Zenro Nihei

Depth of invasion parallels increased cyclooxygenase‐2 levels in patients with gastric carcinoma

Nonsteroidal anti‐inflammatory drugs may reduce the incidence of intestinal carcinoma, presumably through inhibition of cyclooxygenase‐2 (COX‐2). The authors correlated tumor expression of COX‐2 with clinicopathologic features in tissues from patients with gastric carcinoma.

Alterations and hypermethylation of the p14ARF gene in gastric cancer

p14ARF, generated through an alternative splicing process that replaces the first exon, 1α, of p16INK4a with exon 1β, located >15 kb upstream of exon 1α, has been shown to function as a growth suppressor. We examined 11 gastric cancer cell lines for mRNA expression, homozygous deletion, mutation, and promoter methylation of the p14ARF gene. No mRNA expression was detected in 5 of the 7 diffuse‐type cell lines. All intestinal cell lines displayed normal levels of expression except for one with a low level of expression. Of the 5 cell lines without expression, 3 (MKN45, NUGC‐2, and NUGC‐4) and 1 (KATO III) displayed homozygous deletion and methylation of the p14ARF gene, respectively. No mutation was found in the whole coding region of the p14ARF gene in 8 cell lines without homozygous deletion. Our results indicate that the p14ARF gene is more frequently inactivated by homozygous deletion or methylation in diffuse‐type gastric cancer cell lines (5/7, 71.4%) than in intestinal ones (0/4, P = 0.022). When we also analyzed 62 primary gastric cancers for the methylation status of the p14ARF promoter region, the methylation frequency tended to be higher in diffuse‐type gastric cancers (15/33, 45.5%) than in intestinal ones (7/28, 25%). Thus, p14ARF alterations might be involved in diffuse‐type gastric carcinogenesis. Int. J. Cancer 87:654–658, 2000.

Thymidylate synthase predictive power is overcome by irinotecan combination therapy with S-1 for gastric cancer

The predictive values of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) gene expressions were retrospectively evaluated in patients with gastric cancer treated by a regimen containing S-1. The study population consisted of 53 patients registered into different two phase II studies for metastatic gastric cancer; 27 patients treated by S-1-alone study: 26 patients treated with S-1 combined with irinotecan (CPT-11). TS and DPD gene expressions in primary tumours were measured by the real-time reverse transcription PCR method. There was no statistical difference in DPD gene expression in terms of response in cases treated with S-1 alone and those treated with S-1 plus CPT-11. TS mRNA of responding tumours was lower than that of nonresponding ones when treated with S-1 (P<0.005). In the S-1-alone group, taking TS cutoff as the median values, the response rate in the low TS group was 50%, but only 8% in the high TS group (P<0.05). Patients with low TS gene expression survived longer than those with high TS gene expression (P<0.0001). However, there was no statistically significant difference in response rate and survival between patients with low TS tumours and those with high TS tumours, when the cutoff was taken as the median value of TS gene expression in the group treated with S-1 plus CPT-11. In conclusion, treatment effects of S-1 monotherapy for gastric cancer were determined by the status of TS gene expression, regardless of DPD gene expression. TS predictive power was overcome by CPT-11 combination therapy with S-1.

Mutations of the transforming growth factor-β type II receptor gene are strongly related to sporadic proximal colon carcinomas with microsatellite instability

Mutations of the transforming growth factor‐β type II receptor gene (TGF‐β RII) have been found in several replication error‐positive sporadic colorectal carcinomas and hereditary nonpolyposis colorectal carcinoma cell lines. The aim of this study was to clarify the role of TGF‐β RII in sporadic colorectal carcinogenesis.

Simple combinations of 5-FU pathway genes predict the outcome of metastatic gastric cancer patients treated by S-1.

We evaluated the expression of 5‐FU pathway genes in prechemotherapeutic fresh frozen samples obtained from primary tumors to predict response and survival of 59 metastatic gastric cancer patients treated with S‐1 monotherapy as first line treatment. Five 5‐FU pathway genes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP) and uridine phosphorylase (UP), were analyzed by the quantitative real‐time reverse transcriptional PCR method. Median values of each gene were selected for cut‐off values separating high and low gene expressions. In univariate analyses, low TS, high OPRT and low TP were significantly associated with a tumor shrinkage and a long survival, whereas DPD and UP gene expressions did not correlate with response and survival. Multivariate analyses revealed that independent variables were OPRT and TS for response and TS and TP for survival. When OPRT and TS were combined, a significantly increased accuracy rate of 91.5% was seen for response. Similarly, an increased hazard ratio of 10.29 was observed for survival in patients possessing low TS and low TP, compared with those with high TS or high TP. The simple combinations of 2 genes, OPRT and TS for response and TS and TP for survival, may allow identification of gastric cancer patients who will benefit from S‐1 chemotherapy.

Frequent microsatellite instabilities and analyses of the related genes in familial gastric cancers

Microsatellite instability or replication error seems to be related to defective DNA mismatch repair genes, such as hMSH2, hMLH1, hPMS1 and hPMS2, which have been identified as causative genes of hereditary nonpolyposis colorectal cancers (HNPCC). Recently, it was reported that mutations at the simple repeated sequences in the transforming growth factor‐β type II receptor (TGF‐β RII) gene occurred in replication error‐positive colorectal cancers. To determine genetic alterations in familial gastric cancers (FGC), we examined replication error using eight microsatellite DNA markers, and screened mutations in the hMSH2, hMLH1 and TGF‐β RII genes in six cases from four FGC kindreds. Moreover, hMTH1, a human homolog of the bacterial mutT gene, was also screened. Four of six (67%) cancers showed the replication error‐positive phenotype, indicating that microsatellite instability is highly associated with not only HNPCC, but also FGC. No germline mutation was found in the whole coding sequences of hMSH2 and hMTH1, or in the conservative regions of hMLH1 in any patient, while one cancer DNA showed a somatic mutation at codon 682 (threonine to alanine) in hMSH2. No alteration was found at the small repeated sequences in TGF‐β RII in FGC tumor DNA. These results indicate that the carcinogenetic process of FGC may be different from that of HNPCC.

Thymidylate synthase and dihydropyrimidine dehydrogenase gene expression in relation to differentiation of gastric cancer.

Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are important enzymes of DNA de novo synthesis and the salvage pathway in cancer cells, respectively. Intratumoral TS and DPD gene expressions were evaluated to determine the correlation between the expression of the 2 genes in both normal stromal tissues and tissues with different degrees of malignant differentiation in primary gastric cancer. The study population consisted of 78 consecutive patients with advanced gastric cancer who underwent surgical treatment. Laser‐captured microdissection of malignant or normal stromal tissues was performed in formalin‐fixed, paraffin‐embedded specimens. After extraction of RNA, TS and DPD gene expressions were measured by the real‐time reverse transcriptional PCR method. Apart from degree of differentiation, TS and DPD in malignant tissue showed no correlation with clinicopathologic factors. TS in malignant tissue was higher in differentiated type cases than undifferentiated type cases (p < 0.01). However, DPD in malignant tissue of undifferentiated type cases was statistically higher than that of differentiated type cases (p < 0.05). In normal stromal tissue, neither TS nor DPD had any correlation with clinicopathologic factors. TS in malignant tissue was statistically higher than in normal stromal tissue in both differentiated and undifferentiated types (p < 0.0001). DPD in differentiated type malignant tissue was statistically lower than in normal stromal tissue (p < 0.001), but no difference was seen in undifferentiated type cases. TS and DPD gene expressions in primary gastric cancer differ according to degree of differentiation and between malignant and normal stromal tissue.

Expression of endothelin-1 immunoreactivity in breast cancer

This study performed immunohistochemical staining for human ET-1, utilizing avidinbiotin-peroxidase complex detection to examine 47 surgically resected primary breast cancers. Positive immunoreactivity was demonstrated in 19 of the 47 breast cancers (40.4%). There was no significant relationship between the expression of ET-1 and clinicopathological findings. A significant difference was found between ET-1 positive and negative groups in the incidence of recurrence and distant metastasis (P < 0.05). The 5-year overall survival rate was significantly poorer in patients with ET-1-positive cancer (84.2%), compared to 96.4% in patients with ET-1 negative cancer (P < 0.01). The 5-year disease-free survival rate was significantly poorer in patients with ET-1-positive cancer (73.7%) compared to 96.4% in patients with ET-1-negative cancer (P < 0.05). These results suggest that the expression of ET-1 could be used as a possible indicator for predicting the metastatic potential of breast cancer.

Is lymphadenectomy needed for all submucosal gastric cancers

OBJECTIVE To find out if it is feasible to extend the indication for local resection of submucosal gastric cancer without increasing the risk of lymph node metastases. DESIGN Retrospective study. SETTING University hospital, Japan. SUBJECTS 104 patients with gastric cancer confined to the submucosal layer who underwent conventional gastrectomy with lymphadenectomy. INTERVENTIONS The risk of nodal metastases was analysed retrospectively depending on the depth of submucosal invasion, size of the tumour, and other clinicopathological findings. MAIN OUTCOME MEASURES The degree of submucosal invasion, size of the tumour, and incidence of lymph node metastasis. RESULTS 15/104 patients (14%) had lymph node metastases. No patient in whom submucosal invasion was less than 500 microm or tumour was less than 15 mm in diameter developed lymph node metastases. Fewer patients had lymphatic permeation (37/89) and venous involvement (21/89) in the group without lymph node metastases. CONCLUSION These data seem to support the hypothesis that early, minimally invasive, gastric cancer measuring < 15 mm in diameter could be treated by endoscopic mucosal or local resection, and gastrectomy with lymphadenectomy might be unnecessary.

Omental bleeding with spontaneously derotated torsion--a case report.

A case of omental torsion seen in a 16 year old male is reported herein. Abdominal pain in the right lower quadrant suddenly developed just after the patient twisted his waist and an emergency laparotomy revealed a hemorrhagic mass at the edge of the right omentum, which was excised. Histological examination of the resected specimen showed hemorrhage without any venous thrombosis or infarction, possibly suggestive of omental torsion with early spontaneous derotation. The patient was successfully treated as a case of omental torsion.