Shadows Behind Using Simple Risk Models in Selection of Hepatocellular Carcinoma Patients for Liver Transplantation.

OBJECTIVE: To assess the potential influence of replacing Milan criteria with simple risk scores on outcomes of hepatocellular carcinoma (HCC) patients undergoing liver transplantation. SUMMARY BACKGROUND DATA: Several risk scores combining morphological and biological features were recently proposed for precise selection of HCC patients for transplantation. METHODS: This retrospective study included 282 HCC liver transplant recipients. Recurrence-free survival (RFS), the primary outcome measure, was evaluated according to Metroticket 2.0 model and French AFP model with Milan criteria serving as benchmark. RESULTS: Patients were well stratified with respect to RFS by Milan criteria, Metroticket 2.0 criteria, and AFP model cut-off ≤2 points (all P < 0.001) with c-statistics of 0.680, 0.695, and 0.681, respectively. Neither Metroticket 2.0 criteria (0.014, Z = 0.023; P = 0.509) nor AFP model (-0.014, Z = -0.021; P = 0.492) provided significant net reclassification improvement. Both patients within the Metroticket 2.0 criteria and AFP model ≤2 points exhibited heterogeneous recurrence risk, dependent upon alpha-fetoprotein (P = 0.026) and tumor number (P = 0.024), respectively. RFS of patients beyond Milan but within Metroticket 2.0 criteria (75.3%) or with AFP model ≤2 points (74.1%) was inferior to that observed for patients within Milan criteria (87.1%; P = 0.067 and P = 0.045, respectively). Corresponding microvascular invasion rates were 37.2% and 50.0%, compared with 13.6% in patients within Milan criteria (both P < 0.001). Moreover, Milan-out status was associated with significantly higher recurrence risk in subgroups within Metroticket 2.0 criteria (P = 0.021) or AFP model ≤2 points (P = 0.014). CONCLUSION: Utilization of simple risk scores for liver transplant eligibility assessment leads to selection of patients at higher risk of posttransplant HCC recurrence.

The Warsaw Proposal for the Use of Extended Selection Criteria in Liver Transplantation for Hepatocellular Cancer.

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.

Challenging the principle of utility as a barrier for wider use of liver transplantation for hepatocellular cancer.

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.

Cervical human papillomavirus infection in the early postoperative period after liver transplantation: Prevalence, risk factors, and concordance with anal infections.

Solid organ transplant recipients are at increased risk of developing several human papillomavirus (HPV)-related malignancies, including cervical and anal cancers. The purpose of this prospective study was to assess the initial prevalence and risk factors for high-risk HPV (HR-HPV) cervical infections in liver transplant recipients, as well as their concordance with anal infections. A total of 50 female patients were enrolled in the Department of General, Transplant and Liver Surgery at the Medical University of Warsaw (center with >1600 liver transplantations). The initial prevalence of cervical HR-HPV infection was 10.0% (5/50). The only significant risk factor for cervical HR-HPV infection was ≥4 lifetime sexual partners (P=.037). Statistical tendencies toward higher prevalence of cervical HR-HPV infections were found for patients with hepatitis B virus (HBV, P=.082) and with model for end-stage liver disease (MELD) score ≤8 (P=.064). Cervical cytology was abnormal in 10 patients, including three with HR-HPV. Out of 12 patients with available data on anal HR-HPV, one had concordant HPV 16 infection. In conclusion, the initial prevalence of high-risk HPV infection is relatively low, except for patients with ≥4 previous sexual partners and potentially in those with HBV and/or low MELD score.

Effects of Donor Age and Cold Ischemia on Liver Transplantation Outcomes According to the Severity of Recipient Status.

UNLABELLED: BackgroundProlonged cold ischemic time (CIT) and increased donor age are well-known factors negatively influencing outcomes after liver transplantation (LT). AIMS: The aim of this study was to evaluate whether the magnitude of their negative effects is related to recipient model for end-stage liver disease (MELD) score. METHODS: This retrospective study was based on a cohort of 1402 LTs, divided into those performed in low-MELD (<10), moderate-MELD (10­20), and high-MELD (>20) recipients. RESULTS: While neither donor age (p = 0.775) nor CIT (p = 0.561) was a significant risk factor for worse 5-year graft survival in low-MELD recipients, both were found to yield independent effects (p = 0.003 and p = 0.012, respectively) in moderate-MELD recipients, and only CIT (p = 0.004) in high-MELD recipients. However, increased donor age only triggered the negative effect of CIT in moderate-MELD recipients, which was limited to grafts recovered from donors aged ≥46 years (p = 0.019). Notably, utilization of grafts from donors aged ≥46 years with CIT ≥9 h in moderate-MELD recipients (p = 0.003) and those with CIT ≥9 h irrespective of donor age in high-MELD recipients (p = 0.031) was associated with particularly compromised outcomes. CONCLUSIONS: In conclusion, the negative effects of prolonged CIT seem to be limited to patients with moderate MELD receiving organs procured from older donors and to high-MELD recipients, irrespective of donor age. Varying effects of donor age and CIT according to recipient MELD score should be considered during the allocation process in order to avoid high-risk matches.

Maternal liver-related symptoms during pregnancy in primary sclerosing cholangitis.

Background & Aims: Although worsening liver-related symptoms during pregnancy can occur in primary sclerosing cholangitis (PSC), there are insufficient data to effectively counsel patients on their pre-conception risk and no clear recommendations on monitoring and management during pregnancy. We aimed to describe maternal liver-related symptoms in pregnancy, both before and after PSC diagnosis, and explore factors associated with worsening symptoms and liver-related outcomes. Methods: We conducted a multicentre retrospective observational study of females with PSC and known pregnancy with live birth, via the International PSC Study Group. We included 450 patients from 12 European centres. Data included clinical variables, liver-related symptoms (pruritus and/or cholangitis) during pregnancy, and liver biochemistry. A composite primary endpoint of transplant-free survival from time of PSC diagnosis was used. Results: There were 266 pregnancies in 178 patients following PSC diagnosis. Worsening liver-related symptoms were reported in 66/228 (28.9%) pregnancies; they had a reduced transplant-free survival (p = 0.03), which retained significance on multivariate analysis (hazard ratio 3.02, 95% CI 1.24-7.35; p = 0.02).Abnormal biochemistry and/or liver-related symptoms (pruritus and/or cholangitis) were noted during pregnancy before PSC diagnosis in 21/167 (12.6%) patients. They had a reduced transplant-free survival from pregnancy (p = 0.01), which did not retain significance in a multivariable model (hazard ratio 1.10, 95% CI 0.43-2.85; p = 0.84). Conclusions: Liver-related symptoms are frequently encountered during pregnancies before the diagnosis of PSC, and pregnancy may expose the pre-clinical phase of PSC in some patients. Worsening liver-related symptoms were seen in a third of our cohort with known PSC during pregnancy; and this subgroup had a poorer prognosis, which may be related to more advanced liver disease at time of pregnancy and/or a more severe disease phenotype. Impact and implications: Patients with PSC can develop worsening of their liver-related symptoms during pregnancy; however, risk factors for this and the long-term implications are not known. We identified that there is a significant risk of these symptoms in pregnancy, both before and after PSC has been diagnosed, particularly in patients with elevated alkaline phosphatase. Furthermore, our findings suggest that worsening symptoms during pregnancy may be associated with adverse long-term clinical outcomes of liver transplantation and death in patients with known PSC. This may be related to the presence of more advanced liver disease at time of pregnancy. This information can be used to counsel patients with PSC before conception and identify patients who need close follow-up after delivery.

Outcome of pregnancy in patients with primary sclerosing cholangitis.

BACKGROUND: Data on the clinical course of primary sclerosing cholangitis (PSC) during pregnancy remain scarce. Herein, we assessed the maternal and fetal outcomes of pregnancy in this condition. METHODS: We reviewed 104 consecutive female outpatients with PSC using a structured questionnaire. The outcomes were assessed both before and after the diagnosis of PSC. RESULTS: In total, 62 patients (60%) reported 126 pregnancies. Of these, 25 patients reported 44 pregnancies occurring after the diagnosis of PSC. There were two (5%) pregnancies in progress, and among the completed pregnancies there were 34 (80%) live births, six (14%) miscarriages, one (2%) stillbirth, and one (2%) termination. The median neonatal APGAR score was 10, the median body weight was 3375 g and the median body length was 55 cm. In three pregnancies, there was a flare-up of inflammatory bowel disease. In 45 patients, 82 pregnancies occurred before PSC was diagnosed with comparable maternal and fetal outcomes. Out of 42 pregnancies following PSC diagnosis, in 29 UDCA was continued. There was no difference in the fetal outcomes between the UDCA and non-UDCA groups. CONCLUSIONS: Pregnancy in patients with PSC seems to be well tolerated, but should be closely monitored by an obstetrician and an experienced hepatologist.

Dehydroepiandrosterone sulfate indicates decreased sulfation capacity and impaired quality of life in patients with primary sclerosing cholangitis.

INTRODUCTION: Impaired elimination of toxic compounds via inadequate sulfation may contribute to the pathogenesis of primary sclerosing cholangitis (PSC). Dehydroepiandrosterone (DHEA), which is metabolized into its sulfated form (DHEA-S) in the liver, has been linked with health-related quality of life (HRQoL) in various conditions. OBJECTIVES: We aimed to assess the sulfation capacity of the liver in PSC using DHEA-S as a surrogate marker. PATIENTS AND METHODS: We assessed serum levels of DHEA-S in 233 patients with PSC and in 201 patients with other liver conditions serving as controls. We also evaluated the effect of low levels of DHEA-S on the course of PSC and HRQoL assessed using the 36-Item Short Form Health Survey (SF-36) and the PBC-40. RESULTS: The proportion of patients with low DHEA-S in the PSC group was 7-fold higher than in the control group (21% vs 3%; P <⁠0.001). Patients with decreased levels of DHEA-S were younger at the time of PSC diagnosis (median age, 23 vs 29 years; P = 0.007) and presented with lower HRQoL scores, particularly regarding the physical domains of the SF-36. Patients with low DHEA-S also complained of more severe fatigue (31 vs 23; P = 0.006) assessed with the PBC-40. CONCLUSIONS: Our findings support the role of impaired liver sulfation capacity in the development of PSC. Low levels of DHEA-S are associated with increased fatigue, a devastating symptom significantly affecting HRQoL. Thus, the effects of DHEA administration on chronic fatigue and other measures of HRQoL in patients with PSC warrant further attention.

Importance of Intraoperative Transfusions of Packed Red Blood Cells and Fresh Frozen Plasma in Liver Transplantation for Hepatocellular Cancer.

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.

Ischemia-reperfusion injury and the risk of hepatocellular carcinoma recurrence after deceased donor liver transplantation.

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.

Limitations of predicting microvascular invasion in patients with hepatocellular cancer prior to liver transplantation.

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) + 0.164xloge(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.

Effects of continuous use of probiotics before liver transplantation: A randomized, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: Although there is increasing evidence for the benefits of probiotics in patients with liver diseases, data on the benefits of pre-LT administration of probiotics are lacking. The aim of this study was to evaluate the effects of continuous administration of probiotics before liver transplantation (LT) on pre- and post-transplant patient outcomes. METHODS: In this randomized, double-blind, and placebo-controlled trial adult cirrhotic patients listed for LT received a 4-strain probiotic preparation or placebo daily from enrollment until LT. The primary outcome measures were postoperative mortality and infection rates. The secondary outcome measures were 5-day post-transplant aspartate and alanine aminotransferase activities, bilirubin concentration, and international normalized ratio; waiting-list mortality; pre-transplant Model for End-stage Liver Disease score and Child-Turcotte-Pugh class changes; and pre-transplant infections. RESULTS: A total of 55 patients were randomized. The 90-day postoperative mortality rates were 0% and 4.3% in the probiotic and placebo groups, respectively (p > 0.99). Patients receiving probiotics had significantly reduced 30-day (4.8% versus 34.8%, p = 0.02) and 90-day (4.8% versus 47.8%, p = 0.002) infection rates, lower post-LT bilirubin concentration (p = 0.02), and more rapid decrease of aspartate (p = 0.03) and alanine (p = 0.03) aminotransferase activities. Probiotics did not have significant effects on other secondary outcome measures. CONCLUSIONS: Although continuous administration of probiotics before LT does not appear to affect postoperative mortality, it effectively prevents postoperative infections and improves early biochemical parameters of allograft function. CLINICALTRIALS. GOV IDENTIFIER: NCT01735591.

Results of liver transplantation in patients with acute liver failure due to Amanita phalloides and paracetamol (acetaminophen) intoxication.

INTRODUCTION: Amanita phalloides and paracetamol intoxications are responsible for the majority of acute liver failures. AIM: To assess survival outcomes and to analyse risk factors affecting survival in the studied group. MATERIAL AND METHODS: Of 1369 liver transplantations performed in the Department of General, Transplant, and Liver Surgery, Medical University of Warsaw before December 2013, 20 (1.46%) patients with Amanita phalloides (n = 13, 0.95%) and paracetamol (n = 7, 0.51%) intoxication were selected for this retrospective study. Overall and graft survival at 5 years were set as primary outcome measures. RESULTS: Five-year overall survival after liver transplantation in the studied group was 53.57% and 53.85% in patients with paracetamol and Amanita phalloides poisoning, respectively (p = 0.816). Five-year graft survival was 26.79% for patients with paracetamol and 38.46% with Amanita phalloides intoxication (p = 0.737). Risk factors affecting patient survival were: pre-transplant bilirubin concentration (p = 0.023) and higher number of red blood cells (p = 0.013) and fresh frozen plasma (p = 0.004) transfused intraoperatively. Likewise, higher number of red blood cells (p = 0.012) and fresh frozen plasma (p = 0.007) transfused were risk factors affecting 5-year graft survival. Surprisingly, donor and recipient blood type incompatibility was neither the risk factor for 5-year overall survival (p = 0.939) nor the risk factor for 5-year graft survival (p = 0.189). CONCLUSIONS: In selected intoxicated patients urgent liver transplantation is the only successful modality of treatment. Risk factors affecting survival are in correspondence with the patient's pre-transplant status (bilirubin level in serum) and intraoperative status (number of red blood cells and fresh frozen plasma transfused).

Reoperations for Intraabdominal Bleeding Following Deceased Donor Liver Transplantation.

UNLABELLED: Intraabdominal hemorrhage remains one of the most frequent surgical complications after liver transplantation. The aim of the study was to evaluate risk factors for intraabdominal bleeding requiring reoperation and to assess the relevance of the reoperations with respect to short- and long-term outcomes following liver transplantation. MATERIAL AND METHODS: Data of 603 liver transplantations performed in the Department of General, Transplant and Liver Surgery in the period between January 2011 and September 2014 were analyzed retrospectively. Study end-points comprised: reoperation due to bleeding and death during the first 90 postoperative days and between 90 postoperative day and third post-transplant year. RESULTS: Reoperations for intraabdominal bleeding were performed after 45 out of 603 (7.5%) transplantations. Low pre-transplant hemoglobin was the only independent predictor of reoperation (p=0.002) with the cut-off of 11.3 g/dl. Postoperative 90-day mortality was significantly higher in patients undergoing reoperation as compared to the remaining patients (15.6% vs 5.6%, p=0.008). Post-transplant survival from 90 days to 3 years was non-significantly lower in patients after reoperation for bleeding (83.3%) as compared to the remaining patients (92.2%, p=0.096). Nevertheless, multivariable analyses did not reveal any significant negative impact of reoperations for bleeding on short-term mortality (p=0.589) and 3-year survival (p=0.079). CONCLUSIONS: Surgical interventions due to postoperative intraabdominal hemorrhage do not appear to affect short- and long-term outcomes following liver transplantation. Preoperative hemoglobin concentration over 11.3 g/dl is associated with decreased risk of this complication, yet the clinical relevance of this phenomenon is doubtful.