Ultrasound Screening For Hepatocellular Carcinoma Research Articles

MicroRNAs as Plasma Biomarkers of Hepatocellular Carcinoma in Patients with Liver Cirrhosis-A Cross-Sectional Study.

Ultrasound screening for hepatocellular carcinoma (HCC) in patients with liver cirrhosis has a poor sensitivity for small tumors. Circulating microRNAs (miRNAs) have been explored as HCC biomarkers, but results are diverging. Here, we evaluate if miRNAs up-regulated in HCC tissue can be detected in plasma and used as screening biomarkers for HCC. In this cross-sectional study, plasma, HCC tissue and surrounding non-tumorous liver tissue were collected from liver resections. Tissue miRNAs were identified and quantitated by RNA-sequencing analysis, and the fold-changes between HCC and surrounding liver tissue were calculated. The miRNAs up-regulated in HCCs were then re-analyzed in plasma from the same patients, and the miRNAs with the highest plasma levels were subsequently measured in plasma from an independent cohort of patients with cirrhosis or HCC. In tissues from 84 resected patients, RNA-sequencing detected 197 differentially expressed miRNAs, 40 of which had a raw count above 200 and were analyzed in plasma from the same cohort. Thirty-one miRNAs were selected for further analysis in 200 patients with HCC or cirrhosis. Of these, eleven miRNAs were significantly increased in HCC as compared to cirrhosis patients. Only miR-93-5p and miR-151a-3p were significantly associated with HCC, with an AUC of 0.662. In comparison, alpha-fetoprotein and des-gamma-carboxy prothrombin yielded an AUC of 0.816, which increased to 0.832 if miR-93-5p and miR-151a-3p were added. When including sex and age, the addition of miR-93-5p and miR-151a-3p did not further improve the AUC (from 0.910 to 0.911). In conclusion, micro-RNAs up-regulated in HCCs are detectable in plasma but have a poor performance as screening biomarkers of HCC.

Prevalence of extra-hepatic incidental findings on ultrasound screening for hepatocellular carcinoma.

Abdominal ultrasound is a cost-effective method for screening for hepatocellular carcinoma (HCC) in high-risk individuals. Currently, at many institutions the protocol for obtaining HCC screening ultrasounds includes a traditional examination of the right upper quadrant, including the pancreas and right kidney. There is no consensus on the role of imaging of extra-hepatic structures and there are limited data describing the frequency and clinical significance of incidental findings discovered during HCC screening. The purpose of this retrospective study is to assess the prevalence and significance of extra-hepatic incidental findings during HCC screening ultrasounds. A single-center retrospective review of all right upper quadrant HCC screeningultrasounds identified 432 HCC screening ultrasounds performed on 294 adults over a 2.5-year period. Findings in all organs evaluated were recorded. Any incidental finding was classified as minor, moderate, or major clinical significance. At least one extra-hepatic finding was documented in 57.4% of examinations. The most common extra-hepatic findings occurred in the gallbladder (40.3%), most commonly gallstones (25.4%). Four moderate clinically significant incidental findings were recorded (0.9%). Only one of these incidental findings required specific imaging follow up (0.2%). No major clinical significance incidental findings were identified. Potentially clinically significant incidental findings during ultrasound HCC screenings are rare. Incidental findings identified on HCC screening did not result in significant additional follow-up imaging or interventions.

Cost-Effectiveness of a Serum Biomarker Test for Risk-Stratified Liver Ultrasound Screening for Hepatocellular Carcinoma

ObjectivesRisk-stratified ultrasound screening for hepatocellular carcinoma (HCC), informed by a serum biomarker test, enables resources to be targeted to patients at the highest risk of developing cancer. We aimed to investigate the cost-effectiveness of risk-stratified screening for HCC in the Australian healthcare system. MethodsA Markov cohort model was constructed to test 3 scenarios for patients with compensated cirrhosis: (1) risk-stratified screening for high-risk patients, (2) all-inclusive screening, and (3) no formal screening. Probabilistic sensitivity analyses were undertaken to determine the impact of uncertainty. Scenario analyses were used to assess cost-effectiveness in Australia’s Aboriginal and Torres Strait Islander peoples and to determine the impact of including productivity-related costs of mortality. ResultsBoth risk-stratified screening and all-inclusive screening programs were cost-effective compared with no formal screening, with incremental cost-effectiveness ratios of A$39 045 and A$23 090 per quality-adjusted life-year (QALY), respectively. All-inclusive screening had an incremental cost-effectiveness ratio of A$4453 compared with risk-stratified screening and had the highest probability of being cost-effective at a willingness-to-pay (WTP) threshold of A$50 000 per QALY. Risk-stratified screening had the highest likelihood of cost-effectiveness when the WTP was between A$25 000 and A$35 000 per QALY. Cost-effectiveness results were further strengthened when applied to an Aboriginal and Torres Strait Islander cohort and when productivity costs were included. ConclusionsCirrhosis population-wide screening for HCC is likely to be cost-effective in Australia. Risk-stratified screening using a serum biomarker test may be cost-effective at lower WTP thresholds.

Longitudinal change of metabolite profile and its relation to multiple risk factors for the risk of developing hepatitis B-related hepatocellular carcinoma.

Despite considerable knowledge of viral pathogenesis, the pathophysiological changes related to the multifactorial, multistep process of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) development remains unclear. Longitudinal metabolomics study can reveal biological process for disease progression. We performed metabolite profiling with longitudinal prediagnostic plasma samples from two nested case-control studies of hepatitis B surface antigen carriers participating in ultrasound screening for HCC, one within a government employee cohort (870 samples from 109 HCC cases and 107 controls) and the other within a hospital-based cohort (266 samples from 63 HCC cases and 114 controls). Of the 34 measured metabolites, tyrosine, isoleucine, and glutamine were consistently associated with HCC. In analyses combining longitudinal data, a high metabolic risk score based on the three amino acids was robustly associated with increased risk of HCC (OR = 3.71, 95% confidence interval: 2.53-5.42), even after adjustment for clinical factors, or when assessed for different times up to ≥8 years before diagnosis. Similar association was observed in an independent, prospective analysis comprising 633 randomly selected individuals of the government employee cohort. More importantly, this metabolite signature was longitudinally influenced by HBV-infection phase and involved in gradual progression to liver fibrosis and cirrhosis. Furthermore, mediation analysis showed that the score mediated substantial proportions of the associations of key viral factors, insulin resistance, and diabetes status with HCC risk. Our results suggest that an amino-acid dysregulation metabotype may play a role in HBV-related HCC development, and may also be linked to common pathways that mediate increased HCC risks.

Ultrasound Screening and Surveillance in Hepatocellular Carcinoma

To review the current state of the use of ultrasound in hepatocellular carcinoma (HCC) surveillance. Despite limitations in the evidence supporting the use of ultrasound in HCC surveillance, it has been formally recommended by a number of guidelines based on the best available evidence showing that it improves survival and is cost effective. However, ultrasound surveillance is inconsistently adopted and is prone to a number of practical and technical challenges. The recent introduction of ultrasound LI-RADS aims to standardize performance and reporting of these surveillance studies. Despite remaining a controversial topic, semi-annual ultrasound screening for HCC is still supported by multiple hepatology societies. Ongoing evaluation of its performance and cost-effectiveness is required as new standards such as US LI-RADS, as well as evolving therapies and technologies emerge.

Long-Term Evaluation of Outcomes for Abdominal Ultrasound Screening for Hepatocellular Carcinoma

Background: Mass screening for hepatocellular carcinoma (HCC) with abdominal ultrasound (AUS) has been demonstrated in short-term follow-up in Taiwan, but long-term effectiveness and cost-effectiveness of AUS have not been well studied particularly when the recently emerging antiviral therapy has been introduced. The aim of this study is therefore to evaluate long-term outcomes of population-based organized service screening program without control group. Methods: AUS screening based on a risk score–guided invitation has been launched since October 2008 in Changhua. A total of 85,147 subjects aged 40-74 years attended the Changhua community-based integrated screening (CHCIS) program were targeted. Those with high score based on hepatitis virus infection, ALT, AST, type 2 diabetes, platelet count were invited to receive ultrasonography screening performed by board-certified gastroenterologists in town-based health center to identify liver cirrhosis, and suspected HCC cases. We developed a pseudo-control group by building up the disease natural history for HCC embedded with the risk prediction model and the survival by detection modes. The pseudo-control model was further used to the development of health economic decision model for cost-effectiveness of various preventive strategies. Results: We observed a 61% (RR = 0.39, 95% CI: 0.32-0.46) HCC mortality reduction with AUS by risk groups together with ∼30% coverage rate of antiviral therapy in an 8-year period. The simulated results indicates the additional contribution of 30% compliance rate of antiviral therapy (empirical estimate) to HCC mortality reduction was ∼22%. The corresponding figures were raised to 30% and 35% when the compliance rate of antiviral therapy was enhanced to 50% and 70%, respectively. The results of cost-effectiveness analysis shows the incremental cost-effectiveness ratio was $22,849 for the administration of AUS, and $101,849 for the administration of AUS plus 30% compliance to antiviral therapy. The corresponding figures for 50% and 70% compliance rate to antiviral therapy were $141,805 and $181,919, respectively. Conclusion: The population-based screening program for HCC together with antiviral therapy achieved HCC mortality reduction by 60%. The computer study design with a pseudo-control group on the basis of disease natural history of HCC embedded with the predictive model, and the survival part of HCC enables us to quantify the attributable proportion from different preventive regimes, and to estimate long-term effectiveness of the overall and marginal effectiveness and cost-effectiveness of AUS and antiviral therapy under different scenarios. Such approach provides the health policy-makers a reference for resource allocation.

Le dépistage du carcinome hépatocellulaire

Hepatocellular carcinoma related mortality is one of the highest among all cancers. Ninety percent of all hepatocellular carcinoma develop in the context of liver cirrhosis. Liver cirrhosis is not recognized prior to the diagnosis of hepatocellular carcinoma in 25% of the cases, despite the existence of risk factors. Hepatocellular carcinoma is diagnosed within a surveillance program in less than 25% of the cases. Ultrasound screening for hepatocellular carcinoma every 6months increases chances to diagnose HCC at an early stage amenable to curative treatment, and increases survival. Interval greater than 7months between ultrasound imaging has a significant negative impact on survival. All patients diagnosed with cirrhosis have to perform an ultrasound screening for hepatocellular carcinoma and comply with the six months rule.

Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study.

In cirrhosis, portal vein thrombosis (PVT) could be a cause or a consequence of the progression of liver disease. We analyzed data from a prospective trial of ultrasound screening for hepatocellular carcinoma in order to identify risk factors for and the impact of PVT in patients with cirrhosis. In all, 1,243 adults with cirrhosis without PVT were enrolled from 43 liver units in France and Belgium between June 2000 and March 2006. The mean follow-up was 47 months. Doppler ultrasonography was used to check the portal vein. Progression of liver disease was defined by the development of: ascites, hepatic encephalopathy, variceal bleeding, prothrombin <45%, serum bilirubin >45 μmol/L, albumin <28 g/L, and/or creatinine >115 μmol/L. G20210A prothrombin and factor V gene mutations were assessed in sera stored at three large centers. The 5-year cumulative incidence of PVT was 10.7%. PVT was mostly partial and varied over time. The development of PVT was independently associated with baseline esophageal varices (P = 0.01) and prothrombin time (P = 0.002), but not with disease progression before PVT, or prothrombotic mutations. Disease progression was independently associated with baseline age (hazard ratio [HR] 1.55; 95% confidence interval [CI]: 1.11-2.17), body mass index (HR 1.40; 95% CI: 1.01-1.95), prothrombin time (HR 0.79; 95% CI: 0.70-0.90), serum albumin (HR 0.97; 95% CI: 0.94-0.99), and esophageal varices (HR 1.70; 95% CI: 1.21-2.38) but not with the prior development of PVT (HR 1.32; 95% CI: 0.68-2.65). In patients with cirrhosis, the development of PVT is associated with the severity of liver disease at baseline, but does not follow a recent progression of liver disease. There is no evidence that the development of PVT is responsible for further progression of liver disease.

Ultrasound screening for hepatocellular carcinoma in patients with advanced liver fibrosis. An overview

Liver cirrhosis is the major risk factor for hepatocellular carcinoma (HCC). All etiologic forms of liver cirrhosis may be complicated by HCC but the risk is higher in patients with hepatitis B or C viral infection. Patients at high risk for developing HCC should be included in surveillance programs. Groups at high risk are: all cirrhotic patients; non-cirrhotic patients with chronic hepatitis C and advanced liver fibrosis (F3), non-cirrhotic HBV carriers with active hepatitis. Current guidelines issued by AASLD and EASL recommend surveillance among high-risk patients by ultrasound (with or without alpha-fetoprotein) every 6 months. The aim of ultrasound screening and surveillance is to detect HCC at an early stage, when it is amenable to curative therapy, to reduce mortality. For good results, ultrasound examination must be done by highly experienced personnel, with extensive experience in the field of hepatic ultrasound.

Quality assurance in ultrasound screening for hepatocellular carcinoma using a standardized phantom and standard clinical images: a 3-year national investigation in Korea.

The purpose of this study was to investigate the quality of ultrasound (US) imaging for hepatocellular carcinoma screening. The investigation was performed at all medical institutes participating in the National Cancer Screening Program in Korea. For assessment of personnel, we inquired who was performing the US screenings. For phantom image evaluation, the dead zone, vertical and horizontal measurements, axial and lateral resolution, sensitivity, and gray scale/dynamic range were evaluated. For clinical image evaluation, US images of patients were evaluated in terms of the standard images, technical information, overall image quality, appropriateness of depth, foci, annotations, and the presence of any artifacts. Failure rates for phantom and clinical image evaluations at general hospitals, smaller hospitals, and private clinics were 20.9%, 24.5%, 24.1% and 5.5%, and 14.8% and 9.5%, respectively. No statistically significant difference was observed in the failure rates for the phantom images among groups of different years of manufacture. For the clinical image evaluation, the results of radiologists were significantly better than those of other professional groups (P = .0001 and .0004 versus nonradiology physicians and nonphysicians, respectively). The failure rate was also higher when the storage format was analog versus digital (P < .001). Approximately 20% of US scanners failed the phantom image evaluation. The year of scanner manufacture was not significantly associated with the results of the phantom image evaluation. The quality of the clinical images obtained by radiologists was the best.

Hepatocellular carcinoma screening in patients with compensated hepatitis C virus (HCV)-related cirrhosis aware of their HCV status improves survival: A modeling approach

Because of the ongoing debate on the benefit of ultrasound (US) screening for hepatocellular carcinoma (HCC), we assessed the impact of screening on hepatitis C virus (HCV)-related compensated cirrhosis patients aware of their HCV status. A Markov model simulated progression from HCC diagnosis to death in 700 patients with HCV-related compensated cirrhosis aware of their HCV status to estimate life expectancy (LE) and cumulative death at 5 years. Five scenarios were compared: S1, no screening; S2, screening by currently existing practices (57% access and effectiveness leading to the diagnosis of 42% at Barcelona Clinic Liver Cancer stage [BCLC-0/A]); S3, S2 with increased access (97%); S4, S2 with an efficacy of screening close to that achieved in a randomized controlled trial leading to the diagnosis of 87% of patients at stage BCLC-0/A; S5, S3+S4. The analysis was corrected for lead-time bias. Currently existing practices of HCC screening increased LE by 11 months and reduced HCC mortality at 5 years by 6% compared to no screening (P = 0.0013). Compared to current screening practices, we found that: 1) increasing the rate of access to screening would increase LE by 7 months and reduce HCC mortality at 5 years by 5% (P = 0.045); 2) optimal screening would increase LE by 14 months and reduce HCC mortality at 5 years by 9% (P = 0.0002); 3) the combination of an increased rate of access and optimal effectiveness of HCC screening would increase LE by 31 months and decrease HCC mortality at 5 years by 20% (P < 0.0001). The present study shows that US screening for HCC in patients with compensated HCV-related cirrhosis aware of their HCV status improves survival and emphasizes the crucial role of screening effectiveness.

Incidence of hepatocellular carcinoma in hepatitis C cirrhotic patients with and without HIV infection: a cohort study, 1999-2011

Introduction. High activity antiretroviral therapy (HAART) has allowed people infected with human immunodeficiency virus (HIV) to live longer. In the course of time, hepatocellular carcinoma (HCC) began to be found in these patients. Investigations have suggested that, as it has been described for other tumors, HIV infection raises the risk of developing HCC. However, convincing evidence is still required. Our aim was to quantify the incidence of HCC in hepatitis C cirrhotic patients with and without human immunodeficiency virus infection in the HAART era.Material and methods. This prospective cohort study was conducted in hepatitis C cirrhotic patients with and without HIV co-infection, between june 1, 1999 and May 21, 2010. Ultrasound screening for HCC was performed every 6 to 12 months to all the patients until January 15, 2011. Incidence rate and cumulative incidence (Kaplan-Meier) were calculated.Results. One hundred and forty eight patients (69 hepatitis C virus mono-infected and 79 HIV/hepatitis C virus co-infected) were followed for a median time of 43 months, with a total follow-up of 555 person-years (324 for co-infected and 231 for mono-infected patients). Twelve patients developed HCC (5 co-infected and 7 mono-infected). The incidence of HCC in co-infected patients and mono-infected patients was 1.54 (95% confidence interval = 0.5 to 3.6) and 3.03 (95% confidence interval = 1.22 to 6.23) cases per 100 person-year respectively (log-rank p = 0.3225).Conclusion. In the HAART era, HIV co-infection is not associated with a higher incidence of HCC in hepatitis C cirrhotic patients.

Pulmonary Sequestration With CCAM Type II Appearing as Adrenal Tumor Protruding Through a Bochdalek Hernia

A case of a pulmonary sequestration, which almost exclusively consisted of a congenital cystic adenomatoid malformation type II located subdiaphragmatically in the left retroperitoneal area, is reported. This case, in a 24-year-old male patient, is unique in that it appeared as an adrenal incidentaloma and extended through a Bochdalek hernia into the pleural space. It was discovered upon routine ultrasound screening for hepatocellular carcinoma in a patient with a carrier state for hepatitis B. Diagnosis was established only upon histological analysis of the surgically removed tumor after staining with hematoxylin and eosin as well as surfactant A and B. The location of the tumor may indicate that it was formed by an entrapment of a lung bud by the developing diaphragm. This appearance may give us insight into the formation of such tumors. It also highlights the difficulty of diagnosing subdiaphragmatic retroperitoneal tumors without histological examination.

Ultrasound Screening for Hepatocellular Carcinoma (HCC) in Cirrhosis: Correspondence

Ultrasound Screening for Hepatocellular Carcinoma (HCC) in Cirrhosis: Correspondence