Shigeki Tsukamoto

The mechanism of injury in a steatotic liver graft during cold preservation.

BACKGROUND Fatty livers are more prone to primary nonfunction after transplantation. It is known that cell injury is strongly associated with alterations in the content and composition of membrane lipids. We assumed that plasma membrane (PM) fluidity, which is the most important property of the membrane, differed between fatty and normal livers. METHODS The livers from obese and lean Zucker rats were flushed with cold Ringers lactate and University of Wisconsin (UW) solution via the portal vein and preserved in cold UW solution for 24 hr. Histological examinations of electron microscopy were performed to investigate of sinusoidal lining cells (SLCs). PMs were isolated using a discontinuous density gradient of Percoll, and the lipid compositions were determined by chromatography. RESULTS SLCs of fatty livers were markedly injured compared with control livers even after short preservation time. Moreover, many blebs were observed in the obese rats even after short preservation time. As for PM lipid composition, the cholesterol/phospholipid (PL) ratio of total PM was 0.14+/-0.03 in the obese rats and 0.21+/-0.03 in the lean rats (P<0.05). The relative proportions of polyunsaturated fatty acids among PLs in PM were 35.7+/-1.2% vs. 45.9+/-1.5% (P<0.0001). These results indicated that the fluidity of the PM in the obese rats is decreased after exposure to low temperatures. CONCLUSIONS Our results suggest that steatotic livers from obese donors are more susceptible to cold preservation injury than livers without steatosis because of the severe deterioration of SLCs, and it is associated with PM fluidity even after short-term cold preservation.

Tumor necrosis factor-induced, superoxide-mediated neutrophil accumulation in cold ischemic/reperfused rat liver.

The mechanisms of hepatic ischemia/reperfusion injury are complicated and multifactorial. This study was designed to examine superoxide generation and neutrophil accumulation in cold ischemic‐reperfused rat livers after elimination of Kupffer cells and to determine the role of superoxide/tumor necrosis factor (TNF) interactions. Rat Kupffer cells were eliminated by liposome‐encapsulated dichloromethylene diphosphonate injected intravenously. Livers from control and treated rats were isolated and preserved in University of Wisconsin solution (4°C) for 0, 12, and 24 hours and then perfused for 60 minutes with oxygenated Krebs‐Henseleit bicarbonate buffer (37°C) by adding neutrophils into the perfusate. Superoxide generation was measured by using real‐time chemiluminescence (CL) during perfusion, and neutrophil accumulation was assessed by measuring myeloperoxidase activity in the liver tissue. In the control livers, CL intensity markedly increased on reoxygenation, and after neutrophil infusion it increased again with a lag period of 10 minutes. Total CL intensity and myeloperoxidase activity increased with the duration of cold preservation. TNF release into the effluent perfusate was detectable only after 24 hours of preservation, and lactate dehydrogenase release was high. Elimination of Kupffer cells attenuated CL intensity and TNF and lactate dehydrogenase release and resulted in reduced myeloperoxidase activity. Electron microscopy revealed amelioration of hepatocyte swelling and endothelial cell disruption when Kupffer cells were eliminated. After 24 hours of preservation, superoxide generation was inhibited in the control livers by anti‐TNF antiserum, whereas TNF release was not inhibited by superoxide dismutase. These results suggest that TNF induces superoxide generation by Kupffer cells, which mediates neutrophil accumulation and causes cellular injury in the initial phase of reperfusion.

Elimination of Kupffer cells and nafamostat mesilate rinse prevent reperfusion injury in liver grafts from agonal non-heart-beating donors.

BACKGROUND We hypothesized that microcirculatory disturbance was an obstacle to liver transplantation (LTx) from non-heart-beating donors (NHBDs) and that it was attributed mainly to a deterioration of sinusoidal endothelial cells (SECs) and sinusoidal narrowing. This study was designed to examine porcine orthotopic LTx using livers obtained from pretreated agonal NHBDs, and to determine whether the maintenance of the liver microcirculation would result in successful LTx from agonal NHBDs. METHODS Pigs were allocated to five groups: (i) control group; (ii) NM group, in which grafts were rinsed with nafamostat mesilate (NM) rinse; (iii) LD group, in which Kupffer cells in grafts were eliminated by liposome-encapsulated dichloromethylene diphosphonate (L-DMDP); (iv) LDNM group, in which grafts pretreated with L-DMDP were rinsed with NM rinse; (v) heart-beating donor (HBD) group. In all groups, but the HBD group, the livers were pretreated with FK506 and prostaglandin I2 analogue, and were preserved in University of Wisconsin solution after cardiac arrest. Thereafter orthotopic LTx was performed. RESULTS After reperfusion, it was histologically demonstrated that elimination of Kupffer cells prevented SECs deterioration and NM rinse prevented sinusoidal narrowing. The hepatic energy charge recovered in all groups except the control group. In the LDNM group, three of four recipients survived more than 7 days. CONCLUSIONS For a successful LTx from agonal NHBDs, it is important to prevent microcirculatory disturbance caused by SEC deterioration and sinusoidal narrowing after reperfusion. Combination therapy consisting in the elimination of Kupffer cells and NM rinse prevented primary graft non-function in liver grafts from agonal NHBDs.

Complete response to multidisciplinary therapy in a patient with primary gastric choriocarcinoma

Primary gastric choriocarcinoma is a rapidly growing neoplasm with an average survival of several months in untreated patients. Gastrectomy with lymph node dissection followed by chemotherapy is the treatment of choice. Regimens used for gastric adenocarcinoma are usually selected. However, median survival remains less than six months. In this case report, we describe a case of primary gastric choriocarcinoma with a clinical complete response to multidisciplinary treatment including surgery, chemotherapy, and radiofrequency ablation (RFA). The patient was originally referred for general malaise. Esophagogastroduodenoscopy demonstrated a large tumor occupying the fornix, and total gastrectomy with lymph node dissection was performed. Seven days later, multiple liver metastatic recurrences with high serum levels of beta-human chorionic gonadotropin (β-hCG) were recognized. Chemotherapy with a gonadal choriocarcinoma regimen consisting of etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine (EMA/CO), was initiated. After three cycles, serum β-hCG decreased markedly and the tumors disappeared. Six months later, multiple lung metastatic recurrences were found. After one cycle of EMA/CO, only one nodule remained. Computed tomography-guided RFA was performed for this oligometastatic tumor. The patient has been alive with no evidence of disease for 10 years after the initial diagnosis. To the best of our knowledge, this patient with recurrent primary gastric choriocarcinoma has achieved the longest survival. The present case is the first report of choriocarcinoma metastatic to the lung successfully treated with RFA. From our retrospective analysis of recurrent or unresectable primary gastric choriocarcinoma, we propose that gonadal choriocarcinoma regimens can be considered as first-line for primary gastric choriocarcinoma.

Elimination of kupffer cells and administration of protease inhibitor improve graft viability and prevent reperfusion injury In NHBD

T HE SHORTAGE of donors has become a serious problem in liver transplantation (LTX). IF the liver graft from a non-heartbeating donor (NHBD) was available for LTX, the supply could be improved. But a liver graft from NHBD has not been suitable for LTX because the graft viability is deteriorated by warm ischemic injury and severe reperfusion injury. Over the past few years a considerable number of studies has been done on the mechanisms of warm ischemic injury and reperfusion injury. Many agents effective for these injuries, have also been reported. The aim of this study is to determine whether liver grafts from NHBD are suitable for clinical LTX.

New strategy for liver transplantation from non-heart-beating donors.

THE shortage of donors has become a serious problem in liver transplantation (LTx). LTx from controlled non-heart-beating donors (NHBD) has been attempted. However, it has been reported that the grafts from NHBD develop primary graft nonfunction more often than those from heart-beating donors. The aim of this study was to discover a safer method to prevent ischemia and reperfusion injuries in liver grafts from NHBD.

Acinar Cell Carcinoma of the Pancreas Successfully Controlled by IRIS: A Case Report and Literature Review

Acinar cell carcinoma (ACC) of the pancreas is a rare pancreatic tumor with poor prognosis. We present the first case of ACC of the pancreas successfully controlled by S-1 combined with a colorectal regimen. A 49-year-old Japanese female was referred to our clinic for right upper quadrant pain. Imaging studies demonstrated 2 solid tumors under the pancreas, and pancreatoduodenectomy with tumor resection was performed. Based on pathologic examination, the diagnosis of ACC of the pancreas was made according to the World Health Organization criteria. Eleven months after surgery, lymph node recurrence with elevations in serum concentrations of carbohydrate antigens (CA) 19–9 and CA125 were recognized. Treatments with carboplatin combined with paclitaxel, docetaxel, and gemcitabine, respectively, were attempted; however, there were no significant responses to these regimens. After starting S–1/irinotecan combination chemotherapy (IRIS), the concentrations of the tumor markers declined, accompanied by a reducti...

Hypercobalaminemia Induced by an Energy Drink after Total Gastrectomy : A Case Report

We encountered a case of hypercobalaminemia induced by oral intake of an energy drink after total gastrectomy. The patient was referred to our hospital due to findings suspicious for gastric cancer on screening. A 20 mm type 0-IIc lesion was detected in the gastric subcardia on esophagogastroduodenoscopy. Total gastrectomy followed by Roux-en-Y reconstruction was performed. He was discharged without complications. His basal serum vitamin B12 level was initially maintained with monthly intramuscular injections of vitamin B12. After 9 months, his serum vitamin B12 level suddenly increased up to 36-fold higher than the normal range and persisted there for one year without vitamin B12 injections. The patient ultimately reported consuming half a bottle of an energy drink each day during this time period. This case demonstrates the risk of unexpected hypervitaminemia resulting from self-administration of nutritional supplements.

Why is liver preservation performed at 4°C?

Abstract  To establish the most suitable temperature for liver preservation, we preserved rat livers at various temperatures (0, 5, 30, and 15 °C) in UW solution and investi gated, biochemically, the proton ATPase activity, ATP metabolites in mitochondria, and phosphatidyl‐choline hydroperoxide (PC‐OOH) in liver tissue. Liver specimens were taken every 6 h up to 24 h. The proton ATPase activity and the concentration of ATP, ADP, AMP, and adenosine in livers preserved at 0°C showed the best results. The total adenine nucleotide (TAN) in livers preserved for 18 and 24 h had significantly higher concentrations compared with those at other temperatures (5, 10, and 15 °C). In the livers preserved at 5 °C, TAN was degraded to hypoxanthine. On the other hand, those preserved at both 10 and 15 °C showed changes from hypoxanthine to xanthine. The concentration of xanthine in both groups preserved at 10 and 15 °C showed high values at 6 and 12 h, respectively, and similar changes in PC‐OOH concentrations at both 10 and 15 °C were observed. However, the changes in PC‐OOH concentration at various temperatures were not significant for any length of preservation time. In light mi croscopical examinations, there were no morphological changes in the hepatocytes. From these results, we conclude that the capability of ATP synthesis of mitochondria in livers preserved at 0 °C keep them in the best condition compared with livers preserved at 15, 10, and 5°C.