Seiichi Shimizu

Fc-Gamma Receptor Polymorphisms Predispose Patients to Infectious Complications After Liver Transplantation

We investigated the impact of polymorphisms in host innate immunoregulatory genes on the development of infectious complications after liver transplantation (LT). The single‐nucleotide polymorphisms (SNPs) of C1QA [276A/G], FCGR2A [131H/R], and FCGR3A [158F/V], genes encoding the Fc gamma receptor (FcγR), were analyzed in 89 living donor LT recipients in relation to the occurrences of postoperative infectious complications within 30 days after LT. Consistent with a lower affinity of the isoform encoded by FCGR3A [158F] to both IgG1 and IgG3, a significantly higher incidence of bloodstream infections (BSI) was observed in the FCGR3A [158F/V or F/F] than in the FCGR3A [158V/V] individuals. The combination of FCGR2A and FCGR3A SNPs further stratified the incidence of BSI, regardless of C1QA SNP. The predominant causative pathogen of BSI in the FCGR3A [158F/F or F/V] patients was gram‐positive cocci (73.3%), of which one third was methicillin‐resistant Staphylococcus aureus. No differences were observed in the incidence of fungal infections or in cytomegalovirus infections with respect to the three gene polymorphisms. Our findings indicate that FcγR SNPs are predisposing factors for BSI and can predict mortality after LT. This study provides a foundation for further prospective studies on a larger scale.

Synchronous double cancers of primary hepatic adenosquamous carcinoma and hepatocellular carcinoma: report of a case

A 76-year-old male was referred for the treatment of liver tumors detected by abdominal computed tomography (CT). Dynamic CT revealed a low-density tumor with an irregularly enhanced rim in the left lateral sector, and a highly enhanced, well-circumscribed tumor in the caudate lobe, accompanied by dilation of the intrahepatic biliary ducts in the left lobe. Preoperative imaging studies led to the diagnosis of double cancers consisting of intrahepatic cholangiocarcinoma and hepatocellular carcinoma (HCC). Left hemihepatectomy with caudate lobectomy was performed. The postoperative course was uneventful. Microscopic evaluation revealed that the tumor in the left lateral sector was adenosquamous carcinoma (ASC), whereas that in the caudate lobe was HCC. This report presents the first case describing the resection of synchronous double cancers of primary hepatic ASC and HCC.

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 donors iliac vein as an interpositional conduit from the recipients 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 donors external iliac artery. All postoperative studies revealed good graft function with an excellent blood flow through all vascular anastomoses during the first year postoperatively.

Significant association between FOXP3 gene polymorphism and steroid-resistant acute rejection in living donor liver transplantation

Previous studies have found that preferential accumulation of regulatory T (Treg) cells in liver allografts during acute cellular rejection (ACR) is associated with less severe rejection, suggesting a role of Treg cells in preventing excessive progress of ACR. We investigated the impact of single nucleotide polymorphisms (SNPs) in the Forkhead box P3 (FOXP3) gene, a master regulator gene of Treg cells, on ACR severity in liver transplant (LT) recipients. In total, 102 living donor LT patients were enrolled in this study and categorized into no rejection (n = 86), steroid‐sensitive acute rejection (SSAR; n = 11), and steroid‐resistant acute rejection (SRAR; n = 5). FOXP3 SNPs –3499 A/G (rs3761547), –3279 A/C (rs3761548), and –924 A/G (rs2232365) were genotyped using the polymerase chain reaction restriction fragment length polymorphism technique. T‐cell responses to allostimulation were evaluated by the mixed lymphocyte reaction assay. We found no statistical association between the FOXP3 SNP genotype frequencies and ACR incidence. However, significantly higher incidence of SRAR was observed in LT patients with the FOXP3 rs3761548 A/C+A/A genotype than in those with the C/C genotype (A/C+A/A versus C/C; no rejection, SSAR, SRAR, 85.71%, 0%, 14.29% versus 83.58%, 16.42%, 0%, respectively; P =  0.0005). The mixed lymphocyte reaction assay performed at the time of ACR diagnosis showed higher anti‐donor CD4+ T‐cell responses in patients carrying rs3761548 A/C+A/A than in those with the C/C genotype (P =  0.019). No significant association was observed between the incidence of SRAR and either rs3761547A/G or rs2232365 A/G. Infectious complications and overall survival were not related to FOXP3 SNPs.

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 recipients intrahepatic portal vein graft was used to create an interpositional conduit from the recipients 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.

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.

Effect of Fc-γ Receptor Polymorphism on Rituximab-Mediated B Cell Depletion in ABO-Incompatible Adult Living Donor Liver Transplantation

Background The affinity of IgG Fc receptor (Fc&ggr;R) for rituximab, an anti-CD20 IgG1, differs based on single-nucleotide polymorphisms (SNPs) in Fc&ggr;Rs. This study aimed to explore the effect of such SNPs on clinical response to rituximab and outcomes in patients of ABO-incompatible (ABOi) living donor liver transplantation (LDLT). Methods SNPs of FCGR2A[131H/R] and FCGR3A[158F/V], alleles encoding Fc&ggr;R, were identified in 20 patients desensitized with rituximab before ABOi LDLT. The effect of these SNPs on B cell elimination and outcomes was analyzed in the patients. Results The isoform encoded by FCGR2A[131H/H] had a higher affinity for IgG1, and accordingly, the effects of rituximab on B cells were more profound in individuals with FCGR2A[131H/H] than in individuals with FCGR2A[131H/R or R/R]. Specifically, the time to B-cell reappearance in the peripheral blood was significantly delayed, and total serum IgM levels were significantly lower early after LDLT in individuals with FCGR2A[131H/H], even though these SNPs did not significantly affect the reduction of antiblood group A/B antibodies. The incidence of blood stream infection was also significantly higher in individuals with FCGR2A[131H/H], and this SNP was associated with poor prognosis. Despite no significant effect of FCGR3A[158F/V] on survival after ABOi liver grafts, the incidence of infection was significantly higher in individuals with FCGR3A[158F/V or F/F] than in individuals with FCGR3A[158V/V]. Conclusions Our findings indicate FCGR SNPs influence the effect of rituximab on B-cell depletion and are possibly predisposing factors for infectious complications after ABOi LDLT. This study will be a good foundation for further studies on larger cohorts.

Fc-gamma receptor 3A polymorphism predicts the incidence of urinary tract infection in kidney-transplant recipients

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 (FcγR), 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 FcγR SNPs are predisposing factors for UTIs after KT. This study provides a foundation for further prospective studies on a larger scale.

Thoracoscopic resection of congenital cystic adenomatoid malformation in an adolescent

Congenital cystic adenomatoid malformation (CCAM) in adolescents or adults is extremely rare. In this case study, a 17‐year‐old boy was admitted to our clinic for the treatment of a giant bulla in the lower lobe of the right lung. Preoperative imaging studies led to the diagnosis of cystic lung disease. The patient underwent wedge resection of the right lower lobe with VATS, and histological examination confirmed the presentation of type 1 CCAM. A thoracoscopic lobectomy was performed after the second surgery because of postoperative air leakage.Herein, we report a case of CCAM in an adolescent. VATS was a suitable procedure for the operation. Between the parenchyma‐saving resection and lobectomy for CCAM, we believe that the lobectomy is the better treatment option when the extent of the disease cannot be determined clearly or it is extremely large. Therefore, strategies for deciding between parenchyma‐saving resection and lobectomy for the treatment of CCAM should be developed.

B-Cell Depletion with Rituximab Exacerbates Anti-Donor CD4+ T-Cell Responses in Patients with Donor-Specific Anti-Human Leukocyte Antigen Antibodies

Background It has been reported that preformed donor-specific anti-human leukocyte antigen antibodies (DSAs) were associated with poor graft outcomes in transplant recipients. To eliminate preformed DSAs, prior to either kidney or liver transplantation, we desensitized DSA-positive patients by injecting rituximab and then performed plasmapheresis in those patients using a protocol for ABO-incompatible (ABO-I) transplant recipients. B-cell depletion with rituximab may influence T-cell responses to alloantigens since B-cells are effective antigen-presenting cells that are capable of activating donor-specific T-cells. It is also likely that the cytokine release syndrome, which is caused by rituximab, may enhance T-cell activation. In this study, we investigated the impact of pre-transplant desensitization with rituximab on the subsequent response of T-cells to alloantigens in DSA-positive kidney and liver transplant recipients. Methods Twenty DSA-positive patients of kidney or liver allografts were employed in this study, while thirty-eight DSA-negative ABO-I patients of kidney or liver allografts formed the control group that received a similar desensitization preconditioning with rituximab and plasmapheresis. To monitor the patients’ immune status, a mixed lymphocyte reaction assay using a carboxyfluorescein diacetate succinimidyl ester-labeling technique was performed before and after desensitization with the consent of the patinets, donors, and third-party healthy volunteers. Results Before desensitization, there were no significant differences in the average stimulation index (SI) values for the responses of the CD4+ and CD8+ T-cells to donor stimuli between the two groups. However, after desensitization, the average SI values for the CD4+ T-cells were significantly higher in the DSA-positive patients than those in the DSA-negative ABO-I patients. Consistently, in liver transplant recipients, the incidence of acute cellular rejection (ACR) was higher in DSA-positive patients than that in the DSA-negative ABO-I patients (60% and 16.7%, respectively), and none suffered from antibody-mediated rejection. Treatment with either steroid-bolus or rabbit thymocyte globulin (rATG) completely cured ACR. Conclusions These findings demonstrate that B-cell depletion with rituximab exacerbates anti-donor CD4+ T-cell responses in DSA-positive organ transplant recipients, and that it is probably associated with a high rate of ACR events. It might be possible that treatment with rituximab undesirably depletes specific B-cell subsets that could regulate T-cell responses to alloantigens. Although this issue is currently under investigation, T-cell responses could possibly be inhibited by rATG before or after desensitization to prevent ACR events.