Post-hoc analysis of a randomized controlled trial on the impact of pre-transplant use of probiotics on outcomes after liver transplantation.

Perioperative use of probiotics serves as efficient prophylaxis against postoperative infections after liver transplantation, yet data on long-term effects of pre-transplant probiotic intake is lacking. The aim of this study was to assess the effects of pre-transplant probiotic administration on long-term results of liver transplantation. This was secondary analysis of a randomized trial. Patients were randomized to receive either 4-strain probiotic or placebo before liver transplantation. Five year graft survival was set as the primary end-point. Secondary end-points comprised serum bilirubin and C-reactive protein (CRP) concentration, international normalized ratio (INR), serum transaminases and gamma-glutamyl transferase (GGT) activity. Study group comprised 44 patients, of whom 21 received probiotics and 23 received placebo with 5-year graft survival of 81.0% and 87.0%, respectively (p = 0.591). Patients in the probiotic arm exhibited lower INR (p = 0.001) and CRP (p = 0.030) over the first 6 post-transplant months. In the absence of hepatitis B or C virus infection, pre-transplant administration of probiotics also reduced aspartate transaminase activity (p = 0.032). In the intervention arm, patients receiving probiotics for under and over 30 days had 5-year graft survival rates of 100% and 66.7%, respectively (p = 0.061). Duration of probiotic intake > 30 days was additionally associated with increased INR (p = 0.031), GGT (p = 0.032) and a tendency towards increased bilirubin (p = 0.074) over first 6 post-transplant months. Pre-transplant administration of probiotics has mild positive influence on 6-month allograft function, yet should not exceed 30 days due to potential negative effects on long-term outcomes. (ClinicalTrials.gov Identifier: NCT01735591).

Accuracy of Computed Tomography in the Assessment of Milan Criteria in Liver Transplantation for Hepatocellular Carcinoma.

BACKGROUND: Despite worldwide debate on optimal selection of patients with hepatocellular carcinoma (HCC) for liver transplantation, the Milan criteria remain the benchmark for comparisons. Moreover, morphologic tumor features are universally considered important in pretransplant patient evaluation. The aim of this study was to establish the diagnostic accuracy of multiphasic computed tomography (CT) in assessing HCC burden before liver transplantation with special reference to Milan criteria fulfillment. METHODS: This retrospective study was based on a data from 27 HCC patients after liver transplantation with available CT performed within 30 days pretransplant. CT results were compared with explant pathology with respect to Milan criteria fulfillment, tumor number, and diameter of the largest tumor. RESULTS: Out of 19 patients within the Milan criteria on CT, 3 fell beyond the criteria on explant pathology with a gross underestimation rate of 15.8%. Out of 8 patients beyond the Milan criteria on CT, 3 were within the criteria on explant pathology with a gross overestimation rate of 37.5%. Regarding tumor number, CT was accurate only in 14 patients (51.9%), while overestimation and underestimation occurred in 5 (18.5%) and 8 (29.6%) patients, respectively. Overestimation and underestimation of largest tumor size by at least 1 cm occurred in 4 (14.8%) and 7 (25.9%) patients, respectively. DISCUSSION: Multiphasic CT is associated with a remarkable risk of both under- and overestimation of HCC burden before transplantation. Transplant eligibility should not be solely based on CT results.

Profile of Gut Microbiota Associated With the Presence of Hepatocellular Cancer in Patients With Liver Cirrhosis.

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.

Outcomes of Patients With Poorly Differentiated Hepatocellular Carcinoma After Liver Transplantation.

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.

The relevance of intestinal dysbiosis in liver transplant candidates.

BACKGROUND: The gut microbial ecosystem plays an important role in the pathogenesis of liver diseases. However, the association of microbial community structure with the severity of liver dysfunction is not completely understood. METHODS: Fecal microflora was assessed in 40 patients with liver cirrhosis listed for primary liver transplantation (LT). Independent associations between fecal microbial counts and serum bilirubin, serum creatinine, international normalized ratio (INR), and the Model for End-stage Liver Disease (MELD) score were established in multiple linear regression models. RESULTS: Bifidobacterium (standardized regression coefficient [sß] = -0.549; P < 0.001), Enterococcus (sß = 0.369; P = 0.004), and yeast (sß = 0.315; P = 0.018) numbers were independently associated with serum bilirubin, while Escherichia coli counts (sß = 0.318; P = 0.046) correlated with INR, and Bifidobacterium counts (sß = 0.410; P = 0.009) with serum creatinine. Only Bifidobacterium (sß = -0.468; P = 0.003) and Enterococcus (sß = 0.331; P = 0.029) counts were independent predictors of the MELD score. Bifidobacterium/Enterococcus ratio, proposed as a measure of pre-LT gut dysbiosis, was significantly related to the MELD score following the adjustment for the absolute Bifidobacterium (sß = -0.333; P = 0.029) and Enterococcus (sß = -0.966; P = 0.003) numbers. This pre-transplant dysbiosis ratio (PTDR) was significantly correlated with Enterococcus (R = -0.897; P < 0.001) but not with Bifidobacterium (R = 0.098; P = 0.546) counts. Among the other components of gut microflora, only hydrogen peroxide (H2 O2 )-producing Lactobacillus strains significantly influenced Enterococcus counts (sß = 0.349; P = 0.028) and PTDR (sß = -0.318; P = 0.046). CONCLUSION: While the abundance of both Bifidobacterium and Enterococcus is related to liver dysfunction, the size of the Enterococcus population seems to be the most important determinant of pre-LT gut dysbiosis in cirrhotic patients. The H2 O2 -producing Lactobacillus strains potentially ameliorate this dysbiotic state.

Outcomes following liver transplantation for metastatic neuroendocrine tumors.

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.