Mechanisms producing color change in flat early gastric cancers.

BACKGROUND AND STUDY AIMS: Although highly refined endoscopes have made it possible to detect not only early gastric cancers with morphological changes, but also flat-type tumors (type IIb) on the basis of the color changes observed in them, the factors responsible for color changes in type IIb carcinomas have not been fully elucidated. The aim of this study was to analyze the potential mechanisms underlying these color changes. PATIENTS AND METHODS: Thirteen type IIb cancers were selected from a total of 589 resected gastric cancers detected preoperatively using endoscopic examination. All of the tumors showed color changes alone, without surface changes, and the color changes included redness, discoloration, and spotty bleeding. Detailed histological examination of the resected stomachs revealed twelve more II b lesions that had not been identified at endoscopy. The endoscopic appearance of the IIb cancers were correlated with the degree of tumor differentiation, the extent of wall infiltration, and the number of capillaries. RESULTS: In cases that were detectable by endoscopy, the endoscopic color appearance correlated significantly with both tumor size (P < 0.02) and with the extent of mucosal cancer infiltration (P < 0.02). Histological examination of the IIb lesions revealed that redness and discoloration were significantly more frequent in the differentiated and undifferentiated cancer types, respectively (P < 0.01). There was a significant difference in the number of capillaries between type IIb carcinoma and the adjacent normal mucosa, but not between cancers. The numbers for differences in redness and discoloration were 7.0 +/- 5.6 and -14.0 +/- 8.8, respectively. CONCLUSIONS: These results suggest that the main factor underlying color change in type IIb early gastric cancers may be the number of capillaries in the lesions, in comparison with the adjacent mucosa. Whether the lesion is visible on endoscopy, however, depends more on its size than on the number of capillaries.

The effect of dietary selenium deficiency on acute colorectal mucosal nucleotoxicity induced by several carcinogens in the rodent.

BACKGROUND: Selenium (SE) has been inversely associated with colon cancer risk. Two potential mechanisms of this effect were examined in a rodent short-term carcinogenesis assay: whether dietary SE deficiency altered the initiation aspect of carcinogenesis in the colon, and whether SE altered carcinogen metabolism. SETTING: Animal laboratory. SUBJECTS: 52 Sprague-Dawley rats, divided into a SE diet deficient group (0.002 parts per million; ppm) and a SE sufficient (0.2 ppm) group. ENDPOINTS: Weight, serum SE concentration, and karryorhectic index (KI), which is a measure of acute carcinogen induced nuclear toxicity in the colonic mucosa. METHODS: After three weeks of acclimation to the diets, eight animals from each dietary group were injected with one of the following: dimethylhydrazine (DMH), a colon specific carcinogen, its metabolite, methylazoxymethanol (MAM), or 0.9% sodium chloride. Twenty-four hours after injection the colons were removed, blood drawn, and the stained colons assayed for nuclear aberrations. RESULTS: No weight differences were generated by the dietary variations. Low-dietary SE resulted in serum SE declining markedly in the study period to 6 ng/ml versus 33 ng/ml in the SE sufficient group. Diet alone, and variations in weight gain, did not alter the KI. Both carcinogens greatly increased the KI in both the left and right colon. A SE-deficient diet was associated with a higher KI in both carcinogen groups in the right colon, with statistical significance for both the left and right colon in the MAM injection group. CONCLUSIONS: Dietary SE deficiency is associated with increased KI of the colon in MAM treated rats. SE, therefore, has a protective effect in the initiation phase of carcinogenesis.

[Evaluation of endoscopic mucosal resection (EMR) as a curative therapy against early gastric cancer].

This study investigated the effectiveness of EMR as a curative therapy against early gastric cancer, comparing with that of radical operation. In 256 radical operation cases, five year survival rates were 97.5% in m-cancer and 93.2% in sm-cancer. In these cases, postoperative complications occurred in 7.8%, with operative mortality being 0.78%. In 56 EMR cases, nine encountered slight bleeding, which was controlled by ethanol injection under endoscopy. Regarding prognosis of EMR, cancer recurrences occurred in 45.8% of cases with stump involvement in the resected mucosa (stump (+)). In cases without stump involvement in the resected mucosa (stump (-)), no recurrence were found except one case, in which distance from the cancer edge to the stump was only 0.6 mm, suggesting that enough distance (2mm) to the stump is required for curative EMR. Stump (-) rate was high (81.2%) in cases of small cancer less than 1 cm in diameter, but was low in cases of cancer greater than 2 cm and those located in upper body or lesser curvature. To establish EMR as a curative therapy, it must be performed by single collection to check remaining cancer. In conclusion, although radical operation is still the standard curative therapy, EMR should be considered as an alternative therapy.

Expression of blood group-related antigens, ABH, Lewis(a), Lewis(b), Lewis(x), Lewis(y), CA19-9, and CSLEX1 in early cancer, intestinal metaplasia, and uninvolved mucosa of the stomach.

The expression of blood group-related antigens, A, B, H type 2, Lewis type 1 (Lewis(a) [Le(a)] and Lewis(b) [Le(b)]), Lewis type 2 (Lewis(x) [Le(x)] and Lewis(y) [Le(y)]), sialylated Le(a) (CA19-9), and sialylated Le(x) (CSLEX1), was analyzed sequentially with immunohistochemical methods in early gastric cancer, intestinal metaplasia, and uninvolved gastric mucosa obtained from 35 surgical specimens of patients who underwent gastrectomy. The high incidence of the inappropriate expression of Lewis type 1 antigens and the deletion of H and Lewis type 2 antigens was observed similarly in patients with cancer and intestinal metaplasia. The acquisition of CA19-9 and CSLEX1 and the deletion of B antigen frequently were found in intestinal-type cancer and all types of intestinal metaplasia. The simultaneous deletion of A antigen was detected only in the combination of intestinal-type cancer and incomplete-type intestinal metaplasia. Thus the present study shows that similar changes of tissue antigenicities exist in early gastric cancer and intestinal metaplasia.

[Effect of gastrectomy on release of gut hormones].

We investigated the effect of gastrectomy on the digestive system in 87 postoperative long-term survivors under test meal or egg yolk load. After test meal, gastrin and secretin responses were decreased in each of groups of proximal gastrectomy (PG), distal gastrectomy with Billroth-I (DG-B1), that with Billroth-II (DG-B2), total gastrectomy with interposition (TG-I), and that with Roux-Y (TG-RY). However, sufficient acid-secretors after partial gastrectomy showed secretin responses comparable to controls. Furthermore, cases of total gastrectomy given betain-hydrochloride with test meal increased secretin responses. Serum glucose response was higher in the TG-RY group while insulin response was high in the TG-RY and DG-B2 groups, compared with controls. GLI response was high in all groups compared with controls. Postgastrectomy gallstone occurred in 11.6%. Yolk-induced contraction of the gallbladder was decreased, and CCK release increased, for several years postoperatively. Gallbladder contraction with CCK was reduced for one year postoperatively. The contraction was reduced in persons with gallstone than those without it. This study shows that the digestive function after gastrectomy depends on acidification and duodenal passage of food, and that reduced contraction with CCK plays an important role in hypokinesis of the gallbladder.

Hormonal regulation of plasminogen activator and peroxidase activities in 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors and the rat uterus.

Oophorectomy was found to decrease the plasminogen activator activity of rat mammary tumors induced by 7,12-dimethylbenz(a)anthracene (DMBA) to less than 7 per cent, while in vivo estradiol treatment restored its activity in a dose dependent fashion. The peroxidase activity was not changed either by oophorectomy or by the administration of estrogen. In the rat uterus, plasminogen activator activity was not changed by oophorectomy or by the administration of estrogen, however, its peroxidase activity decreased to less than 2 per cent following oophorectomy, while estrogen administration restored its activity. Estrogen regulated plasminogen activator activity in the DMBA-induced rat mammary tumors but not in the uterus and thus, the specific hormonal regulation of this enzyme may be an important factor for the hormonal dependent growth of such tumors.

[A case of multiple tumors].

A 54-year-old man was admitted to our clinic for a further examination of rectal and liver tumors, after which a rectal cancer, a hepatocellular carcinoma (HCC), a hemangioma of the liver a retroperitoneal cyst, and a submucosal tumor of the stomach (SMT) were diagnosed by means of a colonoscopy, a gastroscopy, and US, CT, and angiography, these tests also revealing elevated CEA and AFP levels. A hepatic subsegmentectomy and a Miles's operation, as well as an enucleation of other liver tumors and an SMT, were performed and a retroperitoneal cyst was removed. The histopathological finding of the rectal cancer was a moderately differentiated adenocarcinoma, while the liver tumors were determined as being an HCC of the trabecular type, adenomatas revealing hyperplasia, a hemangioma, and the SMT showing a benign leiomyoblastoma.

Role of Lugol dye endoscopy in the diagnosis of early esophageal cancer.

To evaluate the role of Lugol dye endoscopy in diagnosing early esophageal cancer, we reviewed findings of dye endoscopy and those of conventional endoscopy in 17 early esophageal cancers that were demonstrated as unstained areas on dyeing with Lugol solution. Histologically, all 17 lesions were squamous cell carcinomas; 10 lesions being mucosal carcinomas, the remaining 7 lesions mucosal carcinomas spreading beyond the epithelial layer. The lesions ranged from 0.7 to 4.0 cm in size. Abnormal findings were noted under conventional endoscopy in all but 3 lesions diagnosed only by postoperative pathohistology, regardless of the size and depth of the invasion. Under conventional endoscopy, the following types of morphological changes were noted in 8 (57.1%) of the 14 lesions: slight elevation (1 lesion), depression (6 lesions), and deformed arc (1 lesion). A color change was noted endoscopically in 12 of the 14 lesions (85.7%), this change being redness in all 12 lesions. The unstained area on the resected specimen was consistent with the size of the lesion that was determined by using serially sectioned blocks in all cases. Moreover, the former completely (100%) coincided with the histological area where PAS reaction was weak. In conclusion, under conventional endoscopy, a color change such as redness is an important indicator of minute or superficial esophageal cancer, as is such morphological change as depression, elevation or deformed arc. On the other hand, Lugol dye endoscopy is very helpful in detecting esophageal cancer unassociated with any morphological or color change. It also provides accurate information about the extent of the cancer.

A biometrical study on esophageal invasion of carcinoma of the upper stomach. Part II: Radiographic evaluation of esophageal invasion on the basis of its occurring point and size.

Esophageal invasion of upper stomach cancer was analized on the resected specimen based on its occurring point and size. The distance of esophageal invasion was calculated by subtracting the distance between the occurring point and esophagogastric junction (EJG) from the radius of the cancer on the preoperative X-ray films. Fifty-six (76.7%) out of 73 resected cancers of the upper stomach invaded the esophagus. The average distance of invasion was 19.8 +/- 12.7 mm; the longest distance was 64.0 mm. The shorter was the distance of the occurring point from the EGJ, the longer was the esophageal invasion. The calculated distance of esophageal invasion of the cancer was correlated significantly with its histological distance (p less than 0.01). The distance of esophageal invasion can be seen with acceptable accuracy on the X-ray films preoperatively, even when the proximal edge of esophageal invasion is not clear on the films.

Early diagnosis of esophageal cancer. Analysis of 11 cases of esophageal mucosal cancer.

We reviewed 11 patients with esophageal mucosal carcinoma in various aspects to improve the early diagnosis of the disease. Eighteen lesions measuring 0.5 to 5.0 cm were confirmed histologically in the 11 cases. Histologically 10 of the 18 lesions were carcinomas in situ (ep cancer), and the other 8 lesions were carcinomas confined to the mucosa other than ep cancer (mm cancer); all 18 lesions were squamous cell carcinomas. Six (85.7%) of the seven mm cancers showed abnormal radiographic findings regardless of the size. Similarly these findings were noted on four of five (80%) ep carcinomas 2 cm or larger in size. All 15 lesions diagnosed before operation showed abnormal findings on conventional endoscopy regardless of the size and depth of transmural invasion. Morphologic change was observed in 9 lesions (53.3%), while 13 (86.7%) showed color change; most of the lesions (80%) were manifested as redness. Dyeing of the resected specimen with Lugol solution (Katayama Chemical Industries, Osaka, Japan) showed all 18 cancerous lesions as unstained areas. Among the 18 lesions, two lesions were unstained areas, which agreed with the areas determined histologically. An additional lesion was visible with dye endoscopy as an unstained area but it was not visible with radiography or conventional endoscopy. Dye endoscopy using Lugol solution is very important because it allows detection and evaluation of the extent of esophageal mucosal cancer.

[Estrogen dependent plasminogen activator in breast cancer cells; experimental and clinical studies].

Hormonal regulation of plasminogen activator (PA) in rat mammary tumor induced by 7,12-dimethylbenz (a) anthracene (DMBA) was studied both in vivo and in vitro. PA activity in DMBA-tumor was markedly decreased by ovariectomy, and recovered in a dose-dependent fashion upon estradiol administration. This estrogen-stimulated production of the enzyme was prevented by actinomycin D, cycloheximide and tamoxifen. Furthermore DMBA-tumor cells in primary culture displayed similar estrogen-dependency toward the production of the enzyme without any cell proliferation. This indicates that estrogen might regulate de novo synthesis of PA at a transcriptional level via an estrogen receptor system, and that this hormone might support the growth of DMBA-tumor into adjacent tissues by inducing PA in a direct manner via a route distinct from a prolactin pathway. To examine whether PA reflects the functional state of estrogen receptors in human breast cancer, the enzyme activities were determined in extracts prepared from 160 breast cancer specimens and compared on qualitative and quantitative bases with the levels of steroid receptors. The results strongly suggest that PA can be used as an effective functional marker for hormone dependence in human breast cancer.

The effect of iron on experimental colorectal carcinogenesis.

The effect of parenteral and oral iron was examined in the rat 1,2 dimethylhydrazine (DMH) colorectal carcinogenesis model in a series of experiments. Parenteral supplementation of iron was found to augment tumor yield (p = 0.012) and oral iron was found to augment tumor incidence (p = 0.03, when control groups were combined). In addition, phytic acid, a significant component of dietary fiber was found to reverse the augmenting effect of oral iron on tumor yield and incidence (p = 0.09 for both). Furthermore, in a short term DMH nuclear toxicity assay, analysis of the karyorrhectic index (KI), there was no difference in the KI between oral iron and phytate dietary groups (p = 0.53 for the left colon and p = 0.2 for the right colon), implying that iron's effect on colorectal tumor induction takes place during the promotional phase of carcinogenesis and not during initiation. These experiments support the epidemiologic observation that dietary iron may augment colorectal cancer risk and that the mechanism by which dietary fiber diminishes colorectal cancer risk may be the chelation of dietary iron by the phytic acid component of dietary fiber.

Postoperative results of distal partial gastrectomy, selective vagotomy plus antrectomy, and selective proximal vagotomy for duodenal ulcers.

We investigated the postoperative results of distal partial gastrectomy, selective vagotomy plus antrectomy, and selective proximal vagotomy, to evaluate their effectiveness in the treatment of duodenal ulcers. The operative mortality of selective vagotomy plus antrectomy and selective proximal vagotomy seemed to be lower when compared to distal partial gastrectomy, although each procedure showed a sufficiently low mortality. The acid reduction rate was significantly lower after selective proximal vagotomy than after the other procedures (p less than 0.01). However, the rate of ulcer recurrence following selective proximal vagotomy tended to be higher compared with the other procedures. All three procedures showed good results according to Visick's grading and postoperative symptoms occurred in about 50 per cent of all patients, no matter what the procedure. The regaining of physical ability was significantly greater following selective proximal vagotomy than following distal partial gastrectomy (p less than 0.05) and the capacity to work was also better after vagotomy, particularly selective vagotomy plus antrectomy (p less than 0.05). Thus, although distal partial gastrectomy and selective vagotomy plus antrectomy proved superior regarding the low ulcer recurrence rate and acid reduction, while selective proximal vagotomy proved superior for improving the quality of life, on the whole, the three operations promise almost equivalent results.

A biometrical study on esophageal invasion of carcinoma of the upper stomach. Part I: Determination of occurring point of the cancer and analysis of its horizontal extension.

In order to detect the occurring point of gastric cancer, and to determine its horizontal extension from this point, we performed a histological examination of 30 resected specimens of upper stomach cancer and 31 of middle and lower stomach cancers. The center of the horizontal extension (Oh) and that of the vertical extension (Ov) were calculated using a paper model. The mean distance between Ov and Oh (Ov-Oh D) was as little as 5.7 +/- 5.0 mm, and the ratio of Ov-Oh D to the size of the lesion was as low as 8.3 +/- 6.7%. There was a linear correlation between the oral and anal radii of the cancer. There was also a linear correlation between anterior and posterior radii of the cancer. In conclusion, either the Oh or the Ov can be considered as the occurring point, and the cancer grows concentrically around this point.

Transabdominal operation for carcinoma of the gastric cardia: application of pulling-up retractor and EEA stapler.

In order to ascertain the advantages of the combined use of the pulling-up retractor and EEA stapler, we reviewed 88 patients who underwent surgery for upper stomach cancer between 1978 and 1986. The length of resected esophagus was significantly longer in patients operated on using an abdominal approach with this combination, as in those using a thoracoabdominal approach, than in those who were operated on using an abdominal approach with only the retractor or without the instruments (p less than 0.05). A relatively high incidence of leakage occurred at the anastomosis of the esophagus to the stomach or jejunum following operation using a transabdominal approach without the instruments. Pulmonary complication tended to be decreased in the non-thoracotomized patients compared to the thoracotomized patients. Postoperative radiogram following the combined use showed an esophagogastrostomy at a high level in the mediastinum. Our combination technique enables lymphadenectomy in the lower mediastinum and a sufficiently long enough resection of the esophagus without fatal complications.

[Endoscopic hemostasis against hemorrhage from the upper gastrointestinal tract: its indication and limitation].

We reviewed endoscopic hemostasis that had been performed upon 353 acutely hemorrhagic peptic ulcer cases: Among them, 145 received thrombin spraying; 36, electrocoagulation; 145, topical injection of ethanol; and 27, topical injection of aetoxyscrelol. Hemostasis lasting for more than 24 hours after the treatment was defined as transient hemostasis, and hemostasis lasting for more than two weeks, as permanent hemostasis. The overall rate of transient hemostasis was 87.5%; 84.8% by thrombin spraying, 83.4% by electrocoagulation, 89.0% by injection of ethanol, 100% by injection of aetoxyscrelol, respectively. The overall rate of permanent hemostasis was 71.1%; 75.9% by thrombin spraying, 58.3% by electrocoagulation, 69.7% by injection of ethanol, 70.4% by injection of aetoxyscrelol, respectively. The rate of emergency operation for bleeding was reduced to 9.9% after the induction of endoscopic hemostasis from 64.0% before the induction. The mortality was also reduced to 3.1% from 8.9%. Particularly, over the last 4 years, the emergency operation and the mortality have been reduced, accounting from 7.2% and 2.2%, respectively. In conclusions, thrombin spraying is the first choice for mild and diffuse hemorrhage, and topical injection of ethanol is indicated for hemorrhage from exposed vessels and for localized hemorrhage.

Clinicopathological analysis of synchronous multiple gastric carcinoma.

Clinicopathological analysis was performed on 839 cases surgically resected for gastric carcinoma. The incidence of multiple gastric carcinoma was 4.8% (40 cases, 97 lesions). Multiple carcinoma was more frequently observed in early than in advanced carcinoma (P less than 0.01). The rate of intestinal type lesions was significantly (P less than 0.01) higher in multiple than in single gastric carcinoma, and all of the intestinal type carcinoma correlated with intestinal metaplasia, which is assumed to be closely related to pyloric and atrophic fundic gland area. Eight cases (20.0%) of multiple carcinoma were both in the upper one-third and lower one-third of the stomach. Twenty-nine (51.9%) of the accessory lesions were not detected pre-operatively; 12 (21.1%) of them were detected only by postoperative histology. Twelve (48.0%) of 25 early cancerous foci located in the anterior wall and greater curvature were overlooked before operation. These results indicate that the whole stomach must be carefully examined to detect accessory carcinoma before gastric surgery, especially for intestinal type carcinoma, with greater attention paid to the anterior wall and greater curvature, and that complete removal of the pyloric and atrophic fundic gland area would be required for distal gastrectomy.

Endoscopic diagnosis of minute, small, and flat early gastric cancers.

We reviewed the diagnostic process in 6 minute, 6 small and 9 flat early cancers detected preoperatively, and in additional 12 flat cancers that were found in resected stomachs only at histology between 1976 and 1986. The limit of the size of cancer detectable preoperatively was 4 mm. Endoscopically, 7 out of 12 minute and small cancers detected preoperatively showed obvious morphological changes, while the others showed only color changes with or without erosion. Lesions with morphological changes significantly invaded the mucosa more often than those with no such changes (p = 0.010). Among flat cancers, color change was significantly more frequently observed in cancers involving the whole mucosa than in those confined to the superficial part of the mucosa (p = 0.015). Redness and discoloration were significantly more frequent in the differentiated and undifferentiated groups, respectively (p = 0.005). This study suggests that morphological and color changes are important indicators of minute or small cancers, especially those involving the whole mucosa.

Definition of carcinoma of the gastric cardia.

This study concerns the definition of carcinoma of the gastric cardia. The topography of the esophagogastric mucosal junction (mucosal EGJ) was investigated with an endoscope in 182 patients who were free of hiatal hernias, ulcers, and neoplasms in the esophagus and stomach. The relationship between the EGJ and the cardiac gland area was then examined histologically in 56 resected specimens containing intact EGJs and cardia gland areas. Furthermore the cancerous center was determined; the shortest distance between the cancerous center and the EGJ and the amount of esophageal invasion were measured in 102 resected carcinomas located close to the junction; the carcinomas contained the EGJ and were good enough for pathohistological examination. The EGJ was located 0.5 - 1.0 cm proximal to the His angle (the gastric cardia) in radiological and endoscopic examinations. Histologically the cardiac gland area was found to straddle the EGJ at a range of about 1 cm proximal and 2 cm distal to the junction. Among the upper stomach carcinomas, most of the tumors (87.5%) whose center was located within 2 cm from the EGJ invaded the esophagus. In conclusion, carcinoma of the gastric cardia is defined as a lesion with its center located within 1 cm proximal and 2 cm distal to the EGJ.