV with 75 Gy in 30 fractions, and 23 non-trial patients comprised the control group. OS was estimated using the Kaplan-Meier method and compared using the log-rank test. The effect of TVHCV/TVCBV and Gd-enhanced tumor volume on OS was assessed using multivariable Cox proportional-hazard regression., Results: Most patients had gross total (47%) or subtotal resection (37%), 25% were MGMT-methylated. Patients treated on the dose-escalation trial had significantly greater reduction in TVHCV/TVCBV (41% reduction, IQR 17%-75%) vs non-trial patients (6% reduction, IQR 6%-22%, P = .002). An increase in TVHCV/TVCBV during chemoRT was associated with worse OS (adjusted hazard ratio [aHR] 1.2, 95%CI 1.0-1.4, P = .02), while pre-treatment tumor volumes (P > .5) and changes in Gd-enhanced volume (P = .9) were not., Conclusions: Multiparametric MRI permits identification of therapeutic resistance during chemoRT and supports adaptive strategies in future trials., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: We hypothesized that dose-intensified chemoradiation therapy targeting adversely prognostic hypercellular (TV HCV ) and hyperperfused (TV CBV ) tumor volumes would improve outcomes in patients with glioblastoma., Methods and Materials: This single-arm, phase 2 trial enrolled adult patients with newly diagnosed glioblastoma. Patients with a TV HCV /TV CBV >1 cm 3 , identified using high b-value diffusion-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced perfusion MRI, were treated over 30 fractions to 75 Gy to the TV HCV /TV CBV with temozolomide. The primary objective was to estimate improvement in 12-month overall survival (OS) versus historical control. Secondary objectives included evaluating the effect of 3-month TV HCV /TV CBV reduction on OS using Cox proportional-hazard regression and characterizing coverage (95% isodose line) of metabolic tumor volumes identified using correlative 11 C-methionine positron emission tomography. Clinically meaningful change was assessed for quality of life by the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30, for symptom burden by the MD Anderson Symptom Inventory for brain tumor, and for neurocognitive function (NCF) by the Controlled Oral Word Association Test, the Trail Making Test, parts A and B, and the Hopkins Verbal Learning Test-Revised., Results: Between 2016 and 2018, 26 patients were enrolled. Initial patients were boosted to TV HCV alone, and 13 patients were boosted to both TV HCV /TV CBV . Gross or subtotal resection was performed in 87% of patients; 22% were O 6 -methylguanine-DNA methyltransferase (MGMT) methylated. With 26-month follow-up (95% CI, 19-not reached), the 12-month OS rate among patients boosted to the combined TV HCV /TV CBV was 92% (95% CI, 78%-100%; P = .03) and the median OS was 20 months (95% CI, 18-not reached); the median OS for the whole study cohort was 20 months (95% CI, 14-29 months). Patients whose 3-month TV HCV /TV CBV decreased to less than the median volume (3 cm 3 ) had superior OS (29 vs 12 months; P = .02). Only 5 patients had central or in-field failures, and 93% (interquartile range, 59%-100%) of the 11 C-methionine metabolic tumor volumes received high-dose coverage. Late grade 3 neurologic toxicity occurred in 2 patients. Among non-progressing patients, 1-month and 7-month deterioration in quality of life, symptoms, and NCF were similar in incidence to standard therapy., Conclusions: Dose intensification against hypercellular/hyperperfused tumor regions in glioblastoma yields promising OS with favorable outcomes for NCF, symptom burden, and quality of life, particularly among patients with greater tumor reduction 3 months after radiation therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Predicting individual patient sensitivity to radiation therapy (RT) for tumor control or normal tissue toxicity is necessary to individualize treatment planning. In head and neck cancer, radiation doses are limited by many nearby critical structures, including structures involved in swallowing. Previous efforts showed that imaging parameters correlate with RT dose; here, we investigate the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) blood volume (BV) changes in predicting dysphagia., Methods and Materials: This study included 32 patients with locally advanced oropharyngeal squamous cell carcinoma treated with definitive chemoradiation on an institutional protocol incorporating baseline and early midtreatment DCE-MRI. BV maps of the pharyngeal constrictor muscles (PCM) were created, and BV increases midtreatment were correlated with the following parameters at 3 and 12 months post-RT: RT dose, Dynamic Imaging Grade of Swallowing Toxicity swallow score, aspiration frequency, European Organisation for Research and Treatment of Cancer HN35 patient-reported outcomes, physician-reported dysphagia, and feeding tube (FT) dependence., Results: The mean BV to the PCMs increased from baseline to fraction 10, which was significant for the superior PCM (P = .006) and middle PCM (P < .001), with a trend in the inferior PCM where lower mean doses were seen (P = .077). The factors associated with FT dependence at 3 months included BV increases in the total PCM (correlation, 0.48; P = .006) and middle PCM (correlation, 0.50; P = .004). A post-RT increase in aspiration was associated with a BV increase in the superior PCM (correlation, 0.44; P = .013),and the increase in the total PCMs was marginally significant (correlation, 0.34; P = .06). The best-performing models of FT dependence (area under the receiver operating curve [AUC] = 0.84) and aspiration increases (AUC = 0.78) included BV increases as well as a mean RT dose to middle PCM., Conclusions: Our results suggest that midtreatment BV increases derived from DCE-MRI are an early predictor of dysphagia. Further investigation of these promising imaging markers to assess individual patient sensitivity to treatment and the patient's subsequent risk of toxicities is warranted to improve personalization of RT planning., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response., Methods and Materials: Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m 2 , 8.4 mg/m 2 , 16.5 mg/m 2 , 27.5 mg/m 2 ). Dose escalation was managed by the time-to-event continual reassessment method algorithm. Linear mixed models were used to correlate change in 24-hour T1, Ktrans (capillary permeability), and fractional plasma volume with change in tumor volume., Results: Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The most common tumor types were melanoma (59%) and non-small cell lung cancer (18%). No dose limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2 of 29). The median intracranial response rate was 46% (95% confidence interval, 24-68) and median overall survival was 5.2 months (95% confidence interval, 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing dynamic contrast-enhanced MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (P ≤ .01)., Conclusions: The addition of RRx-001 to WBRT is well tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, the recommended phase 2 dose is 10 mg twice weekly. A reduction in fractional plasma volume on dynamic contrast-enhanced MRI 24 hours after RRx-001 suggests antiangiogenic activity associated with longer-term tumor response., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Accuracy and precision of quantitative imaging (QI) metrics should be assessed in real time in each patient during a clinical trial to support QI-based decision-making. We developed a framework for real-time quantitative assessment of QI metrics and evaluated accuracy and precision of dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI)-derived blood volume (BV) in a clinical trial for head and neck cancers. Patients underwent DCE-MRI before and after 2 weeks of radiation therapy (2wkRT). A mean as a reference value and a repeatability coefficient (RC) of BV values established from n patients in cerebellum volumes of interest (VOIs), which were normal and affected little by therapy, served as accuracy and precision measurements. The BV maps of a new patient were called accurate and precise if the values in cerebellum VOIs and the difference between the 2 scans agreed with the respective mean and RC with 95% confidence. The new data could be used to update reference values. Otherwise, the data were flagged for further evaluation before use in the trial. BV maps from 62 patients enrolled on the trial were evaluated. Mean BV values were 2.21 (±0.14) mL/100 g pre-RT and 2.22 (±0.17) mL/100 g at 2wkRT; relative RC was 15.9%. The BV maps from 3 patients were identified to be inaccurate and imprecise before use in the clinical trial. Our framework of real-time quantitative assessment of QI metrics during a clinical trial can be translated to different QI metrics and organ-sites for supporting QI-based decision-making that warrants success of a clinical trial.

Quantitative mapping of hyperperfused and hypercellular regions of glioblastoma has been proposed to improve definition of tumor regions at risk for local recurrence following conventional radiation therapy. As the processing of the multiparametric dynamic contrast-enhanced (DCE-) and diffusion-weighted (DW-) magnetic resonance imaging (MRI) data for delineation of these subvolumes requires additional steps that go beyond the standard practices of target definition, we sought to devise a workflow to support the timely planning and treatment of patients. A phase II study implementing a multiparametric imaging biomarker for tumor hyperperfusion and hypercellularity consisting of DCE-MRI and high b-value DW-MRI to guide intensified (75 Gy/30 fractions) radiation therapy (RT) in patients with newly diagnosed glioblastoma was launched. In this report, the workflow and the initial imaging outcomes of the first 12 patients are described. Among all the first 12 patients, treatment was initiated within 6 weeks of surgery and within 2 weeks of simulation. On average, the combined hypercellular volume and high cerebral blood volume/tumor perfusion volume were 1.8 times smaller than the T1 gadolinium abnormality and 10 times smaller than the FLAIR abnormality. Hypercellular volume and high cerebral blood volume/tumor perfusion volume each identified largely distinct regions and showed 57% overlap with the enhancing abnormality, and minimal-to-no extension outside of the FLAIR. These results show the feasibility of implementing a workflow for multiparametric magnetic resonance-guided radiation therapy into clinical trials with a coordinated multidisciplinary team, and the unique and complementary tumor subregions identified by the combination of high b-value DW-MRI and DCE-MRI.

This multicenter study evaluated the effect of variations in arterial input function (AIF) determination on pharmacokinetic (PK) analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data using the shutter-speed model (SSM). Data acquired from eleven prostate cancer patients were shared among nine centers. Each center used a site-specific method to measure the individual AIF from each data set and submitted the results to the managing center. These AIFs, their reference tissue-adjusted variants, and a literature population-averaged AIF, were used by the managing center to perform SSM PK analysis to estimate K trans (volume transfer rate constant), v e (extravascular, extracellular volume fraction), k ep (efflux rate constant), and τ i (mean intracellular water lifetime). All other variables, including the definition of the tumor region of interest and precontrast T 1 values, were kept the same to evaluate parameter variations caused by variations in only the AIF. Considerable PK parameter variations were observed with within-subject coefficient of variation (wCV) values of 0.58, 0.27, 0.42, and 0.24 for K trans , v e , k ep , and τ i , respectively, using the unadjusted AIFs. Use of the reference tissue-adjusted AIFs reduced variations in K trans and v e (wCV = 0.50 and 0.10, respectively), but had smaller effects on k ep and τ i (wCV = 0.39 and 0.22, respectively). k ep is less sensitive to AIF variation than K trans , suggesting it may be a more robust imaging biomarker of prostate microvasculature. With low sensitivity to AIF uncertainty, the SSM-unique τ i parameter may have advantages over the conventional PK parameters in a longitudinal study.

Purpose: Advanced imaging modalities such as high b-value diffusion and dynamic contrast enhancement magnetic resonance imaging have the potential to improve the clinical management of glioblastoma by informing prognosis, predicting sites of progression, and guiding dose-escalated radiation to maximize tumor control and minimize toxicity., Methods and Materials: Fifty-two patients with de novo glioblastoma underwent magnetic resonance imaging before chemoradiation therapy. Enhanced tumor volumes (TVs), excluding the surgical cavity, hypercellularity (TV HCV ) and increased cerebral blood volume (TV CBV ) were defined using conventional gadolinium-enhanced T1-weighted images, high b-value (3000 s/mm 2 ) diffusion-weighted images, and cerebral blood volume maps from T1-weighted dynamic contrast enhancement images, respectively. The image-phenotype TVs were analyzed for prediction of progression-free survival (Cox proportional hazard models), and sites of progression (pattern of failure tumor volume)., Results: The median progression-free survival (PFS) of the cohort was 13 months. The TV CBV and TV HCV were spatially distinct, with a mean overlap of only 21%. Univariate analysis showed that increasing age, decreasing radiation dose, larger TV HCV , and larger overlap of TV HCV and TV CBV were significantly associated with inferior PFS. Multivariate analysis identified that TV HCV was the most adversely prognostic imaging-defined variable. Enhanced TVs, excluding the surgical cavity, and the union of TV HCV and TV CBV showed a high likelihood of containing the pattern of failure tumor volume, and the volume composed of the intersection of TV HCV and TV CBV had an especially high likelihood of progression., Conclusions: TV HCV and the overlap of TV HCV and TV CBV are prognostic for PFS. Combinations of gadolinium-enhanced TVs, TV CBV , and TV HCV could predict tumor progression locations better than could individual subvolumes. Radiation dose escalation to these subvolumes could be a promising therapeutic strategy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Purpose: Standard assessment criteria for brain tumors that only include anatomic imaging continue to be insufficient. While numerous studies have demonstrated the value of DSC-MR imaging perfusion metrics for this purpose, they have not been incorporated due to a lack of confidence in the consistency of DSC-MR imaging metrics across sites and platforms. This study addresses this limitation with a comparison of multisite/multiplatform analyses of shared DSC-MR imaging datasets of patients with brain tumors., Materials and Methods: DSC-MR imaging data were collected after a preload and during a bolus injection of gadolinium contrast agent using a gradient recalled-echo-EPI sequence (TE/TR = 30/1200 ms; flip angle = 72°). Forty-nine low-grade ( n = 13) and high-grade ( n = 36) glioma datasets were uploaded to The Cancer Imaging Archive. Datasets included a predetermined arterial input function, enhancing tumor ROIs, and ROIs necessary to create normalized relative CBV and CBF maps. Seven sites computed 20 different perfusion metrics. Pair-wise agreement among sites was assessed with the Lin concordance correlation coefficient. Distinction of low- from high-grade tumors was evaluated with the Wilcoxon rank sum test followed by receiver operating characteristic analysis to identify the optimal thresholds based on sensitivity and specificity., Results: For normalized relative CBV and normalized CBF, 93% and 94% of entries showed good or excellent cross-site agreement (0.8 ≤ Lin concordance correlation coefficient ≤ 1.0). All metrics could distinguish low- from high-grade tumors. Optimum thresholds were determined for pooled data (normalized relative CBV = 1.4, sensitivity/specificity = 90%:77%; normalized CBF = 1.58, sensitivity/specificity = 86%:77%)., Conclusions: By means of DSC-MR imaging data obtained after a preload of contrast agent, substantial consistency resulted across sites for brain tumor perfusion metrics with a common threshold discoverable for distinguishing low- from high-grade tumors., (© 2018 by American Journal of Neuroradiology.)

Purpose: To determine the in vitro accuracy, test-retest repeatability, and interplatform reproducibility of T 1 quantification protocols used for dynamic contrast-enhanced MRI at 1.5 and 3 T., Methods: A T 1 phantom with 14 samples was imaged at eight centers with a common inversion-recovery spin-echo (IR-SE) protocol and a variable flip angle (VFA) protocol using seven flip angles, as well as site-specific protocols (VFA with different flip angles, variable repetition time, proton density, and Look-Locker inversion recovery). Factors influencing the accuracy (deviation from reference NMR T 1 measurements) and repeatability were assessed using general linear mixed models. Interplatform reproducibility was assessed using coefficients of variation., Results: For the common IR-SE protocol, accuracy (median error across platforms = 1.4-5.5%) was influenced predominantly by T 1 sample (P < 10 -6 ), whereas test-retest repeatability (median error = 0.2-8.3%) was influenced by the scanner (P < 10 -6 ). For the common VFA protocol, accuracy (median error = 5.7-32.2%) was influenced by field strength (P = 0.006), whereas repeatability (median error = 0.7-25.8%) was influenced by the scanner (P < 0.0001). Interplatform reproducibility with the common VFA was lower at 3 T than 1.5 T (P = 0.004), and lower than that of the common IR-SE protocol (coefficient of variation 1.5T: VFA/IR-SE = 11.13%/8.21%, P = 0.028; 3 T: VFA/IR-SE = 22.87%/5.46%, P = 0.001). Among the site-specific protocols, Look-Locker inversion recovery and VFA (2-3 flip angles) protocols showed the best accuracy and repeatability (errors < 15%)., Conclusions: The VFA protocols with 2 to 3 flip angles optimized for different applications achieved acceptable balance of extensive spatial coverage, accuracy, and repeatability in T 1 quantification (errors < 15%). Further optimization in terms of flip-angle choice for each tissue application, and the use of B 1 correction, are needed to improve the robustness of VFA protocols for T 1 mapping. Magn Reson Med 79:2564-2575, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

To create tumor "habitats" from the "signatures" discovered from multimodality metabolic and physiological images, we developed a framework of a processing pipeline. The processing pipeline consists of six major steps: (1) creating superpixels as a spatial unit in a tumor volume; (2) forming a data matrix [Formula: see text] containing all multimodality image parameters at superpixels; (3) forming and clustering a covariance or correlation matrix [Formula: see text] of the image parameters to discover major image "signatures;" (4) clustering the superpixels and organizing the parameter order of the [Formula: see text] matrix according to the one found in step 3; (5) creating "habitats" in the image space from the superpixels associated with the "signatures;" and (6) pooling and clustering a matrix consisting of correlation coefficients of each pair of image parameters from all patients to discover subgroup patterns of the tumors. The pipeline was applied to a dataset of multimodality images in glioblastoma (GBM) first, which consisted of 10 image parameters. Three major image "signatures" were identified. The three major "habitats" plus their overlaps were created. To test generalizability of the processing pipeline, a second image dataset from GBM, acquired on the scanners different from the first one, was processed. Also, to demonstrate the clinical association of image-defined "signatures" and "habitats," the patterns of recurrence of the patients were analyzed together with image parameters acquired prechemoradiation therapy. An association of the recurrence patterns with image-defined "signatures" and "habitats" was revealed. These image-defined "signatures" and "habitats" can be used to guide stereotactic tissue biopsy for genetic and mutation status analysis and to analyze for prediction of treatment outcomes, e.g., patterns of failure.

In this study we used magnetic resonance imaging (MRI) biomarkers to monitor the acute temporal changes in tumor vascular physiology with the aim of identifying the vascular signatures that predict response to combined anti-angiogenic and radiation treatments. Forty-three athymic rats implanted with orthotopic U-251 glioma cells were studied for approximately 21 days after implantation. Two MRI studies were performed on each animal, pre- and post-treatment, to measure tumor vascular parameters. Two animal groups received treatment comprised of Cilengitide, an anti-angiogenic agent and radiation. The first group received a subcurative regimen of Cilengitide 1 h before irradiation, while the second group received a curative regimen of Cilengitide 8 h before irradiation. Cilengitide was given as a single dose (4 mg/kg; intraperitoneal) after the pretreatment MRI study and before receiving a 20 Gy radiation dose. After irradiation, the post-treatment MRI study was performed at selected time points: 2, 4, 8 and 12 h (n = ≥5 per time point). Significant changes in vascular parameters were observed at early time points after combined treatments in both treatment groups (1 and 8 h). The temporal changes in vascular parameters in the first group (treated 1 h before exposure) resembled a previously reported pattern associated with radiation exposure alone. Conversely, in the second group (treated 8 h before exposure), all vascular parameters showed an initial response at 2-4 h postirradiation, followed by an apparent lack of response at later time points. The signature time point to define the "synergy" of Cilengitide and radiation was 4 h postirradiation. For example, 4 h after combined treatments using a 1 h separation (which followed the subcurative regimen), tumor blood flow was significantly decreased, nearly 50% below baseline (P = 0.007), whereas 4 h after combined treatments using an 8 h separation (which followed the curative regimen), tumor blood flow was only 10% less than baseline. Comparison between the first and second groups further revealed that most other vascular parameters were maximally different 4 h after combined treatments. In conclusion, the data are consistent with the assertion that the delivery of radiation at the vascular normalization time window of Cilengitide improves radiation treatment outcome. The different vascular responses after the different delivery times of combined treatments in light of the known tumor responses under similar conditions would indicate that timing has a crucial influence on treatment outcome and long-term survival. Tracking acute changes in tumor physiology after monotherapy or combined treatments appears to aid in identifying the beneficial timing for administration, and perhaps has predictive value. Therefore, judicial timing of treatments may result in optimal treatment response.

The objective of this study was to assess the uncertainty in T1 measurement, by estimating the repeatability coefficient (RC) from two repeated scans, in normal appearing brain tissues employing two different T1 mapping methods. All brain MRI scans were performed on a 3 T MR scanner in 10 patients who had low grade/benign tumors and partial brain radiation therapy (RT) without chemotherapy, at pre-RT, 3 weeks into RT, end RT (6 weeks) and 11, 33, and 85 weeks after RT. T1-weighted images were acquired using (1) a spoiled gradient echo sequence with two flip angles (2FA: 5° and 15°) and (2) a progressive saturation recovery sequence (pSR) with five different TR values (100-2000 ms). Manually drawn volumes of interest (VOIs) included left and right normal putamen and thalamus in gray matter, and frontal and parietal white matter, which were distant from tumors and received a total of accumulated radiation doses less than 5 Gy at 3 weeks. No significant changes or even trends in mean T1 from pre-RT to 3 weeks into RT in these VOIs (p ≥ 0.11, Wilcoxon sign test) allowed us to calculate the repeatability statistics of between-subject means of squares, within-subject means of squares, F-score, and RC. The 2FA method produced RCs in the range of (9.7-11.7)% in gray matter and (12.2-14.5)% in white matter; while the pSR method led to RCs ranging from 10.9 to 17.9% in gray matter and 7.5 to 10.3% in white matter. The overall mean (±SD) RCs produced by the two methods, 12.0 (±1.6)% for 2FA and 12.0 (±3.8)% for pSR, were not significantly different (p = 0.97). A similar repeatability in T1 measurement produced by the time efficient 2FA method compared with the time consuming pSR method demonstrates that the 2FA method is desirable to integrate into dynamic contrast-enhanced MRI for rapid acquisition., (Copyright © 2016 John Wiley & Sons, Ltd.)

Dynamic contrast-enhanced MRI (DCE-MRI) has been widely used in tumor detection and therapy response evaluation. Pharmacokinetic analysis of DCE-MRI time-course data allows estimation of quantitative imaging biomarkers such as K trans (rate constant for plasma/interstitium contrast reagent (CR) transfer) and v e (extravascular and extracellular volume fraction). However, the use of quantitative DCE-MRI in clinical prostate imaging islimited, with uncertainty in arterial input function (AIF, i.e. , the time rate of change of the concentration of CR in the blood plasma) determination being one of the primary reasons. In this multicenter data analysis challenge to assess the effects of variations in AIF quantification on estimation of DCE-MRI parameters, prostate DCE-MRI data acquired at one center from 11 prostate cancer patients were shared among nine centers. Each center used its site-specific method to determine the individual AIF from each data set and submitted the results to the managing center. Along with a literature population averaged AIF, these AIFs and their reference-tissue-adjusted variants were used by the managing center to perform pharmacokinetic analysis of the DCE-MRI data sets using the Tofts model (TM). All other variables including tumor region of interest (ROI) definition and pre-contrast T 1 were kept the same to evaluate parameter variations caused by AIF variations only. Considerable pharmacokinetic parameter variations were observed with the within-subject coefficient of variation (wCV) of K trans obtained with unadjusted AIFs as high as 0.74. AIF-caused variations were larger in K trans than v e and both were reduced when reference-tissue-adjusted AIFs were used. The parameter variations were largely systematic, resulting in nearly unchanged parametric map patterns. The CR intravasation rate constant, k ep (= K trans /v e ), was less sensitive to AIF variation than K trans (wCV for unadjusted AIFs: 0.45 for k ep vs. 0.74 for K trans ), suggesting that it might be a more robust imaging biomarker of prostate microvasculature than K trans .

Purpose: We aimed to develop a hippocampal vascular injury surrogate marker for early prediction of late neurocognitive dysfunction in patients receiving brain radiation therapy (RT)., Methods and Materials: Twenty-seven patients (17 males and 10 females, 31-80 years of age) were enrolled in an institutional review board-approved prospective longitudinal study. Patients received diagnoses of low-grade glioma or benign tumor and were treated by (3D) conformal or intensity-modulated RT with a median dose of 54 Gy (50.4-59.4 Gy in 1.8-Gy fractions). Six dynamic-contrast enhanced MRI scans were performed from pre-RT to 18-month post-RT, and quantified for vascular parameters related to blood-brain barrier permeability, K(trans), and the fraction of blood plasma volume, Vp. The temporal changes in the means of hippocampal transfer constant K(trans) and Vp after starting RT were modeled by integrating the dose effects with age, sex, hippocampal laterality, and presence of tumor or edema near a hippocampus. Finally, the early vascular dose response in hippocampi was correlated with neurocognitive dysfunction at 6 and 18 months post-RT., Results: The mean K(trans) Increased significantly from pre-RT to 1-month post-RT (P<.0004), which significantly depended on sex (P<.0007) and age (P<.00004), with the dose response more pronounced in older females. Also, the vascular dose response in the left hippocampus of females correlated significantly with changes in memory function at 6 (r=-0.95, P<.0006) and 18-months (r=-0.88, P<.02) post-RT., Conclusions: The early hippocampal vascular dose response could be a predictor of late neurocognitive dysfunction. A personalized hippocampus sparing strategy may be considered in the future., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The measurement of extracellular pH (pHe ) has significant clinical value for pathological diagnoses and for monitoring the effects of pH-altering therapies. One of the major problems of measuring pHe with a relaxation-based MRI contrast agent is that the longitudinal relaxivity depends on both pH and the concentration of the agent, requiring the use of a second pH-unresponsive agent to measure the concentration. Here we tested the feasibility of measuring pH with a relaxation-based dendritic MRI contrast agent in a concentration-independent manner at clinically relevant field strengths. The transverse and longitudinal relaxation times in solutions of the contrast agent (GdDOTA-4AmP)44 -G5, a G5-PAMAM dendrimer-based MRI contrast agent in water, were measured at 3 T and 7 T magnetic field strengths as a function of pH. At 3 T, longitudinal relaxivity (r1 ) increased from 7.91 to 9.65 mM(-1) s(-1) (on a per Gd(3+) basis) on changing pH from 8.84 to 6.35. At 7 T, r1 relaxivity showed pH response, albeit at lower mean values; transverse relaxivity (r2 ) remained independent of pH and magnetic field strengths. The longitudinal relaxivity of (GdDOTA-4AmP)44 -G5 exhibited a strong and reversible pH dependence. The ratio of relaxation rates R2 /R1 also showed a linear relationship in a pH-responsive manner, and this pH response was independent of the absolute concentration of (GdDOTA-4AmP)44 -G5 agent. Importantly, the nanoprobe (GdDOTA-4AmP)44 -G5 shows pH response in the range commonly found in the microenvironment of solid tumors., (Copyright © 2015 John Wiley & Sons, Ltd.)

MRI estimates of extracellular volume and tumor exudate flux in peritumoral tissue are demonstrated in an experimental model of cerebral tumor. Peritumoral extracellular volume predicted the tumor exudate flux. Eighteen RNU athymic rats were inoculated intracerebrally with U251MG tumor cells and studied with dynamic contrast enhanced MRI (DCE-MRI) approximately 18 days post implantation. Using a model selection paradigm and a novel application of Patlak and Logan plots to DCE-MRI data, the distribution volume (i.e. tissue porosity) in the leaky rim of the tumor and that in the tissue external to the rim (the outer rim) were estimated, as was the tumor exudate flow from the inner rim of the tumor through the outer rim. Distribution volume in the outer rim was approximately half that of the inner adjacent region (p < 1 × 10(-4)). The distribution volume of the outer ring was significantly correlated (R(2) = 0.9) with tumor exudate flow from the inner rim. Thus, peritumoral extracellular volume predicted the rate of tumor exudate flux. One explanation for these data is that perfusion, i.e. the delivery of blood to the tumor, was regulated by the compression of the mostly normal tissue of the tumor rim, and that the tumor exudate flow was limited by tumor perfusion., (Copyright © 2015 John Wiley & Sons, Ltd.)

The purpose of this study was to characterize changes in tumor vascular parameters hours after a single radiation exposure in an orthotopic brain tumor model. U-251 human brain tumors were established intracerebrally in rat brains, and tumor blood flow, forward volume transfer constant (K(trans)) and interstitial volume fraction (v(e)) were measured using magnetic resonance imaging (MRI). Tumors were exposure to a single stereotactic radiation treatment of 20 Gy. Vascular parameters were assessed one additional time between 2 and 24 h after irradiation. After the second MRI session, brain tissue histology was examined for gross changes and apoptosis. In separate studies, cerebral blood flow was measured in nonimplanted controls before radiation exposure and 2 and 24 h after 20 Gy irradiation, and in implanted rats before radiation exposure and at 2 and 24 h after 6 Gy irradiation. Significant changes were observed in tumor-bearing rat brains in the hours after 20 Gy irradiation. Two hours after 20 Gy irradiation, tumor blood flow decreased nearly 80% and ve decreased by 30%. At 4 h, the K(trans) increased by 30% over preirradiation values. Extensive vacuolization and an increase in apoptosis were evident histologically in rats imaged 2 h after irradiation. Between 8 and 12 h after irradiation, all vascular parameters including blood flow returned to near preirradiation values. One day after irradiation, tumor blood flow was elevated 40% over preirradiation values, and other vascular parameters, including K(trans) and ve, were 20-40% below preirradiation values. In contrast, changes in vascular parameters observed in the normal brain 2 or 24 h after 20 Gy irradiation were not significantly different from preirradiation values. Also, tumor blood flow appeared to be unchanged at 2 h after 6 Gy irradiation, with a small increase observed at 24 h, unlike the tumor blood flow changes after 20 Gy irradiation. Large and significant changes in vascular parameters were observed hours after 20 Gy irradiation using noninvasive MRI techniques. It is hypothesized that cellular swelling hours after a high dose of radiation, coinciding with vacuolization, led to a decrease in tumor blood flow and v(e). Four hours after radiation exposure, K(trans) increased in concert with an increase in tumor blood flow. Vascular permeability normalized, 24 h after 20 Gy irradiation, as characterized by a decrease in K(trans). Vascular parameters did not change significantly in the normal brain after 20 Gy irradiation or in the tumor-bearing brain after 6 Gy irradiation.

The distribution of dynamic contrast-enhanced MRI (DCE-MRI) parametric estimates in a rat U251 glioma model was analyzed. Using Magnevist as contrast agent (CA), 17 nude rats implanted with U251 cerebral glioma were studied by DCE-MRI twice in a 24 h interval. A data-driven analysis selected one of three models to estimate either (1) plasma volume (vp), (2) vp and forward volume transfer constant (K(trans)) or (3) vp, K(trans) and interstitial volume fraction (ve), constituting Models 1, 2 and 3, respectively. CA distribution volume (VD) was estimated in Model 3 regions by Logan plots. Regions of interest (ROIs) were selected by model. In the Model 3 ROI, descriptors of parameter distributions--mean, median, variance and skewness--were calculated and compared between the two time points for repeatability. All distributions of parametric estimates in Model 3 ROIs were positively skewed. Test-retest differences between population summaries for any parameter were not significant (p ≥ 0.10; Wilcoxon signed-rank and paired t tests). These and similar measures of parametric distribution and test-retest variance from other tumor models can be used to inform the choice of biomarkers that best summarize tumor status and treatment effects., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: Limiting expansion of the ischemic core lesion by reinstating blood flow and protecting the penumbral cells is a priority in acute stroke treatment. However, at present, methods are not available for effective drug delivery to the ischemic penumbra. To address these issues this study compared the extravasation and subsequent interstitial spread of a magnetic resonance contrast agent (MRCA) beyond the ischemic core into the surrounding brain in a rat model of ischemia-reperfusion for bolus injection and step-down infusion (SDI) protocols., Methods: Male Wistar rats underwent middle cerebral artery (MCA) occlusion for 3 h followed by reperfusion. Perfusion-diffusion mismatched regions indicating the extent of spread were identified by measuring cerebral blood flow (CBF) deficits by arterial spin-labeled magnetic resonance imaging and the extent of the ischemic core by mapping the apparent diffusion coefficient (ADC) of water with diffusion-weighted imaging. Vascular injury was assessed via MRCA, gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) penetration, by Look-Locker T1-weighted MR imaging after either a bolus injection (n = 8) or SDI (n = 6). Spatial and temporal expansion of the MRCA front during a 25 min imaging period was measured from images obtained at 2.5 min intervals., Results: The mean ADC lesion was 20 ± 7% of the hemispheric area whereas the CBF deficit area was 60 ± 16%, with the difference between the areas suggesting the possible presence of a penumbra. The bolus injection led to MRCA enhancement with an area that initially spread into the ischemic core and then diminished over time. The SDI produced a gradual increase in the area of MRCA enhancement that slowly enlarged to occupy the core, eventually expanded beyond it into the surrounding tissue and then plateaued. The integrated area from SDI extravasation was significantly larger than that for the bolus (p = 0.03). The total number of pixels covered by the SDI at its maximum was significantly larger than the pixels covered by bolus maximum (p = 0.05)., Conclusions: These results demonstrate that the SDI protocol resulted in a spread of the MRCA beyond the ischemic core. Whether plasma-borne acute stroke therapeutics can be delivered to the ischemic penumbra in a similar way needs to be investigated.

Purpose: To test the hypothesis that a noninvasive dynamic contrast enhanced MRI (DCE-MRI) derived interstitial volume fraction (ve ) and/or distribution volume (VD ) were correlated with tumor cellularity in cerebral tumor., Methods: T1 -weighted DCE-MRI studies were performed in 18 athymic rats implanted with U251 xenografts. After DCE-MRI, sectioned brain tissues were stained with Hematoxylin and Eosin for cell counting. Using a Standard Model analysis and Logan graphical plot, DCE-MRI image sets during and after the injection of a gadolinium contrast agent were used to estimate the parameters plasma volume (vp ), forward transfer constant (K(trans) ), ve , and VD ., Results: Parameter values in regions where the standard model was selected as the best model were: (mean ± S.D.): vp = (0.81 ± 0.40)%, K(trans) = (2.09 ± 0.65) × 10(-2) min(-1) , ve = (6.65 ± 1.86)%, and VD = (7.21 ± 1.98)%. The Logan-estimated VD was strongly correlated with the standard model's vp + ve (r = 0.91, P < 0.001). The parameters, ve and/or VD , were significantly correlated with tumor cellularity (r ≥ -0.75, P < 0.001 for both)., Conclusion: These data suggest that tumor cellularity can be estimated noninvasively by DCE-MRI, thus supporting its utility in assessing tumor pathophysiology., (Copyright © 2013 Wiley Periodicals, Inc.)

Increased efficacy of radiotherapy (RT) 4-8 h after Cilengitide treatment has been reported. We hypothesized that the effects of Cilengitide on tumor transvascular transfer parameters might underlie, and thus predict, this potentiation. Athymic rats with orthotopic U251 glioma were studied at ~21 days after implantation using dynamic contrast-enhanced (DCE)-MRI. Vascular parameters, viz: plasma volume fraction (v(p)), forward volume transfer constant (K(trans)) and interstitial volume fraction (v(e)) of a contrast agent, were determined in tumor vasculature once before, and again in cohorts 2, 4, 8, 12 and 24 h after Cilengitide administration (4 mg/kg; N = 31; 6-7 per cohort). Perfusion-fixed brain sections were stained for von Willebrand factor to visualize vascular segments. A comparison of pre- and post-treatment parameters showed that the differences between MR indices before and after Cilengitide treatment pivoted around the 8 h time point, with 2 and 4 h groups showing increases, 12 and 24 h groups showing decreases, and values at the 8 h time point close to the baseline. The vascular parameter differences between group of 2 and 4 h and group of 12 and 24 h were significant for K(trans) (p = 0.0001 and v(e) (p = 0,0271). Vascular staining showed little variation with time after Cilengitide. The vascular normalization occurring 8 h after Cilengitide treatment coincided with similar previous reports of increased treatment efficacy when RT followed Cilengitide by 8 h. Pharmacological normalization of vasculature has the potential to increase sensitivity to RT. Evaluating acute temporal responses of tumor vasculature to putative anti-angiogenic drugs may help in optimizing their combination with other treatment modalities.