Dose-response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin.

The vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. In a multisite phase 1 clinical study of crolibulin (NCT00423410), we measured treatment-induced changes in tumor perfusion and water diffusivity (ADC) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI), and computed correlates of crolibulin pharmacokinetics. 11 subjects with advanced solid tumors were imaged by MRI at baseline and 2-3 days post-crolibulin (13-24 mg/m2). ADC maps were computed from DW-MRI. Pre-contrast T1 maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC90s) and the Extended Tofts Model parameters ktrans, ve, and vp were calculated. There was a strong correlation between higher plasma drug [Formula: see text] and a linear combination of (1) reduction in tumor fraction with [Formula: see text] mM s, and, (2) increase in tumor fraction with [Formula: see text]. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with [Formula: see text], and, (2) increase in tumor fraction with [Formula: see text]. These findings are suggestive of cell swelling and decreased tumor perfusion 2-3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents.

Repeatability of Quantitative Imaging Features in Prostate Magnetic Resonance Imaging.

Background: Multiparametric magnetic resonance imaging (mpMRI) has emerged as a non-invasive modality to diagnose and monitor prostate cancer. Quantitative metrics on the regions of abnormality have shown to be useful descriptors to discriminate clinically significant cancers. In this study, we evaluate the reproducibility of quantitative imaging features using repeated mpMRI on the same patients. Methods: We retrospectively obtained the deidentified records of patients, who underwent two mpMRI scans within 2 weeks of the first baseline scan. The patient records were obtained as deidentified data (including imaging), obtained through the TCIA (The Cancer Imaging Archive) repository and analyzed in our institution with an institutional review board-approved Health Insurance Portability and Accountability Act-compliant retrospective study protocol. Indicated biopsied regions were used as a marker for our study radiologists to delineate the regions of interest. We extracted 307 quantitative features in each mpMRI modality [T2-weighted MR sequence image (T2w) and apparent diffusion coefficient (ADC) with b values of 0 and 1,400 mm/s2] across the two sequential scans. Concordance correlation coefficients (CCCs) were computed on the features extracted from sequential scans. Redundant features were removed by computing the coefficient of determination (R 2) among them and replaced with a feature that had the highest dynamic range within intercorrelated groups. Results: We have assessed the reproducibility of quantitative imaging features among sequential scans and found that habitat region characterization improves repeatability in ADC maps. There were 19 T2w features and two ADC features in radiologist drawn regions (native raw image), compared to 18 T2w and 15 ADC features in habitat regions (sphere), which were reproducible (CCC ≥0.65) and non-redundant (R 2 ≥ 0.99). We also found that z-transformation of the images prior to feature extraction reduced the number of reproducible features with no detrimental effect. Conclusion: We have shown that there are quantitative imaging features that are reproducible across sequential prostate mpMRI acquisition at a preset level of filters. We also found that a habitat approach improves feature repeatability in ADC. A validated set of reproducible image features in mpMRI will allow us to develop clinically useful disease risk stratification, enabling the possibility of using imaging as a surrogate to invasive biopsies.

Habitats in DCE-MRI to Predict Clinically Significant Prostate Cancers.

Prostate cancer identification and assessment of clinical significance continues to be a challenge. Routine multiparametric magnetic resonance imaging has shown to be useful in assessing disease progression. Although dynamic contrast-enhanced imaging (DCE) has the ability to characterize perfusion across time and has shown enormous utility, radiological assessment (Prostate Imaging-Reporting and Data System or PIRADS version 2) has limited its use owing to lack of consistency and nonquantitative nature. In our work, we propose a systematic methodology to quantify perfusion dynamics for the DCE imaging. Using these metrics, 7 different subregions or perfusion habitats of the targeted lesions are localized and related to clinical significance. We found that quantitative features describing the habitat based on the late area under the DCE time-activity curve was a good predictor of clinical significance disease. The best predictive feature in the habitat had an AUC of 0.82, CI [0.81-0.83].

An Automated Multiparametric MRI Quantitative Imaging Prostate Habitat Risk Scoring System for Defining External Beam Radiation Therapy Boost Volumes.

PURPOSE: To develop a prostate tumor habitat risk scoring (HRS) system based on multiparametric magnetic resonance imaging (mpMRI) referenced to prostatectomy Gleason score (GS) for automatic delineation of gross tumor volumes. A workflow for integration of HRS into radiation therapy boost volume dose escalation was developed in the framework of a phase 2 randomized clinical trial (BLaStM). METHODS AND MATERIALS: An automated quantitative mpMRI-based 10-point pixel-by-pixel method was optimized to prostatectomy GSs and volumes using referenced dynamic contrast-enhanced and apparent diffusion coefficient sequences. The HRS contours were migrated to the planning computed tomography scan for boost volume generation. RESULTS: There were 51 regions of interest in 12 patients who underwent radical prostatectomy (26 with GS ≥7 and 25 with GS 6). The resultant heat maps showed inter- and intratumoral heterogeneity. The HRS6 level was significantly associated with radical prostatectomy regions of interest (slope 1.09, r = 0.767; P < .0001). For predicting the likelihood of cancer, GS ≥7 and GS ≥8 HRS6 area under the curve was 0.718, 0.802, and 0.897, respectively. HRS was superior to the Prostate Imaging, Reporting and Diagnosis System 4/5 classification, wherein the area under the curve was 0.62, 0.64, and 0.617, respectively (difference with HR6, P < .0001). HRS maps were created for the first 37 assessable patients on the BLaStM trial. There were an average of 1.38 habitat boost volumes per patient at a total boost volume average of 3.6 cm3. CONCLUSIONS: An automated quantitative mpMRI-based method was developed to objectively guide dose escalation to high-risk habitat volumes based on prostatectomy GS.

Automatic Detection and Quantitative DCE-MRI Scoring of Prostate Cancer Aggressiveness.

PURPOSE: To develop a robust and clinically applicable automated method for analyzing Dynamic Contrast Enhanced (DCE-) MRI of the prostate as a guide for targeted biopsies and treatments. MATERIALS AND METHODS: An unsupervised pattern recognition (PR) method was used to analyze prostate DCE-MRI from 71 sequential radiotherapy patients. Identified regions of interest (ROIs) with increased perfusion were assigned either to the peripheral (PZ) or transition zone (TZ). Six quantitative features, associated with the washin and washout part of the weighted average DCE curve from the ROI, were calculated. The associations between the assigned DCE-scores and Gleason Score (GS) were investigated. A heatmap of tumor aggressiveness covering the entire prostate was generated and validated with histopathology from MRI-ultrasound fused (MRI-US) targeted biopsies. RESULTS: The volumes of the PR-identified ROI's were significantly correlated with the highest GS from the biopsy session for each patient. Following normalization (and only after normalization) with gluteus maximus muscle's DCE signal, the quantitative features in PZ were significantly correlated with GS. These correlations straightened in subset of patients with available MRI-US biopsies when GS from the individual biopsies were used. Area under the receiver operating characteristics curve for discrimination between indolent vs aggressive cancer for the significant quantitative features reached 0.88-0.95. When DCE-scores were calculated in normal appearing tissues, the features were highly discriminative for cancer vs no cancer both in PZ and TZ. The generated heatmap of tumor aggressiveness coincided with the location and GS of the MRI-US biopsies. CONCLUSION: A quantitative approach for DCE-MRI analysis was developed. The resultant map of aggressiveness correlated well with tumor location and GS and is applicable for integration in radiotherapy/radiology imaging software for clinical translation.

Association of Radiomics and Metabolic Tumor Volumes in Radiation Treatment of Glioblastoma Multiforme.

PURPOSE: To build a framework for investigation of the associations between imaging, clinical target volumes (CTVs), and metabolic tumor volumes (MTVs) features for better understanding of the underlying information in the CTVs and dependencies between these volumes. High-throughput extraction of imaging and metabolomic quantitative features from magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging of glioblastoma multiforme (GBM) results in tens of variables per patient. In radiation therapy of GBM the relevant metabolic tumor volumes (MTVs) are related to aberrant levels of N-acetyl aspartate (NAA) and choline (Cho). The corresponding clinical target volumes (CTVs) for radiation therapy are based on contrast-enhanced T1-weighted (CE-T1w) and T2-weighted (T2w)/fluid-attenuated inversion recovery MRI. METHODS AND MATERIALS: Necrotic portions, enhancing lesion, and edema were manually contoured on CE-T1w/T2w images for 17 GBM patients. Clinical target volumes and MTVs for NAA (MTVNAA) and Cho (MTVCho) were constructed. Imaging and metabolic features related to size, shape, and signal intensities of the volumes were extracted. Tumors were also scored categorically for 10 semantic imaging traits by a neuroradiologist. All features were investigated for redundancy. Two-way correlations between imaging and CTVs/MTVs features were visualized as heatmaps. Associations between MTVNAA and MTVCho and imaging features were studied using Spearman correlation. RESULTS: Forty-eight imaging features were extracted per patient. Half of the imaging traits were replaced with automatically extracted continuous variables. Twenty features were extracted from CTVs and MTVs. A series of semantic imaging traits were replaced with automatically extracted continuous variables. There were multiple (22) significant correlations of imaging measures with CTVs/MTVNAA, whereas there were only 6 with CTVs/MTVCho. CONCLUSIONS: A framework for investigation of codependencies between MRI and magnetic resonance spectroscopic imaging radiomic features and CTVs/MTVs has been established. The MTV for NAA was found to be closely associated with MRI volumes, whereas very few imaging features were related to MTVCho, indicating that Cho provides additional information to imaging.

Association of multiparametric MRI quantitative imaging features with prostate cancer gene expression in MRI-targeted prostate biopsies.

Standard clinicopathological variables are inadequate for optimal management of prostate cancer patients. While genomic classifiers have improved patient risk classification, the multifocality and heterogeneity of prostate cancer can confound pre-treatment assessment. The objective was to investigate the association of multiparametric (mp)MRI quantitative features with prostate cancer risk gene expression profiles in mpMRI-guided biopsies tissues.Global gene expression profiles were generated from 17 mpMRI-directed diagnostic prostate biopsies using an Affimetrix platform. Spatially distinct imaging areas ('habitats') were identified on MRI/3D-Ultrasound fusion. Radiomic features were extracted from biopsy regions and normal appearing tissues. We correlated 49 radiomic features with three clinically available gene signatures associated with adverse outcome. The signatures contain genes that are over-expressed in aggressive prostate cancers and genes that are under-expressed in aggressive prostate cancers. There were significant correlations between these genes and quantitative imaging features, indicating the presence of prostate cancer prognostic signal in the radiomic features. Strong associations were also found between the radiomic features and significantly expressed genes. Gene ontology analysis identified specific radiomic features associated with immune/inflammatory response, metabolism, cell and biological adhesion. To our knowledge, this is the first study to correlate radiogenomic parameters with prostate cancer in men with MRI-guided biopsy.

Verification of multileaf collimator leaf positions using an electronic portal imaging device.

An automated method is presented for determining individual leaf positions of the Siemens dual focus multileaf collimator (MLC) using the Siemens BEAMVIEW(PLUS) electronic portal imaging device (EPID). Leaf positions are computed with an error of 0.6 mm at one standard deviation (sigma) using separate computations of pixel dimensions, image distortion, and radiation center. The pixel dimensions are calculated by superimposing the film image of a graticule with the corresponding EPID image. A spatial correction is used to compensate for the optical distortions of the EPID, reducing the mean distortion from 3.5 pixels (uncorrected) per localized x-ray marker to 2 pixels (1 mm) for a rigid rotation and 1 pixel for a third degree polynomial warp. A correction for a nonuniform dosimetric response across the field of view of the EPID images is not necessary due to the sharp intensity gradients across leaf edges. The radiation center, calculated from the average of the geometric centers of a square field at 0 degrees and 180 degrees collimator angles, is independent of graticule placement error. Its measured location on the EPID image was stable to within 1 pixel based on 3 weeks of repeated extensions/retractions of the EPID. The MLC leaf positions determined from the EPID images agreed to within a pixel of the corresponding values measured using film and ionization chamber. Several edge detection algorithms were tested: contour, Sobel, Roberts, Prewitt, Laplace, morphological, and Canny. These agreed with each other to within < or = 1.2 pixels for the in-air EPID images. Using a test pattern, individual MLC leaves were found to be typically within 1 mm of the corresponding record-and-verify values, with a maximum difference of 1.8 mm, and standard deviations of <0.3 mm in the daily reproducibility. This method presents a fast, automatic, and accurate alternative to using film or a light field for the verification and calibration of the MLC.