First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure.

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.

Diagnostic Performance in Low- and High-Contrast Tasks of an Image-Based Denoising Algorithm Applied to Radiation Dose-Reduced Multiphase Abdominal CT Examinations.

BACKGROUND. Anatomic redundancy between phases can be used to achieve denoising of multiphase CT examinations. A limitation of iterative reconstruction (IR) techniques is that they generally require use of CT projection data. A frequency-split multi-band-filtration algorithm applies denoising to the multiphase CT images themselves. This method does not require knowledge of the acquisition process or integration into the reconstruction system of the scanner, and it can be implemented as a supplement to commercially available IR algorithms. OBJECTIVE. The purpose of the present study is to compare radiologists' performance for low-contrast and high-contrast diagnostic tasks (i.e., tasks for which differences in CT attenuation between the imaging target and its anatomic background are subtle or large, respectively) evaluated on multiphase abdominal CT between routine-dose images and radiation dose-reduced images processed by a frequency-split multiband-filtration denoising algorithm. METHODS. This retrospective single-center study included 47 patients who underwent multiphase contrast-enhanced CT for known or suspected liver metastases (a low-contrast task) and 45 patients who underwent multiphase contrast-enhanced CT for pancreatic cancer staging (a high-contrast task). Radiation dose-reduced images corresponding to dose reduction of 50% or more were created using a validated noise insertion technique and then underwent denoising using the frequency-split multi-band-filtration algorithm. Images were independently evaluated in multiple sessions by different groups of abdominal radiologists for each task (three readers in the low-contrast arm and four readers in the high-contrast arm). The noninferiority of denoised radiation dose-reduced images to routine-dose images was assessed using the jackknife alternative free-response ROC (JAFROC) figure-of-merit (FOM; limit of noninferiority, -0.10) for liver metastases detection and using the Cohen kappa statistic and reader confidence scores (100-point scale) for pancreatic cancer vascular invasion. RESULTS. For liver metastases detection, the JAFROC FOM for denoised radiation dose-reduced images was 0.644 (95% CI, 0.510-0.778), and that for routine-dose images was 0.668 (95% CI, 0.543-0.792; estimated difference, -0.024 [95% CI, -0.084 to 0.037]). Intraobserver agreement for pancreatic cancer vascular invasion was substantial to near perfect when the two image sets were compared (κ = 0.53-1.00); the 95% CIs of all differences in confidence scores between image sets contained zero. CONCLUSION. Multiphase contrast-enhanced abdominal CT images with a radiation dose reduction of 50% or greater that undergo denoising by a frequency-split multiband-filtration algorithm yield performance similar to that of routine-dose images for detection of liver metastases and vascular staging of pancreatic cancer. CLINICAL IMPACT. The image-based denoising algorithm facilitates radiation dose reduction of multiphase examinations for both low- and high-contrast diagnostic tasks without requiring manufacturer-specific hardware or software.

Technical note: Evaluation of artificial 120-kilovolt computed tomography images for radiation therapy applications.

PURPOSE: The purpose of this work is to evaluate the scaled computed tomography (CT) number accuracy of an artificial 120 kV reconstruction technique based on phantom experiments in the context of radiation therapy planning. METHODS: An abdomen-shaped electron density phantom was scanned on a clinical CT scanner capable of artificial 120 kV reconstruction using different tube potentials from 70 to 150 kV. A series of tissue-equivalent phantom inserts (lung, adipose, breast, solid water, liver, inner bone, 30%/50% CaCO3 , cortical bone) were placed inside the phantom. Images were reconstructed using a conventional quantitative reconstruction kernel as well as the artificial 120 kV reconstruction kernel. Scaled CT numbers of inserts were measured from images acquired at different kVs and compared with those acquired at 120 kV, which were deemed as the ground truth. The relative error was quantified as the percentage deviation of scaled CT numbers acquired at different tube potentials from their ground truth values acquired at 120 kV. RESULTS: Scaled CT numbers measured from images reconstructed using the conventional reconstruction demonstrated a strong kV-dependence. The relative error in scaled CT numbers ranged from 0.6% (liver insert) to 31.1% (cortical bone insert). The artificial 120 kV reconstruction reduced the kV dependence, especially for bone tissues. The relative error in scaled CT number was reduced to 0.4% (liver insert) and 2.6% (30% CaCO3 insert) using this technique. When tube potential selection was limited to the range of 90 to 150 kV, the relative error was further restrained to <1.2% for all tissue types. CONCLUSION: Phantom results demonstrated that using the artificial 120 kV technique, it was feasible to acquire raw projection data at the desired tube potential and then reconstruct images with scaled CT numbers comparable to those obtained directly at 120 kV. In radiotherapy applications, this technique may allow optimization of tube potential without complicating clinical workflow by eliminating the necessity of maintaining multiple sets of CT calibration curves.

Characterization of thrombus composition with multimodality CT-based imaging: an in-vitro study.

BACKGROUND: CT is the most commonly used imaging modality for acute ischemic stroke evaluation. There is growing interest to use pre-operative imaging to characterize clot composition in stroke. We performed an in-vitro study examining the ability of various CT techniques in differentiation between different clot types. METHODS: Five clot types with varying fibrin and red blood cells (RBCs) densities (5% RBC and 95% fibrin; 25% RBC and 75% fibrin; 50% RBC and 50% fibrin; 75% RBC and 25% fibrin; 95% RBC and 5% fibrin) were prepared and scanned using various CT scanning protocols (single-energy, dual-energy, photon-counting detector CT, mixed images, and virtual monoenergetic images). Martius Scarlett Blue trichrome staining was performed to confirm the composition of each clot. Mean CT values of each type of clot under different scanning protocol were calculated and compared. RESULTS: Mean CT values of the CT numbers in the five clot specimens for 5%, 25%, and 50% RBC clot were similar across modalities, and increased significantly for 75% and 95% RBC clots (P<0.0001). Mean CT values are highest in the Mono +50 keV images in each type of clot, and they were also significantly higher than all other imaging protocols (P<0.001). Dual-energy CT with Mono +50 keV images showed the greatest difference between attenuation in each type of clot. CONCLUSION: Mono +50 keV dual-energy CT scan may be helpful for differentiating between RBC-rich and fibrin-rich thrombi seen in large-vessel occlusion patients.

Preconditioning with Foam-mediated External Suction on Flap Microvasculature and Perfusion in a Rodent Model.

Foam-mediated external suction (FMES) has previously shown to improve tissue microcirculation. We hypothesized that preconditioning fasciocutaneous perforator flaps with FMES would augment perfusion and demonstrate greater capillary recruitment. METHODS: Gluteal perforator flaps were designed on sixteen 400 g rats. Continuous FMES at -125 mm Hg was applied on one side (intervention) to precondition tissue for 5 days, with the contralateral side as a paired control. In group A, we assessed changes following pretreatment, after surgery, and 7 days postprocedure, and in group B, we evaluated changes during preconditioning alone. In group A (N = 8), control and intervention flaps were assessed using laser-assisted indocyanine green fluorescence angiography. In group B, flap regions were assessed using 4-dimensional computed tomographic angiography. All flaps were analyzed for microvessel density using micro-computed tomography and histological assessment using hematoxylin and eosin and CD3 immunohistochemistry. RESULTS: Thirty-two flaps were included in this study (N = 16 intervention and matched controls). Four-dimensional computed tomographic angiography demonstrated 17% greater tissue perfusion in preconditioned flaps (mean, 78.7 HU; SD, 8.8) versus controls (mean, 67.3 HU; SD, 15.7; P < 0.01). Laser-assisted indocyanine green fluorescence angiography showed a 30% higher mean absolute intensity in preconditioned flaps versus controls (P < 0.01). Postsurgery mean absolute intensity in preconditioned flaps remained 21% higher than in controls (P = 0.03). Preconditioned flaps demonstrated a 2-fold increase in mean vessel volume of 9.1 mm3 (SD, 7) versus 4.5 mm3 (SD, 3) in controls (P = 0.04); there was a 33% higher mean area fraction of CD31 in preconditioned flaps, 3.9% (SD, 3) versus 2.9% (SD, 3) in controls (P = 0.03). CONCLUSION: FMES preconditioning has the potential to augment vascularity of tissue for flap harvest; however, further experimental studies are required to optimize strategies and evaluate long-term effects for clinical applications.

A Universal Protocol for Abdominal CT Examinations Performed on a Photon-Counting Detector CT System: A Feasibility Study.

OBJECTIVE: The aims of this study were to investigate the feasibility of using a universal abdominal acquisition protocol on a photon-counting detector computed tomography (PCD-CT) system and to compare its performance to that of single-energy (SE) and dual-energy (DE) CT using energy-integrating detectors (EIDs). METHODS: Iodine inserts of various concentrations and sizes were embedded into different sizes of adult abdominal phantoms. Phantoms were scanned on a research PCD-CT and a clinical EID-CT with SE and DE modes. Virtual monoenergetic images (VMIs) were generated from PCD-CT and DE mode of EID-CT. For each image type and phantom size, contrast-to-noise ratio (CNR) was measured for each iodine insert and the area under the receiver operating characteristic curve (AUC) for iodine detectability was calculated using a channelized Hotelling observer. The optimal energy (in kiloelectrovolt) of VMIs was determined separately as the one with highest CNR and the one with the highest AUC. The PCD-CT VMIs at the optimal energy were then compared with DE VMIs and SE images in terms of CNR and AUC. RESULTS: Virtual monoenergetic image at 50 keV had both the highest CNR and highest AUC for PCD-CT and DECT. For 1.0 mg I/mL iodine and 35 cm phantom, the CNRs of 50 keV VMIs from PCD-CT (2.01 ± 0.67) and DE (1.96 ± 0.52) were significantly higher (P < 0.001, Wilcoxon signed-rank test) than SE images (1.11 ± 0.35). The AUC of PCD-CT (0.98 ± 0.01) was comparable to SE (0.98 ± 0.01), and both were slightly lower than DE (0.99 ± 0.01, P < 0.01, Wilcoxon signed-rank test). A similar trend was observed for other phantom sizes and iodine concentrations. CONCLUSIONS: Virtual monoenergetic images at a fixed energy from a universal acquisition protocol on PCD-CT demonstrated higher iodine CNR and comparable iodine detectability than SECT images, and similar performance compared with DE VMIs.

Sustained perfusion of revascularized bioengineered livers heterotopically transplanted into immunosuppressed pigs.

Implanted bioengineered livers have not exceeded three days of continuous perfusion. Here we show that decellularized whole porcine livers revascularized with human umbilical vein endothelial cells and implanted heterotopically into immunosuppressed pigs whose spleens had been removed can sustain perfusion for up to 15 days. We identified peak glucose consumption rate as a main predictor of the patency of the revascularized bioengineered livers (rBELs). Heterotopic implantation of rBELs into pigs in the absence of anticoagulation therapy led to sustained perfusion for three days, followed by a pronounced immune responses directed against the human endothelial cells. A 10 day steroid-based immunosuppression protocol and a splenectomy at the time of rBEL implantation reduced the immune responses and resulted in continuous perfusion of the rBELs for over two weeks. We also show that the human endothelial cells in the perfused rBELs colonize the liver sinusoids and express sinusoidal endothelial markers similar to those in normal liver tissue. Revascularized liver scaffolds that can maintain blood perfusion at physiological pressures might eventually help to overcome the chronic shortage of transplantable human livers.

Author Correction: Sustained perfusion of revascularized bioengineered livers heterotopically transplanted into immunosuppressed pigs.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Spatial Accuracy of a Clinically Established Noninvasive Electrocardiographic Imaging System for the Detection of Focal Activation in an Intact Porcine Model.

BACKGROUND: Noninvasive electrocardiographic imaging (ECGi) is used clinically to map arrhythmias before ablation. Despite its clinical use, validation data regarding the accuracy of the system for the identification of arrhythmia foci is limited. METHODS: Nine pigs underwent closed-chest placement of endocardial fiducial markers, computed tomography, and pacing in all cardiac chambers with ECGi acquisition. Pacing location was reconstructed from biplane fluoroscopy and registered to the computed tomography using the fiducials. A blinded investigator predicted the pacing location from the ECGi data, and the distance to the true pacing catheter tip location was calculated. RESULTS: A total of 109 endocardial and 9 epicardial locations were paced in 9 pigs. ECGi predicted the correct chamber of origin in 85% of atrial and 92% of ventricular sites. Lateral locations were predicted in the correct chamber more often than septal locations (97% versus 79%, P=0.01). Absolute distances in space between the true and predicted pacing locations were 20.7 (13.8-25.6) mm (median and [first-third] quartile). Distances were not significantly different across cardiac chambers. CONCLUSIONS: The ECGi system is able to correctly identify the chamber of origin for focal activation in the vast majority of cases. Determination of the true site of origin is possible with sufficient accuracy with consideration of these error estimates.

Determination of iodine detectability in different types of multiple-energy images for a photon-counting detector computed tomography system.

In addition to low-energy-threshold images (TLIs), photon-counting detector (PCD) computed tomography (CT) can generate virtual monoenergetic images (VMIs) and iodine maps. Our study sought to determine the image type that maximizes iodine detectability. Adult abdominal phantoms with iodine inserts of various concentrations and lesion sizes were scanned on a PCD-CT system. TLIs, VMIs at 50 keV, and iodine maps were generated, and iodine contrast-to-noise ratio (CNR) was measured. A channelized Hotelling observer was used to determine the area under the receiver-operating-characteristic curve (AUC) for iodine detectability. Iodine map CNR ( 0.57 ± 0.42 ) was significantly higher ( P < 0.05 ) than for TLIs ( 0.46 ± 0.26 ) and lower ( P < 0.001 ) than for VMIs at 50 keV ( 0.74 ± 0.33 ) for 0.5 mgI/cc and a 35-cm phantom. For the same condition and an 8-mm lesion, iodine detectability from iodine maps ( AUC = 0.95 ± 0.01 ) was significantly lower ( P < 0.001 ) than both TLIs ( AUC = 0.99 ± 0.00 ) and VMIs ( AUC = 0.99 ± 0.01 ). VMIs at 50 keV had similar detectability to TLIs and both outperformed iodine maps. The lowest detectable iodine concentration was 0.5 mgI/cc for an 8-mm lesion and 1.0 mgI/cc for a 4-mm lesion.

Clinical utility of virtual noncalcium dual-energy CT in imaging of the pelvis and hip.

Dual-energy virtual noncalcium images are increasingly used to identify marrow edema which accompanies bony pelvic injuries and marrow pathology obscured by cancellous bone. We present a clinical perspective of our experience using virtual noncalcium images in the work up of pelvic osseous pathology.

Dual-Energy CT Monitoring of Cryoablation Zone Growth in the Spinal Column and Bony Pelvis: A Laboratory Study.

PURPOSE: To evaluate the use of dual-energy computed tomography (CT) virtual noncalcium imaging (VNCa) to visualize ice ball growth during skeletal cryoablation procedures in the spine and bony pelvis. MATERIALS AND METHODS: Cryoablation was performed in the spine and bony pelvis of swine and human cadavers at 5 and 6 locations, respectively. CT scans were acquired every 2 minutes using a dual-source dual-energy scanner. Artifacts were suppressed using iterative metal artifact reduction, and ablation zones in the bones and surrounding tissue were visualized using multiplanar VNCa and mixed kV imaging. For each probe location and time point, ice detectability was determined and the volume of the ice was measured. RESULTS: At each location, ice was visualized within the bone before reaching critical neural and intraabdominal structures. Within bone, the ice ball could not be visualized on mixed kV images, but was seen using VNCa images before reaching the adjacent soft tissue in 7/11 (64%) scenarios. Volume of the smallest ice ball seen in VNCa images was 18% of the final volume after cryoablation compared with 42% for mixed kV (P = .014). CONCLUSIONS: This application of dual-energy CT and VNCa imaging to cryoablation monitoring permits earlier ice visualization within the vertebral column and pelvic bones in near real time. Because these scanners and imaging techniques increase in availability in interventional suites, cryoablation of tumors along the spine and pelvic bone potentially could be performed with greater confidence.

Dual-source photon counting detector CT with a tin filter: a phantom study on iodine quantification performance.

Photon counting detectors (PCD) can provide spectral information to enable iodine quantification through multi-energy imaging but performance is limited by current PCD technology. The purpose of this work is to evaluate iodine quantification in a phantom study using dual-source PCD-CT (DS-PCD-CT), and compare to single-source (SS)-PCD-CT and traditional DS energy integrating detector (EID)-based dual-energy CT. A multi-energy CT phantom with iodine inserts (0 to 15 mg ml-1 concentration) was imaged on a research SS-PCD-CT scanner (CTDIvol = 18 mGy). A DS-PCD-CT was emulated by acquiring two sequential scans (CTDIvol = 9 mGy each) using tube potentials: 140 kVp/80 kVp, 140 kVp/100 kVp and 140 kVp/120 kVp. For each kVp, 1 or 2 energy bins were reconstructed to achieve either dual-energy or quadruple energy CT. In addition to these energy combinations, a Sn filter was used for the high tube potential (140 kVp) of each kVp pair. For comparison, the same phantom was also scanned on a commercially available DS-EID-CT with matched radiation dose (CTDIvol = 18 mGy). Material decomposition was performed in image space using a standard least-squares based approach to generate iodine and water-specific images. The root-mean-square-error (RMSE) measured over each insert from the iodine image was used to determine iodine accuracy. The iodine RMSE from SS-PCD (140 kVp with 2 energy bins) was 2.72 mg ml-1. The use of a DS configuration with 1 energy bin per kVp (140 kVp/80 kVp) resulted in a RMSE of 2.29 mg ml-1. Two energy bins per kVp further reduced iodine RMSE to 1.83 mg ml-1. The addition of a Sn filter to the latter quadruple energy mode reduced RMSE to 1.48 mg ml-1. RMSE for DS-PCD-CT (2 energy bins per kVp) decreased by 1.3% (Sn140 kVp/80 kVp) and 15% (Sn140 kVp/100 kVp) as compared to DS-EID-CT. DS-PCD-CT with a Sn filter improved iodine quantification as compared to both SS-PCD-CT and DS-EID-CT.

Reappraisal of Perforasomes of the Superficial Femoral, Descending Genicular, and Saphenous Arteries and Clinical Applications to Locoregional Reconstruction.

BACKGROUND: The superficial femoral artery and medial thigh region has been an underused donor site for perforator flaps. This study evaluated perforasomes of the superficial femoral artery and its principal branches to review the clinical applications for locoregional reconstruction. METHODS: Twenty-six fresh cadaveric lower extremities were dissected. Perforator size and anatomical course from the superficial femoral artery, descending genicular artery, and saphenous artery branch were documented. Perforators were selectively injected with iodinated contrast to assess vascular territories using computed tomography. A retrospective chart review was conducted on consecutive patients (2014 to 2015). RESULTS: One hundred thirty perforators were mapped in the medial thigh region. Eleven extended medial thigh perforator flaps and 15 hemicircumferential flaps were harvested. The mean distance from the joint line was 16.7 ± 7.3 cm. Perforators arose from the superficial femoral artery (62 percent), saphenous artery branch (23 percent), and descending genicular artery (15 percent). Superficial femoral artery perforators were located around the mid and proximal thigh region (p < 0.001). The median perforasome surface area was 244 cm, representing 36 percent in hemithigh flaps with preferential filling in the anteromedial region. Proximal perforasomes were the smallest. Perforasome areas based on vessel origin were comparable; however, saphenous artery perforators had a broader perforasome compared with descending genicular (p = 0.01) and superficial femoral artery perforators (p = 0.04). Six clinical case examples were presented for knee, thigh, and lower leg reconstruction. CONCLUSIONS: The superficial femoral artery or its branches can provide nontraditional reconstructive perforator flap options in regional reconstruction. They can be simple to harvest using a free-style approach, do not require preoperative imaging, offer a one-stage reconstructive method with low morbidity, and obviate the need for microsurgery or muscle flaps.

Clinical Assessment of Metal Artifact Reduction Methods in Dual-Energy CT Examinations of Instrumented Spines.

OBJECTIVE: The purpose of this study was to evaluate the performance of three metal artifact reduction methods in dual-energy CT (DECT) examinations of instrumented spines. MATERIALS AND METHODS: Twenty patients with instrumented spines who underwent spine DECT were retrospectively identified. All scans were obtained on a dual-source 128-MDCT scanner. In addition to the original DE mixed images, DECT images were reconstructed using an iterative metal artifact reconstruction algorithm (DE iMAR), virtual monochromatic imaging (VMI) algorithm (DE Mono+), and a combination of the two algorithms DE iMAR and DE Mono+, which we refer to here as "DE iMAR Mono+." The four image series were anonymized and randomized for a reader study. Four experienced neuroradiologists rated the images in terms of artifact scores of four anatomic regions and overall image quality scores in both bone and soft-tissue display window settings. In addition, a quantitative analysis was performed to assess the performance of the three metal artifact reduction methods. RESULTS: There were statistically significant differences in the artifact scores and overall image quality scores among the four methods (both, p < 0.001). DE iMAR Mono+ showed the best artifact scores and quality scores (all, p < 0.001). The intraclass correlation coefficient for the overall image quality score was 0.779 using the bone display window and 0.892 using the soft-tissue display window (both, p < 0.001). In addition, DE iMAR Mono+ reduced the artifacts by the greatest amount in the quantitative analysis. CONCLUSION: The method that used DE iMAR Mono+ showed the best performance of spine metal artifact reduction using DECT data. These results may be specific to this CT vendor and implant type.

Renal Adiposity Does not Preclude Quantitative Assessment of Renal Function Using Dual-Energy Multidetector CT in Mildly Obese Human Subjects.

RATIONALE AND OBJECTIVES: Multidetector computed tomography (MDCT) is useful for measuring in the research setting single-kidney perfusion and function using iodinated contrast time-attenuation curves. Obesity promotes deposition of intrarenal fat, which might decrease tissue attenuation and thereby interfere with quantification of renal function using MDCT. The purpose of this study was to test the hypothesis that background subtraction adequately accounts for intrarenal fat deposition in mildly obese human subjects during renal contrast enhanced dynamic CT. MATERIALS AND METHODS: We prospectively recruited seventeen human subjects stratified as lean or mildly obese based on body mass index below or over 30 kg/m2, respectively. Renal perfusion was quantified from CT-derived indicator-dilution curves after background subtraction. Dual-energy MDCT images were postprocessed to generate iodine and virtual-noncontrast datasets, and the ratios between kidney/aorta CT numbers and iodine values calculated as surrogates of renal function. RESULTS: Subcutaneous adipose tissue was increased in obese subjects. Virtual-noncontrast maps revealed in obese patients a decrease in basal cortical and medullary attenuation. Overall, basal attenuation inversely correlated with body mass index, in line with renal fat deposition. Contrarily, the kidney/aorta CT attenuation (after background subtraction) and kidney/aorta iodine ratios were similar between lean and obese subjects and correlated directly. These observations show that following background subtraction, the CT number reliably reflects basal tissue attenuation. CONCLUSION: Therefore, our findings support our hypothesis that background subtraction enables reliable assessment of kidney function in mildly obese subjects using MDCT, despite decreased basal attenuation due to renal adiposity.

Randomized Trial of Spheroid Reservoir Bioartificial Liver in Porcine Model of Posthepatectomy Liver Failure.

Acute liver failure (ALF) is a catastrophic condition that can occur after major liver resection. The aim of this study was to determine the effects of the spheroid reservoir bio-artificial liver (SRBAL) on survival, serum chemistry, and liver regeneration in posthepatectomy ALF pigs. Wild-type large white swine (20 kg-30 kg) underwent intracranial pressure (ICP) probe placement followed by 85% hepatectomy. Computed tomography (CT) volumetrics were performed to measure the extent of resection, and at 48 hours following hepatectomy to assess regeneration of the remnant liver. Animals were randomized into three groups based on treatment delivered 24-48 hours after hepatectomy: Group1-standard medical therapy (SMT, n = 6); Group2-SMT plus bio-artificial liver treatment using no hepatocytes (0 g, n = 6); and Group3-SMT plus SRBAL treatment using 200 g of primary porcine hepatocyte spheroids (200 g, n = 6). The primary endpoint was survival to 90 hours following hepatectomy. Death equivalent was defined as unresponsive grade 4 hepatic encephalopathy or ICP greater than 20 mmHg with clinical evidence of brain herniation. All animals in both (SMT and 0 g) control groups met the death equivalent before 51 hours following hepatectomy. Five of 6 animals in the 200-g group survived to 90 hours (P < 0.01). The mean ammonia, ICP, and international normalized ratio values were significantly lower in the 200-g group. CT volumetrics demonstrated increased volume regeneration at 48 hours following hepatectomy in the 200-g group compared with the SMT (P < 0.01) and 0-g (P < 0.01) groups. Ki-67 staining showed increased positive staining at 48 hours following hepatectomy (P < 0.01). Conclusion: The SRBAL improved survival, reduced ammonia, and accelerated liver regeneration in posthepatectomy ALF. Improved survival was associated with a neuroprotective benefit of SRBAL therapy. These favorable results warrant further clinical testing of the SRBAL.

Theoretical and experimental analysis of photon counting detector CT for proton stopping power prediction.

PURPOSE: Photon counting detectors (PCDs) are being introduced in advanced x-ray computed tomography (CT) scanners. From a single PCD-CT acquisition, multiple images can be reconstructed, each based on only a part of the original x-ray spectrum. In this study, we investigated whether PCD-CT can be used to estimate stopping power ratios (SPRs) for proton therapy treatment planning, both by comparing to other SPR methods proposed for single energy CT (SECT) and dual energy CT (DECT) as well as to experimental measurements. METHODS: A previously developed DECT-based SPR estimation method was adapted to PCD-CT data, by adjusting the estimation equations to allow for more energy spectra. The method was calibrated directly on noisy data to increase the robustness toward image noise. The new PCD SPR estimation method was tested in theoretical calculations as well as in an experimental setup, using both four and two energy bin PCD-CT images, and through comparison to two other SPR methods proposed for SECT and DECT. These two methods were also evaluated on PCD-CT images, full spectrum (one-bin) or two-bin images, respectively. In a theoretical framework, we evaluated the effect of patient-specific tissue variations (density and elemental composition) and image noise on the SPR accuracy; the latter effect was assessed by applying three different noise levels (low, medium, and high noise). SPR estimates derived using real PCD-CT images were compared to experimentally measured SPRs in nine organic tissue samples, including fat, muscle, and bone tissues. RESULTS: For the theoretical calculations, the root-mean-square error (RMSE) of the SPR estimation was 0.1% for the new PCD method using both two and four energy bins, compared to 0.2% and 0.7% for the DECT- and SECT-based method, respectively. The PCD method was found to be very robust toward CT image noise, with a RMSE of 2.7% when high noise was added to the CT numbers. Introducing tissue variations, the RMSE only increased to 0.5%; even when adding high image noise to the changed tissues, the RMSE stayed within 3.1%. In the experimental measurements, the RMSE over the nine tissue samples was 0.8% when using two energy bins, and 1.0% for the four-bin images. CONCLUSIONS: In all tested cases, the new PCD method produced similar or better results than the SECT- and DECT-based methods, showing an overall improvement of the SPR accuracy. This study thus demonstrated that PCD-CT scans will be a qualified candidate for SPR estimations.

Determination of Optimal Image Type and Lowest Detectable Concentration for Iodine Detection on a Photon Counting Detector-Based Multi-Energy CT System.

Photon counting detector (PCD) based multi-energy CT is able to generate different types of images such as virtual monoenergetic images (VMIs) and material specific images (e.g., iodine maps) in addition to the conventional single energy images. The purpose of this study is to determine the image type that has optimal iodine detection and to determine the lowest detectable iodine concentration using a PCD-CT system. A 35 cm body phantom with iodine inserts of 4 concentrations and 2 sizes was scanned on a research PCD-CT system. For each iodine concentration, 80 repeated scans were performed and images were reconstructed for each energy threshold. In addition, VMIs at different keVs and iodine maps were also generated. CNR was measured for each type of images. A channelized Hotelling observer was used to assess iodine detectability after being validated with human observer studies, with area under the ROC curve (AUC) as a figure of merit. The agreement between model and human observer performance indicated that model observer could serve as an effective approach to determine optimal image type for the clinical practice and to determine the lowest detectable iodine concentration. Results demonstrated that for all size and concentration combinations, VMI at 70 keV had similar performance as that of threshold low images, both of which outperformed the iodine map images. At the AUC value of 0.8, iodine concentration as low as 0.2 mgI/cc could be detected for an 8 mm object and 0.5 mgI/cc for a 4 mm object with a 5 mm slice thickness.

Intrarenal fat deposition does not interfere with the measurement of single-kidney perfusion in obese swine using multi-detector computed tomography.

BACKGROUND: Altered vascular structure or function in several diseases may impair renal perfusion. Multi-detector computed tomography (MDCT) is a non-invasive tool to assess single-kidney perfusion and function based on dynamic changes in tissue attenuation during contrast media transit. However, changes in basal tissue attenuation might hamper these assessments, despite background subtraction. Evaluation of iodine concentration using the dual-energy (DECT) MDCT mode allows excluding effects of basal values on dynamic changes in tissue attenuation. We tested whether decreased basal kidney attenuation secondary to intrarenal fat deposition in swine obesity interferes with assessment of renal perfusion using MDCT. METHODS: Domestic pigs were fed a standard (lean) or a high-cholesterol/carbohydrate (obese) diet (n = 5 each) for 16 weeks, and both kidneys were then imaged using MDCT/DECT after iodinated contrast injection. DECT images were post-processed to generate iodine and virtual-non-contrast (VNC) datasets, and the MDCT kidney/aorta CT number (following background subtraction) and DECT iodine ratios calculated during the peak vascular phase as surrogates of renal perfusion. Intrarenal fat was subsequently assessed with Oil-Red-O staining. RESULTS: VNC maps in obese pigs revealed decreased basal cortical attenuation, and histology confirmed increased renal tissue fat deposition. Nevertheless, the kidney/aorta attenuation and iodine ratios remained similar, and unchanged compared to lean pigs. CONCLUSIONS: Despite decreased basal attenuation secondary to renal adiposity, background subtraction allows adequate assessment of kidney perfusion in obese pigs using MDCT. These observations support the feasibility of renal perfusion assessment in obese subjects using MDCT.