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Although intracholecystic papillary neoplasms (ICPNs) have been increasingly recognized, their features remain unclear because of the lack of standardized definition. This study aimed to elucidate clinicopathologic and genetic features of ICPNs using stringent diagnostic criteria. On the basis of the recently proposed criteria, gallbladder neoplasms showing delicate papillary growth were diagnosed as ICPNs, while polypoid papillary adenocarcinomas arranged in a complex architecture were categorized as papillary gallbladder cancers (GBCs). Clinicopathologic features were compared among ICPNs (n=7), papillary GBCs (n=24), and nonpapillary GBCs (n=44). Whole-exome and validation Sanger sequencing was also conducted. Gross mucin hypersecretion was detected in 3/7 ICPNs (43%), 1/24 papillary GBCs (4%), and 1/44 nonpapillary GBCs (2%) (P

Hepatocellular carcinoma (HCC) remains the third leading cause of cancer death in Japan. Although surgical resection represents the best hope of long-term survival, only 10%1,2 to 30%3 of HCC are amenable to operative resection because of either the extent of disease or cirrhosis-related liver dysfunction. Furthermore, even after resection with curative intent, patients often develop intra or extrahepatic recurrences.2,4–6 These circumstances have led many investigators to pursue less-invasive local therapies. In the past decade, percutaneous ethanol injection under ultrasonographic guidance has been used extensively to treat HCC around the world.7–9 However, it has recently been reported that percutaneous ethanol injection (PEI) was frequently associated with local recurrence.10,11 Other tumor ablation therapies, such as microwave coagulation therapy12 or radiofrequency ablation,13–15 are currently considered as alternative treatment options. These thermal ablative therapies seem to be adequate for the destruction of solitary HCCs associated with cirrhosis and are generally applied to those of less than 3 nodules each smaller than 3 cm. Hence, for HCC patients with larger tumors or multiple macro- and micrometastases, effective multimodality treatment approaches should be explored to improve the overall outcome and survival. Percutaneous isolated hepatic perfusion (PIHP) is a form of high-dose regional chemotherapy that enables the administration of cytotoxic agents at a dose of up to 10 times the maximally tolerated dose while reducing exposure of the entire body to the major side effects of the agents.16–20 Our previous studies have shown that PIHP is a safe and effective treatment to achieve a high rate of tumor regression in multiple HCC and yields long-term survival in a subset of patients with otherwise intractable HCCs.17,19 In this study, we investigated the efficacy of a novel 2-stage treatment combining reductive surgery and PIHP for the local control of multiple advanced HCC. The treatment strategy lies in the attempt to achieve tumor mass reduction during the first stage operation and, at the same time, to increase the efficacy and safety of PIHP for the residual liver tumors in the second stage.

Introduction: Recently, results of the clinical application of the two-layer method have shown the morphologic quality of the human pancreas grafts after reperfusion to be excellent, although ischemia-reperfusion injury is related to early graft loss in pancreas transplantation. However, some reports have indicated that heat shock proteins (HSPs) have important functions in response to the stress-related events. Aim: To examine whether the two-layer method reduced ischemia-reperfusion injury in a canine pancreas autotransplantation model by investigating the expression of HSPs. Methodology: There were three experimental groups in which dogs received segmental autografts after preservation by the two-layer method using University of Wisconsin solution (UW) (group 1), simple storage in UW (group 2) for 24 hours, or no preservation (group 3). Results: In group 1, pancreatic tissue perfusions were high, and pancreatic exocrine functions were well preserved after 1, 2, and 4 hours of reperfusion with low incidence of graft pancreatitis or vessel thrombosis compared with that in group 2. Moreover, ATP rapidly recovered, and HSP 60 was strongly enhanced after reperfusion in group 1. On the other hand, ATP recovery and the enhancement of HSP 60 were weak after reperfusion in group 2. Conclusion: The two-layer method reduced ischemia-reperfusion injury compared with UW simple storage in canine pancreas autotransplantation with a strong expression of HSP 60.

Hypothermia causes vascular endothelial damage that leads to graft microcirculation disorder and eventually thrombosis after reperfusion. The two-layer cold storage method (TL) was previously demonstrated to supply oxygen to the pancreas graft and maintain high adenosine triphosphate tissue concentration. In this study, we evaluated whether mild hypothermic (20 degrees C) preservation using the TL method could reduce endothelial damage while maintaining parenchymal viability. Graft survival by 20 degrees C preservation was investigated using a dog segmental pancreas autotransplantation model (simple storage in University of Wisconsin solution (UW) for 5 and 8 hours or TL for 5, 8, 12, and 24 hrs. respectively). Subsequently, the grafts were preserved in four different conditions (4 and 20 degrees C UW. 4 and 20 degrees C TL) for 8 hours to evaluate microvascular endothelial damage. Trypan blue uptake of vascular endothelium and pancreatic tissue perfusion were evaluated. No graft preserved by 20 degrees C UW for 5 and 8 hours survived (0/7 and 0/4). In contrast, the graft survival rates by 20 degrees C TL for 5, 8, 12, and 24 hours were 100% (5/5), 80% (4/5), 20% (1/5), and 0% (0/4), respectively. In trypan blue uptake analysis, there were significant differences between 4 and 20 degrees C in both UW and TL (4 degrees C UW, 37% [n = 5) vs. 20 degrees C UW, 13% [n = 4] [p < 0.01]; 4 degrees C TL, 29% [n = 5] vs. 20 degrees C TL, 10% [n = 5] [p < 0.011). The perfusion values in 20 degrees C TL were significantly higher than those in other groups at least for up to 120 minutes after reperfusion (p < 0.01 ). In short-term pancreas preservation, mild hypothermic TL reduced vascular endothelial cell damage and ameliorated graft microcirculation while maintaining parenchymal viability. Mild hypothermic TL may lessen vascular complications in clinical pancreas transplantation when used for several-hour preservation.

BACKGROUND FK506 is a clinically effective immunosuppressive agent and promoter of immunologic tolerance. However, limited information is available about the mechanism of FK506-induced immunosuppression. METHODS In the present study, we investigated the molecular mechanism of FK506-mediated enhancement of apoptosis using in vivo activated T lymphocytes. We examined the effects of FK506 on apoptosis-related proteins in superantigen-stimulated peripheral T cells. RESULTS Injection of staphylococcal enterotoxin B (SEB) into BALB/c mice resulted in a selective apoptosis of splenic Vbeta8-positive T cells after 48 hr. Injection of FK506 within 36 hr of SEB injection resulted in a marked enhancement of DNA fragmentation of splenic Vbeta8+ T cells. FK506 did not affect the expression of Fas antigen on SEB-activated Vbeta8+ T cells. As Bcl-2-related proteins are involved in apoptotic process, we also evaluated their role by examining the expression of Bcl-2, Bcl-X(L), and Bax on SEB-FK506-treated murine splenic T cells. Although SEB injection slightly increased the expressions of Bcl-2 and Bax on V138+ T cells, FK506 did not modulate Bcl-2 or Bax expression in these cells. In contrast, the expression of Bcl-x(L) on Vgamma8+ T cells, which was markedly induced by SEB, was abrogated by FK506. CONCLUSIONS Our findings indicate FK506-induced enhancement of apoptosis of activated T cells is mediated by down-regulation of Bcl-X(L) expression on these cells. Our results also suggest that Bcl-x(L) is a critical determinant of apoptosis of activated T cell and may represent a potential target for new therapies designed to achieve immunological tolerance.

Background.FK506 and glucocorticoids are used for allograft rejection, graft-versus-host disease, and autoimmune diseases.Materials.We investigated the combined effect of FK506 and glucocorticoids on T-cell apoptosis.Results.Dexamethasone injection in mice reduced the number of CD4+CD8+thymocytes by

For adult patients with end-stage liver disease, living-donor liver transplantation (LDLT) of right-lobe grafts with or without the middle hepatic vein (MHV) has been increasingly used in recent years. We investigated the role of the MHV in donor remnant liver regeneration after right-lobe LDLT, which has not been described in previous studies. A total of eight living donors were included in this study of right-lobe LDLT. Four donors underwent right lobectomy (without MHV), and the remaining four underwent extended right lobectomy (with MHV). Regeneration of the donor remnant liver was assessed by volumetric computed tomography studies before and 90 days after LDLT. Comparison between the right-lobe and extended right-lobe donors did not show a clear-cut difference in the net increase of remnant liver volume at 3 months. However, the mean volume increase of the medial segment at the 90th postoperative day was 7% in the extended right-lobe donors and 61% in the right-lobe donors, showing a lower value in the remnant livers without MHV. The MHV plays a specific role in remnant liver regeneration of right-lobe living donors. We expect that this knowledge will contribute to securing a margin of safety in right-lobe LDLT.

Rapid graft dysfunction caused by hepatitis C virus (HCV) reinfection, although uncommon, is a disastrous complication in liver transplant patients. Finding an effective therapy for this subgroup of patients with severe recurrent HCV is a priority.We describe a successful rescue of a 46-year-old man with recurrent hepatitis C (HCV genotype 1b) using long-term interferon (IFN) and ribavirin. The patient had a very aggressive type of posttransplantation HCV infection, as judged by biochemical and histologic findings.Despite high pretreatment values of serum alanine aminotransferase (ALT; peak value of 901 IU/L) and HCV-RNA (2.3 x 10(6) copies/ml), the combination therapy with IFN and ribavirin produced a rapid normalization of the serum ALT values, accompanied by the clearance of serum HCV-RNA. Although HCV-RNA reappeared in the serum at 3 months, the patient had continued ALT normalization and histological improvement with follow-up of over 26 months to date after the initiation of the combination therapy.This observation suggests that IFN in combination with ribavirin may offer an effective therapeutic option for liver transplant patients with severe recurrent hepatitis C.