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Current methods of staging liver fibrosis have notable limitations. We investigated the utility of PET in staging liver fibrosis by correlating liver uptake of (68)Ga-labeled fibroblast activation protein inhibitor (FAPI) with histology in a human-sized swine model. Methods: Five pigs underwent baseline (68)Ga-FAPI-46 ((68)Ga-FAPI) PET/MRI and liver biopsy, followed by liver parenchymal embolization, 8 wk of oral alcohol intake, endpoint (68)Ga-FAPI PET/MRI, and necropsy. Regions of interest were drawn on baseline and endpoint PET images, and SUV(mean) was recorded. At the endpoint, liver sections corresponding to regions of interest were identified and cut out. Fibrosis was histologically evaluated using a modified METAVIR score for swine liver and quantitatively using collagen proportionate area (CPA). Box-and-whisker plots and linear regression were used to correlate SUV(mean) with METAVIR score and CPA, respectively. Results: Liver (68)Ga-FAPI uptake strongly correlated with CPA (r = 0.89, P < 0.001). (68)Ga-FAPI uptake was significantly and progressively higher across F2 and F3/F4 fibrosis stages, with a respective median SUV(mean) of 2.9 (interquartile range [IQR], 2.7–3.8) and 7.6 (IQR, 6.7–10.2) (P < 0.001). There was no significant difference between (68)Ga-FAPI uptake of baseline liver and endpoint liver sections staged as F0/F1, with a respective median SUV(mean) of 1.7 (IQR, 1.3–2.0) and 1.7 (IQR, 1.5–1.8) (P = 0.338). Conclusion: The strong correlation between liver (68)Ga-FAPI uptake and the histologic stage of liver fibrosis suggests that (68)Ga-FAPI PET can play an impactful role in noninvasive staging of liver fibrosis, pending validation in patients.

PURPOSE: During hepatic arterial interventions, catheter or guidewire position is determined by referencing or overlaying a previously acquired static vessel roadmap. Respiratory motion leads to significant discrepancies between the true position and configuration of the hepatic arteries and the roadmap, which makes navigation and accurate catheter placement more challenging and time consuming. The purpose of this work was to develop a dynamic respiratory motion compensated device guidance system and evaluate the accuracy and real-time performance in an in vivo porcine liver model. METHODS: The proposed device navigation system estimates a respiratory motion model for the hepatic vasculature from pre-navigational x-ray image sequences acquired under free breathing conditions with and without contrast enhancement. During device navigation, the respiratory state is tracked based on live fluoroscopic images and then used to estimate vessel deformation based on the previously determined motion model. Additionally, guidewires and catheters are segmented from the fluoroscopic images using a deep learning approach. The vessel and device information are combined and shown in a real-time display. Two different display modes are evaluated within this work: 1) a compensated roadmap display, where the vessel roadmap is shown moving with the respiratory motion 2) an inverse compensated device display, where the device representation is compensated for respiratory motion and overlaid on a static roadmap. A porcine study including 7 animals was performed to evaluate the accuracy and real-time performance of the system. In each pig, a guidewire and microcatheter with a radiopaque marker were navigated to distal branches of the hepatic arteries under fluoroscopic guidance. Motion compensated displays were generated showing real-time overlays of the vessel roadmap and intravascular devices. The accuracy of the motion model was estimated by comparing the estimated vessel motion to the motion of the x-ray visible marker. RESULTS: The median (minimum, maximum) error across animals was 1.08 mm (0.92 mm, 1.87 mm). Across different respiratory states and vessel branch levels, the odds of the guidewire tip being shown in the correct vessel branch were significantly higher (odds ratio=3.12, p

Background 2D digital subtraction angiography (DSA) is utilized qualitatively to assess blood velocity changes that occur during arterial interventions. Quantitative angiographic metrics, such as blood velocity, could be used to standardize endpoints during angiographic interventions. Purpose To assess the accuracy and precision of a quantitative 2D DSA (qDSA) technique and to determine its feasibility for in vivo measurements of blood velocity. Materials and methods A quantitative DSA technique was developed to calculate intra-procedural blood velocity. In vitro validation was performed by comparing velocities from the qDSA method and an ultrasonic flow probe in a bifurcation phantom. Parameters of interest included baseline flow rate, contrast injection rate, projection angle, and magnification. In vivo qDSA analysis was completed in five different branches of the abdominal aorta in two 50 kg swine and compared to 4D Flow MRI. Linear regression, Bland-Altman, Pearson’s correlation coefficient and chi squared tests were used to assess the accuracy and precision of the technique. Results In vitro validation showed strong correlation between qDSA and flow probe velocities over a range of contrast injection and baseline flow rates (slope = 1.012, 95% CI [0.989,1.035], Pearson’s r = 0.996, p p = 0.999 and p = 0.956, respectively). In vivo validation showed strong correlation with a small bias between qDSA and 4D Flow MRI velocities for all five abdominopelvic arterial vessels of interest (slope = 1.01, Pearson’s r = 0.880, p = Conclusion The proposed method allows for accurate and precise calculation of blood velocities, in near real-time, from time resolved 2D DSAs.

Objective. Existing clinical C-arm interventional systems use scintillator-based energy-integrating flat panel detectors (FPDs) to generate cone-beam CT (CBCT) images. Despite its volumetric coverage, FPD-CBCT does not provide sufficient low-contrast detectability desired for certain interventional procedures. The purpose of this work was to develop a C-arm photon counting detector (PCD) CT system with a step-and-shoot data acquisition method to further improve the tomographic imaging performance of interventional systems. Approach. As a proof-of-concept, a cadmium telluride-based 51 cm × 0.6 cm PCD was mounted in front of a FPD in an Artis Zee biplane system. A total of 10 C-arm sweeps (5 forward and 5 backward) were prescribed. A motorized patient table prototype was synchronized with the C-arm system such that it translates the object by a designated distance during the sub-second rest time in between gantry sweeps. To evaluate whether this multi-sweep step-and-shoot acquisition strategy can generate high-quality and volumetric PCD-CT images without geometric distortion artifacts, experiments were performed using physical phantoms, a human cadaver head, and an in vivo swine subject. Comparison with FPD-CT was made under matched narrow beam collimation and radiation dose conditions. Main results. Compared with FPD-CT images, PCD-CT images had lower noise and improved visualization of low-contrast lesion models, as well as improved visibility of small iodinated blood vessels. Fine structures were visualized more clearly by the PCD-CT than the highest-available resolution provided by FPD-CBCT and MDCT. No perceivable geometric distortion artifacts were observed in the multi-planar PCD-CT images. Significance. This work is the first demonstration of the feasibility of high-quality and multi-planar (volumetric) PCD-CT imaging with a rotating C-arm gantry.

To determine the risk of mechanical vessel wall damage resulting in hemorrhage during and after hepatic and renal histotripsy in an anticoagulated in vivo porcine model.Non-tumor-bearing pigs (n=8, mean weight=52.5kg) were anticoagulated with warfarin (initial dose 0.08 mg/kg) to a target PT of 30-50% above baseline. A total of 15 histotripsy procedures were performed (kidney n=8, 2.0 cm sphere; liver n=7, 2.5 cm sphere). Treatments were immediately followed by CT imaging. Animals were observed for 7 days while continuing anticoagulation, followed by repeat CT and necropsy.All animals survived to complete the entire protocol with no signs of disability or distress. Three animals had hematuria (pink urine without clots). Baseline prothrombin time (PT) values (mean 16.0 sec) were elevated to 22.0 sec (37.5% above baseline, p=0.003) on the day of treatment, and 28.8 sec (77.8% above baseline, p0.001) on the day of necropsy. At the time of treatment 63% (5/8) of subjects were at a therapeutic anticoagulation level, and 100% (8/8) reached therapeutic levels by the time of necropsy. There were no cases of intra-parenchymal, peritoneal, or retroperitoneal hemorrhage associated with any treatments despite 71% (5/7) of liver and 100% (8/8) of kidney treatments extending to the organ surface.Liver and kidney histotripsy appears safe with no elevated bleeding risk in this anticoagulated animal model supporting the possibility of histotripsy treatments in patients on anti-coagulation.

Purpose: To develop an imaging-based 3D catheter navigation system for transbronchial procedures including biopsy and tumor ablation using a single-plane C-arm x-ray system. The proposed system provides time-resolved catheter shape and position as well as motion compensated 3D airway roadmaps. Approach: A continuous-sweep limited angle (CLA) imaging mode where the C-arm continuously rotates back and forth within a limited angular range while acquiring x-ray images was used for device tracking. The catheter reconstruction was performed using a sliding window of the most recent x-ray images, which captures information on device shape and position versus time. The catheter was reconstructed using a model-based approach and was displayed together with the 3D airway roadmap extracted from a pre-navigational cone-beam CT (CBCT). The roadmap was updated in regular intervals using deformable registration to tomosynthesis reconstructions based on the CLA images. The approach was evaluated in a porcine study (three animals) and compared to a gold standard CBCT reconstruction of the device. Results: The average 3D root mean squared distance between CLA and CBCT reconstruction of the catheter centerline was [Formula: see text] for a stationary catheter and [Formula: see text] for a catheter moving at [Formula: see text]. The average tip localization error was [Formula: see text] and [Formula: see text] , respectively. Conclusions: The results indicate catheter navigation based on the proposed single plane C-arm imaging technique is feasible with reconstruction errors similar to the diameter of a typical ablation catheter.

OBJECTIVE: There is no standardized and objective method for determining the optimal treatment endpoint (sub-stasis) during transarterial embolization. The objective of this study was to demonstrate the feasibility of using a quantitative digital subtraction angiography (qDSA) technique to characterize intra-procedural changes in hepatic arterial blood flow velocity in response to transarterial embolization in an in vivo porcine model. MATERIALS AND METHODS: Eight domestic swine underwent bland transarterial embolizations to partial and sub-stasis angiographic endpoints with intraprocedural DSA acquisitions. Embolized lobes were assessed on histopathology for ischemic damage and tissue embolic particle density. Analysis of target vessels used qDSA and a commercially available color-coded DSA (ccDSA) tool to calculate blood flow velocities and time-to-peaks respectively. RESULTS: Blood flow velocities calculated using qDSA showed a statistically significant difference (p

BACKGROUND: Previous human-scale porcine liver model studies of histotripsy have resulted in ablation zones elongated in the cranial-caudal (CC) dimension due to uninterrupted respiratory motion during the ablation procedure. PURPOSE: The purpose of this study is to compensate for elongation of hepatic histotripsy ablation zones in the cranial-caudal (CC) dimension caused by respiratory motion by prescribing ellipsoid shaped ablations. METHODS: Six female swine underwent 12 hepatic histotripsy ablations using a prototype clinical histotripsy system under general anesthesia. Each animal received two ablation zones prescribed as either an ellipsoid (2.5cm (AP) x 2.5cm (ML) x 1.7cm (CC), prescribed volume=5.8cc) or a sphere (2.5cm all dimensions, prescribed volume 8.2cc). Ventilatory tidal volume was held constant at 400cc for all ablations. Post procedure MRI was followed by sacrifice and gross and microscopic histology. RESULTS: Ablations on MRI were slightly larger than prescribed in all dimensions. Ellipsoid plan ablations (2.8 × 3.0 × 3.1cm, volume 13.2cc, sphericity index 0.987) were closer to prescribed volume than spherical plan ablations (2.9 × 3.1 × 3.7cm, volume 17.1cc, sphericity index 0.953). Ellipsoid plan ablations were more spherical than sphere plan ablations, but the difference did not reach statistical significance (p=.06). Pathologic analysis confirmed complete necrosis within the center of each ablation zone with no widening of the zone of partial ablation on the superior and inferior as compared to the lateral borders (p=.22). CONCLUSION: Altering ablation zone prescription shape when performing hepatic histotripsy ablations can partially mitigate respiratory motion effects to achieve the desired ablation shape and volume.

Catheter-based vascular interventions performed in the interventional radiology suite rely heavily on digital subtraction angiography (DSA) for intraprocedural evaluation of vessel morphology. Recently, DSA methods have been reported which quantify blood flow based on the tracking of temporal oscillations in contrast agent density through vessels. This signal, termed contrast pulsatility, arises naturally from the mixing of a fixed rate contrast injection with periodic arterial blood flow. Although these tools promise quantitative intraprocedural evaluation of flow, quantification is limited by a decline in contrast pulsatility strength in distal arterial vasculature, and, in venous structures, minimally observable or no pulsatility. To improve pulsatility strength in DSA images, a custom dual-barrel power injector was constructed that dynamically modulates the injected contrast flow (or concentration). Each barrel can follow sinusoidal and square wave injection profiles of specified frequency, amplitude, phase, and duty cycle. Improvement in contrast pulsatility was evaluated in a vessel phantom with simulated 60 bpm arterial flow and low-frequency sinusoidal contrast injections of 0.25, 0.50, and 1.0Hz. The ability to establish contrast pulsatility in a venous structure was evaluated in a porcine study. In the arterial phantom, sinusoidal contrast injections at 0.25Hz, 0.5Hz, and 1.0Hz displayed increased distal contrast pulsatility relative to a DC contrast injection at the same mean rate, with energy spectral density (ESD) ratios of 215, 59.9, and 5.3 respectively. In the animal study, a custom 0.67Hz square wave injection into the inferior vena cava showed a large improvement in pulsatility relative to DC injection (ESD ratio of 7208).

Training of deep learning-based segmentation algorithms requires large datasets of annotated images. Obtaining large clinical datasets, particularly for interventional imaging, is difficult and annotating vessels manually in the images is very time-consuming. Simulated images can be used to supplement clinical datasets. We developed a technique for the simulation of realistic, anatomically- and physiologically-motivated hepatic artery trees and subsequent synthesis of fluoroscopic images. The proposed approach creates a network of main feeding arteries for each of the eight liver segments as defined by the Couinaud classification system. A constrained constructive optimization based approach was then used to connect a set of randomly generated endpoints within each segment to the corresponding feeding artery. Vessel curvature was created using cubic splines and the generated vasculature was inserted into the digital XCAT phantom. The simulated 2D fluoroscopic images were generated using ray tracing and included focal spot blur, detector blur and Poisson noise. The length ratio (1.1 ± 1.7) and two parameters from Murray’s law, branching angles (7.9 ± 7.7𝑜 mean absolute difference from Murray’s law) and radius ratio (1.0 ± 0.1) of the generated vasculature were in accordance with values reported in literature (1.3, Murray’s law applied to branching angles, and 1.0 respectively). Simulated vasculature included main branches for each of the eight Couinaud segments, where 87% of all connected endpoints terminated in the same segment. Simulated 2D projection images were analyzed using a vessel phantom study with contrast-enhanced tubes (0.305-3.353 mm diameter). The normalized root mean squared difference between the measured and simulated vessel profiles averaged 3.5%. In conclusion, the proposed method provides realistic simulated fluoroscopic images of the liver vasculature and could prove useful for the training of machine learning based algorithms for vessel segmentation.

Glucagon drives hepatic gluconeogenesis and maintains blood glucose levels during fasting. The mechanism that attenuates glucagon action following refeeding is not understood. The present study demonstrates an increase in perivenous liver hypoxia immediately after feeding, which stabilizes hypoxia-inducible factor 2α (HIF2α) in liver. The transient postprandial increase in hepatic HIF2α attenuates glucagon signaling. Hepatocyte-specific disruption of HIF2α increases postprandial blood glucose and potentiates the glucagon response. Independent of insulin/AKT signaling, activation of hepatic HIF2α resulted in lower blood glucose, improved glucose tolerance, and decreased gluconeogenesis due to blunted hepatic glucagon action. Mechanistically, HIF2α abrogated glucagon-PKA signaling by activating cAMP-phosphodiesterases in a MEK/ERK-dependent manner. Repression of glucagon signaling by HIF2α ameliorated hyperglycemia in streptozotocin-induced diabetes and acute insulin-resistant animal models. This study reveals that HIF2α is essential for the acute postprandial regulation of hepatic glucagon signaling and suggests HIF2α as a potential therapeutic target in the treatment of diabetes.