Takahisa Fujikawa

Teratoma Formation Leads to Failure of Treatment for Type I Diabetes Using Embryonic Stem Cell-Derived Insulin-Producing Cells

Embryonic stem (ES) cells have been proposed to be a powerful tool in the study of pancreatic disease, as well as a potential source for cell replacement therapy in the treatment of diabetes. However, data demonstrating the feasibility of using pancreatic islet-like cells differentiated from ES cells remain controversial. In this study we characterized ES cell-derived insulin-expressing cells and assessed their suitability for the treatment of type I diabetes. ES cell-derived insulin-stained cell clusters expressed insulin mRNA and transcription factors associated with pancreatic development. The majority of insulin-positive cells in the clusters also showed immunoreactivity for C-peptide. Insulin was stored in the cytoplasm and released into the culture medium in a glucose-dependent manner. When the cultured cells were transplanted into diabetic mice, they reversed the hyperglycemic state for approximately 3 weeks, but the rescue failed due to immature teratoma formation. Our studies demonstrate that reversal of hyperglycemia by transplantation of ES cell-derived insulin-producing cells is possible. However, the risk of teratoma formation would need to be eliminated before ES cell-based therapies for the treatment of diabetes are considered.

Liver transplantation from donation after cardiac death: a single center experience.

Background. Liver transplantation (LT) from controlled donation after cardiac death (DCD) donors has increased steadily during the past decade because of the donor shortage in the United States. Although early reports of LT from DCD donors provided evidence for acceptable outcomes, long-term graft and patient survival rates from these procedures have been reviewed only recently. Methods. From February 1990 to June 2006, 1209 LTs were performed from donation after brain death (DBD) donors, and 24 were performed from DCD donors at our institution. Detailed review of donor and recipient characteristics, and survival rates were evaluated in the two groups. Results. One- and 3-year patient survival was similar in both groups, (DCD 86.8%, 81.7% vs. DBD 84.0%, 76.0%, respectively; P=0.713). Graft survival appeared inferior in the DCD group compared with the DBD group at 1 year (69.1% vs. 78.7%) and 3 years (58.6% vs. 70.2%), but there was no statistical difference (P=0.082). There were no significant differences in hepatic artery thrombosis, portal vein thrombosis, primary nonfunction, and biliary stricture between the two groups. All cases with biliary stricture in DCD group finally led to graft loss, and all survived with retransplantation. Conclusion. The outcome of LT from DCD donors remains acceptable in our institution. Although biliary complication rate was similar in two groups, the consequence of this complication in DCD was more severe and often led to graft loss. Close observation of biliary complications after LT from DCD donors would be beneficial.

Effect of prophylaxis on fungal infection and costs for high‐risk liver transplant recipients

We sought to determine whether the prophylactic use of amphotericin B products (conventional amphotericin B and liposomal amphotericin B) reduces the incidence of fungal infections in high‐risk liver transplant recipients, and if so, whether this lowers the cost of care. The study sample comprised 232 adult orthotopic liver transplants performed from 1994 to 2005 at a single center for patients classified as being at high risk for fungal infections. High‐risk patients who received transplants with a prophylaxis regimen of amphotericin B (n = 58 transplants) were compared with high‐risk patients who received no prophylaxis (n = 174 transplants). Fungal infections occurred in 3 transplants (5.17%) of those who received amphotericin B and 28 transplants (16.09%) in those without prophylaxis (P = 0.0432). Regression models were used to analyze fungal infection and costs for the 232 high‐risk transplants. Failure to offer prophylaxis conferred a 4‐fold greater risk of fungal infection (P = 0.046) compared with those who received amphotericin B. A fungal infection in a high‐risk recipient increased mean costs by 46.48%. The indirect effect of prophylaxis (operating through infection reduction) is estimated to reduce overall costs in high‐risk patients by 8.73%. Liver Transpl 13: 1743–1750, 2007.

Combined hepatic resection and radiofrequency ablation for multiple hepatic adenomas

We describe the novel use of radiofrequency ablation (RFA) in combination with surgical resection for treatment of multifocal hepatic adenoma. We show three cases without recurrent lesions detected in follow‐up examination. Two of the patients have subsequently gone on to carry pregnancies successfully to term.

Is Early Recurrence of Hepatitis C Associated With Biliary Anastomotic Stricture After Liver Transplantation

Background. While the main effect of hepatitis C virus (HCV) is hepatitis, HCV is also known to cause a variety of systemic immunologic inflammatory abnormalities. The effect of HCV infection on the biliary tract after liver transplantation (LT) is not well understood. The aim of the current study is to determine if recurrence of hepatitis C affects biliary complications after LT, with special reference to late biliary anastomotic strictures (LBAS). Methods. A total of 688 consecutive adult LT recipients with a choledochocholedochostomy without T-tube placement between 1990 and 2005 were reviewed. Biliary anastomotic stricture was confirmed by endoscopic retrograde cholangiopancreatography. LBAS was defined as stricture that occurred 30 days or more after LT. Early HCV recurrence was defined as recurrence within 6 months after LT. Results. LBAS occurred in 55 patients (8% of total). Patients with HCV infection had a higher occurrence of LBAS than non-HCV patients (11% vs. 5%, P=0.0093). Among HCV patients, those with early HCV recurrence had an exceedingly high rate of LBAS (16%). In multivariate analyses, early recurrence of hepatitis C (P<0.0001), as well as occurrence of hepatic artery thrombosis (P=0.0018) and prolonged cold ischemic time (P=0.034), were independent risk factors affecting LBAS. Among HCV patients, those with LBAS had a significantly higher hepatitis activity index score (3.1 vs. 1.4, P<0.0001) and fibrosis stage (0.9 vs. 0.4, P<0.0001) as compared to patients without LBAS. Conclusion. Patients with early recurrence of HCV have increased occurrence of late biliary anastomotic stricture after liver transplantation.

Adult post-transplant lymphoproliferative disease in the liver graft in patients with recurrent hepatitis C

Aim The aim of this study is to clarify the association between hepatitis C virus (HCV) infection and post-transplant lymphoproliferative disease (PTLD) in the liver allograft. Methods Of the 933 adults who underwent liver transplantation (LT) between 1990 and 2005, 10 patients developed PTLD. Seven of the 10 patients that were HCV(+) (group 1) were compared with three HCV-negative recipients (group 2). Results The mean time between LT and PTLD was 24.5 months. There were no differences between in Epstein–Barr virus antibody status or tumor lymphocyte subsets. In five of the seven HCV-positive recipients who developed PTLD, PTLD recurred preferentially in the liver allograft, whereas none of the three HCV-negative patients who developed PTLD did so in the liver (71.4 vs. 0%, respectively, P=0.038). In all five patients with graft PTLD, HCV recurred within 12 months followed by PTLD. There were significant differences between groups 1 and 2 in mean lymphocyte infiltrate scores (6.0±2.1 vs. 2.0±0.7, P=0.037), fibrosis stage (2.4±0.5 vs. 0.7±0.5, P=0.029), and frequency of lymphoid follicles in portal areas (33.6±14.8% vs. 1.1±2.3%, P=0.0002). Conclusion When PTLD occurs in patients with HCV recurrence after LT, it does so preferentially in the liver allograft.

Psychosocial support after simultaneous pancreas and kidney transplantation

We read with interest the article by Otte on the review of pediatric liver transplantation based on 20 years of experience [1]. In this article, psychological and mental impact of pediatric liver transplantation was discussed. Likely, the similar situation may occur after simultaneous pancreas and kidney transplantation (SPK), as SPK is indicated exclusively for patients with uremic type I diabetes with long-standing disease history from younger age. We recently experienced a case of SPK transplant who required the removal of both kidney and pancreas allografts for organ failure secondary to hypochondriasis-induced medication noncompliance. A 36-year-old female with type I diabetes and diabetic nephropathy was referred to our hospital as a candidate for SPK. The durations of diabetes treatment and dialysis were 26 years and 3.5 months, respectively. She was unmarried and lived with her mother. Her social history includes dropout from the college at second grade. She underwent uneventful SPK, received standardized immunosuppression including daclizumub, mycophenolate mofetil and tacrolimus. Her postoperative course was complicated by only minor gastrointestinal symptoms such as constipation, diarrhea and appetite loss; however, she claimed immediate nursing attention more than necessary during days and nights, and sometimes threatened discharge against medical advice. She was discharged on postoperative day 16 with normal blood glucose and good renal function. During her outpatient follow-up visits, she became malnourished and was admitted to the hospital with severe abdominal pain. Work-up showed no apparent cause of the pain, and the patient recovered without any intervention. Renal function and blood glucose level were within normal limits. During subsequent outpatient follow-up visits, she showed worsening nutritional status, and she also presented with severe recurrent abdominal pain. Blood trough levels of tacrolimus were unmeasurable, and the diagnosis of acute rejection secondary to non-compliance was made. She underwent removal of kidney and pancreas grafts on the day 42 after transplantation. Histological examination revealed massive necrosis of kidney and pancreas allografts secondary to severe acute rejection. She returned to insulin therapy and hemodialysis. Psychosocial background of SPK patients is often complicated due to long-standing disease history. The adverse psychosocial consequences come from dependency on parents and medical personnel, unrelenting lack of respite from illness and continuous need for treatment, restricted diet and fluid intake, and multiple losses (disability, financial insecurity, loss of self-esteem, delayed independence, etc.) [2,3]. Additionally, psychosocial morbidity in transplant patients is common as the incidence of major depression and anxiety neurosis are 2–16% and 2–14%, respectively [2]. The patients sometimes develop poor coping and social skills that ultimately leads to frustration. These inappropriate behaviors may eventually lead to postoperative noncompliance and the loss of transplanted organs. Unfortunately, it is difficult to predict postoperative compliance as preoperative compliance does not necessarily reflect postoperative compliance [2,4–6]. So, it is important for physicians, transplant coordinators and other team members to recognize the signs of psychosocial morbidity in these patients. Addressing these issues earlier may prevent subsequent noncompliance and transplant organ loss.