Linear energy transfer dependent variation in viability and proliferation along the Bragg peak curve in sarcoma and normal tissue cells.

OBJECTIVE: The energy deposition of photons and protons differs. It depends on the position in the proton Bragg peak (BP) and the linear energy transfer (LET) leading to a variable relative biological effectiveness (RBE). Here, we investigate LET dependent alterations on metabolic viability and proliferation of sarcoma and endothelium cell lines following proton irradiation in comparison to photon exposure. Approach: Using a multi-step range shifter (MSRS), each column of a 96-well plate was positioned in a different depth along four BP curves with increasing intensities. The high-throughput experimental setup covers dose, LET, and RBE changes seen in a treatment field. Photon irradiation was performed to calculate the RBE along the BP curve. Two biological information out of one experiment were extracted allowing a correlation between metabolic viability and proliferation of the cells. Main results: The metabolic viability and cellular proliferation were column-wise altered showing a depth-dose profile. Endothelium cell viability recovers within 96 h post BP irradiation while sarcoma cell viability remains reduced. Highest RBE values were observed at the BP distal fall-off regarding proliferation of the sarcoma and endothelial cells. Significance: The high-throughput experimental setup introduced here I) covers dose, LET, and RBE changes seen in a treatment field, II) measures short-term effects within 48 h to 96 h post irradiation, and III) can additionally be transferred to various cell types without time consuming experimental adaptations. Traditionally, RBE values are calculated from clonogenic cell survival. Measured RBE profiles strongly depend on physical characteristics such as dose and LET and biological characteristics for example cell type and time point. Metabolic viability and proliferation proofed to be in a similar effect range compared to clonogenic survival results. Based on limited data of combined irradiation with doxorubicin, future experiments will test combined treatment with systemic therapies applied in clinics e.g. cyclin-dependent inhibitors. .

Optimal length and temporal resolution of dynamic contrast-enhanced MR imaging for the differentiation between prostate cancer and normal peripheral zone tissue.

The value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the detection of prostate cancer is controversial. There are currently insufficient peer reviewed published data or expert consensus to support routine adoption of DCE-MRI for clinical use. Thus, the objective of this study was to explore the optimal temporal resolution and measurement length for DCE-MRI to differentiate cancerous from normal prostate tissue of the peripheral zone of the prostate by non-parametric MRI analysis and to compare with a quantitative MRI analysis. Predictors of interest were onset time, relative signal intensity (RSI), wash-in slope, peak enhancement, wash-out and wash-out slope determined from non-parametric characterisation of DCE-MRI intensity-time profiles. The discriminatory power was estimated from C-statistics based on cross validation. We analyzed 54 patients with 97 prostate tissue specimens (47 prostate cancer, 50 normal prostate tissue) of the peripheral zone, mean age 63.8 years, mean prostate-specific antigen 18.9 ng/mL and mean of 10.5 days between MRI and total prostatectomy. When comparing prostate cancer tissue with normal prostate tissue, median RSI was 422% vs 330%, and wash-in slope 0.870 vs 0.539. The peak enhancement of 67 vs 42 was higher with prostate cancer tissue, while wash-out (-30% vs -23%) and wash-out slope (-0.037 vs -0.029) were lower, and the onset time (32 seconds) was comparable. The optimal C-statistics was 0.743 for temporal resolution of 8.0 seconds and measurement length of 2.5 minutes compared with 0.656 derived from a quantitative MRI analysis. This study provides evidence that the use of a non-parametric approach instead of a more established parametric approach resulted in greater precision to differentiate cancerous from normal prostate tissue of the peripheral zone of the prostate.

Fractional calculus tracer kinetic compartment model for quantification of microvascular perfusion.

Objective. We evaluate a tracer kinetic model for quantification of physiological perfusion and microvascular residue time kurtosis (RTK) in skeletal muscle vasculature with first pass bolus experiments in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).Approach. A decreasing stretched Mittag-Leffler function (f1C model) was obtained as the impulse response solution of a rate equation of real-valued ('fractional') derivation order. The method was validated in skeletal muscle in the lower limb of seven female pigs examined by DCE-MRI. Dynamic imaging during blood pool contrast agent elimination was performed using a 3D gradient echo sequence with k-space sharing. Blood flow was augmented by continuous infusion of the vasodilator adenosine into the femoral artery increasing blood flow up to four times. Blood flow measured by a Doppler flow probe placed at the femoral artery served as ground truth.Main results. Goodness of fit and correlation with the Doppler measurements,r= 0.80 (P< 0.001), of the 4-parameter f1C model was comparable with the results obtained with a previously tested 6-parameter two-compartment (2C) model. The derivation orderαof the f1C model can be interpreted as a measure of microvascular RTK. With increasing blood flow,αdropped significantly, leading to an increase in RTK.Significance. The f1C model is a practical approach based on hemodynamic principles to quantify physiological microvascular perfusion but it is impaired due to its compartmental nature.

Dosimetric impact of the positioning variation of tumor treating field electrodes in the PriCoTTF-phase I/II trial.

PURPOSE: The aim of the present study based on the PriCoTTF-phase I/II trial is the quantification of skin-normal tissue complication probabilities of patients with newly diagnosed glioblastoma multiforme treated with Tumor Treating Field (TTField) electrodes, concurrent radiotherapy, and temozolomide. Furthermore, the skin-sparing effect by the clinically applied strategy of repetitive transducer array fixation around their center position shall be examined. MATERIAL AND METHODS: Low-dose cone-beam computed tomography (CBCT) scans of all fractions of the first seven patients of the PriCoTTF-phase I/II trial, used for image guidance, were applied for the dosimetric analysis, for precise TTField transducer array positioning and contour delineation. Within this trial, array positioning was varied from fixation-to-fixation period with a standard deviation of 1.1 cm in the direction of the largest variation of positioning and 0.7 cm in the perpendicular direction. Physical TTField electrode composition was examined and a respective Hounsfield Unit attributed to the TTField electrodes. Dose distributions in the planning CT with TTField electrodes in place, as derived from prefraction CBCTs, were calculated and accumulated with the algorithm Acuros XB. Dose-volume histograms were obtained for the first and second 2 mm scalp layer with and without migrating electrodes and compared with those with fixed electrodes in an average position. Skin toxicity was quantified according to Lyman's model. Minimum doses in hot-spots of 0.05 cm2 and 25 cm2 ( Δ D0.05cm 2 , Δ D25cm 2 ) size in the superficial skin layers were analyzed. RESULTS: Normal tissue complication probabilities (NTCPs) for skin necrosis ranged from 0.005% to 1.474% (median 0.111%) for the different patients without electrodes. NTCP logarithms were significantly dependent on patient (P < 0.0001) and scenario (P < 0.0001) as classification variables. Fixed positioning of TTField arrays increased skin-NTCP by a factor of 5.50 (95%, CI: 3.66-8.27). The variation of array positioning increased skin-NTCP by a factor of only 3.54 (95%, CI: 2.36-5.32) (P < 0.0001, comparison to irradiation without electrodes; P = 0.036, comparison to irradiation with fixed electrodes). NTCP showed a significant rank correlation with D25cm2 over all patients and scenarios (rs  = 0.76; P < 0.0001). CONCLUSION: Skin-NTCP calculation uncovers significant interpatient heterogeneity and may be used to stratify patients into high- and low-risk groups of skin toxicity. Array position variation may mitigate about one-third of the increase in surface dose and skin-NTCP by the TTField electrodes.

Liver function quantification of patients with portal vein embolization using dynamic contrast-enhanced MRI for assessment of hepatocyte uptake and elimination.

PURPOSE: We evaluated pharmacokinetic models which quantify liver function including biliary elimination based on a dynamic Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) technique with sparse data collection feasible in clinical routine. METHODS: Twelve patients with embolized liver segments following interventional treatment of primary liver cancer or hepatic metastasis underwent MRI. During Gd-EOB-DTPA bolus administration, a 3D dynamic gradient-echo (GRE) MRI examination was performed over approx. 28 min. Interrupted data sampling was started approx. 5 min after contrast agent administration. Different implementations of dual-inlet models were tested, namely the Euler method (DE) and convolution with residue functions (C). A simple uptake model (U) and an uptake- elimination model (UE) extended by incorporating the biliary contrast agent elimination rate (Ke) were evaluated. RESULTS: The uptake-elimination model, calculated via the simple Euler method (UE- DE) and by convolution (UE-C), yielded similar overall estimates in terms of fitting quality and agreement with published values. The Euler method was approx. 50 times faster and yielded a mean elimination rate of Ke=1.8±1.2mL/(min·100 mL) in nonembolized liver tissue, which was significantly higher (p=8.8·10-4) than in embolized tissue Ke=0.4±0.4 mL/(min·100 mL). Fractional hepatocyte volume vh was not significantly higher in nonembolized tissue (52.4 ± 13.4 mL/100 mL) compared to embolized tissue (44.4 ± 26.1 mL/100 mL). CONCLUSIONS: Interrupted late enhancement MRI data sampling in conjunction with the uptake-elimination model, deconvolved by integration of the differential rate equation and combined with the simple uptake model implemented with the Euler method (U-DE), turned out to be a stable and practical method for reliable noninvasive assessment of liver function.

Combined morphological and functional liver MRI using spin-lattice relaxation in the rotating frame (T1ρ) in conjunction with Gadoxetic Acid-enhanced MRI.

Noninvasive early detection of liver cirrhosis and fibrosis is essential for management and therapy. The aim was to investigated whether a combination of the functional parameter relative enhancement (RE) on Gadoxetic Acid magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) and the fibrosis parameter T1ρ distinguishes cirrhosis and healthy liver. We analyzed patients with Gd-EOB-DTPA-enhanced MRI and T1ρ mapping. Signal intensity was measured before and after contrast; RE was calculated. T1ρ was measured with circular regions of interest (T1ρ-cROI). A quotient of RE and T1ρ-cROI was calculated: the fibrosis function quotient (FFQ). Cirrhosis was evaluated based on morphology and secondary changes. 213 datasets were included. The difference between cirrhotic and noncirrhotic liver was 51.11 ms vs. 47.56 ms for T1ρ-cROI (p < 0.001), 0.59 vs. 0.70 for RE (p < 0.001), and 89.53 vs. 70.83 for FFQ (p < 0.001). T1ρ-cROI correlated with RE, r = -0.14 (p < 0.05). RE had an AUC of 0.73. The largest AUC had the FFQ with 0.79. The best cutoff value was 48.34 ms for T1ρ-cROI, 0.70 for RE and 78.59 ms for FFQ. In conclusion T1ρ and RE can distinguish between cirrhotic and noncirrhotic liver. The FFQ, which is the combination of the two, improves diagnostic performance.

Simultaneous multislice acquisition with multi-contrast segmented EPI for separation of signal contributions in dynamic contrast-enhanced imaging.

We present a method to efficiently separate signal in magnetic resonance imaging (MRI) into a base signal S0, representing the mainly T1-weighted component without T2*-relaxation, and its T2*-weighted counterpart by the rapid acquisition of multiple contrasts for advanced pharmacokinetic modelling. This is achieved by incorporating simultaneous multislice (SMS) imaging into a multi-contrast, segmented echo planar imaging (EPI) sequence to allow extended spatial coverage, which covers larger body regions without time penalty. Simultaneous acquisition of four slices was combined with segmented EPI for fast imaging with three gradient echo times in a preclinical perfusion study. Six female domestic pigs, German-landrace or hybrid-form, were scanned for 11 minutes respectively during administration of gadolinium-based contrast agent. Influences of reconstruction methods and training data were investigated. The separation into T1- and T2*-dependent signal contributions was achieved by fitting a standard analytical model to the acquired multi-echo data. The application of SMS yielded sufficient temporal resolution for the detection of the arterial input function in major vessels, while anatomical coverage allowed perfusion analysis of muscle tissue. The separation of the MR signal into T1- and T2*-dependent components allowed the correction of susceptibility related changes. We demonstrate a novel sequence for dynamic contrast-enhanced MRI that meets the requirements of temporal resolution (Δt < 1.5 s) and image quality. The incorporation of SMS into multi-contrast, segmented EPI can overcome existing limitations of dynamic contrast enhancement and dynamic susceptibility contrast methods, when applied separately. The new approach allows both techniques to be combined in a single acquisition with a large spatial coverage.

Evaluation of pharmacokinetic models for perfusion imaging with dynamic contrast-enhanced magnetic resonance imaging in porcine skeletal muscle using low-molecular-weight contrast agents.

PURPOSE: Pharmacokinetic models for perfusion quantification with a low-molecular-weight contrast agent (LMCA) in skeletal muscle using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were evaluated. METHODS: Tissue perfusion was measured in seven regions of interest (ROIs) placed in the total hind leg supplied by the femoral artery in seven female pigs. DCE-MRI was performed using a 3D gradient echo sequence with k-space sharing. The sequence was acquired twice, first after LMCA and then after blood pool contrast agent injection. Blood flow was augmented by continuous infusion of the vasodilator adenosine into the femoral artery, resulting in up to four times increased blood flow. The results obtained with several LMCA models were compared with those of a two-compartment blood pool model (2CBPM) consisting of a capillary and an arteriolar compartment. Measurements performed with a Doppler flow probe placed at the femoral artery served as ground truth. RESULTS: The two-compartment exchange model extended by an arteriolar compartment (E2CXM) showed the highest fit quality of all LMCA models and the most significant correlation with the Doppler measurements, r = 0.78 (P < 0.001). The best correspondence between the capillary perfusion measurements of the LMCA models and those of the 2CBPM was found with the E2CXM (slope of the regression line equal to 1, r = 0.85, P < 0.001). The results for the clinical patient data corresponded very well with the results obtained in the animal experiments. CONCLUSIONS: Double-contrast agent DCE-MRI in combination with the E2CXM yields the most reliable results and can be used in clinical routine. Magn Reson Med 79:3154-3162, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Assessment of micronecrotic tumor tissue using dynamic contrast-enhanced magnetic resonance imaging.

Compartmental models for evaluation of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) datasets assume a homogeneous interstitital volume distribution and homogeneous contrast agent (CA) distribution within each compartment, neglecting effects of CA diffusion within the compartments. When necrotic or micronecrotic tumor tissue is present, these assumptions may no longer be valid. Therefore, the present study investigates the validity of three compartmental models in assessing tumors with necrotic components. The general diffusion equation for inhomogeneous tissue was used to simulate the extravasation of a low-molecular-weight contrast agent from a feeding vessel into the interstitial space. The simulated concentration-time curves were evaluated using the extended Tofts model, a parallel 3-compartment model, and a sequential 3-compartment model. The extended Tofts model overestimated the interstitial volume fraction by a median of 6.9% resp. 10.0% and the parallel 3-compartment model by 8.6% resp. 15.5%, while the sequential 3-compartment model overestimated it by 0.2% resp. underestimated it by 18.8% when simulating a mean vessel distance of 100µm resp. 150µm. Overall, the sequential 3-compartment model provided more reliable results both for the total fractional interstitial volume and for the interstitial subcompartments.

Validation of Blood Volume Fraction Quantification with 3D Gradient Echo Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Porcine Skeletal Muscle.

The purpose of this study was to assess the accuracy of fractional blood volume (vb) estimates in low-perfused and low-vascularized tissue using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The results of different MRI methods were compared with histology to evaluate the accuracy of these methods under clinical conditions. vb was estimated by DCE-MRI using a 3D gradient echo sequence with k-space undersampling in five muscle groups in the hind leg of 9 female pigs. Two gadolinium-based contrast agents (CA) were used: a rapidly extravasating, extracellular, gadolinium-based, low-molecular-weight contrast agent (LMCA, gadoterate meglumine) and an extracellular, gadolinium-based, albumin-binding, slowly extravasating blood pool contrast agent (BPCA, gadofosveset trisodium). LMCA data were evaluated using the extended Tofts model (ETM) and the two-compartment exchange model (2CXM). The images acquired with administration of the BPCA were used to evaluate the accuracy of vb estimation with a bolus deconvolution technique (BD) and a method we call equilibrium MRI (EqMRI). The latter calculates the ratio of the magnitude of the relaxation rate change in the tissue curve at an approximate equilibrium state to the height of the same area of the arterial input function (AIF). Immunohistochemical staining with isolectin was used to label endothelium. A light microscope was used to estimate the fractional vascular area by relating the vascular region to the total tissue region (immunohistochemical vessel staining, IHVS). In addition, the percentage fraction of vascular volume was determined by multiplying the microvascular density (MVD) with the average estimated capillary lumen, [Formula: see text], where d = 8µm is the assumed capillary diameter (microvascular density estimation, MVDE). Except for ETM values, highly significant correlations were found between most of the MRI methods investigated. In the cranial thigh, for example, the vb medians (interquartile range, IQRs) of IHVS, MVDE, BD, EqMRI, 2CXM and ETM were vb = 0.7(0.3)%, 1.1(0.4)%, 1.1(0.4)%, 1.4(0.3)%, 1.2(1.8)% and 0.1(0.2)%, respectively. Variances, expressed by the difference between third and first quartiles (IQR) were highest for the 2CXM for all muscle groups. High correlations between the values in four muscle groups-medial, cranial, lateral thigh and lower leg - estimated with MRI and histology were found between BD and EqMRI, MVDE and 2CXM and IHVS and ETM. Except for the ETM, no significant differences between the vb medians of all MRI methods were revealed with the Wilcoxon rank sum test. The same holds for all muscle regions using the 2CXM and MVDE. Except for cranial thigh muscle, no significant difference was found between EqMRI and MVDE. And except for the cranial thigh and the lower leg muscle, there was also no significant difference between the vb medians of BD and MVDE. Overall, there was good vb agreement between histology and the BPCA MRI methods and the 2CXM LMCA approach with the exception of the ETM method. Although LMCA models have the advantage of providing excellent curve fits and can in principle determine more physiological parameters than BPCA methods, they yield more inaccurate results.

Does IIH Alter Brain Microstructures? - A DTI-Based Approach.

INTRODUCTION: To investigate the correlation of microstructural parameters with CSF pressure and macroscopic changes assessed by diffusion tensor imaging (DTI) in patients with idiopathic intracranial hypertension (IIH). METHODS: Twenty-three patients with IIH as well as age-, sex-, and body mass index (BMI)-matched controls underwent high resolution MR imaging of the optic nerve sheaths (ONS), pituitary gland, and ventricles. For DTI data a voxelwise permutation analysis was performed for the whole brain and ROI analysis was performed for the optic nerve and optic radiation. DTI measurements were correlated to morphometric measurements, CSF opening pressure, and headache intensity. The reliability of diagnostic performance of DTI parameters was assessed using ROC analysis. RESULTS: Analysis of DTI metrics revealed a significant reduction in the fractional anisotropy (FA) of the optic nerve in patients with IIH. In contrast, systematic regional variations between IIH patients and controls were neither observed in the whole brain analysis nor in the optic radiation. FA values of the optic nerve show significant correlations with the optic nerve sheath diameter (P = .003, r = -.589). The correlation of the alterations of the FA values of the optic radiation and the whole brain do not show a significant association to morphometric alterations in the ONS diameter and hypophysis height as well as to CSF opening pressure and headache intensity. CONCLUSIONS: The results indicate that IIH is associated with microstructural changes in the optic nerve. These alterations may be the direct consequence of chronically elevated intracranial pressure.

Validation of Interstitial Fractional Volume Quantification by Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Porcine Skeletal Muscles.

OBJECTIVES: The aim of our study was to assess the accuracy of fractional interstitial volume determination in low perfused and low vascularized tissue by using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: The fractional interstitial volume (ve) was determined in the medial thigh muscle of 12 female pigs by using a 3-dimensional gradient echo sequence with k-space sharing and administering gadolinium-based contrast agent (gadoterate meglumine). Analysis was performed using 3 pharmacokinetic models: the simple Tofts model (TM), the extended TM (ETM), and the 2-compartment exchange model (2CXM). We investigated the effect of varying acquisition durations (ADs) on the model parameter estimates of the 3 models and compared the ve values with the results of histological examinations of muscle sections of the medial thigh muscle. RESULTS: Histological measurements yielded a median value (25%-75% quartile) of 4.8% (3.7%-6.2%) for ve. The interstitial fractional volume determined by DCE-MRI was comparable to the histological results but varied strongly with AD for the TM and ETM. For the TM and the ETM, the results were virtually the same. Choosing arterial hematocrit to Hcta = 0.4, the lowest median ve value determined by DCE-MRI was 5.2% (3.3%-6.1%) for the ETM at a 6-minute AD. The maximum ve value determined with the ETM at a 15-minute AD was 7.7% (4.5%-9.0%). The variation with AD of median ve values obtained with the 2CXM was much smaller: 6.2% (3.1%-9.2%) for the 6-minute AD and 6.3% (4.3%-9.8%) for the 15-minute AD. The best fit for the 2CXM was found at the 10-minute AD with ve values of 6.6% (3.7%-8.2%). No significant correlation between the histological and any DCE-MRI modeling results was found. Considering the expected accuracy of histological measurements, the medians of the MR modeling results were in good agreement with the histological prediction. A parameter determination uncertainty was identified with the use of the TMs. This is due to underfitting and has a major effect even on the analysis of tissues with low vascularization and low perfusion, where the estimated ve values depend on the AD. For the TM and ETM, the results best matched the histological measurements for an AD of 6 minutes. CONCLUSIONS: Owing to more fitting parameters, the 2CXM yielded better fits and the median interstitium-to-plasma rate constant kep was less depending on the AD; however, the uncertainty expressed by the 25% to 75% quartile range was found to be larger. An AD of 10 minutes was needed for the 2CXM to achieve accuracy comparable to those of the TMs with shorter ADs.

Gd-EOB-DTPA-enhanced MRI for monitoring future liver remnant function after portal vein embolization and extended hemihepatectomy: A prospective trial.

OBJECTIVES: To evaluate changes in liver function after right portal vein embolization (PVE) and extended right hemihepatectomy using gadolinium ethoxybenzyl-DTPA-enhanced (Gd-EOB-DTPA) MRI. METHODS: In this prospective trial, 37 patients undergoing PVE were examined before and 14 and 28 days after PVE and 10 days after extended hemihepatectomy using Gd-EOB-DTPA-enhanced MRI. Lobar volume, kinetic growth rate (KGR), relative enhancement (RE) as well as hepatocellular uptake index (HUI) and fat signal fraction (FSF) were calculated for each lobe. RESULTS: RE of the left liver lobe (LLL) was steadily increasing after PVE and decreased to 0.48 ± 0.19 10 days after surgery, which is significantly lower than 14 days and 28 days post PVE (P < 0.05). KGR was 14.06 ± 9.82%/week for the period from PVE to 14 days after PVE. HUI of the LLL increased steadily after PVE and was significantly higher at both 14 and 28 days after PVE compared to pre PVE (P < 0.05). HUI of the residual liver after surgery was lower than before. CONCLUSIONS: Gd-EOB-DTPA-enhanced MRI may be used to monitor the functional increase in the FLR after PVE and to depict the intraoperative liver injury leading to a decrease in liver remnant function. KEY POINTS: • The most significant FLR volume increase happens within the first 14 days. • No MRI parameter was able to predict the success of FLR growth. • Our data suggest an early resection about 14 days after PVE. • Routine Gd-EOB-DTPA-enhanced MRI might be suitable to replace ICG-test.

Targeted Inhibition of Glutamine-Dependent Glutathione Metabolism Overcomes Death Resistance Induced by Chronic Cycling Hypoxia.

AIMS: Tumor hypoxia is a major biological factor causing poor patient outcome. Evidence is increasing that improved protection against reactive oxygen species (ROS) participates in therapy resistance of chronically hypoxic cancer cells. We aimed at characterizing the relevance of improved ROS defense for radiation resistance of cancer cells with tolerance to cycling anoxia/re-oxygenation stress ("anoxia-tolerant") and at designing rational treatment strategies for overcoming the resulting therapy resistance by targeting the underlying mechanisms identified in an in vitro model. RESULTS: We demonstrate that chronic exposure of NCH-H460 lung adenocarcinoma, DU145 prostate cancer, and T98G glioblastoma cells to cycling anoxia/re-oxygenation stress induced upregulation of the aspartate-aminotransferase glutamic-oxaloacetic transaminase (GOT1), particularly in RAS-driven anoxia-tolerant NCI-H460 cells. Altered glutamine utilization of the anoxia-tolerant cancer cells contributed to the observed decrease in cellular ROS levels, the increase in cellular glutathione levels, and improved cell survival on ROS-inducing treatments, including exposure to ionizing radiation. Importantly, targeting glutamine-dependent antioxidant capacity or glutathione metabolism allowed us to hit anoxia-tolerant cancer cells and to overcome their increased resistance to radiation-induced cell death. Targeting glutathione metabolism by Piperlongumine also improved the radiation response of anoxia-tolerant NCI-H460 cells in vivo. INNOVATION: Improved antioxidant capacity downstream of up-regulated GOT1-expression is a characteristic of anoxia-tolerant cancer cells and is predictive for a specific vulnerability to inhibition of glutamine utilization or glutathione metabolism, respectively. CONCLUSION: Unraveling the molecular alterations underlying improved ROS defense of anoxia-tolerant cancer cells allows the design of rational strategies for overcoming radiation resistance caused by tumor cell heterogeneity in hypoxic tumors. Antioxid. Redox Signal. 25, 89-107.

Validation of Perfusion Quantification with 3D Gradient Echo Dynamic Contrast-Enhanced Magnetic Resonance Imaging Using a Blood Pool Contrast Agent in Skeletal Swine Muscle.

The purpose of our study was to validate perfusion quantification in a low-perfused tissue by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with shared k-space sampling using a blood pool contrast agent. Perfusion measurements were performed in a total of seven female pigs. An ultrasonic Doppler probe was attached to the right femoral artery to determine total flow in the hind leg musculature. The femoral artery was catheterized for continuous local administration of adenosine to increase blood flow up to four times the baseline level. Three different stable perfusion levels were induced. The MR protocol included a 3D gradient-echo sequence with a temporal resolution of approximately 1.5 seconds. Before each dynamic sequence, static MR images were acquired with flip angles of 5°, 10°, 20°, and 30°. Both static and dynamic images were used to generate relaxation rate and baseline magnetization maps with a flip angle method. 0.1 mL/kg body weight of blood pool contrast medium was injected via a central venous catheter at a flow rate of 5 mL/s. The right hind leg was segmented in 3D into medial, cranial, lateral, and pelvic thigh muscles, lower leg, bones, skin, and fat. The arterial input function (AIF) was measured in the aorta. Perfusion of the different anatomic regions was calculated using a one- and a two-compartment model with delay- and dispersion-corrected AIFs. The F-test for model comparison was used to decide whether to use the results of the one- or two-compartment model fit. Total flow was calculated by integrating volume-weighted perfusion values over the whole measured region. The resulting values of delay, dispersion, blood volume, mean transit time, and flow were all in physiologically and physically reasonable ranges. In 107 of 160 ROIs, the blood signal was separated, using a two-compartment model, into a capillary and an arteriolar signal contribution, decided by the F-test. Overall flow in hind leg muscles, as measured by the ultrasound probe, highly correlated with total flow determined by MRI, R = 0.89 and P = 10-7. Linear regression yielded a slope of 1.2 and a y-axis intercept of 259 mL/min. The mean total volume of the investigated muscle tissue corresponds to an offset perfusion of 4.7mL/(min ⋅ 100cm3). The DCE-MRI technique presented here uses a blood pool contrast medium in combination with a two-compartment tracer kinetic model and allows absolute quantification of low-perfused non-cerebral organs such as muscles.

Accuracy of applicator tip reconstruction in MRI-guided interstitial 192Ir-high-dose-rate brachytherapy of liver tumors.

BACKGROUND AND PURPOSE: To evaluate the reconstruction accuracy of brachytherapy (BT) applicators tips in vitro and in vivo in MRI-guided (192)Ir-high-dose-rate (HDR)-BT of inoperable liver tumors. MATERIALS AND METHODS: Reconstruction accuracy of plastic BT applicators, visualized by nitinol inserts, was assessed in MRI phantom measurements and in MRI (192)Ir-HDR-BT treatment planning datasets of 45 patients employing CT co-registration and vector decomposition. Conspicuity, short-term dislocation, and reconstruction errors were assessed in the clinical data. The clinical effect of applicator reconstruction accuracy was determined in follow-up MRI data. RESULTS: Applicator reconstruction accuracy was 1.6±0.5 mm in the phantom measurements. In the clinical MRI datasets applicator conspicuity was rated good/optimal in ⩾72% of cases. 16/129 applicators showed not time dependent deviation in between MRI/CT acquisition (p>0.1). Reconstruction accuracy was 5.5±2.8 mm, and the average image co-registration error was 3.1±0.9 mm. Vector decomposition revealed no preferred direction of reconstruction errors. In the follow-up data deviation of planned dose distribution and irradiation effect was 6.9±3.3 mm matching the mean co-registration error (6.5±2.5 mm; p>0.1). CONCLUSION: Applicator reconstruction accuracy in vitro conforms to AAPM TG 56 standard. Nitinol-inserts are feasible for applicator visualization and yield good conspicuity in MRI treatment planning data. No preferred direction of reconstruction errors were found in vivo.

Imaging-based evaluation of liver function: comparison of 99mTc-mebrofenin hepatobiliary scintigraphy and Gd-EOB-DTPA-enhanced MRI.

OBJECTIVES: To compare Gd-EOB-enhanced MRI and (99m)Tc-mebrofenin hepatobiliary scintigraphy (HBS) as imaging-based liver function tests for separate evaluation of right (RLL) and left liver lobe (LLL) function. METHODS: Fourteen patients underwent Gd-EOB-enhanced MRI and (99m)Tc-mebrofenin HBS after portal vein embolization within 24 h. Relative enhancement (RE) and hepatic uptake index (HUI) were determined from MRI; and T max, T 1/2 and mebrofenin uptake were determined from HBS, all values separately for RLL and LLL. RESULTS: Mebrofenin uptake correlated significantly with HUI and RE for both liver lobes. There was strong correlation of mebrofenin uptake with HUI for RLL (r (2) = 0.802, p = 0.001) and RE for LLL (r (2) = 0.704, p = 0.005) and moderate correlation with HUI for LLL (r (2) = 0.560, p = 0.037) and RE for RLL (r (2) = 0.620, p = 0.018). Correlating the percentage share of RLL function derived from MRI (with HUI) with the percentage of RLL function derived from mebrofenin uptake revealed a strong correlation (r (2) = 0.775, p = 0.002). CONCLUSIONS: Both RE and HUI correlate with mebrofenin uptake in HBS. The results suggest that Gd-EOB-enhanced MRI and (99m)Tc-mebrofenin HBS may equally be used to separately determine right and left liver lobe function. KEY POINTS: • Information about liver function can be acquired with routine Gd-EOB-MRI. • Gd-EOB-MRI and (99m) Tc-mebrofenin HBS show elevated function of non-embolized lobe. • Gd-EOB-MRI and (99m) Tc-mebrofenin HBS can determine lobar liver function.

Tract-based spatial statistics of the olfactory brain in patients with multiple sclerosis.

PURPOSE: To investigate diffusion tensor abnormalities, e.g. fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD), in olfactory structures of multiple sclerosis (MS) patients using diffusion tensor imaging (DTI). METHODS: Institutional review board-approved prospective study on 30 MS patients and 12 healthy controls investigated with MRI including DTI. Central olfactory structures were labelled on each patient's and healthy contro''s DTI volume. The diffusion tensor was determined in the central olfactory structures in MS patients. Tract-based spatial statistics (TBSS) was used to quantify the streamlines outgoing from the olfactory structures and to quantify changes in FA, MD, and RD within olfactory structures. These brain changes were correlated with olfactory function measured as TDI (Threshold, Discrimination, Identification) scores in patients and compared to our own reference group of 30 healthy volunteers. RESULTS: Central olfactory structures in the MNI (Montreal Neurological Institute) data volume comprise 4808 voxels (4808 mm(3)). TFCE (Threshold-free cluster enhancement) and cluster analysis of patients identified a total of 127 voxels in one cluster with a significantly decreased FA (p<0.05) and none for MD and RD within olfactory structures compared to healthy controls. The correlation with the age-normalised Identification subscore of the TDI score increased the significant number of voxels with decreased FA to 208 voxels, with increased MD to 370 and with increased RD 364 voxels at the same region. CONCLUSION: The decrease in FA and increase of MD and RD correlate with the degree of identification impairment of olfactory function in MS patients and clusters of abnormalities were identified on a MNI data volume.

Optimized separation of left and right liver lobe in dynamic (99m)Tc-mebrofenin hepatobiliary scintigraphy using a hybrid SPECT-CT scanner.

OBJECTIVE: To correctly display the left and right liver lobe separately on dynamic projection scintigraphy, it is essential to adjust the collimator to the angle of the plane between the two liver lobes. We propose an optimized protocol for separating left and right liver lobe in (99m)Tc-mebrofenin hepatobiliary scintigraphy in a hybrid SPECT-CT device. The protocol uses the inherent attenuation correction low-dose CT (AC-CT) for individually adjusting gamma camera head angulation. The results of this protocol are compared with hypothetical results based on previous MRI, fixed angle, and traditional frontal projection. METHODS: The absolute and relative degrees of overlapping volume between left and right liver lobe parenchyma for frontal projection, 45° right anterior oblique (RAO) projection, RAO angulation based on previously acquired MRI, and RAO based on the AC-CT were measured in 14 patients who underwent (99m)Tc-mebrofenin hepatobiliary scintigraphy. RESULTS: Relative degree of overlap was 31.3 ± 15.2 % for frontal projection, 8.2 ± 6.5 % for 45° RAO, 5.5 ± 3.5 % for RAO based on previous MRI, and 3.6 ± 2.5 % for RAO based on AC-CT. The relative overlap of RAO projections based on previous MRI was significantly lower than for frontal projection (p < 0.05). Use of the angle from the prior AC-CT, however, resulted in an even lower degree of overlap (p < 0.05). CONCLUSIONS: Performing (99m)Tc-mebrofenin hepatobiliary scintigraphy using RAO detector alignment with an angle derived from a prior CT obtained in the SPECT-CT scanner can significantly reduce the degree of overlap between right and left liver lobe. If SPECT-CT is not available, previous CT or MRI or a fixed angle of 45° may be used.