Histoplasty Modification of the Tumor Microenvironment in a Murine Preclinical Model of Breast Cancer.

PURPOSE: To develop a noninvasive therapeutic approach able to alter the biophysical organization and physiology of the extracellular matrix (ECM) in breast cancer. MATERIALS AND METHODS: In a 4T1 murine model of breast cancer, histoplasty treatment with a proprietary 700-kHz multielement therapy transducer using a coaxially aligned ultrasound (US) imaging probe was used to target the center of an ex vivo tumor and deliver subablative acoustic energy. Tumor collagen morphology was qualitatively evaluated before and after histoplasty with second harmonic generation. Separately, mice bearing bilateral 4T1 tumors (n = 4; total tumors = 8) were intravenously injected with liposomal doxorubicin. The right flank tumor was histoplasty-treated, and tumors were fluorescently imaged to detect doxorubicin uptake after histoplasty treatment. Next, 4T1 tumor-bearing mice were randomized into 2 treatment groups (sham vs histoplasty, n = 3 per group). Forty-eight hours after sham/histoplasty treatment, tumors were harvested and analyzed using flow cytometry. RESULTS: Histoplasty significantly increased (P = .0023) liposomal doxorubicin diffusion into 4T1 tumors compared with untreated tumors (2.12- vs 1.66-fold increase over control). Flow cytometry on histoplasty-treated tumors (n = 3) demonstrated a significant increase in tumor macrophage frequency (42% of CD45 vs 33%; P < .05) and a significant decrease in myeloid-derived suppressive cell frequency (7.1% of CD45 vs 10.3%; P < .05). Histoplasty-treated tumors demonstrated increased CD8+ (5.1% of CD45 vs 3.1%; P = .117) and CD4+ (14.1% of CD45 vs 11.8%; P = .075) T-cell frequency. CONCLUSIONS: Histoplasty is a nonablative focused US approach to noninvasively modify the tumor ECM, increase chemotherapeutic uptake, and alter the tumor immune microenvironment.

Motion-compensation approach for quantitative digital subtraction angiography and its effect on in-vivo blood velocity measurement.

Purpose: Quantitative monitoring of flow-altering interventions has been proposed using algorithms that quantify blood velocity from time-resolved two-dimensional angiograms. These algorithms track the movement of contrast oscillations along a vessel centerline. Vessel motion may occur relative to a statically defined vessel centerline, corrupting the blood velocity measurement. We provide a method for motion-compensated blood velocity quantification. Approach: The motion-compensation approach utilizes a vessel segmentation algorithm to perform frame-by-frame vessel registration and creates a dynamic vessel centerline that moves with the vasculature. Performance was evaluated in-vivo through comparison with manually annotated centerlines. The method was also compared to a previous uncompensated method using best- and worst-case static centerlines chosen to minimize and maximize centerline placement accuracy. Blood velocities determined through quantitative DSA (qDSA) analysis for each centerline type were compared through linear regression analysis. Results: Centerline distance errors were 0.3±0.1 mm relative to gold standard manual annotations. For the uncompensated approach, the best- and worst-case static centerlines had distance errors of 1.1±0.6 and 2.9±1.2 mm, respectively. Linear regression analysis found a high R-squared between qDSA-derived blood velocities using gold standard centerlines and motion-compensated centerlines (R2=0.97) with a slope of 1.15 and a small offset of -0.6 cm/s. The use of static centerlines resulted in low coefficients of determination for the best case (R2=0.35) and worst-case (R2=0.20) scenarios, with slopes close to zero. Conclusions: In-vivo validation of motion-compensated qDSA analysis demonstrated improved velocity quantification accuracy in vessels with motion, addressing an important clinical limitation of the current qDSA algorithm.

Spatiotemporal frequency domain analysis for blood velocity measurement during embolization procedures.

BACKGROUND: Currently, determining procedural endpoints and treatment efficacy of vascular interventions is largely qualitative and relies on subjective visual assessment of digital subtraction angiography (DSA) images leading to large interobserver variabilities and poor reproducibility. Quantitative metrics such as the residual blood velocity in embolized vessel branches could help establish objective and reproducible endpoints. Recently, velocity quantification techniques based on a contrast enhanced X-ray sequence such as qDSA and 4D DSA have been proposed. These techniques must be robust, and, to avoid radiation dose concerns, they should be compatible with low dose per frame image acquisition. PURPOSE: To develop and evaluate a technique for robust blood velocity quantification from low dose contrast enhanced X-ray image sequences that leverages the oscillating signal created by pulsatile blood flow. METHODS: The proposed spatiotemporal frequency domain (STF) approach quantifies velocities from time attenuation maps (TAMs) representing the oscillating signal over time for all points along a vessel centerline. Due to the time it takes a contrast bolus to travel along the vessel centerline, the resulting TAM resembles a sheared sine wave. The shear angle is related to the velocity and can be determined in the spatiotemporal frequency domain after applying the 2D Fourier transform to the TAM. The approach was evaluated in a straight tube phantom using three different radiation dose levels and compared to ultrasound transit-time-based measurements. The STF velocity results were also compared to previously published approaches for the measurement of blood velocity from contrast enhanced X-ray sequences including shifted least squared (SLS) and phase shift (PHS). Additionally, an in vivo porcine study (n = 8) was performed where increasing amounts of embolic particles were injected into a hepatic or splenic artery with intermittent velocity measurements after each injection to monitor the resulting reduction in velocity. RESULTS: At the lowest evaluated dose level (average air kerma rate 1.3 mGy/s at the interventional reference point), the Pearson correlation between ultrasound and STF velocity measurements was 99 % $99\%$ . This was significantly higher ( p < 0.0001 $p < 0.0001$ ) than corresponding correlation results between ultrasound and the previously published SLS and PHS approaches ( 91 $\hskip.001pt 91$ and 93 % $93\%$ , respectively). In the in vivo study, a reduction in velocity was observed in 85.7 % $85.7\%$ of cases after injection of 1 mL, 96.4 % $96.4\%$ after 3 mL, and 100.0 % $100.0\%$ after 4 mL of embolic particles. CONCLUSIONS: The results show good agreement of the spatiotemporal frequency domain approach with ultrasound even in low dose per frame image sequences. Additionally, the in vivo study demonstrates the ability to monitor the physiological changes due to embolization. This could provide quantitative metrics during vascular procedures to establish objective and reproducible endpoints.

Quantification of Iliac Arterial Blood Velocity in Stenotic Phantom and Porcine Models Using Quantitative Digital Subtraction Angiography.

PURPOSE: To assess the feasibility of using quantitative digital subtraction angiography (qDSA) to quantify arterial velocity in phantom and porcine stenotic iliac artery models. MATERIALS AND METHODS: Varying stenoses (mild, <50%; moderate, 50%-70%; and severe, >70%) were created in a silicone iliac artery phantom using vessel loops. Two-dimensional digital subtraction angiographies (DSAs) were performed, with velocities calculated using qDSA. qDSA velocities were compared with flow rates and velocities measured with an ultrasonic flow probe. Two-dimensional DSAs of the common and external iliac arteries were then performed in 4 swine (mean weight, 63 kg) before and after a severe stenosis (>70%) was created in the iliac artery using 3-0 silk suture. Peak systolic velocities on pulsed wave Doppler ultrasound (US) before and after stenosis creation were correlated with the qDSA velocities. Pearson correlation, linear regression, and analysis of variance were used for analysis. RESULTS: In the phantom study, ultrasonic probe velocities positively correlated with downstream qDSA (r = 0.65; P < .001) and negatively correlated with peristenotic qDSA velocities (r = -0.80; P < .001). In the swine study, statistically significant reductions in external iliac arterial velocity were noted on US and qDSA after stenosis creation (P < .05). US and qDSA velocities strongly correlated for all flow states with both 50% and 100% contrast concentrations (r = 0.82 and r = 0.74, respectively), with an estimated US-to-qDSA ratio of 1.3-1.5 (P < .001). qDSA velocities with 50% and 100% contrast concentrations also strongly correlated (r = 0.78; P < .001). CONCLUSIONS: In both phantom and swine stenosis models, changes in iliac arterial velocity could be quantified with qDSA, which strongly correlated with standard-of-care US.

A Multimodal Phantom for Visualization and Assessment of Histotripsy Treatments on Ultrasound and X-Ray Imaging.

OBJECTIVE: Histotripsy is an emerging non-invasive, non-ionizing and non-thermal focal tumor therapy. Although histotripsy targeting is currently based on ultrasound (US), other imaging modalities such as cone-beam computed tomography (CBCT) have recently been proposed to enable the treatment of tumors not visible on ultrasound. The objective of this study was to develop and evaluate a multi-modality phantom to facilitate the assessment of histotripsy treatment zones on both US and CBCT imaging. METHODS: Fifteen red blood cell phantoms composed of alternating layers with and without barium were manufactured. Spherical 25-mm histotripsy treatments were performed, and treatment zone size and location were measured on CBCT and ultrasound. Sound speed, impedance and attenuation were measured for each layer type. RESULTS: The average ± standard deviation signed difference between measured treatment diameters was 0.29 ± 1.25 mm. The Euclidean distance between measured treatment centers was 1.68 ± 0.63 mm. The sound speed in the different layers ranged from 1491 to 1514 m/s and was within typically reported soft tissue ranges (1480-1560 m/s). In all phantoms, histotripsy resulted in sharply delineated treatment zones, allowing segmentation in both modalities. CONCLUSION: These phantoms will aid in the development and validation of X-ray-based histotripsy targeting techniques, which promise to expand the scope of treatable lesions beyond only those visible on ultrasound.

In silico simulation of hepatic arteries: An open-source algorithm for efficient synthetic data generation.

BACKGROUND: In silico testing of novel image reconstruction and quantitative algorithms designed for interventional imaging requires realistic high-resolution modeling of arterial trees with contrast dynamics. Furthermore, data synthesis for training of deep learning algorithms requires that an arterial tree generation algorithm be computationally efficient and sufficiently random. PURPOSE: The purpose of this paper is to provide a method for anatomically and physiologically motivated, computationally efficient, random hepatic arterial tree generation. METHODS: The vessel generation algorithm uses a constrained constructive optimization approach with a volume minimization-based cost function. The optimization is constrained by the Couinaud liver classification system to assure a main feeding artery to each Couinaud segment. An intersection check is included to guarantee non-intersecting vasculature and cubic polynomial fits are used to optimize bifurcation angles and to generate smoothly curved segments. Furthermore, an approach to simulate contrast dynamics and respiratory and cardiac motion is also presented. RESULTS: The proposed algorithm can generate a synthetic hepatic arterial tree with 40 000 branches in 11 s. The high-resolution arterial trees have realistic morphological features such as branching angles (MAD with Murray's law = 1.2 ± 1 . 2 o $ = \;1.2 \pm {1.2^o}$ ), radii (median Murray deviation = 0.08 $ = \;0.08$ ), and smoothly curved, non-intersecting vessels. Furthermore, the algorithm assures a main feeding artery to each Couinaud segment and is random (variability = 0.98 ± 0.01). CONCLUSIONS: This method facilitates the generation of large datasets of high-resolution, unique hepatic angiograms for the training of deep learning algorithms and initial testing of novel 3D reconstruction and quantitative algorithms designed for interventional imaging.

Device safety assessment of bronchoscopic microwave ablation of normal swine peripheral lung using robotic-assisted bronchoscopy.

INTRODUCTION: The aim of this study was to assess the safety of bronchoscopic microwave ablation (MWA) of peripheral lung parenchyma using the NEUWAVE™ FLEX Microwave Ablation System, and robotic-assisted bronchoscopy (RAB) using the MONARCH™ Platform in a swine model. METHODS: Computed tomography (CT)-guided RAB MWA was performed in the peripheral lung parenchyma of 17 Yorkshire swine (40-50 kg) and procedural adverse events (AEs) documented. The acute group (day 0, n = 5) received 4 MWAs at 100 W for 1, 3, 5, and 10 min in 4 different lung lobes. Subacute and chronic groups (days 3 and 30, n = 6 each) received one MWA (100 W, 10 min) per animal. RESULTS: The study was completed without major procedural complications. No postprocedural AEs including death, pneumothorax, bronchopleural fistula, hemothorax, or pleural effusions were observed. No gross or histological findings suggestive of thromboembolism were found in any organ. One 3-Day and one 30-Day swine exhibited coughing that required no medication (minor AEs), and one 30-Day animal required antibiotic medication (major AE) for a suspected lower respiratory tract infection that subsided after two weeks. CT-based volumetric estimates of ablation zones in the acute group increased in an ablation time-dependent (1-10 min) manner, whereas macroscopy-based estimates showed an increasing trend in ablation zone size. CONCLUSION: The NEUWAVE FLEX and MONARCH devices were safely used to perform single or multiple RAB MWAs. The preclinical procedural safety profile of RAB MWA supports clinical research of both devices to investigate efficacy in select patients with oligometastatic disease or primary NSCLC.

Hepatic and Renal Histotripsy in an Anticoagulated Porcine Model.

PURPOSE: 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. MATERIALS AND METHODS: Non-tumor-bearing pigs (n = 8; mean weight, 52.5 kg) were anticoagulated with warfarin (initial dose, 0.08 mg/kg) to a target prothrombin time (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 computed tomography (CT) imaging. Animals were observed for 7 days while continuing anticoagulation, followed by repeat CT and necropsy. RESULTS: All animals survived to complete the entire protocol with no signs of disability or distress. Three animals had hematuria (pink urine without clots). Baseline PT values (mean, 16.0 seconds) were elevated to 22.0 seconds (37.5% above baseline, P = .003) on the day of treatment and to 28.8 seconds (77.8% above baseline, P < .001) on the day of necropsy. At the time of treatment, 5 of 8 (63%) animals were at a therapeutic anticoagulation level, and all 8 animals (100%) reached therapeutic levels by the time of necropsy. There were no cases of intraparenchymal, peritoneal, or retroperitoneal hemorrhage associated with any treatments despite 5 of 7 (71%) liver and all 8 (100%) kidney treatments extending to the organ surface. CONCLUSIONS: Liver and kidney histotripsy seems safe with no elevated bleeding risk in this anticoagulated animal model, supporting the possibility of histotripsy treatments in patients on anticoagulation.

An X-Ray C-Arm Guided Automatic Targeting System for Histotripsy.

OBJECTIVE: Histotripsy is an emerging noninvasive, nonionizing and nonthermal focal cancer therapy that is highly precise and can create a treatment zone of virtually any size and shape. Current histotripsy systems rely on ultrasound imaging to target lesions. However, deep or isoechoic targets obstructed by bowel gas or bone can often not be treated safely using ultrasound imaging alone. This work presents an alternative x-ray C-arm based targeting approach and a fully automated robotic targeting system. METHODS: The approach uses conventional cone beam CT (CBCT) images to localize the target lesion and 2D fluoroscopy to determine the 3D position and orientation of the histotripsy transducer relative to the C-arm. The proposed pose estimation uses a digital model and deep learning-based feature segmentation to estimate the transducer focal point relative to the CBCT coordinate system. Additionally, the integrated robotic arm was calibrated to the C-arm by estimating the transducer pose for four preprogrammed transducer orientations and positions. The calibrated system can then automatically position the transducer such that the focal point aligns with any target selected in a CBCT image. RESULTS: The accuracy of the proposed targeting approach was evaluated in phantom studies, where the selected target location was compared to the center of the spherical ablation zones in post-treatment CBCTs. The mean and standard deviation of the Euclidean distance was 1.4 ±0.5 mm. The mean absolute error of the predicted treatment radius was 0.5 ±0.5 mm. CONCLUSION: CBCT-based histotripsy targeting enables accurate and fully automated treatment without ultrasound guidance. SIGNIFICANCE: The proposed approach could considerably decrease operator dependency and enable treatment of tumors not visible under ultrasound.

A C-arm photon counting CT prototype with volumetric coverage using multi-sweep step-and-shoot acquisitions.

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 anin vivoswine 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.

Staging Liver Fibrosis by Fibroblast Activation Protein Inhibitor PET in a Human-Sized Swine Model.

Current methods of staging liver fibrosis have notable limitations. We investigated the utility of PET in staging liver fibrosis by correlating liver uptake of 68Ga-labeled fibroblast activation protein inhibitor (FAPI) with histology in a human-sized swine model. Methods: Five pigs underwent baseline 68Ga-FAPI-46 (68Ga-FAPI) PET/MRI and liver biopsy, followed by liver parenchymal embolization, 8 wk of oral alcohol intake, endpoint 68Ga-FAPI PET/MRI, and necropsy. Regions of interest were drawn on baseline and endpoint PET images, and SUVmean 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 SUVmean with METAVIR score and CPA, respectively. Results: Liver 68Ga-FAPI uptake strongly correlated with CPA (r = 0.89, P < 0.001). 68Ga-FAPI uptake was significantly and progressively higher across F2 and F3/F4 fibrosis stages, with a respective median SUVmean 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 68Ga-FAPI uptake of baseline liver and endpoint liver sections staged as F0/F1, with a respective median SUVmean 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 68Ga-FAPI uptake and the histologic stage of liver fibrosis suggests that 68Ga-FAPI PET can play an impactful role in noninvasive staging of liver fibrosis, pending validation in patients.

Three-dimensional catheter navigation of airways using continuous-sweep limited angle fluoroscopy on a C-arm.

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 1 ± 0.5 mm for a stationary catheter and 2.9 ± 1.1 mm for a catheter moving at ∼ 1 cm / s . The average tip localization error was 1.3 ± 0.7 mm and 2.7 ± 1.8 mm , 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.

Real-time respiratory motion compensated roadmaps for hepatic arterial interventions.

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 prenavigational 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 seven 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 < 0.0001) for motion compensated displays compared to a noncompensated display (median probabilities of 86 and 69%, respectively). The average processing time per frame was 17 ms. CONCLUSIONS: The proposed respiratory motion compensated device guidance system increased the accuracy of the displayed device position relative to the hepatic vasculature. Additionally, the provided display modes combine both vessel and device information and do not require the mental integration of different displays by the physician. The processing times were well within the range of conventional clinical frame rates.

A technique for intra-procedural blood velocity quantitation using time-resolved 2D digital subtraction angiography.

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 < .0001). The application of projection angle and magnification corrections decreased variance to less than 5% the average baseline velocity (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 = <.01, Bias = 0.117 cm/s). CONCLUSION: The proposed method allows for accurate and precise calculation of blood velocities, in near real-time, from time resolved 2D DSAs.

A Quantitative Digital Subtraction Angiography Technique for Characterizing Reduction in Hepatic Arterial Blood Flow During Transarterial Embolization.

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-peak, respectively. RESULTS: Blood flow velocities calculated using qDSA showed a statistically significant difference (p < 0.01) between partial- and sub-stasis endpoints, whereas time-to-peak calculated using ccDSA did not show a significant difference. During the course of embolizations, the average correlation with volume of particles delivered was larger for qDSA (- 0.86) than ccDSA (0.36). There was a statistically smaller mean squared error (p < 0.01) and larger coefficient of determination (p < 0.01) for qDSA compared to ccDSA. On pathology, the degree of embolization as calculated by qDSA had a moderate, positive correlation (p < 0.01) with the tissue embolic particle density of ischemic regions within the embolized lobe. CONCLUSIONS: qDSA was able to quantitatively discriminate angiographic embolization endpoints and, compared to a commercially available ccDSA method, improve intra-procedural characterization of blood flow changes. Additionally, the qDSA endpoints correlated with tissue-level changes.

Histotripsy Ablations in a Porcine Liver Model: Feasibility of Respiratory Motion Compensation by Alteration of the Ablation Zone Prescription Shape.

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 (2.5 cm (AP) × 2.5 cm (ML) × 1.7 cm (CC), prescribed volume = 5.8 cc) or a sphere (2.5 cm all dimensions, prescribed volume 8.2 cc). Ventilatory tidal volume was held constant at 400 cc 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 × 3.1 cm, volume 13.2 cc, sphericity index 0.987) were closer to prescribed volume than spherical plan ablations (2.9 × 3.1 × 3.7 cm, volume 17.1 cc, sphericity index 0.953). Ellipsoid plan ablations were more spherical than sphere plan ablations, but the difference did not reach statistical significance (p = .0.06). 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 = .0.22). 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.

HIF2α Is an Essential Molecular Brake for Postprandial Hepatic Glucagon Response Independent of Insulin Signaling.

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.