Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate.

Consumption of fructose has risen markedly in recent decades owing to the use of sucrose and high-fructose corn syrup in beverages and processed foods1, and this has contributed to increasing rates of obesity and non-alcoholic fatty liver disease2-4. Fructose intake triggers de novo lipogenesis in the liver4-6, in which carbon precursors of acetyl-CoA are converted into fatty acids. The ATP citrate lyase (ACLY) enzyme cleaves cytosolic citrate to generate acetyl-CoA, and is upregulated after consumption of carbohydrates7. Clinical trials are currently pursuing the inhibition of ACLY as a treatment for metabolic diseases8. However, the route from dietary fructose to hepatic acetyl-CoA and lipids remains unknown. Here, using in vivo isotope tracing, we show that liver-specific deletion of Acly in mice is unable to suppress fructose-induced lipogenesis. Dietary fructose is converted to acetate by the gut microbiota9, and this supplies lipogenic acetyl-CoA independently of ACLY10. Depletion of the microbiota or silencing of hepatic ACSS2, which generates acetyl-CoA from acetate, potently suppresses the conversion of bolus fructose into hepatic acetyl-CoA and fatty acids. When fructose is consumed more gradually to facilitate its absorption in the small intestine, both citrate cleavage in hepatocytes and microorganism-derived acetate contribute to lipogenesis. By contrast, the lipogenic transcriptional program is activated in response to fructose in a manner that is independent of acetyl-CoA metabolism. These data reveal a two-pronged mechanism that regulates hepatic lipogenesis, in which fructolysis within hepatocytes provides a signal to promote the expression of lipogenic genes, and the generation of microbial acetate feeds lipogenic pools of acetyl-CoA.

Society of Interventional Radiology Foundation Funding to National Institutes of Health Funding: Report from the Society of Interventional Radiology Foundation/National Institutes of Health Task Force.

The Society of Interventional Radiology Foundation (SIRF) aims to support interventional radiology (IR) investigators by awarding numerous grants to promote the advancement of scientific knowledge in IR. Over the last 19 years, SIRF has awarded 227 research grants, amounting to more than $4.7 million. To increase the engagement of interventional radiologists and IR scientists with the National Institutes of Health (NIH), SIRF created a SIRF/NIH taskforce in 2020. Over the past couple of years, the task force has been working to assess the return on investment of SIRF grants in terms of NIH funding because this metric is an effective measure of assessing the early success of foundation funding. The objectives of this report are to assess SIRF funding from 2002 to 2020 and investigate the conversion of this funding into NIH grants by the same investigators. During the study period, more than $37.6 million in NIH funds were awarded to SIRF awardees, which shows a return of 8 NIH dollars for every 1 SIRF dollar invested.

A 5-Year Update on the IR Residency Match: 2022 National Survey Results of Program Directors and Matched Applicants Compared with 2017.

PURPOSE: To characterize the experiences of matched applicants (MAs) and program directors (PDs) in the 2022 interventional radiology (IR) residency Match and compare with 2017 data. METHODS: Surveys were distributed to IR PDs and MAs from the 2022 Match. Findings were compared with those of 2017 using the 2-sample t test and Fisher exact test. RESULTS: In total, 68 MAs (40%) and 47 PDs (52%) responded. Collected demographic traits were similar, including ongoing male predominance (77% of MAs, 83% of PDs). Moreover, 86% of MAs and 87% of PDs were "satisfied" with Match outcomes. Compared with those in 2017, MAs applied to more IR programs (P < .001). MAs reported more research (P = .003) and abstracts/publications (P < .001) and ranked these as more important than PDs did (P < .001 for both). Approximately 82% of PDs gave special attention to candidates who completed a visiting rotation at their institution; 60% of MAs and 95% of PDs believed virtual interviews resulted in overinterviewing (P < .001); both agreed they provided convenience and accessibility. Furthermore, 63% of MAs believed a Step 1 pass/fail system will be less equitable for applicants. Additional data on demographics, medical school experiences, applications, interviews, intern year, and rank process were reported. CONCLUSIONS: Satisfaction with Match results remained high from 2017 to 2022, although efforts are needed to improve applicants' ability to navigate the application process, address overapplying, and evaluate concerns regarding the Step 1 pass/fail system. These survey findings will help inform applicants and PDs for future match cycles.

Outcomes of Transarterial Embolization for Acute Nonvariceal Upper Gastrointestinal Bleeding: Correlation with Periprocedural Endoscopy.

PURPOSE: To evaluate gastric and intestinal mucosal changes on postembolic endoscopy and mortality after transarterial embolization (TAE) for upper gastrointestinal bleeding (UGIB). MATERIALS AND METHODS: An institutional review board-approved retrospective review of patients who underwent arteriography for refractory UGIB at a multicenter health system from December 2003 to August 2019 was performed. Two hundred sixty-nine patients underwent TAE for UGIB. Data on etiology of bleeding, embolization technique, pre-embolic and postembolic endoscopic results, blood product requirements, and mortality were collected from the medical record. Endoscopy results were compared at the site of the target lesion before and after TAE. Multivariable logistic regressions were performed to assess predictors of new adverse mucosal responses and mortality. RESULTS: The most common etiology of UGIB was peptic ulcer. Twenty-five percent (n = 68) of the patients had clinical evidence of rebleeding after TAE, and the 30-day mortality rate was 26% (n = 73). Eighty-eight (32%) patients underwent post-TAE endoscopy, with only 15% showing new adverse mucosal changes after embolization. Procedural characteristics, including vascular territory and embolic choice, were not significantly predictive of increased risk of development of adverse mucosal response after TAE or increased mortality risk. No patients in the study were found to have bowel lumen stenosis at the time of post-TAE endoscopy or at 6 year follow-up. CONCLUSIONS: TAE is a safe and effective intervention for patients with UGIB. Post-TAE endoscopy demonstrated that most patients had either stability or improvement in the target lesion after TAE, and only a minority of patients demonstrated adverse mucosal changes.

Urine DNA biomarkers for hepatocellular carcinoma screening.

BACKGROUND: Hepatocellular carcinoma (HCC) occurs in a well-defined high-risk patient population, but better screening tests are needed to improve sensitivity and efficacy. Therefore, we investigated the use of urine circulating tumour DNA (ctDNA) as a screening test. METHODS: Candidate markers in urine were selected from HCC and controls. We then enrolled 609 patients from five medical centres to test the selected urine panel. A two-stage model was developed to combine AFP and urine panel as a screening test. RESULTS: Mutated TP53, and methylated RASSF1a, and GSTP1 were selected as the urine panel markers. Serum AFP outperformed the urine panel among all cases of HCC, but the urine panel identified 49% of HCC cases with low AFP < 20 ng/ml. Using the two-stage model, the combined AFP and urine panel identified 148 of the 186 HCC cases (79.6% sensitivity at 90% specificity), which was 30% more than the cases detected with serum AFP alone. It also increased early-stage HCC detection from 62% to 92% (BCLC stage 0), and 40% to 77% (BCLC stage A). CONCLUSION: Urine ctDNA has promising diagnostic utility in patients in HCC, especially in those with low AFP and can be used as a potential non-invasive HCC screening test.

Transarterial Embolization Modulates the Immune Response within Target and Nontarget Hepatocellular Carcinomas in a Rat Model.

Background Transarterial embolization (TAE) is the most common treatment for hepatocellular carcinoma (HCC); however, there remain limited data describing the influence of TAE on the tumor immune microenvironment. Purpose To characterize TAE-induced modulation of the tumor immune microenvironment in a rat model of HCC and identify factors that modulate this response. Materials and Methods TAE was performed on autochthonous HCCs induced in rats with use of diethylnitrosamine. CD3, CD4, CD8, and FOXP3 lymphocytes, as well as programmed cell death protein ligand-1 (PD-L1) expression, were examined in three cohorts: tumors from rats that did not undergo embolization (control), embolized tumors (target), and nonembolized tumors from rats that had a different target tumor embolized (nontarget). Differences in immune cell recruitment associated with embolic agent type (tris-acryl gelatin microspheres [TAGM] vs hydrogel embolics) and vascular location were examined in rat and human tissues. A generalized estimating equation model and t, Mann-Whitney U, and χ2 tests were used to compare groups. Results Cirrhosis-induced alterations in CD8, CD4, and CD25/CD4 lymphocytes were partially normalized following TAE (CD8: 38.4%, CD4: 57.6%, and CD25/CD4: 21.1% in embolized liver vs 47.7% [P = .02], 47.0% [P = .01], and 34.9% [P = .03], respectively, in cirrhotic liver [36.1%, 59.6%, and 4.6% in normal liver]). Embolized tumors had a greater number of CD3, CD4, and CD8 tumor-infiltrating lymphocytes relative to controls (191.4 cells/mm2 vs 106.7 cells/mm2 [P = .03]; 127.8 cells/mm2 vs 53.8 cells/mm2 [P < .001]; and 131.4 cells/mm2 vs 78.3 cells/mm2 [P = .01]) as well as a higher PD-L1 expression score (4.1 au vs 1.9 au [P < .001]). A greater number of CD3, CD4, and CD8 lymphocytes were found near TAGM versus hydrogel embolics (4.1 vs 2.0 [P = .003]; 3.7 vs 2.0 [P = .01]; and 2.2 vs 1.1 [P = .03], respectively). The number of lymphocytes adjacent to embolics differed based on vascular location (17.9 extravascular CD68+ peri-TAGM cells vs 7.0 intravascular [P < .001]; 6.4 extravascular CD68+ peri-hydrogel embolic cells vs 3.4 intravascular [P < .001]). Conclusion Transarterial embolization-induced dynamic alterations of the tumor immune microenvironment are influenced by underlying liver disease, embolic agent type, and vascular location. © RSNA, 2022 Online supplemental material is available for this article. See also the editorials by Kennedy et al and by White in this issue.

Preintervention Computed Tomography Improves the Performance of Endovascular Intervention in Patients with Abdominopelvic Trauma.

PURPOSE: To evaluate the role of computed tomography (CT) and CT angiography in guiding endovascular arteriography (EA) and embolization in hemodynamically (HD) stable and unstable patients with abdominal and/or pelvic (AP) trauma. MATERIALS AND METHODS: A retrospective review was performed of patients with AP trauma who underwent EA with or without embolization (from January 2012 to August 2020) at an urban, level I trauma center. Patients aged <18 years or those undergoing EA outside of the abdomen and/or pelvis were excluded. Demographics, imaging findings, procedure length, contrast agent administration, laboratory values, and outcomes were compared on the basis of preprocedural imaging technique and hemodynamic status. RESULTS: A total of 190 patients with AP trauma underwent EA with or without embolization; among them, 123 were HD stable and underwent CT/CT angiography, whereas 67 were initially HD unstable and underwent operative management prior to EA. Of these patients, 38 underwent CT/CT angiography after hemodynamic stability was achieved prior to postoperative EA. The incidence of therapeutic embolization for arterial injury on EA was significantly higher in patients with preprocedural CT/CT angiography (65.8% vs 44.8%, P = .04). The positive and negative predictive values of CT angiography for arterial injury at the time of EA were 92.3% and 100%, respectively. Prior imaging was associated with a reduced contrast agent requirement at the time of EA and reduced transfusion requirement (P = .05 and P = .02). No significant differences were observed in adverse outcomes for patients undergoing preprocedural imaging. CONCLUSIONS: CT or CT angiography prior to EA for HD stable and unstable patients with AP trauma may improve the likelihood of therapeutic embolization and enable improved procedure metrics without increasing adverse outcomes.

Multicenter assessment of augmented reality registration methods for image-guided interventions.

PURPOSE: To evaluate manual and automatic registration times and registration accuracies on HoloLens 2 for aligning a 3D CT phantom model onto a CT grid, a crucial step for intuitive 3D navigation during CT-guided interventions; to compare registration times between HoloLens 1 and 2. METHODS: Eighteen participants in various stages of clinical training across two academic centers performed registration of a 3D CT phantom model onto a CT grid using HoloLens 2. Registration times and accuracies were compared among different registration methods, clinical experience levels, and consecutive attempts. Registration times were also compared retrospectively to prior HoloLens 1 results. RESULTS: Mean aggregate manual registration times were 27.7 s, 24.3 s, and 72.8 s for one-handed gesture, two-handed gesture, and Xbox controller, respectively; mean automatic registration time was 5.3 s (ANOVA p < 0.0001). No significant difference in registration times was found among attendings, residents and fellows, and medical students (p > 0.05). Significant improvements in registration times were detected across consecutive attempts using hand gestures (p < 0.01). Compared to prior HoloLens 1 data, hand gesture registration was 81.7% faster with HoloLens 2 (p < 0.05). Registration accuracies were not significantly different across manual registration methods, measuring at 5.9 mm, 9.5 mm, and 8.6 mm with one-handed gesture, two-handed gesture, and Xbox controller, respectively (p > 0.05). CONCLUSIONS: Manual registration times decreased significantly on HoloLens 2, approaching those of automatic registration and outperforming Xbox controller registration. Fast, adaptive, and accurate registration of holographic models of cross-sectional imaging is paramount for the implementation of augmented reality-assisted 3D navigation during CT-guided interventions.

Hyperpolarized Metabolic Imaging Detects Latent Hepatocellular Carcinoma Domains Surviving Locoregional Therapy.

BACKGROUND AND AIMS: Advances in cancer treatment have improved survival; however, local recurrence and metastatic disease-the principal causes of cancer mortality-have limited the ability to achieve durable remissions. Local recurrences arise from latent tumor cells that survive therapy and are often not detectable by conventional clinical imaging techniques. Local recurrence after transarterial embolization (TAE) of hepatocellular carcinoma (HCC) provides a compelling clinical correlate of this phenomenon. In response to TAE-induced ischemia, HCC cells adapt their growth program to effect a latent phenotype that precedes local recurrence. APPROACH AND RESULTS: In this study, we characterized and leveraged the metabolic reprogramming demonstrated by latent HCC cells in response to TAE-induced ischemia to enable their detection in vivo using dynamic nuclear polarization (DNP) magnetic resonance spectroscopic imaging (MRSI) of 13 carbon-labeled substrates. Under TAE-induced ischemia, latent HCC cells demonstrated reduced metabolism and developed a dependence on glycolytic flux to lactate. Despite the hypometabolic state of these cells, DNP-MRSI of 1-13 C-pyruvate and its downstream metabolites, 1-13 C-lactate and 1-13 C-alanine, predicted histological viability. CONCLUSIONS: These studies provide a paradigm for imaging latent, treatment-refractory cancer cells, suggesting that DNP-MRSI provides a technology for this application.

Pharmacodynamics and pharmacokinetics of hyperpolarized [1-13 C]-pyruvate in a translational oncologic model.

This study investigates the in vivo pharmacokinetics and pharmacodynamics of hyperpolarized [1-13 C]-pyruvate in a translational cancer model in order to inform the application of dynamic nuclear polarization (DNP)-enhanced magnetic resonance spectroscopic imaging (MRSI) as a tool for imaging liver cancer. Intratumoral metabolism within autochthonous hepatocellular carcinomas in male Wistar rats was analyzed by MRSI following hyperpolarized [1-13 C]-pyruvate injections with 80 mM (low dose [LD]) or 160 mM (high dose [HD]) pyruvate. Rats received (i) LD followed by HD injection, (ii) sequential LD injections with or without an interposed lactate dehydrogenase inhibitor (LDHi) injection, or (iii) a single LD injection. A subset of rats in (ii) were sacrificed immediately after imaging, permitting measurement of active LDH concentrations in tumor extracts. Urine and serum were collected before and after injections for rats in (iii). Comparison of LD and HD injections confirmed concentration-dependent variation of intratumoral metabolite fractions and intermetabolite ratios. In addition, quantification of the lactate-to-pyruvate ratio was sensitive to pharmacologic inhibition with intermetabolite ratios correlating with active LDH concentrations in tumor extracts. Finally, comparison of pre- and post-DNP urine collections revealed that pyruvate and the radical source are renally excreted after injection. These data demonstrate that DNP-MRSI facilitates real-time quantification of intratumoral metabolism that is repeatable and reflective of intracellular processes. A translational model system confirmed that interpretation requires consideration of probe dose, administration frequency and excretion.

Tissue metabolic profiling shows that saccharopine accumulates during renal ischemic-reperfusion injury, while kynurenine and itaconate accumulate in renal allograft rejection.

To examine metabolic differences between renal allograft acute cellular rejection (ACR) and ischemic-reperfusion injury (IRI), we transplanted MHC-mismatched kidneys and induced 28 min warm-IRI, and collected the ACR and IRI kidneys as well as their respective native and collateral control kidneys. We extracted metabolites from the kidney tissues and found the lysine catabolite saccharopine 12.5-fold enriched in IRI kidneys, as well as the immunometabolites itaconate and kynurenine in ACR kidneys. Saccharopine accumulation is known to be toxic to mitochondria and may contribute to IRI pathophysiology, while itaconate and kynurenine may be reflective of counterregulatory responses to immune activation in ACR.

Augmented and Mixed Reality: Technologies for Enhancing the Future of IR.

Augmented and mixed reality are emerging interactive and display technologies. These technologies are able to merge virtual objects, in either 2 or 3 dimensions, with the real world. Image guidance is the cornerstone of interventional radiology. With augmented or mixed reality, medical imaging can be more readily accessible or displayed in actual 3-dimensional space during procedures to enhance guidance, at times when this information is most needed. In this review, the current state of these technologies is addressed followed by a fundamental overview of their inner workings and challenges with 3-dimensional visualization. Finally, current and potential future applications in interventional radiology are highlighted.

Three-Dimensional Augmented Reality Visualization Informs Locoregional Therapy in a Translational Model of Hepatocellular Carcinoma.

PURPOSE: To evaluate the utility of visualizing preprocedural MR images in 3-dimensional (3D) space using augmented reality (AR) before transarterial embolization of hepatocellular carcinoma (HCC) in a preclinical model. MATERIALS AND METHODS: A total of 28 rats with diethylnitrosamine-induced HCCs > 5 mm treated with embolization were included in a prospective study. In 12 rats, 3D AR visualization of preprocedural MR images was performed before embolization. Procedural metrics including catheterization time and radiation exposure were compared vs a prospective cohort of 16 rats in which embolization was performed without AR. An additional cohort of 15 retrospective cases was identified and combined with the prospective control cohort (n = 31) to improve statistical power. RESULTS: A 37% reduction in fluoroscopy time, from 11.7 min to 7.4 minutes, was observed with AR when compared prospectively, which did not reach statistical significance (P = .12); however, when compared with combined prospective and retrospective controls, the reduction in fluoroscopy time from 14.1 min to 7.4 minutes (48%) was significant (P = .01). A 27% reduction in total catheterization time, from 42.7 minutes to 31.0 minutes, was also observed with AR when compared prospectively, which did not reach statistical significance (P = .11). No significant differences were seen in dose-area product or air kerma prospectively. CONCLUSIONS: Three-dimensional AR visualization of preprocedural imaging may aid in the reduction of procedural metrics in a preclinical model of transarterial embolization. These data support the need for further studies to evaluate the potential of AR in endovascular oncologic interventions.

MR Imaging Enables Real-Time Monitoring of In Vitro Electrolytic Ablation of Hepatocellular Carcinoma.

PURPOSE: To evaluate the capability of T2-weighted magnetic resonance (MR) imaging to monitor electrolytic ablation-induced cell death in real time. MATERIALS AND METHODS: Agarose phantoms arranged as an electrolytic cell were exposed to varying quantities of electric charge under constant current to create a pH series. The pH phantoms were subjected to T2-weighted imaging with region of interest quantitation of the acquired signal intensity. Subsequently, hepatocellular carcinoma (HCC) cells encapsulated in an agarose gel matrix were subjected to 10 V of electrolytic ablation for variable lengths of time with and without concurrent T2-weighted MR imaging. Cellular death was confirmed by a fluorescent reporter. Finally, to confirm that real-time MR images corresponded to ablation zones, 10 V electrolytic ablations were performed followed by the addition of pH-neutralizing 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer. RESULTS: Analysis of MR imaging from agarose gel pH phantoms demonstrated a relationship between signal intensity and pH at the anodes and cathodes. The steep negative phase of the anode model (pH < 3.55) and global minimum of the cathode model (pH ≈ 11.62) closely approximated established cytotoxic pH levels. T2-weighted MR imaging demonstrated a strong correlation of ablation zones with regions of HCC cell death (r = 0.986; R2 = 0.916; P < .0001). The addition of HEPES buffer to the hydrogel resulted in complete obliteration of MR imaging-observed ablation zones, confirming that change in pH directly caused the observed signal intensity attenuation of the ablation zone. CONCLUSIONS: T2-weighted MR imaging enabled the real-time detection of electrolytic ablation zones, demonstrating a strong correlation with histologic cell death.

Fructose-1,6-bisphosphatase opposes renal carcinoma progression.

Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is characterized by elevated glycogen levels and fat deposition. These consistent metabolic alterations are associated with normoxic stabilization of hypoxia-inducible factors (HIFs) secondary to von Hippel-Lindau (VHL) mutations that occur in over 90% of ccRCC tumours. However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation, suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed the loss of several chromatin remodelling enzymes in a subset of ccRCC (these included polybromo-1, SET domain containing 2 and BRCA1-associated protein-1, among others), indicating that epigenetic perturbations are probably important contributors to the natural history of this disease. Here we used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) is uniformly depleted in over six hundred ccRCC tumours examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients. Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms. First, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin, thereby inhibiting a potential Warburg effect. Second, in pVHL (the protein encoded by the VHL gene)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in a catalytic-activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF inhibitory domain. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumour suppressors that are not consistently mutated in all tumours.

Angiographic Atlas of the Visceral Vascular Anatomy in Translational Rat Models.

PURPOSE: To characterize angiographic and cross-sectional imaging anatomy of the rat visceral vasculature in 2 translational models. MATERIALS AND METHODS: Animal studies were conducted in accordance with institutional guidelines and approval of the Institutional Animal Care and Use Committees. Retrospective review of digital subtraction arteriography was performed in 65 Wistar and 50 Sprague-Dawley male rats through a left common carotid artery or right common femoral artery approach. MR imaging of the abdomen was performed on the rats to correlate imaging modalities. RESULTS: Aortography was performed in 3 locations, including cranial to the celiac artery, cranial to the renal arteries, and cranial to the caudal (inferior) mesenteric artery, enabling characterization of the visceral branch arteries in all 65 Wistar rats. Selective arteriography of first-, second-, and third-order branch vessels of the aorta was performed allowing characterization of normal and variant anatomy. Dedicated selective arteriography was performed of the celiac artery in 65 Wistar and 10 Sprague-Dawley rats, of the common hepatic artery in 65 Wistar and 50 Sprague-Dawley rats, and of the cranial mesenteric artery in 43 Wistar rats. MR imaging enabled correlation with the lobar and portal venous anatomy. CONCLUSIONS: Analysis of arteriography and MR imaging in these rat models will provide translational researchers with anatomic details needed to develop new endovascular protocols for small animal research in interventional radiology.

Association of Complete Radiologic and Pathologic Response following Locoregional Therapy before Liver Transplantation with Long-Term Outcomes of Hepatocellular Carcinoma: A Retrospective Study.

PURPOSE: To evaluate long-term outcomes of patients with hepatocellular carcinoma (HCC) who show a complete response (CR) vs non-CR on pretransplantation imaging studies or pathologic evaluation of liver explants after locoregional therapy (LRT) before liver transplantation. MATERIALS AND METHODS: Patients listed for liver transplantation for HCC (March 1998 to December 2010) undergoing LRT with available multiphase MR/CT imaging before transplantation were included. Pathologic response was evaluated based on liver explant pathology. A total of 108 patients (17 women; 16%) met the inclusion criteria. RESULTS: Radiologic CR was achieved in 65 patients (60%) vs non-CR in 43 (40%), and pathologic CR was achieved in 36 patients (33%) vs non-CR in 72 (67%). Mean 5-year overall survival (OS) from the time of listing and recurrence-free survival (RFS) after liver transplantation were significantly better for patients with pathologic CR vs non-CR on explant pathology (OS, 83.3% vs 65.2% [28% difference; P = .046]; RFS, 80.6% vs 62.5% [29% difference; P = .045]). Mean 5-y OS and RFS were not significantly different between patients with radiologic CR or non-CR on pretransplantation imaging (OS, 75.4% vs 65.1% [P = .12]; RFS, 74% vs 62.8% [P = .17]). CONCLUSIONS: Achievement of a pathologic CR vs non-CR in response to LRT before liver transplantation for HCC is associated with improved OS from time of listing and improved RFS after liver transplantation. However, current imaging paradigms fall short of accurate delineation of response to LRT, resulting in poor correlation of outcomes between pathologic and radiologic CR.

Transarterial Chemoembolization within First 3 Months of Sorafenib Initiation Improves Overall Survival in Hepatocellular Carcinoma: A Retrospective, Multi-Institutional Study with Propensity Matching.

PURPOSE: The impact of transarterial chemoembolization after initiation of sorafenib (SOR) has not been prospectively compared with SOR alone in unresectable hepatocellular carcinoma (HCC). The objective of this study was to assess whether SOR + transarterial chemoembolization provides benefit over SOR alone in this setting. MATERIALS AND METHODS: A retrospective cohort study with propensity matching using data from patients prescribed SOR for HCC at Veterans Health Administration hospitals from 2007 to 2015. The primary outcome was overall survival from the time of SOR prescription and stratified by receipt of transarterial chemoembolization within 90 days of SOR initiation. RESULTS: A total of 4,896 patients received SOR for HCC, of whom 232 (4.7%) underwent transarterial chemoembolization within 90 days. Patients receiving transarterial chemoembolization + SOR were highly selected, being younger and with less significant hepatic dysfunction, earlier Barcelona Clinic Liver Cancer stage (P < .0001), and fewer tumors with lower rates of macrovascular invasion (MVI) and metastases (all P < .0001) than SOR-alone patients. In unadjusted analysis, SOR + transarterial chemoembolization was associated with reduced mortality (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.53-0.71; P < .0001). After propensity matching, SOR + transarterial chemoembolization continued to show significant associations with reduced mortality with HR 0.75 (95% CI 0.62-0.92; P = .0005). Subgroup analysis suggests that the addition of transarterial chemoembolization to SOR improves outcomes in most patients, particularly those with Model for End-Stage Liver Disease score <15, platelets >50,000/µL, and >3 tumors with or without macrovascular invasion, without local invasion or metastases. CONCLUSIONS: Patients with unresectable HCC started on systemic therapy with SOR appear to benefit from adjuvant transarterial chemoembolization. Optimal application of multimodal therapy in this setting should be prospectively investigated.

Combination of Neoadjuvant Transcatheter Arterial Chemoembolization and Orthotopic Liver Transplantation for the Treatment of Cirrhotomimetic Hepatocellular Carcinoma.

PURPOSE: To examine differences in outcome and response of cirrhotomimetic (CMM) hepatocellular carcinoma (HCC) to a combination of bridging transcatheter arterial chemoembolization and orthotopic liver transplantation (OLT) compared with non-CMM HCC. MATERIALS AND METHODS: All patients with pathologically proven CMM HCC who underwent bridging transcatheter arterial chemoembolization before OLT between 2007 and 2013 (n = 23) were retrospectively compared with a control group of patients with pathologically proven non-CMM HCC (n = 46). RESULTS: There were 29 tumors in the CMM HCC group and 64 tumors in the non-CMM group identified and treated. Objective response rate on MR imaging at 1 and 3 months after transcatheter arterial chemoembolization for CMM HCC tumors (including patients with complete and partial response) was 93.1% and 86.4% compared with 85.2% and 93.2% for non-CMM tumors without statistically significant difference (P = .54 and P = .09, respectively). Pathologic study of liver explants showed complete tumor necrosis in 62.3% of non-CMM tumors (38/61) compared with 10.3% of CMM tumors (3/29) (P < .0001). Overall 2-year survival after transcatheter arterial chemoembolization and OLT was significantly lower for patients with CMM HCC compared with patients non-CMM HCC (65.2% vs 87%, P = .03). Patients with CMM HCC with extranodular tumor extension involving > 50% of liver parenchyma had worse survival with mean 2-year survival of 402 days ± 102 vs 656 days ± 39 for the remaining patients with CMM HCC (P = .02). CONCLUSIONS: Despite similar early imaging response rates, CMM HCC tumors had markedly lower rates of complete pathologic necrosis on liver explants and were associated with reduced survival after OLT compared with conventional HCCs.

Near-Infrared Fluorescence Imaging of Matrix Metalloproteinase 2 Activity as a Biomarker of Vascular Remodeling in Hemodialysis Access.

PURPOSE: To establish the capability of near-infrared fluorescence (NIRF) imaging for the detection of matrix metalloproteinase 2 (MMP-2) activity as a biomarker of vascular remodeling (VR) in arteriovenous fistulae (AVFs) in vivo. MATERIALS AND METHODS: AVFs were created in the right groins of Wistar rats (n = 10), and sham procedures were performed in the contralateral groins. Fistulography via a left common carotid artery approach confirmed stenosis (> 50%) in a subset of animals (n = 5) 4 weeks after AVF creation. After administration of MMP-2-activated NIRF probe, near-infrared imaging was performed in vivo and ex vivo of both the AVF and the sham-treated vessels to measure radiant efficiency of MMP-2-activated NIRF signal over background. Histologic analyses of AVF and sham-treated vessels were performed to measure VR defined as inward growth of the vessel caused by intimal thickening. RESULTS: AVFs demonstrated a significantly higher percentage increase in radiant efficiency over background compared with sham vessels (45.5 ± 56% vs 16.1 ± 17.8%; P = .008). VR in AVFs was associated with increased thickness of neointima staining positively for MMP-2 (161.8 ± 45.5 µm vs 73.2 ± 36.7 µm; P = .01). A significant correlation was observed between MMP-2 activity as measured by relative increase in radiant efficiency for AVFs and thickness of neointima staining positively for MMP-2 (P = .039). CONCLUSIONS: NIRF imaging can detect increased MMP activity in remodeled AVFs compared with contralateral sham vessels. MMP-2-activated NIRF signal correlates with the severity of intimal thickening. These findings suggest NIRF imaging of MMP-2 may be used as a biomarker of the vascular remodeling underlying stenosis.