Shinichi Ota

High expression of cyclooxygenase-2 in macrophages of human colonic adenoma.

Cyclooxygenase (COX)‐2 is a possible molecular target for suppression of colon carcinogenesis by non‐steroidal anti‐inflammatory drugs (NSAIDs). However, the expression of COX‐2 in human colonic tumors during the adenoma‐carcinoma sequence has not been elucidated. In the present study, we examined immuno‐histochemically the expression and localization of the COX‐2 protein in human colonic adenomas and cancers. Twelve human colonic adenomas and 9 advanced cancers were studied. Immunoreactive COX‐2 was predominantly and strongly expressed in sub‐epithelial interstitial cells broadly present in the surface area of adenomas. The staining pattern of macrophages was similar to that observed for COX‐2 in adenomas. Adjacent normal colonic mucosa was negative for COX‐2 expression. In contrast, COX‐2 was relatively weakly expressed in both tumor cells and interstitial cells in advanced colon cancers. In conclusion, the target of NSAIDs in preventing colon carcinogenesis may be the COX‐2 expressed in interstitial cells, possibly macrophages, of colonic adenomas. Int. J. Cancer 83:470–475, 1999.

Case-control study on the association of upper gastrointestinal bleeding and nonsteroidal anti-inflammatory drugs in Japan.

ObjectiveStudies in Western populations have shown the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and upper gastrointestinal bleeding (UGIB). The role of Helicobacter pylori infection in NSAIDs-related UGIB remains to be studied. We conducted a case-control study in Japan to investigate these related topics.MethodsCases of UGIB due to duodenal or gastric ulcer, or gastritis were identified in 14 study hospitals in various areas of Japan. For each case, two controls were identified from population registries in the same district. Information on drugs and other risk factors was obtained from 175 cases and 347 controls by telephone interviews. Anti-H. pylori antibody in the urine was measured in a single laboratory for all the cases and 225 controls.ResultsThe odds ratio (OR) of UGIB was 5.5 for aspirin and 6.1 for other NSAIDs (NANSAIDs) (p<0.01). The OR for regular use was higher than for occasional use both for aspirin (7.7 vs 2.0) and NANSAIDs (7.3 vs 4.1). Loxoprofen (5.9), frequently used in Japan as a safe ‘prodrug’, was significantly associated with UGIB. The odds ratio for H. pylori infection was 4.9 and the relative excess risk due to the interaction between H. pylori and the use of NSAID was 1.2 (95% CI: −5.8–8.1).ConclusionNSAIDs including loxoprofen increase the risk of UGIB in Japan as in Western countries, with a similar magnitude of association. There was no evidence of biological interaction between NSAIDs and H. pylori infection.

Endoscopic mucosal resection: an improved diagnostic procedure for early gastroesophageal epithelial neoplasms.

Endoscopic mucosal resection (EMR), which is advocated for the treatment of early (superficial) gastroesophageal neoplasms, has also been alluded to represent a superior diagnostic and staging modality. We compared the diagnostic concordance of preceding biopsies with EMR specimens in 31 gastric and 10 esophageal EMRs consisting of 6 low-grade and 12 high-grade dysplasias, 21 intramucosal adenocarcinomas, and 2 submucosal invasive adenocarcinomas. Discrepancies were considered as either major or minor if the histologic grades differed by 2 or more, or by only 1, respectively. Discrepant and concordant cases were compared with regard to the size of lesion (maximum dimension and surface area), number of biopsy fragments, and extent of biopsy sampling (ratio between lesion size and number of biopsy fragments). These same variables were used to evaluate the differences seen between gastric and esophageal cases. Of the 41 cases, 16 (39%) had discrepant diagnoses, including 14 gastric and 2 esophageal neoplasms. A major discrepancy was seen in 2% of the cases (n = 1, gastric) and a minor discrepancy, in 15 cases. All but 2 of the discrepant cases were found to have a higher grade on EMR. The average number of biopsy fragments was 4.4 in both concordant and discrepant groups. The maximal dimension, surface area, and biopsy sampling ratios of the lesion were significantly greater in the discrepant cases than in the concordant cases. The esophageal cases trended toward having smaller size and a significantly extensive biopsy sampling. We conclude that EMR is superior to biopsy for diagnosing superficial gastroesophageal tumors. Discrepancies between the specimens occur in larger lesions (>10 mm) with less extensive biopsy sampling. EMR can substantially modify the diagnostic grade of a lesion and therefore facilitate optimal therapeutic decisions by avoiding undertreatment and overtreatment based on inaccurate grading and staging.

Endoscopic mucosal resection for gastric epithelial neoplasms: a study of 39 cases with emphasis on the evaluation of specimens and recommendations for optimal pathologic analysis.

Endoscopic mucosal resection of gastric neoplasms is a curative technique that avoids surgery and its potential complications. Infrequently performed in the West, the limitations, pitfalls and challenges provided by this new therapeutic modality are not well known by general surgical pathologists. We evaluated a series of 39 endoscopic mucosal resections and assessed the correlation between original biopsies and final diagnoses, depth of excision, status of deep and lateral margins, artifactual changes and recurrence rate. The tumors consisted of 24 intramucosal carcinomas, six high-grade dysplasias, eight low-grade dysplasias and one submucosal invasive carcinoma. The preresection diagnoses corresponded to the final evaluation in 63% of the cases with previous biopsies. In 37% of the cases, the biopsies under-diagnosed the neoplasia. The rate of positive margins was 38%. Iatrogenic changes, that is, intramucosal hemorrhage and electrodiathermic burn, were noted in 44% of the cases but hindered the pathologic evaluation in only 10% of the cases. Persistence or recurrence was observed in only seven cases and there was no progression to advanced adenocarcinoma. Based on our experience, we offer some recommendations in order to provide optimal pathologic analysis of endoscopic mucosal resection specimens.

COX‐2, prostanoids and colon cancer

Epidemiological, experimental, and clinical studies have demonstrated that colon carcinogenesis may be prevented by nonsteroidal anti‐inflammatory drugs (NSAIDs). Although controversy remains, recent studies, including ours, have revealed that NSAIDs suppress colon carcinogenesis at the adenoma stage where cyclooxygenase‐2 (COX‐2), a major molecular target in this action, is mainly expressed in interstitial cells but not in tumour cells. Therefore, it is unlikely that NSAIDs prevent colon cancer formation through modulating the functions of tumour cells. A more possible assumption is that NSAIDs suppress colon carcinogenesis through the inhibition of prostaglandin formation. However, the mechanisms by which prostanoids promote colon carcinogenesis have not been elucidated to date. A prostanoids act through both membrane receptors and nuclear receptors such as peroxisome proliferator receptor (PPAR) γ or δ, one focus in this area is to investigate their roles in colon carcinogenesis, including the induction of growth factors.

Nonsteroidal anti-inflammatory drugs may prevent colon cancer through suppression of hepatocyte growth factor expression.

Nonsteroidal anti-inflammatory drugs which inhibit cyclooxygenase have been reported to suppress colon carcinogenesis. However the mechanism has not yet been elucidated. Growth factors such as hepatocyte growth factor, which are produced by fibroblasts, have been shown to be important in carcinogenesis and the progression of various human cancers. In the present study, we tested the hypothesis that nonsteroidal anti-inflammatory drugs inhibit hepatocyte growth factor expression through an endogenous prostaglandin-mediated pathway in cultured human colonic fibroblasts. Human colonic fibroblasts were obtained from a resected colon and cultured. Hepatocyte growth factor and prostaglandin E2 were measured by enzyme-linked immunosorbent assay. Induction of cyclooxygenase-1 and cyclooxygenase-2 protein was estimated by immunoblotting. Prostaglandins increased hepatocyte growth factor production significantly in a dose- and time-dependent manner. Cholera toxin and 8-bromo cAMP also stimulated hepatocyte growth factor production. Further, prostaglandin E1 significantly increased cellular cAMP. The prostaglandin EP2 and EP4 receptors were detected by reverse transcription-polymerase chain reaction. Interleukin-1beta dramatically increased prostaglandin E2 production and significantly stimulated hepatocyte growth factor synthesis. Interleukin-1beta induced cyclooxygenase-2 but not cyclooxygenase-1 protein. Indomethacin significantly reduced interleukin-1beta-induced prostaglandin E2 release and hepatocyte growth factor production. These results suggest that prostaglandin is a factor for the production of hepatocyte growth factor by human colonic fibroblasts. Nonsteroidal anti-inflammatory drugs may suppress colon carcinogenesis, in part, through the suppression of hepatocyte growth factor expression by inhibiting endogenous prostaglandin production.

Relationship between expression of cyclin D1 and impaired liver regeneration observed in fibrotic or cirrhotic rats

Background and Aim:u2002 The mechanisms responsible for impaired regenerative ability after hepatic resection observed in chronic liver disease are not fully understood. We have examined the relationships between an altered expression of cell cycle‐related proteins in regenerating liver after partial hepatectomy and the impaired regenerative process observed in fibrotic and cirrhotic rats.

Post-gastric endoscopic mucosal resection surveillance biopsies: evaluation of mucosal changes and recognition of potential mimics of residual adenocarcinoma.

Endoscopic mucosal resection (EMR) offers curative treatment for patients with node-negative early gastric carcinoma of less than 2u2009cm without ulceration or ulceration scar. Follow-up biopsies are frequently performed to ensure the absence of residual neoplasia. We performed a retrospective analysis of post-EMR biopsies from 33 patients who underwent gastric EMR. Histologic changes included inflammation (100%), stromal edema (97.0%), foveolar hyperplasia (78.8%), ectatic vessels (66.7%), epithelial atypia (60.6%), increased glandular mitoses (57.6%), epithelial anisonucleosis (54.5%), fibrinopurulent materials (51.5%), ischemia (48.5%), stromal hemorrhage (33.3%), mucin depletion (12.1%), clear cell degeneration (15.2%), and signet-ring cell-like change (6.1%). Especially, clear cell degeneration and signet-ring cell-like change were conspicuous in the area of ischemia. Residual adenocarcinomas were noted in 4 of 33 cases, and consistently showed high nuclear-to-cytoplasmic ratio with high glandular density. Glandular clear cell degeneration and/or signet-ring cell-like change were worrisome and sometimes difficult to be distinguished from residual neoplastic glands. However, these degenerative glands were usually embedded in a nondesmoplastic stroma and showed anisonucleosis of glandular epithelia. Mimics of residual adenocarcinoma, namely clear cell degeneration and signet-ring cell-like change should be judiciously assessed to avoid unnecessary surgery.

Clinical response is associated with elevated plasma interleukin-1 receptor antagonist during selective granulocyte and monocyte apheresis in patients with ulcerative colitis

Depletion of granulocytes and monocytes (GM) by selective apheresis (GMA) with an Adacolumn exerts an anti-inflammatory effect in patients with ulcerative colitis (UC) or rheumatoid arthritis. However, the mechanism of the anti-inflammatory effect of GMA is not fully understood yet. We investigated the effect of GMA on the plasma concentration of interleukin-1 receptor antagonist (IL-1ra), a potent anti-inflammatory cytokine. Twenty-six patients with active UC received GMA at one session per week for 5 consecutive weeks. Clinical response was defined as Δclinical activity index (ΔCAI=CAI at entry – CAI at post)≥4, while clinical remission was defined as CAI≤4. Twenty-one of twenty-six patients (80.8%) responded to GMA. In the first session, plasma from responder patients showed a significant (P < 0.01) increase in IL-1ra in the Adacolumn outflow. In contrast, there was no change in IL-1ra in nonresponders. In conclusion, release of IL-1ra during GMA might be one mechanism of clinical efficacy associated with this therapy.

Effect of rebamipide on prostaglandin receptors-mediated increase of inflammatory cytokine production by macrophages

Background :u2002Rebamipide (Reb) is an anti‐ulcer drug, and has unique properties such as anti‐inflammatory action. We previously reported that prostaglandins (PGs) dramatically increased vascular endothelial growth factor (VEGF), a known angiogenic factor and a vascular permeable factor, by activated macrophages through specific PGE receptor and peroxisome proliferator‐activated receptor γ (PPARγ, a nuclear receptor of PG) mediated process. Effects of PGs on the production of other cytokines such as interleukin (IL)‐6 and IL‐8 have been controversial.