Experimental study of the effect of bile juice on the remnant gastric cancer development

Experimental studies were performed to investigate the role, if any, of bile reflux in cancer development in the stomach. A 20% solution of human bile juice and 50 micrograms/ml of the known carcinogenic MNNG were given perorally and heterochronically to male Wistar rat, and the incidence of carcinoma in the gastric gland of the rat was studied. The animals were divided into 4 groups: Group I, to which only MNNG was given. Group II, to which human bile juice and then MNNG were administered. Group III, to which MNNG and then human bile juice were administered. And Group IV, to which only human bile juice was given. The incidence of cancer was 37.5% (3/8) in Group II, 25% (2/8) in Group III, and 0% in Group I (0/12) and IV (0/12). The gastric gland mucosa was histologically examined at various times and also by microautoradiography using 3H-TdR. The results suggested that a reverse flow of bile juice to the human remnant stomach may induce an increase in proliferative cells in the lacunar epithelia of the stomach mucosa and that a predisposed site would then be available for cancer development.     

The influence of reflux of bile and pancreatic juice on gastric carcinogenesis in rats

The effect of reflux of the duodenal contents on the development of gastric stump carcinoma without carcinogen in rats was studied. At the first experiment, seventy male Wistar rats were subjected to gastrojejunostomy for the diversion of duodenal contents into the resected stomach through the afferent and the efferent loops. The incidence of adenocarcinoma in the afferent anastomosis were 0/8 (0%) at the 10th week, 3/16 (18.8%) at the 20th week and 7/20 (35%) at the 40th week, so the incidence was apt to rise in parallel to the time. In the second experiment, ninety rats were divided into 4 groups: Group I received the same operation as the first experiment, group II received the operation with Braun's anastomosis, group III received the operation for reflux of bile alone to the remnant stomach, and group IV received the operation for reflux of pancreatic juice alone. Animals surviving after surgery were sacrificed at the 40th week. The incidence were 33.3% in group I, 0% in group II, 0% in group III, and 8.3% in group IV, respectively. These findings suggest that reflux of duodenal contents (both bile and pancreatic juice) is an important factor in the gastric stump carcinogenesis.     

The extent of bile reflux and development of gastric cancer after resections in rat

Authors performed gastric resections (Billroth II, Billroth I, Billroth II+, Braun anastomosis and Roux Y reconstruction) and laparotomies in five groups, of 110 Wistar male rats. Thirty-eight weeks postoperatively the surviving 91 animals were sacrificed, and histological study was made of the frequency of gastric stump cancer in the individual groups and the extent of bile reflux characteristic of the individual GEA types was measured. Based on their results, the risk of stump cancer was higher in operation types associated with considerable bile reflux (a cancer incidence rate of 50% after Billroth II, 28.5% after Billroth I). Following gastric resections accompanied by insignificant bile reflux (Billroth II + Braun, Roux Y) the risk of gastric stump cancer was significantly lower.     

The effect of cholecystectomy on bile reflux. An experimental study

In an experimental study the effect of cholecystectomy on bile reflux into the stomach was investigated. Five dogs were used and a large number of bile reflux measurements carried out (115 tests). During each test, reflux was measured over a continuous period of 6 hours by estimating the concentration of bile phospholipids (lecithin and lysolecithin) in the gastric juice. The pre-cholecystectomy phospholipid concentration in the stomach was 7,751 +/- 1,621 mg/dl (mean +/- SEM) and the post-cholecystectomy concentration 35,181 +/- 10,653 mg/dl (P less than 0,05). Two dogs developed gastric mucosal changes, mainly foveolar hyperplasia. The importance of measuring reflux repeatedly over long periods of time in order to get a more representative picture of reflux is stressed.     

Effects of reflux of bile and/or pancreaticoduodenal juice on gastric carcinogenesis in rats

The present study was designed to investigate which fraction of duodenal contents was responsible for gastric carcinogenesis, bile or pancreaticoduodenal juice. A series of 61 male Wistar rats were subjected to one of following four operative procedures: total reflux (TR, n = 17), bile reflux (BR, n = 8), or pancreaticoduodenal reflux (PDR, n = 16), and simple laparotomy (control, n = 20). Fifty weeks after operations the animals were sacrificed. The incidence of gastric adenocarcinoma was 7/17 (41%) in TR group, 2/8 (25%) in BR group, 0/16 (0%) in PDR group, and 0/20 (0%) in control group. The incidence of cancer in the both TR and BR groups were significantly higher than PDR and control groups, respectively. Histologically, lesions of gastric cancers showed tubular adenocarcinoma or mucinous adenocarcinoma. There was a significant difference in the intragastric pH between the first three reflux groups and control group. The concentrations of the total bile acids of the both TR and BR groups were significantly higher than PDR and control groups, respectively. These results suggested that duodenogastric reflux induces adenocarcinoma in the rat gastric mucosa and bile rather than pancreatico-duodenal juice is related to increased risk for gastric cancer.     

The effect of bile duct pressure on cholangiovenous reflux. A clinical study

The measurement of the filling pressure of the bile duct during the process of endoscopic retrograde catheter cholangiography, and the determination of blood culture and blood iodine before and after cholangiography were carried out to probe into the effect of bile duct pressure on cholangiovenous reflux. In 32 cases, 2 had positive blood culture after cholangiography, with a bile duct pressure being 2.98 kPa and 3.72 kPa respectively. Nineteen cases with a pressure below 2.94 kPa showed negative blood culture. In 10 cases with a bile duct filling pressure below 2.16 kPa, no increase in blood iodine was noted whereas, blood iodine level was increased in 5 out of 9 cases (55.6%) with a bile duct filling pressure between 2.16-2.94 kPa, and in 9 out of 13 cases 69.2% with the pressure greater than 2.94 kPa. We believed that during direct cholangiography, the bile duct pressure should be lower than 2.94 kPa in order to prevent the complication of bacteremia. For patients hypersensitive to iodine, the bile duct pressure should be lower than 2.16 kPa.     

Significance of duodenogastric reflux in the pathogenesis of primary stomach cancer

Duodenogastric reflux has often been discussed as a causative factor in the pathogenesis of gastric carcinoma. The author's clinical examinations of 135 patients with primary cancer of the stomach revealed slight increase in duodenogastric reflux. Yet, apart from these findings, no correlations were found to exist between reflux incidence and tumour localisation nor between histological tumour type and tumour size.     

Relative contribution of bile and pancreatic juice duodenogastric reflux in gastric ulcer disease and cholelithiasis

Bile acid concentrations, phospholipase A2 activity and pH in the stomach were measured in the fasting state and for 2 h after a fat-containing test meal in patients with an active gastric ulcer (GU), in patients with gallstones before and after cholecystectomy and in normal subjects. Fasting and peak postprandial bile acid concentrations in the stomach were low in all normal controls. Although high concentrations were found in many patients with GU (P less than 0.01), similar concentrations were found in many patients with radiologically non-functioning gallbladders containing gallstones (NFG) (P less than 0.01) and also after cholecystectomy (AC) (P less than 0.01). Fasting intragastric phospholipase A2 activities were similar, and very high in GU and NFG patients compared with control subjects (P less than 0.01). High values were not found after cholecystectomy. There was no difference in pH profile or in postprandial phospholipase A2 between patient groups. Since patients with cholelithiasis or after cholecystectomy are not known to have an increased incidence of gastric ulceration, the significance of duodenogastric reflux in the aetiology of gastric ulcers must be questioned. If reflux does produce ulcers in GU patients then factors in addition to bile acid are probably involved. However, neither patterns of phospholipase A2 reflux nor pH profiles can explain the absence of gastric ulceration in those patients with gallstones who reflux large quantities of bile acid.     

An experimental study on the effect of vagotomy on stress ulcer and the influence of bile reflux

I investigated the significance of bile reflux, when vagotomy was done to stress ulcer, by means of measuring gastric ulcer index, gastric pH and serum gastrin levels of rats. And in order to examine influence of alkali factor of bile, I measured gastric acid output and serum gastrin levels after alkali or acid solution was infused into the untreated rat's stomach. Results were summarized as follows: 1. When I infused alkali solution into the untreated stomach, there was no significant change in serum gastrin level but gastric acid output was significantly accelerated, as compared with infusing acid solution. On the other hand, when I infused alkali solution into the vagotomized stomach, serum gastrin level increased significantly and gastric acid output was significantly accelerated, as compared with infusing acid solution, so, acceleration of acid output observed when I infused alkali solution into the untreated stomach was not suppressed in spite of vagotomy operation. 2. In the vagotomized group, gastric acid output was significantly suppressed and serum gastrin level increased significantly as compared with the untreated group. But, when bile was led into the stomach in the vagotomized group, acid output was accelerated and serum gastrin level also showed a tendency to increase as compared with the group of vagotomy alone. 3. When mild stress was inflicted, stress ulcer formation was significantly prevented in the bile reflux group (vagotomy + pyloroplasty) as well as in the non-bile reflux group (vagotomy + pyloric ligation + gastroileostomy) if vagotomy was done. But, when severe stress was inflicted, stress ulcer formation was significantly prevented in the non-bile reflux group, but not prevented in the bile reflux group. As mentioned above, it was proved that stress ulcer formation was not prevented under a severe stress, if bile reflux existed, even though vagotomy was done. So, if we do vagotomy operation, we need to choose the operation method not to induce bile reflux as much as possible.     

The effect of gastrin on growth of human stomach cancer cells.

Gastrin is known as a trophic factor for some stomach and colorectal cancer cells; however, the roles of gastrin receptors and the intracellular signal transduction pathways by which gastrin regulates cell growth are still unknown. The authors examined the effect of synthetic human gastrin-17 on growth of human stomach cancer cells (the parent line, AGS-P, and two different clones, AGS-10 and AGS-12), which were established (and have been maintained) in our laboratory. Gastrin stimulated growth of AGS-P and AGS-10 cells, which have gastrin receptors, in a dose-dependent fashion. A highly selective gastrin receptor antagonist, JMV 320, inhibited the growth-stimulatory effect of gastrin on AGS-P cells in a dose-dependent fashion. Concentrations of gastrin (10(-8) to 10(-6) M), which stimulated growth of AGS-P cells, did not affect either cyclic adenosine monophosphate production or phosphatidylinositol hydrolysis. Gastrin (10(-11) to 10(-5) M) mobilized calcium from the intracellular organelles to increases intracellular calcium level in AGS-P cells. The AGS-12 clone has no gastrin receptors, and gastrin did not affect growth or mobilization of intracellular calcium in these cells. Our findings indicate that gastrin stimulates growth of AGS cells through a mechanism that involves binding to specific gastrin receptors that are linked to the system for mobilization of intracellular calcium.     

Cholecystectomy with highly selective vagotomy--the effect on bile reflux. An experimental study

An experimental study investigated the effect of highly selective vagotomy (HSV) alone and HSV combined with cholecystectomy on bile reflux into the stomach. The amount of reflux was estimated by measuring the concentration of bile phospholipids in the stomach. Neither HSV alone nor HSV combined with cholecystectomy was associated with increased reflux. In fact HSV seems to prevent reflux and inhibit the production of lysolecithin, which is injurious to the gastric mucosa.     

The effect of reflux on the development of pyelonephritis in urinary diversion: an experimental study

To make an accurate comparison between ileal and colonic conduits, an ileal conduit was created from one kidney and a nonrefluxing colonic conduit from the other kidney in 16 adult mongrel dogs. The major variable between the two was the presence or absence of reflux.The dogs were studied by excretory urography, conduitograms, pressure studies, and urinary cultures. All dogs were sacrificed at 3 months, and urine cultures were collected at necropsy from conduits and both renal pelves. In each of five control experiments, one kidney was connected to either an ileal or a colonic conduit while the other kidney remained in continuity with the bladder.Although most dogs had significant bacterial growth in both conduit and ureteral urine, histologic sections revealed pyelonephritis in 83% of 12 kidneys connected to ileal conduits as compared to 7% of 14 kidneys connected to colonic conduits. All control kidneys were histologically normal.This study demonstrates that ureteral reflux from ileal conduits produces histologic evidence of pyelonephritis. Colonic conduits, by preventing reflux of infected urine, reduce the frequency of pyelonephritis and offer definite advantages for long-term urinary diversion.     

The effect of the patient's hormonal status on the outcome of an operation for stomach cancer

The comparative analysis of the blood serum contents of triiodthyronine (T3), thyroxin (T4), hydrocortisone, prolactin and insulin in 59 survived and in 13 dead patients with gastric cancer was conducted. The prognostical significance of hormonal stress disorders was revealed. The prognosis for gastric cancer patients while the anabolic processes suppression is nonfavourable.     

Prevention of reflux from the stomach into the oesophagus

The results of operating upon 51 patients suffering from gastric reflux are described. The only apparently effective step in the operation was to fix a portion of the oesophagus in the abdominal cavity. The clinical and radiological studies indicate that the lower oesophagus in the abdomen acts as a valve.