Kinichi Yokota

Genetic Polymorphism of Aldehyde Dehydrogenase 2 in Patients With Upper Aerodigestive Tract Cancer

BACKGROUND Alcohol consumption is one of the major risk factors of the upper aerodigestive tract (UADT) cancers, and combined cancers are frequently discovered in the patients with UADT cancer. The association between esophageal cancer and alcohol-related metabolizing enzymes is well studied, but only a few examinations about the association between head and neck cancer and the enzymes were performed. METHODS Fifty-two patients with UADT cancer (head and neck cancer in 25, esophageal cancer in 19, and multiple cancers in 8) were examined in the alcohol habit and in the polymorphisms of aldehyde dehydrogenase 2 (ALDH2) and cytochrome P-4502E1. RESULTS Patients with multiple cancers had significantly higher ethanol consumption than the other two groups (p < 0.001). The frequency of ALDH2* 1/2*2 heterozygote was significantly lower (p= 0.009) in patients with head and neck cancer (5/25) than patients with esophageal cancer (11/19). The allele frequency of P-4502E1 did not show a significant difference between the groups (p= 0.700). CONCLUSIONS These results demonstrated the difference in the frequency of ALDH2 heterozygote between the patients with esophageal cancer and patients with head and neck cancer.

Gastric intestinal metaplasia as detected by a monoclonal antibody is highly associated with gastric adenocarcinoma

Background: Some forms of gastric intestinal metaplasia (GIM) may be precancerous but the cellular phenotype that predisposes to gastric carcinogenesis is not well characterised. Mucin staining, as a means of differentiating GIM, is difficult. A monoclonal antibody, mAb Das-1 (initially called 7E12H12), whose staining is phenotypically specific to colon epithelium, was used to investigate this issue. Methods: Using mAb Das-1, by a sensitive immunoperoxidase assay, we examined histologically confirmed GIM specimens from two countries, the USA and Japan. A total of 150 patients comprised three groups: group A, GIM (fields away from the cancer area) from patients with gastric carcinoma (n=60); group B, GIM with chronic gastritis (without gastric carcinoma) (n=72); and group C, chronic gastritis without GIM (n=18). Results: Fifty six of 60 (93%) patients with GIM (both goblet and non-goblet metaplastic cells) from group A reacted intensely with mAb Das-1. Cancer areas from the same 56 patients also reacted. In contrast, 25/72 (35%) samples of GIM from patients in group B reacted with mAb Das-1 (group A v B, p<0.0001). None of the samples from group C reacted with the mAb. Conclusions: Reactivity of mAb Das-1 is clinically useful to simplify and differentiate the phenotypes of GIM. The colonic phenotype of GIM, as identified by mAb Das-1, is strongly associated with gastric carcinoma.

Morphogenesis of nonpolypoid colorectal adenomas and early carcinomas assessed by cell proliferation and apoptosis.

Abstract Nonpolypoid neoplasms, as well as ordinary polypoid tumours, are occasionally found in the colorectum. To clarify whether cell kinetic status affects the macroscopic morphology of colorectal neoplasms, we investigated proliferative indices (PI), apoptotic indices (AI), and the expression of apoptosis-related gene products. We examined 110 colorectal neoplasms comprised of 36 polypoid, 38 flat elevated and 36 depressed tumours. According to WHO’s criteria these tumours consisted of 61 adenomas with low grade dysplasia (LGD), 30 adenomas with high grade dysplasia (HGD) and 19 carcinomas with submucosal invasion. Apoptotic cells were detected by TUNEL staining. Proliferating cells and apoptosis-related gene products were assessed by immunohistochemistry for Ki-67, p53, Bcl-2, and Bax antigens. AI were closely associated with macroscopic morphology in adenomas but not in carcinomas. PI were relatively constant among the three macroscopic types in adenomas and carcinomas. Median AI values of polypoid, flat elevated and depressed tumours were 1.8%, 2.1% and 4.6% for adenomas with LGD, 0.8%, 2.4% and 6.2% for adenomas with HGD and 2.9%, 4.0% and 3.6% for carcinomas, respectively. Overall PI were significantly higher in carcinomas than in adenomas with LGD, whereas AI were not different. Although the incidence of expression was significantly higher in carcinomas for p53 and in adenomas for Bcl-2 than the others, the expression of apoptosis-related gene products (p53, Bcl-2 and Bax) was similar among polypoid, flat elevated and depressed tumours. Macroscopic morphology of colorectal adenomas is determined by the apoptosis not by proliferation, and high apoptosis found in depressed adenomas implies their low net growth.

Reduction of syndecan-1 expression in differentiated type early gastric cancer and background mucosa with gastric cellular phenotype

BackgroundSyndecan-1 is known to play a role as a cell adhesion molecule, similar to E-cadherin, and is associated with the maintenance of epithelial morphology. The purpose of this study was to elucidate the role and alterations of syndecan-1 expression in comparison with those of E-cadherin in different cellular phenotypes of differentiated-type gastric cancers (DGCs).MethodsA total of 80 DGCs at an early stage, and their adjacent mucosa, were evaluated by both immunohistochemistry and in situ hybridization. Syndecan-1 and E-cadherin were assessed by immunohistochemical staining with an anti-syndecan-1 and an anti-E-cadherin antibody, respectively. Based on immunohistochemistry, DGCs and their surrounding mucosa were divided into four types: gastric type (G-type), ordinary type (O-type), complete-intestinal type (CI-type), and null type.ResultsThe expression sites of syndecan-1 mRNA mostly coincided with those of syndecan-1 protein. Syndecan-1 expression was significantly lower in G-type cancers (30%) than in O- (81%) and CI-type cancers (92%) (P = 0.0001 and P = 0.004, respectively), but E-cadherin did not show this result. In addition, syndecan-1 expression was significantly reduced in DGCs comprised partly of poorly differentiated adenocarcinoma or signet-ring cell carcinoma, compared to DGCs demonstrating papillary and/or tubular adenocarcinoma (P = 0.02). G-type intestinal metaplasia (IM) surrounding the tumors was observed in 21% of G-type cancers, in 0% of O-, and in 10% of CI-type cancers (P = 0.01; G-type vs O-type). Reduction of syndecan-1 expression was significant in G-type IM (25%) compared to non-G-type IM (75%; P = 0.02).ConclusionsSyndecan-1 plays a role in the growth of G-type cancers at an early stage compared with E-cadherin changes, and the reduction of syndecan-1 expression in IM surrounding the tumors may influence the growth of G-type cancer.

Natural history of colorectal nonpolypoid adenomas: a prospective colonoscopic study and relation with cell kinetics and K- ras mutations

OBJECTIVE:Serial colonoscopic observations were prospectively conducted to elucidate the natural history of nonpolypoid tumors. Furthermore, to clarify whether cell kinetic status affects the tumor development, proliferative indices, apoptotic indices, and K-ras codon 12 point mutations on biopsy specimens were investigated.METHODS:Seventy-five colorectal tumors, 13 polypoid and 62 nonpolypoid type (56 flat elevated and six depressed type) were studied. Proliferating and apoptotic cells were detected with anti-Ki-67 antibody and the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling method, respectively. Point mutations at K-ras codon 12 were examined by enriched polymerase chain reaction-based restriction fragment length polymorphism assay.RESULTS:The average follow-up period was 22 months (range 1–50). The lesions of subsequent exophytic growth, unchanged shape, depressed growth, and disappearance were observed in 0%, 92%, 0%, and 8% of polypoid type, in 39%, 39%, 13%, and 9% of flat elevated type, and in 33%, 67%, 0%, and 0% of depressed type, respectively. There was no significant difference in tumor size between initial and follow-up colonoscopy. Nonpolypoid tumors apparently changed to the exophytic growth during 2 yr or more. The tumors with exophytic growth had significantly higher proliferative indices/apoptotic indices ratios than those with unchanged morphology and disappearance/depressed growth (p < 0.05, respectively). K-ras codon 12 point mutations did not correlate with tumor development.CONCLUSIONS:Cell kinetic status plays an important role in determining minute colorectal tumor development, but not K-ras codon 12 mutations. Minute nonpolypoid adenomas frequently tend to grow slowly, and nearly 40% of those become the exophytic growth with time. Most of minute nonpolypoid tumors seem to follow the adenoma-carcinoma sequence.

Preferential expression of cyclooxygenase-2 in colonic-phenotype of gastric intestinal metaplasia : Association with helicobacter pylori and gastric carcinoma

Objectives: Gastric intestinal metaplasia (GIM) associated with H. pylori (HP) has been considered a premalignant lesion. However, GIM phenotype associated with HP infection and gastric cancer is unclear. The expression of COX-2 in relation to GIM phenotype is also unknown. Methods: We evaluated cellular phenotype and COX-2 expression in the GIM from HP-positive and -negative patients from Japan in the absence of gastric cancer (n = 31) by using a colon epithelium specific monoclonal antibody (mAb Das-1) and anti-COX-2 antibody. COX-2 expression was also examined in patients with gastric cancer (n = 34), both in the cancer and in the GIM areas away from the cancer field. Results: Sixty-eight percent of HP-positive GIM reacted with mAb Das-1, whereas the reactivity in the HP-negative GIM was only 25% (P < 0.001). The COX-2 expression was present in 32% of HP-positive GIM and in only 9% of HP-negative GIM (P < 0.001). In the cancer group, COX-2 expression was localized both in the cancer area (94%) and in the GIM (82%) away from the cancer. Each of the COX-2-positive tissue was also positive to mAb Das-1. Conclusion: HP infection is highly associated with the development of colonic-phenotype of GIM, and about half of them expressed COX-2. COX-2 expression was frequent in both gastric cancer and the GIM adjacent to the cancer. The results suggest that the presence of mAb Das-1 and COX-2 reactivity in the GIM identify the subgroup of patients who may be at risk for gastric cancer and may need close surveillance.

Endoscopic Scoring System for Experimental Colitis with Trinitrobenzene Sulfonic Acid in Rats

Abstract: Experimental colitis models require serial sacrifice of animals to confirm the evolution of the inflammatory process. Endoscopy may possibly enable us to detect sequential changes in the lesions throughout the inflammatory process without killing animals. Using rat colitis induced with trinitrobenzene sulfonic acid (TNBS) after the study by Morris et al. the accuracy of endoscopic examination was investigated by comparing endoscopic findings with histologic findings.

⁎4539 Is high-frequency ultrasound probe a useful modality for invasion depth diagnosis of early gastric cancers?

Background: Precise preoperative invasion depth staging is essential to determine a therapeutic strategy for early gastric cancer, because endoscopic mucosal resection (EMR) is satisfactory for intramucosal cancers (m-ca) but gastrectomy is necessary for submucosal cancers (sm-ca). Recently, high-frequency ultrasound probe (HFUP) has become available and it enabled to provide high resolutional images especially for small and superficial gastric cancers. Aims: To clarify whether or not HFUP is useful for invasion depth diagnosis, we prospectively compared its accuracy with endoscopy. Patients and Methods: We prospectively studied 113 consecutive patients with 114 early gastric cancers (T1 stage), consisting of 81 mca and 33 sm-ca, that were subsequently treated by EMR (n=59) or gastrectomy (n=55) between Mar. 1995 and Sep. 1999. The criteria of invasion depth diagnosis were referred to the report for endoscopy (Sano T, et al. Dig Dis Sci 35, 1990) and for HFUP (Yasuda K, et al. Stomach and Intestine 27, 1992). The invasion depth was diagnosed prospectively based on these criteria. HFUP was performed by using 15 or 20 MHz probes. The macroscopic type was divided into Type I (protruded, n=4) and Type II (superficial, n=110). Type II was subdivided into following 3 types; superficial elevated (IIa, n=35), superficial depressed with ulceration (IIc Ul(+), n=26), superficial depressed without ulceration (IIcUl(-), n=42) and flat elevated with depression (IIa+IIc, n=7). Results: No significant difference was found in the overall accuracy between the two modalities, that were 77.8% in endoscopy and 73.7% in HFUP. However, HFUP could provide correct diagnosis in 9 (34.6%) of 26 cases misdiagnosed by endoscopy. Conversely, endoscopy did so in 10 (37.0%) of 27 cases incorrectly diagnosed by HFUP. Both modalities showed a significantly lower accuracy rate in type IIc Ul(+) than in the other macroscopic types (p

Effects of Cyanoacrylate on the Gastric Mucosa of Dogs –Endoscopic and Histopathological Studies for Sclerotherapy of Gastric Varices–

Abstract: The effect of cyanoacrylate tissue adhesive (C. A.) on the gastric mucosa of dogs was investigated endoscopically and histopathologically. When C. A. was applied to the surface of the gastric mucosa, the endoscopic findings the next day showed local redness at the applied site (Fig. 1‐a) and histopathology revealed degenerative changes in the gastric mucosa (Fig. 1‐b). When C. A. was endoscopically injected into the gastric mucosa, the endoscopic findings revealed a submucosal tumor‐like lesion (Fig. 2‐a). One day after treatment, the endoscopic findings showed a hemorrhagic erosion on the surface of the lesion (Fig. 2‐b). An histopathological examination of the resected stomach revealed C. A. in the submucosal layer (Fig. 3‐a, 3‐b) and the lymph duct around the muscularis mucosa with severe acute inflammation (Fig. 4‐a, 4‐b). One week after treatment, a deep ulcer (Ul‐IV) was observed (Fig. 5, 6) and a histopathological examination of the resected specimen revealed C. A. at the site of the ulcer and inflammatory cell infiltration by fibroblasts and giant cells (Fig. 7‐a, 7‐b). One month after treatment, the ulcer had healed and was replaced by a scar (Fig. 8). Histopathological examination of the resected stomach revealed C. A. in both the muscularis mucosa and the submucosa and also inflammatory cell infiltration by giant cells in addition to the fibrosis (Fig. 9). When using endoscopic sclerotherapy with C. A., it should be kept in mind that there is the possibility of such a lesion occurring as demonstrated by our study.