Y Takada

Rapid and aggressive recurrence accompanied by portal tumor thrombus after radiofrequency ablation for hepatocellular carcinoma.

Although radiofrequency ablation (RFA) has been reported to be a safe and effective procedure for the treatment of hepatocellular carcinoma (HCC), patterns of recurrence and complications following RFA treatment have not been fully identified. Recently, we have experienced two cases of HCC patients who developed rapid and aggressive recurrence accompanied by portal tumor thrombus after RFA therapy. The first was a 68-year-old woman with hepatitis C virus (HCV)-positive liver cirrhosis, who received percutaneous RFA therapy for a 27-mm-diameter HCC in segment VII. The other was a 64-year-old man with hepatitis B surface antigen (HBsAg)-positive liver cirrhosis and multiple bilobar HCCs, who underwent left hemihepatectomy and intraoperative RFA for the two tumors in the remnant liver. In both patients, though immediate imaging studies suggested complete necrosis of the tumors, recurrences with massive portal tumor thrombus occurred in 4 and 6 months, respectively. At present, it is unclear whether such a recurrence pattern is directly related to the RFA procedure. However, it is implied that RFA therapy may entail a risk of promoting portal venous invasion of HCC tumors.

Increased intracranial pressure in a porcine model of fulminant hepatic failure using amatoxin and endotoxin

BACKGROUND/AIMSnThe purpose of this study was to develop a clinically relevant porcine model of fulminant hepatic failure (FHF) by means of administration of amatoxin and endotoxin.nnnMETHODSnPigs were intraportally administered only saline in group 1 (n = 3), 1 microg/kg of lipopolysaccharide (LPS) in group 2 (n = 4), 0.1 mg/kg of alpha-amanitin in group 3 (n = 5), and amanitin plus LPS in group 4 (n = 9).nnnRESULTSnAll the pigs in groups 1 and 2 survived with minimal changes in liver function tests. In contrast to the 60% mortality in group 3, all the pigs in group 4 died within 96 h, with a significant increase in aspartate transaminase at 24 h (9,757 +/- 2,167 IU/I). In addition, they demonstrated severe metabolic disorders, such as serum lactate accumulation, hypoglycemia, coagulopathy, plasma amino acid imbalance, and hyperammonemia. The intracranial pressure significantly increased to 17.8 +/- 2.5 mmHg immediately before death. Reversal of FHF in these pigs following orthotopic liver transplantation confirmed that the toxicity is liver-specific and that the graft liver is unaffected.nnnCONCLUSIONSnThis porcine model of FHF induced by a combination of amanitin and LPS will be of much use in the development of new therapies for human FHF.

Prolonged hepatic warm ischemia in non-heart-beating donors: Protective effects of FK506 and a platelet activating factor antagonist in porcine liver transplantation

BACKGROUNDnProlonged warm ischemic injury in non-heart-beating donors (NHBDs) significantly affects hepatic allograft function after liver transplantation (LTx).nnnMETHODSnThe effects of FK506 and the platelet activating factor antagonist E5880 on postoperative function of hepatic allografts procured from NHBDs were evaluated in porcine orthotopic LTx. In donors, livers were subjected to 90 minutes of warm ischemia and a subsequent 4-hour cold preservation. Group 1 (n = 6) was the untreated control group. In group 2 (n = 4), donors were pretreated with FK506 (0.3 mg/kg). In group 3 (n = 4), donors and recipients were treated with E5880 (0.3 mg/kg). In group 4 (n = 6), pigs were treated with both FK506 and E5880.nnnRESULTSnAll of the recipients in group 1 died within 12 hours. In groups 2 and 3, half of the recipients survived more than 12 hours. In group 4, all of the recipients survived more than 2 days (p < 0.01 compared with group 1). The improved survival seen in group 4 was associated with a reduction in the serum concentrations of glutamic oxaloacetic transaminase and lactate, and a restoration of hepatic energy charge.nnnCONCLUSIONSnThe present study suggests that FK506 and E5880 can improve the function of hepatic allografts subjected to prolonged warm ischemia in NHBDs, and that the protective effects of the two drugs seem to be synergistic.

Clonogenic colony-forming ability of flow cytometrically isolated hepatic progenitor cells in the murine fetal liver.

Stem cells are defined as cells having multilineage differentiation potential and self-renewal capability. Hepatic stem cells have aroused considerable interest not only because of their developmental importance but also for their therapeutic potential. However, their presence in the liver has not yet been demonstrated. With the use of a fluorescence-activated cell sorter (FACS) and monoclonal antibodies, we attempted to ascertain whether hepatic stem cells are present in the murine fetal liver. For this purpose, we optimized a cell isolation technique for FACS sorting of fetal liver cells. When isolated CD45–TER119– cells (the non-blood cell fraction in the fetal liver) were tested for their clonogenic colony-forming ability, mechanical dissociation (pipetting) was the most suitable cell isolation technique for FACS sorting. We confirmed that these colonies contained not only cells expressing hepatocyte markers but also cells expressing cholangiocyte markers. To identify hepatic stem cells, studies must focus on CD45–TER119– cells in the murine fetal liver.

Pharmacologic graft protection without donor pretreatment in liver transplantation from non-heart-beating donors.

Background. Non-heart-beating donors (NHBDs) are considered potential sources of transplant organs in an effort to alleviate the problem of donor shortage in clinical liver transplantation. We investigated the possibility of pharmacologic protection of hepatic allograft function from NHBDs without donor pretreatment. Methods. Orthotopic liver transplantation was performed using pigs. In donors, cardiac arrest was induced by stopping the respirator. Forty-five minutes after cessation of the respirator, the liver was flushed with cold lactated Ringer’s solution including heparin and with the University of Wisconsin (UW) solution, and then preserved for 8 hr at 4°C in the UW solution. The pigs were divided into two groups: a control group and a treated group. In the treated group, an endothelin antagonist TAK-044 was added to the UW solutions (10 mg/L), and TAK-044 (10 mg/kg body weight) and a platelet activating factor antagonist E5880 (0.3 mg/kg body weight) were also administered to the recipients. Results. TAK-044 and E5880 treatment significantly increased the 7-day survival rate of the recipients (100% vs. 17%, P <0.05). In the treated group, portal venous pressure immediately after reperfusion of the graft was significantly lower than in the control group, and postoperative increase in serum concentrations of glutamic oxaloacetic transaminase and total bilirubin was attenuated. Moreover, the energy charge and adenosine triphosphate concentration of the liver were rapidly restored after reperfusion. Conclusions. Pharmacologic modulation with TAK-044 and E5880 avoiding donor pretreatment can improve the viability of hepatic allografts procured from NHBDs.

An endothelin receptor antagonist ameliorates injuries of sinusoid lining cells in porcine liver transplantation.

BACKGROUNDnTAK-044 is an endothelin receptor antagonist. Whether the agent has protective effects on liver graft injuries from non-heart-beating donors is unknown.nnnMETHODSnIn donor pigs, cardiac arrest was induced by stopping the respirator. Forty-five minutes after cessation of the respirator, the liver was flushed with University of Wisconsin (UW) solution, preserved for 8 hours at 4 degrees C, and transplanted orthotopically. The pigs were divided into two groups: a control group and a drug-treated group in which TAK-044 was given in the UW solutions (10 mg/L) and was administered to recipients (10 mg/kg body weight).nnnRESULTSnTAK-044 treatment significantly increased recipient survival rate. After reperfusion of the graft, portal venous pressure and 15-minute retention rate of indocyanine green were significantly reduced in the drug-treated group. Electron microscopic findings indicated that TAK-044 attenuated endothelial cell injuries.nnnCONCLUSIONnTAK-044 treatment improves the viability of livers harvested from non-heart-beating donors. The main effect of the agent is protection of endothelial cells from ischemia/reperfusion injuries.

Large-animal models of fulminant hepatic failure

Abstractu2002For the development of an artificial liver support system, a clinically relevant large-animal model of fulminant hepatic failure (FHF) is indispensable. Although several large-animal models have been reported so far, they have not been entirely satisfactory. Recently, we have developed a new porcine model of FHF by means of intraportal administration of 0.1u2009mg/kg of α-amanitin and 1u2009μg/kg of lipopolysaccharide (LPS). This model has the following superior features: 100% mortality within 5 days along with a marked elevation of aspartate transaminase (AST) levels to around 10u2009000u2009IU/l, and severe metabolic disorders such as serum lactate accumulation, hypoglycemia, coagulopathy, plasma amino acid imbalance, and hyperammonemia; an onset of hepatic encephalopathy and a significant increase in intracranial pressure immediately before death; a reversal of FHF by orthotopic liver transplantation, proving that the toxicity is liver-specific and that the graft liver is unaffected; and the capability of the damaged liver to recover and achieve both morphological and functional regeneration in 1 week if supported by an efficient auxiliary graft. Because this porcine model satisfies many of the required criteria of an optimal FHF model, it is expected to provide a useful tool for the study of FHF and the development of new therapies.

Long-Term Results of Donor-Specific Blood Transfusion with Cyclosporine in Living Related Kidney Transplantation

Donor-specific blood transfusion (DST) was introduced to achieve better graft survival. However, its benefits are controversial considering the immunosuppression of cyclosporine (CYA) or tacrolimus (Tac), and its long-term effects have not been well discussed. Of the 40 patients who received DST with CYA, 3 (7.5%) became cross-match positive. Of the 37 patients with negative cross-match, 34 patients received a one-haplotype-matched kidney and were compared to patients with one-haplotype-matched kidney transplant without preoperative DST (n = 13). Acute rejection within 3 months after transplant was 29.4% in the DST group, and 15.4% in the non-DST group. All rejection episodes were steroid resistant in the non-DST group. If the graft survival rates were calculated excluding non-immunological graft loss, graft survival rate was 91.0 and 72.8% at 5 and 10 years in the DST group, and 83.3% at 5 and 10 years in the non-DST group, respectively. The two graft survival lines converged 7 years and 7 months after transplantation. No beneficial effect of DST was statistically evident under CYA immunosuppression. In terms of the severity of acute rejection or the onset of chronic rejection, DST induced a small benefit, however, which seemed to disappear within 8 years after transplantation.

Idiopathic calcifying pancreatitis in a Japanese pediatric patient

Abstract: We recently experienced a rare case of chronic pancreatitis in a 13-year-old Japanese boy. Recently, in hereditary pancreatitis patients, some mutations have been identified in the trypsinogen gene. The purpose of this study was to investigate whether the same mutations could also be found in this patient. Polymerase chain reaction (PCR)-amplified products of his cationic and anionic trypsinogen genes were examined by direct sequence analysis. The gene analysis failed to show any mutation in any exons and their flanking intronic sequences of his trypsinogen genes. These findings indicate that the chronic calcifying pancreatitis in the present patient is idiopathic, and thus a rare case of juvenile pancreatitis.

Radiation therapy for intrahepatic recurrence after hepatectomy for hepatocellular carcinoma

AbstractBackground. The intrahepatic recurrence rate after curative hepatectomy for hepatocellular carcinoma (HCC) is high, and management of recurrence is thus important for long-term survival. The use of radiation therapy has been relatively uncommon in the treatment of recurrent HCC.nMethods. Eight patients underwent radiation therapy for recurrent HCC 12–98 months after hepatectomy. Five of them were treated with protons (250u2009MeV; 68.8–84.5u2009Gy), and three were treated with X-rays (6u2009MV; 60 or 70u2009Gy). One patient received radiation therapy twice for another lesion with a 79-month interval. The target tumors were 1.2–4.5u2009cm. All patients also underwent transcatheter arterial embolization or other regional therapy.nResults. Although transient ascites was found in three patients after radiation therapy, no patient died as a result of the irradiation. Seven patients died 9 months to 4 years (median 1 year 6 months) after radiation therapy. Re-recurrence was observed in the irradiated liver in two patients (local control 78%). Four patients died of lung metastasis after radiation therapy. The median survival time was 3 years 3 months (range 1 year 1 month to 8 years 6 months) after recurrence.nConclusion. Multimodality therapy is necessary for the management of recurrence. Radiation therapy could be beneficial when other therapies present some difficulty regarding application or are performed incompletely. It must be emphasized that radiation therapy should be considered in addition to other regional therapies for the treatment of recurrent or re-recurrent HCC, and that radiation therapy can be repeated in selected patients.