Leigh C. Casadaban

Development, growth, propagation, and angiographic utilization of the rabbit VX2 model of liver cancer: a pictorial primer and "how to" guide

The VX2 tumor is a leporine anaplastic squamous cell carcinoma characterized by rapid growth, hypervascularity, and facile propagation in the skeletal muscle. Since its introduction over 70 years ago, it has been used to model a variety of malignancies, and is commonly employed by interventional radiologists in preclinical investigations of hepatocellular carcinoma. However, despite the widespread and lasting popularity of the model, there are few technical resources detailing its use. Herein, we present a comprehensive pictorial outline of the technical methodology for development, growth, propagation, and angiographic utilization of the rabbit VX2 liver tumor model.

Characteristics of Primary and Secondary Hepatic Malignancies Associated with Hepatopulmonary Shunting

PURPOSE To identify liver tumor characteristics associated with low (<10%), intermediate (10%-20%), and high (>20%) lung shunt fraction (LSF) at technetium 99m ((99m)Tc) macroaggregated albumin (MAA) imaging performed before yttrium 90 ((90)Y) radioembolization (RE). MATERIALS AND METHODS In this single-center retrospective study, 141 patients (70 with hepatocellular carcinoma [HCC], 71 with other tumors; 95 men, 45 women; median age, 61 years) underwent mapping arteriography with (99m)Tc-MAA LSF calculation before (90)Y RE from 2006 to 2012. Tumor characteristics, including tumor type, index lesion size and morphologic structure (circumscribed, infiltrative), focality (solitary oligonodular, multinodular), disease distribution (unilobar, bilobar), tumor burden (≤50%, 50%), portal vein invasion (present, absent), and arterioportal shunting (present, absent) were correlated with (99m)Tc-MAA imaging-calculated LSFs at univariate and multivariate analysis. RESULTS Median LSF was 8.4% (HCC, 9.0%; other tumors, 8.3%). LSF greater than 20% occurred in 14% of HCCs, but only in 3% of other tumors (P = .004). For HCC, tumor morphologic structure (P = .022), tumor burden (P < .001), main portal vein invasion (P = .033), and arterioportal shunting (P < .001) were significantly associated with different LSF categories at univariate analysis; infiltrative morphologic structure, tumor burden greater than 50%, portal vein invasion, and shunting had confirmed association with high LSF at multivariate analysis. For other liver tumors, tumor size (P = .001) and tumor burden (P = .003) were significantly associated with different LSF categories at univariate analysis. Multivariate confirmation was precluded by small sample size. Patients underwent a median of one (90)Y RE session (range, one to six), with median per-treatment and cumulative lung doses of 6.0 Gy and 8.5 Gy, respectively. CONCLUSION LSF greater than 20% periodically occurs in HCC but is uncommon in other liver tumors. Specific tumor characteristics are associated with LSF greater than 20% and may indicate need for interventions to reduce LSF.

Adjuvant chemotherapy is associated with improved survival in patients with stage II colon cancer

The role of adjuvant chemotherapy in patients with stage II colon cancer remains to be elucidated and its use varies between patients and institutions. Currently, clinical guidelines suggest discussing adjuvant chemotherapy for patients with high‐risk stage II disease in the absence of conclusive randomized controlled trial data. To further investigate this relationship, the objective of the current study was to determine whether an association exists between overall survival (OS) and adjuvant chemotherapy in patients stratified by age and pathological risk features.

Should transjugular intrahepatic portosystemic shunt stent grafts be underdilated

Although underdilation of transjugular intrahepatic portosystemic shunt (TIPS) stent grafts is commonly performed to limit complications arising from excessive portosystemic shunting, it is uncertain whether underdilated stents retain their smaller diameter indefinitely or eventually expand to nominal caliber. In this investigation, postprocedure computed tomography (CT) was used to compare diameters of underdilated TIPSs and TIPSs expanded to a nominal diameter of 10 mm in 61 cases. The groups had comparable shunt diameters on post-TIPS imaging (9.8 mm vs 9.9 mm; P = .079), with similar incidences of hepatic encephalopathy (34% vs 20%; P = .372), indicating stent self-expansion over time, and bringing into question the advantages of underdilation for customization of shunt caliber.

Survival benefit of TIPS versus serial paracentesis in patients with refractory ascites: a single institution case-control propensity score analysis

AIM To compare the impact of covered stent-graft transjugular intrahepatic portosystemic shunt (TIPS) versus serial paracentesis on survival of patients with medically refractory ascites. MATERIALS AND METHODS In this retrospective study, cirrhotic patients who underwent covered stent-graft TIPS for refractory ascites from 2003-2013 were compared with similar patients who underwent serial paracentesis during 2009-2013. Demographic and liver disease data, Model for End-Stage Liver Disease (MELD) scores, and survival outcomes were obtained from hospital electronic medical records and the social security death index. After propensity score weighting to match study group characteristics, survival outcomes were compared using Kaplan-Meier statistics with log-rank analysis. RESULTS Seventy TIPS (70% men, mean age 55.7 years, mean MELD 15.1) and 80 paracentesis (58% men, mean age 53.5 years, mean MELD 22.5) patients were compared. The TIPS haemodynamic success rate was 100% (mean portosystemic pressure gradient reduction 13 mmHg). Paracentesis patients underwent a mean of 7.9 procedures. After propensity score weighting to balance group features, TIPS patients showed a trend toward enhanced survival compared with paracentesis patients (median survival 1037 versus 262 days, p = 0.074). TIPS conferred a significant increase or trend toward improved survival compared with paracentesis at 1 (66% versus 44%, p = 0.018), 2 (56% versus 38%, p = 0.057), and 3 year (49% versus 32%, p = 0.077) time points. Thirty and 90 day mortality rates were not statistically increased by TIPS. CONCLUSION Covered stent-graft TIPS improves intermediate- to long-term survival without significantly increasing short-term mortality of ascites patients, and suggests a greater potential role for TIPS in properly selected ascitic patients when medical management fails.

Conventional Ethiodized Oil Transarterial Chemoembolization for Treatment of Hepatocellular Carcinoma: Contemporary Single-Center Review of Clinical Outcomes

OBJECTIVE The purpose of this study is to investigate the outcomes of conventional transarterial chemoembolization (TACE) treatment of hepatocellular carcinoma (HCC) in contemporary clinical practice. MATERIALS AND METHODS In this single-institution retrospective study, 188 patients underwent conventional TACE for HCC between 2007 and 2013. Medical record and imaging review was used to collect baseline demographic and disease data, tumor response, time to progression (TTP), and progression-free survival (PFS) outcomes, as well as transplant-free survival, calculated from the time of the first conventional TACE treatment. Data were censored in April 2014. RESULTS The study cohort included 140 men and 48 women (mean age, 60 years; Barcelona Clinic Liver Cancer [BCLC] stage 0 = 5%, BCLC stage A = 41%, BCLC stage B = 28%, BCLC stage C = 15%, and BCLC stage D = 11%) with 207 index tumors (mean size, 4.0 cm; 11% with portal vein invasion) treated with a mean of 1.6 selective (79%) or lobar (21%) conventional TACE sessions. Concurrent thermal ablation was performed for 19% of patients. Objective response rates included size response in 29% (World Health Organization) and 28% (Response Evaluation Criteria for Solid Tumors [RECIST]) of patients, and necrosis response in 79% (European Association for the Study of the Liver) and 70% (modified RECIST) of patients. Median local TTP, distant site TTP, local PFS, and other site PFS were 51.7, 11.2, 10.8, and 10.5 months. Eighteen percent of patients underwent liver transplantation; 48% of United Network for Organ Sharing stage T3 tumors were downstaged to stage T2. Transplant-free survival for the entire cohort was 16.8 months (not reached, 33.9, 16.0, 4.4, and 6.9 months for BCLC stages 0, A, B, C, and D, respectively). Postembolization syndrome requiring extended hospital stay or readmission occurred in only 6% of patients. CONCLUSION Conventional TACE is effective and safe for HCC therapy and may confer a survival benefit. The current data are in line with reported conventional TACE outcomes, and the minor postembolization syndrome incidence supports the low morbidity of this approach.

Gene Expression in Hepatocellular Carcinoma: Pilot Study of Potential Transarterial Chemoembolization Response Biomarkers

PURPOSE To perform a feasibility study to explore the relationship between hepatocellular carcinoma genetics and transarterial chemoembolization treatment response to identify potential biomarkers associated with enhanced treatment efficacy. MATERIALS AND METHODS In this single-institution study, pretreatment hepatocellular carcinoma biopsy specimens for tumors in 19 patients (14 men, five women; mean age, 59 y) treated with chemoembolization between 2007 and 2013 were analyzed for a panel of 60 chemotherapy-sensitivity, hypoxia, mitosis, and inflammatory genes with the QuantiGene Plex 2.0 mRNA detection assay. Demographic, disease, and procedure data and tumor response outcomes were collected. Quantitative mRNA levels were compared based on radiologic response between tumors exhibiting complete response (CR) versus partial response (PR). RESULTS The study sample included 19 biopsy specimens from tumors (mean size, 3.0 cm; grade 1, n = 6; grade 2, n = 9; grade 3, n = 4) in patients treated with a mean of two conventional chemoembolization sessions. Thirteen and six tumors exhibited CR and PR, respectively, at a mean of 116 days after treatment. Tumors with CR showed a significant increase in (P < .05) or trend toward (P < .1) greater (range, 1.49-3.50 fold) pretreatment chemotherapy-sensitivity and mitosis (ATF4, BAX, CCNE1, KIF11, NFX1, PPP3CA, SNX1, TOP2A, and TOP2B) gene mRNA expression compared with tumors with PR, in addition to lower CXCL10 levels (0.48-fold), and had significantly (P < .05) higher (1.65-fold) baseline VEGFA levels. CONCLUSIONS Genetic signatures may allow prechemoembolization stratification of tumor response probability, and gene analysis may therefore offer an opportunity to personalize locoregional therapy by enhancing treatment modality allocation. Further corroboration of identified markers and exploration of their respective predictive capacity thresholds is necessary.

Characterization of liver function parameter alterations after transjugular intrahepatic portosystemic shunt creation and association with early mortality.

OBJECTIVE The purpose of this article is to characterize the temporal evolution and clinical impact of laboratory liver function parameters after transjugular intrahepatic portosystemic shunt (TIPS) creation. MATERIALS AND METHODS In this single-institution retrospective study, 157 patients (98 men and 59 women; median age, 55 years) underwent TIPS between 2000 and 2012 and had 1-month hepatobiliary laboratory follow-up. Medical record review was used to compare baseline, peak, and low bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and international normalized ratio (INR) levels within 30 days after TIPS in surviving and dying patients to assess laboratory responses to shunt creation. RESULTS TIPSs were created with a hemodynamic success rate of 98%, with median pressure gradient reduction of 13 mm Hg. Ninety-day mortality was 21%. Hepatobiliary laboratory values showed significant increases in the days after TIPS compared with baseline levels (bilirubin, 1.6 vs 3.5 mg/dL; AST, 49 vs 149 U/L; ALT, 26 vs 90 U/L; alkaline phosphatase, 97 vs 177 U/L; and INR, 1.5 vs 2.0; p<0.05 in all cases). Patients surviving to 90 days experienced statistically significant but transient laboratory value elevations-up to twofold over baseline-within days of TIPS, whereas patients dying within 90 days experienced three-to fourfold increases over a longer period that did not return to baseline. Differences in laboratory evolution were statistically significant in surviving versus dying patients. CONCLUSION TIPS results in acute transient elevation of hepatobiliary enzymes, which may be more pronounced in patients with early mortality. An exaggerated laboratory elevation in excess of threefold greater than baseline or a prolonged increase exceeding 1 week may herald poorer clinical outcome.

Presurgical Transarterial Chemoembolization Does Not Increase Biliary Stricture Incidence in Orthotopic Liver Transplant Patients

INTRODUCTION The goal of this study was to compare the incidence of biliary strictures in orthotopic liver transplant (OLT) patients treated with previous transarterial chemoembolization (TACE) versus those with no TACE history. PATIENTS AND METHODS A single-center retrospective review was performed on 248 patients who underwent OLT from 2006 to 2012. Patient demographic characteristics, history of TACE for treatment of hepatocellular carcinoma, OLT data, and biliary stricture data were obtained. TACE was generally performed in a segmental manner using chemotherapy to ethiodized oil mixture (1:1). Clinically significant biliary strictures resulting in cholestasis or obstructive jaundice were diagnosed by using endoscopic retrograde cholangiopancreatography. Group characteristics were compared by using the Wilcoxon rank sum test, χ(2) analysis, and Kaplan-Meier statistics with log-rank comparison. RESULTS Forty-six patients (35 men, 11 women; median age, 58 years) with a history of pre-OLT TACE were compared with 185 patients (111 men, 74 women; median age, 54 years) with no history of TACE. TACE and non-TACE patients had 30% and 31% cumulative incidence of biliary stricture, respectively. The median time to stricture was not reached in either group. There was no statistically significant difference in biliary stricture incidence (P = .928) or time to biliary stricture development (P = .803). Biliary strictures were primarily anastomotic in location in both groups: 79% in TACE patients and 84% in non-TACE patients (P = .233). CONCLUSIONS Selective TACE treatment of hepatocellular carcinoma in pretransplant patients does not increase the rate of posttransplant biliary strictures. These findings corroborate the safety of TACE in the treatment of hepatocellular carcinoma in potential OLT patients as a bridge to transplantation.

Correlation of Doxorubicin Delivery and Tumor Necrosis after Drug-eluting Bead Transarterial Chemoembolization of Rabbit VX2 Liver Tumors

Purpose To quantify the correlation between doxorubicin (DOX) delivery and tumor necrosis after drug-eluting bead (DEB) transarterial chemoembolization (TACE). Materials and Methods In this animal care committee-approved study, New Zealand white rabbit VX2 liver tumors were treated transarterially with DOX-loaded 70-150-μm DEBs in five treatment groups with varying drug doses: sham (saline), 0 mg, 12.5 mg, 25 mg, and 37.5 mg. DEB TACE was followed by 3- and 7-day sacrifice, tumor harvest, and sectioning. Drug delivery was assessed by using fluorescence imaging, and tumor necrosis was quantified by means of histologic analysis. Statistical correlation of DOX delivery and tumor necrosis was performed by using the Spearman rank correlation coefficient (ρ). Results Thirty-six VX2 tumors (median diameter, 1.3 cm) in 20 rabbits (median weight, 2.8 kg) underwent successful DEB TACE. Treatment groups included eight, seven, eight, five, and eight tumors of similar size (P > .05). Tumors showed progressively greater DOX extent (sham, 0%; 0 mg, 0%; 12.5 mg, 3%; 25 mg, 20%; and 37.5 mg, 27%) and intensity (sham, 0.4; 0 mg, 1.9; 12.5 mg, 8.5; 25 mg, 9.6; and 37.5 mg, 18.3) and higher median percentage necrosis (sham, 68%; 0 mg, 64%; 12.5 mg, 76%; 25 mg, 78%; and 37.5 mg, 83%) across DOX treatment groups. Correlation of DOX extent (ρ = 0.975, P = .005) and intensity (ρ = 0.900, P = .037) with percentage tumor necrosis was statistically significant. Conclusion Incremental increases in DOX correlate with greater necrosis in rabbit VX2 liver tumors after DEB TACE. This result indicates an essential role for chemotherapy-induced cytotoxicity in TACE effectiveness and supports the use of chemotherapeutic drugs in transarterial therapy. (©) RSNA, 2016 Online supplemental material is available for this article.