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2. Hepatocellular carcinoma risk in sub-Saharan African and Afro-Surinamese individuals with chronic hepatitis B living in Europe

Author

UMC Utrecht Holding, Unit Opleiding Aios, MS MDL 1, Patmore, Lesley A., van Eekhout, Kirsi M.A., Buti, Maria, Koc, Özgur M., Agarwal, Kosh, de Knegt, Rob J., Janssen, Harry L.A., van der Valk, Marc, Lieveld, Faydra I., Hansen, Bettina E., Kramer, Matthijs, de Bruijne, Joep, Claassen, Mark A.A., Smit, Colette, de Man, Rob A., Takkenberg, Bart, Carey, Ivana, Sonneveld, Milan J., the HARP study group and HepNed, UMC Utrecht Holding, Unit Opleiding Aios, MS MDL 1, Patmore, Lesley A., van Eekhout, Kirsi M.A., Buti, Maria, Koc, Özgur M., Agarwal, Kosh, de Knegt, Rob J., Janssen, Harry L.A., van der Valk, Marc, Lieveld, Faydra I., Hansen, Bettina E., Kramer, Matthijs, de Bruijne, Joep, Claassen, Mark A.A., Smit, Colette, de Man, Rob A., Takkenberg, Bart, Carey, Ivana, Sonneveld, Milan J., and the HARP study group and HepNed

Published
2024

3. Hepatocellular carcinoma risk in sub-Saharan African and Afro-Surinamese individuals with chronic hepatitis B living in Europe

Author

Patmore, Lesley A., van Eekhout, Kirsi M.A., Buti, Maria, Koc, Özgur M., Agarwal, Kosh, de Knegt, Rob J., Janssen, Harry L.A., van der Valk, Marc, Lieveld, Faydra I., Hansen, Bettina E., Kramer, Matthijs, de Bruijne, Joep, Claassen, Mark A.A., Smit, Colette, de Man, Rob A., Takkenberg, Bart, Carey, Ivana, Sonneveld, Milan J., Patmore, Lesley A., van Eekhout, Kirsi M.A., Buti, Maria, Koc, Özgur M., Agarwal, Kosh, de Knegt, Rob J., Janssen, Harry L.A., van der Valk, Marc, Lieveld, Faydra I., Hansen, Bettina E., Kramer, Matthijs, de Bruijne, Joep, Claassen, Mark A.A., Smit, Colette, de Man, Rob A., Takkenberg, Bart, Carey, Ivana, and Sonneveld, Milan J.

Abstract

Background & Aims: Sub-Saharan African (SSA) ethnicity has been associated with a higher risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis B in cross-sectional studies. However, the incidence of HCC and performance of HCC risk scores in this population are unknown. Methods: We conducted an international multicenter retrospective cohort study of all consecutive HBV-monoinfected individuals of SSA or Afro-Surinamese (AS) ethnicity managed at sites in the Netherlands, the United Kingdom and Spain. We assessed the 5- and 10-year cumulative incidences of HCC in the overall study population, among different clinically relevant subgroups and across (m)PAGE-B subgroups. Next, we explored the different risk factors for HCC. Results: During a median follow-up of 8 years, we analyzed 1,473 individuals of whom 34 developed HCC. The 5- and 10-year cumulative incidences of HCC were 1% and 2.4%. The 10-year cumulative incidence of HCC was 0.7% among individuals without advanced fibrosis at baseline, compared to 12.1% among individuals with advanced fibrosis (p <0.001). Higher age (adjusted hazard ratio [aHR] 1.05), lower platelet count (aHR 0.98), lower albumin level (aHR 0.90) and higher HBV DNA log10 (aHR 1.21) were significantly associated with HCC development. The 10-year cumulative incidence of HCC was 0.5% among individuals with a low PAGE-B score, compared to 2.9% in the intermediate- and 15.9% in the high-risk groups (p <0.001). Conclusions: In this unique international multicenter cohort of SSA and AS individuals with chronic hepatitis B, we observed 5- and 10-year cumulative HCC risks of 1% and 2.4%, respectively. The risk of HCC was negligible for individuals without advanced fibrosis at baseline, and among individuals with low baseline (m)PAGE-B scores. These findings can be used to guide HCC surveillance strategies. Impact and implications: Sub-Sahar

Published
2024

5. Functional assessment of liver regeneration after major hepatectomy

Author

Rassam, Fadi, primary, Olthof, Pim B., additional, Takkenberg, Bart, additional, Besselink, Marc G., additional, Busch, Olivier R., additional, Erdmann, Joris I., additional, Swijnenburg, Rutger-Jan, additional, van Lienden, Krijn P., additional, Beuers, Ulrich H., additional, Bennink, Roelof J., additional, and van Gulik, Thomas M., additional

Published
2022
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7. Sorafenib for Patients with Hepatocellular Carcinoma and Child‐Pugh B Liver Cirrhosis: Lessons Learned from a Terminated Study.

Author

Labeur, Tim A., Achterbergh, Roos, Takkenberg, Bart, Van Delden, Otto, Mathôt, Ron, and Klümpen, Heinz‐Josef

Subjects
CLINICAL trials, DRUG efficacy, DRUG toxicity, HEPATOCELLULAR carcinoma, CIRRHOSIS of the liver, SURVIVAL, TREATMENT effectiveness, SEVERITY of illness index, DESCRIPTIVE statistics, SORAFENIB, EVALUATION
Abstract

Lessons Learned: Recruitment of patients with advanced hepatocellular carcinoma and Child‐Pugh B for sorafenib treatment and additional pharmacokinetic studies is challenging.Patients with Child‐Pugh B liver cirrhosis have high rates of cirrhosis‐related adverse events. Background: Few data are available on the pharmacokinetics (PK) of sorafenib in patients with advanced hepatocellular carcinoma (HCC) and Child‐Pugh B liver cirrhosis. This study aimed to explore the sorafenib PK and its relationship with efficacy and toxicity in these patients. Methods: Patients with advanced HCC and Child‐Pugh B7‐8 liver function were prospectively recruited at a tertiary center. Adverse events (AEs), progression‐free survival (PFS), and overall survival (OS) were recorded. Patients received a starting dose of 200 b.i.d. with toxicity‐adjusted dose escalation to a target dose of 400 mg b.i.d. with PK sampling at fixed time points. Results: Between May 2014 and March 2017, 12 patients were screened, of whom 7 progressed to a terminal stage during the screening (n = 6) or shortly after recruitment (n = 1). The five included patients had median PFS of 3.8 months (range, 1.7–10.8) and OS of 7.4 months (range, 1.7–25.8). Three patients had severe AEs and one patient had a partial response with an OS of 25.8 months. In 2017, the trial was aborted for lack of accrual. Conclusion: Because of low accrual, no conclusion can be drawn on the sorafenib PK in patients with advanced HCC and Child‐Pugh B liver cirrhosis. The poor survival and frequent cirrhosis‐related AEs suggest limited benefit for most of these patients. [ABSTRACT FROM AUTHOR]

Published
2020
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8. PD-L1, Galectin-9 and CD8+ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma

Author

Sideras, Kostandinos, primary, Biermann, Katharina, additional, Verheij, Joanne, additional, Takkenberg, Bart R., additional, Mancham, Shanta, additional, Hansen, Bettina E., additional, Schutz, Hannah M., additional, de Man, Robert A., additional, Sprengers, Dave, additional, Buschow, Sonja I., additional, Verseput, Maddy C. M., additional, Boor, Patrick P. C., additional, Pan, Qiuwei, additional, van Gulik, Thomas M., additional, Terkivatan, Turkan, additional, Ijzermans, Jan N. M., additional, Beuers, Ulrich H. W., additional, Sleijfer, Stefan, additional, Bruno, Marco J., additional, and Kwekkeboom, Jaap, additional

Published
2017
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9. PD-L1, Galectin-9 and CD8+tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma

Author

Sideras, Kostandinos, Biermann, Katharina, Verheij, Joanne, Takkenberg, Bart R., Mancham, Shanta, Hansen, Bettina E., Schutz, Hannah M., de Man, Robert A., Sprengers, Dave, Buschow, Sonja I., Verseput, Maddy C. M., Boor, Patrick P. C., Pan, Qiuwei, van Gulik, Thomas M., Terkivatan, Turkan, Ijzermans, Jan N. M., Beuers, Ulrich H. W., Sleijfer, Stefan, Bruno, Marco J., and Kwekkeboom, Jaap

Abstract

ABSTRACTNovel systemic treatments for hepatocellular carcinoma (HCC) are strongly needed. Immunotherapy is a promising strategy that can induce specific antitumor immune responses. Understanding the mechanisms of immune resistance by HCC is crucial for development of suitable immunotherapeutics. We used immunohistochemistry on tissue-microarrays to examine the co-expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM and IDO, as well as tumor CD8+lymphocyte infiltration in HCC, in two independent cohorts of patients. We found that at least some expression in tumor cells was seen in 97% of cases for HVEM, 83% for PD-L1, 79% for Gal-9 and 66% for IDO. In the discovery cohort (n = 94), we found that lack of, or low, tumor expression of PD-L1 (p< 0.001), Galectin-9 (p< 0.001) and HVEM (p< 0.001), and low CD8+TIL count (p= 0.016), were associated with poor HCC-specific survival. PD-L1, Galectin-9 and CD8+TIL count were predictive of HCC-specific survival independent of baseline clinicopathologic characteristics and the combination of these markers was a powerful predictor of HCC-specific survival (HR 0.29; p<0.001). These results were confirmed in the validation cohort (n = 60). We show that low expression levels of PD-L1 and Gal-9 in combination with low CD8+TIL count predict extremely poor HCC-specific survival and it requires a change in two of these parameters to significantly improve prognosis. In conclusion, intra-tumoral expression of these immune inhibiting molecules was observed in the majority of HCC patients. Low expression of PD-L1 and Galectin-9 and low CD8+TIL count are associated with poor HCC-specific survival. Combining immune biomarkers leads to superior predictors of HCC mortality.

Published
2017
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