A change in the timing for starting systemic therapies for hepatocellular carcinoma: the comparison of sorafenib and lenvatinib as the first-line treatment.

Aim: The aim of this retrospective multicenter study was to evaluate the differences in the timing for starting systemic therapies as the first-line treatment for hepatocellular carcinoma (HCC). Methods: A total of 375 patients with HCC treated with sorafenib from May 2009 to March 2018 and 56 patients treated with lenvatinib from March 2018 to November 2018 at our affiliated hospitals were included in this study. Results: The median ages of the sorafenib and lenvatinib groups were 71.0 (interquartile range [IQR]: 64.0-77.0) and 73.5 (IQR: 68.0 -80.0) years old, and 300 (80.0%) and 42 (75.0%) patients were men, respectively. The Barcelona Clinic Liver Cancer stage was early, intermediate and advanced in 39 patients (10.4%), 133 patients (35.5%) and 203 patients (54.1%) in the sorafenib group and 1 patient (1.8%), 17 patients (30.4%) and 38 patients (67.9%) in the lenvatinib group, respectively. In the analysis of intermediate HCC, patients who satisfied the criteria of TACE failure/refractoriness (P=0.017), those with ALBI grade 1 (P=0.040), and those with a serum AFP level < 200 ng/ml (P=0.027) were found more frequently in the lenvatinib group than in the sorafenib group, with statistical significance. The objective response rate (ORR) of lenvatinib was 34.8% in the overall patients and 46.7% in the intermediate-stage HCC patients, which was significantly higher than sorafenib (P=0.001, P=0.017). Conclusions: The emergence of lenvatinib has encouraged physicians to start systemic chemotherapy earlier in intermediatestage HCC patients.

Impact of muscle volume loss on acute oral mucositis in patients undergoing concurrent chemoradiotherapy after oral cancer resection.

This study evaluated the association between skeletal muscle mass depletion and severe oral mucositis in patients undergoing concurrent chemoradiotherapy after oral cancer resection. Skeletal muscle mass was evaluated in 60 patients using the skeletal muscle index, which was based on skeletal muscle cross-sectional area (on computed tomography) at the level of the third lumbar vertebra. In accordance with the grading criteria of the Radiation Therapy Oncology Group, patients with a grade ≥3 were defined as having severe oral mucositis. Multivariate logistic regression analysis was used to evaluate independent risk factors for severe oral mucositis. Eleven patients (18.3%) were diagnosed with low skeletal muscle mass. Severe oral mucositis occurred in 17 (28.3%) patients, and the mean skeletal muscle index was 42.8 cm2/m2. A low skeletal muscle mass (hazard ratio 18.1; P=0.001) and a chemotherapy regimen consisting of 5-fluorouracil and cisplatin (versus cisplatin only) (hazard ratio 5.5; P=0.015) were independent risk factors for severe oral mucositis. Future prospective studies are warranted to identify effective pre- and perioperative exercises and nutrition programmes to increase low skeletal muscle mass and reduce the incidence of severe oral mucositis in patients undergoing concurrent chemoradiotherapy after oral cancer resection.

Right hepatic venous system variation in living donors: a three-dimensional CT analysis.

BACKGROUND: The right hepatic venous system consists of the right hepatic vein (RHV) and inferior RHVs (IRHVs). When the right posterior section is used as a graft for liver transplantation, understanding variations and relationships between the RHV and IRHVs is critical for graft venous return and hepatic vein reconstruction. This study aimed to evaluate variations in the hepatic veins and the relationships between them. METHODS: The medical records and CT images of patients who underwent hepatectomy as liver donors were assessed retrospectively. The relationship between the veins was evaluated by three-dimensional CT. RESULTS: The configuration of the posterior section was classified into one of eight types based on the RHV and IRHVs in 307 patients. Type 1a (103 of 307), type 1b (139 of 307) and type 2a (40 of 307) accounted for 91·9 per cent of the total. The diameter of the RHV extending towards the inferior vena cava had a significant inverse correlation with that of the IRHV (r2  = -0·615, P < 0·001). Type 1a, which had no IRHVs, had the RHV with the largest diameter; conversely, type 2a, which had a large IRHV, had the RHV with the smallest diameter. CONCLUSION: The hepatic venous system of the right posterior section was classified into eight types, with an inverse relationship between RHV and IRHV sizes. This information is useful for segment VII resection or when the right liver is used as a transplant graft.

ANTECEDENTES: El sistema venoso hepático derecho consiste en la vena hepática derecha (right hepatic vein, RHV) y las RHVs inferiores (IRHVs). Cuando se utiliza la sección posterior derecha hepática como injerto para el trasplante hepático, es fundamental conocer las variaciones e interrelaciones entre la RHV y las IRHVs para el retorno venoso del injerto y la reconstrucción de la vena hepática. El objetivo de este estudio fue determinar las variaciones en las venas hepáticas y sus interrelaciones. MÉTODOS: Se evaluaron retrospectivamente las historias clínicas y las imágenes de la tomografía computarizada de los pacientes que se sometieron a una hepatectomía como donantes vivos para trasplante hepático. La interrelación entre las venas se evaluó mediante imágenes de CT tridimensional. RESULTADOS: La configuración de la sección posterior clasificó a 307 pacientes en base a la RHV y a las IRHVs. Se clasificaron en 8 tipos, de los cuales el Tipo 1a (103/307), el Tipo 1b (139/307) y el Tipo 2a (40/307) representaron el 92% del total. El diámetro de la RHV que se extiende hacia la vena cava inferior presentó una correlación inversa significativa con la de las IRHV (r2: −0,632, P < 0,0001). El diámetro mayor de la RHV se observó en el Tipo 1a, que no presentaba IRHVs; por el contrario, el diámetro más pequeño se observó en el Tipo 2a que presentaba una IRHV grande. CONCLUSIÓN: El sistema venoso hepático de la sección posterior derecha se clasificó en 8 subtipos con una relación inversa entre los tamaños de la RHV y las IRHV. Esta información es útil cuando se practica una resección del segmento 7 o cuando se utiliza el hígado derecho como injerto para el trasplante.

Functional Analysis of Human Hepatocytes Isolated From Chimeric Mouse Liver.

Chimeric mice with humanized liver were first established by transplanting primary human hepatocytes (PHHs) isolated from a Japanese 27-year-old donor into complementary DNA-urokinase-type plasminogen activator/severe combined immunodeficiency mice. The PHHs from the Japanese donor increased more than 100-fold in the mouse liver, and human hepatocytes purified from the chimeric mouse liver (hcPHs) were successfully transplanted into second-passaged mice. These PHHs and hcPHs can produce human albumin and preserve many liver-specific enzyme genes, which are important for liver function. Interestingly, hepatitis B virus can be infected with these chimeric mice; hepatitis B viral DNA and hepatitis B surface antigen levels were detectable. In conclusion, hcPHs can be an ideal cell source for analysis of human hepatocytes.

Clinical Outcomes of Living Liver Transplantation According to the Presence of Sarcopenia as Defined by Skeletal Muscle Mass, Hand Grip, and Gait Speed.

BACKGROUND: Sarcopenia is an independent predictor of death after living-donor liver transplantation (LDLT). However, the ability of the Asian Working Group for Sarcopenia criteria for sarcopenia (defined as reduced skeletal muscle mass plus low muscle strength) to predict surgical outcomes in patients who have undergone LDLT has not been determined. METHODS: This study prospectively enrolled 366 patients who underwent LDLT at Kyushu University Hospital. Skeletal muscle area (determined by computed tomography), hand-grip strength, and gait speed were measured in 102 patients before LDLT. We investigated the relationship between sarcopenia and surgical outcomes after LDLT performed in three time periods. RESULTS: The number of patients with lower skeletal muscle area has increased to 52.9% in recent years. The incidence of sarcopenia according to the Asian Working Group for Sarcopenia criteria was 23.5% (24/102). Patients with sarcopenia (defined by skeletal muscle area and functional parameters) had significantly lower skeletal muscle area and weaker hand-grip strength than did those without sarcopenia. Compared with non-sarcopenic patients, patients with sarcopenia also had significantly worse liver function, greater estimated blood loss, greater incidence of postoperative complications of Clavien-Dindo grade IV or greater (including amount of ascites on postoperative day 14, total bilirubin on postoperative day 14, and postoperative sepsis), and longer postoperative hospital stay. Multiple logistic regression analysis revealed sarcopenia as a significant predictor of 6-month mortality. CONCLUSIONS: The combination of skeletal muscle mass and function can predict surgical outcomes in LDLT patients.

Evaluation of resectability after neoadjuvant chemotherapy for primary non-resectable colorectal liver metastases: A multicenter study.

BACKGROUND/AIM: The Kyushu Study Group of Clinical Cancer (KSCC) previously reported the safety and efficacy of neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab for H2/H3 liver metastases of colorectal cancer. The aim of the current study was to evaluate the resectability of these metastases before and after chemotherapy as determined by independent liver surgeons. METHODS: Between May 2008 and April 2010, 40 patients were registered in a multicenter phase 2 trial of neoadjuvant chemotherapy (KSCC 0802). In Study 1, 5 independent liver surgeons from five different KSCC centers evaluated the resectability of liver metastases of colorectal cancer based on imaging studies performed before and after chemotherapy. Each surgeon was blinded to the other surgeons' evaluations. In addition, no information about the patients' characteristics was provided. In Study 2, 3 surgeons evaluated the resectability of these lesions based on imaging studies with discussion with each other, with the surgeons being provided with information on the patients' characteristics. RESULTS: In Study 1, 13 patients (36.1%) were evaluated to be resectable at baseline, whereas 17 patients (47.2%) were evaluated to be resectable after chemotherapy. In Study 2, 4 patients (11.1%) were evaluated to be resectable at baseline, compared to 23 patients (63.9%) after chemotherapy. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab was confirmed to increase the resectability of non-resectable liver metastases of colorectal cancer according to the independent assessments of surgeons.

Functional assessment of the liver with gadolinium-ethoxybenzyl-diethylenetriamine penta-acetate-enhanced MRI in living-donor liver transplantation.

BACKGROUND: A precise estimation of the capacity of the remnant liver following partial liver resection is important. In this study, the regional function of the liver in patients undergoing living-donor liver transplantation was evaluated by gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (EOB)-enhanced MRI, with special reference to the congested region. METHODS: EOB-MRI analysis was performed before hepatectomy in donors, and 7 days after surgery in the donor and recipient. In the hepatocyte phase, from images obtained 15 min after Primovist® injection, the signal intensity in each liver segment was measured and divided by the signal intensity of the erector spinae muscle (liver to muscle ratio, LMR) for standardization. Inter-regional differences in LMRs were analysed in donors and recipients. RESULTS: Thirty-two living donors and 31 recipients undergoing living-donor liver transplantation were enrolled. In donors, the LMRs of the remnant left lobe were almost equivalent among the liver segments. In the remnant right lobe without the middle hepatic vein, the mean(s.d.) LMR for congested segments (S5 and S8) was significantly lower than that for non-congested segments (S6 and S7): 2·60(0·52) versus 3·64(0·56) respectively (P < 0·001). After surgery, values in the non-congested region were almost identical to those in the preoperative donor liver. LMR values in the left and right lobe graft were significantly lower than those in the corresponding segment before donor surgery (P < 0·001). CONCLUSION: The function of the congested region secondary to outflow obstruction in the remnant donor liver was approximately 70 per cent of that in the non-congested region. EOB-MRI is a promising tool to assess regional liver function, with good spatial resolution.

Impact of platelets and serotonin on liver regeneration after living donor hepatectomy.

BACKGROUND: Several animal models have revealed that platelet-derived serotonin initiates liver regeneration after hepatectomy. However, there are few reports regarding the effects of serotonin in the clinical setting. The aim of this study was to explore the impact of serotonin and platelets in the early phase after healthy living donor hepatectomy. STUDY DESIGN: Stored samples from 34 living donors who received left lobectomy with caudate lobectomy (LL+C) or right lobectomy (RL) were available in the study. Serum serotonin levels and platelet counts associated with liver regeneration such as whole liver volume and hepatic graft weight (GW) were retrospectively collected from the database and analyzed. RESULTS: The remnant liver volume rate of RL grafts was smaller than that of LL+C grafts (45.4% vs 64.7%; P < .001). The regeneration rate at 7 days after surgery did not differ between the 2 groups (123% vs 122%). The serotonin levels and platelet counts decreased after surgery until postoperative day 3, then increased thereafter. The platelet counts and serotonin levels of LL+C donors were significantly higher than those of RL donors. CONCLUSIONS: Our findings suggest that platelets and serotonin play a pivotal role in initiating liver regeneration in the remnant liver.

Triple therapy using direct-acting agents for recurrent hepatitis C after liver transplantation: a single-center experience.

BACKGROUND: Hepatitis C viral graft reinfection is almost a universal event after liver transplantation with consequent disease progression. METHODS: We applied triple therapy (n = 21) with the use of telaprevir (TVR; n = 12) or simeprevir (SVR; n = 9). RESULTS: TVR was given at the dose 1,500 mg daily (n = 11) with reduced dose of cyclosporine at 25% to 50%, and SVR was given at the dose 100 mg daily with unadjusted cyclosporine, followed by 12 weeks of dual therapy. The early viral response was achieved in 91.7% (n = 11), end of treatment response rate was 91.7% (n = 11), and sustained viral response rate was 83.3% (n = 10) in the TVR group, and respective rates were 88.9% (n = 8), 77.8% (n = 7), and 77.8% (n = 7) in the SVR group. Although granulocyte colony-stimulating factor was not given in the patients with triple therapy, blood transfusion was performed in 7 cases (58.3%) in the TVR group and 1 case (11.1%) in the SVR group. Interferon-mediated graft dysfunction was observed in 4 cases (33.3%) in the TVR group and 3 cases (33.3%) in the SVR group, respectively. The cumulative viral clearance rates in triple (n = 21) and dual (n = 105) therapy were 95.0% and 18.1% at 12 weeks, and 95.0% and 40.0%, respectively, at 24 weeks (P < .01). CONCLUSIONS: Although careful monitoring for possible adverse events is required during treatment, triple therapy with the use of direct-acting agents are very effective in treating hepatitis C after liver transplantation.

Thymoglobulin for steroid-resistant immune-mediated graft dysfunction during simeprevir-based antiviral treatment for post-transplantation hepatitis C: case report.

INTRODUCTION: Immune-mediated graft dysfunction (IGD), a recently established disease entity with unfavourable outcome, is an antigraft immune reaction during interferon-based antiviral treatment for hepatitis C virus (HCV) infection after liver transplantation (LT). We report a case having steroid-resistant acute cellular rejection (ACR) type IGD, which was successfully treated using thymoglobulin. CASE REPORT: A 56-year-old woman with recurrent HCV after LT was commenced on antiviral treatment including simeprevir, pegylated-interferon (IFN) 2a, and ribavirin. A negative serum HCV-RNA was confirmed after 4 weeks. After 12 weeks of therapy, severe liver dysfunction developed, despite a constantly negative HCV-RNA. Liver biopsy revealed portal and periportal inflammatory infiltrates including numerous eosinophils, lymphocytes, and bile duct damages, indicating ACR. IFN therapy was ceased, and she was treated with steroid pulse treatment, followed by high-level immunosuppression maintenance. However, ACR was irremediable. Thereafter she was treated with thymoglobulin (75 mg/d for 5 days). Her serum alanine aminotransaminase and total bilirubin levels decreased immediately, and her liver biopsy specimen showed no activity. During these periods of the treatment, the HCV-RNA became positive and the liver enzyme elevated, but other liver function tests still remained within normal range. CONCLUSION: Thymoglobulin could be the best choice in steroid-resistant IGD during antiviral treatment for post-transplantation recurrent hepatitis C.

Prognostic impact of des-γ-carboxyl prothrombin in living-donor liver transplantation for recurrent hepatocellular carcinoma.

BACKGROUND: Although the Milan criteria are widely accepted for liver transplantation (LT) in patients for hepatocellular carcinoma (HCC), they have not been fully evaluated for salvage LT in patients with recurrent HCC. We have previously reported outcomes of living-donor LT (LDLT) for HCC and identified 2 risk factors affecting recurrence-free survival (RFS): tumor size >5 cm and des-γ-carboxyl prothrombin (DCP) concentration >300 mAU/mL (Kyushu University criteria). This study was designed to clarify risk factors for tumor recurrence after LDLT in patients with recurrent HCC. METHODS: Outcomes in 114 patients who underwent LDLT for recurrent HCC were analyzed retrospectively. RFS rates after LDLT were calculated, and risk factors for tumor recurrence were identified. RESULTS: The 1-, 3-, and 5-year RFS rates after LDLT were 90.6%, 80.4%, and 78.8%, respectively. Univariate analysis showed that tumor recurrence was associated with alpha-fetoprotein concentration ≥ 300 ng/mL, DCP concentration ≥ 300 mAU/mL, tumor number ≥ 4, tumor size ≥ 5 cm, transarterial chemotherapy before LDLT, duration of last treatment of HCC to LDLT <3 months, bilobar distribution, exceeding Milan criteria, exceeding Kyushu University criteria, poor differentiation, and histologic vascular invasion. Multivariate analysis showed that DCP ≥ 300 mAU/mL (P = .03) and duration from last treatment to LDLT <3 months (P = .01) were independent predictors of RFS. CONCLUSIONS: DCP concentration and time between last treatment and LDLT are prognostic of RFS in patients undergoing LDLT for HCC.

Identification of a bona fide microRNA biomarker in serum exosomes that predicts hepatocellular carcinoma recurrence after liver transplantation.

BACKGROUND: Predictive biomarkers for the recurrence of hepatocellular carcinoma (HCC) have great benefit in the selection of treatment options, including liver transplantation (LT), for HCC. The purpose of this study was to identify specific microRNAs (miRs) in exosomes from the serum of patients with recurrent HCC and to validate these molecules as novel biomarkers for HCC recurrence. METHODS: We employed microarray-based expression profiling of miRs derived from exosomes in the serum of HCC patients to identify a biomarker that distinguishes between patients with and without HCC recurrence after LT. This was followed by the validation in a separate cohort of 59 HCC patients who underwent living related LT. The functions and potential gene targets of the recurrence-specific miRs were analysed using a database, clinical samples and HCC cell lines. RESULTS: We found that miR-718 showed significantly different expression in the serum exosomes of HCC cases with recurrence after LT compared with those without recurrence. Decreased expression of miR-718 was associated with HCC tumour aggressiveness in the validated cohort series. We identified HOXB8 as a potential target gene of miR-718, and its upregulation was associated with poor prognosis. CONCLUSION: Circulating miRs in serum exosomes have potential as novel biomarkers for predicting HCC recurrence.

Correlation between portal vein anatomy and bile duct variation in 407 living liver donors.

Our aim was to determine whether variant bile duct (BD) anatomy is associated with portal vein (PV) and/or hepatic artery (HA) anatomy. We examined the associations between BD anatomy and PV and/or HA anatomy in 407 living donor transplantation donors. We also examined whether the right posterior BD (RPBD) course was associated with the PV and/or HA anatomy. Variant PV, HA and BD anatomies were found in 11%, 25% and 25%, respectively, of 407 donors enrolled in this study. The presence of a variant BD was more frequently associated with a variant PV than with a normal PV (61% vs. 20%, p < 0.0001). By contrast, the presence of a variant HA was not associated with a variant BD. A supraportal RPBD was found in 357 donors (88%) and an infraportal RPBD was found in 50 donors (12%). An infraportal RPBD was significantly more common in donors with a variant PV than in donors with a normal PV (30% vs. 10%, p = 0.0004). Variant PV, but not variant HA, anatomies were frequently associated with variant BD anatomy. Additionally, an infraportal RPBD was more common in donors with a variant PV than in donors with a normal PV.

Detectability of hepatocellular carcinoma on gadoxetic acid-enhanced MRI at 3 T in patients with severe liver dysfunction: clinical impact of dual-source parallel radiofrequency excitation.

AIM: To clarify the detectability of hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced MRI at 3 T with dual-source parallel radiofrequency (RF) excitation. MATERIALS AND METHODS: Twelve patients with 26 HCCs who each underwent multidetector row CT (MDCT), gadoxetic acid-enhanced MRI with dual-source parallel RF excitation, and angiography-assisted CT prior to living related-liver transplantation. Three blinded readers independently reviewed the images obtained by each imaging technique for the presence of HCC on a segment-by-segment basis using a five-point confidence scale. The area under the receiver operating characteristic curve (Az), sensitivity, and specificity were compared among the three techniques. RESULTS: The Az values of gadoxetic acid-enhanced MRI were highest for all readers, although no significant difference in Az value among the three methods was obtained. No significant differences in sensitivity or specificity were observed among the three techniques for each reader. CONCLUSION: Gadoxetic acid-enhanced MRI at 3 T with dual-source parallel RF excitation has relatively high-level diagnostic potential for the detection of HCC in patients with severe liver dysfunction, which was equivalent to that of MDCT and angiography-assisted CT. Dual-source parallel RF excitation would have a clinical impact on 3 T MRI of the liver.

Effect of laparoscopic splenectomy on portal haemodynamics in patients with liver cirrhosis and portal hypertension.

BACKGROUND: The effect of splenomegaly in patients with liver cirrhosis and portal hypertension is not fully understood. This study was designed to determine the effect of laparoscopic splenectomy on portal haemodynamics in these patients. METHODS: Patients with liver cirrhosis and portal hypertension who underwent laparoscopic splenectomy in Kyushu University Hospital from January 2006 to March 2009 were evaluated retrospectively. Correlations between splenic size and portal haemodynamics, and changes in portal haemodynamics and in levels of the vasoactive agents endothelin (ET) 1 and nitric oxide metabolites (NOx) before and 7-10 days after laparoscopic splenectomy were analysed. RESULTS: Portal venous (PV) blood flow, PV cross-sectional area and PV congestion index correlated significantly with splenic size (P < 0·050). All three were significantly reduced following splenectomy in 59 patients. The hepatic venous pressure gradient, measured in 18 patients, decreased by 25 per cent after splenectomy (P < 0·001). Portal vascular resistance was also reduced, by 21 per cent (P = 0·009). The peripheral blood concentration of ET-1 decreased from 2·95 to 2·11 pg/ml (P < 0·001), and that of NOx tended to decrease (from 29·2 to 25·0 pg/ml; P = 0·068). In hepatic venous blood, the level of ET-1 decreased from 2·37 to 1·83 pg/ml (P = 0·006), whereas NOx concentration tended to increase (from 24·5 to 30·9 pg/ml; P = 0·067). CONCLUSION: In patients with liver cirrhosis and portal hypertension, splenectomy reduced portal venous pressure. A decrease in splanchnic blood flow, by eliminating splenic blood flow, and reduction in intrahepatic vascular resistance, by normalizing hepatic concentrations of ET-1 and NOx, may both have contributed.

rs8099917 and viral genotyping as indications for living donor liver transplantation for hepatitis C: a case report.

INTRODUCTION: Appropriate antiviral treatment is essential for living donor liver transplantation (LDLT) to be effective for treating hepatitis C. However, it has never been reported that pre-LDLT genetic analyses of both host and virus, with prediction of the outcome of post-LDLT antiviral treatment, indicated LDLT for a borderline case. CASE REPORT: We have reported the case of a 68-year-old woman with liver cirrhosis caused by genotype 1b hepatitis C, a history of ruptured esophageal varices, and adequately controlled minor ascites. Her liver function was classified as Child-Pugh grade B. The donor was a 42-year-old woman with an estimated left lobe graft volume (GV) of 33.8% based on the standard liver volume of the recipient. Molecular analyses used to confirm the indication of LDLT for this combination revealed the following: The rs8099917 genotype was T/T in the donor and recipient, the HCV core protein was double wild type, there were no mutations in the interferon sensitivity-determining region, and 8 mutations were found in the interferon/ribavirin resistance-determining region. LDLT was performed because very high sensitivity to interferon treatment was predicted. DISCUSSION: Six months after LDLT and uneventful post-LDLT courses, pegylated interferon-α2a and ribavirin were administered under immunosuppression with cyclosporine and mycophenolate mofetil. This regimen was continued for 48 weeks, resulting in a viral response at 10 weeks and a sustained viral response, as predicted. CONCLUSIONS: We have reported the usefulness of molecular analyses of host and viral factors for indicating LDLT to treat hepatitis C in a borderline case.

Chronic immune-mediated reaction syndrome as the cause of late graft mortality in living-donor liver transplantation for primary biliary cirrhosis.

INTRODUCTION: Few studies to date have investigated the causes of late graft mortality after living-donor liver transplantation (LDLT) for primary biliary cirrhosis (PBC). PATIENTS AND METHODS: Fifty-five LDLTs for PBC were retrospectively reviewed. Factors prognostic of graft survival after LDLT were investigated, and histologic findings in patients with late graft loss were assessed. RESULTS: The 1-, 5-, and 10-year cumulative graft survival rates were 85.1%, 82.5%, and 66.9%, respectively. Multivariate Cox regression analysis found that male donor and ≥ 4 HLA mismatches were independently associated with poor graft survival. Among the 13 grafts lost, 5 were lost >1 year after LDLT, including 1 each due to chronic rejection, veno-occlusive disease, and obliterative portal venopathy, and 2 to other causes. Pathologic reviews of the serial biopsy specimens and explanted grafts from these 5 patients, with graft rejections from "chronic immune-mediated reaction syndrome," showed reciprocal changes over time. No patient died of recurrent PBC. CONCLUSIONS: Male donor and ≥ 4 HLA mismatches were independent factors associated with poor graft survival. Late graft mortality after LDLT for PBC in some patients was due to chronic immune-mediated reaction syndrome, including chronic rejection, veno-occlusive disease, and obliterative portal venopathy, but not to recurrent PBC.

Interferon-lambda4 genetic polymorphism is associated with the therapy response for hepatitis C virus recurrence after a living donor liver transplant.

The standard therapy against hepatitis C virus (HCV) recurrence postliver transplantation includes interferon (IFN)α and ribavirin. IFNL4 ss469415590 polymorphism has been reported as a novel predictor of the response to IFN therapy for chronic HCV infection. We examined the impact of IFNL4 polymorphism on the responsiveness to IFN therapy after liver transplantation. Tissue specimens were collected from 80 HCV-infected recipients and 78 liver donors, and their IFNL4 ss469415590 genotype, hepatic IFNL4 and interferon-stimulated genes' mRNA expression levels were examined. The association of the polymorphism and expression levels in terms of the IFN therapy response to HCV recurrence was analysed. Most individuals who had rs8099917 risk alleles also had ss469415590 risk alleles (R(2) = 0.9). Sustained virological response (SVR) rates were higher in both liver graft recipients and transplants with ss469415590 TT/TT alleles than in those with the risk ΔG allele (P = 0.003 and P = 0.005, respectively). In recipients with ss469415590 TT/TT, IFNL4 TT mRNA levels showed no significant differences between livers of patients who responded to therapy and those who did not (P = 0.4). In recipients with the risk ΔG allele, IFNL4 ΔG mRNA expression levels were significantly lower in SVR patients than in non-SVR patients (P = 0.02). Hepatic interferon stimulable genes and IFNL4 mRNA expression were correlated. Our findings suggest that analysing the ss469415590 genotype and IFNL4 ΔG expression provides a novel prediction strategy for the possible response to IFN therapy after liver transplantation.

Decreased immunoglobulin G levels after living-donor liver transplantation is a risk factor for bacterial infection and sepsis.

BACKGROUND: Several studies have suggested an association between post-transplant immunoglobulin (Ig) levels and the development of infection in solid organ transplantation. We therefore conducted exploratory analyses of potential factors associated with bacterial infection/sepsis after living-donor liver transplantation (LDLT). METHODS: Blood samples from 177 recipients who received primary LDLT between September 1999 and November 2011 were available for study. Hypogammaglobulinemia was defined as having at least 1 IgG level <650 mg/dL within 7 days after LDLT. Risk factors for developing post-transplant bacterial infection and sepsis within 3 months after LDLT were analyzed. RESULTS: Fifty (28.2%) recipients experienced bacterial infection within 3 months of LDLT. Eighty-four (47.5%) recipients had hypogammaglobulinemia, although no recipients had hypogammaglobulinemia before LDLT. Hypogammaglobulinemia, undergoing hepaticojejunostomy, and portal pressure at closure >15 mmHg were independent risk factors for developing bacterial infection within 3 months of LDLT (P < 0.0001 P = 0.0008, and P = 0.011, respectively). The odds ratio (OR) and confidence interval (CI) for hypogammaglobulinemia were 4.79 and 2.27-10.7, respectively. Twenty-four (13.6%) recipients developed bacterial sepsis within 3 months. Hypogammaglobulinemia, operative time >14 h, model for end-stage liver disease score >15, and no mycophenolate mofetil use were independent risk factors for developing bacterial sepsis (P = 0.009, P = 0.001, P = 0.003, and P = 0.005, respectively). The OR and CI for hypogammaglobulinemia were 3.83 and 1.38-12.0, respectively. CONCLUSIONS: Hypogammaglobulinemia within 7 days of LDLT was a significant risk factor for post-transplant bacterial infection and sepsis.