Impact of the presence of HLA 1-locus mismatch and the use of low-dose antithymocyte globulin in unrelated bone marrow transplantation.

HLA 1-locus-mismatched unrelated donors (1MMUD) have been used in allogeneic hematopoietic stem cell transplantation (allo-HCT) for patients who lack an HLA-matched donor. We retrospectively analyzed 3313 patients with acute leukemia or myelodysplastic syndrome who underwent bone marrow transplantation from an HLA allele-matched unrelated donor (MUD) or 1MMUD between 2009 and 2014. We compared the outcomes of MUD (n=2089) and 1MMUD with antithymocyte globulin (ATG) (1MM-ATG(+); n=109) with those of 1MMUD without ATG (1MM-ATG(-); n=1115). The median total dose of ATG (thymoglobulin) was 2.5 mg/kg (range 1.0-11.0 mg/kg) in the 1MM-ATG(+) group. The rates of grade III-IV acute GvHD, non-relapse mortality (NRM) and overall mortality were significantly lower in the MUD group than in the 1MM-ATG(-) group (hazard ratio (HR) 0.77, P=0.016; HR 0.74; P<0.001; and HR 0.87, P=0.020, respectively). Likewise, the rates of grade III-IV acute GVHD, NRM and overall mortality were significantly lower in the 1MM-ATG(+) group than in the 1MM-ATG(-) group (HR 0.42, P=0.035; HR 0.35, P<0.001; and HR 0.71, P=0.042, respectively). The outcome of allo-HCT from 1MM-ATG(-) was inferior to that of allo-HCT from MUD even in the recent cohort. However, the negative impact of 1MMUD disappeared with the use of low-dose ATG without increasing the risk of relapse.

Recurrent Hepatitis B and D Virus Infection in a Liver Transplant Recipient.

Hepatitis B virus (HBV) and hepatitis delta virus (HDV) co-infections progress rapidly and lead to cirrhosis. In Japan, the prevalence of HBV and HDV co-infected patients is low. Therefore, there are few reports of patients with HBV and HDV co-infection having undergone liver transplantation. Herein, we report a rare case of recurrence of HBV and HDV in a 41-year-old man who underwent living donor liver transplantation 4 years prior.

The first report of the thyroid function of haemophilic patients with HIV/HCV co-infection in Japan.

INTRODUCTION: A high incidence of thyroid dysfunction is reported in patients with HIV or HCV mono-infection. We have conducted a periodic medical examination including the thyroid function for haemophilic patients with HIV/HCV co-infection due to contaminated blood products. METHODS: We examined the thyroid function (as assessed by the FT3, FT4 and TSH levels) in 45 haemophilic patients, including thyroglobulin and auto-antibody, antithyroglobulin antibody, antithyroid peroxidase antibody and anti-TSH receptor antibody in 28 patients. RESULTS: All the patients were males (median age: 42 years; range: 29-66). The median values of thyroid function were FT3 3.36 pg mL(-1) , FT4 1.125 ng mL(-1) and TSH 1.65 µIU mL(-1) . Five patients (11.1%) had high TSH levels. In 28 patients in whom the presence of auto-antibodies was examined, the median age was 47 years of age. The median value of thyroglobulin was 16 ng mL(-1) and two patients showed high levels of thyroglobulin. The presence of anti-TSH receptor antibody of all the patients was negative, but one patient (3.5%) was positive of antithyroid peroxidase antibody and antithyroglobulin antibody. CONCLUSIONS: Since 0.68-3.6% of the general healthy population is reported to show hypothyroidism, our data showed that the proportion of hypothyroidism in haemophilic patients with HIV/HCV co-infection was more frequent than that of the normal population.

Early application of related SCT might improve clinical outcome in adult T-cell leukemia/lymphoma.

Allogeneic hematopoietic SCT (allo-HSCT) is a curative treatment for aggressive adult T-cell leukemia/lymphoma (ATLL). Considering the dismal prognosis associated with conventional chemotherapies, early application of allo-HSCT might be beneficial for patients with ATLL. However, no previous study has addressed the optimal timing of allo-HSCT from related donors. Hence, to evaluate the impact of timing of allo-HSCT for patients with ATLL, we retrospectively analyzed data from patients with ATLL who received an allo-HSCT from a related donor. The median age was 52 years. Patients were grouped according to the interval from diagnosis to allo-HSCT: early transplant group, <100 days, n=72; late transplant group, ⩾100 days, n=428. The corresponding constituents of disease status were not statistically different between the two groups (P=0.11). The probability of OS in the early transplant group was significantly higher than that in the late transplant group (4-year OS, 49.3% vs 31.2%). Multivariate analysis revealed that late allo-HSCT was an unfavorable prognostic factor for OS (hazard ratio, 1.46; 95% confidence interval (CI), 1.01-2.11; P=0.04). Despite the limitations of a retrospective study, it might be acceptable to consider early application of allo-HSCT for ATLL.

Impact of Donor and Recipient Single Nucleotide Polymorphisms in Living Liver Donor Transplantation for Hepatitis C.

INTRODUCTION: Recently, several studies have shown that specific single nucleotide polymorphisms (SNPs) affect liver fibrosis progression in patients with hepatitis C virus (HCV) infection. In this study, we examined the impact of donor and recipient SNPs on the progression of fibrosis after liver transplantation for HCV infection. METHODS: This cohort study enrolled 43 patients with HCV infection who underwent liver transplantation at our hospital. We evaluated 5 genotypes (rs4374383, rs2629751, rs9380516, rs8099917, and rs738409) that have been reported to be significant predictors of fibrosis in HCV infection using a Taqman assay. RESULTS: Liver fibrosis (stage ≥ F1, New Inuyama classification) was detected at 1 year after liver transplantation in 30 cases (70%). The rs2629751 non-AA-genotype was found to be significantly associated with fibrosis progression at 1 year after liver transplantation (AA:GG or GA = 46%:88%, P < .05). The primary outcome was stage ≥F2 (portoportal septa) or liver-related mortality in 22 patients. The time to stage ≥F2 fibrosis or liver-related mortality was significantly different only in terms of the donor rs2629751 genotype (AA:GG or GA = 5.5 ± 0.6 years:3.6 ± 0.7 years, P = .025). CONCLUSIONS: The rs2629751 genotype may be an important predictor of posttransplant outcome in HCV-infected patients. This result might be useful in donor selection for liver transplantation in HCV-infected patients and may guide therapeutic decisions regarding early antiviral treatment.

Hybrid procedure in living donor liver transplantation.

BACKGROUND: We have previously reported a hybrid procedure that uses a combination of laparoscopic mobilization of the liver and subsequent hepatectomy under direct vision in living donor liver transplantation (LDLT). We present the details of this hybrid procedure and the outcomes of the procedure. METHODS: Between January 1997 and August 2014, 204 LDLTs were performed at Nagasaki University Hospital. Among them, 67 recent donors underwent hybrid donor hepatectomy. Forty-one donors underwent left hemihepatectomy, 25 underwent right hemihepatectomy, and 1 underwent posterior sectionectomy. First, an 8-cm subxiphoid midline incision was made; laparoscopic mobilization of the liver was then achieved with a hand-assist through the midline incision under the pneumoperitoneum. Thereafter, the incision was extended up to 12 cm for the right lobe and posterior sector graft and 10 cm left lobe graft procurement. Under direct vision, parenchymal transection was performed by means of the liver-hanging maneuver. The hybrid procedure for LDLT recipients was indicated only for selected cases with atrophic liver cirrhosis without a history of upper abdominal surgery, significant retroperitoneal collateral vessels, or hypertrophic change of the liver (n = 29). For total hepatectomy and splenectomy, the midline incision was sufficiently extended. RESULTS: All of the hybrid donor hepatectomies were completed without an extra subcostal incision. No significant differences were observed in the blood loss or length of the operation compared with conventional open procedures. All of the donors have returned to their preoperative activity level, with fewer wound-related complaints compared with those treated with the use of the conventional open procedure. In recipients treated with the hybrid procedure, no clinically relevant drawbacks were observed compared with the recipients treated with a regular Mercedes-Benz-type incision. CONCLUSIONS: Our hybrid procedure was safely conducted with the same quality as the conventional open procedure in both LDLT donors and recipients.

E-cadherin expression in hepatocellular carcinoma treated with previous local treatment in patients undergoing living donor liver transplantation.

BACKGROUND: The aim of this study was to evaluate the influence of previous local treatment on the E-cadherin (E-cad) expression in cases of hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) within the Milan criteria. METHODS: Seventy-four of 204 patients with HCC underwent LDLT between 1997 and 2014. Previous local treatment for HCC was performed for 121 lesions in 47 patients (47/74, 63.5%). Histological and immunohistochemical E-cad expression analyses were conducted on the basis of the whole-liver histological examination technique. RESULTS: The interval to LDLT after the initial and last treatments was 24 months (2-206) and 10.5 months (1-58), respectively. Preoperative imaging showed necrosis in 92 (92/121, 76.0%) lesions caused by the effects of local treatment, whereas the histological examinations revealed viable HCC cells in 22 (22/92, 23.9%) lesions, demonstrating well or moderate differentiation without vascular invasion. Immunohistochemically, the expression of E-cad was maintained in 17 viable (17/22, 77.3%) lesions. There were no signs of malignant transformation or sarcomatous changes in the HCCs treated with previous therapy. The recipients who maintained an E-cad expression in the lesion with local treatment showed no recurrence or distant metastasis after LDLT. CONCLUSIONS: HCC cells remained in approximately 20% of the evaluated lesions, even those exhibiting necrosis on imaging of the explanted cirrhotic liver. However, the expression of E-cad was maintained in most of these lesions. Furthermore, there were no significant differences in the rate of recurrence after LDLT between the patients who did and those did not receive previous local treatment for HCC.

Impact of HLA allele mismatch on the clinical outcome in serologically matched related hematopoietic SCT.

In unrelated hematopoietic SCT (HSCT), HLA allele mismatch has been shown to have a significant role. To clarify the importance of HLA allele mismatch in the GVH direction in related HSCT, we retrospectively evaluated 2377 patients who received stem cells from an HLA serologically matched related donor in the GVH direction using the database of the Japan Society for Hematopoietic Cell Transplantation. The cumulative incidences of grade II-IV and grade III-IV acute GVHD in patients with an HLA allele-mismatched donor (n=133, 5.6%) were significantly higher than those in patients with an HLA allele-matched donor. Multivariate analyses showed that the presence of HLA allele mismatch was associated with increased risks of grade II-IV and grade III-IV acute GVHD. In particular, HLA-B mismatch and multiple allele mismatches were associated with an increased risk of acute GVHD. The presence of HLA allele mismatch was associated with an inferior OS owing to an increased risk of non-relapse mortality (NRM). In conclusion, the presence of HLA allele mismatch in the GVH direction in related HSCT was associated with increased risks of GVHD and NRM, which led to an inferior OS. HLA allele typing is recommended in related HSCT.

The efficacy of the ImmuKnow assay for evaluating the immune status in human immunodeficiency virus and hepatitis C virus-coinfected patients.

BACKGROUND: The survival of human immunodeficiency virus (HIV)-infected patients has significantly improved since the introduction of antiretroviral therapy (ART). However, the mortality due to hepatitis C virus (HCV)-related liver disease has not been reduced in HIV/HCV-coinfected patients, and HCV has recently become the most significant cause of death in HIV/HCV-coinfected patients. Liver transplantation might be one of the treatments of choice in such cases, but it is very difficult to evaluate the immune status of these patients due to ART, anti-HCV treatment, and HIV-related immunocompromised state. AIM: The aim of this study was to evaluate the immune status in HIV/HCV-coinfected patients using the Cylex ImmuKnow assay, which was designed to monitor the global immune status by measuring the adenosine triphosphate (ATP) levels produced by activated CD4+ T cells. METHODS: Twenty-eight HIV/HCV-coinfected patients were included in this study. We evaluated their immune activity using the ImmuKnow assay, and compared the data with those of HCV mono-infected patients indicated for liver transplantation as well as healthy controls. RESULTS: The ATP levels of HIV/HCV-coinfected patients were significantly higher than those of HCV mono-infected liver transplant recipients (P < .001), and were significantly lower than those of healthy controls (P = .001). CONCLUSION: The ImmuKnow assay was considered to be a useful tool to evaluate the immune status of HIV/HCV-coinfected patients.

Analysis of the hepatic functional reserve, portal hypertension, and prognosis of patients with human immunodeficiency virus/hepatitis C virus coinfection through contaminated blood products in Japan.

BACKGROUND: As the survival of human immunodeficiency virus (HIV)-infected individuals has improved due to the widespread use of antiretroviral therapy, the mortality rate due to hepatitis C virus (HCV)-related liver disease has increased in HIV/HCV-coinfected patients. AIM: The aims of this study were to establish the appropriate therapeutic strategy for HIV/HCV-coinfected patients by evaluating the liver function, including the hepatic functional reserve and portal hypertension, and to investigate the prognosis of HIV/HCV-coinfected patients in Japan. PATIENTS AND METHODS: In addition to regular liver function tests, the hepatic functional reserve of 41 patients with HIV/HCV coinfection was evaluated using the indocyanine green retention rate and liver galactosyl serum albumin-scintigraphy. The data for 146 patients with HIV/HCV coinfection through blood products were extracted from 4 major HIV centers in Japan. In addition to liver function tests, the platelet counts (PLT) were evaluated as a marker of portal hypertension. RESULTS: In spite of the relatively preserved general liver function test results, approximately 40% of the HIV/HCV-coinfected patients had an impaired hepatic functional reserve. In addition, while the albumin and bilirubin levels were normal, the PLT was <150,000/µL in 17 patients. Compared with HCV mono-infected patients with a PLT <150,000/µL, the survival of HIV/HCV-coinfected patients was shorter (HCV, 5 years, 97%; 10 years, 86% and HIV/HCV, 5 years, 87%; 10 years, 73%; P < .05). CONCLUSION: These results must be taken into account to establish an optimal therapeutic strategy, including the appropriate timing of liver transplantation in HIV/HCV-coinfected patients in Japan.

Impact of a donor source on adult Philadelphia chromosome-negative acute lymphoblastic leukemia: a retrospective analysis from the Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation.

BACKGROUND: We aimed to clarify the impact of the donor source of allogeneic stem cell transplantation (allo-SCT) on Philadelphia chromosome-negative acute lymphoblastic leukemia [Ph(-) ALL] with focus on cord blood (CB). PATIENTS AND METHODS: We retrospectively analyzed data of 1726 patients who underwent myeloablative allo-SCT for adult Ph(-) ALL. The sources of the allo-SCT were related donors (RD; N = 684), unrelated donors (URD; N = 809), and CB (N = 233). RESULTS: Overall survival (OS) in patients after CB allo-SCT in first complete remission (CR1) was comparable with that after RD or URD allo-SCT (RD: 65%, URD: 64% and CB: 57% at 4 years, P = 0.11). CB was not a significant risk factor for relapse or non-relapse mortality as well as for OS in multivariate analyses. Similarly, the donor source was not a significant risk factor for OS in subsequent CR or non-CR (RD: 47%, URD: 39% and CB: 48% in subsequent CR, P = 0.33; RD: 15%, URD: 21% and CB: 18% in non-CR, P = 0.20 at 4 years). CONCLUSION: Allo-SCT using CB led to OS similar to those of RD or URD in any disease status. To avoid missing the appropriate timing, CB is a favorable alternative source for adult Ph(-) ALL patients without a suitable RD or URD.

Unrelated cord blood transplantation vs related transplantation with HLA 1-antigen mismatch in the graft-versus-host direction.

Little information is available regarding whether an unrelated cord blood (UCB) unit or a related donor with a 1-antigen mismatch at the HLA-A, HLA-B or HLA-DR locus in the graft-versus-host direction (RD/1AG-MM-GVH) should be selected as an alternative donor for patients without an HLA-matched related/unrelated donor. Therefore, we conducted a retrospective study using national registry data on patients with leukemia or myelodysplastic syndrome who received transplantation using a single UCB (n=2288) unit or an RD/1AG-MM-GVH (n=525). We found that the survival rate in the UCB group was comparable to that in the RD/1AG-MM-GVH group, although the RD/1AG-MM-GVH group with an HLA-B mismatch showed significantly higher overall and non-relapse mortality. Neutrophil and platelet engraftment were significantly faster, whereas the incidence of acute or chronic graft-versus-host disease (GVHD) was significantly higher in the RD/1AG-MM-GVH group. The incidence of acute or chronic GVHD in the RD/1AG-MM-GVH group with in vivo T-cell depletion was comparable to that in the UCB group, which translated into a trend toward better overall survival, regardless of the presence of an HLA-B mismatch. In conclusion, UCB and RD/1AG-MM-GVH are comparable for use as an alternative donor, except for RD/1AG-MM-GVH involving an HLA-B mismatch.

Intraoperative portal venous pressure and long-term outcome after curative resection for hepatocellular carcinoma.

BACKGROUND: Outcomes of liver resection for hepatocellular carcinoma (HCC) have improved owing to better surgical techniques and patient selection. Portal hypertension may influence outcome but the preoperative definition and role of portal hypertension are far from clear. The aim of this study was to elucidate the influence of portal venous pressure (PVP) measured directly during surgery on outcomes of liver resection in patients with HCC. METHODS: Patients who had resection of HCC between 1997 and 2009, and who underwent direct measurement of PVP immediately after laparotomy were enrolled. These patients were divided into groups with high (at least 20 cmH(2)O) and low (less than 20 cmH(2)O) PVP. The influence of PVP on overall and recurrence-free survival was analysed and prognostic factors were identified. RESULTS: A total of 177 patients were enrolled, 129 in the low-PVP group and 48 in the high-PVP group. The 5-year overall survival rate (63·7 versus 31 per cent; P < 0·001) and recurrence-free survival rate (52·5 versus 12 per cent; P < 0·001) were significantly higher in patients with low PVP. In multivariable analysis, two or more tumours, tumour diameter at least 5 cm, high PVP, grade B liver damage and Hepatic Activity Index (HAI) grade 7 or more were significant predictors of poorer survival after liver resection. Two or more tumours, tumour diameter at least 5 cm and HAI grade 7 or more were significant predictors of poorer recurrence-free survival. CONCLUSION: High PVP was associated with poor long-term outcome after liver resection for HCC.

Standardized less invasive living donor hemihepatectomy using the hybrid method through a short upper midline incision.

BACKGROUND: Recently, applications of less invasive liver surgery in living donor hepatectomy (LDH) have been reported. The objective of this study was to evaluate the safety and efficacy of a hybrid method with a midline incision for LDH. METHODS: Hemihepatectomy using the hybrid method was performed in the fifteen most recent among 150 living donors who underwent surgery between 1997 and August 2011. Six donors underwent right hemihepatectomy and 9 underwent left hemihepatectomy. An 8-cm subxiphoid midline incision was created for hand assistance during liver mobilization and graft extraction. After sufficient mobilization of the liver, the hand-assist/extraction incision was extended to 12 cm for the right hemihepatectomy and 10 cm for a left hemihepatectomy. Encircling the hepatic veins and hilar dissection were performed under direct vision. Parenchymal transection was performed with the liver hanging maneuver. Bile duct division was performed after visualizing the planned transection point by encircling the bile duct using a radiopaque marker filament under real-time C-arm cholangiography. RESULTS: All procedures were completed without any extra subcostal incision. All grafts were safely extracted through the 10-12-cm upper midline incision without mechanical injury. No donors required an allogeneic transfusion; all of them have returned to their preoperative activity levels. CONCLUSION: LDH by the hybrid method with a short upper midline incision is a safe procedure.

Is liver-targeted FOXp3 staining beneficial after living-donor liver transplantation?

As treatments for acute cellular rejection (ACR) and recurrent hepatitis caused by hepatitis C virus (HCV) are dramatically different, making a precise diagnosis is considered to be essential in patients after liver transplantation. Therefore, we investigated whether immunohistochemical detection of FOXp3, a marker for regulatory T cells (CD4+ CD25+), could be used to differentiate between recurrent hepatitis C and ACR. From a group of 103 cases of living-donor liver transplantation (LDLT), 48 samples were taken via liver biopsy from 20 patients with HCV infection. An initial diagnosis was made based on hematoxylin and eosin staining, which was scored with the hepatitis activity index (HAI) grading, whereas ARC was scored with the rejection activity index (RAI). The FOXp3 immunohistochemical staining on serial specimens was retrospectively analyzed, scoring from 0 to III. The time after LDLT was a median of 270 (range: 14-2000) days, whereas the median number of biopsies per patient was 3 (range: 1-8). The HAI was significantly different between 0 vs. I, and II vs. III, in terms of the FOXp3 score. On the other hand, a significant difference in the RAI was only found between 0 vs. I. In conclusion, FOXp3 may represent a surrogate marker for recurrent HCV infection after LDLT.

Inhibition of CXCL10 release by monomeric C3bi and C4b.

Cellulose acetate (CA) beads are often used for leucocyte apheresis therapy against inflammatory bowel disease. In order to clarify the mechanism of the anti-inflammatory effects of CA, global analysis of the molecules generated in blood by the interaction with CA beads was performed in this study. An activated medium was collected from whole blood that had been preincubated with CA beads, and the effects of the CA-activated medium on leucocyte function were investigated. Fresh blood was stimulated with lipopolysaccharide (LPS) or interferon (IFN)-ß in the presence of the activated medium, and levels of chemokines and cytokines, including CXCL10 (IFN-inducible protein-10), and phosphorylated STAT1 (signal transducer and activator of transcription 1), which is known to be essential for CXCL10 production in leucocytes, were measured. IFN-ß- or LPS-induced CXCL10 production, expression of CXCL10 mRNA and phosphorylation of STAT1 were significantly reduced in the presence of the medium pretreated with CA beads compared with the control without the CA bead treatment. The factors inhibiting CXCL10 production were identified as the C3 and C4 fragments by mass spectrometry. The monomeric C3bi and C4b proteins were abundant in the medium pretreated with CA beads. Furthermore, purified C3bi and C4b were found to inhibit IFN-ß-induced CXCL10 production and STAT1 phosphorylation. Thus, STAT1-mediated CXCL10 production induced by stimulation with LPS or IFN was potently inhibited by monomeric C3bi and C4b generated by the interaction of blood with CA beads. These mechanisms mediated by monomeric C3bi and C4b may be involved in the anti-inflammatory effects of CA.