Magnetic resonance biomarkers in radiation oncology: The report of AAPM Task Group 294.

PURPOSE: A magnetic resonance (MR) biologic marker (biomarker) is a measurable quantitative characteristic that is an indicator of normal biological and pathogenetic processes or a response to therapeutic intervention derived from the MR imaging process. There is significant potential for MR biomarkers to facilitate personalized approaches to cancer care through more precise disease targeting by quantifying normal versus pathologic tissue function as well as toxicity to both radiation and chemotherapy. Both of which have the potential to increase the therapeutic ratio and provide earlier, more accurate monitoring of treatment response. The ongoing integration of MR into routine clinical radiation therapy (RT) planning and the development of MR guided radiation therapy systems is providing new opportunities for MR biomarkers to personalize and improve clinical outcomes. Their appropriate use, however, must be based on knowledge of the physical origin of the biomarker signal, the relationship to the underlying biological processes, and their strengths and limitations. The purpose of this report is to provide an educational resource describing MR biomarkers, the techniques used to quantify them, their strengths and weakness within the context of their application to radiation oncology so as to ensure their appropriate use and application within this field.

Validation of automated magnetic resonance image segmentation for radiation therapy planning in prostate cancer.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) is increasingly used in radiation therapy planning of prostate cancer (PC) to reduce target volume delineation uncertainty. This study aimed to assess and validate the performance of a fully automated segmentation tool (AST) in MRI based radiation therapy planning of PC. MATERIAL AND METHODS: Pelvic structures of 65 PC patients delineated in an MRI-only workflow according to established guidelines were included in the analysis. Automatic vs manual segmentation by an experienced oncologist was compared with geometrical parameters, such as the dice similarity coefficient (DSC). Fifteen patients had a second MRI within 15 days to assess repeatability of the AST for prostate and seminal vesicles. Furthermore, we investigated whether hormonal therapy or body mass index (BMI) affected the AST results. RESULTS: The AST showed high agreement with manual segmentation expressed as DSC (mean, SD) for delineating prostate (0.84, 0.04), bladder (0.92, 0.04) and rectum (0.86, 0.04). For seminal vesicles (0.56, 0.17) and penile bulb (0.69, 0.12) the respective agreement was moderate. Performance of AST was not influenced by neoadjuvant hormonal therapy, although those on treatment had significantly smaller prostates than the hormone-naïve patients (p < 0.0001). In repeat assessment, consistency of prostate delineation resulted in mean DSC of 0.89, (SD 0.03) between the paired MRI scans for AST, while mean DSC of manual delineation was 0.82, (SD 0.05). CONCLUSION: Fully automated MRI segmentation tool showed good agreement and repeatability compared with manual segmentation and was found clinically robust in patients with PC. However, manual review and adjustment of some structures in individual cases remain important in clinical use.

MRI-based IMPT planning for prostate cancer.

PURPOSE: Treatment planning for proton therapy requires the relative proton stopping power ratio (RSP) information of the patient for accurate dose calculations. RSP are conventionally obtained after mapping of the Hounsfield units (HU) from a calibrated patient computed tomography (CT). One or multiple CT are needed for a given treatment which represents additional, undesired dose to the patient. For prostate cancer, magnetic resonance imaging (MRI) scans are the gold standard for segmentation while offering dose-less imaging. We here quantify the clinical applicability of converted MR images as a substitute for intensity modulated proton therapy (IMPT) treatment of the prostate. METHODS: MRCAT (Magnetic Resonance for Calculating ATtenuation) is a Philips-developed technology which produces a synthetic CT image consisting of five HU from a specific set of MRI acquisitions. MRCAT and original planning CT data sets were obtained for ten patients. An IMPT plan was generated on the MRCAT for each patient. Plans were produced such that they fulfill the prostate protocol in use at Massachusetts General Hospital (MGH). The plans were then recomputed onto the nominal planning CT for each patient. Robustness analyses (±5 mm setup shifts and ±3.5 % range uncertainties) were also performed. RESULTS: Comparison of MRCAT plans and their recomputation onto the planning CT plan showed excellent agreement. Likewise, dose perturbations due to setup shifts and range uncertainties were well within clinical acceptance demonstrating the clinical viability of the approach. CONCLUSIONS: This work demonstrate the clinical acceptability of substituting MR converted RSP images instead of CT for IMPT planning of prostate cancer. This further translates into higher contouring accuracy along with lesser imaging dose.

Clinical workflow for MR-only simulation and planning in prostate.

PURPOSE: To describe the details and experience of implementing a MR-only workflow in the clinic for simulation and planning of prostate cancer patients. METHODS: Forty-eight prostate cancer patients from June 2016 - Dec 2016 receiving external beam radiotherapy were scheduled to undergo MR-only simulation. MR images were acquired for contouring (T2w axial, coronal, sagittal), synthetic-CT generation (3D FFE-based) and fiducial identification (3D bFFE-based). The total acquisition time was 25 min. Syn-CT was generated at the console using commercial software called MRCAT. As part of acceptance testing of the MRCAT package, external laser positioning system QA (< 2 mm) and geometric fidelity QA (< 2 mm within 50 cm LR and 30 cm AP) were performed and baseline values were set. Our current combined CT + MR simulation process was modified to accommodate a MRCAT-based MR-only simulation workflow. An automated step-by-step process using a MIM™ workflow was created for contouring on the MR images. Patient setup for treatment was achieved by matching the MRCAT DRRs with the orthogonal KV radiographs based on either fiducial ROIs or bones. 3-D CBCTs were acquired and compared with the MR/syn-CT to assess the rectum and bladder filling compared to simulation conditions. RESULTS: Forty-two patients successfully underwent MR-only simulation and met all of our institutional dosimetric objectives that were developed based on a CT + MR-based workflow. The remaining six patients either had a hip prosthesis or their large body size fell outside of the geometric fidelity QA criteria and thus they were not candidates for MR-only simulation. A total time saving of ~15 min was achieved with MR-based simulation as compared to CT + MR-based simulation. An automated and organized MIM workflow made contouring on MR much easier, quicker and more accurate compared with combined CT + MR images because the temporal variations in normal structure was minimal. 2D and 3D treatment setup localization based on bones/fiducials using a MRCAT reference image was successfully achieved for all cases. CONCLUSIONS: MR-only simulation and planning with equivalent or superior target delineation, planning and treatment setup localization accuracy is feasible in a clinical setting. Future work will focus on implementing a robust 3D isotropic acquisition for contouring.

Noninvasive, in vivo determination of uterine fibroid thermal conductivity in MRI-guided high intensity focused ultrasound therapy.

PURPOSE: To estimate the local thermal conductivity of uterine fibroid in vivo at a high temperature range (60-80°C) typically encountered in magnetic resonance imaging-guided high-intensity focused ultrasound (MRgHIFU) surgery. The thermal conductivity of uterine fibroids in vivo is unknown and knowledge about tissue thermal conductivity may aid in effective delivery of thermal energy for ablation. MATERIALS AND METHODS: All subjects (nine women) provided written informed consent to participate in this Institutional Review Board-approved study. A total of 10 fibroids were treated using MRgHIFU surgery with real-time temperature monitoring during both heating and cooling periods. The local thermal conductivity was determined by analyzing the spatiotemporal spread of temperature during the cooling period. RESULTS: The thermal conductivity of MRgHIFU-treated uterine fibroids was 0.47 ± 0.07 W·m(-1) ·K(-1) (range: 0.25∼0.67 W·m(-1) ·K(-1) ) which is slightly lower than the reported value for skeletal muscle at temperatures of <40°C (0.52 to 0.62 W·m(-1) ·K(-1) ). CONCLUSION: It is possible to estimate the thermal conductivity of uterine fibroids in vivo from the spatiotemporal spread of temperature around the HIFU focus during the cooling period.

Measurement of renal tissue oxygenation with blood oxygen level-dependent MRI and oxygen transit modeling.

Blood oxygen level-dependent (BOLD) MRI data of kidney, while indicative of tissue oxygenation level (Po2), is in fact influenced by multiple confounding factors, such as R2, perfusion, oxygen permeability, and hematocrit. We aim to explore the feasibility of extracting tissue Po2 from renal BOLD data. A method of two steps was proposed: first, a Monte Carlo simulation to estimate blood oxygen saturation (SHb) from BOLD signals, and second, an oxygen transit model to convert SHb to tissue Po2. The proposed method was calibrated and validated with 20 pigs (12 before and after furosemide injection) in which BOLD-derived tissue Po2 was compared with microprobe-measured values. The method was then applied to nine healthy human subjects (age: 25.7 ± 3.0 yr) in whom BOLD was performed before and after furosemide. For the 12 pigs before furosemide injection, the proposed model estimated renal tissue Po2 with errors of 2.3 ± 5.2 mmHg (5.8 ± 13.4%) in cortex and -0.1 ± 4.5 mmHg (1.7 ± 18.1%) in medulla, compared with microprobe measurements. After injection of furosemide, the estimation errors were 6.9 ± 3.9 mmHg (14.2 ± 8.4%) for cortex and 2.6 ± 4.0 mmHg (7.7 ± 11.5%) for medulla. In the human subjects, BOLD-derived medullary Po2 increased from 16.0 ± 4.9 mmHg (SHb: 31 ± 11%) at baseline to 26.2 ± 3.1 mmHg (SHb: 53 ± 6%) at 5 min after furosemide injection, while cortical Po2 did not change significantly at ∼58 mmHg (SHb: 92 ± 1%). Our proposed method, validated with a porcine model, appears promising for estimating tissue Po2 from renal BOLD MRI data in human subjects.

Magnetic resonance elastography noninvasively detects in vivo renal medullary fibrosis secondary to swine renal artery stenosis.

OBJECTIVES: Magnetic resonance elastography (MRE) can noninvasively sample tissue stiffness in vivo. Renal fibrosis secondary to renal artery stenosis (RAS), which is aggravated in atherosclerotic RAS (ARAS), may increase its stiffness. An increase in cortical stiffness in vivo can be masked by intrinsic hemodynamic determinants, whereas renal medullary stiffness is less dependent on renal hemodynamics. Therefore, this study tested the hypothesis that MRE-determined medullary stiffness would correspond to the histological degree of medullary fibrosis in stenotic kidneys in RAS and detect its exacerbation in ARAS. MATERIALS AND METHODS: Seventeen pigs were studied 10 weeks after induction of unilateral RAS (n = 6), ARAS (n = 5), or sham (n = 6). Stiffness of the cortex and the medulla was determined through 3-dimensional MRE, and renal perfusion and function were determined using multidetector computed tomography. Kidney fibrosis was subsequently assessed ex vivo using the Masson trichrome staining. RESULTS: Renal stenotic cortex and medulla were significantly more fibrotic in RAS and ARAS compared with healthy kidney. However, MRE detected increased stiffness in RAS compared with the healthy kidney (12.7 ± 0.41 kPa vs 10.7 ± 0.18 kPa; P = 0.004) only in the medulla, which was further increased in ARAS (16.6 ± 1.3 kPa; P = 0.017 vs RAS). Magnetic resonance elastography-derived medullary, but not cortical, stiffness significantly correlated with histological degree of fibrosis, although cortical and medullary fibroses were correlated. Renal blood flow and function were similarly decreased in RAS and ARAS compared with the healthy kidney. CONCLUSIONS: Noninvasive 3-dimensional MRE detects increased renal medullary stiffness in RAS and ARAS in vivo, which correlates with its fibrosis ex vivo and may also reflect cortical fibrosis. Hence, MRE-derived medullary stiffness can be potentially useful in detecting renal fibrosis and track disease progression.

A novel phase-corrected 3D cine ultra-short te (UTE) phase-contrast MRI technique.

Phase-contrast (PC) MRI is a non-invasive technique to assess cardiovascular blood flow. However, this technique is not accurate for instance at the carotid bifurcation due to turbulent and disturbed blood flow in atherosclerotic disease. Flow quantification using conventional PC MRI distal to stenotic vessels suffers from intravoxel dephasing and flow artifacts. Previous studies have shown that short echo time (TE) potentially decreases the phase errors. In this work, a novel 3D cine UTE-PC imaging method is designed to measure the blood velocity in the carotid bifurcation using a UTE center-out radial trajectory and short TE time compared to standard PC MRI sequences. With a new phase error correction technique based on autocorrelation method, the proposed 3D cine UTE-PC has the potential to achieve high accuracy for quantification and visualization of velocity jet distal to a stenosis. Herein, we test the feasibility of the method in determining accurate flow waveforms in normal volunteers.

Noninvasive In vivo assessment of renal tissue elasticity during graded renal ischemia using MR elastography.

OBJECTIVES: : Magnetic resonance elastography (MRE) allows noninvasive assessment of tissue stiffness in vivo. Renal arterial stenosis (RAS), a narrowing of the renal artery, promotes irreversible tissue fibrosis that threatens kidney viability and may elevate tissue stiffness. However, kidney stiffness may also be affected by hemodynamic factors. This study tested the hypothesis that renal blood flow (RBF) is an important determinant of renal stiffness as measured by MRE. MATERIAL AND METHODS: : In 6 anesthetized pigs MRE studies were performed to determine cortical and medullary elasticity during acute graded decreases in RBF (by 20%, 40%, 60%, 80%, and 100% of baseline) achieved by a vascular occluder. Three sham-operated swine served as time control. Additional pigs were studied with MRE 6 weeks after induction of chronic unilateral RAS (n = 6) or control (n = 3). Kidney fibrosis was subsequently evaluated histologically by trichrome staining. RESULTS: : During acute RAS the stenotic cortex stiffness decreased (from 7.4 ± 0.3 to 4.8 ± 0.6 kPa, P = 0.02 vs. baseline) as RBF decreased. Furthermore, in pigs with chronic RAS (80% ± 5.4% stenosis) in which RBF was decreased by 60% ± 14% compared with controls, cortical stiffness was not significantly different from normal (7.4 ± 0.3 vs. 7.6 ± 0.3 kPa, P = 0.3), despite histologic evidence of renal tissue fibrosis. CONCLUSION: : Hemodynamic variables modulate kidney stiffness measured by MRE and may mask the presence of fibrosis. These results suggest that kidney turgor should be considered during interpretation of elasticity assessments.

Determinations of renal cortical and medullary oxygenation using blood oxygen level-dependent magnetic resonance imaging and selective diuretics.

OBJECTIVE: This study was undertaken to test the hypothesis that blood O2 level-dependent magnetic resonance imaging (BOLD MRI) can detect changes in cortical proximal tubule (PT) and medullary thick ascending limb of Henle (TAL) oxygenation consequent to successive administration of furosemide and acetazolamide (Az). Assessment of PT and TAL function could be useful to monitor renal disease states in vivo. Therefore, the adjunct use of diuretics that inhibit Na reabsorption selectively in PT and TAL, Az and furosemide, respectively, may help discern tubular function by using BOLD MRI to detect changes in tissue oxygenation. MATERIAL AND METHODS: BOLD MRI signal R2* (inversely related to oxygenation) and tissue oxygenation with intrarenal O2 probes were measured in pigs that received either furosemide (0.05 mg/kg) or Az (15 mg/kg) alone, Az sequentially after furosemide (n = 6 each, 15-minute intervals), or only saline vehicle (n = 3). RESULTS: R2* decreased in the cortex of Az-treated and medulla of furosemide-treated kidneys, corresponding to an increase in their tissue O2 assessed with probes. However, BOLD MRI also showed decreased cortical R2* following furosemide that was additive to the Az-induced decrease. Az administration, both alone and after furosemide, also decreased renal blood flow (-26% ± 3.5% and -29.2% ± 3%, respectively, P < 0.01). CONCLUSION: These results suggest that an increase in medullary and cortical tissue O2 elicited by selective diuretics is detectable by BOLD MRI, but may be complicated by hemodynamic effects of the drugs. Therefore, the BOLD MRI signal may reflect functional changes additional to oxygenation, and needs to be interpreted cautiously.

Revascularization of swine renal artery stenosis improves renal function but not the changes in vascular structure.

Renal revascularization by percutaneous transluminal angioplasty improves blood pressure and stenotic kidney function in selected groups of patients, but the reversibility of intrarenal and microvascular remodeling remains unknown. Here, we tested the hypothesis that renal angioplasty improves the function and structure of renal microcirculation in experimental chronic renal artery stenosis. Stenotic kidney function, hemodynamics, and endothelial function were assessed in vivo in pigs after 10 weeks of unilateral renal artery stenosis. Renal microvascular remodeling, angiogenic pathways, and fibrosis were measured ex vivo. Angioplasty and stenting carried out 4 weeks before measurement decreased blood pressure, improved glomerular filtration rate, and improved microvascular endothelial function. It also promoted the expression of angiogenic factors and decreased renal apoptosis due to stenosis, compared with a sham intervention. The spatial density of renal microvessels, however, was partially improved after angioplasty. Renal blood flow was incompletely restored compared with the kidneys of sham-treated animals, as was interstitial fibrosis. Renal microvascular media-to-lumen ratio remained unchanged by angioplasty. Thus, our study shows that revascularization of a stenotic renal artery restores the glomerular filtration rate and renal endothelial function 4 weeks later. Renal hemodynamics and structure, however, are incompletely resolved.

In vitro renal cortex elasticity and viscosity measurements with Shearwave Dispersion Ultrasound Vibrometry (SDUV) on swine kidney.

Renal fibrosis threatens kidney viability and fibrosis has been associated with altered tissue structure affecting the biomechanical properties of the kidney, quantifiable as elasticity and viscosity. Importantly, early detection of renal fibrosis may guide therapy and eliminate invasive biopsy procedures. The ability to detect fibrosis early and monitor it regularly with sufficient sensitivity and specificity is an active area of research. A newly emerging method called Shearwave Dispersion Ultrasound Vibrometry (SDUV), that quantifies both elasticity and viscosity by evaluating dispersion of shear wave propagation speed versus its frequency, offers a potential tool to determine renal elasticity and viscosity in vivo. The purpose of this study was to evaluate the feasibility of SDUV for in vitro measurements of renal cortex elasticity and viscosity in the kidney.

Increased hypoxia and reduced renal tubular response to furosemide detected by BOLD magnetic resonance imaging in swine renovascular hypertension.

Oxygen consumption beyond the proximal tubule is mainly determined by active solute reabsorption, especially in the thick ascending limb of the Loop of Henle. Furosemide-induced suppression of oxygen consumption (FSOC) involves inhibition of sodium transport in this segment, which is normally accompanied by a marked decrease in the intrarenal deoxyhemoglobin detectable by blood oxygen level-dependent (BOLD)-magnetic resonance imaging (MRI). This study tested the hypothesis that the magnitude of BOLD-MRI signal change after furosemide is related to impaired renal function in renovascular hypertension. In 16 pigs with unilateral renal artery stenosis, renal hemodynamics, function, and tubular function (FSOC and fluid concentration capacity) were evaluated in both kidneys using MR and multidetector computerized tomography (MDCT) imaging. Animals with adequate FSOC (23.6 +/- 2.2%, P > 0.05 vs. baseline) exhibited a mean arterial pressure (MAP) of 113 +/- 7 mmHg, and relatively preserved glomerular filtration rate (GFR) of 60 +/- 4.5 ml/min, comparable to their contralateral kidney (66 +/- 4 ml/min, P > 0.05). In contrast, animals with low FSOC (3.1 +/- 2.1%, P = NS vs. baseline) had MAP of 124 +/- 9 mmHg and GFR (22 +/- 6 ml/min) significantly lower than the contralateral kidneys (66 +/- 4 ml/min, P < 0.05). The group with preserved GFR and FSOC showed an increase in intratubular fluid concentration as assessed by MDCT that was greater than that observed in the low GFR group, suggesting better preservation of tubular function in the former group. These results suggest that changes in BOLD-MRI after furosemide can differentiate between underperfused kidneys with preserved tubular function and those with tubular dysfunction. This approach may allow more detailed physiologic evaluation of poststenotic kidneys in renovascular hypertension than previously possible.

Regional decreases in renal oxygenation during graded acute renal arterial stenosis: a case for renal ischemia.

Ischemic nephropathy describes progressive renal failure, defined by significantly reduced glomerular filtration rate, and may be due to renal artery stenosis (RAS), a narrowing of the renal artery. It is unclear whether ischemia is present during RAS since a decrease in renal blood flow (RBF), O(2) delivery, and O(2) consumption occurs. The present study tests the hypothesis that despite proportional changes in whole kidney O(2) delivery and consumption, acute progressive RAS leads to decreases in regional renal tissue O(2). Unilateral acute RAS was induced in eight pigs with an extravascular cuff. RBF was measured with an ultrasound flow probe. Cortical and medullary tissue oxygen (P(t(O(2)))) of the stenotic kidney was measured continuously with sensors during baseline, three sequentially graded decreases in RBF, and recovery. O(2) consumption decreased proportionally to O(2) delivery during the graded stenosis (19 +/- 10.8, 48.2 +/- 9.1, 58.9 +/- 4.7 vs. 15.1 +/- 5, 35.4 +/- 3.5, 57 +/- 2.3%, respectively) while arterial venous O(2) differences were unchanged. Acute RAS produced a sharp reduction in O(2) efficiency for sodium reabsorption (P < 0.01). Cortical (P(t(O(2)))) decreases are exceeded by medullary decreases during stenosis (34.8 +/- 1.3%). Decreases in tissue oxygenation, more pronounced in the medulla than the cortex, occur despite proportional reductions in O(2) delivery and consumption. This demonstrates for the first time that hypoxia is present in the early stages of RAS and suggests a role for hypoxia in the pathophysiology of this disease. Furthermore, the notion that arteriovenous shunting and increased stoichiometric energy requirements are potential contributors toward ensuing hypoxia with graded and progressive acute RAS cannot be excluded.

Bayesian tracking of a nonlinear model of the capnogram.

Capnography, the monitoring of expired carbon dioxide (CO2) has been employed clinically as a non-invasive measure for the adequacy of ventilation of the alveoli of the lung. In combination with air flow measurements, the capnogram can be used to estimate the partial pressure of CO2 in the alveolar sacs. In addition, physiologically relevant parameters, such as the extent of CO2 rebreathing, the airway dead space, and the metabolic CO2 production can be predicted. To calculate these parameters, mathematical models have been previously formulated and applied to experimental data using off-line optimization procedures. Unfortunately, this does not permit online identification of the capnogram to detect changes in the physiological model parameters. In the present study, a Bayesian method for breath-by-breath identification of the volumetric capnogram is presented. The method integrates a model of CO2 exchange in the lungs, which is nonlinear due to the nature of human tidal breathing, with a particle filtering algorithm for estimation of the model parameters and changes therein. In addition, this allowed for a dynamic prediction of the unmeasured alveolar CO2 tension. The method is demonstrated using simulations of the capnogram. The proposed method could aid the clinician in the interpretation of the capnogram.