Wing Y. Chan

Association of Human-Leukocyte-Antigen Class I (B*0703) and Class II (DRB1*0301) Genotypes with Susceptibility and Resistance to the Development of Severe Acute Respiratory Syndrome

Abstract Severe acute respiratory syndrome (SARS) is a public health concern worldwide. By studying the human leukocyte antigen (HLA) types A, B, DR, and DQ alleles in 90 Chinese patients with serologically confirmed SARS infections, we identified a strong association between HLA-B*0703 (OR, 4.08; 95% CI, 2.03–8.18; P = .00072 [Bonferroni-corrected P value, Pc<.0022]) and -DRB1*0301 (OR, 0.06; 95%, 0.01–0.47; P = .00008 [after Bonferroni correction, P<.0042]) and the development of SARS. Moreover, the frequency of B*0703 and B60 coinheritance (9.6%; 95% CI, 4.6%–19.0%) in our SARS group was significantly higher (P = 3×10−9) than that expected in the general population (0.4%). These genetic data will critically affect both the study of the pathogenesis of SARS and the design of vaccination programs.

Effect of Helicobacter pylori eradication on expression of cyclin D2 and p27 in gastric intestinal metaplasia

Cyclins and cyclin‐dependent kinase inhibitors play a crucial role in the control of cell cycle transitions. Enhanced expression of cyclin D2 and reduced expression of p27kip1 (p27) have been implicated in the pathogenesis of cancer. Because intestinal metaplasia has been regarded as a pre‐malignant lesion, we investigated the expression of cyclin D2 and p27 in Helicobacter pylori‐associated chronic gastritis with and without intestinal metaplasia, and followed the changes after H. pylori eradication.

Multimodality treatment of primary lymphoepithelioma‐like carcinoma of the lung

Lymphoepithelioma‐like carcinoma (LELC) of the lung occurs at a higher frequency in Asian compared with Western patients. Its association with Epstein‐Barr virus varies among different ethnic groups.

Effects of Long-term Rofecoxib on Gastric Intestinal Metaplasia: Results of a Randomized Controlled Trial

Purpose: Gastric cancer and its premalignant gastric lesion, intestinal metaplasia (IM), frequently express cyclooxygenase-2 (COX-2) at high levels. We tested whether long-term use of specific COX-2 inhibitors regress gastric IM. Experimental Design: This is a double-blind, randomized, placebo-controlled trial. Individuals with confirmed IM and Helicobacter pylori clearance were randomized to receive rofecoxib 25 mg daily or placebo. Endoscopy was done at baseline, at the end of year 1, and at the end of year 2, with multiple biopsies taken from the antrum and corpus. The primary end point was the proportion of subjects with regression of IM. Secondary end points were the severity of other histologic variables and the proportion of subjects with complete regression of IM. Results: Two-hundred and thirteen subjects with confirmed IM were randomized. The proportion of subjects with the regression of IM did not differ significantly between rofecoxib and placebo groups (antrum, 24.5% versus 26.9%; P = 0.74; corpus, 4.3% versus 2.2%; P = 0.68). Patients on rofecoxib (19.1%) and on placebo (16.1%) had no IM detected in the stomach (P = 0.59). There was also no significant difference in the severity of IM between the two treatment groups (P ≥ 0.3). Conclusions: There was no trend to suggest that treatment with rofecoxib for 2 years resulted in the regression of gastric IM. Although our findings cast doubt on the reversibility of gastric IM by COX-2 inhibitor, further studies are needed to establish the role of COX-2 inhibitors in different stages of gastric carcinogenesis.

Risk factors associated with the development of intestinal metaplasia in first-degree relatives of gastric cancer patients

Family relatives of gastric cancer patients have a higher risk of gastric cancer and premalignant gastric lesions. We sought to determine the risk factors associated with the presence of intestinal metaplasia in a large cohort of gastric cancer relatives. First-degree relatives of gastric cancer patients were invited for screening gastroscopy. Endoscopic gastric biopsies were obtained from the antrum and corpus. Gastric biopsies were analyzed for Helicobacter pylori infection, severity of inflammation, and presence of intestinal metaplasia. Stepwise logistic regressions were used to identify for risk factors associated with presence of intestinal metaplasia in cancer relatives. Two hundred seventy cancer relatives underwent screening endoscopy (median age, 42; 47% male and 48% siblings). Among them, 161 (59.6%) were H. pylori positive and 81 (30%) had confirmed intestinal metaplasia. The following factors were found to be associated with the presence of intestinal metaplasia: age, male sex, H. pylori infection, birth order, alcohol use, siblings with stomach cancer, childhood living conditions, and water supply. Individuals with intestinal metaplasia had more severe acute and chronic inflammation in the antrum and corpus (P < 0.003). With multiple logistic regression, H. pylori infection [odds ratio (OR), 3.23], male gender (OR, 2.09), age (OR, 1.07), and a history of gastric cancer in siblings (OR, 1.91) were independent factors associated with the development of intestinal metaplasia in cancer relatives. In conclusion, we have identified risk factors associated with gastric intestinal metaplasia in stomach cancer relatives, which may be useful in the understanding of gastric carcinogenesis in these high-risk individuals. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2982–6)

Gastric choriocarcinoma shows characteristics of adenocarcinoma and gestational choriocarcinoma: a comparative genomic hybridization and fluorescence in situ hybridization study.

The authors report two cases of the rare primary gastric choriocarcinoma. These tumors showed an overwhelming predominance of cytotrophoblast-and syncytiotrophoblast-like tumor cells that were positive for &bgr;-human chorionic gonadotrophin, with small foci of glandular differentiation. &bgr;-human chorionic gonadotrophin was also detected serologically in one patient. Comparative genomic hybridization study was performed on one specimen. Copy number gains of chromosomes 12, 17, 20, 22, and X, together with losses on 18q, were the major findings. Except for the gain of chromosome 12, which is known to be uncommon in primary gastric adenocarcinoma but frequently associated with choriocarcinoma, the remaining genomic imbalances were among the most common comparative genomic hybridization findings reported in primary gastric adenocarcinoma. Fluorescence in situ hybridization on paraffin sections of both specimens confirmed the presence of polysomy 17 and trisomy 12. These results suggest that primary gastric choriocarcinoma genetically possesses characteristics of both adenocarcinoma and gestational choriocarcinoma. The authors believe this is the first interphase cytogenetics study on this rare tumor, and that the results support the theory that gastric choriocarcinoma arises from alternate differentiation pathways of adenocarcinoma.

Epstein-Barr virus-associated gastric lymphoma in Hong Kong Chinese.

We report 11 cases of gastric lymphoma that harbor the Epstein-Barr virus (EBV) encoded small messenger RNA, EBER-1, detected by in situ hybridization. The cases represented 18% of 61 consecutive gastric lymphomas from three institutions in Hong Kong between 1988 and 1993. The mean age of patients was 62 years (range, 33 to 87). The male to female ratio was 5:6. Nine of the 11 (81.8%) EBER-1+ gastric lymphomas were diffuse large cell lymphomas of B-cell type without low grade components. Macroscopically these lymphomas appeared either as large noncleaved cell (centroblastic) or immunoblastic type. From the available follow-up data, five of the nine patients with B-cell lymphoma were alive and well 48, 40, 14, 13, and 12 months, respectively, after gastrectomy and chemotherapy. One patient died of postoperative pneumonia and one died of a second malignancy (esophageal squamous carcinoma) 40 months after gastrectomy. None of the EBER-1+ B-cell gastric lymphomas showed histological features characteristic of low grade lymphoma of the mucosa-associated lymphoid tissue (MALT) type reported to be common in some Western countries. Of the two patients with T-cell lymphoma, one had a pleomorphic T-cell lymphoma and the other had an angiocentric lymphoma. The former was lost to follow-up after the biopsy and the latter presented with gastric perforation and died 1.5 months after gastrectomy. It is concluded that a significant proportion of gastric lymphomas in Hong Kong Chinese are EBV-related and that they show histological features more akin to conventional node-based lymphomas than to MALT-type lymphomas.

Allelic Loss of Chromosome 6q in Gastric Carcinoma

Loss of the long arm of chromosome 6 (6q) has frequently been reported in gastric carcinoma, and most gastric cancer patients have evidence of intestinal metaplasia in the stomach. However, the relationship between loss of chromosome 6q and intestinal metaplasia has not been studied. In the first part of the study, we define the critical deletion region of chromosome 6q using loss of heterozygosity technique (LOH). Seventeen microsatellite markers were used to detect loss of heterozygosity (LOH) in 37 microdissected gastric tumors. We also examined intestinal metaplasia (IM) foci of the stomach in the same cancer patient (17 cases). Losses on chromosome 6q were detected in high frequency (51%) by LOH. Two distinct regions of common allelic loss were identified: one centered on the marker D6S300 (at 6q16.1) and the second on D6S446 (at 6q27), with LOH frequency of 36% and 31.3%, respectively. The deletions fall into 2 discrete regions, suggesting the existence of at least 2 tumor suppressor genes in 6q. The losses at 6q27 were confirmed by fluorescence in situ hybridization study (FISH). In the cases with LOH in the tumor, no LOH were detected in the autologous IM areas, but losses were detected by FISH. In some cases, these genetic changes may be acquired in the transition from normal gastric mucosa to intestinal metaplasia.

Changes of Interleukin Expression Correlate with helicobacter pylori Infection and Lymph Node Metastases in Gastric Carcinoma

Helicobacter pylori (HP) infection induces expression of IL-8 and IL-10 in benign gastric epithelium. This study compared the expression of cytokines in CD4+ and CD8+ lymphocyte subsets of peripheral blood lymphocytes (PBL), benign mucosal lymphocytes (ML), and tumor infiltrative lymphocytes (TIL) as well as in the benign and malignant epithelial cells of the same patient, with respect to the presence of HP infection, lymph node metastases, and tumor histologic type. The mRNA of the cytokines was measured by a semiquantitative RT-PCR method. The levels were ranked and compared using the Wilcoxon sign-ranked test. Compared with CD8+ ML, the CD8+ TIL expresses higher levels of IL-6 and IL-8 but lower level of IL-4 in patients with lymph node metastases. In patients with HP infection, expression of IL-8 and IL-10 was higher in the gastric carcinoma cells than in the benign epithelial cells while expression of IL-6 and IL-8 were higher in CD8+ TIL than CD8+ ML. Overexpression of IL-8 in HP associated gastric carcinomas suggested that they might have arisen from HP-infected epithelial cells.

Helicobacter pylori infection in 1st degree relatives of Chinese gastric cancer patients

Objective. Familial aggregation of gastric cancer has been linked to familial clustering of Helicobacter pylori infection. Patterns and risk factors associated with H. pylori infection were investigated in 1st degree relatives of Chinese gastric cancer patients. Material and methods. Gastric cancer relatives were invited for screening endoscopy. H. pylori infection was diagnosed by endoscopic and serological methods. Results. Among the 270 cancer relatives examined, 161 (59.6%) were found to be infected with H. pylori. The prevalence of infection in cancer relatives was significantly higher than age- and gender-matched dyspeptic control (45.5%, p = 0.0006). The mean age of H. pylori-infected relatives was significantly older than that of non-infected relatives (43.9 versus 38.3 years; p < 0.001). The prevalence of H. pylori infection was higher in those with more siblings (p = 0.013, χ2 test for trend). Moreover, individuals whose siblings had stomach cancer were more likely to have H. pylori infection than those with a parental history of cancer (68.2% versus 51.8%, p=0.007). In contrast, the youngest sibling had a significantly lower H. pylori infection rate than other siblings (39.2% versus 64.2%, p = 0.001). Using multiple logistic regression, it was found that age >45 years (OR = 1.8; 95% CI, 1.02–3.3) and a history of gastric cancer in siblings (OR = 1.9; 95% CI, 1.06–3.3) were independent risk factors for H. pylori infection, and that the youngest sibling in the family had a reduced risk (OR = 0.45; 95% CI, 0.24–0.84). Conclusions. This study identifies the patterns and risk factors for H. pylori in gastric cancer relatives, which may shed light on the evolving epidemiology of H. pylori infection in Chinese patients.