Publications by authors named "Robert A de Man"

195 Publications

Editorial: HBV cure-the quest for biomarkers to predict off-treatment sustained response. Authors' reply.

Aliment Pharmacol Ther 2021 Feb;53(4):555-556

Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

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http://dx.doi.org/10.1111/apt.16233DOI Listing
February 2021

Letter: rates and determinants of significant liver inflammation in chronic hepatitis B virus-infected patients with low ALT levels in the absence of significant fibrosis-authors' reply.

Aliment Pharmacol Ther 2021 01;53(1):215-216

Departments of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

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http://dx.doi.org/10.1111/apt.16183DOI Listing
January 2021

Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity.

J Hepatol 2020 Nov 23. Epub 2020 Nov 23.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands. Electronic address:

Background And Aims: HCV-infected patients with cirrhosis achieve high sustained virological response (SVR) rates with direct-acting antivirals (DAAs) even after hepatic decompensation. We aimed to assess the clinical outcome following DAAs among patients with compensated and decompensated cirrhosis in relation to SVR and changes in MELD score.

Methods: d chronic HCV-infected patients with cirrhosis from 4 hepatology clinics were included. The primary endpoint in survival analyses was clinical disease progression, defined as liver failure, hepatocellular carcinoma, liver transplantation or death.

Results: In total, 868 patients were included with a median age of 59 (IRQ 54-65) years; 719 (83%) with CP-A cirrhosis and 149 (17%) with CP-B/C cirrhosis. SVR was attained by 647 (90%) CP-A patients and 120 (81%) CP-B/C patients. During a median follow-up of 28 (IQR 20-36) months, 102 (14%) CP-A patients and 96 (64%) CP-B/C patients experienced clinical disease progression. SVR was independently associated with an improved event-free survival in patients with CP-A cirrhosis (adjusted HR 0.47, 95%CI 0.27-0.82, p=0.007), but not in patients with CP-B/C cirrhosis (adjusted HR 1.23, 95% CI 0.67-2.26, p=0.51). Twelve weeks post-DAAs, 28 (19%) patients with CP-B/C cirrhosis had ≥2-point MELD decline, but their 2-year event-free survival did not differ from those with a stable MELD (47.9% [95%CI 28.7-67.1] vs 48.9% [95%CI 38.1-59.7], respectively, p=0.99).

Conclusions: Among patients with chronic HCV infection, DAA-induced SVR was associated with a reduced risk of clinical disease progression in patients with CP-A cirrhosis but not in patients with CP-B/C cirrhosis. In CP-B/C cirrhosis, a ≥2-point MELD decline did not translate to improved clinical outcome.
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http://dx.doi.org/10.1016/j.jhep.2020.11.021DOI Listing
November 2020

Hepatitis B virus RNA decline without concomitant viral antigen decrease is associated with a low probability of sustained response and hepatitis B surface antigen loss.

Aliment Pharmacol Ther 2021 01 21;53(2):314-320. Epub 2020 Nov 21.

Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Background: Serum hepatitis B virus (HBV) RNA may reflect intrahepatic HBV replication. Novel anti-viral drugs have shown potent HBV RNA decline without concomitant hepatitis B surface antigen (HBsAg) decrease. How this relates to off-treatment response is yet unclear.

Aim: To study the degree of on-treatment viral antigen decline among patients with pronounced HBV RNA decrease in relation to off-treatment sustained response and HBsAg loss.

Methods: HBV RNA, HBsAg and hepatitis B core-related antigen (HBcrAg) were quantified in patients with chronic hepatitis B who participated in two randomised controlled trials of peginterferon-based therapy. Sustained response (HBV DNA <2000 IU/mL) and/or HBsAg loss were assessed in patients with and without on-treatment HBV RNA response (either >2 log HBV RNA decline or >1 log decline resulting in an undetectable value at on-treatment week 24), stratified by concomitant HBsAg decline (<0.5/0.5-1/>1 log).

Results: We enrolled 279 patients; 176 were hepatitis B e antigen (HBeAg)-positive, and 103 were HBeAg-negative. Sustained response was achieved in 20.4% of patients. At on-treatment week 24, HBV RNA response was associated with higher sustained response rates (27.4% vs 13.0% in non-responders, P =  0.004). However, among patients with an HBV RNA response (n = 135), 56.4% did not experience >0.5 log HBsAg decline. Among HBV RNA responders, sustained response was achieved in 47.6% of those with >1 log HBsAg decline (n = 20/42), vs 16.0% with <0.5 log decline (n = 12/75, P = 0.001). Similar results were obtained with HBcrAg and when response was defined as HBsAg loss.

Conclusions: In this cohort, many patients with HBV RNA response during peginterferon-based treatment did not experience HBsAg and/or HBcrAg decline. The absence of concomitant decline in these viral antigens was associated with low rates of treatment response and HBsAg loss. Future trials should therefore consider kinetics of combined biomarkers to assess anti-viral efficacy. Trial registration, ClinicalTrials.gov: NCT00114361, NCT00146705.
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http://dx.doi.org/10.1111/apt.16172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839551PMC
January 2021

Drug screening identified gemcitabine inhibiting hepatitis E virus by inducing interferon-like response via activation of STAT1 phosphorylation.

Antiviral Res 2020 12 31;184:104967. Epub 2020 Oct 31.

Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands. Electronic address:

Exposure to hepatitis E virus (HEV) bears a high risk of developing chronic infection in immunocompromised patients, including organ transplant recipients and cancer patients. We aim to identify effective anti-HEV therapies through screening and repurposing safe-in-human broad-spectrum antiviral agents. In this study, a safe-in-human broad-spectrum antiviral drug library comprising of 94 agents was used. Upon screening, we identified gemcitabine, a widely used anti-cancer drug, as a potent inhibitor of HEV replication. The antiviral effect was confirmed in a range of cell culture models with genotype 1 and 3 HEV strains. As a cytidine analog, exogenous supplementation of pyrimidine nucleosides effectively reversed the antiviral activity of gemcitabine, but the level of pyrimidine nucleosides per se does not affect HEV replication. Surprisingly, similar to interferon-alpha (IFNα) treatment, gemcitabine activates STAT1 phosphorylation. This subsequently triggers activation of interferon-sensitive response element (ISRE) and transcription of interferon-stimulated genes (ISGs). Cytidine or uridine effectively inhibits gemcitabine-induced activation of ISRE and ISGs. As expected, JAK inhibitor 1 blocked IFNα, but not gemcitabine-induced STAT1 phosphorylation, ISRE/ISG activation, and anti-HEV activity. These effects of gemcitabine were completely lost in STAT1 knockout cells. In summary, gemcitabine potently inhibits HEV replication by triggering interferon-like response through STAT1 phosphorylation but independent of Janus kinases. This represents a non-canonical antiviral mechanism, which utilizes the innate defense machinery that is distinct from the classical interferon response. These results support repurposing gemcitabine for treating hepatitis E, especially for HEV-infected cancer patients, leading to dual anti-cancer and antiviral effects.
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http://dx.doi.org/10.1016/j.antiviral.2020.104967DOI Listing
December 2020

Determining the therapeutic range for ribavirin in transplant recipients with chronic hepatitis E virus infection.

J Viral Hepat 2021 Feb 15;28(2):431-435. Epub 2020 Nov 15.

Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

The aim of this study was to define the therapeutic range for ribavirin (RBV) in transplant recipients with chronic hepatitis E virus (HEV) infection. In this retrospective multicentre cohort study, data of adult transplant recipients with chronic HEV infection, who had been treated with RBV monotherapy between 01-3-2008 and 01-08-2018, were included. ROC curve analyses were performed, and the half-maximal effective RBV concentration was calculated to determine a representative therapeutic range. In 96 patients, RBV monotherapy for a median of three months resulted in a sustained virologic response in 63.5% of the patients, while 88.5% of the patients developed anaemia. RBV plasma concentrations at steady state were significantly higher in clinical responders compared with clinical non-responders: median 1.96 (IQR 1.81-2.70) versus 0.49 (IQR 0.45-0.73) mg/L, P = .0004. RBV caused a dose-dependent haemoglobin reduction with higher RBV plasma concentrations resulting in more haemoglobin reduction. The therapeutic range for RBV for chronic HEV infection in transplant recipients ranges between 1.8 and 2.3 mg/L.
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http://dx.doi.org/10.1111/jvh.13432DOI Listing
February 2021

Differential gene expression in peripheral blood between low viremic inactive carrier and NUC-treated HBV patients irrespective of circulating HBsAg levels.

J Infect Dis 2020 Oct 3. Epub 2020 Oct 3.

Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands.

Long-term viremia in chronic HBV patients occurs either spontaneous in inactive carrier (IC) patients or therapy-induced by nucleos(t)ide analogues (NUC). To better understand the characteristics of viremia control, we evaluated gene expression of purified leukocyte subsets from IC versus NUC-treated patients, and evaluated the putative modulatory effects of HBsAg.We observed that gene expression of NUC-treated patients differed markedly from IC patients, especially in DC, monocytes and CD8+ T cells, while serum HBsAg levels had little effect. Nevertheless, based on our findings it cannot be excluded that HBsAg may act locally in the infected liver or affects preferentially HBV-specific cells.
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http://dx.doi.org/10.1093/infdis/jiaa614DOI Listing
October 2020

Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis.

Aliment Pharmacol Ther 2020 10 4;52(8):1399-1406. Epub 2020 Sep 4.

Rotterdam, The Netherlands.

Background: Guidelines recommend liver biopsy to rule out significant inflammatory activity in chronic hepatitis B (CHB) patients with elevated hepatitis B virus (HBV) DNA but without other indications for treatment.

Aim: To study rates and determinants of clinically significant liver inflammation.

Methods: We selected patients with HBV DNA > 2000 IU/mL from the SONIC-B database. The presence of significant inflammation (METAVIR ≥ A2 or HAI ≥ 9) was assessed by liver biopsy and correlated with alanine aminotransferase (ALT) levels (according to AASLD upper limits of normal [ULN]) and stratified by the presence of significant liver fibrosis (Ishak ≥ 3 or METAVIR ≥ F2).

Results: The cohort included 2991 patients; 1672 were HBeAg-positive. ALT was < ULN in 270 (9%), 1-2 times ULN in 852 (29%) and > 2 times ULN in 1869 (63%). Significant fibrosis was found in 1419 (47%) and significant inflammatory activity in 630 (21%). Significant inflammatory activity was found in 34% of patients with liver fibrosis, compared to 9.5% of those without (P < 0.001). Among patients without fibrosis, significant inflammatory activity was detected in 3.6% of those with normal ALT, 5.0% of those with ALT 1-2 times ULN and in 13% of those with ALT > 2 times ULN (P < 0.001). ALT < 2 times ULN had a negative predictive value of 95% for ruling out significant inflammatory activity among patients without liver fibrosis.

Conclusions: Among patients without significant fibrosis, an ALT level < 2 times ULN is associated with < 5% probability of significant inflammatory activity. If fibrosis can be ruled out using non-invasive methods, liver biopsy solely to assess inflammatory activity should be discouraged.
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http://dx.doi.org/10.1111/apt.16067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540526PMC
October 2020

Hepatitis B core-related antigen levels predict recurrence-free survival in patients with HBV-associated early-stage hepatocellular carcinoma: results from a Dutch long-term follow-up study.

J Viral Hepat 2021 Jan 14;28(1):205-208. Epub 2020 Sep 14.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Prognosis of hepatitis B (HBV)-associated hepatocellular carcinoma (HCC) is poor due to high rates of HCC recurrence and progression of underlying liver disease. We studied whether serum hepatitis B core-related antigen (HBcrAg) levels could predict HCC recurrence and outcome in HBV associated. Higher HBcrAg levels at HCC diagnosis were independently associated with reduced overall and recurrence-free survival in patients with early, but not advanced, stage HCC.
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http://dx.doi.org/10.1111/jvh.13394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756674PMC
January 2021

Trends in incidence, diagnosis, treatment and survival of hepatocellular carcinoma in a low-incidence country: Data from the Netherlands in the period 2009-2016.

Eur J Cancer 2020 09 13;137:214-223. Epub 2020 Aug 13.

The Netherlands Comprehensive Cancer Organisation, P.O. Box 19079, 3501 DB Utrecht, the Netherlands. Electronic address:

Objective: Evaluation of the trends in incidence, diagnostics, treatment and survival of patients with hepatocellular carcinoma (HCC) in the Netherlands.

Method: Data regarding incidence, diagnostics, primary treatment and survival of patients with HCC in the period 2009-2016 were obtained from the Netherlands Cancer Registry. Trends in incidence, diagnostics, various treatment modalities (except liver transplantation, due to inaccurate data) and regional treatment preferences were analysed. Survival was evaluated using Kaplan-Meier curves and multivariable Cox proportional hazard regression modelling.

Results: In the period of 2009-2016, 3838 patients were diagnosed with HCC. A distinct decrease in the percentage of patients who underwent tumour biopsy was observed (from 51% in 2009-2010 to 42% in 2015-2016). Percentage of patients who underwent cancer treatment increased markedly (from 49% in 2009-2010 to 57% in 2015-2016), mainly because of an increasing use of resection and ablation. The number of hospitals where resections were performed or sorafenib treatment prescribed decreased slightly. The number of hospitals sporadically (<1 ablation per year) performing ablations increased. There were significant differences between regions in the application of resection, ablation and transarterial chemoembolisation /radioembolisation (p < 0.05 after 'case mix'-correction). One-, 3- and 5-year survival of patients with HCC significantly improved in the studied period. Receiving cancer treatment was associated with increased survival, whereas increasing age and an advanced tumour stage were both associated with decreased survival.

Conclusion: From 2009 to 2016, patients with hepatocellular carcinoma more often received cancer treatment and their survival improved. There were significant differences in types of treatment between various regions.
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http://dx.doi.org/10.1016/j.ejca.2020.07.008DOI Listing
September 2020

Hepatitis B core-related antigen levels predict pegylated interferon-α therapy response in HBeAg-positive chronic hepatitis B.

Antivir Ther 2020 Aug 3. Epub 2020 Aug 3.

Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Background: Serum hepatitis B core-related antigen (HBcrAg) levels reflect intrahepatic HBV replication activity. We aimed to study whether HBcrAg levels predict response to pegylated interferon (PEG-IFN) treatment in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients.

Methods: We studied HBcrAg levels in 222 HBeAg-positive patients treated with PEG-IFN with or without lamivudine for 52 weeks in a global randomized trial and compared kinetics across treatment arms and types of response. Optimal HBcrAg cutoffs for stopping therapy were compared to and combined with the currently recommended hepatitis B surface antigen (HBsAg)-based stopping-rules.

Results: Baseline HBcrAg levels could not discriminate between responders and non-responders (P=0.91). HBcrAg levels of patients responding to PEG-IFN therapy showed a more pronounced on-treatment decline (mean declines 3.4 versus 1.0 log U/ml; P<0.0001), which was sustained until the end of follow-up (mean declines week 78, 3.8 versus 1.0 log U/ml; P<0.0001). In the PEG-IFN monotherapy group, HBcrAg levels of >8.35 log U/ml at week 24 identified 19 patients (19%) of whom 1 (negative predicitve value [NPV]=95%) achieved a response. The performance of this HBcrAg-based stopping rule alone was not superior to the one based on HBsAg >20,000 IU/ml. Among patients with an HBsAg <20,000 (n=56), 9 (16%) had an HBcrAg >8.35, of whom 8 achieved no response (NPV 89%).

Conclusions: HBeAg-positive CHB patients with a response to PEG-IFN therapy achieve a more pronounced HBcrAg decline. HBcrAg levels at week 24 of therapy could be used to identify non-responders in combination with the established HBsAg-based stopping-rules.
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http://dx.doi.org/10.3851/IMP3367DOI Listing
August 2020

Association between a progesterone receptor mutation and hepatitis E sero-positivity in liver transplant recipients.

J Med Virol 2020 Jun 30. Epub 2020 Jun 30.

Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Problem: We investigated if the PROGINS mutation increases the risk of hepatitis E virus (HEV) infection in liver transplant recipients. PROGINS was analyzed through KASP assay; HEV serologies assessed via enzyme-linked immunosorbent assay and multiplex cytokine assays were evaluated in plasma with the ProcartaPlex human immunoassay. Seventy liver transplant recipients were evaluated, of which 23 (33%) were HEV immunoglobuln G (IgG)-positive (HEV+). The frequency of PROGINS in the HEV+ group was 34%, compared with 14% in those that were HEV IgG negative (HEV-). Cytokine measurements in a sub-set of samples from HEV+/PROGINS+ individuals showed decreased plasma levels of monokine induced by gamma interferon, a proliferation-inducing ligand, and stem cell factor, as well as increased levels of eotaxin-3 and interleukin-31 compared with those HEV-/PROGINS- samples. Our findings suggest an association between the PROGINS mutation and seropositivity for HEV in liver transplant recipients with consequent distorted cytokine levels.
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http://dx.doi.org/10.1002/jmv.26236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772260PMC
June 2020

New insights in the management of Hepatocellular Adenoma.

Liver Int 2020 07 11;40(7):1529-1537. Epub 2020 Jun 11.

Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Hepatocellular adenoma (HCA) are benign liver tumours that may be complicated by haemorrhage or malignant transformation to hepatocellular carcinoma. Epidemiological data are fairly outdated, but it is likely to assume that the incidence has increased over the past decades as HCA are more often incidentally found due to the more widespread use of imaging techniques and the increased incidence of obesity. Various molecular subgroups have been described. Each of these molecular subgroups are defined by specific gene mutations and pathway activations. Additionally, they are all related to specific risk factors and show a various biological behaviour. These molecular subgroups may be identified using immunohistochemistry and molecular characterization. Contrast-enhanced MRI is the recommended imaging modality to analyse patients with suspected hepatocellular adenoma allowing to determine the subtype in up to 80%. Surgical resection remains to be the golden standard in treating HCA, although resection is deemed unnecessary in a large number of cases, as studies have shown that the majority of HCA will regress over time without complications such as haemorrhage or malignant transformation occurring. It is preferable to treat patients with suspected HCA in high volume centres with combined expertise of liver surgeons, hepatologists, radiologists and (molecular) pathologists.
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http://dx.doi.org/10.1111/liv.14547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383747PMC
July 2020

Hepatocellular carcinoma risk stratification in HBV cirrhosis: Time to turn the page?

J Hepatol 2020 Sep 15;73(3):728-729. Epub 2020 May 15.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

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http://dx.doi.org/10.1016/j.jhep.2020.04.018DOI Listing
September 2020

The global epidemiology of hepatitis E virus infection: A systematic review and meta-analysis.

Liver Int 2020 07 24;40(7):1516-1528. Epub 2020 Apr 24.

Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.

Background And Aims: Hepatitis E virus (HEV), as an emerging zoonotic pathogen, is a leading cause of acute viral hepatitis worldwide, with a high risk of developing chronic infection in immunocompromised patients. However, the global epidemiology of HEV infection has not been comprehensively assessed. This study aims to map the global prevalence and identify the risk factors of HEV infection by performing a systematic review and meta-analysis.

Methods: A systematic searching of articles published in Medline, Embase, Web of science, Cochrane and Google scholar databases till July 2019 was conducted to identify studies with HEV prevalence data. Pooled prevalence among different countries and continents was estimated. HEV IgG seroprevalence of subgroups was compared and risk factors for HEV infection were evaluated using odd ratios (OR).

Results: We identified 419 related studies which comprised of 1 519 872 individuals. A total of 1 099 717 participants pooled from 287 studies of general population estimated a global anti-HEV IgG seroprevalence of 12.47% (95% CI 10.42-14.67; I  = 100%). Notably, the use of ELISA kits from different manufacturers has a substantial impact on the global estimation of anti-HEV IgG seroprevalence. The pooled estimate of anti-HEV IgM seroprevalence based on 98 studies is 1.47% (95% CI 1.14-1.85; I  = 99%). The overall estimate of HEV viral RNA-positive rate in general population is 0.20% (95% CI 0.15-0.25; I  = 98%). Consumption of raw meat (P = .0001), exposure to soil (P < .0001), blood transfusion (P = .0138), travelling to endemic areas (P = .0244), contacting with dogs (P = .0416), living in rural areas (P = .0349) and receiving education less than elementary school (P < .0001) were identified as risk factors for anti-HEV IgG positivity.

Conclusions: Globally, approximately 939 million corresponding to 1 in 8 individuals have ever experienced HEV infection. 15-110 million individuals have recent or ongoing HEV infection. Our study highlights the substantial burden of HEV infection and calls for increasing routine screening and preventive measures.
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http://dx.doi.org/10.1111/liv.14468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384095PMC
July 2020

A multicentre retrospective analysis on growth of residual hepatocellular adenoma after resection.

Liver Int 2020 09 28;40(9):2272-2278. Epub 2020 Apr 28.

Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background & Aims: Hepatocellular adenoma (HCA) is a benign liver tumour that may require resection in select cases. The aim of this study was to the assess growth of residual HCA in the remnant liver and to advise on an evidence-based management strategy.

Method: This multicentre retrospective cohort study included all patients with HCA who underwent surgery of HCA and had residual HCA in the remnant liver. Growth was defined as an increase of >20% in transverse diameter (RECIST criteria). Data on patient and HCA characteristics, diagnostic work-up, treatment and follow-up were documented and analysed.

Results: A total of 134 patients were included, one male. At diagnosis, median age was 38yrs (IQR 30.0-44.0) and median BMI was 29.9 kg/m (IQR 24.6-33.3). After resection, median number of residual sites of HCA was 3 (IQR 2-6). Follow-up of residual HCA showed regression in 24.6%, stable HCA in 61.9% and growth of at least one lesion in 11.2%. Three patients (2.2%) developed new HCA that were not visible on imaging prior to surgery. Four patients (3%, one male) underwent an intervention as growth was progressive. No statistically significant differences in clinical characteristics were found between patients with growing residual or new HCA versus those with stable or regressing residual HCA.

Conclusion: In patients with multiple HCA who undergo resection, growth of residual HCA is not uncommon but interventions are rarely needed as most lesions stabilize and do not show progressive growth. Surveillance is indicated when residual HCA show growth after resection, enabling intervention in case of progressive growth.
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http://dx.doi.org/10.1111/liv.14467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497037PMC
September 2020

Hepatitis E virus seroprevalence in pets in the Netherlands and the permissiveness of canine liver cells to the infection.

Ir Vet J 2020 2;73. Epub 2020 Apr 2.

1Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, room Na-1005, 's-Gravendijkwal 230, NL-3015 CE Rotterdam, The Netherlands.

Hepatitis E virus (HEV) as an emerging zoonotic pathogen causes a major public health issue. Transmission from domestic, wildlife and zoo animals to human has been widely reported. Whether pets also serve as reservoirs remains an intriguing question. In this study, we found the sero-positive rates of HEV-specific antibodies in pet dogs, cats and horses of 18.52% (30/162), 14.89% (7/47) and 18.18% (4/22) in the Netherlands. Although HEV viral RNA was not detected in these animals, we have demonstrated that dog liver cells are susceptible to HEV infection in vitro. These results call more attention to address the potential role of pets in the zoonotic transmission of HEV.
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http://dx.doi.org/10.1186/s13620-020-00158-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7119158PMC
April 2020

Identification and prognostic impact of malnutrition in a population screened for liver transplantation.

Clin Nutr ESPEN 2020 04 5;36:36-44. Epub 2020 Mar 5.

Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. Electronic address:

Background & Aims: Sarcopenia is prevalent in patients with liver cirrhosis and is negatively associated with clinical outcomes. In a population screened for liver transplantation we aimed to assess the prevalence of abnormal nutritional status and to what extent a clinical screening tool is able to reliably select patients for extensive nutritional assessment including CT. We also evaluated which nutritional parameters are independently associated with clinical outcomes.

Methods: Analysis of consecutive patients undergoing detailed nutritional assessment during pre-liver transplantation screening from October 2015 to April 2017.

Results: In 102 included patients (66.7% male; median age of 56.3 years (IQR 43.9-64.0); median MELDNa score of 14.7 (IQR 9.4-19.0)), presarcopenia was diagnosed in 30/102 patients (29.4%), sarcopenia in 20/102 (19.6%), and impaired muscle quality in 19/102 (18.6%). Application of the European association for the Study of the Liver rapid screen tool as the primary instrument for nutritional assessment would have resulted in selection of 40/69 cases, thus 42.0% of patients with actual muscle mass depletion and/or impaired muscle function would not have been selected for further nutritional evaluation. In contrast to muscle mass depletion, impaired muscle function was a significant predictor for 6-month decompensation-free (p = 0.006) and hospitalization-free (p = 0.003) survival, when adjusted for age and MELDNa score.

Conclusions: In our population the efficacy of a clinical screening tool for malnutrition was unsatisfactory. A detailed nutritional assessment is therefore recommended in all patients undergoing liver transplantation screening. Impaired muscle function might be clinically more relevant than muscle mass depletion, and muscle function testing should be considered an integral part of nutritional assessment in chronic liver disease.
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http://dx.doi.org/10.1016/j.clnesp.2020.02.013DOI Listing
April 2020

Response to Letter: Intrapatient Comparison of the Hepatobiliary Phase of Gd-BOPTA and Gd-EOB-DTPA in the Differentiation of HCA From FNH.

J Magn Reson Imaging 2020 10 23;52(4):1281-1282. Epub 2020 Mar 23.

Department of Radiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Level Of Evidence: 5 TECHNICAL EFFICACY STAGE: 3 J. Magn. Reson. Imaging 2020;52:1281-1282.
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http://dx.doi.org/10.1002/jmri.27137DOI Listing
October 2020

Design of TLR2-ligand-synthetic long peptide conjugates for therapeutic vaccination of chronic HBV patients.

Antiviral Res 2020 06 17;178:104746. Epub 2020 Feb 17.

Department of Gastroenterology and Hepatology, Erasmus University Medical Center (Eramus MC), Rotterdam, the Netherlands. Electronic address:

Synthetic long peptide (SLP) vaccination is a promising new treatment strategy for patients with a chronic hepatitis B virus (HBV) infection. We have previously shown that a prototype HBV-core protein derived SLP was capable of boosting CD4 and CD8 T cell responses in the presence of a TLR2-ligand in chronic HBV patients ex vivo. For optimal efficacy of a therapeutic vaccine in vivo, adjuvants can be conjugated to the SLP to ensure delivery of both the antigen and the co-stimulatory signal to the same antigen-presenting cell (APC). Dendritic cells (DCs) express the receptor for the adjuvant and are optimally equipped to efficiently process and present the SLP-contained epitopes to T cells. Here, we investigated TLR2-ligand conjugation of the prototype HBV-core SLP. Results indicated that TLR2-ligand conjugation reduced cross-presentation efficiency of the SLP-contained epitope by both monocyte-derived and naturally occurring DC subsets. Importantly, cross-presentation was improved after optimization of the conjugate by either shortening the SLP or by placing a valine-citrulline linker between the TLR2-ligand and the long SLP, to facilitate endosomal dissociation of SLP and TLR2-ligand after uptake. HBV-core SLP conjugates also triggered functional patient T cell responses ex vivo. These results provide an import step forward in the design of a therapeutic SLP-based vaccine to cure chronic HBV.
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http://dx.doi.org/10.1016/j.antiviral.2020.104746DOI Listing
June 2020

MDA5 against enteric viruses through induction of interferon-like response partially via the JAK-STAT cascade.

Antiviral Res 2020 04 10;176:104743. Epub 2020 Feb 10.

Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands. Electronic address:

Enteric viruses including hepatitis E virus (HEV), human norovirus (HuNV), and rotavirus are causing global health issues. The host interferon (IFN) response constitutes the first-line defense against viral infections. Melanoma Differentiation-Associated protein 5 (MDA5) is an important cytoplasmic receptor sensing viral infection to trigger IFN production, and on the other hand it is also an IFN-stimulated gene (ISG). In this study, we investigated the effects and mode-of-action of MDA5 on the infection of enteric viruses. We found that MDA5 potently inhibited HEV, HuNV and rotavirus replication in multiple cell models. Overexpression of MDA5 induced transcription of important antiviral ISGs through IFN-like response, without triggering of functional IFN production. Interestingly, MDA5 activates the expression and phosphorylation of STAT1, which is a central component of the JAK-STAT cascade and a hallmark of antiviral IFN response. However, genetic silencing of STAT1 or pharmacological inhibition of the JAK-STAT cascade only partially attenuated the induction of ISG transcription and the antiviral function of MDA5. Thus, we have demonstrated that MDA5 effectively inhibits HEV, HuNV and rotavirus replication through provoking a non-canonical IFN-like response, which is partially dependent on JAK-STAT cascade.
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http://dx.doi.org/10.1016/j.antiviral.2020.104743DOI Listing
April 2020

Discovery and Selection of Hepatitis B Virus-Derived T Cell Epitopes for Global Immunotherapy Based on Viral Indispensability, Conservation, and HLA-Binding Strength.

J Virol 2020 03 17;94(7). Epub 2020 Mar 17.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands

Immunotherapy represents an attractive option for the treatment of chronic hepatitis B virus (HBV) infection. The HBV proteins polymerase (Pol) and HBx are of special interest for antigen-specific immunotherapy because they are essential for viral replication and have been associated with viral control (Pol) or are still expressed upon viral DNA integration (HBx). Here, we scored all currently described HBx- and Pol-derived epitope sequences for viral indispensability and conservation across all HBV genotypes. This yielded 7 HBx-derived and 26 Pol-derived reported epitopes with functional association and high conservation. We subsequently predicted novel HLA-binding peptides for 6 HLA supertypes prevalent in HBV-infected patients. Potential epitopes expected to be the least prone to immune escape were subjected to a state-of-the-art assay to validate their HLA-binding capacity. Using this method, a total of 13 HLA binders derived from HBx and 33 binders from Pol were identified across HLA types. Subsequently, we demonstrated interferon gamma (IFN-γ) production in response to 5 of the novel HBx-derived binders and 17 of the novel Pol-derived binders. In addition, we validated several infrequently described epitopes. Collectively, these results specify a set of highly potent T cell epitopes that represent a valuable resource for future HBV immunotherapy design. Multiple HBV-derived T cell epitopes have been reported, which can be useful in a therapeutic vaccination strategy. However, these epitopes are largely restricted to HLA-A*02, which is not dominantly expressed in populations with high HBV prevalence. Thus, current epitopes are falling short in the development of a global immunotherapeutic approach. Therefore, we aimed to identify novel epitopes for 6 HLA supertypes most prevalent in the infected population. Moreover, established epitopes might not all be equally effective as they can be subject to different levels of immune escape. It is therefore important to identify targets that are crucial in viral replication and conserved in the majority of the infected population. Here, we applied a stringent selection procedure to compose a combined overview of existing and novel HBV-derived T cell epitopes most promising for viral eradication. This set of T cell epitopes now lays the basis for the development of globally effective HBV antigen-specific immunotherapies.
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http://dx.doi.org/10.1128/JVI.01663-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081907PMC
March 2020

Response to Chen et al.

Am J Gastroenterol 2020 01;115(1):147-148

Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

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http://dx.doi.org/10.14309/ajg.0000000000000488DOI Listing
January 2020

Machine-learning based patient classification using Hepatitis B virus full-length genome quasispecies from Asian and European cohorts.

Sci Rep 2019 12 11;9(1):18892. Epub 2019 Dec 11.

Department of Viroscience, Erasmus Medical Center, Rotterdam, 's-Gravendijkwal 230, 3015 CE, Rotterdam, Netherlands.

Chronic infection with Hepatitis B virus (HBV) is a major risk factor for the development of advanced liver disease including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The relative contribution of virological factors to disease progression has not been fully defined and tools aiding the deconvolution of complex patient virus profiles is an unmet clinical need. Variable viral mutant signatures develop within individual patients due to the low-fidelity replication of the viral polymerase creating 'quasispecies' populations. Here we present the first comprehensive survey of the diversity of HBV quasispecies through ultra-deep sequencing of the complete HBV genome across two distinct European and Asian patient populations. Seroconversion to the HBV e antigen (HBeAg) represents a critical clinical waymark in infected individuals. Using a machine learning approach, a model was developed to determine the viral variants that accurately classify HBeAg status. Serial surveys of patient quasispecies populations and advanced analytics will facilitate clinical decision support for chronic HBV infection and direct therapeutic strategies through improved patient stratification.
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http://dx.doi.org/10.1038/s41598-019-55445-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906359PMC
December 2019

Ribavirin for Hepatitis E Virus Infection After Organ Transplantation: A Large European Retrospective Multicenter Study.

Clin Infect Dis 2020 Aug;71(5):1204-1211

Department of Virology, INSERM U1043, IFR-BMT, University Paul Sabatier, Toulouse, France.

Background: Ribavirin is currently recommended for treating chronic hepatitis E virus (HEV) infection. This retrospective European multicenter study aimed to assess the sustained virological response (SVR) in a large cohort of solid organ transplant (SOT) recipients with chronic HEV infection treated with ribavirin monotherapy (N = 255), to identify the predictive factors for SVR, and to evaluate the impact of HEV RNA mutations on virological response.

Methods: Data from 255 SOT recipients with chronic HEV infection from 30 European centers were analyzed. Ribavirin was given at the median dose of 600 (range, 29-1200) mg/day (mean, 8.6 ± 3.6 mg/kg/day) for a median duration of 3 (range, 0.25-18) months.

Results: After a first course of ribavirin, the SVR rate was 81.2%. It increased to 89.8% when some patients were offered a second course of ribavirin. An increased lymphocyte count at the initiation of therapy was a predictive factor for SVR, while poor hematological tolerance of ribavirin requiring its dose reduction (28%) and blood transfusion (15.7%) were associated with more relapse after ribavirin cessation. Pretreatment HEV polymerase mutations and de novo mutations under ribavirin did not have a negative impact on HEV clearance. Anemia was the main adverse event.

Conclusions: This large-scale retrospective study confirms that ribavirin is highly efficient for treating chronic HEV infection in SOT recipients and shows that the predominant HEV RNA polymerase mutations found in this study do not affect the rate of HEV clearance.This large-scale retrospective study that included 255 solid organ transplant recipients confirms that ribavirin is highly efficient for treating chronic hepatitis E virus (HEV) infection and shows that HEV RNA polymerase mutations do not play a role in HEV clearance.
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http://dx.doi.org/10.1093/cid/ciz953DOI Listing
August 2020

Hepatitis E Virus Shows More Genomic Alterations in Cell Culture than In Vivo.

Pathogens 2019 11 22;8(4). Epub 2019 Nov 22.

Department of Viroscience, Erasmus University Medical Center, Postbus 2040 3000 CA Rotterdam, The Netherlands.

Hepatitis E Virus (HEV) mutations following ribavirin treatment have been associated with treatment non-response and viral persistence, but spontaneous occurring genomic variations have been less well characterized. We here set out to study the HEV genome composition in 2 patient sample types and 2 infection models. Near full HEV genome Sanger sequences of serum- and feces-derived HEV from two chronic HEV genotype 3 (gt3) patients were obtained. In addition, viruses were sequenced after in vitro or in vivo expansion on A549 cells or a humanized mouse model, respectively. We show that HEV acquired 19 nucleotide mutations, of which 7 nonsynonymous amino acids changes located in Open Reading Frame 1 (ORF1), ORF2, and ORF3 coding regions, after prolonged in vitro culture. In vivo passage resulted in selection of 8 nucleotide mutations with 2 altered amino acids in the X domain and Poly-proline region of ORF1. Intra-patient comparison of feces- and serum-derived HEV gt3 of two patients showed 7 and 2 nucleotide mutations with 2 and 0 amino acid changes, respectively. Overall, the number of genomic alterations was up to 1.25× per 1000 nucleotides or amino acids in in vivo samples, and up to 2.84× after in vitro expansion of the same clinical HEV strain. In vitro replication of a clinical HEV strain is therefore associated with more mutations, compared to the minor HEV genomic alterations seen after passage of the same strain in an immune deficient humanized mouse; as well as in feces and blood of 2 immunosuppressed chronically infected HEV patients. These data suggest that HEV infected humanized mice more closely reflect the HEV biology seen in solid organ transplant recipients.
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http://dx.doi.org/10.3390/pathogens8040255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963849PMC
November 2019

Hepatic angiomyolipoma: an international multicenter analysis on diagnosis, management and outcome.

HPB (Oxford) 2020 04 13;22(4):622-629. Epub 2019 Oct 13.

Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands. Electronic address:

Background: Hepatic angiomyolipoma (HAML) may easily be misdiagnosed as a malignancy. The study aim was to assess diagnostic dilemmas, clinical management and outcome of this rare tumor.

Methods: This retrospective international multicenter study included all patients with pathologically proven HAML diagnosed between 1997 and 2017. Data on patient characteristics, diagnostic work-up, management and follow-up were analyzed.

Results: Thirty-eight patients were included, 32 female. Median age was 56yrs (i.q.r. 43-64) and median HAML-diameter was 57.5 mm (i.q.r. 38.5-95.3). Thirty patients had undergone CT and 27/38 MRI of the liver, diagnostic biopsy was performed in 19/38. Initial diagnosis was incorrect in 15/38 patients, of which 13 were thought to have malignancy. In 84% biopsy resulted in a correct preoperative diagnosis. Twenty-nine patients were managed with surgical resection, 4/38 with surveillance and 3/38 with liver transplantation. Recurrence after resection occurred in two cases. No HAML related deaths or progression to malignancy were documented.

Conclusion: HAML diagnosis proved problematic even in hepatobiliary expertise centers. Biopsy is indicated and may provide valuable additional information when HAML diagnosis is considered on cross-sectional imaging, especially when surgical resection imposes a risk of complications. Conservative management with regular imaging follow-up might be justified when biopsy confirms (classic type) HAML.
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http://dx.doi.org/10.1016/j.hpb.2019.09.004DOI Listing
April 2020

Body Composition Is an Independent Predictor of Outcome in Patients with Hepatocellular Carcinoma Treated with Sorafenib.

Liver Cancer 2019 Jul 2;8(4):255-270. Epub 2018 Nov 2.

Cancer Center Amsterdam, Amsterdam, The Netherlands.

Background: Previous studies have suggested body composition as a predictor of sorafenib toxicity and outcome in patients with advanced hepatocellular carcinoma (HCC). Large studies on the impact of body composition parameters in European HCC patients are lacking. Our aim was to validate the prognostic value of body composition parameters in Dutch patients with HCC treated with sorafenib.

Patients And Methods: A retrospective analysis was performed in a cohort of HCC patients treated with sorafenib at two Dutch tertiary referral centers between 2007 and 2016. Body composition (adipose and skeletal muscle tissue) was measured at baseline by computed tomography (CT). Low skeletal muscle mass (SMM) and density were defined using published cut-offs. Body composition parameters were correlated with overall survival (OS), time to progression, response rate, and toxicity.

Results: A total of 278 patients were included, mostly Child-Pugh class A (85%) and Barcelona Clinic Liver Cancer (BCLC) stage C (73%), with a median OS of 9.5 months (95% CI 8.1-11.0). Patients with combined low SMM and low total adipose tissue index (TATI) ( = 68, 25%) had a poor median OS (5.8, 95% CI 4.8-6.8) compared with other patients (11.7, 95% CI 9.4-14.0). Combined low SMM and low TATI remained an independent predictor of OS (HR 1.56, 95% CI 1.15-2.11, = 0.004) after adjusting for known prognostic factors. There was no association between body composition and sorafenib toxicity.

Conclusions: In Dutch HCC patients treated with sorafenib, the combined presence of low SMM and low TATI was associated with impaired survival, independent of known prognostic factors. CT assessment of body composition may provide additional prognostic information prior to sorafenib treatment.
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http://dx.doi.org/10.1159/000493586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738194PMC
July 2019

Improved survival prediction and comparison of prognostic models for patients with hepatocellular carcinoma treated with sorafenib.

Liver Int 2020 01 18;40(1):215-228. Epub 2019 Nov 18.

Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.

Background: The 'Prediction Of Survival in Advanced Sorafenib-treated HCC' (PROSASH) model addressed the heterogeneous survival of patients with hepatocellular carcinoma (HCC) treated with sorafenib in clinical trials but requires validation in daily clinical practice. This study aimed to validate, compare and optimize this model for survival prediction.

Methods: Patients treated with sorafenib for HCC at five tertiary European centres were retrospectively staged according to the PROSASH model. In addition, the optimized PROSASH-II model was developed using the data of four centres (training set) and tested in an independent dataset. These models for overall survival (OS) were then compared with existing prognostic models.

Results: The PROSASH model was validated in 445 patients, showing clear differences between the four risk groups (OS 16.9-4.6 months). A total of 920 patients (n = 615 in training set, n = 305 in validation set) were available to develop PROSASH-II. This optimized model incorporated fewer and less subjective parameters: the serum albumin, bilirubin and alpha-foetoprotein, and macrovascular invasion, extrahepatic spread and largest tumour size on imaging. Both PROSASH and PROSASH-II showed improved discrimination (C-index 0.62 and 0.63, respectively) compared with existing prognostic scores (C-index ≤0.59).

Conclusions: In HCC patients treated with sorafenib, individualized prediction of survival and risk group stratification using baseline prognostic and predictive parameters with the PROSASH model was validated. The refined PROSASH-II model performed at least as good with fewer and more objective parameters. PROSASH-II can be used as a tool for tailored treatment of HCC in daily practice and to define pre-planned subgroups for future studies.
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http://dx.doi.org/10.1111/liv.14270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973249PMC
January 2020

Performance of Contrast-Enhanced Sonography Versus MRI With a Liver-Specific Contrast Agent for Diagnosis of Hepatocellular Adenoma and Focal Nodular Hyperplasia.

AJR Am J Roentgenol 2020 01 1;214(1):81-89. Epub 2019 Oct 1.

Department of Radiology & Nuclear Medicine, Erasmus University Medical Center, Abdominal Imaging, Rm Hs-222, 's-Gravendijkwal 230, 3000 CA Rotterdam, The Netherlands.

The purpose of this article is to compare contrast-enhanced sonography (CEUS) with sulfur hexafluoride with MRI with the liver-specific contrast agent gadobenate dimeglumine in the diagnosis of hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH) in a cohort of consecutive patients. Patients referred to a tertiary center for hepatobiliary disease who had suspected HCA or FNH on MRI performed with an extracellular gadolinium-based contrast agent underwent a prospective workup including CEUS and MRI with a liver-specific contrast agent. Diagnosis was definite when the findings of CEUS and MRI with a liver-specific contrast agent were concordant; histopathologic examination (HPE) was performed for cases with discordant findings. Descriptive statistics and the association between categoric variables were presented as numbers and percentages and were assessed using the Fisher exact test. The primary analysis was patient based. Sensitivity, specificity, and AUC and predictive values for the diagnosis of HCA and FNH were calculated separately for CEUS and MRI with a liver-specific contrast agent. A total of 181 patients were selected for the first analysis. Findings from CEUS and MRI with a liver-specific contrast agent were concordant for 132 patients (73%) and discordant for 49 (27%). HPE was performed for 26 of the 49 patients with discordant findings (53%), with findings indeterminate for two of these patients, the findings of MRI with a liver-specific contrast agent correct for 21 of the remaining 24 patients (87.5%), and the findings of CEUS correct for three of these 24 patients (12.5%) ( < 0.05). For further analysis, 156 patients with concordant findings or HPE-proven cases were included. For CEUS, the sensitivity and specificity for the diagnosis of HCA and FNH were 85% and 87%, respectively; the ROC AUC value was 0.856; and the positive predictive value and negative predictive value were 79% and 90%, respectively. For MRI with a liver-specific contrast agent, the sensitivity and specificity were 95% each, the ROC AUC value was 0.949, and the positive predictive value and negative predictive value were 92% and 97%, respectively, for the diagnosis of HCA and FNH. The findings of CEUS and MRI with a liver-specific contrast agent showed fair agreement for the diagnosis of HCA and FNH. MRI with a liver-specific contrast agent is diagnostically correct significantly more often than CEUS in cases with discordant findings that are HPE proven.
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http://dx.doi.org/10.2214/AJR.19.21251DOI Listing
January 2020