Toru Hiyama

Genetic polymorphisms and esophageal cancer risk.

The aim of this paper is to review and evaluate, in a comprehensive manner, the published data regarding the contribution of genetic polymorphisms to risk of esophageal cancer, including squamous cell carcinoma (SCC) and adenocarcinoma, in humans. All relevant studies available in MEDLINE and published before February 2007 were identified. Studies carried out in humans and that compared esophageal cancer patients with at least 1 standard control group were considered for analysis. One‐hundred studies and 3 meta‐analyses were identified. Eighty (80%) studies were conducted in Asian countries, particularly China including Taiwan (60 (60%) studies). The most intensively examined genes were those encoding carcinogen metabolic enzymes. The most widely studied gene was GSTM1 (15 studies), followed by ALDH2 (11 studies). ALDH2, MTHFR C677T, CYP1A1 Ile/Val, CYP1A1MspI, CYP2E1, GSTP1, GSTM1 and GSTT1 were examined by meta‐analyses and significant relations were found between ALDH2*1*2 and the CYP1A1 Val allele and increased risk of esophageal cancer. In addition, increased risk of esophageal SCC was consistently associated with the ADH2*1*2 and the p53 codon 72 Pro/Pro genotypes. Cohort studies that simultaneously consider multiple genetic and environmental factors possibly involved in esophageal carcinogenesis are needed to ascertain not only the relative contribution of these factors to tumor development but also the contributions of their putative interactions.

Frequent p53 gene mutations in serrated adenomas of the colorectum.

Serrated adenoma has been recently proposed as a distinct histological lesion of the colorectum. This study examined p53 immunoreactivity, mutations of exons 5–8 of the p53 gene, codon 12 of the Ki‐ras gene by PCR–SSCP analyses, and microsatellite instability in 19 serrated adenomas, ten adenocarcinomas in/with serrated adenomas, 23 hyperplastic nodules, four hyperplastic polyps and 29 tubular adenomas of the colorectum. Eleven of 11 (100 per cent) serrated adenomas had p53 immunoreactivity and all six (100 per cent) adenocacinomas in/with serrated adenomas exhibited moderate to severe p53 immunoreactivity. It was confirmed that 9 of 19 (47 per cent) serrated adenomas and 5 of 10 (50 per cent) adenocarcinomas in/with serrated adenomas harboured p53 gene mutations. On the other hand, no p53 gene mutation was detected in the other colorectal lesions. Meanwhile, 11 (58 per cent) serrated adenomas and six (60 per cent) adenocarcinomas in/with serrated adenomas had Ki‐ras gene mutations, as also did 9 of 23 (39 per cent) hyperplastic nodules, 3 of 4 (75 per cent) hyperplastic polyps, and 12 of 29 (41 per cent) tubular adenomas. Microsatellite instability was detected in one (5 per cent) serrated adenoma and one (10 per cent) adenocarcinoma in a serrated adenoma. The other lesions did not show microsatellite instability. Serrated adenomas had significantly frequent p53 gene mutations compared with hyperplastic lesions or tubular adenomas (p<0·005). On the other hand, they did not exhibit significant differences in mutations of the Ki‐ras gene or in microsatellite instability. Genetic changes were then examined in small parts of serrated adenomas, such as the upper or lower parts of crypts, to determine the extent of gene mutations by using a microdissection technique. Exon 15 of the APC gene and the DCC gene, in addition to the p53 and Ki‐ras genes and microsatellite instability, were analysed. Identical mutations of the p53 gene were found in both invasive adenocarcinomas and adjacent serrated adenomas by direct sequencing, suggesting single clonal origins for those lesions. Mutations of the APC gene and microsatellite instability were heterogeneous in some lesions. No loss of heterozygosity (LOH) of the DCC gene was found. These findings suggest that mutations of the p53 gene are the most characteristic genetic alterations in serrated adenomas, as a relatively early event in a multistep carcinogenic pathway of this type of colorectal lesion, that might be distinct from the ordinary adenoma–carcinoma sequence or from carcinogenesis via mutations of mismatch repair genes. Copyright

Meta-analysis of the effects of prokinetic agents in patients with functional dyspepsia.

Background:  Functional dyspepsia (FD) is often treated with prokinetic agents; however, the efficacy of prokinetic agents in patients with FD has been questioned recently. The aim of this study was to perform a meta‐analysis of the effects of prokinetic agents in patients with FD.

Infliximab Therapy for Crohn's Disease in a Patient with Chronic Hepatitis B

Infliximab, a chimeric anti‐tumor necrosis factor-α (TNFα) monoclonal antibody, has proven to be an effective treatment for Crohn’s disease (CD). However, the safety of infliximab has not been evaluated in patients infected with hepatitis B virus (HBV). We describe herein the case of a 28-year-old woman, positive for HBV surface antigen (HBsAg), who developed a mild transient increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and HBV DNA levels after a single infusion of infliximab for refractory CD.

Clinicopathologic and endoscopic features of colorectal serrated adenoma: differences between polypoid and superficial types.

BACKGROUND Serrated adenoma is a distinct histologic colorectal lesion. There are two macroscopic types: polypoid and superficial. The aim of this study was to clarify clinicopathologic and endoscopic differences between polypoid and superficial serrated adenomas. METHODS An analysis was conducted of the clinicopathologic and endoscopic features for 240 polypoid and 127 superficial serrated adenomas examined by colonoscopy, and the surface pit patterns of 114 polypoid and 64 superficial serrated adenomas examined by magnifying videoendoscopy. RESULTS The male:female gender ratio for the polypoid serrated adenomas (3.5:1) was significantly higher than that for the superficial serrated adenomas (1.7:1). Superficial serrated adenomas were significantly larger than polypoid serrated adenomas (mean [standard deviation], respectively, 10.1 [7.9] mm vs. 6.3 [4.6] mm). In the distal segments of the colorectum, polypoid serrated adenomas were more common than superficial serrated adenomas. Granulonodular and lobular appearances at endoscopy were significantly more common for polypoid (23.3%) than for superficial serrated adenomas (7.1%). Pit patterns differed between the lesion types: polypoid serrated adenomas had type III(L) or IV pit patterns; all superficial serrated adenomas had the type II pit pattern. The relative frequency of occurrence of high-grade dysplasia and carcinoma in situ among superficial serrated adenomas (25.2%) was significantly greater than that among polypoid serrated adenomas (9.2%). The tubulovillous growth pattern was significantly more common in polypoid tumors (31.5%) than in superficial tumors (0%). CONCLUSIONS Polypoid and superficial serrated adenomas have different clinicopathologic characteristics and growth patterns.

p53 Codon 72 polymorphism in gastric cancer susceptibility in patients with Helicobacter pylori-associated chronic gastritis

p53 codon 72, which produces variant proteins with an arginine (Arg) or proline (Pro), has been reported to be associated with cancers of the lung, esophagus and cervix. However, there have been no reports on the p53 codon 72 polymorphism in gastric cancer susceptibility in patients with Helicobacter pylori‐associated chronic gastritis (H. pylori‐CG). We, therefore, examined the polymorphism in 117 gastric cancer patients (72 intestinal type and 45 diffuse type) with H. pylori‐CG and 116 H. pylori‐CG patients without gastric cancer as controls. Polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) analysis was performed to analyze the p53 codon 72 polymorphism. The crude genotypic frequencies in the gastric cancer patients were similar to those of the controls. However, when gastric cancers were classified by histologic subtype, the Pro/Pro was more frequent in the patients with diffuse type gastric cancer than in the controls (22.2% of cases vs. 12.1% of controls). The Pro/Pro genotype was associated with a 2.98‐fold higher risk of diffuse‐type cancer compared to the Arg/Arg genotype (95% confidence interval [CI] 1.07–8.32, p = 0.038). These results suggest that the Pro/Pro genotype at p53 codon 72 contributes to susceptibility for diffuse‐type gastric cancer in patients with H. pylori‐CG. The p53 codon 72 polymorphism may serve as the genetic marker for the risk assessment of the diffuse‐type gastric cancer development in patients with H. pylori‐CG.

Nodular Gastritis in Adults Is Caused by Helicobacter pylori Infection

A close relationship exists between nodular gastritis and Helicobacter pylori infection in children. The pathogenesis and optimal management of nodular gastritis in adults, however, are unclear. This study describes the clinicopathologic features of nodular gastritis in adults and correlates treatment with outcome. Of 97,262 adult patients who underwent endoscopy, 187 (0.19%) were diagnosed with nodular gastritis, 151 (81%) of whom had dyspepsia. Nodular gastritis predominantly affects young women (49 men and 138 women, mean age, 32.6 years). All 134 patients tested for Helicobacter pylori infection were infected, and 65/66 (98%) had inflammation of both the antrum and the corpus. Twenty-five (13%) had associated lesions (peptic ulcers or cancer). Dyspepsia improved after eradication of Helicobacter pylori infection, but did not improve spontaneously. Nodular gastritis in adults is caused by Helicobacter pylori infection and shows a predilection for females and young adults. Helicobacter pylori eradication decreases symptoms and reduces the risk of peptic ulcers and possibly gastric cancer.

K-ras mutation in helicobacter pylori-associated chronic gastritis in patients with and without gastric cancer

Mutations of an oncogene, K‐ras, are associated with the development and progression of many types of human cancer. To elucidate the significance of K‐ras mutations in gastric carcinogenesis, we examined K‐ras mutations in gastric cancers and in Helicobacter pylori‐associated chronic gastritis (H. pylori‐CG), which is associated with an increased risk for the gastric cancer development. Specimens of gastric cancer and H. pylori‐CG were obtained from 64 gastric cancer patients with H. pylori‐CG, 99 cancer‐free H. pylori‐CG patients and 30 H. pylori‐negative healthy subjects. K‐ras mutations were examined by polymerase chain reaction‐single strand conformation polymorphism (PCR‐SSCP), followed by DNA sequencing analysis. K‐ras mutations were detected in 4 of 48 (8.3%) gastric cancers, in 10 of 163 (6.1%) H. pylori‐CG and none of the 30 H. pylori‐negative healthy subjects. In the gastric cancer patients, mutated K‐ras was detected in differentiated type cancers but not in any of the undifferentiated type cancers. K‐ras mutations in H. pylori‐CG were significantly more frequent in gastric cancer patients than in cancer‐free patients (10.9% vs. 3.0%, p = 0.044). In addition, K‐ras mutations in H. pylori‐CG were significantly more frequent in patients with K‐ras mutated gastric cancer than in patients with K‐ras unmutated gastric cancer (50.0% vs. 3.7%, p = 0.037). These data suggest that the genetic mechanism(s) of carcinogenesis differs between the differentiated type and the undifferentiated type of gastric cancer and that K‐ras mutations may be involved in the early stages of gastric carcinogenesis of the differentiated type.

Microsatellite instability is a genetic marker for the development of multiple gastric cancers

Multiple gastric cancers are found in 5–15% of all patients with gastric cancer. However, no molecular markers have yet been shown to be clinically useful for predicting which patient will or will not have multiple gastric cancers. Recently, microsatellite instability (MSI) has been identified as a molecular marker for multiple colorectal cancers. To elucidate whether MSI could be used as a molecular marker for multiple gastric cancers, we examined MSI in 38 patients with a single gastric cancer, in 26 patients with synchronous multiple gastric cancers and in 14 patients with metachronous multiple gastric cancers. In the patients with synchronous multiple gastric cancers, 1 of the larger tumors was examined. In the patients with metachronous multiple gastric cancers, the first gastric cancer was examined. Five microsatellite loci, including D17S855, D18S58, D18S61, BAT25 and BAT40, were examined with microsatellite assay. MSI was divided into low frequency of MSI (MSI‐L) and high frequency of MSI (MSI‐H) by the number of affected loci. MSI‐L was detected in 3 of the 38 (8%) patients with a single gastric cancer, in 7 of the 26 (27%) patients with synchronous multiple gastric cancers and in 6 of the 14 (43%) patients with metachronous multiple gastric cancers. MSI‐H was detected only in 1 of the 38 (3%) patients with a single gastric cancer. The frequency of MSI‐L was significantly higher in patients with multiple gastric cancers, both synchronous and metachronous, than in those with a single gastric cancer (p < 0.05 and p < 0.01, respectively). Patients with MSI(+) gastric cancer developed a significantly higher frequency of secondary gastric cancer, when compared with patients with MSI(‐) gastric cancer (p < 0.05). These data suggest that MSI may play an important role in the development of multiple gastric cancers, and it may be used clinically as a molecular marker for the prediction of multiple gastric cancers.

Lymphatic Vessel Density at the Site of Deepest Penetration as a Predictor of Lymph Node Metastasis in Submucosal Colorectal Cancer

PurposeLymph node metastasis is an important factor that influences curability after endoscopic treatment of submucosal colorectal cancer. This study was designed to determine the usefulness of identification of lymphatic vessels by immunohistochemistry in predicting lymph node metastasis of submucosal colorectal cancer.MethodsLymphatic involvement was assessed by hematoxylin and eosin staining and podoplanin immunostaining on samples resected from 268 patients with submucosal colorectal cancer. Lymphatic vessel density was estimated by two investigators by average count of three fields (×200) in the area of greatest number of podoplanin-positive capillaries at the site of deepest submucosal penetration. Relations with other clinicopathologic parameters also were investigated.ResultsLesions with high lymphatic vessel density (≥9 vessels per field) showed a significantly greater incidence of lymph node metastasis than did those with low lymphatic vessel density (<9 vessels per field; 23.3 vs. 8.4 percent). By multivariate analysis, lymphatic vessel density was determined to be an independent risk factor for lymph node metastasis of submucosal colorectal cancer (P = 0.0044). Lymphatic vessel density also correlated with tumor budding and the degree of inflammation at the invasive front.ConclusionsIdentification of lymphatic vessels by podoplanin immunostaining provides objective and accurate evaluation of lymphatic involvement. Lymphatic vessel density at the site of deepest penetration is a useful predictor of lymph node metastasis of submucosal colorectal cancer.