Biopsy-proven Hepatocellular Carcinoma Research Articles

Preprocedural Video Education on Liver Ablation Treatment

BackgroundAnxiety is a common problem in patients scheduled for a procedure, and their level of anxiety increases as the procedure date approaches; pre-procedural anxiety is observed in hepatocellular carcinoma (HCC) patients scheduled for liver ablation treatment. There is currently a lack of standardized education provided to patients about liver ablation treatment, which may contribute to patients’ anxiety. PurposeTo test the effectiveness of a pre-procedural video educational tool to reduce patient anxiety and increase knowledge in HCC patients in an interventional radiology clinic setting. MethodsThis was a quasi-experimental, single-arm study, with a pre-test/post-test. Participant recruitment was based on a convenience sample. Inclusion criteria included: patients ages 18 and older; have biopsy-proven HCC or have a liver mass suspicious for HCC based on LI-RADS criteria imaging; no prior liver ablation treatment within three months of study onset. Participants watched a 7:04 minutes video and completed a 40-item State-Trait Anxiety Inventory and 10-item Knowledge Questionnaire before and after the video intervention to assess changes in anxiety and knowledge. Demographic variables evaluated included age, gender, education, and primary language. ResultsThere were 16 participants who met inclusion criteria. The state anxiety scores were significantly lower after the intervention (Md = 33.50, n = 16) compared to before (Md = 47.50, n = 16), z = −2.67, p = .009, with a medium effect size, r = 0.47. The trait anxiety scores did not show sufficient evidence for a difference after the intervention (Md = 40.00, n = 16) compared to before (Md = 39.50, n = 16), z = 0.71, p = .50, with a small effect size, r = 0.13. The knowledge scores were significantly higher after the intervention (Md = 9.00, n = 16) compared to before (Md = 2.00, n = 16), z = −3.53, p = .0005, with a large effect size, r = 0.62. A nonparametric bootstrap and nonparametric permutation test also showed evidence for a difference in mean between the distributions of the state anxiety and knowledge pre- and post-intervention scores. DiscussionThe results of this study showed evidence for the effectiveness of video education in decreasing anxiety and increasing knowledge in HCC patients. A standardized pre-procedural video educational tool can be a useful practice across all interventional radiology departments as it is associated with improved quality of care and positive health outcomes.

Analysis of treatment response based on 1.5T magnetic resonance imaging texture analysis in stereotactic body radiotherapy of hepatocellular carcinoma

PurposeMagnetic Resonance Image (MRI)-guided stereotactic body radiotherapy (MRgSBRT) is a promising technique in the treatment of hepatocellular carcinoma (HCC). However, treatment response varies among patients. The aim of this study was to evaluate the treatment response using radiomics features extracted from 1.5 T MRI in HCC patients treated with SBRT. Materials and methods19 patients with biopsy-proven HCC who were treated with SBRT by 1.5 T MRI-guided were enrolled, all of whom were treated with 8–10 fractions with biological effective dose (BED) range of 95.2–107.1 Gy. We acquired images of pretreatment, delivered BEDs of 35–40 Gy, and delivered BEDs of 55–60 Gy. We combined three classic feature selection methods: least absolute shrinkage and selection operator (LASSO), extreme gradient boosting (XGBoost), and random forest (RF) to extract the intersection of radiomics features from the gross tumor volume (GTV) and features were averaged over the three fractions. We used the receiver operating characteristic (ROC) area under curve (AUC) obtained using leave-one-out cross-validation (LOOCV) to assess the predictive capacity. ResultsSeven patients showed response to treatment based on post-treatment imaging studies. The optimum intersection of radiomics features selected by three methods was Neighborhood Grey Tone Difference Matrix (NGTDM) contrast and NGTDM strength. The logistic regression-based model achieved an AUC of 0.821 (95% confidence interval, 0.618–1). ConclusionsRadiomics features containing biological prognostic information extracted during MRgSBRT could predict tumor treatment response, facilitating stratification of high-risk patients and providing clinical application value for individualized care of patients with different response to treatment.

MiR-21-5p promotes NASH-related hepatocarcinogenesis.

The mechanisms governing the progression of non-alcoholic fatty liver disease (NAFLD) towards steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain elusive. Here, we evaluated the role of hsa-miRNA-21-5p in NASH-related hepatocarcinogenesis. Hepatic hsa-miR-21-5p expression was evaluated in two cohorts of patients with biopsy-proven NAFLD (n = 199) or HCC (n = 366 HCC and n = 11 NAFLD-HCC). Serum/liver metabolomic profiles were correlated with hsa-miR-21-5p in NAFLD obese patients. Wild-type (WT) and Mir21 KO mice were fed a choline-deficient, amino acid-defined (CDAA) diet for 32 and 66 weeks to induce NASH and NASH-HCC, respectively. In obese individuals, hsa-miR-21-5p expression increased with NAFLD severity and associated with a hepatic lipotoxic profile. CDAA-fed WT mice displayed increased hepatic mmu-miR-21-5p levels and progressively developed NASH and fibrosis, with livers presenting macroscopically discernible pre-neoplastic nodules, hyperplastic foci and deregulated cancer-related pathways. Mir21 KO mice exhibited peroxisome-proliferator-activated receptor α (PPARα) activation, augmented mitochondrial activity, reduced liver injury and NAS below the threshold for NASH diagnosis, with the pro-inflammatory/fibrogenic milieu reversing to baseline levels. In parallel, Mir21 KO mice displayed reduced number of pre-neoplastic nodules, hepatocyte proliferation and activation of oncogenic signalling, being protected from NASH-associated carcinogenesis. The hsa-miRNA-21-5p/PPARα pathway was similarly deregulated in patients with HCC- or NASH-related HCC, correlating with HCC markers and worse prognosis. Hsa-miR-21-5p is a key inducer of whole-spectrum NAFLD progression, from simple steatosis to NASH and NASH-associated carcinogenesis. The inhibition of hsa-miR-21-5p, leading to a pro-metabolic profile, might constitute an appealing therapeutic approach to ameliorate NASH and prevent progression towards HCC.

Immunohistochemical and genetic profiles do not predict behavior of mixed hepatocellular intrahepatic cholangiocarcinoma.

516 Background: Combined hepatocellular intrahepatic cholangiocarcinoma (HCC CC) is a rare tumor defined by pathologic characteristics of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immunohistochemical (IHC) and genetic profiles (GP) are used for diagnosis and therapeutic decisions, however often mixed tumors are treated as ICC given the presumption this subtype dominates response. Recent studies challenged this practice by demonstrating improved response with immune oncology (IO) therapy. Methods: We identified nine patients with biopsy-proven mixed HCC CC between September 2013 and March 2022. We classified IHC as related to either HCC (HepPar1, Glypican3, CD10, Glutamine Synthetase, CEA, AFP, Arginase1) or ICC (CK19, CK7, CK20, CDX2, Mucicarmine, CA9, MOC31). GP results were classified as HCC-related (TERT, CTNNB1, MYC) or ICC-related (ARID1A, FGFR2, IDH1). Treatment selection, duration of response, and survival were recorded. Results: All subjects had a mix of IHC markers, although six had a preponderance of HCC-related IHC. GP information was available for seven patients, of whom six demonstrated mutations relating only to HCC, and one demonstrated mutations relating only to ICC. All sequenced tumors were MSS, and six of the seven were TMB low. Four subjects used only liver directed therapy for small intrahepatic tumors. Four subjects underwent systemic therapy, a mix of HCC and ICC regimens, three of whom used IO agents. Median survival was 12 months. Conclusions: HCC CC tumor profiling by IHC and GP was more closely aligned with HCC than ICC. However, the median survival for these patients was lower than expected for liver-restricted HCC, more congruent with an ICC phenotype. Although liver-directed therapy was used, the duration of response was shorter than expected for HCC, even in HCC-like tumors. For those receiving systemic therapy, most subjects did not achieve median response with any regimen. Although a previous case series showed good response to IO agents, in our cohort we did not see this effect. In this series, mixed HCC CC was more aggressive than HCC, with largely poor response to both liver directed and systemic therapy. We have insufficient information to correlate systemic treatment response relative to IHC or GP.[Table: see text]

Phase IIclinical trial of cabozantinib for the treatment of recurrent hepatocellular carcinoma after liver transplantation.

Recurrent hepatocellular carcinoma (HCC) develops in 15-20% of liver transplant recipients, and it tends to be more aggressive due to underlying immunosuppression. The multikinase inhibitor cabozantinib has been shown to be effective for the treatment of advanced HCC. However, there is no study evaluating this medication in patients with recurrent HCC. Adult patients with measurable biopsy-proven recurrent HCC are eligible for enrollment provided they are not amenable to curative treatmentsand no prior treatment with cabozantinib. In thisstudy, 60mg once daily cabozantinib will be administered orally. Participants will receive study treatment as long as they continue to experience clinical benefit or until there is unacceptable toxicity. Tumor measurements will be repeated every 8weeks to evaluate response. The primary end point of this study will be thedisease control rateat 4months after treatment. The secondary end points will be overall survival, progression-free survivaland safety profile of cabozantinib. Furthermore, potential biomarkers will be evaluated to identify their role in tumor progression. The total duration of this trial is expected to be 3years. We anticipate that this trial will show the effectiveness and safety of cabozantinib in the treatment of post-liver transplant recurrent HCC. Cabozantinib is expected to be an effective treatment due to its activity against many protein kinases, including MET and AXL which are not inhibited by sorafenib.

Cell-free DNA methylation markers for differential diagnosis of hepatocellular carcinoma

BackgroundAberrant DNA methylation may offer opportunities in revolutionizing cancer screening and diagnosis. We sought to identify a non-invasive DNA methylation-based screening approach using cell-free DNA (cfDNA) for early detection of hepatocellular carcinoma (HCC).MethodsDifferentially, DNA methylation blocks were determined by comparing methylation profiles of biopsy-proven HCC, liver cirrhosis, and normal tissue samples with high throughput DNA bisulfite sequencing. A multi-layer HCC screening model was subsequently constructed based on tissue-derived differentially methylated blocks (DMBs). This model was tested in a cohort consisting of 120 HCC, 92 liver cirrhotic, and 290 healthy plasma samples including 65 hepatitis B surface antigen-seropositive (HBsAg+) samples, independently validated in a cohort consisting of 67 HCC, 111 liver cirrhotic, and 242 healthy plasma samples including 56 HBsAg+ samples.ResultsBased on methylation profiling of tissue samples, 2321 DMBs were identified, which were subsequently used to construct a cfDNA-based HCC screening model, achieved a sensitivity of 86% and specificity of 98% in the training cohort and a sensitivity of 84% and specificity of 96% in the independent validation cohort. This model obtained a sensitivity of 76% in 37 early-stage HCC (Barcelona clinical liver cancer [BCLC] stage 0-A) patients. The screening model can effectively discriminate HCC patients from non-HCC controls, including liver cirrhotic patients, asymptomatic HBsAg+ and healthy individuals, achieving an AUC of 0.957(95% CI 0.939–0.975), whereas serum α-fetoprotein (AFP) only achieved an AUC of 0.803 (95% CI 0.758–0.847). Besides detecting patients with early-stage HCC from non-HCC controls, this model showed high capacity for distinguishing early-stage HCC from a high risk population (AUC=0.934; 95% CI 0.905–0.963), also significantly outperforming AFP. Furthermore, our model also showed superior performance in distinguishing HCC with normal AFP (< 20ng ml−1) from high risk population (AUC=0.93; 95% CI 0.892–0.969).ConclusionsWe have developed a sensitive blood-based non-invasive HCC screening model which can effectively distinguish early-stage HCC patients from high risk population and demonstrated its performance through an independent validation cohort.Trial registrationThe study was approved by the ethic committee of The Second Xiangya Hospital of Central South University (KYLL2018072) and Chongqing University Cancer Hospital (2019167). The study is registered at ClinicalTrials.gov(#NCT04383353).

Circulating Tumor DNA Methylation Markers for Differential Diagnosis of Hepatocellular Carcinoma

Background: An effective blood-based method for hepatocellular carcinoma (HCC) early detection has not yet been developed. Aberrant DNA methylation may offer opportunities in revolutionizing cancer screening and diagnosis. We sought to identified a non-invasive DNA methylation-based diagnostic approach using cell-free DNA for HCC early detection in high risk population. Methods: Differentially methylated DNA methylation blocks were determined by comparing methylation profiles of biopsy-proven HCC, cirrhotic and healthy liver tissues using targeted bisulfite sequencing. A multi-layer HCC screening model was subsequently constructed based on tissue-derived differentially methylated makers using plasma samples from 120 HCC patients, 92 cirrhotic patients and 290 healthy individuals. This model was independently validated in a cohort consisting of 67 HCC patients, 115 cirrhotic patients and 242 healthy individuals. The clinical parameters of misclassified samples were also investigated. Findings: Based on methylation profiling of tissue samples, a total of 2,321 DNA methylation markers were derived, which were subsequently used to construct a cfDNA-based HCC screening model, achieving a sensitivity of 86% and specificity of 97% in the training cohort and a sensitivity of 82% and specificity of 96% in the independent validation cohort. The HCC screening model can effectively discriminate HCC patients from non-HCC patients, including patients with cirrhosis, HBV infection and healthy individuals, achieving an AUC of 0.956; whereas serum alpha-fetoprotein (AFP) achieved an AUC of 0.803. Interpretation: We have developed and validated an HCC screening model which can effectively distinguish early stage HCC patients from cirrhotic patients and symptomatic HBsAg-seropositive individuals. Funding: Key Research and Development Program of Hunan Province, Natural Science Foundation of Hunan Province, China. Declaration of Interest: None to declare. Ethical Approval: The study was approved by the ethic committee of The Second Xiangya Hospital of Central South University (KYLL2018072) and Chongqing University Cancer Hospital (2019167). All collection and usage of human sample and clinical data were in accordance with the principles of the Declaration of Helsinki. Written informed content was obtained from every participant for the use of their tissue or plasma samples.

Hepatocellular carcinoma after Fontan surgery: A systematic review

Fontan surgery is often the procedure of choice for patients with congenital single effective ventricle. In the long term, elevated systemic venous pressure and chronic ischemia following this procedure could lead to advanced chronic liver disease and there is also a risk of hepatocellular carcinoma (HCC). This review systematically summarizes the characteristics and outcomes of this rare condition. PubMed and Embase databases were searched from inception to January 2020 for studies reporting on HCC after Fontan surgery. The factors analyzed were clinical presentation, histology, imaging findings, treatments, and survival. Our primary analysis was based on biopsy-proven HCC. The records selected were 26 observational studies (19 case reports/case series and seven cohort studies) including 65 biopsy-proven HCC. Age at the time of HCC diagnosis ranged from 12 to 52years, and 62% of the patients were female. Only one case occurred earlier than 10 years after Fontan surgery. Twenty patients had no imaging or histological evidence of liver cirrhosis and 78.3% had elevated α-fetoprotein levels. Advanced stage was the most common at diagnosis. The most frequent treatments were transarterial chemoembolization (n = 18) and surgery (n = 12). One-year survival was 50% and only four patients (6.2%) were under liver imaging surveillance. We also analyzed 17 patients with non-biopsy-proven HCC. After Fontan surgery, HCC usually occurs at least 10 years later and can develop in the absence of cirrhosis. Biopsy is mandatory to confirm the diagnosis. Patients were diagnosed at a late stage and survival outcomes were poor, highlighting a need for liver surveillance.

Response prediction of hepatocellular carcinoma undergoing transcatheter arterial chemoembolization: unlocking the potential of CT texture analysis through nested decision tree models

ObjectivesTo investigate if nested multiparametric decision tree models based on tumor size and CT texture parameters from pre-therapeutic imaging can accurately predict hepatocellular carcinoma (HCC) lesion response to transcatheter arterial chemoembolization (TACE).Materials and methodsThis retrospective study (January 2011–September 2017) included consecutive pre- and post-therapeutic dynamic CT scans of 37 patients with 92 biopsy-proven HCC lesions treated with drug-eluting bead TACE. Following manual segmentation of lesions according to modified Response Evaluation Criteria in Solid Tumors criteria on baseline arterial phase CT images, tumor size and quantitative texture parameters were extracted. HCCs were grouped into lesions undergoing primary TACE (VT-lesions) or repeated TACE (RT-lesions). Distinct multiparametric decision tree models to predict complete response (CR) and progressive disease (PD) for the two groups were generated. AUC and model accuracy were assessed.ResultsThirty-eight of 72 VT-lesions (52.8%) and 8 of 20 RT-lesions (40%) achieved CR. Sixteen VT-lesions (22.2%) and 8 RT-lesions (40%) showed PD on follow-up imaging despite TACE treatment. Mean of positive pixels (MPP) was significantly higher in VT-lesions compared to RT-lesions (180.5 vs 92.8, p = 0.001). The highest AUC in ROC curve analysis and accuracy was observed for the prediction of CR in VT-lesions (AUC 0.96, positive predictive value 96.9%, accuracy 88.9%). Prediction of PD in VT-lesions (AUC 0.88, accuracy 80.6%), CR in RT-lesions (AUC 0.83, accuracy 75.0%), and PD in RT-lesions (AUC 0.86, accuracy 80.0%) was slightly inferior.ConclusionsNested multiparametric decision tree models based on tumor heterogeneity and size can predict HCC lesion response to TACE treatment with high accuracy. They may be used as an additional criterion in the multidisciplinary treatment decision-making process.Key Points• HCC lesion response to TACE treatment can be predicted with high accuracy based on baseline tumor heterogeneity and size.• Complete response of HCC lesions undergoing primary TACE was correctly predicted with 88.9% accuracy and a positive predictive value of 96.9%.• Progressive disease was correctly predicted with 80.6% accuracy for lesions undergoing primary TACE and 80.0% accuracy for lesions undergoing repeated TACE.

S2671 Chest Wall Metastasis as the First Clinical Manifestation of Hepatocellular Carcinoma: A Rare Case Report

INTRODUCTION: Hepatocellular carcinoma (HCC) is a highly malignant tumor that is mostly diagnosed at an advanced stage. Here, we report a metastatic HCC in an elderly man with hepatitis C virus (HCV) and alcoholic cirrhosis. Literature is sparse on chest wall metastasis. CASE DESCRIPTION/METHODS: A 69-year-old Caucasian man presented because of a growing left chest wall mass, back pain, and weight loss for three months. He had never visited a physician before; history was pertinent for tobacco smoking and alcohol dependence. He was hemodynamically stable, cachectic on examination with a >10 cm large left upper chest wall non-erythematous firm, fixed palpable mass. Labs were pertinent for elevated liver enzymes, with ALT of 141, AST of 374, ALP of 675, normal total bilirubin, and HCV antibody positive, with an elevated viral PCR of 6.1 log IU/ml. A CT chest, abdomen, and pelvis showed a left extrapleural chest wall mass measuring 10.8 × 15.5 × 11.0 cm with erosions of adjacent ribs, destructive lytic bony lesions, and liver cirrhosis; features suspicions of metastatic HCC. Subsequent chest wall mass biopsy confirmed a moderately differentiated metastatic HCC with Immunostain positive for CAM 5.2, Hep Par, glutamine synthetase, and glypican-3. A serum AFP was elevated at 2376.15 ng/ml. Abdominal MRI demonstrated a total of five large enhancing masses with the largest measuring 4.1 × 3.5 cm with arterial enhancement, washout, diffusion restriction, and internal hemorrhage consistent with biopsy-proven HCC (LR-5). A brain and spine MRI were unremarkable except for the previously reported bony metastases. Consequently, he received localized spine and left chest wall radiotherapy, and upon completion, he was discharged home, and currently, he is on systemic chemotherapy with Lenvatinib. DISCUSSION: HCC is the second most lethal neoplasm with an 18% five-year survival. Common etiologies are HBV, HCV, alcoholic cirrhosis, and NAFLD. The most frequent metastatic locations include bones, lymphatics, and adrenals. Spread occurs heterogeneously or via a lymphatic route or by direct invasion. Extrahepatic metastasis is rare and even rarer, with poorer prognosis when the first presentation is a mass at the metastatic site. This should be in the differential of rapidly growing chest wall masses, particularly in alcoholic and/or treatment-naïve hepatitis virus-infected patients. Timely recognition of risk factors can prevent and aid early diagnosis of such aggressive tumors.Figure 1.: Chest Wall Metastasis.Figure 2.: MRI Abdomen showing the Primary Liver Lesion.Figure 3.: Pathology Slide: H & E stain showing features suggestive of HCC on a liver biopsy.

Effect of sarcopenia on systemic targeted therapy response in patients with advanced hepatocellular carcinoma.

Sarcopenia is an independent prognostic indicator for hepatocellular carcinoma (HCC). Our objective was to determine the effect of sarcopenia on response to systemic targeted therapy in patients with advanced HCC. This was a retrospective, Institutional Review Board approved study of 36 patients on systemic targeted therapy with immune checkpoint blockade (n = 25) or tyrosine kinase inhibitor (n = 11) for biopsy-proven advanced HCC. Skeletal muscle index (SMI) was calculated from erector spinae muscle area (SMA) at the level of T12 on pretreatment CT: [SMI = SMA (cm2)/height (m2)]. SMI was compared to treatment response defined as overall survival ≥ 1year (nonsurgical patients) or > 50% HCC necrosis (surgical patients). Receiver operating characteristic curve and area under the curve was used for analysis with p < 0.05 for statistical significance. Median age of men and women was 66.5years (range 32-83) and 70years (range 54-78), respectively. Liver disease etiology was nonalcoholic steatohepatitis (n = 9), hepatitis C (n = 10), hepatitis B (n = 5), alcohol (n = 3) and unknown (n = 9). Mean (± SD) height and SMI for men were 1.7m (± 0.1) and 11.4 (± 3.6); values for women were 1.7m (± 0.1) and 8.2 (± 1.9). Treatment was withdrawn in five patients due to treatment intolerance. Response occurred in 10/31 (32.3%) patients (23 men, 8 women). T12SMI correlated with treatment response using a threshold of 7.21-8.23 for women (AUC = 1; p = 0.037), and 11.47 for men (AUC = 0.83; p = 0.015); correlation was increased for men ≥ 60years, (AUC = 0.87; p = 0.023). Sarcopenia was associated with reduced survival and HCC necrosis in patients treated with systemic targeted therapy. Sarcopenia may help in predicting outcomes to targeted therapy in advanced HCC.

Abstract 1853: Lipiodol-based emulsion to disrupt oxygenation and lipid homeostasis of liver tumors

Abstract Trans-arterial embolic therapies for liver tumors are used routinely in patients with hepatocellular carcinoma (HCC) and patients with liver dominant metastatic disease. Lipiodol® (Ethiodized oil; ethyl esters of iodized fatty acids of poppy seed oil) has been historically used as a vehicle for delivering chemotherapeutic agents as part of chemoembolization (cTACE) of liver tumors. Lipiodol's role in cTACE is to visualize the delivery of the mixture under fluoroscopy, emulsification and delivery of the chemotherapeutic agent, and as a microembolic agent itself. Contrary to previous studies that showed better outcome in patients with HCC treated with cTACE compared to bland embolization (TAE), more recent studies demonstrated no significant difference between drug-eluting chemoembolization and bland embolization (TAE), negating the added benefit of chemotherapy as a required agent when performing liver embolization of HCC. Therefore, we hypothesized that the added benefit of cTACE over TAE stems from the Lipiodol-based emulsion and not chemotherapy. We performed embolization of liver tumors using Lipiodol-Isovue emulsion and bland particles (TALE) but replacing chemotherapy with Isovue-300® (Iopamidol, a non-ionic iodinated contrast agent). Our preliminary data of 5 patients with non-resectable HCC (1 to 14.9 cm) treated with TALE without systemic therapy were followed for at least 5 months and response was evaluated using RECIST and mRECIST. By mRECIST, 3 patients had complete response (CR), one had a partial response (PR) and one could not be evaluated since the biopsy-proven HCC was hypovascular. Using RECIST 1.1 criteria, two patients had a stable disease (SD), and 3 had PR, including Interestingly CR of one of 2 tumors. We also treated 5 patients with metastatic renal cell carcinoma (RCC) using TALE with tumors ranging from 2.2 to 4.3 cm; using RECIST, three patients had PR, one SD, and one PD (progressive disease). Based on these results, we investigated the cytotoxic effects of Lipiodol in HCC and RCC cell lines Huh7 and A498. Lipiodol-Isovue emulsions were cytotoxic to these cells while viability of a normal/primary cell line HEK293 was not affected. Additionally, Lipiodol alone showed similar cytotoxic effects as the emulsions. Furthermore, Lipiodol was taken up by cells as seen by staining with Nile Red, a fluorescent dye that stains neutral lipids in lipid droplets using confocal microscopy. Our in vitro data indicate that RCC and HCC cells are more vulnerable to Lipiodol-induced lipotoxicity than non-cancerous primary kidney epithelial cells. There might be a synergistic effect between causing hypoxia as a result of blocking blood flow to the tumors during liver embolization and disrupting lipid homeostasis with the use of a Lipid-based emulsion. Our studies unravel a potential metabolic vulnerability that can be exploited therapeutically with liver-directed therapies. Citation Format: Smitha R. Pillai, Pravin Phadatare, Antonio Ortiz, Elie Barakat, Ghassan El-Haddad. Lipiodol-based emulsion to disrupt oxygenation and lipid homeostasis of liver tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1853.

2262 Too Much TAE: A Case of Tumor Lysis Syndrome After Repeat Transarterial Embolization of Hepatocellular Carcinoma

INTRODUCTION: Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world &amp; the second highest cause of cancer-related deaths globally. In the US, HCC incidence has almost tripled since the 1980s &amp; has become the fastest rising etiology of cancer-related deaths. Tumor lysis syndrome (TLS) is a condition that results when malignant cells release their intracellular contents, either spontaneously or in response to cytoxic treatment. The cellular contents result in hyperuricemia, hyperkalemia, hyperphosphatemia, &amp; hypocalcemia; these disturbances can lead to arrhythmias, AKI &amp; death. TLS is common in leukemias &amp; lymphomas but is rare in solid tumors. CASE DESCRIPTION/METHODS: A 50-year-old female with biopsy proven HCC without cirrhosis was admitted for planned transarterial chemoembolization (TACE) of her large right lobe &amp; medial left lobe HCC, measuring 13.3 × 17.9 × 21.8 cm (Image 1), as too advanced for surgical resection or transplant &amp; she had large liver-lung shunt preventing radioembolization treatment. Interventional Radiology (IR) placed two vials of LC beads containing doxirubicin 100mg &amp; bland transarterial embolization (TAE) via 2.5 vials of Embospheres into right hepatic artery. Afterwards, she had acute drop in Hgb with CTA revealing multiple areas of active bleeding in the liver &amp; new hematoma centrally in the mass. IR performed complete embolization of the right hepatic artery using coils &amp; gelfoam to achieve hemostasis; patient was transferred to ICU. She received blood products &amp; lab monitoring, the latter demonstrated new hyperkalemia of 5.5 mmol/L, previously normal. Creatinine increased from 0.55mg/dL to 1.23, thought to be multifactorial. Additional workup revealed uric acid of 12.5mg/dL, calcium 6.9mg/dL &amp; phosphorous 7.4mg/dL. TLS was diagnosed &amp; treated with intravenous fluids for dilution, rasburicase for hyperuricemia, furosemide for renal dysfunction &amp; minimal urine output, &amp; insulin for hyperkalemia. DISCUSSION: HCC is a growing health burden, &amp; advanced tumors that are not candidates for surgical resection are commonly treated with radiofrequency ablation, TACE, TAE, &amp; chemotherapy. Early recognition of TLS is key for treatment &amp; involves awareness of the propensity for development of TLS in large tumor burdens, rapidly dividing tumors, multiple treatment sessions, &amp; pretreatment renal dysfunction. Oliguria after IR treatment of HCC should raise the suspicion for possible TLS &amp; not be easily dismissed as the common but less fatal contrast induced nephropathy.

2264 Hyperammonemia Secondary to an Acquired Urea Cycle Disorder in a Patient With Metastatic Hepatocellular Carcinoma

INTRODUCTION: Urea cycle disorders are rare but critically important to consider in the differential diagnosis of hyperammonemia. Delayed treatment may result in disastrous neurologic consequences. CASE DESCRIPTION/METHODS: A 45-year-old woman with past history of gastric sleeve, no known liver disease, and biopsy-proven hepatocellular carcinoma (HCC) with peritoneal metastases on sorafenib presented with acute onset confusion and seizures. She was found to have severe hyperammonemia to 331 µMol/L. Labs were also notable for normal urine organic acids and low plasma citrulline (Table 1). She started on emergent dialysis as well as levetiracetam, lactulose, rifaximin, citrulline, and a low protein diet; sorafenib was discontinued. Her ammonia levels and mentation gradually improved over 3 days. She underwent genetic testing for 14 genes associated with primary urea cycle defects and further testing for another 72 genes associated with secondary hyperammonemia, all of which were negative. DISCUSSION: Urea cycle disorders (UCDs), whether genetic or acquired, can lead to life-threatening hyperammonemia. While classically seen in children, an increasing number of late-onset genetic UCDs have been reported. Ornithine transcarbamylase (OTC) deficiency in particular is X-linked and late-onset, and mild forms are more common than in other genetic UCDs. Individuals may also develop acquired urea cycle defects, with symptoms and lab results consistent with the genetic forms but without an identifiable mutation, as seen in this patient. Acquired UCDs have been reported secondary to tyrosine kinase inhibitors such as sorafenib, and a few cases described in untreated fibrolamellar-type HCC (Table 2). Whether these are primary acquired deficiencies in the setting of hypermetabolic states, as seen in advanced tumors, or an unmasking of an underlying genetic predisposition remains unknown. Further, this patient’s bariatric surgery could have resulted in nutritional deficiencies, revealing an occult UCD. Regardless of etiology, treatment for UCDs includes aggressive ammonia control with nitrogen scavengers, amino acid supplements, and appropriate dietary protein intake. Suspected offending agents should be stopped immediately and emergent hemodialysis initiated if hyperammonemia does not improve with conservative measures. Empiric therapy should be initiated even without confirmation of the diagnosis, as prolonged exposure to high ammonia can lead to irreversible neurological ramifications.

Diagnostic Value of Quantitative Perfusion Computed Tomography Technique in the Assessment of Tumor Response to Sorafenib in Patients With Advanced Hepatocellular Carcinoma

The aim of this study was to assess the role of dynamic contrast-enhanced perfusion computed tomography (pCT) imaging in the early detection of blood flow changes related to antiangiogenic treatment with sorafenib, in patients with advanced hepatocellular carcinoma (HCC), being the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria the standard of reference. Between 2012 and 2016, 43 cirrhotic patients (male, n = 39; female, n = 4) with biopsy-proven multifocal HCC underwent multi-detector-row computed tomography, and pCT examinations were performed before and every 2 months after sorafenib administration. Perfusion CT technique is based on the acquisition of 16 dynamic slices/scan per 40 scans, performed on a 256-slice multi-detector-row computed tomography scanner, after intravenous bolus injection of 50 mL of iodinated contrast agent (350 mg I/mL) at a flow rate of 5 mL/s. According to mRECIST, patients were stratified into complete (CR) or partial response (PR) and stable (SD) or progressive disease (PD). The following pCT parameters were calculated: hepatic perfusion (mL/s per 100 g), time to peak (seconds), arterial perfusion (mL/s), and hepatic perfusion index (%). Perfusion CT values at baseline and first follow-up were reported for all mRECIST groups and then compared between the nonprogressor (CR, PR, SD) and progressor groups (PD). Most pCT values were significantly higher (P < 0.01) between baseline and follow-up in the CR and PR groups, whereas nonsignificant differences were found among SD patients, and a nonsignificant trend (P > 0.05) toward increase was observed among PD patients. Moreover, pCT values were significantly higher (P = 0.05) at baseline in the nonprogressor group compared with the progressor. Preliminary results suggest that pCT adds quantitative data of vascularization, thus demonstrating its usefulness in the assessment of therapeutic response to sorafenib in advanced HCC, in line with mRECIST criteria, offering 1-step information on tissue cellularity and vascularization.

Histogram analysis of apparent diffusion coefficient predicts response to radiofrequency ablation in hepatocellular carcinoma.

ObjectiveThe aim of this study was to predict tumor progression in patients with hepatocellular carcinoma (HCC) treated with radiofrequency ablation (RFA) using histogram analysis of apparent diffusion coefficients (ADC).MethodsBreath-hold diffusion weighted imaging (DWI) was performed in 64 patients (33 progressive and 31 stable) with biopsy-proven HCC prior to RFA. All patients had pre-treatment magnetic resonance imaging (MRI) and follow-up computed tomography (CT) or MRI. The ADC values (ADC10, ADC30, ADCmedian and ADCmax) were obtained from the histogram’s 10th, 30th, 50th and 100th percentiles. The ratios of ADC10, ADC30, ADCmedian and ADCmax to the mean non-lesion area-ADC (RADC10, RADC30, RADCmedian, and RADCmax) were calculated. The two patient groups were compared. Key predictive factors for survival were determined using the univariate and multivariate analysis of the Cox model. The Kaplan-Meier survival analysis was performed, and pairs of survival curves based on the key factors were compared using the log-rank test. ResultsThe ADC30, ADCmedian, ADCmax, RADC30, RADCmedian, and RADCmax were significantly larger in the progressive group than in the stable group (P<0.05). The median progression-free survival (PFS) was 22.9 months for all patients. The mean PFS for the stable and progressive groups were 47.7±1.3 and 9.8±1.3 months, respectively. Univariate analysis indicated that RADC10, RADC30, and RADCmedian were significantly correlated with the PFS [hazard ratio (HR)=31.02, 43.84, and 44.29, respectively, P<0.05 for all]. Multivariate analysis showed that RADCmedian was the only independent predictor of tumor progression (P=0.04). And the cutoff value of RADCmedian was 0.71. ConclusionsPre-RFA ADC histogram analysis might serve as a useful biomarker for predicting tumor progression and survival in patients with HCC treated with RFA.

Supervised learning reveals circulating biomarker levels diagnostic of hepatocellular carcinoma in a clinically relevant model of non-alcoholic steatohepatitis; An OAD to NASH.

Although cirrhosis is a key risk factor for the development of hepatocellular carcinoma (HCC), mounting evidence indicates that in a subset of patients presenting with non-alcoholic steatohepatitis (NASH) HCC manifests in the absence of cirrhosis. Given the sheer size of the ongoing non-alcoholic fatty liver disease (NAFLD) epidemic and the dismal prognosis associated with late-stage primary liver cancer there is an urgent need for HCC surveillance in the NASH population. Using serum levels of HCC biomarkers as vectors and biopsy-proven HCC or no HCC as outputs / binary classifier, a supervised learning campaign was undertaken to develop a minimally invasive technique for making a diagnosis of HCC in a clinically relevant model of NASH. Adult mice randomized to control diet or a fast food diet (FFD) were followed for up to 14 mo and serum level of a panel of HCC-relevant biomarkers was compared with liver biopsies at 3 and 14 mo. Both NAFLD Activity Score (NAS) and hepatic hydroxyproline content were elevated at 3 and 14 mo on FFD. Picrosirius red staining of liver sections revealed a filigree pattern of fibrillar collagen deposition with no cirrhosis at 14 mo on FFD. Nevertheless, 46% of animals bore one or more tumors on their livers confirmed as HCC in hematoxylin-eosin-stained liver sections. In this training set, receiver operating characteristic (ROC) curves analysis for serum levels of the HCC biomarkers osteopontin (OPN), alpha-fetoprotein (AFP) and Dickkopf-1 (DKK1) returned concordance-statistic/area under ROC curve of ≥ 0.89. Serum levels of OPN (threshold, 218 ng/mL; sensitivity, 82%; specificity, 86%), AFP (136 ng/mL; 91%; 97%) and DKK1 (2.4 ng/mL; 82%; 81%) diagnostic for HCC were confirmed in a test set comprising mice on control diet or FFD and mice subjected to hepatic ischemia-reperfusion injury. These data suggest that levels of circulating OPN, AFP and DKK1 can be used to make a diagnosis of HCC in a clinically relevant model of NASH.

Pilot Evaluation of Angiogenesis Signaling Factor Response after Transcatheter Arterial Embolization for Hepatocellular Carcinoma.

Purpose To identify changes in a broad panel of circulating angiogenesis factors after bland transcatheter arterial embolization (TAE), a purely ischemic treatment for hepatocellular carcinoma (HCC). Materials and Methods This prospective HIPAA-compliant study was approved by the institutional review board. Informed written consent was obtained from all participants prior to entry into the study. Twenty-five patients (21 men; mean age, 61 years; range, 30-81 years) with Liver Imaging Reporting and Data System category 5 or biopsy-proven HCC and who were undergoing TAE were enrolled from October 15, 2014, through December 2, 2015. Nineteen plasma angiogenesis factors (angiopoietin 2; hepatocyte growth factor; platelet-derived growth factor AA and BB; placental growth factor; vascular endothelial growth factor A and D; vascular endothelial growth factor receptor 1, 2, and 3; osteopontin; transforming growth factor β1 and β2; thrombospondin 2; intercellular adhesion molecule 1; interleukin 6 [IL-6]; stromal cell-derived factor 1; tissue inhibitor of metalloproteinases 1; and vascular cell adhesion molecule 1 [VCAM-1]) were measured by using enzyme-linked immunosorbent assays at 1 day, 2 weeks, and 5 weeks after TAE and were compared with baseline levels by using paired Wilcoxon tests. Tumor response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Angiogenesis factor levels were compared between responders and nonresponders by mRECIST criteria by using unpaired Wilcoxon tests. Results All procedures were technically successful with no complications. Fourteen angiogenesis factors showed statistically significant changes following TAE, but most changes were transient. IL-6 was upregulated only 1 day after the procedure, but showed the largest increases of any factor. Osteopontin and VCAM-1 demonstrated sustained upregulation at all time points following TAE. At 3-month follow-up imaging, 11 patients had responses to TAE (complete response, n = 6; partial response, n = 5) and 11 patients were nonresponders (stable disease, n = 9; progressive disease, n = 2). In nonresponders, the percent change in IL-6 on the day after TAE (P = .033) and the mean percent change in osteopontin after TAE (P = .024) were significantly greater compared with those of responders. Conclusion Multiple angiogenesis factors demonstrated significant upregulation after TAE. VCAM-1 and osteopontin demonstrated sustained upregulation, whereas the rest were transient. IL-6 and osteopontin correlated significantly with radiologic response after TAE. © RSNA, 2017.

Spontaneous regression of hepatocellular carcinoma in a Caucasian male patient: A case report and review of the literature.

Hepatocellular carcinoma (HCC) is the most common primary hepatic cancer. As it often presents at an advanced stage, it generally has a poor prognosis. Spontaneous regression is a rare finding in HCC, and is often associated with tumour ischemia or a systemic inflammatory response. We herein present the case of a Caucasian patient with spontaneous regression of advanced HCC, not associated with either mechanism. Our patient was a 74-year old Caucasian male who presented with advanced biopsy-proven HCC, with α-fetoprotein levels of >16,600 kU/l. On computed tomography examination, multiple metastases were identified. Due to the poor performance status and as the patient declined treatment, he was referred to a general practitioner for supportive palliative care. Six months later, the patient was alive and feeling well. He had suffered a cerebrovascular accident with ensuing partial hemiparesis, and had been initiated on enalapril, furosemide and curcumin. On re-evaluation, the lung lesions had disappeared, whereas both the liver and peritoneal lesions had decreased in size. Following a review of the literature, the conclusion was that this case of spontaneous regression of advanced HCC was not caused by ischemia, inflammation, or any other previously reported mechanism. Further research is required to elucidate the mechanisms underlying spontaneous regression of HCC.

Hepatocellular carcinoma recurrence pattern following liver transplantation and a suggested surveillance algorithm

PurposeThis study aims to evaluate the recurrence pattern of hepatocellular carcinoma (HCC) following liver transplantation. Materials and methodsA total of 54 patients underwent liver transplantation for HCC; 9 patients developed biopsy-proven recurrent HCC (16.6%). The site of HCC recurrence along with other factors was analyzed. ResultsSeven patients were diagnosed with HCC prior to liver transplantation and 2 patients had incidental HCC in the explanted liver. Two patients had locoregional recurrence, 4 patients had distant metastasis, and 3 patients had synchronous locoregional recurrence and distant metastasis. ConclusionA significant proportion of HCC recurrence following liver transplantation is extrahepatic.