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.

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.

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.

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.

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.

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.

Two-step selection criteria for living donor liver transplantation in patients with hepatocellular carcinoma.

We have proposed risk factors for tumor recurrence, such as tumor nodule ≥ 5 cm and des-gamma-carboxy prothrombin ≥ 300 mAU/mL after living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC). The aim of this study was to clarify the risk factors for HCC recurrence and mortality within our criteria. We enrolled 152 adult recipients who had undergone LDLT for end-stage liver disease with HCC who met our criteria. The recurrence-free survival rates after LDLT were calculated. Risk factors for tumor recurrence were identified. On univariate analysis, factors affecting recurrence-free survival were pretransplant treatment for HCC, neutrophil-to-lumphocyte ratio (NLR) >4, alpha-fetoprotein ≥ 400 ng/mL, ≥ 5 nodules, and bilobar tumor distribution. Multivariate analysis identified that NLR >4 and ≥ 5 nodules were independent risk factors for tumor recurrence after LDLT (P = .003 and P = .002, respectively). Two-step selection criteria enable selection of patients who have high-risk of tumor recurrence.

Sarcopenia as a predictor of prognosis in patients following hepatectomy for hepatocellular carcinoma.

BACKGROUND: Sarcopenia was identified recently as a poor prognostic factor in patients with cancer. The present study investigated the effect of sarcopenia on short- and long-term outcomes following partial hepatectomy for hepatocellular carcinoma (HCC), and aimed to identify prognostic factors. METHODS: Data were collected retrospectively for all consecutive patients who underwent hepatectomy for HCC with curative intent between January 2004 and December 2009. Patients were assigned to one of two groups according to the presence or absence of sarcopenia, assessed by computed tomographic measurement of muscle mass at the level of the third lumbar vertebra. Clinicopathological, surgical outcome and long-term survival data were analysed. RESULTS: Sarcopenia was present in 75 (40·3 per cent) of 186 patients, and was significantly correlated with female sex, lower body mass index and liver dysfunction, as indicated by abnormal serum albumin levels and indocyanine green retention test at 15 min values. In patients with, and without sarcopenia, the 5-year overall survival rate was 71 and 83·7 per cent respectively, and the 5-year recurrence-free survival rate was 13 and 33·2 per cent respectively. Multivariable analysis revealed that reduced skeletal muscle mass was predictive of an unfavourable prognosis. CONCLUSION: Sarcopenia was predictive of worse overall survival even when adjusted for other known predictors in patients with HCC after partial hepatectomy.

Human early liver regeneration after hepatectomy in patients with hepatocellular carcinoma: special reference to age.

BACKGROUND AND AIMS: This study was conducted to clarify the effects of age on human liver regeneration. PATIENTS AND METHODS: Thirty major hepatectomies, equal to or more than two segmentectomies for hepatocellular carcinoma, were performed. Ages ranged from 37 to 85 years and five octogenarians were included. The early regenerative index was defined: (liver volume after 7 days after hepatectomy - estimated remnant liver volume before hepatectomy)/estimated remnant liver volume, using three-dimensional computed tomographic volumetry. Farnesoid X receptor and forkhead box m1 expression in the liver, which has been reported to age-related decrease of liver regeneration in animal model, were examined using real-time polymerase chain reaction. The patients were divided into two groups: low early regenerative index (n = 15), early regenerative index less than 55% and high early regenerative index (n = 15), early regenerative index equal to or more than 55%. RESULTS: The mean early regenerative index was 57%. Age (R (2) = 0.274, P = 0.003) and estimated blood loss (R (2) = 0.134, P = 0.0466) were inversely correlated with the early regenerative index, and the expression of farnesoid X receptor and forkhead box m1 was not. The incidence of post-hepatectomy liver failure in the low early regenerative index group was higher than that in the high early regenerative index group (P = 0.0421). CONCLUSIONS: Age and intraoperative blood loss are inversely correlated with early liver regeneration in humans. In elderly patients, massive blood loss should be avoided in view of liver regeneration.

Impact of human T cell leukemia virus type 1 in living donor liver transplantation.

Human T cell leukemia virus type 1 (HTLV-1) is an endemic retrovirus in southwestern Japan, which causes adult T cell leukemia (ATL) or HTLV-1 associated myelopathy in a minority of carriers. Here, we investigated the impact of HTLV-1 status in living donor liver transplantation (LDLT). Twenty-six of 329 (7.9%) HTLV-1 carriers underwent primary LDLT. One recipient negative for HTLV-1 before LDLT received a graft from an HTLV-1 positive donor. Eight donors were HTLV-1 positive. Twenty-seven recipients (13 male and 14 female; mean age 52.5 years) were reviewed retrospectively. ATL developed in four recipients who ultimately died. The intervals between LDLT and ATL development ranged from 181 to 1315 days. Of the four ATL recipients, two received grafts from HTLV-1 positive donors and two from negative donors. The 1-, 3- and 5-year HTLV-1 carrier survival rates were 91.3%, 78.3% and 66.3%, respectively. Fulminant hepatic failure as a pretransplant diagnosis and a pretransplant MELD score ≥ 15 was identified as risk factors for ATL development in this study (p = 0.001 and p = 0.041, respectively). In conclusion, LDLT can be performed for HTLV-1 positive recipients. However, when fulminant hepatic failure is diagnosed, LDLT should not be performed until further studies have revealed the mechanisms of ATL development.

Primary graft dysfunction after living donor liver transplantation is characterized by delayed functional hyperbilirubinemia.

The purpose of this study is to propose a new concept of primary graft dysfunction (PGD) after living donor liver transplantation (LDLT), characterized by delayed functional hyperbilirubinemia (DFH) and a high early graft mortality rate. A total of 210 adult-to-adult LDLT grafts without anatomical, immunological or hepatitis-related issues were included. All of the grafts with early mortality (n = 13) caused by PGD in LDLT had maximum total bilirubin levels >20 mg/dL after postoperative day 7 (p < 0.001). No other factors, including prothrombin time, ammonia level or ascites output after surgery were associated with early mortality. Thus, DFH of >20 mg/dL for >seven consecutive days occurring after postoperative day 7 (DFH-20) was used to characterize PGD. DFH-20 showed high sensitivity (100%) and specificity (95.4%) for PGD with early mortality. Among the grafts with DFH-20 (n = 22), those with early mortality (n = 13) showed coagulopathy (PT-INR > 2), compared with those without mortality (p = 0.002). Pathological findings in the grafts with DFH-20 included hepatocyte ballooning and cholestasis, which were particularly prominent in the centrilobular zone. PGD after LDLT is associated with DFH-20 caused by graft, recipient and surgical factors, and increases the risk of early graft mortality.

The impact of IL28B genetic variants on recurrent hepatitis C in liver transplantation: significant lessons from a dual graft case.

IL28B genetic polymorphism is related to interferon-sensitivity in chronic hepatitis C, but the significance of grafts carrying different genotypes from recipients is still unclear in liver transplantation. A 51-year-old Japanese male carrying a minor genotype underwent dual liver transplantation for liver cirrhosis due to hepatitis C virus (HCV). The left lobe graft carried a major genotype, and the right a minor genotype. He achieved virological response during the course of pegylated-interferon and ribavirin therapy against recurrent hepatitis C for 2 years, but HCV relapsed immediately at the end of the therapy. Two years after antiviral therapy, liver biopsy was performed from each graft. The specimens showed A1F0 in the left lobe graft and A2F2 in the right. Moreover, quantitative polymerase chain reaction was performed using RNA extracted from each specimen to see there was no HCV RNA in the left lobe whereas there was in the right. This case provides clear evidence that IL28B genetic variants determine interferon sensitivity in recurrent hepatitis C following liver transplantation, which could result in new strategies for donor selection or for posttransplant antiviral therapy to HCV positive recipients.

End-stage liver cirrhosis with severe autoimmune hemolytic anemia, treated by blood type-incompatible living donor liver transplantation: a case report.

We present a case of successful living donor liver transplantation (LDLT) for liver cirrhosis caused by hepatitis B virus with severe autoimmune hemolytic anemia (AIHA) using an ABO-incompatible (ABOi) graft. The patient was a 47-year-old woman who had a history of ruptured esophageal varices, accumulation of intractable ascites, frequent hepatic encephalopathy and severe anemia, with a hemoglobin value of approximately 3 g/dL due to AIHA. We treated the patient by LDLT using an ABOi liver graft. The treatment strategy included anti-CD20 antibody, plasma exchange and transfusion before LDLT. The patient's anemia improved after surgery; she required only 2 units of irradiated red blood cell concentrates-leukocytes reduced. The patient was discharged from the hospital on postoperative day 35. Two years after surgery, the patient still shows normal hepatic and hematological findings. The immunomodulation protocol for ABOi LDLT was effective not only to avoid humoral reactions associated with ABOi LDLT, but also those associated with AIHA.