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      C-reactive protein is an independent predictor for hepatocellular carcinoma recurrence after liver transplantation

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          Abstract

          Background

          Serum C-reactive protein (CRP) is a prognostic factor for overall survival (OS) and recurrence of hepatocellular carcinoma (HCC) in patients treated with resection or non-surgical treatment. Here, we investigated the association of elevated CRP (≥1 vs. <1 mg/dL) with (i) recurrence of HCC and (ii) OS after liver transplantation (LT).

          Methods

          Adult HCC patients undergoing orthotopic deceased donor LT at the Medical University of Vienna between 1997 and 2014 were retrospectively analysed.

          Results

          Among 216 patients included, 132 (61.1%) were transplanted within the Milan criteria and forty-two patients (19.4%) had microvascular invasion on explant histology. Seventy patients (32.4%) showed elevated CRP (≥ 1 mg/dL). On multivariate analysis, a CRP ≥ 1 mg/dL was an independent risk factor for HCC recurrence with a 5-year recurrence rate of 27.4% vs. 16.4% (HR 2.33; 95% CI 1.13–4.83; p = 0.022). OS was similar in patients with normal vs. elevated CRP levels.

          Conclusions

          Elevated serum CRP is associated with HCC recurrence after LT and may be a marker for more aggressive tumor biology. Future studies should evaluate whether patients with elevated pre-transplant CRP levels benefit from closer monitoring for HCC recurrence.

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          Most cited references35

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          C-reactive protein: a critical update.

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            Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.

            The precise staging of hepatocellular carcinoma (HCC) based on the size and number of lesions that predict recurrence after orthotopic liver transplantation (OLT) has not been clearly established. We therefore analyzed the outcome of 70 consecutive patients with cirrhosis and HCC who underwent OLT over a 12-year period at our institution. Pathologic tumor staging of the explanted liver was based on the American Tumor Study Group modified Tumor-Node-Metastases (TNM) Staging Classification. Tumor recurrence occurred in 11.4% of patients after OLT. The Kaplan-Meier survival rates at 1 and 5 years were 91.3% and 72.4%, respectively, for patients with pT1 or pT2 HCC; and 82.4% and 74.1%, respectively, for pT3 tumors (P =.87). Patients with pT4 tumors, however, had a significantly worse 1-year survival of 33.3% (P =.0001). An alpha-fetoprotein (AFP) level > 1,000 ng/mL, total tumor diameter > 8 cm, age > or = 55 years and poorly differentiated histologic grade were also significant predictors for reduced survival in univariate analysis. Only pT4 stage and total tumor diameter remained statistically significant in multivariate analysis. Patients with HCC meeting the following criteria: solitary tumor < or = 6.5 cm, or < or = 3 nodules with the largest lesion < or = 4.5 cm and total tumor diameter < or = 8 cm, had survival rates of 90% and 75.2%, at 1 and 5 years, respectively, after OLT versus a 50% 1-year survival for patients with tumors exceeding these limits (P =.0005). We conclude that the current criteria for OLT based on tumor size may be modestly expanded while still preserving excellent survival after OLT.
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              Current strategy for staging and treatment: the BCLC update and future prospects.

              Staging and treatment indication are relevant topics in the management of patients with hepatocellular carcinoma (HCC) and for optimal results, they have to take into account liver function, tumor stage, and physical status. For any staging system to be meaningful it has to link staging with treatment indication; this should be based on robust scientific data. Currently, the sole proposal that serves both aims is the Barcelona Clinic Liver Cancer (BCLC) approach. It takes into account the relevant parameters of all important dimensions and divides patients into very early/early, intermediate, advanced, and end-stage. Early-stage HCC patients should be considered for potentially curative options such as resection, ablation, and transplantation. Patients at intermediate stage benefit from chemoembolization, whereas patients at an advanced stage, or who cannot benefit from options of higher priority, have sorafenib as the standard treatment. Finally, patients at end-stage should merely receive palliative care.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing – original draft
                Role: Writing – review & editing
                Role: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Writing – review & editing
                Role: SupervisionRole: Writing – review & editing
                Role: Writing – review & editing
                Role: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                29 May 2019
                2019
                : 14
                : 5
                : e0216677
                Affiliations
                [1 ] Division of Gastroenterology und Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
                [2 ] Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
                [3 ] Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria
                [4 ] Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
                University of Navarra School of Medicine and Center for Applied Medical Research (CIMA), SPAIN
                Author notes

                Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests: T.M. declares no competing interests. S.R.-R. declares no competing interests. G.G. declares no competing interests. W.S. received speaker and consulting fees and research grants from Bayer Schering Pharma; he also served as consultant for Eisai, Lilly, and BMS. T.R. has received grant support from Abbvie, Boehringer-Ingelheim, Gilead, MSD, Philips Healthcare, Gore; speaking honoraria from Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fee from Abbvie, Boehringer-Ingelheim, Gilead, MSD; and travel support from Boehringer-Ingelheim, Gilead and Roche. M.T. served as speaker for BMS, Falk, Gilead, and MSD; advisory boards for Albireo, Falk, Genfit, Gilead, Intercept, MSD, Novartis, Phenex, and Regulus. He further received travel grants from Abbvie, Falk, Gilead, and Intercept, and unrestricted research grants from Albireo, Cymabay, Falk, Gilead, Intercept, MSD, and Takeda. He is also co-inventor of a patent on the medical use of norUDCA. T.S. declares no competing interests. G.B. has received grant support from Sandoz, Chiesi, MSD, Shire; speaking honoraria from Neovii, Chiesi, Astellas; consulting/advisory board fee from Astellas, Neovii, Chiesi, Sanofi; and travel support from Astellas, Chiesi, Neovii, Biotest. M.P. served as consultant for Bayer, BMS, Eisai, and Ipsen, and received travel support from Bayer and speaking fees from Bayer and BMS. He is also an investigator for Bayer, BMS and Lilly. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0002-1716-9166
                Article
                PONE-D-19-06969
                10.1371/journal.pone.0216677
                6541257
                31141535
                b8994b78-4dc7-4b93-8fd1-f5ff4295c33e
                © 2019 Meischl et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 10 March 2019
                : 26 April 2019
                Page count
                Figures: 7, Tables: 4, Pages: 15
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Digestive System Procedures
                Liver Transplantation
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Transplantation
                Organ Transplantation
                Liver Transplantation
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Carcinomas
                Hepatocellular Carcinoma
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Gastrointestinal Tumors
                Hepatocellular Carcinoma
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Hepatocellular Carcinoma
                Biology and Life Sciences
                Biochemistry
                Proteins
                C-Reactive Proteins
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Medicine and Health Sciences
                Health Care
                Patients
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Multivariate Analysis
                Physical Sciences
                Mathematics
                Statistics
                Statistical Methods
                Multivariate Analysis
                Medicine and Health Sciences
                Diagnostic Medicine
                Prognosis
                Biology and Life Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Inflammation
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Inflammation
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                All relevant data are within the paper and its Supporting Information files.

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