Prospective randomized trial of short-term neoadjuvant chemotherapy for advanced gastric cancer.

BACKGROUND: We performed short-term neoadjuvant chemotherapy (s-NAC) to examine whether anticancer drugs can change the proliferative ability of cancer cells in gastric cancer patients. METHODS: Chemotherapy was performed for 72 h before gastrectomy in 63 gastric cancer patients. Patients were classed into four groups: Group F, 16 cases who received a single administration of 5-fluorouracil (5-FU); Group C, 15 cases who received a single administration of cis-diamminedichloroplatinum (CDDP; cisplatin); Group FC, 16 cases who received both 5-FU+CDDP; and a Control group, 16 cases who did not receive chemotherapy. We reviewed neoadjuvant biopsy tissue and gastric cancer tissue delivered by operation in these cases. The TUNEL method and immunohistochemistry with an anti-MIB-1 antibody were used to evaluate cellular apoptosis and proliferative ability, respectively. The apoptotic index (AI) and an MIB-1 index (MI) were also calculated. RESULTS: There were no differences in AI or MI in biopsy tissue between the groups. The AI of gastric cancer tissue in Group FC was significantly higher than in the other groups (P < 0.01). The MI of Group FC was significantly lower than in the other groups (P < 0.05). In addition, after s-NAC operation there was a significant inhibition of proliferative potency and an induction of apoptosis in Group FC. CONCLUSION: Combination of CDDP and 5-FU reduced proliferative potency and increased cellular apoptosis in gastric cancer cells.

Significant expression of interleukin 15 in rat experimental severe acute pancreatitis.

PURPOSE: In severe acute pancreatitis (SAP), multiple organ dysfunction syndrome is a contributor to high mortality. We recently demonstrated that the serum interleukin (IL)-15 level is a predictor of the complications and mortality in clinical SAP. The aim was to investigate the role of IL-15 in experimental SAP. MATERIALS AND METHODS: SAP was induced by retrograde injection of 3 and 20% sodium deoxycholate (DCA) into biliopancreatic ducts in rats (DCA pancreatitis). Expressions of IL-15 were evaluated by Western blotting and immunohistochemical staining. Recombinant IL-15 protein was administered intraperitoneally, and the effects were investigated. RESULTS: Western blotting revealed the expressions of IL-15 in the pancreas, liver, lung and intestine in 3% DCA pancreatitis. Immunohistochemical staining showed the expression of IL-15 in the cytoplasm of each organ. In 3% DCA pancreatitis, administration of recombinant IL-15 protein attenuated the elevation of serum alanine aminotransferase (ALT) levels and improved the morphological change of the lung 18 h after the induction of SAP. Moreover, in 20% DCA pancreatitis, IL-15 improved the elevation of serum amylase and ALT levels 6 h after the induction. CONCLUSIONS: These results suggest that IL-15 is related to organ dysfunction during SAP, and that IL-15 functions as a protective factor against the organ injuries.

Laparoscopic intervention for intrathoracic stomach in infants.

BACKGROUND: Intrathoracic stomach is an uncommon condition in infants. We report our experience managing such a condition successfully by laparoscopy in four patients. METHODS: Patients' ages at the time of operation ranged from 30 days to 14 months. In all cases, the intrathoracic stomach was easily pulled down into the abdominal cavity. The phrenoesophageal ligament was completely resected, and the enlarged hiatus was narrowed by intraabdominal suturing technique. The esophagus was wrapped with the mobilized fundus in a floppy fundoplication. Anchoring sutures were placed between the wrapping cuff and crura. RESULT: One patient had paraesophageal hernia (type 2), whereas the other had combined hiatal hernia (type 3). No adverse complications were observed in any of the cases. Symptomatic gastroesophageal reflux and radiographic recurrence of hernia were not seen in any case. The cosmesis was excellent in all cases. CONCLUSIONS: We conclude that laparoscopic repair for intrathoracic stomach is a safe and feasible method when preoperative evaluation is conducted adequately.

Metabolic effects of systemic venous drainage in small bowel transplantation.

Small bowel transplantation has proved feasible in rats and in larger animals, but several important questions remain to be addressed before it becomes routine therapy in humans. One consideration is the site of venous outflow of the allograft. While portal drainage reestablishes the physiologic route of venous outflow, systemic drainage creates a partial mesocaval shunt, the metabolic consequences of which have not been studied in detail. Using a canine model of orthotopic small bowel autotransplantation, we compared the metabolic changes following transplantation with portal versus systemic venous drainage. Changes in blood ammonia levels, plasma amino acid composition, and hepatic blood flow were studied, since the Eck procedure produces metabolic changes of hyperammonemia and amino acid imbalances, while portocaval venous drainage of small bowel transplant produces a profile similar to that in controls. These data suggest that there is no metabolic disadvantage of systemic venous drainage as compared with controls. Because of its technical simplicity, systemic venous drainage may be preferable for small bowel transplantation.

Benign transient non-organic ileus of neonates.

There are a substantial number of neonates who present with Hirschsprung's disease-like symptoms, but respond very well to conservative therapy. However, once Hirschsprung's disease is ruled out, little attention is paid to these infants, because of the lack of necessity for surgical treatment and their excellent prognosis. The purpose of this study was to elucidate the clinical features of functional ileus of neonates, which we named benign transient non-organic ileus of neonates (BTNIN). Out of 61 neonates referred to our institution with suspected neonatal Hirschsprung's disease (NH), 10 were diagnosed as having NH and 51 as having BTNIN. All the cases of BTNIN showed marked abdominal distension, and 12 showed explosive defecation on digital examination at the first visit. Plain X-ray demonstrated marked whole intestinal dilatation in 12 cases including cases with niveau formation and segmental dilatation. These findings were indistinguishable from those of NH. However, all had a normal anorectal reflex, and rectal suction biopsy revealed normal acetylcholinesterase activity and submucosal ganglion cells. All the cases of BTNIN were treated with periodic glycerin enemas until daily spontaneous defecation was established, which took 2 to 14 months, with an average of 5.0 +/- 2.9 months. None of them showed residual symptoms during the follow-up period.

Proinflammatory cytokines induce liver and activation-regulated chemokine/macrophage inflammatory protein-3alpha/CCL20 in mucosal epithelial cells through NF-kappaB [correction of NK-kappaB].

Liver and activation-regulated chemokine (LARC)/CCL20 is expressed by surface-lining epithelial and epidermal cells, and is likely to link innate and acquired immunity by attracting immature dendritic cells, effector memory T cells and B cells via CCR6. Here we examined the mechanism of LARC expression in epithelial-type cells. Either IL-1beta or tumor necrosis factor (TNF)-alpha strongly induced LARC mRNA in intestinal cell lines Caco-2 and T84, while both were effective on HEK 293T cells. Induction of LARC was also demonstrated in the intestinal epithelium of BALB/c mice upon treatment with IL-1alpha or TNF-alpha. Transient transfection assays using murine LARC promoter-reporter constructs identified a region essential for IL-1beta- or TNF-alpha-induced promoter activation in Caco-2 and 293T cells. Using site-directed mutagenesis, we demonstrated that an NF-kappaB site located between -96 and -87 bp upstream from the transcriptional start site was both necessary and sufficient for IL-1beta- or TNF-alpha-induced promoter activation in Caco-2 and 293T cells. Electrophoretic mobility shift assays demonstrated that p50/p65 heterodimer and p65 homodimer of NF-kappaB bound to this site in 293T cells upon treatment with IL-1beta and TNF-alpha, and p50/p65 heterodimer bound to this site in Caco-2 cells upon treatment with IL-1beta. Co-expression of constitutively active p65 strongly activated the promoter construct carrying the intact NF-kappaB site in 293T and Caco-2 cells. Collectively, LARC expression in intestinal epithelial-type cells is induced by proinflammatory cytokines such as IL-1 and TNF-alpha primarily through activation of NF-kappaB.

The preparation of the chronic hyper-endotoxemia experimental animal model by means of a drug delivery system.

A drug delivery system (DDS) consisting of lipopolysaccharide (LPS) as a drug and 2-hydroxyethyl methacrylate (HEMA)-diethylene glycol dimethacrylate (2G) or -polyethylene glycol dimethacrylate (4G, 9G) copolymer was prepared, and used for the efficient preparation of an experimental animal model of chronic hyper-endotoxemia. The release profiles of LPS in the in-vitro test were greatly influenced by the composition of HEMA-2G, 4G, 9G in the copolymer. It was found that LPS release from the DDS continued gradually and constantly throughout 2 weeks. In the in-vivo experiment with rats, the DDS maintained a high blood concentration level of LPS for 3 days. These results strongly suggest the possibility of convenient and reproducible preparation of a chronic hyper-endotoxemia animal model.

Application of a drug delivery system in a novel rat model of chronic hyperendotoxemia.

There has not been an ideal reproducible small-animal model of chronic hyperendotoxemia to date. Our drug delivery system (DDS) is a new technology that can deliver a drug conveniently to a target organ at an optional rate. 2-Hydroxyethyl methacrylate (HEMA) was used as a carrier of lipopolysaccharide (LPS), and diethylene glycol and polyethylene glycol dimethacrylates (2G, 4G, 9G) were used as cross-linking agents. A mixed solution of HEMA and di(poly)ethylene glycol dimethacrylate was charged into a glass tube with or without LPS and polymerized by ultraviolet irradiation. This polymer was cut into DDS tablets of the same size with or without LPS. A mixture with HEMA:4G = 1:3 was the most suitable composition to release a constant concentration of LPS. We also developed a novel rat model of chronic hyperendotoxemia. Four DDS tablets, each containing 15 mg LPS, were implanted into the abdominal cavity of rats in the LPS group. The control group was implanted with four DDS tablets without LPS. Plasma levels of LPS in the study group were maintained at more than 2,000 pg/ml for 72 h after implantation. Weight gain was lower and body temperature was higher in the LPS group than in the control group. Plasma levels of inter leukin (IL)-6 in the LPS group were higher than in the control group only during the initial 12 h after implantation of DDS tablets. The white blood cell count at 24 h and platelet counts at 24, 48, and 72 h in the LPS group were lower than those in the control group. These results indicate that chronic hyperendotoxemia was maintained for 72 h by continuous release of LPS from the DDS. Moreover, the intensity of endotoxemia could be varied by varying the number of DDS tablets. It is concluded that our new rat model using LPS-DDS will be applicable and useful as a model of chronic hyperendotoxemia.

IGF-1 stimulates mucosal growth in ileal Thiry-Vella fistulas.

BACKGROUND/AIMS: We determined whether the trophic effects of IGF-1 (Insulin-like growth factor-1) on the small bowel mucosa are mediated by either nonluminal factors or endogenous luminal secretion. The gut hormone IGF-1 stimulates growth of small bowel mucosa. The mechanisms responsible for this trophic effect are not known. METHODOLOGY: Rats underwent construction of a Thiry-Vella fistula of ileum. On postoperative day 10, the two groups were subdivided to receive either saline (control) or IGF-1. After 7 days, rats were killed and the Thiry-Vella fistula was removed. The mucosa was scraped and weighed, and protein content and alkaline phosphatase activity was determined. RESULTS: IGF-1 significantly increased mucosal weight and alkaline phosphatase activity and protein content of ileal Thiry-Vella fistula compared with the control rats. CONCLUSIONS: IGF-1 mediated stimulation of small bowel mucosal growth is mediated by factors that are independent of luminal contents and pancreaticobiliary secretion. IGF-1 may prove to be an important enterotrophic factor for gut mucosal proliferation.

Hepatobiliary scintigraphy after biliary reconstruction--a comparative study on Roux-Y and ESCD.

BACKGROUND/AIMS: Reconstruction of extrahepatic biliary tract with benign lesion still has some unsettled problems, such as postoperative cholangitis. This study was conducted to compare bile through the remnant alimentary tract in patients undergoing end-to-side choledochoduodenostomy, and those undergoing Roux-Y choledochojejunostomy, using hepatobiliary scintigraphy. METHODOLOGY: Five normal human volunteers and 13 patients underwent end-to-side choledochoduodenostomy (n = 5), Roux-Y choledochojejunostomy (n = 8), using hepatobiliary scintigraphy. RESULTS: Postoperative acute cholangitis developed in 1 patient (12%) with Roux-Y choledochojejunostomy and none with end-to-side choledochoduodenostomy. Hepatobiliary scintigraphy showed prominent stasis of 99mTc in the proximal jejunum loop of the patients who underwent the Roux-Y choledochojejunostomy procedure, which was not found in the upper jejunum of the patients with end-to-side choledochoduodenostomy. The time taken before visualization of 99mTC at the upper jejunum in the patient who underwent Roux-Y choledochojejunostomy (66.5 +/- 5 min) was significantly longer than that in the healthy controls (40 +/- 5 min). On the other hand, the time taken before visualization of 99mTc at the upper jejunum in end-to-side choledochoduodenostomy (35 +/- 5 min) was similar to that of healthy controls. CONCLUSIONS: This data suggested that end-to-side choledochoduodenostomy procedure for reconstructing the extrahepatic biliary tract was more physiological with less postoperative complication than Roux-Y choledochojejunostomy procedure.

Laparoscopic splenopexy for adult wandering spleen: sandwich method with two sheets of absorbable knitted mesh.

Wandering spleen is a rare entity with a constant danger of splenic torsion leading to splenomegaly and infarction, which requires surgery. The authors describe a 30-year-old woman with intermittent left hypochondralgia and back pain with wandering spleen, who was successfully treated with a new method of laparoscopic splenopexy. In this procedure, two sheets of absorbable knitted mesh were used to sandwich the detorsed spleen. The procedure is feasible and less invasive, without impaired splenic function, and is applicable even for adult splenomegalic wandering spleen.

Massive bleeding from multiple jejunal diverticula associated with an angiodysplasia: report of a case.

We report herein the case of a 70-year-old woman who presented with massive bleeding from multiple jejunal diverticula. She was initially admitted to our hospital with massive melena. An upper gastrointestinal endoscopic examination revealed no bleeding site. Colonoscopy revealed clotted and red blood throughout the colon, and a small diverticulum in the ascending colon which was thought to be the source of bleeding. Following admission, she was treated conservatively at first, but melena continued and the anemia did not improve despite blood transfusions. A laparotomy was performed and multiple jejunal diverticula, distributed from 10 to 40 cm distal to the ligament of Treitz, were found. A segment of the jejunum containing all diverticula was resected. The most distal diverticulum contained a clot of blood, but no ulceration was observed. A histological examination revealed many dilated blood vessels in the mucosa and submucosa of this diverticulum, which were compatible with the findings of angiodysplasia. Based on these findings, we believe that angiodysplasia was the cause of bleeding from the jejunal diverticula in this case.

In vivo evaluation of long-term patency of pancreaticoenterostomy after Whipple operation.

BACKGROUND/AIMS: The aim of this study was to examine the long-term patency of pancreaticoenterostomy in vivo. METHODOLOGY: Evaluation of the patency of the pancreaticoenterostomy was conducted in 12 patients who had undergone the Whipple procedure. After intravenous infusion of secretin (1 microgram/kg), the diameter of the pancreatic duct was taken at 1, 3, 5, 15, 20 and 25 min by means of ultrasonography. We estimated the degree of anastomotic stricture by the maximal dilatation ratio [MDR: Maximal value (Dmax)/basal value (D0)]. The patients underwent pancreatic exocrine function tests before and 1-2 years after surgery. RESULTS: Maximal ductal dilatation was noted from 3 min of 15 min after secretin infusion, thereafter ductal diameter gradually diminished and returned to its basal value at 25 min. Maximal dilatation ratio ranged from 1.3-2.5, 1.7 +/- 0.12. There was a good negative relationship between the maximal dilatation ratio and pancreatic exocrine function. Based on the result of chi 2 analysis, we judged anastomotic stricture to be present in 2 patients with maximal dilatation ratio above 2.0. In these 2 patients, preoperative pancreatic exocrine function recoveries were 69 and 48%, while postoperative pancreatic exocrine function recoveries were 13.8 and 18%, respectively. In the other 10 patients, there was no difference between preoperative and postoperative value of pancreatic exocrine function. CONCLUSIONS: The present method permits safe and non-invasive evaluation of the patency of pancreaticoenterostomy.

Combining the selective arterial calcium injection test and intraoperative blood glucose monitoring for multiple insulinomas: report of two cases.

To date, no precise methods of preoperatively localizing multiple insulinomas or intraoperatively confirming their complete removal have been established. We describe herein the effectiveness of combining the selective arterial calcium injection (SACI) test to locate tumors preoperatively, with intraoperative continuous blood glucose monitoring (IOBGM) to confirm their complete removal. During the 8-year period from 1990 to 1997, we experienced two patients with multiple insulinomas. The first patient required resection of a residual tumor in the remnant pancreas for persistent hyperinsulinemia after a distal pancreatectomy performed under conventional diagnostic procedures. In the second patient, a SACI test was performed in addition to other diagnostic imaging procedures, and while computed tomography scan, endoscopic ultrasonography, and arteriography demonstrated multiple tumors in the body and tail of pancreas, the SACI test suggested that there were also tumors in the head of pancreas. Intraoperative ultrasonography showed a tumor measuring 5 mm in diameter on the surface of the head of the pancreas, apart from the multiple tumors in the body and tail of the pancreas. Complete removal of all tumors was assessed by the hyperglycemic rebound after resection of the tumors, determined by IOBGM. Based upon our experience, we believe that the SACI test and IOBGM are helpful for establishing precise localization and achieving complete removal of multiple insulinomas.

Effectiveness of acidic oxidative potential water in preventing bacterial infection in islet transplantation.

At a number of points in the current procedures of islet isolation and islet culture after the harvesting of donor pancreata, microorganisms could potentially infect the islet preparation. Furthermore, the use of islets from multiple donors can compound the risks of contamination of individual recipients. Acidic oxidative potential water (also termed electrolyzed strong acid solution, function water, or acqua oxidation water), which was developed in Japan, is a strong acid formed on the anode in the electrolysis of water containing a small amount of sodium chloride. It has these physical properties: pH, from 2.3 to 2.7; oxidative-reduction potential, from 1,000 to 1,100 mV; dissolved chlorine, from 30 to 40 ppm; and dissolved oxygen, from 10 to 30 ppm. Because of these properties, acidic oxidative potential water has strong bactericidal effects on all bacteria including methicillin-resistant Staphylococcus aureus (MRSA), viruses including HIV, HBV, HCV, CMV, and fungi as a result of the action of the active oxygen and active chlorine that it contains. We conducted this study to evaluate the effect of acidic oxidative potential water irrigation on bacterial contamination on the harvesting of porcine pancreata from slaughterhouses for islet xenotransplantation by counting the number of pancreatic surface bacteria using the Dip-slide method, and on the results of islet culture; and to evaluate the direct effect on isolated islets when it is used to prevent bacterial contamination by the static incubation test and by morphological examination. Direct irrigation of the pancreas by acidic oxidative potential water was found to be very effective in preventing bacterial contamination, but direct irrigation of isolated islets slightly decreased their viability and function.