High mortality associated with gram-negative bacterial bloodstream infection in liver transplant recipients undergoing immunosuppression reduction.

BACKGROUND: Immunosuppression is an important factor in the incidence of infections in transplant recipient. Few studies are available on the management of immunosuppression (IS) treatment in the liver transplant (LT) recipients complicated with infection. The aim of this study is to describe our experience in the management of IS treatment during bacterial bloodstream infection (BSI) in LT recipients and assess the effect of temporary IS withdrawal on 30 d mortality of recipients presenting with severe infection. AIM: To assess the effect of temporary IS withdrawal on 30 d mortality of LT recipients presenting with severe infection. METHODS: A retrospective study was conducted with patients diagnosed with BSI after LT in the Department of Liver Surgery, Renji Hospital from January 1, 2016 through December 31, 2017. All recipients diagnosed with BSI after LT were included. Univariate and multivariate Cox regression analysis of risk factors for 30 d mortality was conducted in the LT recipients with Gram-negative bacterial (GNB) infection. RESULTS: Seventy-four episodes of BSI were identified in 70 LT recipients, including 45 episodes of Gram-positive bacterial (GPB) infections in 42 patients and 29 episodes of GNB infections in 28 patients. Overall, IS reduction (at least 50% dose reduction or cessation of one or more immunosuppressive agent) was made in 28 (41.2%) cases, specifically, in 5 (11.9%) cases with GPB infections and 23 (82.1%) cases with GNB infections. The 180 d all-cause mortality rate was 18.5% (13/70). The mortality rate in GNB group (39.3%, 11/28) was significantly higher than that in GPB group (4.8%, 2/42) (P = 0.001). All the deaths in GNB group were attributed to worsening infection secondary to IS withdrawal, but the deaths in GPB group were all due to graft-versus-host disease. GNB group was associated with significantly higher incidence of intra-abdominal infection, IS reduction, and complete IS withdrawal than GPB group (P < 0.05). Cox regression showed that rejection (adjusted hazard ratio 7.021, P = 0.001) and complete IS withdrawal (adjusted hazard ratio 12.65, P = 0.019) were independent risk factors for 30 d mortality in patients with GNB infections after LT. CONCLUSION: IS reduction is more frequently associated with GNB infection than GPB infection in LT recipients. Complete IS withdrawal should be cautious due to increased risk of mortality in LT recipients complicated with BSI.

The Incidence and Risk Factors of Low Oxygenation After Orthotropic Liver Transplantation.

BACKGROUND This study was designed to observe incidence and risk factors of low oxygenation after orthotropic liver transplantation (OLT). MATERIAL AND METHODS We retrospectively evaluated all adult patients who underwent living-donor OLT between January 1, 2017 and December 31, 2017. Postoperative low oxygenation was defined as PaO2/FiO2 <300 mmHg within 24 hours after surgery. Early acute kidney injury (AKI) after OLT was also defined when AKI was happened with 24 hours after operative. RESULTS A total of 301 patients, aged 50.35±10.29 years were enrolled. Of these patients, 100 patients (33.2%) suffered postoperative low oxygenation (PaO2/FiO2=251.80±35.84). Compared with the normal oxygenation group, body mass index (BMI) (24.48±3.53 versus 23.1±3.27 kg/m², P=0.001), preoperative hemoglobin (115.79±29.27 versus 111.52±29.80 g/L, P=0.033), preoperative MELD (22.25±6.54 versus 20.24±5.74, P=0.008), and intraoperative urinary volume (1.25 [0.76, 1.89] versus 2.04 [1.49, 3.68] mL/kg/h, P=0.003) were higher in low oxygenation group. There were more cases of earlier AKIs that occurred after OLT in low oxygenation patients than that in normal group (47% versus 23.4%, P<0.001). Logistic analysis showed that the preoperative BMI (hazard ration [HR]=1.107, [1.010, 1.212], P=0.029) and early AKI after OLT (HR=2.115, [1.161, 3.855], P=0.014) were independent risk factors for postoperative low oxygenation. CONCLUSIONS The incidence of postoperative low oxygenation after liver transplantation in adults was 33.2%. BMI and early AKI after OLT were correlated with postoperative hypoxemia.

Expression of VEGFR-3 in intrahepatic cholangiocarcinoma correlates with unfavorable prognosis through lymphangiogenesis.

Background & aims: VEGFR-3 has been shown of great significance in lymph node metastasis and some malignancies, however, its expression in tumors and impact on outcome of intrahepatic cholangiocarcinoma (iCCA) remains unknown. The aim of this study was to assess the role of VEGFR-3 positive tumors for prognosis of iCCA and tumor-associated lymphangiogenesis. Methods: Clinicopathological features, prognostic factors and survival rate were analyzed to evaluate the influence of VEGFR-3 positive expression on prognosis of iCCA. In addition, tumor-associated lymphangiogenesis quantified as micro-lymphatic vessel density (MLVD) was assessed to explore the correlation between VEGFR-3 expression and lymph node metastasis for iCCA. Results: Patients with VEGFR-3 positive tumors had increased lymph node metastasis (p=0.025) and were more likely to suffer from tumor recurrence compared with VEGFR-3 negative tumors (p<0.001). VEGFR-3 expression in tumors was identified as an independent prognostic factor for both overall and recurrence-free survival in surgical resected patients with iCCA. In addition, higher MLVD was significantly associated with VEGFR-3 positive expression in tumors (p<0.001), which facilitate lymph node metastasis and significantly worse survival rates. Conclusions: Our study reveals that VEGFR-3 positive expression in tumors represents an independent prognostic factor for both overall and recurrence-free survival in hepatic resected patients with iCCA. VEGFR-3 positive tumors favor lymph node metastasis, tumor recurrence and worse outcomes through tumor-associated lymphangiogenesis.

Risk stratification system to predict recurrence of intrahepatic cholangiocarcinoma after hepatic resection.

BACKGROUND: Previous nomograms for intrahepatic cholangiocarcinoma (ICC) were conducted to predict overall survival, which could be influenced by various factors. Herein, we conducted our nomogram to predict recurrence of the tumor only after hepatic resection. METHODS: The nomogram was established with prognostic factors for the relapse-free survival (RFS) analyzed from our single center cohort and was evaluated by comparing with the American Joint Committee on Cancer (AJCC) staging system for the predictive accuracy. RESULTS: Seropositivity of hepatitis B surface antigen (hazard ratio [HR], 0.505; 95% confidence interval [CI], 0.279 to 0.914; P = 0.024), tumor size of larger than 5 cm (HR, 1.947; 95% CI, 1.177 to 3.219; P = 0.009), Child-Pugh score of B (HR, 3.067; 95% CI, 1.293 to 7.275; P = 0.011), and lymph node metastasis (HR, 2.790; 95% CI, 1.628 to 4.781; P < 0.001) were found to be independent prognostic factors that significantly affected RFS. The calibration curve for the prediction revealed excellent agreement between estimation by our stratification system and actual RFS. The concordance C index of the nomogram (0.71; 95% CI, 0.65 to 0.77) revealed to be significantly higher than the AJCC staging system (0.66; 95% CI, 0.60 to 0.72). In the validation cohort, our risk stratification system (C-index 0.65; 95% CI, 0.59 to 0.71) also revealed more precise prediction than the AJCC staging system (C-index, 0.57; 95% CI, 0.50 to 0.64). CONCLUSIONS: Our nomogram could more accurately predict recurrence of ICC after hepatic resection than the AJCC staging system.

Diagnosis and outcomes of collateral arterial formation after irreversible early hepatic artery thrombosis in pediatric liver recipients.

BACKGROUND: Early hepatic artery thrombosis (eHAT) has been recognized as an important cause of graft loss and mortality. However, the incidence, etiology and outcome are not clear, especially for children. The present study was to investigate the formation of collateral artery flow after irreversible eHAT and its impact on patient's prognosis. METHODS: We analyzed eHAT after liver transplantation in children from October 2006 to April 2015 in our center, illustrated the formation of collateral hepatic artery flow after irreversible eHAT and explored the diagnosis, complications, treatment and prognosis. The basic and follow-up ultrasonographic images were also compared. RESULTS: Of the 330 pediatric liver recipients, 22 (6.67%) developed eHAT within 1 month. Revascularization attempts including surgical thrombectomy, interventional radiology and conservational treatment (thrombolysis) were successful in 5 patients. Among the 17 patients who had irreversible eHAT, follow-up ultrasonography revealed that collateral artery flow was developed as early as 2 weeks after eHAT. Liver abscess and bile duct complication occurred secondary to eHAT in variable time. CONCLUSIONS: Collateral arterial formation is a compensatory adaptation to eHAT to supply blood to liver grafts. However, the severe bile duct damage secondary to eHAT is irreversible and retransplantation is unavoidable.

MicroRNA-499 Rs3746444 polymorphism and biliary atresia.

BACKGROUND: Single nucleotide polymorphisms within microRNAs are known to affect the risk in development and prognosis of many diseases. This study was designed to investigate whether polymorphism of microRNA-499 (miR-499, rs3746444 A>G) is associated with risk to biliary atresia (BA). METHODS: A hospital-based cases-control study was performed on a total of 507 Han Chinese (207 BA cases and 300 ethnically-matched healthy controls without any evidence of liver diseases) so as to analyze the association between miR-499 rs3746444 polymorphism and BA risk as well as liver function remission (LFR) after liver transplantation. RESULTS: A significant higher frequency of the rs3746444 G alleles was found in the BA cases than the control group (odd ratio, 1.55, 95% confidence intervals [CIs], 1.15-2.10). This polymorphism was also observed to correlate with some clinic-pathological features of BA cases such as liver inflammatory. Further research found both higher levels of IL-6 (P<0.05) and TNF-α (P<0.05) in removed liver as well as in serum. What is more, the miR-499 rs3746444 polymorphism significantly affected the status of LFR (hazard ratio, 1.37; 95% CI, 1.08-1.83). CONCLUSIONS: MiR-499 (rs3746444) gene polymorphisms may be genetic determinants for increased risk of BA and prolonged recovery of BA patients after liver transplantation in Han Chinese.

Down-Regulated NRSN2 Promotes Cell Proliferation and Survival Through PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Neurensin-2 (NRSN2) is a neuronal membrane protein; previous reports indicated that it might function as a tumor suppressor in hepatocellular carcinoma (HCC). However, its biological functions and associated mechanisms remain unknown. In the current study, we aimed to investigate the biological functions and possible mechanisms of neurensin-2. METHODS: The mRNA and protein level of NRSN2 in HCC has tissues and cell lines were detected by quantitative real-time PCR, immunohistochemistry staning and western blot. Overexpressing and silencing the level of NRSN2 in HCC cell lines were used to investigate the role of NRSN2 in HCC. CCK-8 assays, SA-ß gel staining, Annexin V/PI staining, quantitative real-time PCR and western blot were employed to explore the role and mechanisms of HCC. RESULTS: NRSN2 was more commonly down-regulated HCC tissues compared with adjacent tissues, and the expression pattern of NRSN2 was not only closely correlated with tumor size and TNM stage but also negatively correlated with patient prognosis. Both loss and gain function assays revealed that NRSN2 inhibits cancer cell proliferation and promotes cancer cell senescence and apoptosis. We further found that NRSN2 might regulate PI3K/AKT signaling and p53/p21 pathway to exert its role in HCC cell proliferation, senescence and apoptosis. CONCLUSION: Our study validates the suppressive role of NRSN2 in both clinicopathologic and biological aspects in HCC tumorigenesis.

A Potential Profibrogenic Role of Biliary Epithelium-Derived Cardiotrophin-1 in Pediatric Cholestatic Liver Disease.

As a cytokine of the interleukin-6 family, cardiotrophin-1 (CT-1) has been shown to be an important endogenous protector in liver injury. Our study aimed to investigate the role of CT-1 in liver fibrosis in pediatric cholestatic liver disease (PCLD). CT-1 mRNA and protein expression levels were upregulated in PCLD liver biopsy tissues compared with controls. Immunohistochemistry and confocal microscopy of liver sections showed that CT-1 was predominantly expressed by biliary epithelium cells. Serum CT-1 was elevated significantly in the children with PCLD compared with controls. Serum CT-1 levels exhibited a moderate positive correlation with the Scheuer stage of hepatic fibrosis and serum TB levels and a weak correlation with serum ALP levels. In vitro analysis indicated that LX-2 cells preconditioned with CT-1 exhibited significant increments in proliferation and accumulation of extracellular matrix components, while also positively regulating the STAT3 and p38MAPK pathways. In conclusion, biliary epithelium-derived CT-1 may exert a profibrogenic potential in PCLD.

Living-donor or deceased-donor liver transplantation for hepatic carcinoma: a case-matched comparison.

AIM: To compare the surgical outcomes between living-donor and deceased-donor liver transplantation in patients with hepatic carcinoma. METHODS: From January 2007 to December 2010, 257 patients with pathologically confirmed hepatic carcinoma met the eligibility criteria of the study. Forty patients who underwent living-donor liver transplantation (LDLT) constituted the LDLT group, and deceased-donor liver transplantation (DDLT) was performed in 217 patients. Patients in the LDLT group were randomly matched (1:2) to patients who underwent DDLT using a multivariate case-matched method, so 40 patients in the LDLT group and 80 patients in the DDLT group were enrolled into the study. We compared the two groups in terms of clinicopathological characteristics, postoperative complications, long-term cumulative survival and relapse-free survival outcomes. The modified Clavien-Dindo classification system of surgical complications was used to evaluate the severity of perioperative complications. Furthermore, we determined the difference in the overall biliary complication rates in the perioperative and follow-up periods between the LDLT and DDLT groups. RESULTS: The clinicopathological characteristics of the enrolled patients were comparable between the two groups. The duration of operation was significantly longer (553 min vs 445 min, P < 0.001) in the LDLT group than in the DDLT group. Estimated blood loss (1188 mL vs 1035 mL, P = 0.055) and the proportion of patients with intraoperative transfusion (60.0% vs 43.8%, P = 0.093) were slightly but not significantly greater in the LDLT group. In contrast to DDLT, LDLT was associated with a lower rate of perioperative grade II complications (45.0% vs 65.0%, P = 0.036) but a higher risk of overall biliary complications (27.5% vs 7.5%, P = 0.003). Nonetheless, 21 patients (52.5%) in the LDLT group and 46 patients (57.5%) in the DDLT group experienced perioperative complications, and overall perioperative complication rates were similar between the two groups (P = 0.603). No significant difference was observed in 5-year overall survival (74.1% vs 66.6%, P = 0.372) or relapse-free survival (72.9% vs 70.9%, P = 0.749) between the LDLT and DDLT groups. CONCLUSION: Although biliary complications were more common in the LDLT group, this group did not show any inferiority in long-term overall survival or relapse-free survival compared with DDLT.

Serum levels of preoperative α-fetoprotein and CA19-9 predict survival of hepatic carcinoma patients after liver transplantation.

OBJECTIVE: The aim of this study was to assess serum levels of presurgical α-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9) as prognostic markers in patients with hepatic carcinoma after liver transplantation (LT). METHODS: A total of 226 patients were recruited for the analysis of serum AFP and CA19-9 levels, on the basis of which the tumor marker type (TMT) was defined and evaluated for prognostic prediction. Overall survival (OS) and relapse-free survival (RFS) were analyzed using Kaplan-Meier curves, and univariate and multivariate Cox models. RESULTS: One-year and 5-year OS were 79.0 and 58.0%, respectively, whereas RFS were 70.3 and 62.2%, respectively, in this cohort of patients. There were six variables predicting both OS and RFS, including TMT, tumor size, number of tumor lesions, extrahepatic or vascular invasion, and histopathological grade. Among these, TMT, tumor size, and extrahepatic invasion were all independent predictors of OS and RFS among these patients. Further, on the basis of TMT, novel LT selection criteria for patients with hepatic carcinoma, which supplemented the Milan criteria, were adopted, because the patients within the Milan criteria (n=107) and those exceeding Milan but fulfilling the proposed criteria (n=30) had similar 5-year OS (77.8 vs. 79.3%, P=0.862) and RFS (85.5 vs. 75.1%, P=0.210) rates. CONCLUSION: The data from this study showed that serum levels of preoperative AFP and CA19-9 were able to predict survival of patients with hepatic carcinoma after LT. This study included novel criteria, adding serum AFP and CA19-9 levels to the selection criteria for LT eligibility of patients, in addition to the Milan criteria.

Liver transplantation for hepatocellular carcinoma exceeding the Milan criteria: a single-center experience.

PURPOSE: To establish a prognostic prediction system for patients with hepatocellular carcinoma (HCC) exceeding Milan criteria after liver transplantation (LT). METHODS: A total of 130 patients undergoing LT for HCC exceeding Milan criteria were enrolled into the study. Independent predictors for relapse-free survival (RFS) were adopted to establish a grading system to predict the risk of post-LT tumor recurrence. RESULTS: Multivariate Cox analysis revealed that tumor size >10 cm [vs. ≤ 5 cm: relative risk (RR) = 4.214, P < 0.001], preoperative alpha fetoprotein > 400 ng/ml (vs. ≤ 400 ng/ml: RR = 1.657, P < 0.001), extrahepatic invasion (RR = 2.407, P = 0.005) and vascular invasion (RR = 1.917, P = 0.013) were independent predictors for RFS. The risk index of each patient was defined as the sum of the RR obtained in the Cox analysis for RFS. The risk of tumor recurrence was classified into four grades: grade I-risk index equal to 0, grade II-risk index from 0 to 2, grade III-risk index from 2 to 6 and grade IV-risk index >6. RFS rates of patients with grade I-IV (n = 35, 46, 30 and 19) were 87.5, 57.8, 34.7 and 0 % in 1 year; and 74.4, 41.7, 14.4 and 0 % in 5 years. Both of overall survival (OS) and RFS correlated well with the risk index grade. Patients with grade I achieved comparable prognostic outcomes with the Milan group patients (n = 119) (5-year OS = 73.7 vs. 74.7 %, P = 0.748; 5-year RFS = 74.4 vs. 85.7 %, P = 0.148). CONCLUSIONS: The new grading system was proved to be a promising system in predicting the patient prognosis after LT for HCC exceeding Milan criteria.

Immune cell functional assay in monitoring of adult liver transplantation recipients with infection.

PURPOSE: To identify the levels of functional immunity measured by the ImmuKnow assay in Chinese liver transplantation recipients and its application in monitoring the risk of posttransplant infection. METHODS: Forty-five apparent healthy Chinese and 106 adult liver transplant (LT) recipients were under investigation. LTs were grouped in stable status or infection according to their clinical diagnosis. Whole blood samples were collected freshly and cultured within 6 hr, the CD4(+) T cells were selected, and their adenosine triphosphate (ATP) value was assayed the next day. Before stimulation, we also examined the percentage of T-helper (Th; CD3(+) CD4(+)) and T-suppress (Ts; CD3(+) CD8(+)) lymphocyte subpopulations and the ratio of Th/Ts. RESULTS: The average ImmuKnow assay in infectious LT recipients was 128 + or - 84 ng/mL, significantly lower (P<0.05) than that in stable LTs (305 + or - 149 ng/mL) or in normal adults (301+ or - 101 ng/mL). The ImmuKnow values in LTs had a good negative correlation to infection clinically (r = -0.6217, P<0.001). Infectious risk was high when the ImmuKnow value was less than 130 ng/mL (odds ratio=13, 95% confidence interval 6.0-29.4, P<0.01). The sensitivity of low ImmuKnow values in posttransplant infection was 85.2%, significantly higher than those of Th/Ts ratio and immunosuppressant trough levels (P<0.01); specificity was 76.3%, comparable with that of Th/Ts ratio (75.5%), but greatly higher than immunosuppressant trough levels (P<0.01). ImmuKnow ATP values had no correlation with Th/Ts ratio or immunosuppressant trough levels. CONCLUSION: ImmuKnow ATP levels are lower in LT recipients with infection, which provides a new tool in monitoring posttransplant infection, and an index of tailoring immunosuppression clinically.

[Prospective study of liver parenchyma volume in hepatectomy of primary liver cancer].

OBJECTIVE: To explore the secure resection margin (RM) of hepatectomy for primary liver cancer (PLC) with the coexistence of cirrhosis or hepatitis by studying the correlations of the resected liver parenchyma volume with postoperative liver function, complication and RM clinically. METHODS: The volume of tumor and the surrounding liver in resected liver specimen was measured and calculated in continuous 76 PLC patients prospectively, and the total liver parenchyma volume was measured and calculated using computed tomography (CT) images in former 40 patients. Under ideal circumstances, the surrounding liver volume, which would be resected theoretically, was calculated according to various sizes of tumors and RMs. The correlations of the resected liver volume or hepatic parenchyma-resected rate (HPRR) with postoperative liver function, complication and RM were analysed. RESULTS: The RM was (5 +/- 7) mm in 76 patients. The volume of the tumors and the surrounding liver in the specimens were (107 +/- 203) cm(3) and (153 +/- 120) cm(3), respectively. In 40 patients, the total nontumorous liver volume using CT images was (1079 +/- 179) cm(3), and HPRR was (14 +/- 9)%. There were statistically significant differences in HPRR (P < 0.05) between three groups with complication score 0, 1-2 and 3-6 points, the value of the first group were lower than that of the third group at the level P < 0.05. The significant factors affecting liver function and complication are HPRR, the size of operation, the time of hepatic portal occlusion and the resected liver volume (P < 0.05) apart from preoperative liver function. CONCLUSIONS: When hepatectomy was performed in PLC patients with preoperative liver function of Child A grade and the coexistence of cirrhosis or hepatitis, 30% HPRR was a lower limit for greatly increasing the chance of developing serious postoperative complications, while 20% HPRR was a safe upper limit for achieves quick postoperative recovery or developing only a few mild complications. When PLC patients without macroscopic tumor thrombi or macrosatellites undergo hepatectomy, 10 mm RM is enough to ensure sufficient liver function residue and achieve complete micrometastasis clearance in liver parenchyma surrounding the lesion if the diameter of a tumor is less than 10 cm and 6 mm RM is enough to ensure sufficient liver function residue and obtain 99% micrometastasis clearance if the diameter of a tumor is greater than 10 cm, while with macroscopic tumor thrombi or macrosatellites, 20 mm RM is enough to ensure sufficient liver function residue and achieve 99% micrometastasis clearance if the diameter of a tumor is less than 6 cm.