Hepatocellular Carcinoma Surveillance Program Research Articles

Epidemiological projections of viral-induced hepatocellular carcinoma in the perspective of WHO global hepatitis elimination.

Hepatitis B is an eminent risk factor for hepatocellular carcinoma (HCC) in Southeast Asia and sub-Saharan Africa, whereas hepatitis C is a key risk factor for HCC in Western Europe and North America. Increased awareness of the global burden of viral hepatitis resulted, in May 2016, in the adoption of the first global health sector strategy on viral hepatitis by the World Health Assembly, which calls for the elimination of viral hepatitis as a public health threat by 2030. Although the incidence of liver cancer resulting from viral infections has increased since the 1990s, the implementation of public health interventions, such as hepatitis B vaccination and antiviral therapies might have reduced the global burdens of HCC. Hepatitis B immunization in infancy has been associated with a reduction in the risk of infant fulminant hepatitis, chronic liver disease, and HCC in Taiwan. Achieving viral hepatitis elimination by 2030 can be accelerated by improving the access to HCC screening programs. HCC surveillance programs in developed countries must be refined to increase an access to personalized surveillance program, whereas the limited access to surveillance and treatment of HCC in developing countries remains a significant public health issue.

Effectiveness of Hepatocellular Carcinoma Surveillance and an Optimal Surveillance Interval: Nationwide Cohort of Korea.

PurposeTo assess associations between surveillance intervals in a national hepatocellular carcinoma (HCC) surveillance program and receiving curative treatment and mortality using nationwide cohort data for Korea.Materials and MethodsUsing the National Health Insurance Service Database of Korea, we retrospectively identified 3201852 patients, the target population of the national HCC surveillance program, between 2008 and 2017. After exclusion, a total of 64674 HCC patients were divided based on surveillance intervals: never screened, ≤6 months (6M), 7–12 months (1Y), 13–24 months (2Y), and 25–36 months (3Y). Associations for surveillance interval with the chance to receive curative therapy and all-cause mortality were analyzed.ResultsThe 6M group (51.9%) received curative therapy more often than the other groups (1Y, 48.3%; 2Y, 43.8%; 3Y, 41.3%; never screened, 34.5%). Odds ratio for receiving curative therapy among the other surveillance interval groups (1Y, 0.87; 2Y, 0.76; 3Y, 0.77; never screened, 0.57; p<0.001) were significantly lower than that of the 6M group. The hazard ratios (HRs) of all-cause mortality were 1.07, 1.14, and 1.37 for 2Y, 3Y, and never screened groups. The HR for the 1Y group (0.96; p=0.092) was not significantly different, and it was lower (0.91; p<0.001) than that of the 6M group after adjustment for lead-time bias. Curative therapy was associated with survival benefits (HR, 0.26; p<0.001).ConclusionHCC surveillance, especially at a surveillance interval of 6 months, increases the chance to receive curative therapy.

Hepatocellular Carcinoma Among Aboriginal and Torres Strait Islander Peoples of Australia

Background: Liver disease and hepatocellular carcinoma (HCC) are important contributors to the mortality gap between Indigenous and non-Indigenous Australians. However, there is a lack of population based high quality data assessing the differences in HCC epidemiology and outcomes according to Indigenous status. The aim of this study was therefore to perform a large epidemiological study of HCC investigating differences between Indigenous and non-Indigenous Australians with HCC. Methods: Data linkage methodology was used to link data from cancer registries with hospital separation summaries across three Australian jurisdictions during 2000-2017. Cumulative survival (Kaplan-Meier) and the differences in survival (Multivariable Cox-regression) by Indigenous status were assessed. Findings: A total of 229 Indigenous and 3587 non-Indigenous HCC cases were included in the analyses. Significant epidemiological differences identified for Indigenous HCC cases included younger age at onset, higher proportion of females, higher rurality, lower socioeconomic status, and higher comorbidity burden (all p<0.001). The distribution of cofactors was also significantly different for Indigenous Australians including higher prevalence of alcohol misuse, hepatitis B, and diabetes and more frequent presence of multiple HCC cofactors (all p<0.001). Indigenous Australians received curative HCC therapies less frequently (6.6% vs. 14.5%, p<0.001) and had poorer 5-year survival (10.0% vs. 17.3%, p<0.001; unadjusted hazard ratio (HR) =1.42 96%CI 1.21-1.65) compared to non-Indigenous Australians. Indigenous status was not independently associated with poorer survival on multivariable analysis. The survival difference was largely accounted for by other factors including rurality, comorbidity burden and lack of curative therapy (adjusted-HR=1.20 95%CI 0.97-1.47). Interpretation: Such data provide a call to action to help design and implement education, liver management and HCC surveillance programs for Indigenous people to help close the liver cancer mortality gap. Funding: The work was supported by an unrestricted educational grant from the Gastroenterology Society of Australia. Declaration of Interests: There are no financial disclosures. Ethics Approval Statement: This study was approved by the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (2019-3365), SA Department for Health (HREC/19/SAH/45), Aboriginal Health Research Ethics Committee (04-19-829), QIMR Berghofer Medical Research Institute (P3506), and Queensland Health (HREC/17/QPAH/23).

Issue Highlights

Although the introduction of biologics for the treatment of Crohn’s in 1998 revolutionized our approach to this disease, primary non-response and secondary loss of response remain vexing problems for a large subset of patients in clinical practice. For anti-TNF agents, common reasons for loss of response include subtherapeutic drug concentrations and development of neutralizing anti-drug antibodies. Therapeutic drug monitoring, dose escalation and interval shortening are approaches with demonstrated effectiveness recapturing response to these agents and are commonly employed in clinical practice. 1 Papamichael K. Cheifetz A.S. Melmed G.Y. et al. Appropriate therapeutic drug monitoring of biologic agents for patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2019; 17: 1655-1668.e3 Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Shortening the dose interval or dose intensification for Vedolizumab has also been shown to permit recapturing of response in some patients, 2 Peyrin-Biroulet L. Danese S. Argollo M. et al. Loss of response to vedolizumab and ability of dose intensification to restore response in patients with crohn's disease or ulcerative colitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2019; 17: 838-846.e2 Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar but whether this approach can be extrapolated to Ustekinumab remains unclear. This retrospective study by Ollech et al 3 Ollech J.E. Normatov I. Peleg N. et al. Effectiveness of Ustekinumab dose escalation in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2021; 19: 104-110 Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar is the first to evaluate real-world effectiveness of interval shortening from 8- to 4-week dosing for Ustekinumab. The authors describe pre- and post-dose escalation parameters including Harvey Bradshaw Index (HBI), C-reactive protein (CRP), and fecal calprotectin for a subset of 110 patients not responding to Ustekinumab every 8 weeks. Although not all patients in the subset had all parameters pre- and post-dose increase, of the 78 patients (71%) with pre-and post-HBI metrics, the median HBI decreased from 4.5 to 3 (P = .002). Of 60 patients (55%) with CRP measurements, median CRP decreased from 8 mg/L to 3 mg/L (P = .031). Among patients with HBI >4, CRP ≥5 mg/L, fecal calprotectin >250 μg/g, or endoscopic evidence of active disease, 28% achieved clinical remission (HBI<4), 22% normalized CRP, and 36% endoscopic remission with a median follow up of 9 months post-dose increase. 38% of patients on steroids were able to discontinue, and 45% with active perianal disease reported resolution within 6 months of dose-escalation. Twenty-three patients (20.9%) discontinued therapy following dose escalation, most (78%) due to lack of response; only 1 due to side effects (rash). This is the first study to demonstrate improvement in objective measures of Crohn’s disease activity with dose-intensification of Ustekinumab from 8- to 4-week intervals. Effectiveness of Ustekinumab Dose Escalation in Patients With Crohn’s DiseaseClinical Gastroenterology and HepatologyVol. 19Issue 1PreviewA subset of patients with Crohn’s disease (CD) do not respond to ustekinumab at the standard dose of 90 mg every 8 weeks. Little is known about the efficacy of shortening the interval between doses. Full-Text PDF Type 2 Diabetes and Metformin Use Associate With Outcomes of Patients With Nonalcoholic Steatohepatitis–Related, Child–Pugh A CirrhosisClinical Gastroenterology and HepatologyVol. 19Issue 1PreviewFactors that affect outcomes of patients with nonalcoholic steatohepatitis (NASH)-related cirrhosis are unclear. We studied associations of type 2 diabetes, levels of hemoglobin A1c (HbA1c), and use of antidiabetic medications with survival and liver-related events in patients with NASH and compensated cirrhosis. Full-Text PDF Intragastric Balloon Placement Induces Significant Metabolic and Histologic Improvement in Patients With Nonalcoholic SteatohepatitisClinical Gastroenterology and HepatologyVol. 19Issue 1PreviewObese patients with nonalcoholic steatohepatitis (NASH) are at risk for cirrhosis if significant weight loss is not achieved. The single fluid-filled intragastric balloon (IGB) induces meaningful weight loss and might be used in NASH treatment. We performed an open-label prospective study to evaluate the effects of IGB placement on metabolic and histologic features of NASH. Full-Text PDF Serum Levels of α-Fetoprotein Increased More Than 10 Years Before Detection of Hepatocellular CarcinomaClinical Gastroenterology and HepatologyVol. 19Issue 1PreviewUltrasound (US)-based screening has been recommended for patients with an increased risk of hepatocellular carcinoma (HCC). US analysis, however, is limited in patients who are obese or have small tumors. The addition of serum level of α-fetoprotein (AFP) measurements to US analysis can increase detection of HCC. We analyzed data from patients with chronic liver disease, collected over 15 years in an HCC surveillance program, to develop a model to assess risk of HCC. Full-Text PDF

From the Editor's Desk…

From the Editor's Desk…

A multi-centre study of trends in hepatitis B virus-related hepatocellular carcinoma risk over time during long-term entecavir therapy.

The risk of developing hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is reduced by antiviral therapy. Here, we evaluated the chronological trends in HCC development risk starting in 2007, when entecavir reimbursement was first initiated in South Korea. Treatment-naïve patients with chronic hepatitis B (CHB) receiving entecavir 0.5mg/d were stratified into three groups according to entecavir start time: early (2007-2010), middle (2011-2012) and late (2013-2014) cohorts Among 2442 patients, cumulative probabilities of developing HCC after 1, 3 and 5years were, respectively, 1.7%, 5.1%, and 8.2% (early cohort; n=672); 1.5%, 5.1% and 8.9% (middle cohort; n=757); and 1.2%, 5.3% and 10.6% (late cohort; n=1013; P>.05 between each pair). Older age, male, positive hepatitis B e antigen, liver cirrhosis, Child-Pugh class B (vs A) and lower platelet count significantly predicted HCC development in univariate analysis (P<.001), whereas entecavir start time (early vs middle vs late cohorts) did not affect the risk of HCC development (P=.457). A multivariate analysis revealed that older age (adjusted hazard ratio [aHR]=1.041), male gender (aHR=2.069), liver cirrhosis (aHR=3.771) and Child-Pugh class B (vs A, aHR=1.548) were independently associated with an increased risk of HCC development, whereas higher platelet count was independently associated with a reduced risk of HCC development (aHR=0.993; all P<.05). In conclusion, the risk of developing HCC among patients receiving entecavir in South Korea has been stable since 2007. To establish more effective HCC surveillance programs, further studies regarding the carcinogenic roles of nonviral factors are required.

Hepatocellular Carcinoma in Oman: An analysis of 284 cases.

ObjectivesHepatocellular carcinoma (HCC) is the most common type of primary liver tumour worldwide and is increasing in incidence. This study aimed to describe the clinical characteristics of HCC among Omani patients, along with its major risk factors, outcomes and the role of surveillance.MethodsThis retrospective case-series study was conducted between January 2008 and December 2015 at the three main tertiary care hospitals in Oman. All adult Omani patients diagnosed with HCC and visited these hospitals during the study period were included. Relevant data were collected from the patients’ electronic medical records.ResultsA total of 284 HCC patients were included in the analysis. The mean age was 61.02 ± 11.41 years and 67.6% were male. The majority had liver cirrhosis (79.9%), with the most common aetiologies being chronic hepatitis C (46.5%) and B (43.2%). Only 13.7% of cases were detected by the HCC surveillance programme. Approximately half of the patients (48.5%) had a single liver lesion and 31.9% had a liver tumour of >5 cm in size. Approximately half (49.2%) had alpha-fetoprotein levels of ≥200 ng/mL. The majority (72.5%) were diagnosed using multiphase computed tomography alone. Less than half of the patients (48.9%) were offered one or more HCC treatment modalities.ConclusionThe majority of Omani HCC patients were male and had cirrhosis due to viral hepatitis. In addition, few patients were identified by the national surveillance programme and presented with advanced disease precluding therapeutic or even palliative treatment.

Current status of image-based surveillance in hepatocellular carcinoma.

Although the overall prognosis of patients with hepatocellular carcinoma (HCC) remains poor, curative treatment may improve the survival of patients diagnosed at an early stage through surveillance. Accordingly, ultrasonography (US)-based HCC surveillance programs proposed in international society guidelines are now being implemented and regularly updated based on the latest evidence to improve their efficacy. Recently, other imaging modalities such as magnetic resonance imaging have shown potential as alternative surveillance tools based on individualized risk stratification. In this review article, we describe the current status of US-based surveillance for HCC and summarize the supporting evidence. We also discuss alternative surveillance imaging modalities that are currently being studied to validate their diagnostic performance and cost-effectiveness.

Personalized surveillance for hepatocellular carcinoma in cirrhosis – using machine learning adapted to HCV status

Refining hepatocellular carcinoma (HCC) surveillance programs requires improved individual risk prediction. Thus, we aimed to develop algorithms based on machine learning approaches to predict the risk of HCC more accurately in patients with HCV-related cirrhosis, according to their virological status. Patients with compensated biopsy-proven HCV-related cirrhosis from the French ANRS CO12 CirVir cohort were included in a semi-annual HCC surveillance program. Three prognostic models for HCC occurrence were built, using (i) Fine-Gray regression as a benchmark, (ii) single decision tree (DT), and (iii) random survival forest for competing risks survival (RSF). Model performance was evaluated from C-indexes validated externally in the ANRS CO22 Hepather cohort (n= 668 enrolled between 08/2012-01/2014). Out of 836 patients analyzed, 156 (19%) developed HCC and 434 (52%) achieved sustained virological response (SVR) (median follow-up 63 months). Fine-Gray regression models identified 6 independent predictors of HCC occurrence in patients before SVR (past excessive alcohol intake, genotype 1, elevated AFP and GGT, low platelet count and albuminemia) and 3 in patients after SVR (elevated AST, low platelet count and shorter prothrombin time). DT analysis confirmed these associations but revealed more complex interactions, yielding 8 patient groups with varying cancer risks and predictors depending on SVR achievement. On RSF analysis, the most important predictors of HCC varied by SVR status (non-SVR: platelet count, GGT, AFP and albuminemia; SVR: prothrombin time, ALT, age and platelet count). Externally validated C-indexes before/after SVR were 0.64/0.64 [Fine-Gray], 0.60/62 [DT] and 0.71/0.70 [RSF]. Risk factors for hepatocarcinogenesis differ according to SVR status. Machine learning algorithms can refine HCC risk assessment by revealing complex interactions between cancer predictors. Such approaches could be used to develop more cost-effective tailored surveillance programs. Patients with HCV-related cirrhosis must be included in liver cancer surveillance programs, which rely on ultrasound examination every 6 months. Hepatocellular carcinoma (HCC) screening is hampered by sensitivity issues, leading to late cancer diagnoses in a substantial number of patients. Refining surveillance periodicity and modality using more sophisticated imaging techniques such as MRI may only be cost-effective in patients with the highest HCC incidence. Herein, we demonstrate how machine learning algorithms (i.e. data-driven mathematical models to make predictions or decisions), can refine individualized risk prediction.

Serum Levels of α-Fetoprotein Increased More Than 10 Years Before Detection of Hepatocellular Carcinoma

Ultrasound (US)-based screening has been recommended for patients with an increased risk of hepatocellular carcinoma (HCC). US analysis, however, is limited in patients who are obese or have small tumors. The addition of serum level of α-fetoprotein (AFP) measurements to US analysis can increase detection of HCC. We analyzed data from patients with chronic liver disease, collected over 15 years in an HCC surveillance program, to develop a model to assess risk of HCC. We collected data from 3450 patients with chronic liver disease undergoing US surveillance in Japan from March 1998 through April 2014, and followed them up for a median of 8.83 years. We performed longitudinal discriminant analysis of serial AFP measurements (median number of observations/patient, 56; approximately every 3 months) to develop a model to determine the risk of HCC. We validated the model using data from 2 cohorts of patients with chronic liver disease in Japan (404 and 2754 patients) and 1 cohort in Scotland (1596 patients). HCC was detected in 413 patients (median tumor diameter, 1.8 cm), during a median follow-up time of 6.60 years. In the development data set, the model identified patients who developed HCC with an area under the curve of 0.78; it correctly identified 74.3% of patients who did develop HCC, and 72.9% of patients who did not. Overall, 73.1% of patients were classified correctly. The model could be used to assign patients to a high-risk group (27.5 HCCs/1000 patient-years) vs a low-risk group (4.9 HCCs/1000 patient-years). A similar performance was observed when the model was used to assess patients with cirrhosis. Analysis of the validation cohorts produced similar results. We developed and validated a model to identify patients with chronic liver disease who are at risk for HCC based on change in serum AFP level over time. The model could be used to assign patients to high-risk vs low-risk groups, and might be used to select patients for surveillance.

Hepatocellular carcinoma surveillance with liver imaging is not associated with improved survival

Objective: International guidelines recommend hepatocellular carcinoma (HCC) surveillance with ultrasound in high-risk patients with chronic liver diseases. However, there is low-strength evidence about the effects on mortality. The aim of our study was to assess the impact of surveillance on the clinical course and survival of HCC patients seen at a tertiary referral center in Germany.Material and methods: We retrospectively evaluated the data of 401 HCC patients, who presented to our clinic between 1997 and 2015. Two groups were compared regarding patient and disease outcomes: one group included patients who received at least two ultrasound examinations for surveillance purposes prior to first diagnosis (n = 111). The other group consisted of patients with HCC at first presentation without foregoing HCC surveillance (n = 290).Results: Median follow-up in the surveillance group was 76 months (range 4–310 months). Patients in the surveillance group had smaller median tumor sizes (3.5 cm vs. 4.5 cm; p < .001), fulfilled more often Milan criteria (64% vs. 42%; p < .001) and received more often liver transplantation (27% vs. 9%, p < .001) when compared with the non-surveillance group. However, HCC surveillance was not associated with an improved survival (14 months in the surveillance group vs. 12 months in the non-surveillance group, p = .375), hazard ratio regarding overall mortality for the surveillance group: 0.80 (95% CI: 0.62–1.04, p = .09).Conclusions: HCC surveillance with ultrasound led to the detection of earlier disease stages but was not significantly associated with improved survival. Further prospective and long-term studies are needed to clarify benefits and harms of HCC surveillance programs on mortality.

Diabetes is not associated with an increased risk of hepatocellular carcinoma in patients with alcoholic or hepatitis C virus cirrhosis.

diabetes has been reported as a risk factor for hepatocellular carcinoma (HCC) in population-based studies but there are controversial data in patients with cirrhosis. Metformin could have a protective role in HCC development. The aim of this study was to determine the influence of diabetes on the risk of developing HCC in patients with alcohol- and hepatitis C virus (HCV)-related cirrhosis. a cohort of 982 Caucasian patients were analyzed with alcoholic or HCV cirrhosis, included from 1992 to 2014 in a HCC surveillance program and prospectively followed. The influence of diabetes on the development of HCC was analyzed by Kaplan Meier analysis and adjusted with a Cox regression for relevant co-factors. after a median follow-up of 49.5 (24.0-96.0) months, 156 patients (15.8 %) developed HCC. There were no differences in the cumulative incidences of HCC after 20 years between diabetic and non-diabetic patients in the global (53.5 % vs 45.4 %; p = 0.26), alcoholic (50.4 % vs 45.4 %; p = 0.21) or HCV (60 % vs 43.1 %; p = 0.57) cirrhosis series. Diabetes did not constitute a risk factor after adjusting for other potential co-factors, neither in the whole series (hazard ratio [HR]: 1.12, 95 % CI: 0.78-1.51; p = 0.26), alcoholic (HR: 1.160, 95 % CI: 0.74-1.82; p = 0.50) or HCV cirrhosis cohort (HR: 1.17, 95 % CI: 0.63-2.19; p = 0.60). These figures did not change after excluding patients treated with metformin. in Caucasian patients with alcoholic or HCV cirrhosis, diabetes is not a risk factor for developing HCC. This lack of an association does not seem to be a consequence of the protective effect of metformin.

Effect of Propranolol Treatment on the Incidence of Hepatocellular Carcinoma in Patients Waiting for Liver Transplant With Cirrhosis: A Retrospective, Surveillance Study in a Tertiary Center.

Hepatocellular carcinoma is the most frequent primary malignant tumor of the liver and the third most common cause of all cancer-related mortalities. There is a need to develop new strategies to prevent hepatocellular carcinoma, as the incidence of this cancer continues to increase despite all advancements. In this study, our aim was to determine the effects of propranolol treatment on the incidence of hepatocellular carcinoma in cirrhotic patients waiting for liver transplant. We retrospectively reviewed the data of patients waiting for liver transplant with cirrhosis due to various causes registered at the Hepatocellular Carcinoma Surveillance Program between June 2011 and December 2017 in our center. These data were compared between patients using propranolol and those not using propranolol. Of the 231 patients, 135 (58.4%) were male and 96 (41.6%) were female. The mean age was 58.1 ± 14 years. We noted that 153 of total patients (66.2%) were using propranolol. Three patients (2%) were using 20 mg propranolol, 125 (81.7%) were using 40 mg propranolol, 10 (6.5%) were using 60 mg propranolol, and 15 (9.8%) were using 80 mg propranolol. Of total patients, 36 (15.6%) developed hepatocellular carcinoma, including in 12 patients (7.8%) using propranolol and 24 patients (30.8%) who did not use this agent (P < .001). Thus, the hepatocellular carcinoma frequency was 5.22 times lower in patients receiving propranolol than in those not receiving propranolol. Although causes of cirrhosis and initial stages were similar in both groups using and not using propranolol, incidence of hepatocellular carcinoma was significantly lower in the propranolol group than in the group without propranolol. This result showed that propranolol treatment has a protective effect for hepatocellular carcinoma in patients waiting for liver transplant with cirrhosis.

Surveillance for Hepatocellular Carcinoma: Current Best Practice and Future Direction.

Hepatocellular cancer (HCC) is the fourth leading cause of cancer-related deaths worldwide and the fastest growing cause of cancer deaths in the United States. The overall prognosis of HCC remains dismal, except for the subset of patients who are diagnosed at early stage and receive potentially curative therapies, such as surgical resection and liver transplantation. Given this, expert society guidelines recommend HCC surveillance every 6 months in at-risk individuals. Despite these recommendations, the effectiveness of HCC surveillance remains a subject of debate. We discuss current best practices for HCC surveillance and the evidence that support these recommendations. We also describe several initiatives that are underway to improve HCC surveillance and outline areas that may serve as high-yield targets for future research. Overall, we believe these efforts will help the field move toward precision surveillance, where surveillance tests and intervals are tailored to individual HCC risk. Doing so can maximize surveillance benefits, minimize surveillance harms, and optimize overall value for all patients.

Frequency and Outcomes of Abnormal Imaging in Patients With Cirrhosis Enrolled in a Hepatocellular Carcinoma Surveillance Program.

There are limited data on the downstream effects of hepatocellular carcinoma (HCC) surveillance, including the frequency of false-positive results. We aimed to quantify the incidence of indeterminate nodules (INs) and the follow-up testing needed to resolve these findings among patients enrolled in a structured HCC surveillance program. We retrospectively analyzed adult patients with cirrhosis enrolled in a structured HCC surveillance program in a large tertiary care center. Outcomes included surveillance benefits, defined as early HCC detection, and harm, defined as INs prompting additional diagnostic evaluation. Among 999 patients followed for a median of 2.2 years, HCC surveillance imaging was consistently completed every 6, 9, and 12 months in 46%, 51%, and 68% of patients, respectively. Of 256 (25.6%) patients with abnormal imaging, 69 (27.0%) were diagnosed with HCC and 187 (73.0%) with INs. Most HCC (n = 54, 78.3%) were found within Milan criteria. Among those with an IN, 78.1% returned to ultrasound surveillance after a median of 2 (interquartile range [IQR], 1-3) negative computed tomography (CT)/magnetic resonance imaging (MRI) scans, and 21.9% continued CT/MRI imaging (median, 1; IQR, 1-2). Eleven patients underwent diagnostic liver biopsy. Hypoalbuminemia, thrombocytopenia, and larger nodule size were independently associated with HCC diagnosis. In conclusion, 1 in 4 patients enrolled in an HCC surveillance program had abnormal surveillance imaging, but three-fourths of the lesions were INs, resulting in downstream harm. Improved risk-stratification tools are needed to identify nodules that are benign to reduce follow-up diagnostic evaluation.

Incidence of Hepatocellular Carcinoma After Direct Antiviral Therapy for HCV in Patients With Cirrhosis Included in Surveillance Programs

Retrospective studies have found an unexpectedly high incidence of hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV)-associated cirrhosis who received direct-acting antiviral (DAA) agents. We analyzed data from the ANRS CO12 CirVir cohort to compare the incidence of HCC in patients with cirrhosis who received DAA therapy vs patients treated with interferon (IFN). Data were collected from 1270 patients with compensated biopsy-proven HCV-associated cirrhosis recruited from 2006 through 2012 at 35 centers in France. For descriptive purpose, patients were classified as follows: patients who received DAA treatment (DAA group, n= 336), patients who achieved a sustained virologic response (SVR) following an IFN-based regimen (SVR-IFN group, n= 495), or patients who never received DAA treatment and never had an SVR following IFN therapy (non-SVR group, n= 439). The patients were included in HCC surveillance programs based on ultrasound examination every 6 months, and clinical and biological data were recorded. To account for confounding by indication due to differences in patient characteristics at treatment initiation, we constructed a time-dependent Cox regression model weighted by the inverse probability of treatment and censoring (IPTCW) to assess the treatment effects of DAA on time until HCC. Compared with patients in the SVR-IFN group, patients in the DAA group were older, higher proportions had diabetes or portal hypertension, and liver function was more severely impaired. The crude 3-year cumulative incidences of HCC were 5.9% in the DAA group, 3.1% in the SVR-IFN group, and 12.7% in the non-SVR group (overall P < .001; unadjusted hazard ratio [HR] for HCC 2.03; 95% confidence interval [CI] 1.07-3.84; P= .030 for the DAA group vs the SVR-IFN group). HCC characteristics were similar among groups. Among patients with HCC, the DAA group received less-frequent HCCscreening than the other 2 groups (P= .002). After Cox analyses weighted by the IPTCW, we found no statistically significant increase in risk of HCC associated with DAA use (HR0.89; 95% CI 0.46-1.73; P= .73). Analysis of data from the ANRS CO12 CirVir cohort reveals that the apparent increase in HCC incidence observed in patients with cirrhosis treated with DAAs compared with patients who achieved SVR following an IFN therapy can be explained by patient characteristics (age, diabetes, reduced liver function) and lower screening intensity.

Abstract 3047: Development and initial application of a porcine-specific MRI and MRE protocol for liver imaging in a large animal cancer model

Abstract While global cancer mortality is generally decreasing, the incidence of hepatocellular carcinoma (HCC) is projected to increase given the growing prevalence of chronic liver diseases that increase the risk for carcinogenesis. The current diagnosis of liver cirrhosis is invasive tissue biopsy, and those at-risk undergo an HCC surveillance program of ultrasound imaging to survey tumor development. Such screening programs center on static radiologic imaging snapshots prescribed at arbitrary intervals based on empiric histologic cirrhosis staging schemes and observational tumor developmental data that neither reflect the transition between normal and diseased states nor biologically relevant disease thresholds. In contrast, magnetic resonance imaging (MRI) and magnetic resonance elastography (MRE) may provide a more foundational portrayal of early stages of liver disease and liver oncogenesis that could result in early diagnosis when curative therapies could be employed. In addition, MRI/MRE-correlated systemic molecular biomarkers indicative of specific disease stages also have potential to serve as important non-invasive diagnostic tools. In this study, we developed a clinically translatable MRI/MRE liver imaging protocol in a clinically relevant large animal platform, the Oncopig Cancer Model (OCM). The OCM is a novel transgenic swine model that recapitulates human HCC through development of site and cell specific tumors after Cre recombinase induced expression of heterozygous KRASG12D and TP53R167H transgenes. A clinical imaging workflow consisting of respiratory gated acquisitions was developed with the Siemens 3 T Prisma MRI scanner to include the following: T1 Flash in-phase and out-of-phase, T2-HASTE/BLADE acquisitions to provide motion-robust imaging, VIBE imaging, diffusion-weighted imaging with IntraVoxel Incoherent Motion (IVIM) for estimating blood flow, and MRE for quantifying liver stiffness. Additional MRI imaging for tumor characterization was also performed, spanning multiphase (arterial, venous, delayed) contrast-enhanced T1-weighted imaging. This novel imaging protocol was successfully applied in normal control Oncopig subjects (n = 2), resulting in high quality, high resolution MRI/MRE images for clinical interpretation. In the future, integration of MRI/MRE, histology, and molecular measures in Oncopigs presenting with liver cirrhosis and HCC may be employed to investigate biomarkers that may define normal versus diseased liver, and may serve as a new approach to identify optimal time points for initiation of disease screening and treatment administration for clinical translation. Citation Format: Faith M. Thomas, Bradley P. Sutton, Tracey M. Wszalek, Megan J. Dailey, Kyle M. Schachtschneider, Lawrence B. Schook, Ron C. Gaba. Development and initial application of a porcine-specific MRI and MRE protocol for liver imaging in a large animal cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3047.

Utilisation of hepatocellular carcinoma screening in Australians at risk of hepatitis B virus-related carcinoma and prescribed anti-viral therapy.

To investigate hepatocellular carcinoma screening utilisation and factors associated with utilisation among patients prescribed hepatitis B virus anti-viral therapy and at risk of hepatocellular carcinoma. The incidence of hepatocellular carcinoma has increased in Australia over the past three decades with chronic hepatitis B virus infection a major contributor. hepatocellular carcinoma surveillance programs aim to detect cancers early enabling curative treatment options, longer survival and longer times to recurrence. Multi-site cross-sectional survey. An online study questionnaire was administered to eligible participants attending three Sydney tertiary hospitals. Data were grouped into six mutually exclusive hepatocellular carcinoma risk factor categories as per American Association for the Study of Liver Diseases guidelines. All analyses were undertaken in STATA. Logistic regression was used to assess the associations between covariates and screening utilisation. Multivariate models described were assessed using the Hosmer-Lemeshow goodness of fit. Of the 177 participants, 137 (77.4%) self-reported that US had been performed in the last six months. Awareness that screening should be performed and knowing the correct frequency of US screening were independently associated with screening utilisation. Participants who knew that screening should be undertaken were three times more likely to have had pretreatment education or were prescribed hepatitis B virus anti-viral treatment for >4years. Participants reporting a family history of hepatocellular carcinoma were less likely to know that screening should be undertaken every 6months. While utilisation of hepatocellular carcinoma surveillance programs was higher in this study than in previous reports, strategies to further improve surveillance remain necessary. Findings from this research form the basis for proposing strategies to improve utilisation of hepatocellular carcinoma screening, inform hepatitis B virus-related clinical practice and for the delivery of care and nursing education to people receiving hepatitis B virus anti-viral therapy and at risk of developing hepatocellular carcinoma.

Nonalcoholic fatty liver disease and hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease is becoming more common globally. The incidence of HCC due to nonalcoholic steatohepatitis in comparison to other etiologies is increasing. This is due to the pandemic of obesity and diabetes mellitus, two important risk factors for HCC. HCC arising in this context occurs in about 40% of the cases in a liver which is not yet cirrhotic. This has implications regarding the population which should be enrolled in an HCC surveillance program and regarding the treatment options. Surgery is more frequently contemplated in patients with HCC and no cirrhosis. However, patients with nonalcoholic steatohepatitis-induced HCC have frequent co-morbidities which have to be taken into account when developing a management strategy. Interestingly, these patients are frequently on medications which have been suggested to decrease the risk to develop HCC.

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Potential conflict of interest: Dr. Seror consults for and received grants from Angiodynamics, General Electric, and Olympus Celon. Dr. Durand‐Zaleski consults for AbbVie and MSD. The authors did not receive funding for this study. All authors are employees of public hospitals, universities, or public research institutions. REPLY: 1 Dr Braillon highlights classical methodological issues discussed in the hepatology community regarding both utility of hepatocellular carcinoma (HCC) screening and risk factors for this tumor. Prospective cohorts of patients with cirrhosis included in HCC surveillance programs are currently the only reliable source of information. A randomized trial (RCT) assessing benefits of screening is indeed impractical and unethical, given that it has been shown that patients favor surveillance over randomization once informed consent has been provided.1 Furthermore, recent studies included analysis of lead time bias and have suggested a survival benefit in case of HCC screening,2 which is as close as we can get to robust evidence in the absence of RCT. As well, prospective cohorts have not confirmed alarming reports regarding direct antivirals, nor highlighted smoking habit as an established HCC risk factor,3 explaining why international recommendations do not endorse smoking cessation for HCC prevention. Dr. Braillon's skepticism is strengthened by his believing that 90 days of mean doubling growing time for HCC is an “incredible speed.” However, results of several studies using different robust methodological approaches converged to a mean doubling time around 3 months.4 Finally, Markov models have been used for the past 40 years with over 400 publications in hepatology that have provided policy makers with estimates of the long‐term medical benefits as well as of the uncertainty surrounding those benefits. Our results show that the probability of patients benefiting from screening is 100%, which makes a strong case for implementing a policy.5 We thus believe that despite a “nonideal level of evidence,” doubters should cautiously develop their theoretical arguments given that implementation of curative procedures in the largest rates of patients is the most reliable way to improve HCC prognosis. Meanwhile, reporting that HCC surveillance is cost‐effective5 is hopefully good news for believers, mostly patients and physicians who struggle every day with this deadly cancer.