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FGFR2 gene is frequently amplified in gastric cancer. Recently, targeting FGFR2 has drawn attention as a form of gastric cancer therapy, and FGFR-selective inhibitors have shown promising efficacy in clinical studies. Because overcoming acquired resistance is a common problem with molecular targeting drugs, we investigated a resistant mechanism of FGFR inhibitors using the gastric cancer cell line SNU-16, which harbors FGFR2 amplification. We established single-cell clones of FGFR inhibitor-resistant SNU-16 (AZD-R) by continuous exposure to AZD4547, a selective FGFR inhibitor. To screen the genetic alterations acquired in AZD-R, we ran a comparative genomic hybridization assay and found an amplification of Chr7q34 region. The chromosomal breakpoints were located between the 12th and the 13th exon of jumonji C domain containing histone demethylase 1 homolog D ( JHDM1D ) and between the 3rd and the 4th exon of BRAF We sequenced cDNA of the AZD-R clones and found fusion kinase JHDM1D-BRAF , which has previously been identified in primary ovarian cancer. Because JHDM1D-BRAF fusion lacks a RAS-binding domain, the dimerization of JHDM1D-BRAF was enhanced. A cell growth inhibition assay using MEK inhibitors and RAF-dimer inhibitors indicated the dependence of AZD-R clones for growth on the MAPK pathway. Our data provide a clinical rationale for using a MEK or RAF dimer inhibitor to treat FGFR2 -amplified gastric cancer patients who have acquired resistance through the JHDN1D-BRAF fusion. Mol Cancer Ther; 17(10); 2217-25. ©2018 AACR ., (©2018 American Association for Cancer Research.)

A 70-year-old man with gastric cancer of Borrmann type 3, liver metastases and peritoneal dissemination was treated by combination therapy of S-1 and docetaxel (DOC). He received DOC intravenously at 40 mg/m(2) on day 1 and S-1 orally at 100 mg/body on day 1 to 14, repeated every 28 days. After 2 courses of treatment, a CT scan revealed improvement of the gastric wall thickness, the eminent decrease of the peritoneal fluid and the reduction of the liver metastasis. After 3 courses of treatment, the primary lesion was remarkably improved on endoscopic examination, and the tumor marker normalized after 4 courses of treatment. Toxicities included leukocytopenia (WHO grade 3), neutropenia ( grade 3), anorexia (grade 2), and nausea (grade 2). Outpatient chemotherapy was possible by reduction of dose (S-1 100--> 80 mg/body, DOC 40--> 32 mg/m2). The response was maintained on CT and endoscopic examination after 21 courses of treatment. A case of an advanced gastric cancer patient successfully treated by combination therapy of S-1 and DOC was reported.

Matriptase/MT-SP1, a type II membrane serine protease widely expressed in normal epithelial cells and human carcinoma cells, is thought to be involved in cancer progression. To clarify this possibility, we overexpressed exogenous matriptase in the human stomach cancer cell line AZ521. In vitro, the matriptase transfectant (Mat-AZ521) and the control transfectant (Mock-AZ521) showed a similar growth rate, although the saturation cell density was significantly higher with the Mat-AZ521. When implanted into nude mice subcutaneously or intraperitoneally, Mat-AZ521 cells grew faster and produced much larger solid tumors than Mock-AZ521 cells. The overexpression of matriptase in AZ521 cells shortened the survival time of tumor-bearing mice. Histological analysis showed that both the number and the size of blood vessels in tumor tissues were significantly higher in the Mat-AZ521 tumors than the Mock-AZ521 ones. Moreover, it was found that purified matriptase activated one of the important matrix metalloproteinases, stromelysin (MMP-3). These results suggest the possibility that the matriptase-dependent activation of MMP-3, as well as the direct activity of matriptase, promotes tumor growth and angiogenesis by enhancing extracellular matrix degradation in tumor cell microenvironments.

We report a case of advanced gastric cancer that responded to docetaxel with low-dose 5-FU and cisplatin combination chemotherapy after becoming chemoresistant to M-FLP. A 52-year-old male was diagnosed with type 3 gastric cancer of angulus (poorly differentiated adenocarcinoma) with left neck, Virchow, mediastinal and abdominal lymph nodes metastases. The patient was treated with 5 courses of M-FLP (MTX + 5-FU + LV + CDDP), and the effect of this therapy was PR, but the tumor was chemoresistant to the sixth course of this therapy. After 7 courses of M-FLP, docetaxel (TXT) with low-dose FP (5-FU + CDDP) was administered to the patient as second-line chemotherapy. After 2 courses of TXT with low-dose FP, the gastric cancer and metastatic lymph nodes were remarkably reduced and the effect of this therapy was PR. The toxic events were anemia (grade 2) and leukopenia (grade 3), which were treated with G-CSF. CDDP and 5-FU based regimens are considered as the first-line chemotherapy for metastatic advanced gastric cancer in Japan; however, a second-line chemotherapy has not been established. As in this case, a TXT based regimen is effective and well tolerated therapy as a second-line chemotherapy for metastatic gastric cancer after prior exposure to CDDP and 5-FU.

Patients who have undergone distal gastrectomy for peptic ulcer are at higher risk of developing gastric remnant cancer, and chronic bile reflux is believed to increase the risk of cancer in remnant stomach. In remnant stomach, carcinogenesis may be prevented by selecting the anastomosis method with a few reflux of intestinal juice including a bile acid. How Helicobacter pylori(H. pylori) infection participate in stomal gastritis and gastric remnant cancer, same as early gastric cancer in the intact stomach, is attended. H. pylori positive rate of remnant stomach is different by examination method and a report, but its rate is decreased every year after gastrectomy and in particular low in Billroth-II(B-II) anastomosis. B-II anastomosis is followed by a significantly lower rate than B-1. This may reflect the role of bile reflux because bile reflux interferes with colonization by H. pylori. Gastric cancer excision usual increase complicates gastric remnant stomach and H. pylori infection, but while H. pylori infection lasts after gastrectomy for gastric cancer, cell proliferation increase in remnant stomach. In remnant stomach after gastrectomy for gastric cancer, while H. pylori infection continues, H. pylori infection may cause remnant gastritis and a second cancer of remnant stomach. H. pylori infection and bile reflux seem to have a synergistic effect on cell proliferation in remnant stomach and may explain the increased risk of gastric remnant cancer. The cancer-causing dominant role might changed from H. pylori infection predominance to bile reflux every year after gastrectomy. Furthermore, a prophylactic effect to carcinogenesis by H. pylori eradication therapy is expected. Eradication of H. pylori after gastrectomy for gastric cancer has been recommended.

A 73-year-old woman was admitted to our hospital in June 1998, suffering from upper abdominal pain. The upper G-I series and endoscopic examination revealed stenosis of the pylorus and antrum by a type 2 cancer, and a poorly differentiated adenocarcinoma and a signet-ring cell carcinoma were confirmed on endoscopic biopsy. A CT scan showed the enlargement of many regional and abdominal para-aortic lymph nodes. FLP therapy combined with cisplatin (50 mg/m2 drip i.v., day 1-8), 5-fluorouracil (333 mg/m2 drip i.v.) and leucovorin (30 mg/body i.v., day 1-8) was planned for neoadjuvant chemotherapy (NAC) in order to reduce or eliminate the tumor and increase curability. After two cycles of the FLP therapy, the tumor size shrunk remarkably and the enlargement of the para-aortic lymph nodes disappeared. Distal gastrectomy with extended lymphadenectomy and cholecystectomy was performed. The histological findings of the primary tumor and metastatic lymph nodes demonstrated massive cancer cell degeneration such as pycnosis and vacuolation, xanthogranulomatous inflammation and dense fibrosis. The effect of NAC was judged to be grade 2 histologically. FLP therapy is an effective and safe regimen for NAC.

An improved cDNA selection method was established to isolate expressed genes efficiently from an amplified chromosome region in human cancer. Biotinylated yeast artificial chromosome DNA containing c-ERBB-2 was hybridized in solution with PCR-amplifiable cDNAs of an esophageal cancer cell line bearing the c-ERBB-2 amplification. After capturing the hybrids on avidin-coated magnetic beads, the cDNAs were amplified by PCR. Four new genes (A39, C51, CAB1, and GRB-7) coamplified with c-ERBB-2 were isolated from the enriched cDNA library. CAB1, GRB-7, and c-ERBB-2 were overexpressed in gastric and esophageal cancer cells in correspondence with the amplification. The deduced amino acid sequence of the CAB1 gene had significant homology to the recently discovered steroidogenic acute regulatory protein, StAR, which plays an essential role in cholesterol transport to mitochondria. It was established that multiple overexpressed genes are frequently present in a single amplicon.

Many amplified-chromosome regions in human cancers have been identified, while there are only a limited number of reports for amplified genes in a single amplicon. We recently isolated four cDNA clones, A39, B47, C51, and CAB1, from 500 kilobases of yeast artificial chromosome DNA containing the c-ERBB-2 gene. B47 consisted of 615 base pairs and had about 85% homology with the corresponding sequence of mouse Grb-7. We report here the structure of human GRB-7 cDNA, and we report that the amounts of mRNA for c-ERBB-2, CAB1, and GRB-7 were elevated in concordance with the amplification.

A new DACH platinum complex, l-OHP, was developed by Kidani as an anticancer agent. A clinical trial took place in Europe which demonstrated its therapeutic efficacy for colorectal cancer. An effective treatment, especially chemotherapy for patients with a advanced scirrhous type gastric cancer, has not yet been established. An in vitro study showed that l-HOP inhibited cell growth in human gastric cancer cell lines. Our pilot study determined the efficacy of preoperative administration of l-OHP, 67 mg/m2 to 100 mg/m2, every 2-3 weeks, for two to three cycles, in five patients with this disease (Stage III and IV) roentogenoscopically and histologically. The platinum concentration in the tissues was also measured. By X-ray examination of the stomach at the time of pre- and post-administration of l-OHP, extension of the lesional gastric wall was observed. Histologically three Grade 2 responses and two Grade 1a responses were obtained according to the criteria presented by Japanese Research Society for Gastric Cancer. The mean platinum concentrations in the lesional tissues were 0.98 ppm and 0.5 ppm in the patients administered l-OHP for three and two cycles respectively. There was no toxicity that prevented surgery. These preliminary results showed the possibility that 1-OHP would be effective for patients with advanced scirrhous type gastric cancer as a neoadjuvant therapy.

Of 122 patients hospitalized for early gastric cancer in 1974-1989, 15 were histologically found to have regional lymph node metastases. Tumor invasion was limited to the mucosa in 3 cases and to the submucosa in 12. An ulcer or ulcer scar was found in the tumor in 12 cases. Metastasis had occurred only to the perigastric nodes in 13 cases and also along the left gastric and/or common hepatic arteries in two. Preoperative endoscopic injection of Chinese ink into the submucosa revealed a high rate of uptake in regional lymph nodes along the left gastric, splenic and common hepatic arteries. Patients with early cancer should undergo gastrectomy with lymphadenectomy, particularly if the cancer contains an ulcer or has invaded the submucosa. If the patient's general health and life expectancy are poor, restricted surgery or endoscopic treatment should be considered.

Six cases of type A gastritis associated with multiple carcinoids and/or endocrine cell micronests (ECM) in the atrophic fundic mucosa were examined light microscopically, immunohistochemically, and ultrastructurally. The ECM and carcinoids were mainly composed of enterochromaffin-like (ECL) cells. The cells were hyperplastic only in the atrophic fundic glands and pseudopyloric glands, but not in the intestinal metaplastic gland. It is suggested that the development of both the ECM and the carcinoids is highly related to the atrophic change of the fundic mucosa and a trophic action of subsequently raised serum gastrin in type A gastritis and that the both lesions arise from the pseudopyloric glands or atrophic fundic glands. In addition, the definition of neoplastic ECM (microcarcinoid) of the stomach was made with comparative study on both the cases with ECM and multiple carcinoids and the cases with ECM alone.