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Background: Individuals carrying the risk variant p.I148M of patatin-like phospholipase domain-containing protein 3 (PNPLA3) have a higher susceptibility to fatty liver diseases and associated complications, including HCC, a cancer closely linked to chronic inflammation. Here, we assessed circulating cytokine profiles for patients with chronic liver diseases genotyped for PNPLA3., Methods: Serum concentrations of 22 cytokines were measured by multiplex sandwich-ELISA. The cohort comprised 123 individuals: 67 patients with NAFLD without cirrhosis (57 steatosis, 10 NASH), 24 patients with NAFLD with cirrhosis, 21 patients with HCC (15 cirrhosis), and 11 healthy controls. Receiver operator characteristic analyses were performed to assess the suitability of the cytokine profiles for the prediction of steatosis, cirrhosis, and HCC., Results: HGF, IL-6, and IL-8 levels were increased in patients, with ∼2-fold higher levels in patients with cirrhosis versus healthy, while platelet derived growth factor-BB (PDGF-BB) and regulated on activation, normal T cell expressed and secreted (RANTES) showed lower concentrations compared to controls. Migration inhibitory factor and monocyte chemoattractant protein-1 (MCP-1) were found at higher levels in NAFLD samples (maximum: NAFLD-cirrhosis) versus healthy controls and HCC samples. In receiver operator characteristic analyses, migration inhibitory factor, IL-8, IL-6, and monocyte chemoattractant protein-1 yielded high sensitivity scores for predicting noncirrhotic NAFLD (vs. healthy). The top combination to predict cirrhosis was HGF plus PDGF-BB. Migration inhibitory factor performed best to discriminate HCC from NAFLD; the addition of monokine induced gamma (MIG), RANTES, IL-4, macrophage colony-stimulating factor (M-CSF), or IL-17A as second parameters further increased the AUC values (> 0.9). No significant impact of the PNPLA3I148M allele on cytokine levels was observed in this cohort., Conclusions: Cytokines have biomarker potential in patients with fatty liver, possibly suited for early HCC detection in patients with fatty liver. Patients carrying the PNPLA3 risk allele did not present significantly different levels of circulating cytokines., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

BACKGROUND Malignant and benign neuroendocrine tumors (NET) share many histopathological features. Liver transplantation (LT) is one of the liver-directed therapies for neuroendocrine liver metastases (NELM). The aim of this study was to determine the outcomes of patients undergoing LT for NELM. MATERIAL AND METHODS This was a retrospective study that included 19 patients who underwent LT for unresectable NELM between December 1989 and December 2022 in the Department of General, Transplant, and Liver Surgery of the Medical University of Warsaw. Kaplan-Meier estimator and Cox proportional hazards regression were used for statistical analyses. RESULTS The primary tumor was located most frequently in the pancreas. The median follow-up was 72.5 months. The overall survival (OS) was 94.7%, 88.0%, 88.0%, 70.4%, and 49.3% after 1, 3, 5, 10, and 15 years, respectively. Accordingly, the recurrence-free survival (RFS) rates were 93.8%, 72.9%, 64.8%, 27.8%, and 27.8% after 1, 3, 5, 10, and 15 years, respectively. Ki-67 index ≥5% was found as a risk factor for both worse OS (hazard ratio (HR) 7.13, 95% confidence intervals (95% CI) 1.32-38.63, P=0.023) and RFS (HR 13.68, 95% CI 1.54-121.52, P=0.019). Recipient age ≥55 years was a risk factor for worse RFS (P=0.046, HR 5.47, 95% CI 1.03-29.08). Multivariable analysis revealed Ki-67 ≥5% as the sole independent factor for worse OS (HR 13.78, 95% CI 1.48-128.56, P=0.021). CONCLUSIONS Patients with unresectable NELM achieve great OS and satisfying RFS after LT. The risk factors associated with worse outcomes are attributed to primary tumor aggressiveness.

Background & Aims: Cholangiocarcinoma (CCA), heterogeneous biliary tumours with dismal prognosis, lacks accurate early diagnostic methods especially important for individuals at high-risk (i.e. those with primary sclerosing cholangitis [PSC]). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs)., Methods: EVs from patients with isolated PSC (n = 45), concomitant PSC-CCA (n = 44), PSC who developed CCA during follow-up (PSC to CCA; n = 25), CCAs from non-PSC aetiology (n = 56), and hepatocellular carcinoma (n = 34) and healthy individuals (n = 56) were characterised by mass spectrometry. Diagnostic biomarkers for PSC-CCA, non-PSC CCA, or CCAs regardless of aetiology (Pan-CCAs) were defined and validated by ELISA. Their expression was evaluated in CCA tumours at a single-cell level. Prognostic EV biomarkers for CCA were investigated., Results: High-throughput proteomics of EVs identified diagnostic biomarkers for PSC-CCA, non-PSC CCA, or Pan-CCA, and for the differential diagnosis of intrahepatic CCA and hepatocellular carcinoma, which were cross-validated by ELISA using total serum. Machine learning-based algorithms disclosed CRP/FIBRINOGEN/FRIL for the diagnosis of PSC-CCA (local disease [LD]) vs. isolated PSC (AUC = 0.947; odds ratio [OR] =36.9) and, combined with carbohydrate antigen 19-9, overpowers carbohydrate antigen 19-9 alone. CRP/PIGR/VWF allowed the diagnosis of LD non-PSC CCAs vs. healthy individuals (AUC = 0.992; OR = 387.5). It is noteworthy that CRP/FRIL accurately diagnosed LD Pan-CCA (AUC = 0.941; OR = 89.4). Levels of CRP/FIBRINOGEN/FRIL/PIGR showed predictive capacity for CCA development in PSC before clinical evidence of malignancy. Multi-organ transcriptomic analysis revealed that serum EV biomarkers were mostly expressed in hepatobiliary tissues, and single-cell RNA sequencing and immunofluorescence analysis of CCA tumours showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EV prognostic biomarkers, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively and positively with patients' survival, respectively., Conclusions: Serum EVs contain protein biomarkers for the prediction, early diagnosis, and prognostication of CCA that are detectable using total serum, representing a tumour cell-derived liquid biopsy tool for personalised medicine., Impact and Implications: The accuracy of current imaging tests and circulating tumour biomarkers for cholangiocarcinoma (CCA) diagnosis is far from satisfactory. Most CCAs are considered sporadic, although up to 20% of patients with primary sclerosing cholangitis (PSC) develop CCA during their lifetime, constituting a major cause of PSC-related death. This international study has proposed protein-based and aetiology-related logistic models with predictive, diagnostic, or prognostic capacities by combining two to four circulating protein biomarkers, moving a step forward into personalised medicine. These novel liquid biopsy tools may allow the (i) easy and non-invasive diagnosis of sporadic CCAs, (ii) identification of patients with PSC with higher risk for CCA development, (iii) establishment of cost-effective surveillance programmes for the early detection of CCA in high-risk populations (e.g. PSC), and (iv) prognostic stratification of patients with CCA, which, altogether, may increase the number of cases eligible for potentially curative options or to receive more successful treatments, decreasing CCA-related mortality., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis., Design: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina)., Results: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10 -9 , OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10 -5 , OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10 -44 )., Conclusion: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis., Competing Interests: Competing interests: JT has received speaking and/or consulting fees from Versantis, Gore, Bayer, Alexion, Norgine, Grifols and CSL Behring., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the most common liver disorders worldwide and the major causes of non-viral liver cirrhosis in the general population. In NAFLD, metabolic abnormalities, obesity, and metabolic syndrome are the driving factors for liver damage with no or minimal alcohol consumption. ALD refers to liver damage caused by excess alcohol intake in individuals drinking more than 5 to 10 daily units for years. Although NAFLD and ALD are nosologically considered two distinct entities, they show a continuum and exert synergistic effects on the progression toward liver cirrhosis. The current view is that low alcohol use might also increase the risk of advanced clinical liver disease in NAFLD, whereas metabolic factors increase the risk of cirrhosis among alcohol risk drinkers. Therefore, special interest is now addressed to individuals with metabolic abnormalities who consume small amounts of alcohol or who binge drink, for the role of light-to-moderate alcohol use in fibrosis progression and clinical severity of the liver disease. Evidence shows that in the presence of NAFLD, there is no liver-safe limit of alcohol intake. We discuss the epidemiological and clinical features of NAFLD/ALD, aspects of alcohol metabolism, and mechanisms of damage concerning steatosis, fibrosis, cumulative effects, and deleterious consequences which include hepatocellular carcinoma.

Background and Aims: Intrahepatic cholangiocarcinoma (iCCA) with liver metastases is perceived to have a poor prognosis, but the American Joint Committee on Cancer (AJCC) classifies them as early stage in the absence of lymph nodes or extrahepatic spread., Approach and Results: Patients with iCCA from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and Surveillance, Epidemiology, and End Results (SEER) registries with survival/staging (AJCC v.7) data were eligible. Modified staging was used (mAJCC v.7): group A: stages I-III (excluding T2bN0); group B: stage IVa (excluding T2bN1M0); group C: liver metastases (T2bN0/1); and group D: stage IVb (extrahepatic metastases). Survival analysis (Kaplan-Meier and Cox regression) was performed in an ENS-CCA training cohort (TC) and findings internally (ENS-CCA iVC) and externally (SEER) validated. The aim was to assess whether liver metastases (group C) had a shorter survival compared to other early stages (group A) to propose a modified version of AJCC v.8 (mAJCC v.8). A total of 574 and 4,171 patients from the ENS-CCA and SEER registries were included. Following the new classification, 19.86% and 17.31% of patients from the ENS-CCA and SEER registries were reclassified into group C, respectively. In the ENS-CCA TC, multivariable Cox regression was adjusted for obesity (p = 0.026) and performance status (P < 0.001); patients in group C (HR, 2.53; 95% CI, 1.18-5.42; P = 0.017) had a higher risk of death (vs. group A). Findings were validated in the ENS-CCA iVC (HR, 2.93; 95% CI, 2.04-4.19; P < 0.001) and in the SEER registry (HR, 1.88; 95% CI, 1.68-2.09; P < 0.001)., Conclusions: iCCA with liver metastases has a worse outcome than other early stages of iCCA. Given that AJCC v.8 does not take this into consideration, a modification of AJCC v.8 (mAJCC v.8), including "liver metastases: multiple liver lesions, with or without vascular invasion" as an "M1a stage," is suggested., (© 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Biliary cancer, comprising cholangio- and gallbladder carcinomas, is associated with high mortality due to asymptomatic disease onset and resulting late diagnosis. Currently, no robust diagnostic biomarker is clinically available. Therefore, we explored the feasibility of extracellular vesicles (EVs) as a liquid biopsy tool for biliary cancer screening and hepatobiliary cancer differentiation., Methods: Serum EVs of biliary cancer, hepatocellular carcinoma, colorectal cancer and non-small cell lung cancer patients, as well as from healthy individuals, were isolated by sequential two-step centrifugation and presence of indicated EVs was evaluated by fluorescence activated cell sorting (FACS) analysis., Results: Two directly tumour-related antigen combinations (AnnV + CD44v6 + and AnnV + CD44v6 + CD133 + ) and two combinations related to progenitor cells from the tumour microenvironment (AnnV + CD133 + gp38 + and AnnV + EpCAM + CD133 + gp38 + ) were associated with good diagnostic performances that could potentially be used for clinical assessment of biliary cancer and differentiation from other cancer entities. With 91% sensitivity and 69% specificity AnnV + CD44v6 + EVs showed the most promising results for differentiating biliary cancers from HCC. Moreover using a combined approach of EV levels of the four populations with serum AFP values, we obtained a perfect separation of biliary cancer and HCC with sensitivity, specificity, positive and negative predictive value all reaching 100% respectively., Conclusions: EV phenotyping, especially if combined with serum AFP, represents a minimally invasive, accurate liquid biopsy tool that could improve cancer screening and differential diagnosis of hepatobiliary malignancies., (© 2020 The Authors. Liver International published by John Wiley & Sons Ltd.)

BACKGROUND The impact of packed red blood cells (PRBCs) and fresh frozen plasma (FFP) transfusions in patients with hepatocellular cancer (HCC) undergoing liver transplantation has rarely been evaluated. The aim of the current study was to assess the impact of intraoperative transfusions on posttransplant outcomes. MATERIAL AND METHODS This retrospective cohort study was based on 229 HCC transplant recipients. The primary outcome measure was 5-year recurrence-free survival. Secondary outcome measures comprised overall and long-term survival at 5 years and 90-day mortality. Cox proportional hazard models and logistic regression were used to assess risk factors. RESULTS After adjustment for potential confounders, no association was found with respect to tumor recurrence for PRBCs (P=0.368) or FFP (P=0.081) transfusions. Similarly, PRBC transfusion (P=0.623) and FFP transfusion (P=0.460) had no impact on survival between 90 days and 5 years. PRBC transfusion increased the risk of 90-day mortality (P=0.005), while FFP transfusion was associated with a lower risk (P=0.036). CONCLUSIONS Intraoperative transfusions of blood products does not impair recurrence-free and long-term survival of patients with HCC undergoing liver transplantation. Intraoperative PRBC transfusion increases the risk of early mortality, whereas adequate supplementation of FFP plays a protective role.

Background and Aims: Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC., Approach and Results: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 × 10 -6 ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 × 10 -4 ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 × 10 -26 ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 × 10 -23 ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (OR allelic , 0.75; 95% CI, 0.64-0.87; P = 1.72 × 10 -4 )., Conclusions: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population., (© 2019 by the American Association for the Study of Liver Diseases.)

Background: A complete pathologic response (CPR) after neoadjuvant treatment is reported to be associated with an exceptionally low risk of recurrence after liver transplantation for hepatocellular carcinoma (HCC). This study aimed to evaluate the prognostic role of CPR in liver transplantation for HCC., Methods: This retrospective cohort study was based on 222 HCC transplant recipients. Incidence of recurrence and survival at 5 years were the primary and secondary outcome measures, respectively. Competing risk analyses were applied to evaluate recurrence incidence and its predictors. Propensity score matching was performed to compare the outcomes for patients after neoadjuvant treatment with and without CPR., Results: Neoadjuvant treatment was performed for 127 patients, 32 of whom achieved CPR (25.2%). Comparison of baseline characteristics showed that the patients with CPR were at lowest baseline recurrence risk, followed by treatment-naïve patients and patients without CPR. Adjusted for potential confounders, CPR did not have any significant effects on tumor recurrence. No significant net reclassification improvement was noted after addition of CPR to existing criteria. Neoadjuvant treatment without CPR was associated with increased risk of recurrence in subgroups within the Milan criteria (p = 0.016), with alpha-fetoprotein concentration (AFP) model not exceeding 2 points (p = 0.021) and within the Warsaw criteria (p = 0.007) compared with treatment-naïve patients who were at risk similar to those with CPR. The 5-year incidences of recurrence in propensity score-matched patients with and without CPR were respectively 14.0% and 15.9% (p = 0.661), with corresponding survival rates of 73.2% and 67.4%, respectively (p = 0.329)., Conclusions: The findings showed that CPR is not independently associated with long-term outcomes after liver transplantation for HCC.

This study aimed to evaluate the effects of ischemia-reperfusion injury (IRI) on the risk of hepatocellular carcinoma (HCC) recurrence after liver transplantation. Data of 195 patients were retrospectively analysed. Post-reperfusion aspartate (AST), alanine transaminase, and lactate dehydrogenase (LDH) levels were the primary measures of IRI. Tumour recurrence was the primary endpoint. Post-reperfusion AST was a continuous risk factor for tumour recurrence in patients within Milan criteria (p = 0.035), with an optimal cut-off of 1896 U/L. Recurrence-free survival of patients within Milan criteria and post-reperfusion AST of <1896 and ≥1896 U/L was 96.6% and 71.9% at 5 and 3.7 years, respectively (p = 0.006). Additionally, post-reperfusion AST and LDH exceeding the upper quartile significantly increased the risk of HCC recurrence in patients within Milan criteria (p = 0.039, hazard ratio [HR] = 5.99 and p = 0.040, HR = 6.08, respectively) and to a lesser extent, in patients within Up-to-7 criteria (p = 0.028, HR = 3.58 and p = 0.039, HR = 3.33, respectively). No other significant IRI effects were found in patients beyond the Up-to-7 criteria and in analyses stratified for independent risk factors for recurrence: tumour number and differentiation, alpha-fetoprotein, and microvascular invasion. Thus, IRI exerts major negative effects on the risk of HCC recurrence after liver transplantation in patients within standard and extended criteria.

An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumour DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive 'liquid biopsy' for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation marker panel by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumour DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1,098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P < 0.001) and was highly correlated with tumour burden, treatment response, and stage. Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P < 0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC.

Background: Although transplant benefit appears superior for patients with advanced hepatocellular cancer (HCC), liver transplantation remains limited to selected low-risk HCC patients to keep their outcomes similar to heterogeneous group of non-HCC patients. The purpose of this study was to assess the rationale for current policy of restricting access to liver transplantation to minority of HCC patients based on utility principle., Methods: This retrospective cohort study comprised 1246 liver transplant recipients, including 206 HCC and 1040 non-HCC patients. Patient survival was the primary outcome measure. Patients with HCC and benign diseases were divided into low-, moderate-, and high-risk subgroups basing on independent risk factors for disease-free survival and model for end-stage liver disease (MELD) score (<30, 30-40, >40), respectively., Results: MELD (p < 0.001) and presence of HCC (p = 0.008) were independent risk factors for early and late mortality, respectively. Total tumor volume (p = 0.008) and alpha-fetoprotein (p = 0.013) were independent predictors of recurrence and mortality used for division of HCC patients into low-, moderate-, and high-risk subgroups, with disease-free survival rates of 74.9% (5 years), 51.7% (5 years), and 8.0% (3 years), respectively (p < 0.001). There were no differences in 5-year overall survival between low-risk HCC (74.9%) and non-HCC (81.9%) patients (p = 0.210), moderate-risk HCC (63.3%) and non-HCC (68.0%) patients (p = 0.372), and high-risk HCC (55.0%) and non-HCC (56.0%) patients (p = 0.559)., Conclusions: The principle of utility is unequally applied for restriction of access to liver transplantation for HCC patients. The results provide rationale for discussion on reinitiation of liver transplantation for advanced HCCs.

Background & Aims: Large extracellular vesicles, specifically AnnexinV + EpCAM + CD147 + tumour-associated microparticles (taMPs), facilitate the detection of colorectal carcinoma (CRC), non-small cell lung carcinoma (NSCLC) as well as pancreas carcinoma (PaCa). Here we assess the diagnostic value of taMPs for detection and monitoring of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Specifically, the aim of this study was to differentiate liver taMPs from other cancer taMPs, such as CRC and NSCLC., Methods: Fluorescence-activated cell scanning (FACS) was applied to detect various taMP populations in patients' sera that were associated with the presence of a tumour (AnnexinV + EpCAM + CD147 + taMPs) or could discriminate between cirrhosis (due to HCV or HBV) and liver cancers (AnnexinV + EpCAM + ASGPR1 + taMPs). In total 172 patients with liver cancer (HCC or CCA), 54 with cirrhosis and no liver neoplasia, and 202 control subjects were enrolled., Results: The results indicate that AnnexinV + EpCAM + CD147 + taMPs were elevated in HCC and CCA. Furthermore, AnnexinV + EpCAM + ASGPR1 + CD133 + taMPs allowed the distinction of liver malignancies (HCC or CCA) and cirrhosis from tumour-free individuals and, more importantly, from patients carrying other non-liver cancers. In addition, AnnexinV + EpCAM + ASGPR1 + taMPs were increased in liver cancer-bearing patients compared to patients with cirrhosis that lacked any detectable liver malignancy. The smallest sizes of successfully detected cancers were ranging between 11-15mm. AnnexinV + EpCAM + ASGPR1 + taMPs decreased at 7days after curative R0 tumour resection suggesting close correlations with tumour presence. ROC values, sensitivity/specificity scores and positive/negative predictive values (>78%) indicated a potent diagnostic accuracy of AnnexinV + EpCAM + ASGPR1 + taMPs., Conclusion: These data provide strong evidence that AnnexinV + EpCAM + ASGPR1 + taMPs are a novel biomarker of HCC and CCA liquid biopsy that permit a non-invasive assessment of the presence and possible extent of these cancers in patients with advanced liver diseases., Lay Summary: Microparticles (MPs) are small vesicles that bleb from the membrane of every cell, including cancer cells, and are released to circulate in the bloodstream. Since their surface composition is similar to the surface of their underlying parental cell, MPs from the bloodstream can be isolated and by screening their surface components, the presence of their parental cells can be identified. This way, it was possible to detect and discriminate between patients bearing liver cancer and chronic liver cirrhosis., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Combination of the University of California, San Francisco (UCSF) and the up-to-7 criteria with alpha-fetoprotein (AFP) cutoff of 100 ng/ml was proposed as the Warsaw expansion of the Milan criteria in selection of hepatocellular cancer (HCC) patients for liver transplantation. The purpose of this retrospective study was to validate this proposal., Methods: A total of 240 HCC patients after liver transplantation were included. Recurrence-free survival and overall survival at 5 years were set as the primary and secondary outcome measures, respectively., Results: The Warsaw expansion increased transplant eligibility rate by 20.3 %. AFP >100 ng/ml significantly increased the recurrence risk in patients within the Milan criteria (p = 0.025) and in those beyond, yet within either the UCSF or the up-to-7 criteria (p < 0.001). Recurrence-free survival at 5 years was 90.8 % for patients within the Milan criteria, 100.0 % in patients within the Warsaw expansion, 54.9 % in patients beyond the Warsaw expansion but within either the UCSF or the up-to-7 criteria, and 45.1 % in patients beyond both the UCSF and the up-to-7 criteria (p < 0.001). The corresponding overall survival rates were 71.6, 82.4, 64.3, and 55.3 %, respectively (p = 0.027)., Conclusions: The Warsaw expansion of the Milan criteria substantially increases the recipient pool without compromising outcomes.

Microvascular invasion (MVI) is well known to negatively influence outcomes following surgical treatment of hepatocellular cancer (HCC) patients. The aim of this study was to evaluate the rationale for prediction of MVI before liver transplantation (LT). Data of 200 HCC patients after LT were subject to retrospective analysis. MVI was present in 57 patients (28.5%). Tumor number (p = 0.001) and size (p = 0.009), and alpha-fetoprotein (p = 0.049) were independent predictors of MVI used to create a prediction model, defined as: 0.293x(tumor number) + 0.283x(tumor size in cm) + 0.164xlog e (alpha-fetoprotein in ng/ml) (c statistic  =  0.743). The established cut-off (≥2.24) was associated with sensitivity and specificity of 72%. MVI was not an independent risk factor for recurrence (p = 0.307), in contrast to tumor number (p = 0.047) and size (p < 0.001), alpha-fetoprotein (p < 0.001) and poor differentiation (p = 0.039). Recurrence-free survival at 5 years for patients without MVI was 85.9% as compared to 83.3% (p = 0.546) and 55.3% (p = 0.001) for patients with false negative and true positive prediction of MVI, respectively. The use of both morphological and biological tumor features enables effective pre-transplant prediction of high-risk MVI. Provided that these parameters are combined in selection of HCC patients for LT, pre-transplant identification of all patients with MVI does not appear necessary.

Introduction: Breast cancer (BC) makes up nearly 26% of malignant tumours worldwide and is the leading cause of cancer-related deaths in European women. With approximately 18,000 new cases of BC diagnosed in Polish women annually, breast cancer liver metastasis (BCLM) is respectively an increasing issue. Recent data found in literature indicates improved survival following liver resection with systemic therapy., Objective: The aim of study was to evaluate surgical treatment in patients with isolated BCLM., Materials and Method: During 2009-2013, a retrospective study was undertaken and 30 cases analysed. From nearly 2,000 liver resections performed, 11 female patients at the mean age of 59.18 years with BCLM were qualified for surgery., Results: The median time between primary and secondary treatment was 3.5 years (1-7). One patient (9.1%) presented an extrahepatic lesion - bone metastasis. The left lobe, right lobe and both lobes of the liver were affected, respectively, in 3 (27.3%), 4 (36.4%) and 4 (36.4%) patients. 5 patients (45.5%) presented single hepatic lesion, in contrast to the maximum number of lesions which equalled 6 in the right lobe. Average hospitalisation period was 13.27 days and discharge on the 11.3 postoperative day. One-year survival was 72.7% (8 patients); therefore, three-year survival was 36.4% (4 patients)., Conclusions: Oncological centres should assess BCLM patients more openly and qualify them for hepatic resection along with adjuvant systemic treatment in order to improve overall survival. This, however, needs to be studied in a multicentre randomized trial.

Background: Changes within the gut microbiota contribute to the progression of chronic liver diseases. According to the results of several studies performed in animal models, gut dysbiosis plays an important role in hepatocarcinogenesis. The aim of this study was to explore the characteristics of gut microbiota associated with the presence of hepatocellular cancer (HCC) in patients with cirrhosis of the liver undergoing liver transplantation., Methods: A total of 15 patients with HCC and 15 non-HCC patients matched according to etiology of cirrhosis and Model for End-Stage Liver Disease (MELD) scores who underwent liver transplantations between 2012 and 2014 were included. Analysis of their gut microbial profile was based on prospectively collected stool samples from the pretransplant period., Results: Patients with and without HCC were similar with respect to age (P = .506), sex (P = .700), hepatitis C virus (P > .999) and hepatitis B virus (P = .715) infection status, alcoholic liver disease (P > .999), and MELD score (P = .337). Notably, the presence of HCC was associated with significantly increased fecal counts of Escherichia coli (P = .025). Prediction of HCC presence based on E coli counts was associated with the area under the receiver-operating curve of 0.742 (95% confidence interval, 0.564-0.920), with the optimal cutoff on the level of 17.728 (natural logarithm of colony-forming units per 1 g of feces). Sensitivity and specificity rates for the established cutoff were 66.7% and 73.3%, respectively., Conclusions: The profile of gut microbiota associated with the presence of HCC in cirrhotic patients is characterized by increased fecal counts of E coli. Therefore, intestinal overgrowth of E coli may contribute to the process of hepatocarcinogenesis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Liver transplantation (LT) outcomes for patients with poorly differentiated (G3) hepatocellular carcinoma (HCC) are unsatisfactory. The aim of this study was to evaluate outcomes in patients with poorly differentiated HCC undergoing LT., Patients and Methods: There were 192 HCC patients after LT in the Department of General, Transplant and Liver Surgery, Medical University of Warsaw, between January 2001 and April 2014. The study group comprised 24 patients with poorly differentiated tumors., Results: Disease-free survival (DFS) for all patients was 49.5% at 5 years. The 5-year DFS for patients who met the Milan criteria (n = 9, 88.9%) was significantly better compared to those who did not (n = 15, 28.0%, P = .025). Multivariable analysis revealed that only the largest tumor diameter (P = .014) and α-fetoprotein (AFP) concentration (P = .001) were independent risk factors for DFS. The optimal cut-off AFP and tumor size that could distinguish patients with the highest risk were ≥500 ng/mL and ≥3.5 cm, respectively. DFS for patients with AFP <500 ng/mL and tumor size <3.5 cm was 100% after 2.8 years, and for those with ≥500 ng/mL or tumor size ≥3.5 cm was 46.9% after 5 years. However, the DFS for patients with AFP ≥500 ng/mL and tumor size ≥3.5 cm was only 12.5% after 4.7 years (P = .002)., Conclusions: Outcomes of patients with poorly differentiated HCC treated with LT can be characterized with acceptable survival when applying criteria based on tumor size <3.5 cm and AFP <500 ng/mL., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The magnitude of pre-transplant a-fetoprotein (AFP) changes has been advocated to be a superior predictor of hepatocellular cancer (HCC) recurrence following liver transplantation. The aim of this study was to compare AFP dynamics and last pre-transplant AFP as risk factors for post-transplant HCC recurrence., Material and Methods: Data of 146 patients after liver transplantation for HCC were analyzed retrospectively., Results: While last pre-transplant AFP was a significant predictor of microvascular invasion (p=0.006) and poor tumor differentiation (p=0.020), AFP slope was associated only with microvascular invasion (p=0.029). Notably, last pre-transplant AFP (p<0.001), but not AFP slope (p=0.279), was an independent risk factor for recurrence. No significant effects of AFP slope were also found following division of patients into those with pre-transplant AFP <100 (p=0.260) and those with AFP >100 (p=0.178) ng/mL. Moreover, prediction of recurrence based on last pre-transplant AFP was superior (p=0.018) to those based on AFP slope. Recurrence-free survival at 5 years was superior in patients with pre-transplant AFP persistently at (97.3%) or dropping to <100 ng/mL (100.0%) as compared to patients with AFP rising to (75.0%) or persistently at >100 ng/mL (38.4%; p<0.001)., Conclusions: The risk of post-transplant HCC recurrence is dependent on the last pre-transplant AFP regardless of its previous dynamics.

Background: Transarterial chemoembolization (TACE) induces ischemic tumor necrosis, which is intensified by regional chemotherapy. By reducing the active tumor tissue, it can be assumed that patients on the waiting list for liver transplantation may benefit from this locoregional treatment. The aim of this study was to assess the relevance of TACE in hepatocellular carcinoma (HCC) patients before liver transplantation., Material and Methods: A retrospective analysis was performed on data of 229 patients who were transplanted for HCC. A group of 75 patients were treated with TACE prior to liver transplantation. Tumor necrosis related to pretransplantation locoregional treatment was assessed in an explanted liver and classified into extensive (51-100%), moderate (26-50%) and limited (<25%) grades. Five-year recurrence-free survival was estimated using the Kaplan-Meier method and compared using the log-rank test., Results: In total, 143 HCC lesions were treated with TACE. Extensive necrosis was found in 63 (44.0%) tumors. Moderate and limited necrosis were observed in 42 (29.4%) and 38 (26.6%) tumors, respectively. In 36 (58.1%) explanted livers, every tumor was classified as extensively necrotic. The 5-year recurrence-free survival was estimated as 81.6% in the group not treated with TACE prior to liver transplantation (TACE-) and as 73.1% in the TACE+ group (p=0.169). Among patients not fulfilling the Milan criteria, 5-year recurrence-free survival was 63.1% in TACE- and 65.1% in TACE+ (p=0.656)., Conclusions: In conclusion, TACE prior to liver transplantation is effective in inducing tumor necrosis. However, evidence of benefits in long-term results after liver transplantation requires further confirmation.

Background and Objectives: The use of neo-adjuvant chemotherapy in resectable synchronous liver metastasis is ill defined. The aim of this study was to evaluate neo-adjuvant chemotherapy on outcomes following liver resection for synchronous CLM., Methods: An analysis of a multi-centric cohort from the LiverMetSurvey International Registry, who had undergone curative resections for synchronous CLM was undertaken. Patients who received neo-adjuvant chemotherapy prior to liver surgery (group NAS; n = 693) were compared with those treated by surgery alone (group SG; n = 608). Baseline clinicopathological variables were compared. Predictors of overall (OS) and disease free survival (DFS) were subsequently identified., Results: Clinicopathological comparison of the groups revealed a greater proportion of solitary metastasis in the SG compared to the NAS group (58.8% versus 38.4%; P < 0.001) therefore a separate analysis of solitary versus multi-centric analysis was performed. N-stage (> N1), number of metastasis (> 3), serum CEA (> 5 ng/ml) and no adjuvant chemotherapy independently predicted poorer OS, while N-stage (> N1), serum CEA (> 5 ng/ml) and no adjuvant chemotherapy independently predicted poorer DFS. Neo-adjuvant chemotherapy did not independently affect outcome., Conclusion: We present an analysis of a large multi-center series of the role of neo-adjuvant chemotherapy in resectable CLM and demonstrate no survival advantage in this setting., (© 2015 Wiley Periodicals, Inc.)

Purpose: Literature is void of data on the relationship between pre- and postoperative levels of hepatocyte growth factor (HGF), interleukin 6 (IL-6), and tumor growth factor α (TGF-α) after liver resection performed for particular benign liver tumors. The purpose of this study was to assess whether there is a different degree of liver regeneration through the kinetics of HGF, IL-6, and TGF-α in 2 particular types of benign liver lesions., Material/methods: The study included 9 patients diagnosed with hepatic hemangioma and 13 patients with focal nodular hyperplasia (FNH) who underwent liver resection. HGF, IL-6, and TGF-α were measured using enzyme-linked immunosorbent assay (ELISA) from blood serum drawn at 6 time points during an 8-day period. Statistical analysis was based on two-factor variance analysis with replicate measurements., Results: The HGF, IL-6, and TGF-α levels in patients who underwent FNH resection were not significantly different from the levels observed in hemangioma resection patients. Significant increases in HGF, IL-6, and TGF-α concentrations were observed only during the first 24h after resection in both groups of patients., Conclusions: Obtained results suggest that the pre- and post-operative levels of HGF, IL-6, and TGF-α do not depend on the particular type of benign tumor. After resection of FNH and hemangioma tumors, the serum levels of HGF, IL-6, and TGF-α increased at similar rates during the first 24h, followed by significant declines back to pre-operative levels., (Copyright © 2015 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Hemangiomas are the most common benign primary hepatic neoplasms, often being incidentally discovered. In most of the cases they are small and asymptomatic. It is widely accepted that clinical intervention is indicated only for symptomatic hemangiomas. We present a case of an asymptomatic giant hemangioma managed by enucleation due to its atypical localization. The hemangioma, originally located in segment 5, was now described in Computer Tomography (CT) Imaging as separating the gallbladder from the liver parenchyma. A careful evaluation of images revealed proximity to the portal vein (PV), right hepatic artery (RHA), right hepatic duct (RHD) and right branch of the portal vein (RBPV). Thus, in the case of an emergent operation, surgical maneuvers in the area of the altered hepatic anatomy and proximity to the hemangioma itself, would in fact increase the risk endangering the patient's life. After patient's consent, a surgical enucleation en block with the gall-bladder was performed. It is of great importance that specifically selected, asymptomatic patients diagnosed with a giant hemangioma, with the above mentioned or similar localization should be considered for surgical treatment.

Background: Hepatitis B (HBV) and C (HCV) virus infection are the 2 most important risk factors for the development of the hepatocellular carcinoma (HCC). The aim of this study was to assess the importance of the type of viral infection in evaluation of HCC recurrence risk after liver transplantation (LT)., Material and Methods: This retrospective study was based on 130 HCC patients undergoing LT. Patients were subdivided by HBV or HCV infection only or HBV and HCV co-infection (HBV-HCV). The primary outcome measure was recurrence-free survival (RFS) 5 years after transplantation., Results: The 5-year RFS did not differ significantly according to HBV infection, HCV infection, or HBV-HCV co-infection in the entire study cohort (p=0.902) or among patients who fulfilled (p=0.454) or did not fulfill (p=0.999) the Milan criteria. Neither HCV (p=0.869) nor HBV (p=0.968) infection significantly affected 5-year RFS following adjustment for covariates. Higher lesion number (p=0.004), increased alpha-fetoprotein (p=0.017), microvascular invasion (p=0.004), and female donor sex (p=0.025) were significant risk factors for poor RFS in HBV patients; older recipient age (p=0.010) and increased total tumor volume (p=0.028) were significant risk factors in HCV patients., Conclusions: Although the viral infection type does not affect post-LT outcomes in HCC patients, the influence of other risk factors is markedly different in HBV- and HCV-related HCC.

Unlabelled: Liver is the most common location of the colorectal cancer metastases occurrence. Liver resection is the only curative method of treatment. Unfortunately it is feasible only in 25% of patients with colorectal liver metastases, often because of the extensiveness of the disease. The aim of the study was to evaluate the predictive value of total tumor volume, size and number of colorectal liver metastases in patients treated with right hemihepatectomy., Material and Methods: A retrospective analysis was performed in a group of 135 patients with colorectal liver metastases, who were treated with right hemihepatectomy. Total tumor volume was estimated based on the formula (4/3)πr³. Moreover, the study included an analysis of data on the number and size of tumors, radicality of the resection, time between primary tumor resection and liver resection, pre-operative blood serum concentration of carcinoembryonal antigen (CEA) and carcinoma antigen Ca 19-9. The predictive value of the factors was evaluated by applying a Cox proportional hazards model and the area under the ROC curve., Results: The univariate analysis has shown the predictive value of size of the largest tumor (p=0.033; HR=1.065 per each cm) on the overall survival, however no predictive value of number of tumors (p=0.997; HR=1.000) and total tumor volume (p=0.212; HR=1.002) was observed. The multivariate analysis did not confirm the predictive value of the size of the largest tumor (p=0.141; HR=1.056). In the analysis of ROC curves, AUROC for the total tumor volume, the size of the largest tumor and the number of tumors were 0.629, 0.608, 0.520, respectively., Conclusions: Total tumor volume, size and number of liver metastases are not independent risk factors for the worse overall survival of patients with colorectal liver metastases treated with liver resection, therefore increased values of these factors should not be a contraindication for surgical treatment.

Background: Serum α-fetoprotein concentration (AFP) might be a useful addition to morphologic criteria for selecting patients with hepatocellular carcinoma (HCC) for liver transplantation (LT). The aim of this study was to evaluate the role of AFP in selecting HCC patients at minimal risk of posttransplant tumor recurrence in the setting of existing criteria., Methods: This retrospective cohort study was based on 121 HCC patients after LT performed at a single institution. AFP was evaluated as a predictor of posttransplant tumor recurrence with respect to fulfillment of the Milan, University of California, San Francisco (UCSF), and Up-to-7 criteria., Results: There was a nearly linear association between AFP and the risk of HCC recurrence (p < 0.001 for linear effect; p = 0.434 for nonlinear effect). AFP predicted HCC recurrence in patients (1) beyond the Milan criteria (p < 0.001; optimal cutoff 200 ng/ml); (2) within the UCSF criteria (p = 0.001; optimal cutoff 100 ng/ml) and beyond them (p = 0.015; optimal cutoff 200 ng/ml); and (3) within the Up-to-7 criteria (p = 0.001; optimal cutoff 100 ng/ml) and beyond them (p = 0.023; optimal cutoff 100 ng/ml) but not in patients within the Milan criteria (p = 0.834). Patients within either UCSF and Up-to-7 criteria with AFP level <100 ng/ml exhibited superior (100 %) 5-year recurrence-free survival-significantly higher than those within UCSF (p = 0.005) or Up-to-7 (p = 0.001) criteria with AFP levels higher than the estimated cutoffs or beyond with AFP levels less than the estimated cutoffs., Conclusions: Combining the UCSF and Up-to-7 criteria with an AFP level <100 ng/ml is associated with minimal risk of tumor recurrence. Hence, this combination might be useful for selecting HCC patients for LT.

Introduction: After liver transplantation for cholangiocarcinoma (CCC), patients have a poor prognosis without use of specific therapeutic strategies. Accordingly, recipients with incidental CCC might have the highest risk of recurrent disease; however, sparse data on the long-term outcome of unselected patients with incidental CCC have been published. The aim of this study was to evaluate the post-transplantation outcomes of patients with incidental CCC with special focus on tumor localization., Material and Methods: There were 11 primary liver transplantations in patients with incidental CCC of 1310 liver transplantation procedures performed between December 1994 and August 2013. All patients with incidental CCC received a chemotherapy regiment including gemcitabine/5 fluorouracil, doxorubicin, and mitomycin. The patients were switched from calcineurin inhibitors to mammalian target of rapamycin inhibitor-based immunosuppression shortly after CCC diagnosis., Results: Intra- and extrahepatic tumors were found in 6 and 5 patients, respectively. At median follow-up examination of 26.3 months there were 8 CCC recurrences and 7 patient deaths. Overall survival after liver transplantation for incidental CCC was 88.9% at 1 year, 44.4% at 2 years, and 14.8% at 3 years. The corresponding rates of recurrence-free survival were 45.7%, 45.7%, and 0.0%, respectively. Post-transplantation CCC recurrences were universal with 0% 3-year recurrence-free survival both in patients with intra- and extrahepatic tumors (P = .475)., Conclusions: Incidental CCC in liver transplantation is associated with poor outcomes irrespective of tumor localization. Introduction of new adjuvant multimodal treatment concepts is necessary to improve the prognosis for this subgroup of patients.

Introduction: Metastatic disease is generally considered as an absolute contraindication for liver transplantation. However, due to relatively low aggressiveness and slow progression rates, liver metastases from neuroendocrine tumors (NETs) form an exception to this rule. Given the scarcity of available data, the purpose of this study was to evaluate long-term outcomes following liver transplantation for NET metastases., Material and Methods: There were 12 primary liver transplantations in patients with NET metastases out of 1334 liver transplantations performed in the Department of General, Transplant and Liver Surgery (Medical University of Warsaw) in the period between December 1989 and October 2013. Overall survival (OS) and disease-free survival (DFS) were set as primary and secondary outcome measures, respectively., Results: Median follow-up was 7.9 years. For all patients, OS rate was 78.6% at 10 years and DFS rate was 15.5% at 9 years. Intraoperative transfusions of packed red blood cells (P = .021), Ki-67 proliferative index more than 2% (P = .048), and grade 2 tumors (P = .037) were identified as factors significantly associated with worse DFS. Notably, loss of E-cadherin expression (P = .444), mitotic rate (P = .771), extent of liver involvement (P = .548), primary tumor site (P = .983), and recipient age (P = .425) were not significantly associated with DFS., Conclusions: Excellent long-term OS rates support liver transplantation for unresectable NET metastases despite almost universal post-transplantation tumor recurrence. Selection of patients with G1 tumors with Ki-67 index not exceeding 2% and reducing the requirement for intraoperative blood transfusions might improve DFS rates.

Aim: To investigate the indications and outcomes of liver transplantation for hepatic epithelioid hemangioendothelioma (HEHE)., Methods: Between 1989 and August 2013, in the Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, 1306 orthotopic liver transplantations (OLTx) were performed, including 72 retransplantations. Unresectable HEHE was an indication for OLTx in 10 patients (0.8% of primary OLTx), the mean age of the patients was 40.5 ± 13.3 years (range 23-65 years), and the male-to-female ratio was 2:8. Kaplan-Meier survival analysis in HEHE, hepatocellular carcinoma (HCC), and other OLTx recipients groups was performed. The differences in mortality were compared using the χ(2) test. A P-value < 0.05 indicated statistical significance., Results: No concomitant liver disease was found in any patient. There was no neoadjuvant chemotherapy or radiotherapy. Liver function test results were normal in most of the patients. The levels of alpha-fetoprotein, carcinoembryonic antigen, and carbohydrate antigen 19-9 were normal. In immunohistochemical staining, the neoplastic cells were positive for factor VIII-related antigen, CD31, and CD34, which are endothelial cell markers, and negative for cytokeratin 19, cytokeratin 7, and HepPar-1. Nine patients were alive without tumor recurrence. One patient died 2 mo after OLTx due to septic complications. No morbidity was observed. Maximum follow-up was 11.4 years, with a minimum of 1 mo. The cumulative survival rate at the end of follow-up in HEHE patients was 87.5% compared with 54.3% in the HCC group and 76.3% in the other OLTx recipients group (χ(2) test = 1.784, df = 2, P = 0.409)., Conclusion: Unresectable HEHE, without extrahepatic metastases is an excellent indication for liver transplantation. Long-term survival is very good and much better than in HCC patients and the entire group of OLTx patients.

Hepatocellular carcinoma (HCC) represents the major histological subtype of liver cancer. Tumorigenic changes in hepatic cells potentially result from aberrant expression of microRNAs (miRNAs). Individual microRNA gene may give rise to miRNAs of different length, named isomiRNAs that proved to be functionally relevant. Since microRNA length heterogeneity in hepatic tissue has not been described before, we employed next-generation sequencing to comprehensively analyze microRNA transcriptome in HCC tumors (n=24) and unaffected tissue adjacent to tumors (n=24), including samples with (n=15) and without cirrhosis (n=9). We detected 374 microRNAs expressed in liver, including miR-122-5p that constituted over 39% of the hepatic miRnome. Among the liver expressed miRs, the levels of 64 significantly differed between tumor and control samples (FDR<0.05, fold change>2). Top deregulated miRNAs included miR-1269a (T/N=22.95), miR-3144-3p (T/N=5.24), miR-183-5p (T/N=4.63), miR-10b-5p (T/N=3.87), miR-490-3p (T/N=0.13), miR-199a-5p (T/N=0.17), miR-199a-3p/miR-199b-3p (T/N=0.19), miR-214-5p (T/N=0.20) and miR-214-3p (T/N=0.21). Almost all miRNA genes produced several mature molecules differing in length (isomiRNAs). The reference sequence was not the most prevalent in 38.6% and completely absent in 10.5% of isomiRNAs. Over 26.1% of miRNAs produced isoforms carrying≥2 alternative seed regions, of which 35.5% constituted novel, previously unknown seeds. This fact sheds new light on the percentage of the human genome regulated by microRNAs and their variants. Among the most deregulated miRNAs, miR-199a-3p/miR-199b-3p (T/N fold change=0.18, FDR=0.005) was expressed in 9 isoforms with 3 different seeds, concertedly leading to upregulation of TGF-beta signaling pathway (OR=1.99; p=0.004). In conclusion, the study reveals the comprehensive miRNome of hepatic tissue and provides new tools for investigation of microRNA-dependent pathways in cirrhotic liver and hepatocellular carcinoma. This article is part of a Directed Issue entitled: Rare Cancers., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Unlabelled: Liver metastases are diagnosed synchronously with the primary tumour in 25% of patients with colorectal cancer. A half of the remaining patients develop liver metastases within 3 years following colectomy. At present, the only radical treatment of metastases is liver resection. Only 2.6% of patients survive 3 years if such treatment is not implemented. The aim of the study was to assess predictive factors of long-term survival in the group of patients with unresectable colorectal liver metastases carcinoma., Material and Methods: Of 1029 patients with colorectal liver metastases, who were treated in the Department of General, Transplant and Liver Surgery of the Medical University of Warsaw in the years 2006-2012, cases of liver metastases assessed intraoperatively as unresectable were selected. The retrospective analysis included 85 patients. Based on the medical documentation, information concerning age, sex, characteristics of primary and secondary tumours, reasons for unresectability, neoadjuvant chemotherapy as well as local treatment of liver tumours was collected. Preoperative serum concentrations of CEA and CA 19-9 markers were considered. The Cox regression model, Kaplan- Meier estimator and log-rank test were applied in the statistical analyses., Results: The most common reason for unresectability were: number of metastases in 31 patients (36.5%) and extrahepatic metastases in 19 cases (22.4%). Overall survival in the entire group was 56.1% and 15.5% after 1 and 3 years respectively. A single-factor analysis showed that CEA serum levels (p=0.032; HR=1.002 per increase by 1 ng/ml) and the presence of extrahepatic metastases (p=0.037; HR=2.06) were predictors of worse survival. In a multivariate analysis, CEA concentration (p=0.017; HR=1.002 per increase by 1 ng/ml) was an independent predictor of death whereas the presence of extrahepatic metastases were not statistically significant (p=0.059; HR=2.09)., Conclusions: Serum concentration of CEA marker is an independent predictor of worse survival, but the presence of extrahepatic metastases shows a similar tendency.

Background: Although piggyback technique has gained widespread acceptance for liver transplantation in general, there is an exceptional lack of data on the choice of appropriate surgical technique for patients with hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the impact of surgical technique on outcomes after liver transplantation for HCC., Material and Methods: We conducted a retrospective cohort study on 90 HCC patients who underwent liver transplantation with the conventional (n=19) or piggyback (n=71) technique. Both techniques were compared with respect to intraoperative variables and long-term outcomes, determined by 3-year overall (OS) and recurrence-free (RFS) survival. The potential role of confounding factors was excluded in a series of Cox proportional regression models., Results: The piggyback technique was associated with shorter procedure duration (p=0.0005), shorter anatomical anhepatic phase (p<0.0001), shorter duration of total (p=0.018) and warm ischemia (p<0.0001), and fewer blood transfusions (p=0.006). Three-year OS was 89.1% after piggyback and 49.9% after conventional transplantation (p=0.0008), with 3-year RFS of 89.4% and 56.0% (p=0.0006), respectively. Piggyback transplantations provided outcomes superior to conventional procedures both in patients within (p=0.019 for OS; p=0.003 for RFS) and beyond (p=0.023 for OS; p=0.031 for RFS) Milan criteria. Multivariate analysis of the risks of death and recurrence confirmed the benefits of piggyback technique., Conclusions: Given its superior long-term outcome, piggyback transplantation might be considered primarily for HCC patients.

Background: The aim of this study was to determine if the appearance of hepatic epithelioid hemangioendothelioma (HEHE) on state-of-the-art MRI including hepatocyte phase after administration of hepatobiliary contrast agent can facilitate preoperative diagnosis and identification of potential candidates for liver transplantation., Material and Methods: The study group comprised 6 patients with pathologically confirmed HEHE. Analysis included signal characteristics of 55 tumor nodules (maximum of 10 lesions per patient) on T2-weighted images, dynamic contrast-enhanced, 5-minute delayed, and hepatobiliary phase images., Results: The most common feature of HEHE, observed in 84% of lesions, was progressive contrast-enhancement, followed by subcapsular location (66%), confluent appearance (60%) and hyper- or isointensity on hepatobiliary phase images (53%). In 5 of 6 patients, capsular retraction was observed., Conclusions: The appearance of HEHE on hepatobiliary phase images was variable, but examined tumors often demonstrated hyper- or isointensity, most probably due to prolonged retention of contrast material. These features, along with typical morphology (subcapsular, confluent nodules, with progressive enhancement and capsular retraction), may contribute to correct diagnosis and recognition of potential candidates for liver transplantation.

Introduction: Appropriate selection of hepatocellular cancer (HCC) patients for liver transplantation is crucial to minimize the risk of recurrence and provide long-term outcomes comparable with those for other indications. Selection criteria based on total tumor volume (TTV) and α-fetoprotein (AFP) concentrations were proposed in a recent large study. The aim of this study was to evaluate the results of liver transplantation for HCC within and beyond these criteria., Material and Methods: This retrospective study included 104 patients with HCC who underwent liver transplantation. Risk factors for overall survival and tumor recurrence were evaluated. Overall survival and cumulative tumor recurrence rate for patients with TTV <115 cm(3), AFP concentration <400 ng/mL, and no macrovascular invasion (76/104; 73.1%) were evaluated and compared with those for the remaining patients (28/104; 26.9%)., Results: Pretransplantation AFP concentration >400 ng/mL (P = .016; hazard ratio [HR], 3.36; 95% confidence intervals [CI], 1.25-9.03) was the only risk factor for overall survival. TTV >115 cm(3) (P = .021; HR 4.29; 95% CI, 1.24-14.81) and AFP concentration >400 ng/mL (P = .002; HR 6.97; 95% CI, 2.02-24.03) were independent risk factors for recurrence. The estimated 3-year tumor recurrence rate was 4.2% for patients with TTV <115 cm(3), AFP concentration <400 ng/mL, and no macrovascular invasion compared with 57.2% for the remaining patients (P < .00001). The 3-year overall survival rate of patients within and beyond this criteria was 81.7% and 64.6%, respectively (P = .0628)., Conclusions: In contrast to other criteria, selection of HCC patients for liver transplantation on the basis of TTV and AFP concentration relates to both morphological features and tumor biology. Although fulfillment of these criteria was more than 1.5-fold higher than that of the Milan criteria, the rate of tumor recurrence was exceptionally low., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to assess outcomes and indications in a large cohort of patients who underwent liver transplantation (LT) for liver metastases (LM) from neuroendocrine tumors (NET) over a 27-year period., Background: LT for NET remains controversial due to the absence of clear selection criteria and the scarcity and heterogeneity of reported cases., Methods: This retrospective multicentric study included 213 patients who underwent LT for NET performed in 35 centers in 11 European countries between 1982 and 2009. One hundred seven patients underwent transplantation before 2000 and 106 after 2000. Mean age at the time of LT was 46 years. Half of the patients presented hormone secretion and 55% had hepatomegaly. Before LT, 83% of patients had undergone surgical treatment of the primary tumor and/or LM and 76% had received chemotherapy. The median interval between diagnosis of LM and LT was 25 months (range, 1-149 months). In addition to LT, 24 patients underwent major resection procedures and 30 patients underwent minor resection procedures., Results: Three-month postoperative mortality was 10%. At 5 years after LT, overall survival (OS) was 52% and disease-free survival was 30%. At 5 years from diagnosis of LM, OS was 73%. Multivariate analysis identified 3 predictors of poor outcome, that is, major resection in addition to LT, poor tumor differentiation, and hepatomegaly. Since 2000, 5-year OS has increased to 59% in relation with fewer patients presenting poor prognostic factors. Multivariate analysis of the 106 cases treated since 2000 identified the following predictors of poor outcome: hepatomegaly, age more than 45 years, and any amount of resection concurrent with LT., Conclusions: LT is an effective treatment of unresectable LM from NET. Patient selection based on the aforementioned predictors can achieve a 5-year OS between 60% and 80%. However, use of overly restrictive criteria may deny LT to some patients who could benefit. Optimal timing for LT in patients with stable versus progressive disease remains unclear.

Background: An early prediction of poor outcomes is essential in the management of patients after a liver resection. The aim of this study was to evaluate the role of selected biochemical parameters on post-operative day 1 (POD 1) in the prediction of morbidity and mortality after a liver resection for colorectal metastases., Method: This retrospective study was based on 236 major liver resections for colorectal metastases performed between 2006 and 2011. Results of biochemical tests of blood samples obtained on POD 1 were assessed as predictors of primary outcome measures (hepatic and overall morbidity, 90-day mortality) using multiple regression and receiver-operating characteristics (ROC)., Results: Hepatic morbidity, overall morbidity and 90-day mortality rates were 18.6%, 28.0% and 4.7%, respectively. On the basis of multiple regression analysis and comparisons of the prediction models, serum bilirubin was selected for the prediction of hepatic (>2.05 mg/dl, sensitivity 69.2%, specificity 71.2%) and overall (>2.05 mg/dl, sensitivity 61.1% and specificity 71.2%) morbidity, and aspartate aminotransferase (AST) was selected for the prediction of 90-day mortality (>798 U/l, sensitivity 62.5% and specificity 90.4%)., Discussion: Biochemical analyses of blood on POD1 enables stratification of patients into low- and high-risk groups for negative outcomes, with serum bilirubin associated with overall and hepatic morbidity and AST associated with mortality., (© 2012 International Hepato-Pancreato-Biliary Association.)

We present imaging findings (ultrasound, computed tomography, and magnetic resonance imaging) of eight patients with hepatic angiomyolipoma (HAML). The lesions were solitary in seven patients, and one patient had multiple tumors (n=11). Angiomyolipoma, even though a rare liver tumor, should be included in the differential diagnosis in cases of highly vascularized lesion containing a significant amount of fat. Suggestion of the diagnosis of HAML might be helpful for the pathologist in the selection of the typical histochemical staining of the tumor, allowing accurate diagnosis, which, in turn, determines the implementation of appropriate therapeutic intervention., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To compare the efficacy of two quantitative methods for discrimination between benign and malignant focal liver lesions (FLLs): apparent diffusion coefficient (ADC) values and T2 relaxation times., Methods: Seventy-three patients with 215 confirmed FLLs (115 benign, 100 malignant) underwent 1.5-T MRI with respiratory-triggered single-shot SE DWI (b = 50, 400, 800) and dual-echo T2TSE (TR = 3,000 ms; TE1 = 84 ms; TE2 = 228 ms). ADC values and T2 relaxation times of FLLs were calculated. Sensitivity, specificity and accuracy of both techniques in diagnosing malignancy were assessed., Results: The mean ADC value of malignant tumours (1.07 × 10(-3) mm(2)/s) was significantly lower (P < 0.05) than that of benign lesions (1.86 × 10(-3) mm(2)/s ); however, with the use of the optimal cut-off value of 1.25 × 10(-3) mm(2)/s, 20 false positive (FP) and 20 false negative (FN) diagnoses of malignancy were noted, generating 79 % sensitivity, 82.6 % specificity and 80.9 % accuracy. The mean T2 relaxation time of malignant tumours (64.4 ms) was significantly lower (P < 0.05) than that of benign lesions (476.1 ms). At the threshold of 107 ms 22 FP and 1 FN diagnoses were noted; the sensitivity was 99 %, specificity 80.9 % and accuracy 89.3 %., Conclusions: Quantitative analysis of T2 relaxation times yielded significantly higher sensitivity and accuracy in diagnosing malignant liver tumour than ADC values., Key Points: • Diffusion-weighted magnetic resonance imaging is increasingly used for liver lesions. • But ADC values demonstrated only moderate accuracy for differentiation of liver lesions. • T2 relaxation times yielded higher accuracy in diagnosing malignant liver tumours. • Both ADC and T2 values overlapped between focal nodular hyperplasia and malignant lesions. • Nevertheless T2 liver mapping could be valuable for evaluating focal liver lesions.

Context: Fibrolamellar hepatocellular carcinoma is a rare liver tumor with the propensity to metastasize to the lymph nodes months or years after initial surgery. However, its metastatic spread to the pancreas was previously reported only in a child., Case Report: We present an unusual case of a young female patient who was repeatedly treated by surgical excision of abdominal and mediastinal lymph node recurrences between 2 and 6 years after left hepatic lobectomy for fibrolamellar hepatocellular carcinoma. At 8 years following her initial surgery, the patient was diagnosed with pancreatic head metastasis and a pancreaticoduodenectomy was performed. Postoperative course was uneventful and the patient did not experience recurrence within the last 18 months., Conclusion: The metastasis of fibrolamellar hepatocellular carcinoma to the pancreas is highly exceptional but possible and its excision appears warranted as well.

Background & Aims: The role of liver transplantation in the treatment of hepatocellular carcinoma in livers without fibrosis/cirrhosis (NC-HCC) is unclear. We aimed to determine selection criteria for liver transplantation in patients with NC-HCC., Methods: Using the European Liver Transplant Registry, we identified 105 patients who underwent liver transplantation for unresectable NC-HCC. Detailed information about patient, tumor characteristics, and survival was obtained from the transplant centers. Variables associated with survival were identified using univariate and multivariate statistical analyses., Results: Liver transplantation was primary treatment in 62 patients and rescue therapy for intrahepatic recurrences after liver resection in 43. Median number of tumors was 3 (range 1-7) and median tumor size 8 cm (range 0.5-30). One- and 5-year overall and tumor-free survival rates were 84% and 49% and 76% and 43%, respectively. Macrovascular invasion (HR 2.55, 95% CI 1.34 to 4.86), lymph node involvement (HR 2.60, 95% CI 1.28 to 5.28), and time interval between liver resection and transplantation < 12 months (HR 2.12, 95% CI 0.96 to 4.67) were independently associated with survival. Five-year survival in patients without macrovascular invasion or lymph node involvement was 59% (95% CI 47-70%). Tumor size was not associated with survival., Conclusions: This is the largest reported series of patients transplanted for NC-HCC. Selection of patients without macrovascular invasion or lymph node involvement, or patients ≥ 12months after previous liver resection, can result in 5-year survival rates of 59%. In contrast to HCC in cirrhosis, tumor size is not a predictor of post-transplant survival in NC-HCC., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The Aim of the Study: was to analyze indications and results of the first one thousand liver transplantations at Chair and Clinic of General, Transplantation and Liver Surgery, Medical University of Warsaw., Material and Methods: Data from 1000 transplantations (944 patients) performed at Chair and Clinic of General, Transplantation and Liver Surgery between 1994 and 2011 were analyzed retrospectively. These included 943 first transplantations and 55 retransplantations and 2 re-retransplantations. Frequency of particular indications for first transplantation and retransplantations was established. Perioperative mortality was defined as death within 30 days after the transplantation. Kaplan-Meier survival analysis was used to estimate 5-year patient and graft survival., Results: The most common indications for first transplantation included: liver failure caused by hepatitis C infection (27.8%) and hepatitis B infection (18%) and alcoholic liver disease (17.7%). Early (< 6 months) and late (> 6 months) retransplantations were dominated by hepatic artery thrombosis (54.3%) and recurrence of the underlying disease (45%). Perioperative mortality rate was 8.9% for first transplantations and 34.5% for retransplantations. Five-year patient and graft survival rate was 74.3% and 71%, respectively, after first transplantations and 54.7% and 52.9%, respectively, after retransplantations., Conclusions: Development of liver transplantation program provided more than 1000 transplantations and excellent long-term results. Liver failure caused by hepatitis C and B infections remains the most common cause of liver transplantation and structure of other indications is consistent with European data.

Unlabelled: The aim of the study was the analysis of the results of liver resection in the treatment of patients with hepatocellular carcinoma, taking into consideration the selected factors based on the department's material., Material and Methods: Data of 122 patients subject to liver resection due to hepatocellular carcinoma at the Department of General, Transplantation and Liver Surgery, Medical University of Warsaw, were subject to retrospective analysis. The influence of selected factors on the long-term treatment results was determined, and the patient survival depending on the tumor stage as per the TNM scale was compared. The statistical significance threshold was set at p = 0.05., Results: 1- and 3-year overall survival and recurrence-free survival in the whole patient group was 82.1% and 56.3%, and 57.7% and 20.1%, respectively. The perioperative mortality rate was 1.6%. The neoplasm advancement exceeding the first stage on the TNM scale was associated with lower values of overall survival (p = 0.001, HR = 3.7) and recurrence-free survival (p = 0.00008, HR = 3.8). Elevation of AFP was the only independent prognostic factor for overall survival (p = 0.04, HR = 1.04 at alpha-fetoprotein levels > 1000 ng/ml), while the presence of neoplastic emboli in small blood vessels was an independent risk factor for HCC recurrence (p = 0.02, HR = 2.24)., Conclusions: The alpha-fetoprotein levels and presence in the histopathological examination of neoplastic emboli in small blood vessels are independent prognostic factors for outcome of patients operated for hepatocellular carcinoma. The diagnosis of neoplasm at stage 1 as per TNM significantly improves long-term results of resective treatment.

Type 1 iodothyronine deiodinase (D1) is a crucial enzyme which converts the prohormone thyroxine (T4) into active tri-iodothyronine (T3). There has been strong evidence that the metabolism of thyroid hormones is disturbed in some neoplastic tissues such as thyroid, renal, and breast cancer. However, there are few available data about D1 enzyme activity in benign tumors such as hemangioma, which is the most common primary liver tumor. Hence this study aimed to determine the enzymatic activity of D1 in hemangiomas in relation to healthy liver tissue. Seven tumors and healthy control tissues were obtained from patients who had liver resection due to hemangioma. The activity was assessed by measurement of radioactive iodine released by deiodination catalyzed by D1. It was found that D1 activity was significantly lower in the hemangiomas than in the healthy surrounding tissue (p = 0.0017). The results indicated that thyroid hormones play important roles not only in the regulation of cell metabolism, but also in cell growth, division, and apoptosis. The active form T3 acts through its nuclear receptors and influences the up- and down-regulation of target genes. Healthy liver tissue expresses a high level of D1, but disturbed D1 activity may result in changes in the local concentration of T3 which may impair gene transcription. These finding demonstrate a low enzymatic activity of D1 in liver hemangioma and suggest an as yet unknown role of thyroid hormones in this type of benign liver tumor.

Introduction: Orthotopic liver transplantation (OLT) is a well-established treatment for cirrhotic patients with hepatocellular carcinoma (HCC) who meet the Milan criteria. The aim of this study was to identify predictors of survival among 65 patients with HCC in cirrhotic livers who underwent liver transplantation (OLT)., Methods: From January 2001 to December 2008, we performed 655 OLT in 615 patients. HCC was diagnosed in 58 patients before OLT and in 65 by histological examination of the explanted livers; 74% of the patients met Milan criteria by histological examination., Results: The median follow-up was 27 months (range = 1-96). We analyzed patient age and gender, etiology of liver disease, Child score at transplantation, rejection episodes, tumor number/size, vascular invasion, and differentiation grade. There was no significant difference in survival among patients grouped according to the Model for End-stage Liver Disease staging system for HCC. The 5-year survival of patients with low differentiated (G3) HCC was significantly worse than that of those with moderately differentiated (G2) or well-differentiated (G1) HCC: 50%, 81%, and 86% respectively, (P < .01). Patients with microvascular invasion displayed a worse 5-year survival than those without vascular invasion (42% vs 80%; P < .01)., Conclusions: The analysis indicated that the histological grade of the tumors and evidences of microscopic vascular invasion were the most useful predictive factors for overall survival among patients with cirrhosis after liver transplantation for HCC.

Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide affecting preferentially patients with liver cirrhosis. The studies were performed on tissues obtained during surgery from 50 patients with HCC, 40 with liver cirrhosis and 40 control livers. It was found that arginase activity in HCC was nearly 5- and 15-fold lower than in cirrhotic and normal livers, respectively. Isoenzymes AI (so-called liver-type arginase) and AII (extrahepatic arginase) were identified by Western blotting in all studied tissues, however the amount of AI, as well as the expression of AI-mRNA were lower in HCC, in comparison with normal liver, and those of AII were significantly higher. Since HCC is arginine-dependent, and arginine is essential for cells growth, the decrease of AI may preserve this amino acid within tumor cells. Concurrently, the rise of AII can increase the level of polyamines, compounds crucial for cells proliferation. Thus, both arginase isoenzymes seem to participate in liver cancerogenesis.