Factors predicting perioperative cytokine response in patients undergoing liver transplantation.

OBJECTIVES: An exaggerated production of proinflammatory cytokines during liver transplantation stimulates the inflammatory process within the graft, and eventually promotes liver failure. This study was conducted to evaluate factors predicting perioperative response of proinflammatory cytokines during liver transplantation. DESIGN: Prospective, consecutive entry study of liver transplant candidates. SETTING: University hospital. PATIENTS: Thirty liver transplant recipients. INTERVENTIONS: Arterial blood samples were obtained perioperatively. MEASUREMENTS: Interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha were measured by ELISA. Endotoxin was determined by a chromogenic endotoxin-specific method. MAIN RESULTS: The peak concentrations of IL-1beta and IL-6 in the patients with complications were significantly higher than those in the patients without complications. The peak concentration of IL-1beta was significantly correlated with the level of bilirubin at admission and the intraoperative blood product requirement. The peak concentration of IL-6 was significantly correlated with the admission bilirubin and the intraoperative blood product requirement. A multivariate regression model revealed that the serum bilirubin and the intraoperative blood product requirement were the independent factors that influenced the peak concentration of IL-1beta or IL-6. The severely jaundiced patients had a significantly higher plasma concentration of endotoxin at the end of the anhepatic phase. In addition, there was a tendency for these patients to have a higher postoperative peak concentration of endotoxin. CONCLUSIONS: Serum level of bilirubin may be a potent preoperative factor influencing perioperative cytokine response in patients undergoing liver transplantation. An enhanced perioperative response of endotoxin seen in severely jaundiced patients suggests the clinical implication of endotoxin removal during the anhepatic phase in liver transplant surgery.

Serum hepatocyte growth factor as an index of extensive catabolism of patients awaiting liver transplantation.

BACKGROUND: Whole body catabolism as the result of intrahepatic metabolic derangement is common in liver transplant candidates. However, individual nutritional assessment parameters lack sensitivity and specificity in determining energy status of these patients. Recently, serum hepatocyte growth factor (HGF) has been shown to reflect the recovery of hepatic energy metabolism after liver transplantation. AIMS: The relation between preoperative levels of serum HGF and metabolic variables was investigated to clarify the clinical value of measuring HGF in evaluations of the catabolism. PATIENTS/METHODS: Blood samples were obtained from 30 liver transplant recipients, and biopsy specimens were taken from each recipient's rectus muscle and the explanted liver. Preoperative serum concentration of HGF was determined. Whole body energy metabolism was assessed by measuring glycogen contents of biopsy specimens and plasma or serum levels of glucose, insulin, total ketone bodies, total carnitine, and amino acids. RESULTS: Serum HGF concentration was elevated in 22 of 30 patients and correlated with the Child-Pugh score. It showed a negative association with muscle glycogen content, and a positive correlation with serum levels of glucose, total carnitine, and total ketone bodies. Patients with elevated serum HGF concentrations had higher preoperative plasma levels of aromatic amino acids and branched chain amino acids, associated with lower branched chain to aromatic amino acid ratios. CONCLUSIONS: The elevated serum concentration of HGF in liver transplant candidates reflected inhibition of peripheral glucose storage, enhanced lipid oxidation, and increased peripheral release of branched chain amino acids, and thus extensive energy catabolism.

Energy storage and cytokine response in patients undergoing liver transplantation.

Overproduction of pro-inflammatory cytokines during surgery has been known to exert tissue-damaging and lethal effects on the host. Hypermetabolism-associated malnutrition, a common feature of patients with end-stage liver diseases, is related to the presence of a systemic inflammatory response, as reflected by enhanced levels of proinflammatory cytokines. The present study was designed to evaluate energy status of 29 liver transplant recipients, and to assess the relation of energy storage to post-operative cytokine response. The glycogen contents of the graft, and the recipient's abdominal muscle and old liver were measured. The plasma concentrations of tumour necrosis factor alpha, interleukin 1beta, interleukin 6, lactate, pyruvate and total ketone bodies were determined during and after surgery. In undernourished patients, ketone bodies seemed to be the major fuel available to muscle. The concentration of ketone bodies decreased rapidly after the incision, and remained at a low level after reperfusion. These patients had higher plasma levels of lactate/pyruvate ratio and aromatic amino acids during the anhepatic phase, followed by an exaggerated response of cytokines. Depletion of energy storage of the recipients may be involved in the deterioration of peri-operative energy metabolism and the exaggerated post-operative cytokine response.

Prognostic significance of the DNA index in a colorectal cancer.

DNA flow cytometry was performed on paraffin-embedded tissue blocks made from 230 surgically resected colorectal cancers, 109 (47.4%) of which were diploid tumors, and 121 (52.6%) aneuploid tumors. The DNA index (DI) was calculated as the ratio of the G0/G1 channel number of tumor cells to the G0/G1 channel number of stromal cells. There was no significant difference in survival between patients with diploid tumors and those with aneuploid tumors (P = 0.322), although the survival rate was significantly lower in patients with a high DI (> or = 1.5) than in those with a low DI (< 1.5) (P = 0.004). A multivariate analysis of prognostic factors using Cox's proportional hazard model showed that Dukes' staging was the strongest predictor of survival, followed by the DI of tumor cells, then histological differentiation. In conclusion, it is suggested that the DI of tumor cells is instructive for predicting the survival of patients with colorectal cancer.

Hepatic infarction as a complication of gastric cancer surgery: report of four cases.

Four cases of patients who developed hepatic infarction caused by an operative injury to the hepatic circulation during gastric cancer surgery are reported herein. In two patients, the hepatic infarction resulted from accidental injury to the proper hepatic artery, and in the other two, it was possibly due to persistent pressure on the folded liver by a retractor during surgery. In the former two patients, the proper hepatic artery had been collapsed by the spread of enlarged metastatic lymph nodes before the onset of the arterial injury. In the latter two patients, postoperative laboratory data and computed tomography scanning revealed hepatic infarction even though preservation of the proper hepatic artery was confirmed by angiography. Elevated serum levels of hepatic enzymes released from the infarcted tissue recovered to the normal range within three weeks in all four patients. In conclusion, when an operative injury to the hepatic artery is encountered, the hepatoduodenal ligament should not be manipulated any more than necessary to preserve the collaterals, and the gallbladder should be removed to prevent necrotic perforation. Although close observation is mandatory, conservative therapy seems to be sufficient when an infarcted area is restricted to the lateral segment and a small part of the medial segment of the liver.

Serum cell adhesion molecules in patients with colorectal cancer.

The serum levels of intercellular adhesion molecule-1 (sICAM-1) and endothelial leukocyte adhesion molecule-1 (sELAM-1) were determined in 40 patients with colorectal cancer. The sICAM-1 and sELAM-1 levels in the drainage venous blood adjacent to a tumor were significantly correlated with those in the peripheral venous blood in patients without evident hematogenous dissemination of tumor cells. The sICAM-1 levels in peripheral venous blood were significantly higher in patients with hepatic metastases, while the sELAM-1 levels were significantly higher in those with pulmonary metastases. An immunohistochemical study of metastatic sites in the liver revealed that ICAM-1 was expressed in cancer stroma, but not in the cancer cells. In conclusion, the sICAM-1 and sELAM-1 levels in the peripheral venous blood in colorectal cancer patients without any distant metastasis are likely to reflect the topical production of these cell adhesion molecules, and appear to be instructive in predicting hematogenous dissemination in patients with colorectal cancer.

Constant infusion rates of lipid emulsions to stabilize plasma triglyceride concentrations: medium-chain triglyceride/long-chain triglyceride emulsions (MCT/LCT) versus LCT.

As medium-chain triglyceride emulsions (MCT) are more rapidly hydrolyzed than long-chain triglyceride emulsions (LCT), MCT/LCT tends to be infused faster than LCT. The purpose of the present study was to determine the most appropriate infusion rate for MCT/LCT to stabilize plasma concentrations of triglyceride (TG), being equivalent to the optimal infusion rate of the emulsion. A TG clamp was set up by raising the mean +/- SD concentrations of TG in plasma, being 1.08 +/- 0.18 delta mmol l(-1) for LCT, and 1.65 +/- 0.31 delta mmol l(-1) for MCT/LCT after a 50-min priming infusion of each emulsion. Thereafter, the infusion rate of lipid was controlled every 10 min to maintain a steady concentration of TG for a period of 150 min. A constant infusion of glucose at 0.32 g/kg body weight (BW) per h was administered for the test period. The weight-based rate of the infusion to maintain a steady state of plasma TG concentrations did not differ between MCT/LCT and LCT, being 0.125 +/- 0.013 vs 0.117 +/- 0.021 g/kg BW per h, while the molar-based infusion rate was 0.203 +/- 0.021 mmol/kg BW per h for MCT/LCT and 0.132 +/- 0.023 mmol/kg BW per h for LCT (P < 0.05). These results suggest that although 54% more molar MCT/LCT-TG can be hydrolyzed during a constant infusion, MCT/LCT should not be infused at a rate faster than 0.1 g/kg BW per h under a steady state.

Demonstration of microcystic disease of the pancreas by magnetic resonance cholangiopancreatography: report of a case.

A case of microcystic disease of the pancreas which was clearly demonstrated by magnetic resonance cholangiopancreatography (MRCP) is reported herein. Cystic dilatation of the pancreatic duct was recognized by computed tomography scanning and endoscopic retrograde cholangiopancreatography (ERCP). Furthermore, the existence of microcystic clusters surrounding the dilated pancreatic duct were clearly visualized by MRCP. These microcystic clusters were strongly suspected preoperatively of having caused dilatation of the major pancreatic duct. Based on these findings, a distal pancreatectomy was performed. The operative specimen showed no accumulation of mucin and no evident lesions in the dilated pancreatic duct, being inconsistent with the entity of a mucus-producing tumor. Pathological examination revealed that the inner parts of microcysts constituted columnar epithelium with mucus production and papillary growth. Thus, a final histological diagnosis of intraductal papillary adenoma with idiopathic pancreatic duct ectasia was confirmed. In conclusion, MRCP, being a less aggressive diagnostic procedure than ERCP, proved extremely useful for obtaining precise information on cystic lesions of the pancreas in this patient.

Analysis of tenascin mRNA expression in the murine mammary gland from embryogenesis to carcinogenesis: an in situ hybridization study.

The expression of tenascin gene during murine mammary gland development was analyzed by in situ hybridization with non-radioactive cRNA probes. The aim was to identify whether cells that synthesize tenascin are mesenchymal or epithelial. During embryogenesis, tenascin mRNAs were demonstrated in the epithelial cells of the mammary bud on the 14th and 15th day of gestation, and in the mesenchymal cells from the 14th day to the 17th day, at the epithelial-mesenchymal border of the growing bud. However, cells displaying tenascin mRNAs were not found beyond the bifurcation of the mammary sprout at the beginning of the branching morphogenesis. In post-natal development, tenascin mRNAs were demonstrated in mesenchymal cells surrounding end buds in juvenile mice, in mesenchymal cells surrounding the epithelial cells of plaques, in epithelial cells of the lactating mammary gland, in malignant epithelial cells and in the mesenchymal cells surrounding cancer nests. By immunohistochemistry, tenascin immunoreactivity was shown to have the same spatiotemporal distribution as that of tenascin mRNAs, but was observed to be restricted to the stroma, except in the lactating mammary gland where tenascin was demonstrated in the milk by Western blot. The present study thus showed that both epithelial and mesenchymal cells are sources of tenascin at different stages of murine mammary gland development.

Influence of intraoperative blood loss on plasma levels of cytokines and endotoxin and subsequent graft liver function.

BACKGROUND: Excessive blood transfusion during orthotopic liver transplantation (OLT) is correlated with a lower graft survival rate. Experimentally, excessive hemorrhage is associated with endotoxemia and release of proinflammatory cytokines. OBJECTIVES: To measure the concentrations of plasma endotoxin and proinflammatory cytokines during OLT and to investigate their relation to intraoperative blood loss and graft viability. DESIGN AND SETTING: A prospective case series in a liver transplantation center. PATIENTS: Thirty patients who underwent OLT. Group 1 comprised 6 patients whose operative blood transfusion requirement was 10 U or more; group 2 comprised 24 patients whose operative blood transfusion requirement was less than 10 U. INTERVENTIONS: The following factors were measured in the plasma before and after OLT: interleukin (IL)-1 beta, IL-6, tumor necrosis factor alpha, hepatocyte growth factor, endotoxin, hyaluronic acid, and lactate. MAIN OUTCOME MEASURE: Graft viability. RESULTS: Two patients in group 1 died. All 24 patients in group 2 survived after they underwent OLT. The responses of IL-6 and IL-1 beta in group 1 were striking compared with those in group 2, and they were accompanied by an elevation of the endotoxin concentration and a subsequent elevation of the concentrations of hepatocyte growth factor, hyaluronic acid, lactate, and other factors that reflected graft viability. CONCLUSIONS: The changes in IL-6 seemed to respond to the excessive intraoperative hemorrhage, to provoke the elevation of the endotoxin concentration, and to be associated with the graft viability. The prevention of excessive intraoperative bleeding and the subsequent response of proinflammatory cytokines may be contributing factors to the success of liver transplant surgery.

Nonoperative treatment for a ruptured pseudoaneurysm of the celiac trunk: report of a case.

We report the case of a 67-year-old man in whom hemorrhage from a ruptured celiac trunk pseudoaneurysm, which occurred as a consequence of leakage at the site of gastroduodenostomy, was successfully controlled by transcatheter arterial embolization (TAE) with stainless steel coils and N-butyl cyanoacrylate (NBCA). The occurrence of a pseudoaneurysm of the celiac trunk associated with anastomotic leakage is etiologically rare. We compiled reports from the literature on TAE for ruptured aneurysms of the celiac trunk, and compared its therapeutic value with that of surgical treatment. Operative death occurred in 4 of a series of 43 patients with aneurysms of the celiac trunk that were surgically treated (9.3%). In 5 patients with ruptured aneurysms, the operative mortality rate was 40% (2/5). Conversely, while the unsuccessful rate of TAE therapy was 17% (1/6), the mortality rate was nil. The patient whose case is presented here was affected by methicillin-resistant staphylococcus aureus (MRSA) at the site of leakage and in the lung. Under septic conditions such as hemorrhage secondary to pancreatitis, the mortality rate of surgical therapy was 23%-29%, whereas the success rate of TAE therapy was 79% and the mortality rate was 4%. Based on these findings, it is suggested that TAE therapy is a viable alternative to surgery for patients even with ruptured pseudoaneurysms of the celiac trunk.

Effects of low dose X-ray irradiation on purine metabolism in mouse splenocytes.

This study examines the influence of low dose X-ray irradiation on purine nucleotide metabolites such as adenosine, inosine, hypoxanthine, xanthine and uric acid, and hence generation of ATP-mediated energy in mouse splenocytes. It was found that, unlike high dose irradiation which promotes membrane damage, low dose irradiation enhances the ability to regulate the energy metabolisms as reflected by the increase in Na+, K(+)-ATPase activity and the adequate activation of the above salvage pathway. Namely, the levels of adenosine, inosine and uric acid significantly increased, while the levels of xanthine and hypoxanthine decreased significantly. Moreover, the cysteine level and superoxide dismutase activity significantly increased at a dosage of 20 cGy.

Prognostic significance of the bromodeoxyuridine labeling index in primary colorectal carcinoma.

The bromodeoxyuridine (BrdU) labeling index was determined in 40 primary colorectal carcinomas by DNA flow cytometry using a BrdU-specific monoclonal antibody. The labeling index, or the fraction of cells in the S-phase of the cell cycle, ranged from 12% to 52%, with a mean of 28% (SEM, 2%). The labeling index in 19 patients was over 30%, which was termed a higher labeling index. There was no significant difference in the labeling index based on the clinical stage of the disease. During the 5-year follow-up after the apparently curative resection, 14 patients died of the disease, 1 died of an unrelated cause, 1 is alive with a recurrence of the disease, and 24 are alive without the disease. The higher labeling index was thus associated with a significantly poorer patient survival (P = 0.03 based on the generalized Wilcoxon test). The present study therefore disclosed that the S-phase fraction of tumor cells thus determined had prognostic significance in primary colorectal carcinoma.

Male inflammatory breast cancer.

We report herein the case of a 68-year-old man diagnosed with inflammatory breast cancer. The patient presented following the rapid onset of redness and swelling over the left anterior chest wall. On examination, the left chest wall and left axilla were extensively hard, and the left upper limb was swollen. Ultrasonography and computed tomography (CT) scanning disclosed a mass in the left breast, about 2 cm in diameter with an unclear margin, and swelling of the major and minor pectoral muscles. Needle biopsy of the breast mass confirmed invasive lobular carcinoma. As a radical operation was considered contraindicated, systemic and intraarterial chemotherapy using 5-fluorouracil (5-FU) and Adriamycin (ADR) were performed. Nevertheless, the patient died of carcinomatous pleurisy 6 months after the initial onset of the disease.

Clinical significance of the DNA index in hematogenous dissemination of aneuploid colorectal cancer.

The DNA index (DI), defined as the ratio of the G0/G1 channel number of tumor cells to the G0/G1 channel number of stromal cells, was analyzed in 121 aneuploid colorectal cancers. In patients with aneuploid tumors, a high DI significantly correlated with tumor penetration beyond the proper muscle layer, positive vascular invasion, and the presence of liver metastasis. This observation led us to conclude that a high DI is likely to be associated with hematogenous dissemination in aneuploid colorectal cancer.

Elimination of fat emulsion particles from plasma during glucose infusion.

To determine the optimal rate of infusion of a fat emulsion (long-chain triglycerides; LCTs) for parenteral nutrition, the rate of elimination of triglycerides from plasma was measured on two occasions in three healthy subjects, once while receiving LCTs alone (study I) and once while receiving a combined infusion of glucose and LCTs (study 2). In study 1 a hypertriglyceridaemic clamp was set up by raising the concentration of triglycerides to 2 mmol l(-1) (60-min priming infusion at 0.2 g LCTs per kg body-weight per h) and maintaining this value for 300 min. In study 2 a constant infusion of glucose at a rate of 0.32 g per kg body-weight per h was given throughout the 420-min test, and the hypertriglyceridaemic clamp was set up after 70 min. The infusion of glucose induced a progressive increase in the mean(s.d.) concentration of insulin from 4.3(0.4) microU ml(-1) to a plateau value of 11.0(0.2) microU ml(-1) which was sustained during the last 310 min of the study. During the steady state of the hypertriglyceridaemic clamp, the concentration of triglycerides (2.16(0.17) versus 2.12(0.20) mmol l(-1), P = 0.26), as well as the mean(s.d.) rates of infusion of LCTs (0.12(0.08) versus 0.12(0.04) per kg body-weight per h, P = 0.38), did not differ between studies 1 and 2. Thus, an infusion of glucose (and the associated physiological increase in the concentration of insulin) at doses commonly used in parenteral nutrition does not influence the rate of elimination of triglycerides from plasma in normal subjects.

Clinical significance of serum hepatocyte growth factor in orthotopic liver transplantation.

BACKGROUND: Hepatocyte growth factor (HGF) plays a key role in the regulation of liver regeneration after hepatocyte damage. Changes in HGF production reflect the status of the regeneration process. METHODS: Serum concentrations of HGF and energy substrates were measured during and after liver transplantation in 30 recipients. RESULTS: In the patients with compromised grafts (group A) HGF concentrations were persistently high after reperfusion, whereas in the patients with well-functioning grafts (group B), HGF concentrations decreased rapidly and remained low 4 hours after reperfusion. The patients in group A who died had persistently high concentrations of HGF. The surviving patients with reversible primary graft dysfunction in group A exhibited low concentrations 48 hours after reperfusion. The decrease in HGF concentration preceded the decrease in aspartate aminotransferase concentration. The metabolic parameters that reflect carbohydrate metabolism by the graft paralleled the changes in HGF. CONCLUSIONS: HGF may be more sensitive and specific in predicting early graft function than prothrombin time, ratio, aspartate aminotransferase, or arterial ketone body ratio. The determination of HGF levels after liver transplantation may yield valuable information for evaluating early graft function and making an early decision to repeat a graft procedure in an acutely ill patient.

The metabolic distinctiveness of emulsified lipid particles in the bloodstream and its clinical implications.

The advantages of administering intravenous fat emulsions are well known. Primarily, they are important sources of essential fatty acids; they allow the administration of many calories within a small volume; and they are isotonic compared to body fluid. In this review, the metabolic distinctiveness of parenterally infused fat particles in the bloodstream is evaluated under four main headings: (1) the structure and metabolism of fat emulsion particles; (2) the metabolism of phospholipid-rich fat emulsion; (3) the interactions between fat emulsion particles and plasma lipoproteins; and (4) the acquisition of protein moieties (apolipoproteins) by fat emulsion particles and its clinical implications.

Colorectal cancer in a patient younger than 20 years of age: report of a case and a review of the Japanese literature.

This article presents a case of advanced cancer of the transverse colon seen in an 18-year-old woman who underwent a potentially curative resection. The histological type of cancer was well-differentiated adenocarcinoma. After reviewing the clinicopathological features of 110 colorectal cancer cases in patients younger than 20 years of age compiled from the Japanese literature, the high incidence of poorly differentiated carcinoma (51.5% for poorly differentiated adeno-carcinoma, signet-ring cell carcinoma, mucinous carcinoma, and undifferentiated carcinoma) and of more advanced stages (67.1% for clinical stages IIIb and IV) were found to be characteristic for patients with colorectal cancer younger than 20 years of age. The presence of more advanced disease and the high incidence of poorly differentiated carcinoma thus seem to be related to the low postoperative survival rates. The 2-year survival rate was 19.8% and the 5-year survival rate was 8.8% in colorectal cancer patients younger than 20 years of age.