Curative Therapy For Hepatocellular Carcinoma Research Articles

Adjuvant atezolizumab-bevacizumab after curative therapy for hepatocellular carcinoma

Adjuvant atezolizumab-bevacizumab after curative therapy for hepatocellular carcinoma

Increased plasma levels of monocyte chemoattractant protein-1 in patients with hepatitis B virus pre-S2 gene deletion mutation predict a higher risk of hepatocellular carcinoma recurrence after curative surgical resection.

Despite resection surgery as a curative therapy for hepatocellular carcinoma (HCC), the high rate of postoperative HCC recurrence remains a big challenge for patient survival. Chronic hepatitis B virus (HBV) infection is the most important risk factor for HCC. Deletion mutation in the HBV pre-S2 gene leads to expression of an essential viral oncoprotein called pre-S2 mutant and represents an independent prognostic biomarker for HCC recurrence after curative surgical resection. Additionally, cytokines are multifunctional secreted proteins and implicated in all stages of HBV-related HCC tumorigenesis. This study aimed to identify the cytokines whose plasma levels were associated with pre-S2 gene deletion mutation and HCC recurrence and evaluate their potential to be combined with pre-S2 gene deletion mutation in predicting HCC recurrence. Among a panel of 27 cytokines examined, plasma levels of monocyte chemoattractant protein-1 (MCP-1) were significantly upregulated in patients with pre-S2 gene deletion mutation or HCC recurrence. MCP-1 was validated as an independent prognostic biomarker for HCC recurrence. Moreover, patients with both the presence of pre-S2 gene deletion mutation and high levels of MCP-1 displayed a higher risk of HCC recurrence than patients with either one or none of these two biomarkers. The combination of pre-S2 gene deletion mutation and MCP-1 levels exhibited a better prognostic performance for HCC recurrence than each biomarker alone. This study discovered that MCP-1 levels had a significance to be as a combination biomarker with pre-S2 gene deletion mutation providing an improved performance in predicting HCC recurrence after curative surgical resection.

Current status of liver transplantation for non-B non-C liver cirrhosis and hepatocellular carcinoma.

Recently, non-B non-C chronic liver diseases, including alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), have markedly increased worldwide. Liver transplantation (LT) is an effective curative therapy for hepatocellular carcinoma (HCC) as well as decompensated liver cirrhosis. In Japan, where the source of liver grafts is strongly dependent on living donors, efforts have been made to unify the indications for eligibility of HCC patients for LT, leading to the development of 5-5-500 criteria. Along with the expansion of eligibility for LT, the current changing trends in underlying liver diseases of LT recipients, which are related to the rising tide of non-B non-C cirrhosis and HCC, are highlighting the importance of peri-transplant management of patients with various comorbidities. The post-LT prognosis of patients with ALD is significantly affected by de novo malignancies and metabolic syndrome-related complications as well as posttransplant alcohol relapse. NAFLD/NASH patients often suffer from obesity, type 2 diabetes mellitus, and other metabolic syndrome-related disorders, and nonneoplastic factors such as cardiovascular events and recurrence of NAFLD/NASH have a significant impact on post-LT outcomes. Patient management in the peri-transplant period as well as risk assessment for LT are key to improving post-LT outcomes in the era of a growing number of cases of LT for non-B non-C liver diseases.

Association of Increased Programmed Death Ligand 1 Expression and Regulatory T Cells Infiltration with Higher Hepatocellular Carcinoma Recurrence in Patients with Hepatitis B Virus Pre-S2 Mutant after Curative Surgical Resection.

Although surgical resection is available as a potentially curative therapy for hepatocellular carcinoma (HCC), high recurrence of HCC after surgery remains a serious obstacle for long-term patient survival. Therefore, the discovery of valuable prognostic biomarkers for HCC recurrence is urgently needed. Pre-S2 mutant is a mutant form of hepatitis B virus (HBV) large surface protein which is expressed from the HBV surface gene harboring deletion mutations spanning the pre-S2 gene segment. Pre-S2 mutant-positive HCC patients have been regarded as a high-risk population of HCC recurrence after resection surgery and display increased immune checkpoint programmed death ligand 1 (PD-L1) expression and pro-tumor regulatory T cells (Tregs) infiltration in tumor tissues. In this study, the association of higher levels of PD-L1 expression and Tregs infiltration in tumor tissues with post-operative HCC recurrence in pre-S2 mutant-positive HCC patients was evaluated. We found that patients with pre-S2 mutant in combination with higher levels of PD-L1 expression and Tregs infiltration in tumor tissues were independently associated with a higher risk of HCC recurrence (hazard ratio, 4.109; p value = 0.0011) and poorer recurrence-free survival (median, 8.2 versus 18.0 months; p value = 0.0004) than those of patients with either one or two of these three biomarkers. Furthermore, a combination of pre-S2 mutant, intra-tumoral PD-L1 expression, and tumor-infiltrating Tregs exhibited superior performance in identifying patients at a higher risk of HCC recurrence (area under the receiver operating characteristic curve, 0.8400). Collectively, this study suggests that higher levels of PD-L1 expression and Tregs infiltration in tumor tissues predicted a higher risk of HCC recurrence in pre-S2 mutant-positive HCC patients after curative surgical resection.

Different Models to Predict the Risk of Recurrent Hepatocellular Carcinoma in the Setting of Liver Transplantation.

Simple SummaryLiver transplantation is considered the first-choice curative therapy for hepatocellular carcinoma in the early phase of the disease, when surgical resection is not possible. Even when implementing restrictive criteria to select patients for liver transplantation, there is a risk of recurrence in the transplanted liver, influencing the long-term outcome and prognosis. As it is challenging to predict the individual risk of recurrence, there is a need for validated and predictive scoring systems to use to stratify patients before and/or after liver transplantation. Most of the proposed scorings include biological markers for tumour behavior, in addition to the number and size of tumoral nodules. In this review, we discuss different published models to assess the risk of recurrent hepatocellular carcinoma after transplantation. Our aim is to refine clinical decisions about prioritization and listing for liver transplantation, to better inform patients and provide an appropriate surveillance strategy to influence their prognosis.Liver transplantation is the preferred therapeutic option for non-resectable hepatocellular carcinoma in early-stage disease. Taking into account the limited number of donor organs, liver transplantation is restricted to candidates with long-term outcomes comparable to benign indications on the waiting list. Introducing the morphometric Milan criteria as the gold standard for transplant eligibility reduced the recurrence rate. Even with strict patient selection, there is a risk of recurrence of between 8 and 20% in the transplanted liver, and this is of even greater importance when using more expanded criteria and downstaging protocols. Currently, it remains challenging to predict the risk of recurrence and the related prognosis for individual patients. In this review, the recurrence-risk-assessment scores proposed in the literature are discussed. Currently there is no consensus on the optimal model or the implications of risk stratification in clinical practice. The most recent scorings include additional biological markers for tumour behavior, such as alfa-foetoprotein, and the response to locoregional therapies, in addition to the number and diameter of tumoral nodules. The refinement of the prediction of recurrence is important to better inform patients, guide decisions about prioritization and listing and implement individualized surveillance strategies. In the future, this might also provide indications for tailored immunosuppressive therapy or inclusion in trials for adjuvant treatment.

Efficacy of hepatitis C virus eradication after curative treatment for hepatocellular carcinoma in patients with advanced hepatocellular carcinoma and decreased hepatic functional reserve: A nationwide, multicentre study by the Japanese Red Cross Liver Study Group.

Improvements in the hepatocellular carcinoma (HCC) recurrence rate and survival have been frequently reported following virus eradication after hepatitis C virus (HCV)-related HCC cure. However, the efficacy of direct-acting antiviral (DAA) therapy in patients who included those with advanced HCC and decreased hepatic functional reserve is unknown. A comparative examination was retrospectively conducted of 141 patients with hepatitis C who started DAA therapy within 1 year after undergoing curative HCC treatment and showed a sustained viral response (SVR) and 327 patients who underwent curative treatment for HCV-related HCC and did not subsequently receive antiviral therapy. Whether DAA therapy was given was identified as an independent factor related to both HCC recurrence and survival. Both the recurrence and survival rates improved significantly with DAA therapy in Child-Pugh (CP)-A, whereas no difference in the recurrence rate was seen with DAA therapy in CP-B. However, the survival rate was significantly higher in the DAA group in this class. Similarly, dividing the patients by the Milan criteria showed significant improvements in the recurrence rate and survival with DAA therapy in patients within the Milan criteria. Patients with HCC beyond the Milan criteria showed no difference in recurrence rates, but the DAA group tended to have higher survival rates. Thus, DAA after curative therapy for HCC can be expected to improve survival in patients with advanced HCC or decreased hepatic functional reserve. HCV should be aggressively eradicated in all patients eligible for curative treatment of HCC.

Differential prognoses among male and female patients with hepatocellular carcinoma.

The incidence of hepatocellular carcinoma (HCC) is significantly higher in men than women. Nonetheless, the impact of sex disparities on HCC outcomes remains unclear. We aimed to compare the clinical manifestations and prognoses between male and female patients with HCC. This retrospective study enrolled 5337 consecutive patients (3976 men, 1361 women) who were diagnosed with HCC from 2007 to 2020. The prognostic factors were identified by the Cox proportional hazards model. Male patients were younger upon HCC diagnosis (median age 64 vs 69 years; p < 0.001) with more favorable hepatic functional reserves (39.0% vs 35.1% albumin-bilirubin grade 1; p = 0.025) but had greater tumor burdens than the female patients. Furthermore, fewer male patients underwent curative therapies for HCC compared with the female patients (49.0% vs 57.0%; p < 0.001). After a median follow-up of 20.1 months (interquartile range, 5.8-47.3 months), 3133 patients died. The cumulative 5-year overall survival rates were 37.1% and 41.9% for male and female patients, respectively (p < 0.001). From the multivariate analysis, male sex was not an independent factor predictive of poor overall survival in all patients and in the subgroup analysis stratified by treatment modalities. When stratified by age, the female sex was an independent factor associated with lower mortality in younger (≤50 years) patients but not in older patients with HCC. Sex was not an independent predictor of the outcome of patients with HCC, especially for those aged more than 50 years.

The combination of transcatheter arterial chemoembolisation (TACE) and thermal ablation versus TACE alone for hepatocellular carcinoma.

Hepatocellular carcinoma is the sixth most common cancer worldwide. Hepatic resection is regarded as the curative therapy for hepatocellular carcinoma. However, only about 20% of people with hepatocellular carcinoma are candidates for resection, which highlights the importance of effective nonsurgical therapies. Until now, transcatheter arterial chemoembolisation (TACE) is the most common palliative therapy for hepatocellular carcinoma, but its clinical benefits remain unsatisfactory. During recent years, some studies have reported that the combination of TACE plus thermal ablation can confer a more favourable prognosis than TACE alone. However, clear and compelling evidence to prove the beneficial or harmful effects of the combination of TACE and thermal ablation therapy is lacking. To assess the beneficial and harmful effects of the combination of thermal ablation with TACE versus TACE alone in people with hepatocellular carcinoma. We performed searches in the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in the Cochrane Library, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science. We endeavoured to identify relevant randomised clinical trials also in the China National Knowledge Infrastructure (CNKI) and Wanfang databases. We searched trial registration websites for ongoing studies. We also handsearched grey literature sources. The date of last search was 22 December 2020. We planned to include all randomised clinical trials comparing the combination of TACE plus thermal ablation versus TACE alone for hepatocellular carcinoma, no matter the language, year of publication, publication status, and reported outcomes. We planned to use standard methodological procedures expected by Cochrane. We planned to calculate risk ratios (RRs) with the corresponding 95% confidence intervals (CIs). For time-to-event variables, we planned to use the methods of survival analysis and express the intervention effect as a hazard ratio (HR) with 95% Cl. If the log HR and the variance were not directly reported in reports, we planned to calculate them indirectly, following methods for incorporating summary time-to-event data into meta-analysis. We planned to assess the risk of bias of the included studies using the RoB 2 tool. We planned to assess the certainty of evidence with GRADE and present the evidence in a summary of findings table. Out of 2224 records retrieved with the searches, we considered 135 records eligible for full-text screening. We excluded 21 of these records because the interventions used were outside the scope of our review or the studies were not randomised clinical trials. We listed the remaining 114 records, reporting on 114 studies, under studies awaiting classification because we could not be sure that these were randomised clinical trials from the information in the study paper. We could not obtain information on the registration of the study protocol for any of the 114 studies. We could not obtain information on study approval by regional research ethics committees, either from the study authors or through our own searches of trial registries. Corresponding authors did not respond to our enquiries about the design and conduct of the studies, except for one from whom we did not receive a satisfactory response. We also raised awareness of our concerns to editors of the journals that published the 114 studies, and we did not hear back with useful information. Moreover, there seemed to be inappropriate inclusion of trial participants, based on cancer stage and severity of liver disease, who should have obtained other interventions according to guidelines from learned societies. Accordingly, we found no confirmed randomised clinical trials evaluating the combination of TACE plus thermal ablation versus TACE alone for people with hepatocellular carcinoma for inclusion in our review. We identified five ongoing trials, by handsearching in clinical trial websites. We could not find for inclusion any confirmed randomised clinical trials assessing the beneficial or harmful effects of the combination of TACE plus thermal ablation versus TACE alone in people with hepatocellular carcinoma. Therefore, our results did not show or reject the efficiency of the combination of TACE plus thermal ablation versus TACE alone for people with hepatocellular carcinoma. We need trials that compare the beneficial and harmful effects of the combination of TACE plus thermal ablation versus TACE alone in people with hepatocellular carcinoma, not eligible for treatments with curative intent (liver transplantation, ablation surgical resection) and who have sufficient liver reserve, as assessed by the Child Pugh score, and who do not have extrahepatic metastases. Therefore, future trial participants must be classified at Barcelona Clinic Liver Cancer Stage B (intermediate stage) (BCLC-B) or an equivalent, with other staging systems.

Hepatocellular Carcinoma: Downstaging to Liver Transplantation as Curative Therapy.

Hepatocellular carcinoma (HCC) ranks among the leading cancer-related causes of morbidity and mortality worldwide. Downstaging of HCC has prevailed as a key method to curative therapy for patients who present with unresectable HCC outside of the listing criteria for liver transplantation (LT). Even though LT paves the way to lifesaving curative therapy for HCC, perpetually severe organ shortage limits its broader application. Debate over the optimal protocol and assessment of response to downstaging treatment has fueled immense research activity and is pushing the boundaries of LT candidate selection criteria. The implicit obligation of refining downstaging protocol is to ensure the maximization of the transplant survival benefit by taking into account the waitlist life expectancy. In the following review, we critically discuss strategies to best optimize downstaging HCC to LT on the basis of existing literature.

Use of Contrast-Enhanced Ultrasound with Sonazoid for Evaluating the Radiotherapy Efficacy for Hepatocellular Carcinoma.

Radiotherapy is one of the available curative therapies for hepatocellular carcinoma (HCC). We investigate the use of contrast-enhanced ultrasound using Sonazoid (SCEUS) in evaluating the efficacy of radiotherapy for HCC. We enrolled 59 patients with 59 HCCs in this retrospective study. Tumor size and tumor vascularity were evaluated using SCEUS before and 1, 3, 7, 10, and 13 months after radiotherapy. The median follow-up period was 44.5 months (range: 16–82 months). Of the HCCs, 95% (56/59) had no local recurrence, while 5% (3/59) did. At 13 months after radiotherapy, in cases with no local recurrence, SCEUS showed a reduction in tumor vascularity in all cases, while tumor size reduction (>30% reduction, compared with pre-radiotherapy) was observed in 82.1% (46/56). In all three cases of local recurrence, vascularity and tumor size reduction were not observed during the follow-up period and residual HCCs were demonstrated pathologically. Compared with cases with local recurrence, tumor size reduction and reduction in tumor vascularity (p < 0.001) were significantly greater in cases with no local recurrence at 13 months after radiotherapy. SCEUS may be useful in evaluating radiotherapy efficacy for HCC.

Lenvatinib as first-line therapy for recurrenthepatocellular carcinoma after liver transplantation: Is the current evidence applicable to these patients?

Liver transplantation (LT) is one of the leading curative therapies for hepatocellular carcinoma (HCC). Despite recent optimization of transplant selection criteria, including alpha-feto protein, HCC recurrence after LT is still the leading cause of death in these patients. During the last decades, effective systemic treatments for HCC, including tyrosine kinase inhibitors and immunotherapy, have been approved. We describe the clinical scenario of a patient with recurrence of HCC five years after LT, who received lenvatinib as first-line systemic therapy to introduce systemic treatment options in this clinical setting. In this opinion review, we detail first and second-line systemic treatment options, focusing on those feasible for patients with recurrent HCC after LT. Several trials have evaluated new drugs to treat HCC patients in first and second-line therapy, but patients with recurrent HCC after LT have been excluded from these trials. Consequently, most of the evidence comes from observational retrospective studies. Whether tyrosine kinase inhibitors will remain the primary therapeutic approach in these patients, due to a relative contraindication for immunotherapy, may be clarified in the near future.

Prognostic significance of controlling nutritional status score-based nomogram for hepatocellular carcinoma within Milan criteria after radiofrequency ablation.

Radiofrequency ablation (RFA) is a curative therapy for hepatocellular carcinoma (HCC) within Milan criteria. This study was conducted to evaluate the association between controlling nutritional status (CONUT) score and oncological outcomes in HCC patients within Milan criteria after RFA. Nomograms were constructed for the prediction of prognosis. The study included 403 HCC patients within Milan criteria who underwent RFA at National Cancer Center and the First Hospital of Shanxi Medical University from January 2010 to December 2014. Oncological outcomes included disease-free survival (DFS) and overall survival (OS). The clinical variables were assessed by univariate and multivariate Cox regression analyses. C-index, time-dependent receiver operating characteristic (t-ROC) curve (t-AUC) and calibration plots were used to evaluate discrimination and calibration of the nomograms. Patients were divided into CONUT ≤4 and ≥5 groups. The common prognostic factors affecting DFS and OS were number of lesions, tumor differentiation, and CONUT score. Age and total bilirubin (TBIL) were prognostic factors for OS only. Both DFS and OS rates in CONUT ≤4 group were significantly higher than those in CONUT ≥5 group (P=0.033, P<0.001). Two well-discriminated and calibrated nomograms were constructed to predict the probability of 1-, 2-, and 3-year DFS and 1-, 2-, 3-, 5-year OS with C-indexes of 0.798 and 0.757, respectively. CONUT score is an independent prognostic factor for HCC after RFA treatment and a reliable indicator for nutritional interventions. Higher CONUT scores were associated with poor oncological outcomes. Nomograms based on CONUT score could efficiently predict DFS and OS for HCC patients within Milan criteria after RFA.

A concise review of the changing landscape of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer-related deaths in the United States, increasing by 2% to 3% annually, with a dismal 5-year survival rate of 18%. The Barcelona Clinic Liver Cancer criteria used to guide treatment considers performance status and assessment of liver function by Child-Pugh score in addition to tumor size and location. Curative therapies for HCC include surgical resection, liver transplantation, and tumor ablation. Patients with unresectable or inoperable lesions should be considered for arterially directed embolic therapy, systemic therapy, or radiation. Options for first-line systemic therapy of advanced HCC include sorafenib, lenvatinib, and atezolizumab plus bevacizumab. Nivolumab may be an option in patients with advanced HCC who are ineligible for tyrosine kinase inhibitors or other anti-angiogenic agents. Options for subsequent therapy following disease progression include regorafenib, cabozantinib, ramucirumab, lenvatinib, nivolumab, nivolumab plus ipilimumab, sorafenib, or pembrolizumab. Patients with advanced HCC are at a high risk of adverse effects because of baseline hepatic dysfunction, comorbidities associated with chronic liver disease, and potential drug-drug interactions. Improved tolerance of therapies for advanced HCC may lead to reduction in treatment discontinuation and contribute to better patient outcomes. Managed care pharmacists should understand the recent efficacy and safety data, guideline recommendations, and treatment algorithms for management of HCC.

Predictors of post-operative complications after surgical resection of hepatocellular carcinoma and their prognostic effects on outcome and survival: A propensity-score matched and structural equation modelling study

IntroductionAlthough hepatectomy is the mainstay of curative therapy for hepatocellular carcinoma (HCC), post-operative complications remain high. Presently there is conflicting data on the impact of morbidity on oncologic outcomes. We sought to identify predictors for the occurrence of post-hepatectomy complications, as well as to analyse the impact on overall survival (OS) and recurrence-free survival (RFS). Materials and methodsWe performed a retrospective review of 888 patients who underwent resection for HCC from 2001 to 2016 in our institution. ResultsA total of 237 patients (26.7%) developed 254 complications of Clavien-Dindo Grade ≥2. Hepatitis B (p = 0.0397), elevated ASA score (p = 0.0002), higher platelet counts (p = 0.0277), raised pre-operative APRI scores (p = 0.0105) and bloodloss (p < 0.0001) were independently associated with the development of complications. After propensity-score matching, 458 patients were compared in a 1:1 ratio (229 with complications versus 229 without). Patients with complications had significantly longer median length of stay (9 days [IQR 7-15] versus 6 days [IQR 5-8], p < 0.0001), higher 90-day mortality rates as well as inferior OS (p = 0.0139), but there was no difference in RFS (p = 0.4577). Age (p = 0.0006), elevated Child Pugh points (p < 0.0001), microvascular invasion (p = 0.0002), multifocal tumours (p = 0.0002), R1 resection (p = 0.0443) and development of complications (p = 0.0091) were independent predictors of inferior OS. ConclusionPost-operative morbidity affected both short-term and OS outcomes after hepatectomy for HCC. Hepatitis B, higher ASA scores, elevated preoperative APRI and increased blood loss were found to predict a higher likelihood of developing complications. This may potentially be mitigated by careful patient selection and adopting strict measures to minimise intraoperative bleeding.

Meta-analysis: The efficacy of metformin and other anti-hyperglycemic agents in prolonging the survival of hepatocellular carcinoma patients with type 2 diabetes

IntroductionThis study aimed to compare the therapeutic efficacy of metformin and other anti-hyperglycemic agents in hepatocellular carcinoma (HCC) patients with type 2 diabetes (T2D). MaterialsA systematic electronic search on keywords including HCC and different anti-hyperglycemic agents was performed through electronic databases including Medline and EMBASE. The primary outcome was the overall survival (OS). The secondary outcomes were the recurrence-free survival (RFS) and progression-free survival (PFS). ResultsSix retrospective cohort studies were included for analysis: Four studies with curative treatment for HCC (618 patients with metformin and 532 patients with other anti-hyperglycemic agents) and two studies with non-curative treatment for HCC (92 patients with metformin and 57 patients with other anti-hyperglycemic agents). Treatment with metformin was associated with significantly longer OS (OR1yr=2.62, 95%CI: 1.76–3.90; OR3yr=3.14, 95%CI: 2.33–4.24; OR5yr=3.31, 95%CI: 2.39–4.59, all P<0.00001) and RFS (OR1yr=2.52, 95%CI: 1.84–3.44; OR3yr=2.87, 95%CI: 2.15–3.84; all P<0.00001; and OR5yr=2.26, 95%CI: 0.94–5.45, P=0.07) rates vs. those of other anti-hyperglycemic agents after curative therapies for HCC. However, both of the two studies reported that following non-curative HCC treatment, there were no significant differences in the OS and PFS rates between the metformin and non-metformin groups (I2>50%). ConclusionsMetformin significantly prolonged the survival of HCC patients with T2D after the curative treatment of HCC. However, the efficacy of metformin needs to be further determined after non-curative therapies for HCC patients with T2D.

2385 Multifocal Hepatocellular Carcinoma Masquerading as Cirrhosis

INTRODUCTION: Hepatocellular carcinoma (HCC) is a primary tumor of the liver that is usually seen in patients with chronic liver disease, such as cirrhosis. The only curative therapy for HCC is liver resection or liver transplantation. For patients with HCC that undergo liver transplantation, immunosuppressive therapy is necessary but associated with a risk for tumor recurrence given the intrinsic hepatoproliferative effects. Here, we present a case of a patient who underwent simultaneous liver and kidney transplantation and was found to have multifocal hepatocellular carcinoma that mimicked cirrhosis. CASE DESCRIPTION/METHODS: A 58-year-old male with a past medical history of hepatitis B and C associated liver cirrhosis and CKD-IV presents to the transplant clinic. The patient completed a course of ledipasvir/sofosbuvir therapy for his hepatitis C with sustained virologic response. He also has chronic hepatitis B which is treated with tenofovir alafenamide. His presumed cirrhosis was complicated by recurrent ascites requiring scheduled weekly paracenteses. Ascites fluid studies were bloody but negative for malignancy on path review. Multiple CT and MRI of the abdomen without contrast due to eGFR showed signs of portal hypertension but no liver lesions. A blood type and HLA matched donor was found, and the patient underwent successful simultaneous liver and kidney transplant. He was subsequently started on standard 3 drug immunosuppressive therapy after induction. Upon path review of the explant, more than 150 small hepatocellular carcinomas were discovered. On review of his liver no fibrosis was found and these innumerable HCC’s created the illusion of cirrhosis on imaging. Secondary to this discovery, tacrolimus was decreased and everolimus was started in hopes to decrease risk for recurrent HCC. The patient is doing well without recurrence 18 months post-transplant. DISCUSSION: In patients with HCC who undergo liver transplantation, it is important to consider alternative immunosuppresives. Studies have shown in animal models the potential positive effects of mTOR inhibitors in decreasing recurrence; however human data is controversial. There is some thought that the benefit of the mTOR inhibitor is to decrease the dose of calcineurin agents with known hepatoproliferative properties.

Cost-utility analysis of primary liver transplant versus salvage liver transplant after hepatectomy for hepatocellular carcinoma

Background: Liver transplantation and hepatectomy remain the main curative therapies for hepatocellular carcinoma (HCC). Although transplant offers better disease-free survival than resection, the shortage of organs and current donor utilization policies limit its utilization in the setting HCC. Herein, we aim to determine the cost-utility between primary liver transplant (PLT) and salvage liver transplant (SLT) after resection for HCC. Methods: A Markov cohort model was created to simulate a cohort of 55-year-old patients, diagnosed with early-stage HCC within Milan criteria, eligible to undergo transplant or hepatectomy. The patients transitioned through different health states in 1-month cycles and were followed for a time horizon of 10 years. The primary outcome was quality-adjusted-life-years (QALY) gained. The ceiling ratio of US$100.000/QALY was adopted. Our analysis assumed the perspective of a third-party payer. Probabilities and utilities were obtained from literature review, and costs from Medicare database and Agency for Health Research and Quality. Results: The base-case analysis revealed SLT after hepatectomy for HCC as the dominant strategy. Primary liver transplant (PLT) had an incremental cost of US$ 535.530,00 when compared to SLT. In addition, it generated 0.23 QALYs less than SLT, therefore PLT was dominated. Sensitive analysis showed the most sensitive variables, that could affect the results of our analysis, were the rate of recurrence after hepatectomy and the probability of drop out while in the waiting list for SLT. When the recurrence rate after resection was more than 90% in 5-years (monthly rate > 4.2%), PLT was no longer dominated. Likewise, when the probability of drop out from the waiting list for SLT was more than 48% in 6 months (monthly probability > 10.3%), SLT was no longer dominated. On both scenarios the Incremental Cost-Effectiveness Ratio (ICER) was above the ceiling ratio of US$100.000/QALY, therefore SLT remained the more cost-effective strategy. Conclusion: In this study, Salvage Liver Transplant after Hepatectomy for HCC within Milan criteria was more cost-effective than Primary Liver Transplant.

3550 Understanding Racial Disparities in Hepatocellular Carcinoma Treatments and Outcomes

OBJECTIVES/SPECIFIC AIMS: Black patients with hepatocellular carcinoma (HCC) receive fewer curative therapies and have higher mortality than other groups. Reducing this disparity will require an in-depth understanding of patient comorbidities, tumor characteristics, and social determinants of health. Our objectives are to a) perform a multi-center retrospective cohort study of black and white patients diagnosed with HCC in the Indianapolis area. b) prospectively enroll black and white patients with HCC to collect clinical characteristics as well as data on the social determinants of health. METHODS/STUDY POPULATION: A retrospective chart review of patients with a diagnosis of HCC from 2010-2017 from five area Indianapolis hospitals will be performed. Demographics, comorbidities, liver disease severity, and tumor characteristics will be collected using the Indiana Network for Patient Care database and compared between black and white patients. Concomitantly, a prospective cohort of black and white patients will be enrolled and surveyed to collect data on socioeconomic status and income adequacy, literacy, functional status, substance abuse history, social support, activation, and adherence. The primary outcomes are the receipt of curative therapies for HCC including liver transplantation, resection or ablation. The secondary outcome is mortality. Multivariable logistic regression models will be used to explore disparities seen in the primary and secondary outcomes. RESULTS/ANTICIPATED RESULTS: These preliminary results include Indiana University Hospital (IUH) findings; a multicenter analysis is underway. The IUH cohort included 1,032 (86%) white and 164 (14%) black patients. Black and white patients had similar Model for End-Stage Liver Disease and Child-Pugh scores. There was a trend toward larger tumor size (5.3 cm vs. 4.7 cm; P = 0.05) in black patients; however, Barcelona Clinic Liver Cancer staging and Milan criteria were similar. Black patients were less likely to undergo liver transplantation than white patients—a disparity that was not attenuated (odds ratio [OR], 0.43; 95% confidence interval [CI]: 0.21-0.90) on multivariable analysis. Substance abuse was more frequently cited as the reason black patients within Milan criteria failed to undergo transplantation than white patients. Survival was similar between the two groups. DISCUSSION/SIGNIFICANCE OF IMPACT: Racial differences in patient and tumor characteristics were small in our single center analysis and did not explain the disparity in liver transplantation. This analysis however only reflects 25% of patients diagnosed with HCC in the Indianapolis metropolitan, highlighting the need for a multicenter study. Higher rates of substance abuse in black patients within Milan criteria who failed to undergo transplantation suggest social factors contribute to this disparity and highlight the need for a prospective study that can explore these and other social factors.

Goals and targets for personalized therapy for HCC.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide and its incidence continues to rise. While cirrhosis underlies most cases of HCC, many molecular pathways are implicated in HCC carcinogenesis, including the TERT promoter mutation, Wnt/β-catenin, P53, Akt/mTOR, vascular endothelial growth factor receptor (VEGFR), and endothelial growth factor receptor (EGFR)/RAS/MAPK pathways. While the most widely used staging and treatment algorithm for HCC-the Barcelona Clinic Liver Cancer (BCLC) system-does not recommend systemic molecular therapy for early HCC, a variety of treatment options are available depending upon the stage of HCC at diagnosis. Determining the best treatment options must take into account not only the burden and extent of HCC, but also the patient's performance status, underlying liver function, extra-hepatic disease and co-morbidities. Radiofrequency or microwave ablation, liver resection, or liver transplantation, all potential curative therapies for HCC, should be the first-line treatments when possible. For patients who are not candidates of curative treatments, locoregional therapies such as transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and stereotactic body radiation (SBRT) can improve survival and quality of life. Sorafenib, a multi-kinase VEGF inhibitor, is the most widely used systemic chemotherapy approved as a first-line agent for unresectable or advanced HCC. Clinical trials are underway directed towards molecular therapies that target different aspects of the hepatocellular carcinogenesis cascade. Ideally, the goal of future therapy should be to target multiple pathways in the HCC cascade with combination treatments to achieve personalized care aimed at improving overall survival.

Liver Transplantation and Hepatic Resection can Achieve Cure for Hepatocellular Carcinoma.

The aim of this study was to estimate probabilities of achieving the statistical cure from hepatocellular carcinoma (HCC) with hepatic resection (HR) and liver transplantation (LT). Statistical cure occurs when the mortality of a specific population returns to values of that of general population. Resection and transplantation are considered potentially curative therapies for HCC, but their effect on the residual entire life-expectancy has never been investigated. Data from 3286 HCC patients treated with LT (n = 1218) or HR (n = 2068) were used to estimate statistical cure. Disease-free survival (DFS) was the primary survival measure to estimate cure fractions through a nonmixture model. Overall survival (OS) was a secondary measure. In both, patients were matched with general population by age, sex, year, and race/ethnicity. Cure variations after LT were also adjusted for different waiting-list drop-outs. Considering DFS, the cure fraction after LT was 74.1% and after HR was 24.1% (effect size >0.8). LT outperformed HR within all transplant criteria considered (effect size >0.8), especially for multiple tumors (>0.9) and even in presence of a drop-out up to 20% (>0.5). Considering OS, the cure fraction after LT marginally increased to 75.8%, and after that HR increased to 40.5%. The effect size of LT over HR in terms of cure decreased for oligonodular tumors (<0.5), became small for drop-out up to ∼20% (<0.2), and negligible for single tumors <5 cm (∼0.1). As other malignancies, statistical cure can occur for HCC, primarily with LT and secondarily with HR, depending on waiting-list capabilities and efficacy of tumor recurrence therapies after resection.