Prognostic evaluation of mucin-5AC expression in intrahepatic cholangiocarcinoma, mass-forming type, following hepatectomy.

AIM: This study aimed to investigate the clinicopathological predictors of survival in patients with intrahepatic cholangiocarcinoma, mass-forming type (ICC-MF), following curative intent hepatectomy. METHODS: Clinical characteristics and outcomes were analyzed in a series of 42 patients who underwent curative hepatectomy for ICC-MF between February 1987 and December 2012. The relationship between immunohistochemical expression profiles of mucin (MUC) core proteins (MUC2, MUC5AC, and MUC6) and surgical outcomes was examined. RESULTS: The overall median follow-up period was 2.6 years (0.2-17.9). Bile duct reconstruction (p = 0.017), lymph node metastasis (p = 0.049), maximal mass diameter ≥5.0 cm (p = 0.002), and MUC5AC expression (p = 0.003) were identified as significant adverse predictors of overall survival by univariate analysis. Bile duct reconstruction (p = 0.048), maximal mass diameter ≥5.0 cm (p = 0.002), and MUC5AC expression (p = 0.005) were found to be independent predictors of poor prognosis by multivariate analysis. Maximal mass diameter ≥5.0 cm (p = 0.011) was found to be an independent predictor for the tumor recurrence. There was a strong correlation between MUC5AC expression and lymph node metastasis (p = 0.021). MUC6 expression was more frequent in patients with concurrent MUC5AC expression (p = 0.019). CONCLUSIONS: MUC5AC expression was significantly related to long-term prognosis and aggressive tumor development, and may be a useful prognostic marker.

Two patients treated with simeprevir plus pegylated-interferon and ribavirin triple therapy for recurrent hepatitis C after living donor liver transplantation: case report.

We previously reported our data on telaprevir (TVR) used in combination with pegylated-interferon and ribavirin (PEG-IFN/RBV) for the treatment of recurrent hepatitis C virus (HCV) genotype 1 infection after liver transplantation (LT). TVR substantially increases the blood levels of immunosuppressive agents such as cyclosporine and tacrolimus for drug-drug interactions. On the other hand, the effect of simeprevir (SMV) on the blood levels of these immunosuppressive agents is unclear. We report 2 patients who achieved viral responses with little effect on the blood levels of cyclosporine and tacrolimus using SMV plus PEG-IFN/RBV treatment. The first was a 71-year-old woman with HCV-related liver cirrhosis and hepatocellular carcinoma who failed to respond to PEG-IFN/RBV after living donor LT. She was treated with 40 mg/d of cyclosporine, and received SMV plus PEG-IFN/RBV treatment. The second was a 65-year-old man with HCV-related liver cirrhosis who failed to respond to PEG-IFN/RBV after living donor LT. He was treated with 3 mg/d of tacrolimus, and received SMV plus PEG-IFN/RBV treatment. Serum HCV RNA became undetectable using TaqMan polymerase chain reaction (PCR) test after 4 weeks of treatment in both patients, and no remarkable fluctuation in blood concentration was observed either in cyclosporine or tacrolimus during the 12 weeks of SMV treatment. Completion of 12-week SMV triple therapy was followed by PEG-IFNα2b plus RBV, and both patients achieved sustained virological response 12 weeks after the end of treatment. SMV plus PEG-IFNRBV treatment showed a remarkable viral response with little effect on blood levels of immunosuppressive agents for recurrent HCV genotype 1 infection after LT.

Clinical efficacy of simultaneous splenectomy in liver transplant recipients with hepatitis C virus.

BACKGROUND: Interferon (IFN) therapy is a well-established antiviral treatment for hepatitis C virus (HCV) - infected patients. However, susceptibility to thrombocytopenia is a major obstacle in its initiation or continuation, particularly in patients with HCV who underwent liver transplantation (LT). We previously showed that the coexistence of splenomegaly and thrombocytopenia could result in persistent thrombocytopenia after LT. Here we retrospectively evaluated the validity of this criterion for simultaneous splenectomy in recipients with HCV. PATIENTS AND METHODS: Subjects included 36 recipients with HCV who received LT between January 2006 and February 2012 at Hiroshima University. We analyzed the spleen volume, body surface area, platelet (PLT) count, and rate of completion or continuation with IFN therapy in these recipients. RESULT: Of these recipients, 30 did not require simultaneous splenectomy according to the criterion, and 24 actually did not receive simultaneous splenectomy. In this group, 21 (87.5%) started IFN therapy. Fifteen (71.4%) of these recipients completed or continued IFN therapy, whereas 13 (61.9%) achieved either a sustained virological response (SVR) or an end-of-treatment response. The PLT count increased to >100,000/mm(3) 1 month after LT in 16 (66.7%) recipients from this group. CONCLUSION: Our criterion detected the PLT count outcome after LT in recipients with HCV and achieved a better SVR result after IFN therapy.

Potential benefit of mixed lymphocyte reaction assay-based immune monitoring after living donor liver transplantation for recipients with autoimmune hepatitis.

BACKGROUND: Recipients with autoimmune hepatitis (AIH) have a higher incidence of both rejection and recurrence after liver transplantation (LT) when compared with cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). This is due to the lack of an immune monitoring system, making it difficult to control immunosuppressant agents. In this study, we examine the benefit of the carboxyfluorescein diacetate succinimidyl ester-mixed lymphocyte reaction (CFSE-MLR) monitoring system for evaluating the immune status in recipients with AIH and PBC/PCS after LT. METHOD: Recipients who underwent LT (9 AIH and 11 PBC/PSC) from 2002 to 2013 at Hiroshima University were enrolled in this study. The correlation between the result of CFSE-MLR and the outcome, bacteremia, rejection, and/or recurrence was examined. RESULT: The cumulative survival rates for 5 years after LT revealed preferable outcomes for both groups (AIH 85.7%, PBC/PCS 80%). None of the recipients in the AIH group developed bacteremia during 90 days after LT, whereas three recipients from the PBC/PCS group (27%) developed bacteremia. The recurrence rate (AIH 33%, PBC/PSC 27%) was the same as the reported data; however, there was a lower incidence of acute rejection rate in our institution (AIH 11%, PBC/PSC 27%). In the CFSE-MLR assay, the stimulation index of CD4(+) T cells in the anti-self reaction was increased in recurrent cases, whereas no elevation of anti-donor reaction was observed in either CD4(+) or CD8(+) T cells. CONCLUSION: Optimization of the immunosuppressant agents based on the CSFE-MLR assay after LT achieved a preferable outcome in recipients with both AIH and PBC/PCS. Therefore, CFSE-MLR assay might be a useful tool for predicting the recurrence of autoimmune liver diseases by monitoring anti-self reactivity of CD4(+) T cells.

Bile CXC motif chemokine 10 levels correlate with anti-donor cytotoxic T cell responses after liver transplantation.

BACKGROUND: CXC motif chemokine 10 (CXCL10), known as interferon-γ-induced protein 10, is an inflammatory cytokine secreted by various cells in response to interferon-γ. CXCR3, the receptor of CXCL10, is predominantly expressed on activated T, B, natural killer, and dendritic cells, as well as macrophages. CXCR3 promotes chemotaxis upon binding CXCL10. Serum CXCL10 levels have recently attracted attention as a post-transplantation biomarker for graft rejection. However, the correlation between the degree of T cell response to allostimulation and CXCL10 levels remains unclear. In this study, we investigated the serum and bile CXCL10 levels of patients who underwent living donor liver transplantation (LDLT) and compared them with the T cell responses to allostimulation. PATIENTS AND METHODS: Between February 2009 and August 2012, 41 patients underwent LDLT at Hiroshima University Hospital. Serum and bile CXCL10 levels were measured weekly for 4 weeks after surgery, while the T cell responses to allostimulation were evaluated using a mixed lymphocyte reaction with an intracellular carboxyfluorescein diacetate succinimidyl ester-labeling technique that we regularly use to monitor the immune response to anti-donor and anti-third-party stimulation after liver transplantation. The stimulation index (SI) and CD25 expression of the CD4+ and CD8+ T cell subsets in response to allostimulation were then analyzed using flow cytometry. RESULTS: Serum CXCL10 levels were significantly correlated with the SI values for CD8+ T cells in response to both types of allostimulation. Bile CXCL10 levels were significantly correlated with CD25 expression of CD8+ T cell subsets, especially in response to anti-donor stimulation. Patients with higher bile CXCL10 levels suffered from severe acute cellular rejection that was refractory to steroid pulse. CONCLUSION: Measurements of bile CXCL10 levels could predict anti-donor cytotoxic T cell responses in liver transplant recipients.

Risk factors for development of new-onset diabetes mellitus and progressive impairment of glucose metabolism after living-donor liver transplantation.

BACKGROUND: New-onset diabetes mellitus (NODM) has a negative impact on graft and patient survivals. Hepatitis C virus (HCV) infection, high body mass index, increased donor and recipient ages, and calcineurin inhibitor (CNI) type have been identified as risk factors for the development of NODM. We aimed to elucidate the risk factors for the development of NODM and those for progressive glucose intolerance in adult living-donor liver transplant (LDLT) recipients. METHODS: We collected data from 188 primary liver transplant recipients (age > 16 years) who underwent LDLT from June 1991 to December 2011 at Hiroshima University Hospital. Risk factors for NODM and progressive impairment of glucose metabolism in pre-transplantation diabetes mellitus (DM) recipients were examined. RESULTS: Pre-transplantation DM was diagnosed in 32 recipients (19.3%). The overall incidence of NODM was 6.0% (8/134 recipients). Multivariate analysis revealed that old recipient age (≥55 years) is a unique predictive risk factor for developing NODM. The incident of pre-transplantation DM was significantly higher in recipients with HCV infection than in those without HCV. A high pre-transplantation triglyceride level was an independent risk factor for progressive impairment of glucose tolerance among 32 LDLT recipients with pre-transplantation DM. All of the NODM patients were being treated with tacrolimus at the time of diagnosis. Switching the CNI from tacrolimus to cyclosporine allowed one-half of the patients (4/8) to withdraw from insulin-dependent therapy. NODM and post-transplantation glucose intolerance had no negative impact on patient and graft outcomes. CONCLUSIONS: Older age of the recipient (≥55 years) was a significant risk factor for NODM. Hypertriglyceridemia in the recipients with DM is an independent risk factor for post-transplantation progressive impairment of glucose metabolism. NODM had no negative impact on outcomes in the LDLT recipients.

Multiple hepatic vein reconstruction using an all-in-one sleeve patch graft technique in living donor liver transplantation: a case report.

Maintaining hepatic inflow and appropriate venous drainage is important for maximizing the capacity of the retrieved graft in liver transplantation. Here, we report a successful case of multiple hepatic vein (HV) reconstruction using an all-in-one sleeve patch graft of the autologous great saphenous vein to ensure adequate blood flow through the HV. A patient with hepatocellular carcinoma caused by hepatitis C virus-induced cirrhosis underwent living donor liver transplantation using a right lobe graft. A preoperative dynamic computed tomography scan and intraoperative findings revealed that the graft had three middle HV tributaries, a superficial vein, segment VIII HV (V8), and segment V HV (V5). The openings of the superficial vein and V8 were located very close to that of the right hepatic vein (RHV) in the cutting surface. Each HV had significant diameter and drainage territory requiring reconstruction. An autologous great saphenous vein was used to create a sleeve patch to incorporate the close-packed HV openings. The autologous sleeve patch graft was sutured to the openings of the RHV and the superficial vein and the hole created on the sleeve patch graft was anastomosed to the openings of V8 directly on the back table to create an all-in-one sleeve patch. For the V5 reconstruction, the recipient's intrahepatic portal vein graft was used to create an interpositional conduit from the recipient's V5 to the inferior vena cava. The postoperative course was uneventful and postoperative studies revealed good graft function with excellent blood flow in the HV.

Effect of related donor availability on outcome of AML in the context of related and unrelated hematopoietic cell transplantation.

Although allogeneic hematopoietic cell transplantation (HCT) from a related donor is effective therapy for younger patients with AML, it remains unknown how the availability of a related donor affects the outcome when unrelated HCT is a treatment option for patients without a related donor. To address this issue, we retrospectively analyzed 605 cytogenetically non-favorable AML patients younger than 50 years for whom a related donor search was performed during first CR (CR1). The 4-year OS was 62% in 253 patients with a related donor and 59% in 352 patients without a related donor (P=0.534). Allogeneic HCT was performed during CR1 in 62% and 41% of patients with and without a related donor, respectively. Among patients transplanted in CR1, the cumulative incidence of non-relapse mortality was significantly higher in patients without a related donor (P=0.022), but there was no difference in post-transplant OS between the groups (P=0.262). These findings show the usefulness of unrelated HCT in younger patients with cytogenetically non-favorable AML who do not have a related donor. The extensive use of unrelated HCT for such patients may minimize the potential disadvantage of lacking a related donor.

Renal vein extension using an autologous renal vein in a living donor with double inferior vena cava: a case report.

BACKGROUND: When the kidney from a living donor with a double inferior vena cava (IVC) is harvested for renal transplantation, the short length of the renal vein may eventually create a technical problem for graft implantation. Herein, we have reported a rare case of renal vein extension using an autologous renal vein in a living donor with a double IVC. CASE REPORT: A 70-year-old man with end-stage renal disease owing to autosomal-dominant polycystic kidney disease underwent a living donor kidney graft from his wife who had a double IVC. Because of the enlarged kidneys, the patient underwent a bilateral native nephrectomy with concomitant renal transplantation to create space in the pelvis. At nephrectomy, the recipient's renal vein was used to extend the donor renal vein. On the back table, the vein graft was sutured to the donor renal vein, permitting a 3.0-cm extension. RESULTS: The transplantation was performed safely without any complications; the recipient's renal function and blood flow were excellent after the operation. CONCLUSION: This case illustrated that an autologous renal vein graft is a preferable option to extend of short donor renal vein for recipients who require a simultaneous native nephrectomy.

Optimization of immunosuppressive therapy based on a multiparametric mixed lymphocyte reaction assay reduces infectious complications and mortality in living donor liver transplant recipients.

AIM: We investigated the clinical relevance of immune monitoring by a multiparametric mixed lymphocyte reaction (MLR) assay, wherein the number and phenotype of alloreactive precursors can be quantified by combining the results of carboxyfluorescein diacetate succinimidyl ester labeling and flow cytometry analysis. METHODS: In 51 adult patients undergoing living donor liver transplantation (OLT), immunosuppressive drugs were dosed on the basis of immune monitoring by the MLR assay (optimized protocol: group O). In 64 other patients, the agents were prescribed according to empirical regimens (empirical protocol: group E). In group O, MLR assays were performed at 2- to 4-week intervals until 3 months after OLT and thereafter at 3- to 6-month intervals. Therapeutic adjustments for immunosuppressants were determined by tapering the doses in cases of anti-donor hyporesponsiveness for both CD4+ and CD8+ T-cell subsets. RESULTS: The 1-year patient and graft survivals in groups O versus E were 90.2% versus 76.6%, respectively. The incidence of acute rejection episodes (ARE) among group O (13.7%) were lower than in cohort E (28.1%). None of the patients in group O while four patients (3%) in group E already have shown chronic rejection to date. The incidences of bacteremia and fungal infections in group O (9.8% and 7.5%, respectively) were lower than in cohort E (18.8% and 12.6%, respectively). CONCLUSION: A multiparametric MLR assay may facilitate the development of adequate immunosuppressive regimens.

Complex vascular reconstruction using donor's vessel grafts in orthotopic liver transplantation.

The vascular abnormalities of recipients are associated with reconstructive difficulties with an increased risk of postoperative complications. We performed an orthotopic liver transplantation that required a complex vascular reconstruction using donor vascular grafts. A patient with hepatitis B virus cirrhosis received a liver from a brain-dead donor. Dynamic computed tomography revealed complete obstruction of the portal vein due to thrombosis as well as narrowing of the hepatic arteries. We employed orthotopic liver transplantation using the piggy-back technique with complex reconstruction of the portal vein and the hepatic arteries. For portal vein reconstruction, we used the donor's iliac vein as an interpositional conduit from the recipient's gastric coronary vein to graft the portal vein. The hepatic arteries of the graft were reconstructed at the back-table before anastomosis to the side of superior mesenteric artery using an interpositional conduit of the donor's external iliac artery. All postoperative studies revealed good graft function with an excellent blood flow through all vascular anastomoses during the first year postoperatively.

IL28B polymorphism may guide pegylated interferon plus ribavirin therapy even after curative treatment for hepatitis C virus-related hepatocellular carcinoma.

The present study was designed to determine the predictive factors for the viral response to pegylated interferon-alpha plus ribavirin combination therapy (PEGIFN/RBV) administered after curative treatment for hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). The study group was 78 patients treated between January 2005 and January 2009. The sustained viral response (SVR) rate was 25.8% (15/58) in patients infected with HCV-genotype 1 and 55.0% (11/20) in those with genotype 2. Among the 78 patients, 32 (41.0%) could not complete the treatment protocol, and this was because of HCC recurrence in 17 (53%) of them. Multivariate analysis identified partial early viral response (pEVR) as the only independent determinant of SVR [odds ratio (OR) 14.73, P = 0.013] for patients with genotype 1. Multivariate analysis identified male gender (OR 8.72, P = 0.001) and interleukin-28B (IL-28B) genotype (rs8099917) TT (OR 7.93, P = 0.007) as independent predictors of pEVR. Multivariate analysis also identified IL-28B genotype GG+TG (OR 14.1, P = 0.021) and α-fetoprotein >30 (OR 5.4, P = 0.031) as independent predictors of null response. Patients with SVR showed a better survival rate than those without SVR (P = 0.034). The second HCC recurrence rate tended to be lower in patients with SVR than in those without SVR (P = 0.054). With regard to the prognosis of patients with SVR, it is desirable to achieve SVR with interferon therapy even when administered after HCC treatment. IL-28B genotype is a potentially useful marker for the response to PEGIFN/RBV therapy administered after curative treatment of HCV-related HCC.

Kinetics of cellular and humoral immunity in a successful case of positive crossmatch kidney transplantation: a case report.

A positive crossmatch remains one of the major barriers to successful kidney transplantation. Highly sensitized patients are at greater risk of hyperacute rejection and subsequent graft loss after transplantation. Although recent advances in desensitization therapy allow kidney transplantation in these patients, the success rate is quite low. Herein, we have reported a successful case of positive crossmatch living donor kidney transplantation using a desensitization protocol with an immune monitoring assay. A 42-year-old woman with end-stage renal disease due to IgA nephropathy had been on hemodialysis for 36 months. She showed positive T-cell and B-cell cytotoxic crossmatches with her husband owing to pretransplantation blood transfusions. We performed a preconditioning regimen comprising a single dose of rituximab (375 mg/m(2)) combined with double-filtration plasmapheresis (DFPP) followed by low doses of intravenous immunoglobulin (DFPP/IVIG treatment). Tacrolimus (target trough level, 5-10 ng/mL) and mycophenolate mofetil (1500 mg/body) were started 2 weeks before the DFPP/IVIG treatment. After 6 DFPP/IVIG sessions, the crossmatch became negative. An induction quadruple immunosuppression protocol included tacrolimus, mycophenolate mofetil, basiliximab, and methylprednisolone. After the transplantation, the patient's immune status was evaluated regularly by mixed lymphocyte reactions (MLR) using an intracellular carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeling technique (CFSE-MLR assay) and immunosuppressant therapy was adjusted accordingly. During the observation period, neither antibody-mediated rejection nor acute cellular rejection was encountered in this patient.

Long-term outcome of hepatic artery reconstruction during living-donor liver transplantation.

BACKGROUND: Hepatic artery thrombosis (HAT) after living-donor liver transplantation (LDLT) is a potentially life-threatening complication. Although the introduction of microsurgical techniques has significantly decreased the incidence of HAT after LDLT, it remains a challenge for microsurgeons. We previously reported the use of the microsurgical hepatic arterial reconstruction technique during LDLT using the head-mounted surgical binocular system. METHODS: In this study, we describe the long-term outcome of microsurgical hepatic artery reconstruction using the head-mounted surgical binocular system and our hepatic arterial reconstruction techniques on LDLT patients, including intimal dissection cases and clinical courses. Between August 2001 and February 2010, 146 patients underwent LDLT at our institution. Using a surgical loupe, the Varioscope AF3, which is a head-mounted surgical binocular system with automatic focusing and continuous zoom magnification from 3.6× to 7.2×, 150 arteries of 146 liver grafts were reconstructed. When the tunica intima was separated from the tunica media, suturing was performed from the inside of the vessels to the outside using an 8-0 monofilament Prolene with double needles, which facilitates secure sutures with good intima adaptation. RESULTS: The 1- and 3-year survival rates of the 146 patients were 80.3% and 74.9%, respectively, with a mean follow-up of 40.2 months. The mean diameter of the graft hepatic artery was 2.79 mm. HAT was not encountered in this series of patients. CONCLUSION: The use of the Varioscope and the application of our suturing techniques have provided entirely satisfactory long-term results of hepatic artery reconstruction during LDLT, even in intimal dissection cases.

CMOS-based smart-electrode-type retinal stimulator with bullet-shaped bulk Pt electrodes.

A CMOS-based flexible retinal stimulator equipped with bullet-shaped bulk Pt electrodes was fabricated and demonstrated. We designed a new CMOS unit chip with an on-chip stimulator, single- and multi-site stimulation modes, and monitoring functions. We have developed a new structure and packaging process of flexible retinal stimulator with bullet-type bulk Pt electrode. We have confirmed the retinal stimulation functionality in an in vivo stimulation trial on rabbit's retina.

Successful living donor left liver transplantation by using liver graft with multiple large cysts: a case report.

There are few reports regarding the use of liver grafts with multiple large cysts in living donor liver transplantation. A 40-year-old woman who was diagnosed with Wilson's disease underwent living donor left liver transplantation; the donor was her 67-year-old mother. The liver graft had multiple large cysts, with a maximum diameter of 9 cm. At donor hepatectomy, the largest cyst and one small cyst were fenestrated, because they were located in the left paramedian sector; the other cysts were left intact. After transplantation, the liver graft exhibited good function with no cyst-related complications, such as hemorrhage, infection, or rupture, despite slight enlargement of the cysts. Thus, a liver graft with multiple large cysts is transplantable. However, the necessity of treating large cysts remains debatable.

Twisted ovarian tumor causing progressive hemothorax: a case report of porous diaphragm syndrome.

BACKGROUND: Porous diaphragm syndrome is caused by a defect in the diaphragm. The defect may induce pleural effusion in a patient with an ovarian tumor. CASE REPORT: A 59-year-old Japanese woman with an ovarian tumor and right hemothorax underwent thoracotomy and presented with a fenestra in the right diaphragm through which bloody fluids were flowing from the peritoneal cavity into the pleural space. Following suturing of the fenestra, laparotomy revealed intraabdominal bleeding due to torsion of an ovarian tumor. CONCLUSION: This is the first report in which the diaphragmatic defect was identified in a patient with an ovarian tumor and hemothorax. Porous diaphragm syndrome may be involved in the pathophysiology of right pleural effusion observed in other medical conditions such as Meigs' syndrome, ovarian hyperstimulated syndrome, and ovarian cancer.

Splenic artery steal syndrome in living donor liver transplantation: a case report.

Splenic artery steal syndrome (SASS) has only recently been recognized as a potential threat to transplanted livers. We report a case of SASS with progressive liver dysfunction that developed after living donor right lobe liver transplantation. SASS suspected by serial pre- and postoperative computed tomographic (CT) scans was diagnosed by celiac trunk angiography. It was successfully salvaged by splenic artery embolization. In this case, serial examinations of CT scans were useful to diagnose SASS. This case showed that portal hyperperfusion injury is a cause of liver graft dysfunction in SASS. The splenic artery embolization technique is a safe procedure that can be applied to treat such injury.