Association of interleukin-18 gene single-nucleotide polymorphisms with susceptibility to inflammatory bowel disease.

Interleukin-18 (IL-18) is believed to be one of the most important cytokines in the pathogenesis of inflammatory bowel disease (IBD). The aim of the study was to clarify the significance of single-nucleotide polymorphisms (SNPs) at the 5'-end of the IL-18 gene in the development of IBD. DNA was obtained from peripheral blood of 99 patients with ulcerative colitis (UC), 79 patients with Crohn's disease (CD), and 102 healthy controls. All participants were Japanese. SNPs at -656G/T, -607C/A, -137G/C, +113T/G, and +127C/T were determined by means of direct sequencing, and a genetic association with IBD was examined. The frequencies of the G allele at +113 and the T allele at +127 were significantly higher in patients with CD and UC compared with controls. The differences in allelic frequencies were more striking in patients with CD than in patients with UC, and at position +127 than at position +113. The haplotype estimation, according to the E-M algorithm, suggested that TACGT is closely associated with IBD, especially with CD. It was concluded that SNPs at the 5'-end of IL-18 gene might be closely related to the etiology of IBD.

Efficacy of argon plasma coagulation in nonvariceal upper gastrointestinal bleeding.

BACKGROUND AND STUDY AIMS: Various methods of endoscopic hemostasis have been described. However, few reports have investigated the efficacy of argon plasma coagulation (APC) in the treatment of upper gastrointestinal bleeding. The aim of this study was to evaluate the efficacy of APC in various types of upper gastrointestinal bleeding. PATIENTS AND METHODS: The present study was designed as a prospective and observational study. A total of 254 consecutive patients with upper gastrointestinal bleeding (excluding variceal bleeding) were primarily treated using APC. If it was difficult to achieve complete hemostasis with APC alone, injection of a hypertonic saline-epinephrine solution and clipping were carried out. The initial hemostasis rate, rate of recurrent bleeding after APC, permanent hemostasis rate, and mean procedure time were evaluated. RESULTS: Initial hemostasis with APC alone was achieved in 193 of the 254 patients (75.9 %). With the assistance of other methods as well, initial hemostasis was achieved in 253 patients (99.6 %). Among the 193 patients treated with APC alone, recurrent bleeding was observed in 11 cases (11 of 193, 5.7 %). With one exception, these cases of recurrent bleeding were controlled with APC alone again; permanent hemostasis was thus ultimately achieved with APC alone in 192 of the 254 patients (75.5 %). The mean procedure time was 8 min. No complications (such as perforation) were observed with the APC treatment. CONCLUSIONS: These data indicate that APC is a safe, quick, and effective method of treating various types of nonvariceal upper gastrointestinal bleeding and that it can be a powerful tool for endoscopic hemostasis.

[Alternations of p53 gene, microsatellite instability and proliferation associated antigen Ki-67 in the synchronous multiple colorectal cancers].

To evaluate the malignant potential of synchronous multiple colorectal cancers, we studied clinicopathologically 31 synchronous multiple colorectal cancers resected at our hospital. We also compared the p53 gene mutation rate, replication error (RER) rate, and Ki-67 antigen positivity rate between these cancers and 90 sporadic colorectal cancers. There was no significant difference in lymphoid and venous invasion, hepatic metastasis, or stage of colon cancer between the two types of cancers. The p53 gene mutation rate was lower in synchronous multiple colorectal cancers (p < 0.05). The RER rate and positivity rate for Ki-67 antigen was significantly higher in these cancers (p < 0.05). These results suggest that some synchronous multiple colorectal cancers result from carcinogenesis in which RER genes are involved, as HNPCC does. In the patients with synchronous multiple colorectal cancers, it is clinically important to follow them carefully focusing on multiple metachronous colorectal cancers and multiple organ cancers.

Vascular smooth muscle cells and pericytes express MMP-1, MMP-9, TIMP-1 and type I procollagen in inflammatory bowel disease.

AIMS: Matrix metalloproteinases (MMPs) are involved in tissue remodelling, which is one of the important aspects of inflammatory disease. To assess the balance between the matrix degradation and production, we analysed the in situ expression of MMP-1, -3, -8 and -9, tissue inhibitor of metalloproteinases (TIMP)-1 and -2, and type I procollagen (PC-I) in inflammatory bowel disease. METHODS AND RESULTS: Immunohistochemistry using frozen sections was performed in 17 patients with ulcerative colitis (UC) and 16 with Crohn's disease (CD). In both UC and CD, MMPs and TIMPs were expressed by inflammatory cells as well as by fibroblastic cells most prominently in actively inflamed areas in ulcer bases, but sparsely in intact inflamed mucosa in both UC and CD. In UC, inflamed mucosa with erosions expressed these substances focally. Fibroblasts also expressed PC-I. We identified that vascular smooth muscle cells of venules in ulcer bases expressed MMP-1 and -9, TIMP-1 and PC-I. These venules also expressed E-selectin, a cell adhesion molecule to facilitate the leucocyte extravasation, and vascular endothelial growth factor (VEGF) receptor 2, consistent with their property of newly formed vessels. CONCLUSIONS: Our results suggest that MMPs are involved in the tissue remodelling, angiogenesis and promotion of leucocyte extravasation in the actively inflamed area in the ulcer base in both UC and CD. MMP-1 expression in the mucosa may be related to the initial step of ulceration in UC. Therapeutic manipulation of extracellular matrix turnover would be an effective therapy to alleviate active inflammation and accelerate ulcer healing.

Pancreatic ductal myofibroblasts. Proliferative patterns in various pathologic situations.

Myofibroblasts in the periacinar area of the pancreas have been demonstrated to mediate fibrogenesis in pancreatic fibrosis. However, only a few reports have described myofibroblasts in the pancreatic duct. To elucidate the presence of myofibroblasts in the pancreatic ductal wall, we performed an immunohistochemical study, using immunostains for both alpha-smooth muscle actin (alphaSMA) and desmin, and an electron microscopic study on surgically resected pancreatic specimens from 10, 23, 23, and 56 cases of focal pancreatitis (FP), chronic pancreatitis (CP), pancreatic carcinoma (PCa), and carcinoma of the papilla of Vater (VPCa), respectively. All cases showed localized stenosis of the main pancreatic duct by means of preoperative pancreatography. As controls, 20 autopsy cases were studied. alphaSMA-positive and desmin-negative cells existed in the ductal walls of controls and were revealed as myofibroblasts by means of electron microscopy. In six FPs, proliferation of myofibroblasts was observed at the stenotic portion. In VPCas, myofibroblasts mainly proliferated in the pancreatic ductal wall. In CPs and PCas, no myofibroblast proliferation was observed at the stenotic portion. The proliferation of myofibroblasts might occur as a wound healing process in FP, while acting against elevation of intraductal pressure in VPCa. In conclusion, proliferation of myofibroblasts plays an important role in ductal changes in various pathological situations.

Appendectomy protects against the development of ulcerative colitis and reduces its recurrence: results of a multicenter case-controlled study in Japan.

OBJECTIVES: Studies in the US and Europe have shown that appendectomy may prevent the development of ulcerative colitis, but no detailed study has been conducted in Japan, where ulcerative colitis is uncommon and the population is racially homogeneous. In addition, there has been no detailed analysis of the relationship between appendectomy and the clinical course of ulcerative colitis. In this multicenter clinical study, we evaluated the effects of appendectomy on ulcerative colitis in Japan. METHODS: A case-control study was undertaken in seven medical institutions comparing the incidence of appendectomy and tonsillectomy in 325 patients with ulcerative colitis and 325 controls matched for age (10-yr intervals) and sex. Disease duration, extent, and prognosis were determined in 21 patients with ulcerative colitis who underwent appendectomies and 304 patients with ulcerative colitis who did not undergo appendectomies. RESULTS: Appendectomy was performed in a significantly lower percentage of patients in the ulcerative colitis group (21/325, 6.5%) than in the control group (53/325, 16.3%) (p < 0.001) (odds ratios = 0.355, 95% CI = 0.208-0.603). In contrast, no significant difference was observed between the groups with respect to tonsillectomy. The mean age (25.7 +/- 10.9 yr) of patients with ulcerative colitis at the time of appendectomy was significantly higher than the mean age (20.1 +/- 8.7 yr) of patients in the control group at the time of appendectomy (p < 0.05). The incidence of proctitis was higher in the appendectomy group than in the group that did not undergo appendectomies (38.1% vs 18.1%). In addition, the recurrence rates were significantly lower in the appenectomy group than in the group that did not undergo appendectomies (57. 1% vs 78.6%, p < 0.05), although both groups were similar in composition as to sex, age, duration of disease, smoking status, and previous medical treatment. CONCLUSIONS: Our results indicate that appendectomy has a negative association with and perhaps a preventive effect on the development of ulcerative colitis in the Japanese population. Furthermore, appendectomy also appears to reduce the extent and recurrence of ulcerative colitis.

Asymmetric hydrosilylation of styrenes catalyzed by palladium-MOP complexes: ligand modification and mechanistic studies.

In the palladium-catalyzed asymmetric hydrosilylation of styrene (3a) with trichlorosilane, several chiral monophosphine ligands, (R)-2-diarylphosphino-1,1'-binaphthyls (2a-g), were examined for their enantioselectivity. The highest enantioselectivity was observed in the reaction with (R)-2-bis[3,5-bis(trifluoromethyl)phenyl]phosphino-1,1'-binaphthyl (2g), which gave (S)-1-phenylethanol (5a) of 98% ee after oxidation of the hydrosilylation product, 1-phenyl-1-(trichlorosilyl)ethane (4a). The palladium complex of 2g also efficiently catalyzed the asymmetric hydrosilylation of substituted styrenes on the phenyl ring or at the beta position to give the corresponding chiral benzylic alcohols of over 96% ee. Deuterium-labeling studies on the hydrosilylation of regiospecifically deuterated styrene revealed that beta-hydrogen elimination from 1-phenylethyl(silyl)palladium intermediate is very fast compared with reductive elimination giving hydrosilylation product when ligand 2g is used. The reaction of o-allylstyrene (9) with trichlorosilane catalyzed by (R)-2g/Pd gave (1S,2R)-1-methyl-2-(trichlorosilylmethyl)indan (10) (91% ee) and (S)-1-(2-(propenyl)phenyl)-1-trichlorosilylethanes (11a and 11b) (95% ee). On the basis of their opposite configurations at the benzylic position, a rationale for the high enantioselectivity of ligand 2g is proposed.

Prognostic significance of entrapped liver cells in hepatic metastases from colorectal cancer.

OBJECTIVE: To correlate the microscopic finding of entrapped liver cells in hepatic metastases from colorectal cancer with outcome after hepatectomy. SUMMARY BACKGROUND DATA: Reliable histopathologic prognostic factors in resected liver metastases from colorectal cancer have not been identified. METHODS: Seventy-one patients undergoing radical hepatectomy for liver metastases were assigned to rare (n = 36) or frequent (n = 35) groups according to the microscopically observed frequency of hepatocyte entrapment in the tumor. RESULTS: Five-year survival rates after hepatectomy were 44. 4% for the rare group and 27.2% for the frequent group. Multivariate analysis using the Cox proportional hazards model by a stepwise method identified this morphologic variable as a significant independent prognostic factor. CONCLUSIONS: The finding of entrapped liver cells in metastases from colorectal cancer reflects the biologic activity of the tumor and may be a useful prognostic indicator.

Primary gastric B cell lymphoma: audit of 82 cases treated with surgery and classified according to the concept of mucosa-associated lymphoid tissue lymphoma.

There has been a trend toward stomach conservation during treatment for primary gastric lymphoma, but surgery ensures accurate pathologic diagnosis through the examination of resected specimens. A histopathologic classification for primary gastric lymphoma had been established with the knowledge that the low grade and high grade components occasionally coexist in a single lesion. Efficacy of this classification as an indicator of biologic behavior and prognosis was evaluated. The classification was performed by reexamining surgically resected specimens from 82 patients with stage IE and IIE gastric lymphoma. Clinical characteristics of the low grade and high grade lymphomas were then evaluated and the survival data analyzed. Despite the larger tumor diameter, the depth of invasion for the low grade type was mostly submucosal, and none had serosal invasion. In contrast, 50% of the high grade type had serosal involvement and were also found to have a higher incidence of node metastasis. Prognosis of the low grade type, a 10-year survival rate exceeding 90%, was significantly better than that of the high grade type. Multivariate analysis revealed that curability of the operation followed by the histopathologic grade were significant independent prognostic factors. Some characteristics of the low grade lymphoma were not consistent with what has been reported in the studies involving stomach-conserving strategies. Investigators are advised to note that the histopathologic grade determined with biopsy specimens alone could be misleading.

Adenocarcinoma of the gastroesophageal junction in Japan: relevance of Siewert's classification applied to 177 cases resected at a single institution.

BACKGROUND: There had been a lack of international consensus about the definition of cancer of the gastric cardia until Siewert's classification was approved at a consensus conference during the second International Gastric Cancer Congress held in 1997. STUDY DESIGN: A review of the prospective gastric cancer database at Aichi Cancer Center from 1983 to 1992 identified 1,913 gastric carcinoma patients who underwent gastrectomy. These patients were classified retrospectively according to the Siewert classification, and 177 patients who fell into one of the three types form the basis of this study. Survival analyses were performed after stratifying patients by clinicopathologic variables. RESULTS: There were 33 patients with type II and 144 with type III, although none had type I, a type frequently observed in the west. No evidence of a change in the frequency of types II or III cancers (approximately 9.3% overall) among gastric carcinoma patients was observed over the 10-year period. Clinical staging of gastric carcinoma by the TNM classification was found to reflect accurately the prognosis of these patients. There were no longterm survivors among the few patients with metastasis to the perigastric nodes of the distal stomach. CONCLUSIONS: A striking difference in the distribution of types of adenocarcinoma of the gastroesophageal junction was observed in Japan compared with previously reported western data. A subgroup of carcinoma of the proximal stomach identified as types II and III may not require proximal gastrectomy from the viewpoint of sufficient lymphadenectomy.

Case of intraductal papillary mucinous tumor (noninvasive adenocarcinoma) of the pancreas resected 27 years after onset.

A case of intraductal papillary mucinous tumor (IPMT) of the pancreas resected 27 yr after onset is presented. In March of 1997, a 71-yr-old man was admitted to our hospital with a complaint of severe epigastric pain. He had initially undergone endoscopic retrograde pancreatography (ERP) in April 1971 in our hospital and the patient had been followed up for pancreatografic changes for 26 yr. Dilatation of the main pancreatic duct gradually progressed during follow-up, and the filling defect owing to the tumor became demonstrable. On admission, ERP revealed diffuse dilatation of the main pancreatic duct, which was 20 mm in diameter, and the filling defect of 35 mm in diameter. We diagnosed this patient as having an IPMT of the pancreas. Considering his general condition, pancreatic segmentectomy was carried out, and the postoperative course was favorable. Histological findings were compatible with those of noninvasive papillary adenocarcinoma. This is a precious case for studying the natural history of intraductal papillary tumor of the pancreas and to evaluate the application of surgery, because the biologic behavior of this tumor is much less aggressive than that of pancreatic ductal cell carcinoma.

Disruption of E-cadherin-mediated cell adhesion systems in gastric cancers in young patients.

The aim of this study was to elucidate the pathogenetic backgrounds of early-onset gastric cancers. Mutations of the E-cadherin and beta-catenin genes were analyzed by subjecting microdissected cancer cells and corresponding non-cancerous epithelial cells obtained from 9 gastric cancer patients under 35 years old to polymerase chain reaction-single strand conformation polymorphism analysis. Somatic, but no germline, E-cadherin gene mutations were detected in 6 (67%) of the patients. The cancer cells of 2 patients were exon 9-deleted E-cadherin molecule-immunoreactive. Neither somatic nor germline mutations in exon 3 of the beta-catenin gene were observed in any patient. One patient lacked beta-catenin immunoreactivity and the cancer cells of 6 others showed cytoplasmic beta-catenin immunoreactivity. The E-cadherin-mediated cell adhesion system in the cancer cells of all the patients examined appeared to be disrupted, indicating that somatically acquired dysfunction of this system plays an important role in early-onset diffuse-type gastric cancers. Helicobacter pylori infection was observed in 6 (67%) of our 9 patients, an incidence higher than the average in young Japanese individuals. Thus, early-onset gastric cancers may be attributable to environmental factors such as Helicobacter pylori infection.

Peritoneal washing cytology: prognostic value of positive findings in patients with gastric carcinoma undergoing a potentially curative resection.

BACKGROUND AND OBJECTIVES: Free cancer cells in the abdominal cavity exfoliated from a tumor are considered to be responsible for peritoneal dissemination, the most frequent pattern of failure in gastric carcinoma patients treated with curative surgery. METHODS: A prospective survival analysis was performed with 91 gastric carcinoma patients treated by potentially curative resection. Cytology was performed for all the patients. The method of Kaplan and Meier was used to construct curves with diagnosis of peritoneal dissemination and cancer death as the end points. Multivariate analysis by Cox's proportional hazards model was performed to identify independent prognostic factors of significance. RESULTS: Patients with a positive cytology result were confirmed to have a greater risk for recurrence in the pattern of peritoneal carcinomatosis and hence a significantly inferior prognosis. Positive cytology was the only significant independent prognostic factor among the curatively resected patients with advanced gastric carcinoma. CONCLUSIONS: Peritoneal lavage cytology should be employed for all advanced cancer undergoing potentially curative resection for added accuracy in the stage classification. The results should also reflect the eligibility of the patients for future clinical trials involving perioperative intraperitoneal chemotherapy.

The number of metastatic lymph nodes: a promising prognostic determinant for gastric carcinoma in the latest edition of the TNM classification.

BACKGROUND: The number of metastatic regional lymph nodes determines the new pN categories in the 5th edition of the TNM classification. STUDY DESIGN: Our retrospective study was conducted to compare the new method of defining lymph node status with the conventional classification, consisting of the anatomic extent of lymph node metastases, a well-established prognostic factor. The study was based on clinical data for 493 patients with gastric carcinomas who underwent potentially curative operations and had histologically confirmed nodal metastases. These patients were stratified into 1) n categories according to the Japanese Classification of Gastric Carcinoma, 2) the new pN categories, and 3) the pN categories determined by the number of metastatic perigastric nodes resected by standard D1 gastrectomy. Survival data were analyzed for each group. RESULTS: The number of metastatic nodes after D2 lymphadenectomy reflected prognosis well and was shown by multivariate analysis to be a strong independent prognostic factor. When the classification was performed limited to the metastatic perigastric nodes, stage migration was evident, but the variable remained competent as a prognostic indicator. CONCLUSIONS: The number of metastatic nodes is a promising determinant in the new international stage classification.

Lymph node status assessment for gastric carcinoma: is the number of metastatic lymph nodes really practical as a parameter for N categories in the TNM Classification? Tumor Node Metastasis.

BACKGROUND AND OBJECTIVES: The anatomical extent of nodal metastasis has been replaced by the number of metastatic nodes as a key indicator of prognosis (pN categories) in the fifth edition of Tumor Node Metastasis Classification for gastric carcinoma by the International Union Against Cancer. The rate of metastatic nodes among all the nodes harvested is also a good prognostic factor. The object of this study is to evaluate which of the three parameters for the assessment of nodal status is the most appropriate for use in the stage classification. METHODS: Retrospective survival analyses were performed in 656 consecutive patients with advanced gastric carcinoma who underwent D2 lymphadenectomy and for whom histopathologic data of more than 20 lymph nodes were available. RESULTS: Although all three systems served well to classify the patients into distinct groups in terms of survival curves, stratification by the number of metastatic nodes was vulnerable to stage migration because of differences in the number of lymph nodes harvested. Such stage migration was not evident for the other two parameters. CONCLUSIONS: Lymph node metastatic rate can be recommended as an internationally applicable parameter for lymph node involvement of gastric carcinoma.

Prognostic value and clinical implications of disseminated cancer cells in the peritoneal cavity detected by reverse transcriptase-polymerase chain reaction and cytology.

Free cancer cells exfoliated from the cancer-invaded serosa contribute to peritoneal dissemination, the most frequent pattern of recurrence in gastric carcinoma patients. This study was designed to evaluate the prognostic relevance of such free cells in peritoneal washes detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and cytology. RT-PCR analysis with primers specific for carcinoembryonic antigen and conventional cytologic examination by Papanicolaou staining were performed on peritoneal washes, collected at laparotomy from 148 gastric carcinoma patients. Prognostic analyses were performed with 1) death due to cancer recurrence and 2) peritoneal dissemination as endpoints. RT-PCR was found to be more sensitive than cytologic examination for detection of free cancer cells in the peritoneal washes, with a higher detection rate for each of the T categories in the tumor-node-metastasis (TNM) classification. Five patients with synchronous or recurrent peritoneal dissemination were found among 17 patients with positive RT-PCR and negative cytologic results. Both positive cytologic results and positive RT-PCR results had significant influences over the survival of patients with advanced gastric carcinomas (n = 75, p < .002). Detection of free cancer cells in peritoneal washes, most reliably by RT-PCR, is promising as a predictor of peritoneal dissemination in patients with gastric carcinoma.