Fumiaki Nozawa

Systemic inflammatory response syndrome and organ dysfunction following gastrointestinal surgery.

OBJECTIVES Progression from systemic inflammatory response syndrome (SIRS) to sepsis, severe sepsis, and septic shock has been demonstrated in a variety of patients. However, the presence of SIRS alone was not helpful in predicting the development of multiple organ dysfunction syndrome (MODS) since SIRS includes many nonprogressive conditions. This study was conducted to investigate the clinical significance of SIRS in postoperative patients. DESIGN Retrospective study. SETTING The surgical department of a university hospital. PATIENTS Two hundred ninety-two consecutive patients who received elective common gastrointestinal surgery (esophagectomy, pancreatoduodenectomy, hepatectomy, gastrectomy, colorectal resection, and laparoscopic cholecystectomy) between 1992 and 1995. INTERVENTIONS Patients were analyzed for preoperative physiologic status, surgical stress parameters, and postoperative status of SIRS, complications, and end-organ dysfunction. MEASUREMENTS AND MAIN RESULTS Duration of SIRS or positive criterias number of SIRS after surgery significantly correlated with surgical stress parameters (blood loss/body weight and operation time) and peak serum C-reactive protein concentrations. SIRS that continued or reappeared after postoperative day 3 was an early sign of postoperative complications. SIRS continuing consecutively for 2 days after postoperative day 3 had a 70.6% positive predictive value and a 92.5% negative predictive value for postoperative complications. Septic complications and prolongation of SIRS were associated with MODS. Five of six patients who met the SIRS criteria for >30 days developed severe MODS, and three of them died. CONCLUSIONS SIRS is a useful criterion for the recognition of postoperative complications and end-organ dysfunctions. Early recovery from SIRS may arrest the progression of organ dysfunction.

Indications for EMR/ESD in cases of early gastric cancer: relationship between histological type, depth of wall invasion, and lymph node metastasis.

BackgroundLimited surgery by endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) for gastric cancer is frequently performed in many institutions. These techniques do preserve gastric function and maintain a high quality of life but may compromise survival. The treatment strategy for early tumors should therefore be based on a complete cure, and limited surgery must thus have clear indications.MethodsD2 gastric resection was performed in 278 early gastric adenocarcinomas, and a retrospective histological review of the specimens was made. The extended indications for EMR or ESD, according to the Japanese Gastric Cancer Association Treatment guidelines for gastric cancer in Japan, were also assessed.ResultsOf the 278 early gastric cancers, 115 were mucosal (M) cancers without ulcer. No lymph node metastases were seen in these specimens. Six of the 41 specimens of M cancer with ulcers had lymph node metastases at the N1 level only. One of these had lymph node metastases from a tumor measuring less than 3 cm in size. Twenty-eight of 122 submucosal cancers had lymph node metastases (23%). Twenty of these were SM1 tumors and 5 had lymph node metastases; 4 of these 5 had lymph node metastases despite the absence of vascular invasion.ConclusionThree cases had lymph node metastases that met the extended criteria for EMR/ESD. EMR and/or ESD should be limited to M cancers without ulcer or differentiated-type M cancer with ulcers smaller than 2 cm. When the depth of tumor invasion is deeper than M, then a gastric resection with lymph node dissection is necessary.

Relationship between plasma cytokine concentration and multiple organ failure in patients with acute pancreatitis.

The dynamic aspects of circulating cytokines and cytokine modulators and their relationship with development of multiple organ failure (MOF) in patients with acute pancreatitis were analyzed. All cytokine and C-reactive protein levels in the circulation were higher than those in the MOF group. In particular, plasma concentrations of soluble tumor necrosis factor receptors (sTNF-RI and sTNF-RII) were significantly higher in patients with MOF than in those without even at admission. Furthermore, plasma concentrations of sTNF-Rs and interleukin-1 (IL-1) receptor antagonist (IL-1ra) were much higher than those of their counterparts, TNF-&agr; and IL-1&bgr;, respectively. These results suggest that the plasma concentrations of sTNF-Rs are useful predictors for the development of MOF, and actions of TNF-&agr; and IL-1&bgr; could be regulated by their modulators (soluble receptor and receptor antagonist, respectively) in the pathologic condition of severe acute pancreatitis.

The combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) and Genistein is effective in inhibiting pancreatic cancer growth.

Objectives: Our previous studies have shown that, contrary to many other human pancreatic adenocarcinoma cell lines, AsPC1 cells are resistant to the apoptotic effect of the tumor necrosis factor-related apoptosis-inducing ligand, also called Apo2L (TRAIL/Apo2L). In our in vitro studies, the combination of TRAIL/Apo2L and protein synthesis inhibitor, genistein, but not genistein alone, was, however, effective in inducing apoptosis in AsPC1 cells. In the present study, we examined the effect of TRAIL/Apo2L with genistein on the growth of AsPC1 cells in vitro and in vivo. Methods: Mice with orthotopically transplanted AsPC1 cells were treated either with TRAIL/Apo2L, Genistein (Gen) or a combination of both (TRAIL/Apo2L + Gen) for 14 days. After 14 days, the size and weight of the tumors were registered and the apoptosis of the tumor cells were determined by the TUNEL method. In vitro, the effect of combination treatment on cytotoxicity was assessed by MTT assay and apoptosis was assessed by DAPI staining. FADD, caspase 3, and PARP proteins were determined by Western blot. Results: No toxic side effects were observed in either group. The tumor volume was significantly smaller and the apoptotic ratio was higher in the TRAIL + Gen group than in the other 2 groups. The apoptotic effect was associated with the caspase-3 activation. Z-VAD-FMK partially inhibited apoptosis by TRAIL + Gen. Conclusions: These results indicate that the combination of TRAIL/Apo2L with genistein presents a promising therapeutic approach for the treatment of pancreatic cancer. Further detail investigations are needed, however, to verify the mechanisms of this combination therapy.

Altered Cytokine Response in Rat Acute Pancreatitis Complicated with Endotoxemia

We demonstrated that the dynamic aspects of cytokine production in rat acute pancreatitis, which was induced by cerulein and aggravated by subsequent lipopolysaccharide (LPS) injection. A priming effect by induction of mild pancreatitis with cerulein enhanced the subsequent cytokine production by LPS injection. Alternatively, after induction of severe pancreatitis with cerulein and LPS, cytokine production was markedly suppressed for ≥90 hours. Production of interleukin-2 (IL-2) by splenocytes decreased, and mortality rate after cecal ligation and puncture (CLP) increased significantly after induction of severe acute pancreatitis. These results suggest that the suppression of a cytokine response in severe acute pancreatitis may alter the defense system and, as a result, increase mortality after CLP.

Tumor Necrosis Factor α Acts on Cultured Human Vascular Endothelial Cells to Increase the Adhesion of Pancreatic Cancer Cells

We studied the effect of tumor necrosis factor a (TNFa), one of the major inflammatory cytokines, on the adhesive reaction of pancreatic cancer cells to human umbilical vein endothelial cells (HUVECs) and on the hepatic metastasis of cancer cells in vivo. After TNFa stimulation, the expression of E-selectin, an adhesion molecule to neutrophils on HUVECs, increased. In addition, the adhesion of pancreatic cancer cells to HUVECs increased after TNFa stimulation, as was observed with neutrophils. The TNFa-induced adhesive response depended on the extent of sialyl Lewis a expression on cancer cells. The hepatic metastasis in vivo was often observed when cancer cells expressing a high amount of sialyl Lewis a were inoculated intrasplenically after increase in plasma TNFa concentration by lipopolysaccharide administration. Because sialyl Lewis a on cancer cells is a ligand for E-selectin on HUVECs, as sialyl Lewis x on neutrophils, TNFa upregulated the adhesive interaction between sialyl Lewis a on cancer cells and E-selectin on HUVECs. These results suggest that production of TNFa after surgical trauma may stimulate the hematogenic metastasis of cancer cells with a high sialyl Lewis a expression.

Pancreatic Enzyme Extract Improves Survival in Murine Pancreatic Cancer

Objectives: The disappointing current therapeutic approaches for pancreatic cancer (PC) represent an urgent need for the development of novel methods to control the disease. Based on a recent report on the effectiveness of pancreatic enzyme therapy, we examined the effect of porcine pancreatic enzyme extracts (PPE) on human PC xenografts in nude mice. Methods: The malignant human PC cell line AsPC1 was transplanted into the pancreas of male beige XID nude mice that were treated or not with PPE in drinking water. The survival, size, and volume of tumors, plasma pancreatic enzyme levels, fecal fat, and urine were examined as were the expression of transforming growth factor α, insulinlike growth factor-I, epidermal growth factor, epidermal growth factor receptor, apoptosis, and proliferation rate of tumor cells. Results: PPE-treated mice survived significantly longer than the control group (P < 0.002). Tumors in the PPE-treated group were significantly smaller than in the control group. All mice in the control group showed steatorrhea, hyperglucosuria, hyperbilirubinuria, and ketonuria at early stages of tumor growth, whereas only a few in the treated group showed some of these abnormalities at the final stage. There were no differences in the expression of growth factors, epidermal growth factor receptor, or the apoptotic rate between the tumors of treated and control mice. Conclusions: The treatment with PPE significantly prolongs the survival of mice with human PC xenografts and slows the tumor growth. The data indicate that the beneficial effect of PPE on survival is primarily related to the nutritional advantage of the treated mice.

ErbB2 oncogene expression supports the acute pancreatitis-chronic pancreatitis sequence

Abstract. The pathogenesis of chronic pancreatitis remains controversial. According to the general opinion, chronic pancreatitis is a de novo disease with a silent but progressive restructure of the pancreas in response to environmental, nutritional or genetic factors. The necrosis-fibrosis sequence hypothesis, on the other hand, postulates that relapsing attacks of acute pancreatitis with subsequent development of fibrosis leads to chronic pancreatitis. Since in our previous studies the expression of two anti-ErbB2 growth factor receptor (ErbB2) antibodies was shown to discriminate between primary chronic pancreatitis, normal tissue, and secondary chronic pancreatitis caused by pancreatic cancer, we studied the ErbB2 expression in tissues obtained from acute, recurrent acute, and chronic pancreatitis to investigate a possible evolution of the ErbB2 expression pattern during the course of the disease. We subjected 14 normal pancreas, 15 chronic pancreatitis, and 12 acute pancreatitis (three with recurrent acute pancreatitis) specimens to immunohistochemical studies using polyclonal anti-ErbB2 antibodies from Santa Cruz and Dako. The immunoreactivity of islet cells in acute pancreatitis cases with the Santa Cruz antibody was less than that in normal pancreas in relation to the degree of tissue damage and fibrosis, and was negative in recurrent acute and chronic pancreatitis tissues. The Dako antibody, on the other hand, revealed a membrane staining of ductal and ductular cells only in chronic pancreatitis specimens and in some areas of recurrent acute pancreatitis. In conclusion, the similarities in the immunoreactivity of anti-ErbB2 antibodies in recurrent acute pancreatitis and chronic pancreatitis support the hypothesis that acute pancreatitis can be a forerunner of chronic pancreatitis.

Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 1: Basic Studies

CONTEXT Porcine pancreatic enzymes (PPE) extracted from glandular stomach has been used for the treatment of pancreatic cancer patients. Unfortunately, no information is available on the in vitro and in vivo effect on the pancreas and other tissues. OBJECTIVE We used Syrian Golden hamsters, a unique pancreatic cancer model, to obtain basic information on PPE for its eventual use for the treatment of pancreatic cancer. DESIGN PPE was used in different concentrations in vitro and in vivo. The stability of the enzyme in the water solution was investigated. It was given to the hamsters by gavage in concentrations of 1g/kg and 400 mg/kg for short periods and in aqueous solution for 65 days. Plasma enzyme and insulin, the size of islets and the number of the insulin cells per islet were examined. RESULTS The enzyme activity of PPE was maintained in water solution for at least 24 hours. Due to its content of calcium chloride it showed a high toxicity to normal and malignant hamster pancreatic cancer cells and human pancreatic cancer cell lines in vitro. PPE did not alter the plasma pancreatic enzyme levels regardless of the dose, duration and application route. On the contrary, PPE reduced their levels significantly. Remarkably, it also reduced the level of insulin, the size of the islets and the number of insulin cells in the islets significantly. CONCLUSION The results imply that PPE does not enter the blood circulation but it appears to slow down the function of both the exocrine and endocrine pancreas.

Effects of Porcine Pancreatic Enzymes on the Pancreas of Hamsters. Part 2: Carcinogenesis Studies

CONTEXT Our previous study suggested that porcine pancreatic extract in hamsters with peripheral insulin resistance, normalizes insulin output, islet size and pancreatic DNA synthetic rate. It also inhibited the growth of human pancreatic cancer cells in nude mice. OBJECTIVE To examine the potential value of the porcine pancreatic extract in controlling pancreatic carcinogenesis in this model, the present experiment was performed. DESIGN Hamsters were fed a high fat diet and four weeks later when insulin resistance emerges, they were divided into two groups. One group received 1 g/kg BW of porcine pancreatic extract in drinking water and the other group received tap water. One week later, when insulin output normalizes in porcine pancreatic extract-treated hamsters, a single subcutaneous injection of N-nitrosobis-(2-oxopropyl) amine (BOP) at a dose of 40 mg/kg BW was given to all hamsters. The experiment was terminated at 43 weeks after the porcine pancreatic extract treatment. The number and size of pancreatic tumors, blood glucose, insulin, amylase and lipase levels, the average size of islets and the number of insulin cells/islets were determined. RESULTS The incidence of pancreatic cancer was significantly lower in the porcine pancreatic extract group (P=0.043), as well as the plasma insulin level and the size of the islets in the porcine pancreatic extract group were significantly lower (P<0.001) than in the control group. No significantly differences were found in the glucose level between the groups. CONCLUSION These results show that porcine pancreatic extract has a potential to inhibit pancreatic cancer growth.