Hepatobiliary infection after transjugular intrahepatic portosystemic shunt creation in patients with prior biliary intervention: A multi-institution retrospective study.

PURPOSE: To estimate the risk of hepatobiliary infection, including endoTIPSitis, liver abscesses, and cholangitis, after transjugular intrahepatic portosystemic shunt (TIPS) creation in patients with prior biliary intervention. MATERIALS AND METHODS: This multi-institution, retrospective study identified 76 patients (n=48 males; mean age 54.9; mean model for end stage liver disease score=13.2; n=45 for ascites and n=23 for varices; n=31 with prior liver transplantation) among 2,130 undergoing TIPS (3.6%) who had prior biliary intervention (n=19 bilioenteric anastomoses, n=35 sphincterotomies, n=28 internal plastic stents, n=4 internal metal stents, and n=6 percutaneous biliary drains). The baseline risk of post-TIPS hepatobiliary infection was estimated from a control group of 1,202 TIPS procedures in patients without prior biliary intervention. RESULTS: Eleven of 76 patients (14.5%) developed hepatobiliary infection after TIPS, including 7 with endoTIPSitis, 4 with hepatic abscesses, and 2 with cholangitis. The 30-day risk of infection was 10.9% (95% CI=3.5-17.8%), significantly higher than the 0.4% risk (95% CI=0.1-0.8%) observed in patients without prior biliary intervention (hazard ratio (HR)=25.56, 95% CI=8.36-78.13, p<0.001). All types of biliary intervention were associated with increased risk of infection, with bilioenteric anastomoses conferring the highest risk. Paradoxically, among patients with prior biliary intervention, use of post-procedural antibiotic prophylaxis was associated with an increased infection risk (HR=19.85; 95% CI=2.44-161.50; p=0.005). Microbial culture data showed high rates of Enterococcus, Klebsiella, and Candida species. CONCLUSIONS: Prior biliary intervention was associated with a 10.9% risk of hepatobiliary infection, including endoTIPSitis, liver abscess, and cholangitis, within 30 days after TIPS creation.

Society of Interventional Radiology Research Reporting Standards for Genicular Artery Embolization.

Genicular artery embolization (GAE) is an emerging, minimally invasive therapy to address the global burden of knee osteoarthritis (OA) and the unmet needs for medically refractory disease. Although total knee arthroplasty has been a standard intervention for severe cases, GAE is developing into a promising alternative, particularly for patients ineligible for or unwilling to undergo surgery. GAE targets the inflammatory cascade underlying OA pathophysiology by arresting neoangiogenesis and preventing pathological neoinnervation, offering potential pain relief. Although early studies have established safety and short-term effectiveness, ensuing studies are needed to validate long-term safety, durability, and comparative effectiveness and to optimize patient selection, embolic agent selection, and administration techniques. Standardized reporting guidelines are therefore essential to enhance transparency and reproducibility across clinical trials, facilitating data aggregation and comparison. This Society of Interventional Radiology (SIR)-endorsed reporting standards consensus document provides a framework to harmonize future research efforts and to improve the interpretation of outcomes.

Hepatocellular Carcinoma Epigenetic Patterns Correspond to Differences in Ethnoracial Status and Treatment Response in a Single-Center Retrospective Study.

PURPOSE: To correlate epigenetic patterns with ethnoracial status and locoregional therapy (LRT) response in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: DNA and RNA were extracted from 47 distinct formalin-fixed paraffin-embedded tumor samples from 42 patients with HCC (n = 14 Black, n = 19 White, n = 9 Hispanic). LRT response was determined using computed tomography (CT) or magnetic resonance (MR) imaging 3 months posttreatment of 35 tumors (n = 22 complete response, n = 13 retreatment candidates). RNA expression and DNA methylation were used to stratify patients by ethnoracial status and treatment response using partial least-squares discriminant analysis (PLS-DA). Results were validated using hierarchical clustering. Ingenuity pathway analysis was performed to identify upstream regulators and pathways. RESULTS: PLS-DA identified 100 genes and 12 methylated regions that differentiated tumors from Black from White/Hispanic patients. Hierarchical clustering clustered samples with the top 16 genes or the top 5 methylation regions. Dysregulated pathways included adrenomedullin pathway (P = .030), EIF2 signaling (P = .007), and several metabolic pathways. AGTR1 (log2fold = 1.59) and GSTM3 (log2fold = 2.53) represented potential differentially expressed therapeutic targets. PLS-DA identified 100 genes and 150 methylation regions that differentiated between complete responders and retreatment candidates. Hierarchical clustering clustered samples with the top 30 genes or the top 13 methylation regions. Dysregulated pathways included metabolic and DNA repair-related pathways. ASAP2 (log2fold = 0.29) and RAD50 (log2fold = 0.22) represented potential differentially expressed therapeutic targets. CONCLUSIONS: Variation in gene expression and DNA methylation patterns in patients with HCC corresponded to ethnoracial status and LRT response. These initial results suggest tumor profiling has the potential to close ethnoracial disparities and improve treatment stratification.

Combined Spontaneous Portosystemic Shunt Embolization and Transjugular Intrahepatic Portosystemic Shunt Creation for Treatment of Hepatic Encephalopathy.

This retrospective case series assessed the early effectiveness of combined spontaneous portosystemic shunt (SPSS) embolization and preemptive transjugular intrahepatic portosystemic shunt (TIPS) creation for alleviation of medically refractory hepatic encephalopathy (HE) and prevention of portal hypertension complications in patients with liver cirrhosis. Eight patients with liver cirrhosis (5 men and 3 women; mean age, 61 years [SD ± 10]) and HE (overt [West-Haven Grade 2-4], n = 7; covert [West-Haven Grade 1], n = 1) refractory to lactulose and rifaximin therapy who underwent concurrent or staged SPSS embolization and TIPS creation between 2018 and 2022 were included in this study. The primary outcomes were 3-month improvement in HE and postprocedural HE-related hospitalizations. HE improvement was achieved in 7 (87.5%) of 8 cases. Among all patients, there was 1 HE-related hospitalization within 90 days that responded to repeat embolization with no further admissions. No patients developed new ascites, variceal hemorrhage, or other portal hypertension complications within 3 months.

Pigs as Clinically Relevant Models for Synergizing Interventional Oncology and Immunotherapy.

Traditionally, rodent cancer models have driven preclinical oncology research. However, they do not fully recapitulate characteristics of human cancers, and their size poses challenges when evaluating tools in the interventional oncologists' armamentarium. Pig models, however, have been the gold standard for validating surgical procedures. Their size enables the study of image-guided interventions using human ultrasound (US), computed tomography (CT), and magnetic resonance (MR) imaging platforms. Furthermore, pigs have immunologic features that are similar to those of humans, which can potentially be leveraged for studying immunotherapy. Novel pig models of cancer are being developed, but additional research is required to better understand both the pig immune system and malignancy to enhance the potential for pig models in interventional oncology research. This review aims to address the main advantages and disadvantages of using a pig model for interventional oncology and outline the specific characteristics of pig models that make them more suitable for investigation of locoregional therapies.

Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt Creation.

Transjugular intrahepatic portosystemic shunt (TIPS) creation is effective in treating the sequelae of decompensated liver cirrhosis-including medically refractory ascites and variceal bleeding-by decompressing the portal venous system through a manmade portosystemic conduit within the liver. However, the altered physiology in which splenomesenteric blood bypasses intrahepatic portal venous perfusion can precipitate varying degrees of hepatic encephalopathy (HE). While the majority of post-TIPS HE cases can be treated medically, some require escalated management strategies, including endovascular interventions to modify the indwelling TIPS and/or occlude competitive physiologic spontaneous portosystemic shunts. This review article details the epidemiology, risk factors, diagnosis, classification, and treatment of post-TIPS HE.

Endovascular Assessment of Liver Hemodynamics in Patients with Cirrhosis Complicated by Portal Hypertension.

The hepatic venous pressure gradient (HVPG) is currently considered the gold standard to assess portal hypertension (PH) in patients with cirrhosis. A meticulous technique is important to achieve accurate and reproducible results, and values obtained during measurement are applied in risk stratification of patients with PH, allocating treatment options, monitoring follow-up, and deciding management options in surgical patients. The use of portosystemic pressure gradients in patients undergoing placement of transjugular intrahepatic portosystemic shunts has been studied extensively and has great influence on decisions on shunt diameter. The purpose of this study was to describe the recommended technique to measure HVPG and portosystemic pressure gradient and to review the existing literature describing the importance of these hemodynamic measurements in clinical practice.

Clinical Outcomes and Patency after Transjugular Intrahepatic Portosystemic Shunt Reduction for Overshunting Adverse Events.

PURPOSE: To assess clinical outcomes and patency after transjugular intrahepatic portosystemic shunt (TIPS) reduction for overshunting adverse events. MATERIALS AND METHODS: This multicenter, retrospective observational study included 33 patients (male-to-female ratio, 20:13; mean age, 59 years; mean Model for End-Stage Liver Disease [MELD] score, 15) who underwent TIPS reduction between 2007 and 2020. Procedure indications included medically refractory hepatic encephalopathy (HE) (85%), post-TIPS hepatic insufficiency (HI) (12%), and heart failure (3%). The measured outcomes included improvement in HE (classified using the West Haven system) and HI, patency of reduced TIPS, and transplant-free survival (TFS). RESULTS: TIPS reductions were successfully performed using parallel stent (94%) or other (6%) techniques at a median of 120 days after TIPS creation (HE, median, 164 days; HI, median, 5 days). The portosystemic pressure gradient increased from a mean of 10 to 17 mm Hg (P < .001). The overall HE rate after TIPS reduction was 54%; HE was persistent, improved, and resolved in 21%, 32%, and 46% cases, respectively. In patients with HI, the MELD score increased from a mean of 22 before TIPS to 34 after TIPS (P = .061), but without improvement (0%) in HI after TIPS reduction (mean MELD score, 30; P = .266). Recurrent ascites occurred in 14% of the patients. The median shunt patency was 961 days (95% confidence interval, 476-1,447). The 30-day, 6-month, 1-year, and 3-year shunt patency rates were 92%, 81%, 74%, and 37%, respectively. The median TFS was not reached. The 30-day, 6-month, 1-year, and 3-year survival rates were 97%, 90%, 81%, and 60%, respectively. CONCLUSIONS: Although TIPS reduction may be an effective and durable approach to treat post-TIPS medically refractory HE, shunt reduction may not achieve meaningful benefit for HI.

Pharmacokinetics and Early Tumor Response to Conventional Transarterial Chemoembolization with Sorafenib and Doxorubicin in a VX2 Rabbit Tumor Model.

PURPOSE: To investigate the pharmacokinetics (PK) and early effects of conventional transarterial chemoembolization (TACE) using sorafenib and doxorubicin on tumor necrosis, hypoxia markers, and angiogenesis in a rabbit VX2 liver tumor model. MATERIALS AND METHODS: VX2 tumor-laden New Zealand White rabbits (N = 16) were divided into 2 groups: 1 group was treated with hepatic arterial administration of ethiodized oil and doxorubicin emulsion (DOX-TACE), and the other group was treated with ethiodized oil, sorafenib, and doxorubicin emulsion (SORA-DOX-TACE). Animals were killed within 3 days of the procedure. Levels of sorafenib and doxorubicin were measured in blood, tumor, and adjacent liver using mass spectrometry. Tumor necrosis was determined by histopathological examination. Intratumoral hypoxia-inducible factor (HIF) 1α, vascular endothelial growth factor (VEGF), and microvessel density (MVD) were determined by immunohistochemistry. RESULTS: The median intratumoral concentration of sorafenib in the SORA-DOX-TACE group was 17.7 µg/mL (interquartile range [IQR], 7.42-33.5 µg/mL), and its maximal plasma concentration (Cmax) was 0.164 µg/mL (IQR, 0.0798-0.528 µg/mL). The intratumoral concentration and Cmax of doxorubicin were similar between the groups: 4.08 µg/mL (IQR, 3.18-4.79 µg/mL) and 0.677 µg/mL (IQR, 0.315-1.23 µg/mL), respectively, in the DOX-TACE group and 1.68 µg/mL (IQR, 0.795-4.08 µg/mL) and 0.298 µg/mL (IQR, 0.241-0.64 µg/mL), respectively, in the SORA-DOX-TACE group. HIF-1α expression was increased in the SORA-DOX-TACE group than in the DOX-TACE group. Tumor volume, tumor necrosis, VEGF expression, and MVD were similar between the 2 groups. CONCLUSIONS: The addition of sorafenib to DOX-TACE delivered to VX2 liver tumors resulted in high intratumoral and low systemic concentrations of sorafenib without altering the PK of doxorubicin.

Effect of CRISPR Knockout of AXIN1 or ARID1A on Proliferation and Migration of Porcine Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive disease lacking effective treatment. Animal models of HCC are necessary for preclinical evaluation of the safety and efficacy of novel therapeutics. Large animal models of HCC allow testing image-guided locoregional therapies, which are widely used in the management of HCC. Models with precise tumor mutations mimicking human HCC provide valuable tools for testing precision medicine. AXIN1 and ARID1A are two of the most frequently mutated genes in human HCC. Here, we investigated the effects of knockout of AXIN1 and/or ARID1A on proliferation, migration, and chemotherapeutic susceptibility of porcine HCC cells and we developed subcutaneous tumors harboring these mutations in pigs. Gene knockout was achieved by CRISPR/Cas9 and was validated by Next Generation Sequencing. AXIN1 knockout increased the migration of porcine HCC cells but did not alter the cell proliferation. Knockout of ARID1A increased both the proliferation and migration of porcine HCC cells. Simultaneous knockout of AXIN1 and ARID1A increased the migration, but did not alter the proliferation of porcine HCC cells. The effect of gene knockout on the response of porcine HCC cells to two of the most commonly used systemic and locoregional HCC treatments was investigated; sorafenib and doxorubicin, respectively. Knockout of AXIN1 and/or ARID1A did not alter the susceptibility of porcine HCC cells to sorafenib or doxorubicin. Autologous injection of CRISPR edited HCC cells resulted in development of subcutaneous tumors in pigs, which harbored the anticipated edits in AXIN1 and/or ARID1A. This study elucidates the effects of CRISPR-mediated knockout of HCC-associated genes in porcine HCC cells, and lays the foundation for development and utilization of genetically-tailored porcine HCC models for in vivo testing of novel therapeutic approaches in a clinically-relevant large animal model.

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.

Evaluation of a clinical decision support tool to predict permanence of retrievable inferior vena cava filters.

OBJECTIVE: To evaluate the usefulness of a published clinical decision support tool to predict the likelihood of a retrievable inferior vena cava (IVC) filter being maintained as a permanent device. METHODS: This multicenter retrospective cohort study included 1498 consecutive patients (852 men and 646 women; median age, 60 years; range, 18-98 years) who underwent retrievable IVC filter insertion between January 2012 and December 2019. The indications for IVC filtration, baseline neurologic disease, history of venous thromboembolism (VTE), and underlying malignancy were recorded. Accuracy, sensitivity, and specificity of a published clinical support tool were calculated to determine the usefulness of the tool. RESULTS: The majority of filters (1271/1498 [85%]) were placed for VTE with a contraindication to anticoagulation. A history of VTE was present in 811 of 1498 patients (54%) patients; underlying malignancy in 531 of 1498 patients (35%), and neurological disease in 258 of 1498 patients (17%). Of the 1498 filters, 456 (30%) were retrieved, 276 (18%) were maintained as permanent devices on follow-up, and 766 (51%) filters were not retrieved. The accuracy of the clinical prediction model was 61%, sensitivity was 60%, and specificity was 62%. CONCLUSIONS: A previously published clinical decision support tool to predict permanence of IVC filters had modest usefulness in the examined population; this factor should be taken into account when using this clinical decision support tool outside of the original study population. Future studies are required to refine the predictive capability of IVC filter decision support tools for broader use across different patient populations.

Conventional versus drug-eluting embolic transarterial chemoembolization with doxorubicin: comparative drug delivery, pharmacokinetics, and treatment response in a rabbit VX2 tumor model.

The purpose of this study was to compare intra-tumoral drug delivery, pharmacokinetics, and treatment response after doxorubicin (DOX) conventional (c-) versus drug-eluting embolic (DEE-) transarterial chemoembolization (TACE) in a rabbit VX2 liver tumor model. Twenty-four rabbits with solitary liver tumors underwent c-TACE (n = 12) (1:2 water-in-oil emulsion, 0.6 mL volume, 2 mg DOX) or DEE-TACE (n = 12) (130,000 70-150 µm 2 mg DOX-loaded microspheres). Systemic, intra-tumoral, and liver DOX levels were measured using mass spectrometry up to 7-day post-procedure. Intra-tumoral DOX distribution was quantified using fluorescence imaging. Percent tumor necrosis was quantified by a pathologist blinded to treatment group. Lobar TACE was successfully performed in all cases. Peak concentration (CMAX, µg/mL) for plasma, tumor tissue, and liver were 0.666, 4.232, and 0.270 for c-TACE versus 0.103, 8.988, and 0.610 for DEE-TACE. Area under the concentration versus time curve (AUC, µg/mL ∗ min) for plasma, tumor tissue, and liver were 18.3, 27,078.8, and 1339.1 for c-TACE versus 16.4, 26,204.8, and 1969.6 for DEE-TACE. A single dose of intra-tumoral DOX maintained cytotoxic levels through 7-day post-procedure for both TACE varieties, with a half-life of 1.8 (c-TACE) and 0.8 (DEE-TACE) days. Tumor-to-normal liver DOX ratio was high (c-TACE, 20.2; DEE-TACE, 13.3). c-TACE achieved significantly higher DOX coverage of tumor vs. DEE-TACE (10.8% vs. 2.3%; P = 0.003). Percent tumor necrosis was similar (39% vs. 37%; P = 0.806). In conclusion, in a rabbit VX2 liver tumor model, both c-TACE and DEE-TACE achieved tumoricidal intra-tumoral DOX levels and high tumor-to-normal liver drug ratios, though c-TACE resulted in significantly greater tumor coverage.

Transcriptional Profiling of Porcine HCC Xenografts Provides Insights Into Tumor Cell Microenvironment Signaling.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, representing the most common form of liver cancer. As HCC incidence and mortality continue to increase, there is a growing need for improved translational animal models to bridge the gap between basic HCC research and clinical practice to improve early detection and treatment strategies for this deadly disease. Recently the Oncopig cancer model-a novel transgenic swine model that recapitulates human cancer through Cre recombinase induced expression of KRAS G12D and TP53 R167H driver mutations-has been validated as a large animal translational model for human HCC. Due to the similar size, anatomy, physiology, immunology, genetics, and epigenetics between pigs and humans, the Oncopig has the potential to improve translation of novel diagnostic and therapeutic modalities into clinical practice. Recent studies have demonstrated the importance of tumor cells in shaping its surrounding microenvironment into one that is more proliferative, invasive, and metastatic; however, little is known about the impact of microenvironment signaling on HCC tumor biology and differential gene expression between HCC tumors and its tumor microenvironment (TME). In this study, transcriptional profiling was performed on Oncopig HCC xenograft tumors (n = 3) produced via subcutaneous injection of Oncopig HCC cells into severe combined immunodeficiency (SCID) mice. To differentiate between gene expression in the tumor and surrounding tumor microenvironment, RNA-seq reads originating from porcine (HCC tumor) and murine (microenvironment) cells were bioinformatically separated using Xenome. Principle component analysis (PCA) demonstrated clustering by group based on the expression of orthologous genes. Genes contributing to each principal component were extracted and subjected to functional analysis to identify alterations in pathway signaling between HCC cells and the microenvironment. Altered expression of genes associated with hepatic fibrosis deposition, immune response, and neo angiogenesis were observed. The results of this study provide insights into the interplay between HCC and microenvironment signaling in vivo, improving our understanding of the interplay between HCC tumor cells, the surrounding tumor microenvironment, and the impact on HCC development and progression.