Dataset Information

External Validation of LCR1-LCR2, a Multivariable Hepatocellular Carcinoma Risk Calculator, in a Multiethnic Cohort of Patients With Chronic Hepatitis B.

ABSTRACT:

Background and aims

The liver cancer risk test (LCR1-LCR2) is a multianalyte blood test combining proteins involved in liver cell repair (apolipoprotein A1, haptoglobin), hepatocellular carcinoma (HCC) risk factors (gender, age, gamma glutamyl transpeptidase), a marker of fibrosis (alpha2-macroglobulin), and alpha-fetoprotein, a specific marker of HCC. The aim was to externally validate LCR1-LCR2 in hepatitis B.

Methods

Preincluded patients were from the Hepather cohort, a multicenter, multiethnic prospective study in 6071 patients. The coprimary study outcome was the negative predictive value of LCR1-LCR2 at 5 years for the occurrence of HCC and survival without HCC according to the predetermined LCR1-LCR2 cutoffs, adjusted for risk covariables and for chronic hepatitis B treatment and quantified using time-dependent Cox proportional hazards models. A post hoc analysis compared the number of patients needed to screen one cancer by LCR1-LCR2 and PAGE-B.

Results

A total of 3520 patients, 191 (5.4%) with cirrhosis, with at least 1 year of follow-up were included. A total of 76 HCCs occurred over a median (interquartile range) of 6.0 years (4.8-7.3) of follow-up. Among the 3367 patients with low-risk LCR1-LCR2, the 5-year negative predictive value was 99.3% (95% confidence interval = 99.0-99.6), with a significant Cox hazard ratio (6.4, 3.1-13.0; P < .001) obtained after adjustment for exposure to antivirals, age, gender, geographical origin, HBe-Ag status, alcohol consumption, and type-2 diabetes. LCR1-LCR2 outperformed PAGE-B for number of patients needed to screen mean (95% CI), 8.5 (3.2-8.1) vs 26.3 (17.5-38.5; P < .0001), respectively.

Conclusion

The performance of LCR1-LCR2 to identify patients with chronic hepatitis B at very low risk of HCC at 5 years was externally validated. ClinicalTrials.gov: NCT01953458.

SUBMITTER: Poynard T

PROVIDER: S-EPMC11308549 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

External Validation of LCR1-LCR2, a Multivariable Hepatocellular Carcinoma Risk Calculator, in a Multiethnic Cohort of Patients With Chronic Hepatitis B.

Poynard Thierry T Lacombe Jean Marc JM Deckmyn Olivier O Peta Valentina V Akhavan Sepideh S Zoulim Fabien F de Ledinghen Victor V Samuel Didier D Mathurin Philippe P Ratziu Vlad V Thabut Dominique D Housset Chantal C Fontaine Hélène H Pol Stanislas S Carrat Fabrice F

Gastro hep advances 20220525 4

<h4>Background and aims</h4>The liver cancer risk test (LCR1-LCR2) is a multianalyte blood test combining proteins involved in liver cell repair (apolipoprotein A1, haptoglobin), hepatocellular carcinoma (HCC) risk factors (gender, age, gamma glutamyl transpeptidase), a marker of fibrosis (alpha2-macroglobulin), and alpha-fetoprotein, a specific marker of HCC. The aim was to externally validate LCR1-LCR2 in hepatitis B.<h4>Methods</h4>Preincluded patients were from the Hepather cohort, a multice ...[more]

PMID: 39132068

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Project description:Background & aimsThe Liver Cancer Risk test algorithm (LCR1-LCR2) is a multianalyte blood test combining proteins involved in liver cell repair (apolipoprotein-A1 and haptoglobin), known hepatocellular carcinoma (HCC) risk factors (sex, age, and gamma-glutamyl transferase), a marker of fibrosis (alpha2-macroglobulin) and alpha-fetoprotein (AFP), a specific marker of HCC. The aim was to externally validate the LCR1-LCR2 in patients with chronic HCV (CHC) treated or not with antivirals.MethodsPre-included patients were from the Hepather cohort, a multicentre prospective study in adult patients with CHC in France. LCR1-LCR2 was assessed retrospectively in patients with the test components and AFP, available at baseline. The co-primary study outcome was the negative predictive value (NPV) of LCR1-LCR2 for the occurrence of HCC at 5 years and for survival without HCC according to the predetermined LCR1-LCR2 cut-offs. The cut-offs were adjusted for risk covariables and for the response to HCV treatment, and were quantified using time-dependent proportional hazards models.ResultsIn total, 4,903 patients, 1,026 (21.9%) with baseline cirrhosis, were included in the study. Patients were followed for a median of 5.7 (IQR 4.2-11.3) years. A total of 3,788/4,903 (77.3%) patients had a sustained virological response. There were 137 cases of HCC at 5 years and 214 at the end of follow-up. HCC occurred at 5 years in 24/3,755 patients with low-risk LCR1-LCR2 compared with 113/1,148 patients with high-risk LCR1-LCR2. The NPV was 99.4% (95% CI 99.1-99.6). Similar findings (hazard ratio, 10.8; 95% CI, 8.1-14.3; p <0.001) were obtained after adjustment for exposure to antivirals, age, sex, geographical origin, HCV genotype 3, alcohol consumption, and type 2 diabetes mellitus.ConclusionsThe results showed that LCR1-LCR2 can be used to successfully identify patients with HCV at very low risk of HCC at 5 years.Lay summaryHepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide and the fastest growing cause of cancer death in many countries. We constructed and internally validated a new multianalyte blood test to assess this Liver Cancer Risk (LCR1-LCR2). This study confirmed the performance of LCR1-LCR2 in patients with chronic HCV in the national French cohort Hepather, and its ability to identify patients at a very low risk of HCC at 5 years.Clinical trials registrationThe study is registered at ClinicalTrials.gov (NCT01953458).

Project description:Background & aimsSeveral hepatocellular carcinoma (HCC) risk-models have been developed to individualise patient surveillance following sustained viral response (SVR) in Hepatitis C Virus patients. Validation of these models in different cohorts is an important step to incorporate a more personalised risk assessment in clinical practice. We aimed at applying these models to stratify the risk in our patients and potentially determine cost-saving associated with individualised HCC risk-stratification screening strategy.MethodsPatients with baseline F3-4 fibrosis treated with new oral direct-acting antivirals who had reached a SVR were regularly followed as part of the HCC surveillance strategy. Six models were applied: Pons, aMAP, Ioannou, HCC risk, Alonso and Semmler. Validation of the models was performed based on sensitivity and the proportion of patients labelled as "high risk".ResultsAfter excluding 557 with less than 3 fibrosis, 12 without SVR, 18 with a follow up (FU) <1 year, 17 transplant recipients, 16 lost to FU and 31 with HCC at time of antiviral therapy, our cohort consisted of 349 F3-4 SVR patients. Twenty-three patients (6.6%) developed HCC after a median FU of 5.12 years. The sensitivity of the different models varied between 0.17 (Semmler7noalcohol) and 1 (Alonso A and aMAP). The lowest proportion of high-risk patients corresponded to the Semmler-noalcohol model (5%). Sixty-three and 90% of the Alonso A and aMAP patients, respectively were labelled as high risk. The most reliable HCC risk-model applied to our cohort to predict HCC development is the Alonso model (based on fibrosis stage assessed by liver stiffness measurements or Fibrosis-4 index (FIB-4) at baseline and after 1 year, and albumin levels at 1 year) with a-100% sensitivity in detecting HCC among those at high risk and 63% labelled as high risk. The application of the model would have saved the cost of 1290 ultrasound no longer being performed in the 37% low-risk group.ConclusionIn our cohort, the Alonso A model allows the most reliable reduction in HCC screening resulting in safely stopping life-long monitoring in about a third of F3-F4 patients achieving SVR with DAAs.

Project description:Take Home Message Results from this population-based screening cohort show that the calibration of risk prediction tools need to be assessed in the local setting before using in clinical practice. The Prostate Biopsy Collaborative Group Risk Calculator provided benefit in the online version. The Rotterdam Prostate Cancer Risk Calculator needed recalibration for similar benefit. Background External validation of risk calculators (RCs) is necessary to determine their clinical applicability beyond the setting in which these were developed. Objective To assess the performance of the Rotterdam Prostate Cancer RC (RPCRC) and the Prostate Biopsy Collaborative Group RC (PBCG-RC). Design, setting, and participants We used data from the prospective, population-based STHLM3 screening study, performed in 2012–2015. Participants with prostate-specific antigen ≥3 ng/ml who underwent systematic prostate biopsies were included. Outcome measurements and statistical analysis Probabilities for clinically significant prostate cancer (csPCa), defined as International Society of Urological Pathology grade ≥2, were calculated for each participant. External validity was assessed by calibration, discrimination, and clinical usefulness for both original and recalibrated models. Results and limitations Out of 5841 men, 1054 (18%) had csPCa. Distribution of risk predictions differed between RCs; median risks for csPCa using the RPCRC and PBCG-RC were 3.3% (interquartile range [IQR] 2.1–7.1%) and 20% (IQR 15–28%), respectively. The correlation between RC risk estimates on individual level was moderate (Spearman’s r = 0.55). Using the RPCRC’s recommended risk threshold of ≥4% for finding csPCa, 36% of participants would get concordant biopsy recommendations. At 10% risk cut-off, RCs agreed in 23% of cases. Both RCs showed good discrimination, with areas under the curves for the RPCRC of 0.74 (95% confidence interval [CI] 0.72–0.76) and the PBCG-RC of 0.70 (95% CI 0.68–0.72). Calibration was adequate using the PBCG-RC (calibration slope: 1.13 [95% CI 1.03–1.23]), but the RPCRC underestimated the risk of csPCa (calibration slope: 0.73 [0.68–0.79]). The PBCG-RC showed a net benefit in a decision curve analysis, whereas the RPCRC showed no net benefit at clinically relevant risk threshold levels. Recalibration improved clinical benefit, and differences between RCs decreased. Conclusions Assessment of calibration is essential to ensure the clinical value of risk prediction tools. The PBCG-RC provided clinical benefit in its current version online. On the contrary, the RPCRC cannot be recommended in this setting. Patient summary Predicting the probability of finding prostate cancer on biopsy differed between two assessed risk calculators. After recalibration, the agreement of the models improved, and both were shown to be clinically useful.

Project description:Background & aimsExposure to poly- and perfluoroalkyl substances (PFAS), a class of persistent organic pollutants, is ubiquitous. Animal studies suggest that PFAS may increase risk of fatty liver and hepatocellular carcinoma (HCC) via impacts on hepatic lipid, amino acid, and glucose metabolism, but human data is lacking. We examined associations between PFAS exposure, altered metabolic pathways, and risk of non-viral HCC.MethodsIn this nested case-control study, pre-diagnostic plasma PFAS and metabolomics were measured in 50 incident HCC cases and 50 individually matched controls from the Multiethnic Cohort (MEC) study. Cases/controls were matched by age, sex, race, and study area. PFAS exposure and risk of HCC were examined using conditional logistic regression. A metabolome-wide association study and pathway enrichment analysis was performed for PFAS exposure and HCC risk, and key metabolites/metabolic pathways were identified using a meet in the middle approach.ResultsHigh perfluorooctane sulfonic acid (PFOS) levels (90th percentile from NHANES; >55 μg/L) were associated with 4.5-fold increased risk of HCC (odds ratio 4.5, 95% CI 1.2-16.0). Pathway enrichment analysis showed that PFOS exposure was associated with alterations in amino acid and glycan biosynthesis pathways, which were also associated with HCC risk. We identified 4 metabolites linking PFOS exposure with HCC, including glucose, butyric acid (a short-chain fatty acid), α-ketoisovaleric acid (a branched-chain α-keto acid), and 7α-hydroxy-3-oxo-4-cholestenoate (a bile acid), each of which was positively associated with PFOS exposure and risk of HCC.ConclusionThis proof-of-concept analysis shows that exposure to high PFOS levels was associated with increased risk of non-viral HCC, likely via alterations in glucose, amino acid, and bile acid metabolism. Larger studies are needed to confirm these findings.Lay summaryPer- and polyfluoroalkyl substances (PFAS), often referred to as "forever chemicals" because they are difficult to break down and stay in the human body for years, are extremely common and can cause liver damage. In a first of its kind study, we found that exposure to high levels of perfluorooctanesulfonic acid, one of the most common PFAS chemicals, was linked to increased risk of hepatocellular carcinoma in humans. Hepatocellular carcinoma is difficult to treat and is one of the most common forms of liver cancer, and these findings may provide new avenues for helping to prevent this disease.

Project description:Background & aimsThe Toronto hepatocellular carcinoma (HCC) risk index (THRI) is a predictive model to determine the risk of HCC in patients with cirrhosis. This study aimed to externally validate the THRI in a Swedish setting to investigate whether it could identify patients not requiring HCC surveillance.MethodsFrom 2004-2017, 2,491 patients with cirrhosis at the Karolinska University Hospital were evaluated. Patients were classified into low-, intermediate- and high-risk groups for future HCC according to the THRI. Harrell's C-index, calibration-in-the-large, calibration slope and goodness-of-fit estimates were calculated to assess model discrimination and calibration. Cox proportional hazards regression was used to determine the risk of HCC.ResultsMost patients were male (n = 1,638, 66%). The most common etiologies of cirrhosis were steatohepatitis (n = 1,182, 48%) followed by viral hepatitis (n = 987, 40%). In all, 131 patients (5.3%) were designated as low risk for HCC. Harrell's C-index was 0.69. Calibration-in-the-large (0.11), calibration slope (1.24, not different from 1, p = 0.66) and goodness-of-fit showed good model calibration. Patients in the high-risk group had a 7.1-fold (95% CI 2.9-17.2) higher risk of HCC and patients in the intermediate-risk group had a 2.5-fold (95% CI 1.0-6.3) higher risk compared to the low-risk group.ConclusionsIn a Swedish setting, the THRI could differentiate between low- and high-risk of HCC development. However, because the low-risk group was relatively small (5.3%), the clinical applicability of the THRI could be limited.Lay summaryThe Toronto hepatocellular carcinoma (HCC) risk index (THRI) is a novel prediction model used to stratify patients with cirrhosis based on future risk of HCC. In this study, the THRI was validated in an external cohort using the TRIPOD guidance. Few patients were identified as low-risk, and the THRI had a modest discriminative ability, limiting its clinical applicability.

Dataset Information

External Validation of LCR1-LCR2, a Multivariable Hepatocellular Carcinoma Risk Calculator, in a Multiethnic Cohort of Patients With Chronic Hepatitis B.

Background and aims

Methods

Results

Conclusion

Publications

External Validation of LCR1-LCR2, a Multivariable Hepatocellular Carcinoma Risk Calculator, in a Multiethnic Cohort of Patients With Chronic Hepatitis B.

Similar Datasets

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