Multiparametric Quantitative MRI of Peripheral Nerves in the Leg: A Reliability Study.

BACKGROUND: Patients with polyneuropathies typically have demyelination and/or axonal degeneration in peripheral nerves. Currently, there is a lack of imaging biomarkers to track the changes in these pathologies. PURPOSE: To develop and evaluate the reliability of a multiparametric quantitative magnetic resonance imaging (qMRI) method of peripheral nerves in the leg. STUDY TYPE: Prospective. SUBJECTS: Seventeen healthy volunteers (36.2 ± 13.8 years old, 9 males) with 10 of them scanned twice for test-retest. FIELD STRENGTH/SEQUENCE: 3 T, three-dimensional gradient echo and diffusion tensor imaging. ASSESSMENT: A qMRI protocol and processing pipeline was established for quantifying the following nerve parameters that are sensitive to myelin and axonal pathologies: magnetization transfer (MT) ratio (MTR), MT saturation index (MTsat), T2 *, T1 , proton density (PD), fractional anisotropy (FA), and mean/axial/radial diffusivities (MD, AD, and RD). The qMRI protocol also measures the volume of nerve fascicles (fVOL) and the fat fraction (FF) of muscles. STATISTICAL TESTS: The intersession reproducibility and inter-rater reliability of each qMRI parameter were assessed by Bland-Altman analysis and intraclass correlation coefficient (ICC). Pairwise Pearson correlation analyses were performed to investigate the intrinsic association between qMRI parameters. Distal-to-proximal variations were evaluated by paired t-tests with Bonferroni-Holm multiple comparison corrections. P < 0.05 was considered statistically significant. RESULTS: The MTR, MTsat, T2 *, T1 , PD, FA, AD, and fVOL of the sciatic and tibial nerves, and the FF of leg muscles, had an overall good-to-excellent test-retest agreement (ICC varying from 0.78 to 0.99). All the qMRI parameters had good-to-excellent inter-rater reliability (ICC > 0.80). The data demonstrated a pattern of distal-to-proximal changes of an increased nerve MTsat and FA, and a decreased nerve T1 , PD, MD, and RD, as well as a significantly increased muscle FF. DATA CONCLUSION: The proposed multiparametric qMRI method of the peripheral nerves is highly reproducible and provided healthy control data which will be used in developing monitoring biomarkers in patients with polyneuropathies. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

Comparison of automated full-body bone metastases delineation methods and their corresponding prognostic power.

Objective.Manual disease delineation in full-body imaging of patients with multiple metastases is often impractical due to high disease burden. However, this is a clinically relevant task as quantitative image techniques assessing individual metastases, while limited, have been shown to be predictive of treatment outcome. The goal of this work was to evaluate the efficacy of deep learning-based methods for full-body delineation of skeletal metastases and to compare their performance to existing methods in terms of disease delineation accuracy and prognostic power.Approach.1833 suspicious lesions on 3718F-NaF PET/CT scans of patients with metastatic castration-resistant prostate cancer (mCRPC) were contoured and classified as malignant, equivocal, or benign by a nuclear medicine physician. Two convolutional neural network (CNN) architectures (DeepMedic and nnUNet)were trained to delineate malignant disease regions with and without three-model ensembling. Malignant disease contours using previously established methods were obtained. The performance of each method was assessed in terms of four different tasks: (1) detection, (2) segmentation, (3) PET SUV metric correlations with physician-based data, and (4) prognostic power of progression-free survival.Main Results.The nnUnet three-model ensemble achieved superior detection performance with a mean (+/- standard deviation) sensitivity of 82.9±ccc 0.1% at the selected operating point. The nnUnet single and three-model ensemble achieved comparable segmentation performance with a mean Dice coefficient of 0.80±0.12 and 0.79±0.12, respectively, both outperforming other methods. The nnUNet ensemble achieved comparable or superior SUV metric correlation performance to gold-standard data. Despite superior disease delineation performance, the nnUNet methods did not display superior prognostic power over other methods.Significance.This work showed that CNN-based (nnUNet) methods are superior to the non-CNN methods for mCRPC disease delineation in full-body18F-NaF PET/CT. The CNN-based methods, however, do not hold greater prognostic power for predicting clinical outcome. This merits more investigation on the optimal selection of delineation methods for specific clinical tasks.

Candidate imaging biomarkers for PMP22-related inherited neuropathies.

OBJECTIVE: Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsy (HNPP) are caused by mutations to the peripheral myelin protein 22 (PMP22) gene. A need exists for sensitive and reliable biomarkers of progression and treatment response. Magnetic resonance imaging (MRI) metrics of nerve pathology and morphology were investigated for this purpose. METHODS: MRI was performed at 3.0 T in the thigh of CMT1A (N = 11) and HNPP patients (N = 12) and controls (N = 23). Three potential imaging biomarkers of the sciatic nerve were investigated: 1) magnetization transfer ratio (MTR), which assays myelin content, and 2) cross-sectional area (CSA) and 3) circularity, which assay morphological changes. Potential imaging biomarkers were compared across cohorts and assessed for relationships with disability in the legs (CMTESL ), compound motor action potentials (CMAP), and motor conduction velocities (MCV). Inter-rater reliability and test-retest repeatability were established for each imaging metric. RESULTS: Significant differences in MTR, CSA, and circularity were observed in CMT1A relative to controls (p = 0.02, p < 0.001, and p = 0.003, respectively, via Wilcoxon rank-sum tests). Differences were not observed in the HNPP cohort. Significant relationships were observed between MTR and clinical metrics (CMTESL : p = 0.003, CMAP: p = 0.03, MCV: p = 0.01); and between CSA and electrophysiology (CMAP: p = 0.002, MCV: p < 0.001). All metrics were reliable and repeatable with MTR the most reliable (intraclass correlation coefficient [ICC] >0.999, CV = 0.30%) and repeatable (ICC = 0.84, CV = 3.16%). INTERPRETATION: MTR, CSA, and circularity showed promise as reliable and sensitive biomarkers of CMT1A, but not HNPP. These warrant longitudinal investigation as response biomarkers in upcoming clinical trials of CMT1A, while other methods should be considered for HNPP.

Exploring Spatial-Temporal Changes in 18F-Sodium Fluoride PET/CT and Circulating Tumor Cells in Metastatic Castration-Resistant Prostate Cancer Treated With Enzalutamide.

PURPOSE: Intrapatient treatment response heterogeneity is under-recognized. Quantitative total bone imaging (QTBI) using 18F-NaF positron emission tomography/computed tomography (PET/CT) scans is a tool that allows characterization of interlesional treatment response heterogeneity in bone. Understanding spatial-temporal response is important to identify individuals who may benefit from treatment beyond progression. PATIENTS AND METHODS: Men with progressive metastatic castration-resistant prostate cancer (mCRPC) with at least two lesions on bone scintigraphy were enrolled and treated with enzalutamide 160 mg daily (ClinicalTrials.gov identifier: NCT02384382). 18F-NaF PET/CT scans were obtained at baseline (PET1), week 13 (PET2), and at the time of prostate-specific antigen (PSA) progression, standard radiographic or clinical progression, or at 2 years without progression (PET3). QTBI was used to determine lesion-level response. The primary end point was the proportion of men with at least one responding bone lesion on PET3 using QTBI. RESULTS: Twenty-three men were enrolled. Duration on treatment ranged from 1.4 to 34.1 months. In general, global standardized uptake value (SUV) metrics decreased while on enzalutamide (PET2) and increased at the time of progression (PET3). The most robust predictor of PSA progression was change in SUVhetero (PET1 to PET3; hazard ratio, 3.88; 95% CI, 1.24 to 12.1). Although overall functional disease burden improved during enzalutamide treatment, an increase in total burden (SUVtotal) was seen at the time of progression, as measured by 18F-NaF PET/CT. All (22/22) evaluable men had at least one responding bone lesion at PET3 using QTBI. CONCLUSION: We found that the proportion of progressing lesions was low, indicating that a substantial number of lesions appear to continue to benefit from enzalutamide beyond progression. Selective targeting of nonresponding lesions may be a reasonable approach to extend benefit.

Phase II Trial of a DNA Vaccine Encoding Prostatic Acid Phosphatase (pTVG-HP [MVI-816]) in Patients With Progressive, Nonmetastatic, Castration-Sensitive Prostate Cancer.

PURPOSE: We previously reported the safety and immunologic effects of a DNA vaccine (pTVG-HP [MVI-816]) encoding prostatic acid phosphatase (PAP) in patients with recurrent, nonmetastatic prostate cancer. The current trial evaluated the effects of this vaccine on metastatic progression. PATIENTS AND METHODS: Ninety-nine patients with castration-sensitive prostate cancer and prostate-specific antigen (PSA) doubling time (DT) of less than 12 months were randomly assigned to treatment with either pTVG-HP co-administered intradermally with 200 µg granulocyte-macrophage colony-stimulating factor (GM-CSF) adjuvant or 200 µg GM-CSF alone six times at 14-day intervals and then quarterly for 2 years. The primary end point was 2-year metastasis-free survival (MFS). Secondary and exploratory end points were median MFS, changes in PSA DT, immunologic effects, and changes in quantitative 18F-sodium fluoride (NaF) positron emission tomography/computed tomography (PET/CT) imaging. RESULTS: Two-year MFS was not different between study arms (41.8% vaccine v 42.3%; P = .97). Changes in PSA DT and median MFS were not different between study arms (18.9 v 18.3 months; hazard ratio [HR], 1.6; P = .13). Preplanned subset analysis identified longer MFS in vaccine-treated patients with rapid (< 3 months) pretreatment PSA DT (12.0 v 6.1 months; n = 21; HR, 4.4; P = .03). PAP-specific T cells were detected in both cohorts, including multifunctional PAP-specific T-helper 1-biased T cells. Changes in total activity (total standardized uptake value) on 18F-NaF PET/CT from months 3 to 6 increased 50% in patients treated with GM-CSF alone and decreased 23% in patients treated with pTVG-HP (n = 31; P = .07). CONCLUSION: pTVG-HP treatment did not demonstrate an overall increase in 2-year MFS in patients with castration-sensitive prostate cancer, with the possible exception of a subgroup with rapidly progressive disease. Prespecified 18F-NaF PET/CT imaging conducted in a subset of patients suggests that vaccination had detectable effects on micrometastatic bone disease. Additional trials using pTVG-HP in combination with PD-1 blockade are under way.

Impact of Anatomic Location of Bone Metastases on Prognosis in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Whole-body assessments of 18F-NaF positron emission tomography (PET)/computed tomography (CT) provide promising quantitative imaging biomarkers of metastatic castration-resistant prostate cancer (mCRPC). This study investigated whether the distribution of metastases across anatomic regions is prognostic of progression-free survival. PATIENTS AND METHODS: Fifty-four mCRPC patients with osseous metastases received baseline NaF PET/CT. Patients received chemotherapy (n = 16) or androgen receptor pathway inhibitors (n = 38). Semiautomated analysis using Quantitative Total Bone Imaging software extracted imaging metrics for the whole, axial, and appendicular skeleton as well as 11 skeletal regions. Five PET metrics were extracted for each region: number of lesions (NL), standardized maximum uptake value (SUVmax), average uptake (SUVmean), sum of uptake (SUVtotal), and diseased fraction of the skeleton (volume fraction). Progression included that discovered by clinical, biochemical, or radiographic means. Univariate and multivariate Cox proportional hazard regression analyses were performed between imaging metrics and progression-free survival, and were assessed according to their hazard ratios (HR) and concordance (C)-indices. RESULTS: The strongest univariate models of progression-free survival were pelvic NL and SUVmax with HR = 1.80 (NL: false discovery rate adjusted P = .001, SUVmax: adjusted P = .001). Three other region-specific metrics (axial NL: HR = 1.59, adjusted P = .02, axial SUVmax: HR = 1.61, adjusted P = .02, and skull SUVmax: HR = 1.58, adjusted P = .04) were found to be stronger prognosticators relative to their whole-body counterparts. Multivariate model including region-specific metrics (C-index = 0.727) outperformed that of whole-body metrics (C-index = 0.705). The best performance was obtained when region-specific and whole-body metrics were included (C-index = 0.742). CONCLUSION: Quantitative characterization of metastatic spread by anatomic location on NaF PET/CT enhances potential prognostication. Further study is warranted to optimize the prognostic and predictive value of NaF PET/CT in mCRPC patients.