Efficacy of auxiliary partial orthotopic liver transplantation for cure of hemophilia in a canine hemophilia A model.

Metabolic liver disease can be cured by orthotopic liver transplantation. Some successful cases of whole or partial liver transplantation have been reported. Because liver function in these recipients is normal save for the production of the responsive metabolic factor, auxiliary partial orthotopic liver transplantation (APOLT) may produce a benefit. However, no experimental model of APOLT for metabolic liver diseases has been reported. We established a canine APOLT model to evaluate the clinical feasibility and efficacy of APOLT to cure hemophilia. The donor normal beagle dog was used to establish an APOLT model. A left lobe partial liver graft taken from the donor was orthotopically transplanted to the recipient after resection of the native left lobe preserving the native right lobe. Recipients showed no atrophy and comparable blood flow in both the graft and the native liver at the time of exploration after APOLT. Thus, APOLT was performed from a normal donor to a recipient with hemophilia A. In this recipient, blood factor VIII activity markedly increased after APOLT and was maintained for 7 weeks. No episode of bleeding was seen during the observation. In conclusion, a canine APOLT model was successfully established as evidenced by sustained production of factor VIII in a hemophilia recipient. These findings suggest the clinical feasibility and efficacy of APOLT for metabolic liver diseases.

Intragraft expression of p38 and activated p38 MAPK (mitogen-activated protein kinase) in rat small bowel transplantation.

Recent studies suggest that cytotoxic T-lymphocytes expressing p38 mitogen-activated protein kinase (p38MAP kinase) contribute to allograft rejection in clinical heart transplantation. Interleukin-2 (IL-2), a potent T cell mitogen, activates the p38MAP kinase pathway, resulting in phosphorylation of target transcription factors. In this study we investigated the expression of activated p38MAP kinase in intragraft cell infiltrates following rat heterotopic small bowel transplantation and examined the effects of the immunosuppressant FK506 on intragraft expression of activated p38MAP kinase and allograft rejection. Allografts receiving FK506 (0.5 mg/kg per day i. m.) for 7 days as primary anti-rejection therapy had a significant reduction in histopathological evidence of allograft rejection on Day 7, compared to allograft controls. In addition, Western blotting analysis of intragraft cell infiltrates showed a reduction in the expression of activated p38MAP kinase in allografts treated with FK506. We conclude that intragraft cell infiltrate expression of activated p38MAP kinase is an important marker of acute rejection in this animal model of small bowel transplantation, and that FK506 is an effective immunosuppressant, in this situation, that may act in part by preventing the activation of p38MAP kinase.

The impact of interferon gamma receptor expression on the mechanism of escape from host immune surveillance in hepatocellular carcinoma.

Interferon gamma (IFN-gamma) plays an important role in host defense mechanism and participates in the progression of chronic liver disease. IFN-gamma exerts its pleiotrophic effects by transcriptional regulation of expression of numerous genes, such as major histocompatibility complex (MHC) class I and Fas, through interaction with IFN-gamma receptor (IFN-gamma-R). Although hepatocytes in normal liver express weak or no IFN-gamma-R, those in acute and chronic liver disease up-regulate its expression. A study using IFN-gamma-R alpha-chain knock-out mice revealed the actions of IFN-gamma on tumor cells as an extrinsic tumor-suppressor mechanism. However, it is unclear whether or how hepatocellular carcinoma (HCC) blocks the signal transduction of IFN-gamma to evade host immune surveillance. We examined the expression of IFN-gamma-R and IFN-gamma-inducible genes in 44 cases with HCC using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. In noncancerous liver tissues (n = 38), IFN-gamma-R expression on the cell surface was up-regulated in 27 cases. In IFN-gamma-R-negative cases (n = 15), tumor size was larger (P =.032), serum alpha-fetoprotein (AFP) level was higher (P =.001), intrahepatic and extrahepatic metastasis was more common (P =.044 and.013, respectively), and Ki-67 labeling index (LI) was higher (P =.041), compared with IFN-gamma-R-positive cases. Accordingly, the evasion mechanism may play an important role in progression, especially metastasis, in HCC. The significant correlation between the status of IFN-gamma-R and the expression of Fas and MHC implies that the loss of IFN-gamma-R might contribute to the mechanism of escape from host immune rejection in HCC.

The evaluation of meconium disease by distribution of cathepsin D in intestinal ganglion cells.

Meconium disease (MD) results in intestinal obstruction in the neonate where tenacious meconium is found in the distal ileum and proximal colon. The obstructive symptoms improve at several days of age after some of the meconium is passed. We observed premature infants with MD who underwent ileostomy for intestinal obstruction due to tenacious meconium. Afterward, meconium was passed well and the clinical symptoms improved. After closing the ileostomy, growth and defecation became normal. The MD in our cases was documented by histologic changes in the maturation of ganglion cells observed at the time of ileostomy creation and closure. For an objective evaluation of the maturation of intestinal ganglion cells (IGC), we attempted to distinguish immature from mature cells by the expression of cathepsin D. We examined the distribution of cathepsin D in IGC in patients with MD to test the hypothesis that ganglion-cell immaturity might be related to MD. In ganglion cells at the time of ileostomy, cathepsin D was detected in the perinuclear cytoplasm (immature staining pattern), while at the time of ileostomy closure it was detected in intense granules throughout the cytoplasm (mature staining pattern). We propose that it would be possible to evaluate the maturation of IGC by the intracellular distribution of cathepsin D in MD and suggest that immaturity of IGC might be the cause of MD.

A new evaluation of pancreatic function after pancreatoduodenectomy using secretin magnetic resonance cholangiopancreatography.

BACKGROUND: The remnant pancreatic function after pancreatoduodenectomy influences greatly postoperative quality of life. However, it has been difficult to evaluate the exocrine remnant pancreatic function postoperatively. The aim of this study was to assess the usefulness of secretin-stimulated magnetic resonance cholangiopancreatography (secretin MRCP) in evaluating the remnant pancreatic function and ascertaining the anastomotic patency after pancreatoduodenectomy. METHODS: Thirty-four patients who underwent pancreatoduodenectomy were evaluated with secretin MRCP. The results of MRCP were determined by the amount of exocrine pancreatic secretion, and were graded as follows: grade I (poor secretion), grade II (moderate secretion), and grade III (good secretion). RESULTS: Secretin MRCP could visualize the pancreatic secretion dynamically. MRCP grades were grade I in 11 patients, grade II in 12, and grade III in 11. There was a significant correlation between MRCP grade and glucose tolerance. We confirmed visually the patency of the anastomotic site in 24 patients (71%). MRCP grades correlated significantly with clinical symptoms. CONCLUSION: Our results demonstrated secretin MRCP was feasible for evaluating the remnant pancreatic function after pancreatoduodenectomy.

Pattern of recurrence after resection for intraductal papillary mucinous tumors of the pancreas.

The objective of this study was to clarify the patterns of recurrence and prognosis after resection of intraductal papillary mucinous tumors (IPMTs). Fourteen patients with IPMT were reviewed histologically; intraductal papillary adenocarcinoma was present in 12 cases and intraductal papillary adenoma in 2. Six patients were alive with no evidence of disease. Two patients died from other causes. Six patients had recurrences. The median survival time was 46 months. In the six recurrent cases, the median postoperative disease-free interval was 38 months. Four patients died of recurrence, and the median survival time after recurrence was 6 months. The major site of recurrence was the remnant pancreas. The other sites were the liver in two cases, peritoneum in two, and local in one. These results suggest the multicentric or metachronous oncogenesis of IPMT. Because of the low frequency of lymph node metastases, an operation to preserve pancreatic function may be recommended, especially for localized tumors such as the branch type. It is important to avoid an incomplete resection using intraoperative pancreatoscopy and ultrasonography. Long-term follow-up after surgery is necessary even for a curative resection. We should perform total pancreatectomy for recurrences without distant metastases.