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Hepatic encephalopathy that occurs long after liver transplantation (LT) is an uncommon condition. Here, we describe the successful case of a 65-year-old patient who underwent interventional radiology (IVR) using a transmesenteric approach under minilaparotomy for hepatic encephalopathy because of a portosystemic shunt 11 years after ABO-incompatible living donor LT with splenectomy. Enhanced computed tomography confirmed a huge portosystemic shunt and left gastric vein (LGV)-esophageal-azygos vein, which was not treated during LT. Liver stiffness measurements based on transient elastography did not show severe fibrosis in the liver graft. Since the hyperammonemia could not be managed with conventional medical treatment, balloon-occluded retrograde transvenous obliteration (BRTO) was indicated. However, it was difficult to perform because the drainage vein could not be approached from the inferior vena cava (IVC). Surgical shunt ligation was also difficult because of the history of multiple laparotomies. Although intraperitoneal adhesion was severe, the portosystemic shunt was successfully embolized with metallic coils and a plug by IVR using a transmesenteric approach under minilaparotomy. No complications occurred during the operation. His symptoms improved after the operation. The ammonia level and portal flow by ultrasound also improved. He was discharged 14 days after surgery without any complications.

Among the recent topics in the field of liver transplantation (LT), one of the significant therapeutic breakthroughs is the introduction of direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) infection. With cure rates close to 100%, a better proportion of LT candidates and recipients can be cured of HCV infection by DAA therapies that are simple and well-tolerated. Other critical topics include the issue of indication of LT for patients with hepatocellular carcinoma, which has been continuously studied. Several expanded criteria beyond the Milan criteria with acceptable results have been recently reported. The role of donor-specific antibodies (DSAs) in intractable rejection is also an important matter that has been studied. Although long recognized as an important factor in antibody-mediated rejection and even graft survival in renal transplantation, the impact of DSAs on graft and patient survival in LT remains to be elucidated. Including the issues described above, this article focuses on recent advances in LT, management to avoid recurrence of primary diseases, optimization of immunosuppressive treatment, and extended donor criteria.

Through multiple mechanisms, regulatory B cells (Breg) have been shown to play an important role in the development of allograft tolerance. However, a careful understanding of the role of antigen-specificity in Breg-mediated allograft tolerance has remained elusive. In experimental models of islet and cardiac transplantation, it has been established that Bregs can be induced in vivo by anti-CD45RB ± anti-TIM1antibody treatment, resulting in prolonged, Breg-dependent allograft tolerance. The importance of Breg antigen recognition has been suggested but not confirmed through adoptive transfer experiments, using tolerant WT C57BL/6 animals challenged with either BALB/c or C3H grafts. However, the importance of receptor-specificity has not been formally tested. Here, we utilize the novel ovalbumin-specific B cell receptor transnuclear (OBI) mice in multiple primary tolerance and adoptive transfer experiments to establish that Breg-dependent allograft tolerance relies on antigen recognition by B cells. Additionally, we identify that this Breg-dependent tolerance relies on the function of transforming growth factor-β. Together, these experiments mark important progress toward understanding how best to improve Breg-mediated allograft tolerance.

The liver exhibits intrinsic immune regulatory properties that maintain tolerance to endogenous and exogenous antigens, and provide protection against pathogens. Such an immune privilege contributes to susceptibility to spontaneous acceptance despite major histocompatibility complex mismatch when transplanted in animal models. Furthermore, the presence of a liver allograft can suppress the rejection of other solid tissue/organ grafts from the same donor. Despite this immune privilege of the livers, to control the undesired alloimmune responses in humans, most liver transplant recipients require long-term treatment with immune-suppressive drugs that predispose to cardiometabolic side effects and renal insufficiency. Understanding the mechanism of liver transplant tolerance and crosstalk between a variety of hepatic immune cells, such as dendritic cells, Kupffer cells, liver sinusoidas endothelial cells, hepatic stellate cells and so on, and alloreactive T cells would lead to the development of strategies for deliberate induction of more specific immune tolerance in a clinical setting. In this review article, we focus on results derived from basic studies that have attempted to elucidate the immune modulatory mechanisms of liver constituent cells and clinical trials that induced immune tolerance after liver transplantation by utilizing the immune-privilege potential of the liver.

BACKGROUND

We investigated the impact of polymorphisms in host innate immunoregulatory genes on the development of infectious complications after kidney transplantation (KT). The single-nucleotide polymorphisms (SNPs) of C1QA [276 A/G], FCGR2A [131 H/R], and FCGR3A [158 F/V], genes encoding the Fc gamma receptor (Fc gamma R), were analyzed in 81 KT recipients in relation to the occurrences of postoperative infectious complications within 30days after KT. Consistent with a lower affinity of the isoform encoded by the FCGR3A [158 F] to both IgG1 and IgG3, a significantly higher incidence of urinary tract infections (UTIs) was observed in the FCGR3A [158 F/V or F/F] individuals (65.5%) than in the FCGR3A [158 V/V] individuals (34.5%) following KT. The combination of FCGR2A and FCGR3A SNPs further stratified the incidence of UTIs, regardless of C1QA SNP following KT. No differences were observed in the incidence of fungal or cytomegalovirus infections with respect to the 3 gene polymorphisms. In conclusion, our findings indicate that Fc gamma R SNPs are predisposing factors for UTIs after KT. This study provides a foundation for further prospective studies on a larger scale.

Background. The role and phenotypic alterations of intrahepatic natural killer (NK) cells in liver disease were investigated. Although intrahepatic NK cells reportedly functionally deteriorate in the fibrotic liver, it remains unclear how the clinical severity of liver disease affects intrahepatic NK cells in patients with advanced liver failure. Methods. We analyzed the phenotypic properties of intrahepatic NK cells by using mononuclear cells extracted from ex vivo liver perfusate effluents from patients who underwent liver transplantation. The relationship between the clinical severity of liver disease and the phenotype of intrahepatic NK cells in these patients was also evaluated. To estimate the immunological responsiveness of intrahepatic NK cells, phenotypic enhancement after interleukin-2 stimulation was analyzed. Results. Intrahepatic NK cells from patients with advanced liver failure exhibited down regulated monomodal expression of NKp46, a major activating molecule. Notably, the expression level of NKp46 decreased depending on the severity of liver disease, Model for End-Stage Liver Disease score, and Child-Pugh score rather than the etiology. After in vitro recombinant interleukin-2 stimulation, the enhancement of expression of cytotoxic molecules, NKp44, and tumor necrosis factor related apoptosis-inducing ligand was significantly impaired in intrahepatic NK cells from patients with liver failure, concurrently with decreased expression of CD122 and interleukin-2 receptor beta. Conclusions. Our results suggest that terminal deterioration of liver environments by chronic liver disease impairs the potential of local NK cells, depending on the severity of the deterioration. These influences of advanced liver failure on intrahepatic NK cells may be attributed to multicentric carcinogenesis in patients with liver failure.

Background. NKp46 expression in natural killer (NK) cells has recently been shown to affect the responsiveness to antiviral treatment in hepatitis C virus (HCV)-infected patients. However, the density of NKp46 on intrahepatic NK cells is remarkably higher than that on peripherally circulating NK cells, whereas the biophylactic function of intrahepatic NK cells against HCV reinfection remains unclear. Methods. We analyzed the phenotypic and functional properties of intrahepatic NK cells using mononuclear cells extracted from ex vivo liver perfusates from living liver transplantation donors. To investigate the role of intrahepatic NK cells in relation to HCV infection, we evaluated posttransplant HCV load kinetics in HCV-related patients. Results. Intrahepatic NK cells from healthy donors showed a distinctive phenotype even in each of the CD56(bright) and CD56(dim) fractions compared with peripheral blood NK cells. In the assays using a Huh7-HCV replicon system, anti-HCV activity was induced via recognition of the NK cell receptors, including NKp46, NKp30, and NKG2D, which was demonstrated by the use of monoclonal antibodies that neutralized neutralizing molecules. Unexpectedly, the density of NKp46 on intrahepatic NK cells varied considerably among individuals, allowing us to demonstrate that HCV reload in the early posttransplant period was delayed in recipients of liver allografts containing a higher proportion of NKp46(high) NK cells. Conclusions. Intrahepatic NKp46(high) NK cells exhibited anti-HCV activity via cell-to-cell contact. The variation of the NKp46(high) proportion in individuals could be attributed to the diversity of HCV resistance observed in these individuals, which possibly reflects the clinical outcome of infection in patients.

BACKGROUND/AIMS

Introduction Objective and quantitative intraoperative methods of bowel viability assessment could decrease the risk of postoperative ischemic complications in gastrointestinal surgery. Because the remnant stomach and the pancreas share an arterial blood supply, it is often unclear whether the remnant stomach can be safely preserved when performing pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) post gastrectomy. We herein report two cases in which the remnant stomach was safely preserved using near-infrared spectroscopy to assess the regional saturation of oxygen (rSO2) in the remnant stomach during operation. Presentation of case The first patient, a 68-year-old man, was diagnosed with cancer of the pancreatic head and underwent PD a year after proximal gastrectomy for gastric cancer. The remnant stomach was safely preserved by evaluation of the rSO2 before and after reconstruction of the arteries. The second patient, an 82-year-old woman with a history of distal gastrectomy for gastric cancer 40 years previously, was diagnosed with a main duct intraductal papillary mucinous neoplasm of the pancreatic body, requiring DP. As in the previous case, we could safely preserve the remnant stomach through assessing the intraoperative rSO2 of the remnant stomach. Discussion Through comparing changes in the rSO2 during surgery, near-infrared spectroscopy provides objective and quantitative assessments of intestinal viability to predict ischemic complications. Conclusion This method may be a viable option to evaluate the blood supply to the alimentary tract.

Background/Aims

Hepatopulmonary syndrome (HPS) is a severe complication in patients with chronic liver disease with poor prognosis. Liver transplantation (LT) is a promising treatment for HPS; however, very severe HPS, which is defined by an arterial oxygen pressure (PaO2) of less than 50mmHg and a right-left intrapulmonary shunt rate of more than 20%, may be a contraindication to LT, including living donor LT (LDLT). Here, we report two cases of decompensated liver cirrhosis with very severe HPS which were resolved after adult-to-adult LDLT including ABO-incompatible LDLT. Both patients required oxygen supportive therapy in combination with specialized respiratory care postoperatively, followed by improvement of oxygenation and substantial decreases of intrapulmonary shunt rate. These findings suggest very severe HPS can be resolved by LDLT, including ABO-incompatible LDLT, and reduced graft volume did not impede the reversal of intrapulmonary shunting. Our current report may indicate that adult-to-adult LDLT, including ABO-incompatible LDLT, is becoming an effective therapeutic method and prompt a review of previous reports as well as our own files with particular regard to the indication of LDLT for decompensated liver cirrhosis with very severe HPS.

Natural killer (NK) cells are potential immune components against hepatocellular carcinoma (HCC) after curative hepatectomy. Patients at high risk of HCC recurrence can be identified by quantifying NK cell licensing. Therefore, therapeutic strategies that manipulate NK cell activity may possibly improve the prognosis of HCC patients.

Natural killer (NK) cells have a potential role in immune surveillance of hepatocellular carcinoma (HCC). Self-recognition of human leukocyte antigens (HLA) through killer immunoglobulin-like receptors (KIR) confers competence to NK cells-a process termed "licensing." We investigated the effect of NK-cell licensing on the susceptibility of patients to HCC recurrence. A total of 170 Japanese patients with HCC who underwent primary curative hepatectomy between 1996 and 2010 were enrolled in this study. The median follow-up period was 5.4 years. We analyzed their KIR-HLA genotypes with sequence-specific polymorphism-based typing and estimated their susceptibility to HCC recurrence by performing propensity score-matching analyses. The presence of KIR2DL1-C2, KIR2DL2-C1, KIR3DL1-BW4, or KIR3DL2-A3/11, functional compound genotypes that intrinsically license NK cells, did not markedly affect HCC recurrence. However, the multiplicity of those compound KIR-HLA genotypes was significantly associated with the HCC recurrence rate, i.e., the cumulative risk of recurrence in patients with at least three compound genotypes was significantly lower than that in patients with one or two compound genotypes, suggesting that the effect of NK-cell licensing on HCC recurrence is quantitative. Patients at high risk of HCC recurrence after curative hepatectomy could be identified by KIR-HLA genotyping. (C) 2014 AACR.

Background. CXC motif chemokine 10 (CXCL10), known as interferon-gamma induced protein 10, is an inflammatory cytokine secreted by various cells in response to interferon-y. 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 posttransplantation 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 antidonor 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.

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.

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.

Surgical site infection (SSI) is a frequent complication of elective surgery for colorectal cancer. The classical clinical markers of infection-elevations in white blood cell count, C-reactive protein (CRP) level, and body temperature-do not precisely predict SSI after elective colorectal resection. The objective of this study was to evaluate the efficacy of procalcitonin (PCT) as a tool for diagnosis of SSI in elective surgery for colorectal cancer. A total of 114 consecutive patients undergoing elective colorectal resection for cancer were evaluated. Routine blood samples, for determining PCT level, CRP plasma concentration, and white blood cell count, were obtained on postoperative days (POD) 1 and 3. Predictive values for each of the laboratory markers were examined. SSI was diagnosed in 18 (15.7 %) of 114 patients. Patients with SSI exhibited significantly higher PCT levels (on PODs 1 and 3) and CRP levels (on POD 3) than did patients without SSI. According to receiver operating characteristic analysis, PCT showed the highest area under the curve (AUC) for predicting SSI on both PODs 1 and 3 (AUC, 0.76 and 0.77, respectively). Multivariate logistic regression analysis showed that PCT (on PODs 1 and 3) was an independent predictor for SSI (odds ratio = 14.41 and 9.79, respectively). Serum PCT is more reliable laboratory marker for the early diagnosis of SSI after elective colorectal cancer surgery, compared with conventional inflammatory indicators. PCT could serve as an additional diagnostic tool for the early identification of SSI to improve clinical decision making.

Micropapillary carcinoma was originally reported to be an aggressive variant of breast carcinoma, and it is associated with frequent lymphovascular invasion and a dismal clinical outcome. It has subsequently been found in other organs however, at present, only a limited number of cases of colorectal micropapillary carcinoma have been reported. We present a case of early colon cancer with extensive nodal metastases in a Japanese patient. An 82-year-old man was found by colonoscopy to have a 20-mm pedunculated polyp in his sigmoid colon. Endoscopic resection of the sigmoid colon tumor was performed, and pathological examination of the resected specimen revealed a poorly differentiated adenocarcinoma component and a micropapillary component. Despite the tumor being confined within the submucosa, massive lymphatic invasion was noted. Thereafter, the patient underwent laparoscopic sigmoidectomy with lymph node dissection, and multiple lymph node metastases were observed. Our case suggests that when a micropapillary component is identified in a pre-operative biopsy specimen, even for early colorectal cancer, surgical resection with adequate lymph node dissection would be required because of the high potential for nodal metastases. © 2013 S. Karger AG, Basel.

Background

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.