[CDDP+CPT-11 therapy is useful for stage IVb esophageal small cell carcinoma].

The patient was a 59-year-old man who suffered from discomfort during swallowing. An esophageal small cell carcinoma was pointed out at another clinic by gastrointestinal fiberscopy. He was hospitalized in our hospital on May 15, 2003. He was diagnosed as esophageal small cell carcinoma with mediastinum lymph node, pancreas and multiple liver metastasis by CT scan. Then he was administered CDDP+CPT-11 therapy. CDDP 60 mg/m2 (day 1) and CPT-11 60 mg/m2 (day 1, 8, 15)were infused once a week for 3 weeks followed by 1-week interval as one cycle. At one cycle after the first infusion therapy, primary tumor, pancreas and liver metastasis were markedly reduced. His quality of life was greatly improved. No particular toxic events occurred. Five cycles after the first infusion therapy, he was diagnosed with a lymph node recurrence around the pancreas on January 19, 2004. Then we started CBDCA and VP-16 combination therapy as second-line chemotherapy. But obstructive jaundice and skull metastasis occurred, and he died on July 21, 2004.

Neutrophil elastase induces cell proliferation and migration by the release of TGF-alpha, PDGF and VEGF in esophageal cell lines.

Rapid regrowth or recurrent growth of occult cancer cells are often observed after esophagectomy or postoperative complications. In order to clarify the mechanism of such oncological circumstances, we focused on neutrophil elastase (NE), which degrades a broad spectrum of extracellular matrix and cell surface proteins. In the present study, we demonstrated that NE stimulated the growth of all of the five esophageal cell lines (TE-1, -7, -8, -12 and -13) by MTT assay and promoted cell invasion by cell migration assay. Pro-transforming growth factor-alpha (pro-TGF-alpha) from the cell membrane was released to the culture medium as a mature form after treatment with 5 microg/ml NE, and it reached the maximum level of 153% compared to the control values at 15 min of treatment in TE-13 cells. The phosphorylation of epidermal growth factor receptor (EGFR) rapidly occurs after treatment with NE and triggered the extracellular signal-regulated kinases 1 and 2 (ERK) signaling pathway. Moreover, NE induced release of platelet-derived growth factor-AA (PDGF-AA), PDGF-BB and vascular endothelial growth factor (VEGF) to 141.9, 227.7, and 171.6% of the control values, respectively. A specific NE inhibitor, sivelestat, significantly inhibited the NE-induced cell proliferation, cell invasion and subsequently inhibited the signal transduction pathway. Furthermore, sivelestat significantly inhibited NE-induced release of TGF-alpha, PDGF-AA, PDGF-BB and VEGF in the medium in TE-13 esophageal carcinoma cells. These results strongly indicate that NE released from activated neutrophils stimulates the growth and progression of esophageal cancer cells by releasing the growth factors on the cell surface and that sivelestat, a specific NE inhibitor, blocks these processes. Furthermore, we postulate that postoperative administration of sivelestat might be useful as a new molecular-targeting cancer therapy as well as for the treatment of postoperative respiratory complications.

The expression profiles of orotate phosphoribosyltransferase and dihydropyrimidine dehydrogenase in gastric cancer and their clinical significance.

Orotate phosphoribosyltransferase (OPRT) is an enzyme that causes the activation of 5-fluorouracil (5-FU). Dihydropyrimidine dehydrogenase (DPD) is known to catabolize 5-FU, which is widely used in chemotherapeutic treatments for patients with a variety of malignant tumors including gastric and colorectal cancer. The expression and activities of these two enzymes therefore play important roles in the response of cancer patients to chemotherapy. However, little is known about the expression of these enzymes in gastric cancer. In the present study, we further elucidate the expression patterns of ORPT and DPD and their clinicopathological significance by immunohistochemical analysis in 221 and RT-PCR in 36 gastric cancer samples. The expression of OPRT by immunohistochemical analysis was detected in 117 (52.9%) cases, whereas DPD was detected in 66 (29.9%) cases. Moreover, the level of expression of OPRT was found to correlate with the depth of tumor invasion and a poorer prognosis. Although the mRNA and protein expression of OPRT and DPD levels did not correlate, an inverse correlation in the expression of OPRT and DPD was observed by RT-PCR. The survival benefit of post-operative adjuvant chemotherapy could not be confirmed in our present analysis. However, among the patients who had received such treatment with 5-FU or its derivatives, the prognosis in cases with low DPD levels was better than that in cases with high DPD expression by immunohistochemical analysis. These results indicate that the expression of OPRT and DPD are important predictors of both survival and the response to adjuvant chemotherapy in gastric cancer patients.

Sivelestat, a specific neutrophil elastase inhibitor, suppresses the growth of gastric carcinoma cells by preventing the release of transforming growth factor-alpha.

Neutrophil elastase is a neutral serine proteinase produced by polymorphonuclear leukocytes and monocytes/macrophages, especially under surgical stress. In the present study, we investigated whether NE promotes cell growth by activation of EGFR to elucidate whether surgical stress induces tumor proliferation and progression. Furthermore, we examined the antitumor effect of a specific NE inhibitor, sivelestat. Cell growth assays were carried out in vitro and in vivo using TMK-1 gastric cancer cells. TMK-1 cell growth was stimulated to 118% of that of the control cells after 48 h stimulation with 1 microg/mL NE according to an MTT assay. Sivelestat inhibited cell growth to 23.4 and 58.0% of control values at concentrations of 100 and 1,000 microg/mL, respectively. NE rapidly phosphorylated EGFR in only 5 min and triggered the ERK1/2-mitogenic signaling pathway in TMK-1. It was further demonstrated that NE-induced EGFR phosphorylation was transactivated through TGF-alpha, using ELISA. NE increased the cleavage of TGF-alpha from the cell surface 30-fold compared with the cells without treatment. Interestingly, sivelestat significantly reduced NE-induced EGFR phosphorylation and ERK1/2 activation and completely blocked the release of TGF-alpha from the TMK-1 cell surface. In a xenograft study, the addition of ventrotomy as a surgical stress promoted tumor growth. Sivelestat significantly suppressed the tumor growth induced by surgical stress. These results indicate that sivelestat suppresses the growth of gastric cancer cells by inhibiting the release of TGF-alpha stimulated by NE, which often occurs after surgical stresses.

Synergistic effects of docetaxel and S-1 by modulating the expression of metabolic enzymes of 5-fluorouracil in human gastric cancer cell lines.

We have recently demonstrated in a Phase I/II study that combination chemotherapy with docetaxel (TXT) and S-1 is active against metastatic gastric carcinomas. To elucidate the mechanisms underlying the synergistic effects of these drugs, both the growth inhibitory effects and the expression profiles of enzymes involved in fluorouracil (5-FU) metabolism were examined in vitro and in vivo. TXT alone and in combination with 5-FU inhibited the growth of each of the 5 gastric cancer cell lines that we examined (TMK-1, and MKN-1, -28, -45 and -74), in a time- and dose-dependent manner. Moreover, striking synergistic effects were observed in TMK-1 cells in vitro with IC50 values of between 4.73 and 0.61 nM 5-FU. Furthermore, in TMK-1 xenografts, 5-FU/TXT cotreatments exhibited synergistic antitumor effects. The combination of S-1 and TXT, however, exhibited greater growth-inhibitory effects than the 5-FU/TXT cotreatments. The mechanisms underlying these synergistic effects of S-1 and TXT were examined by expression and activity analyses of the 5-FU metabolic enzymes. The expression of thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) were decreased 50 and 73% of control levels, respectively, and that of orotate phosphorybosyl transferase (OPRT) was increased by 3.9-fold at the protein level. These findings suggested that biochemical modulation of the 2 drugs had occurred, which was further confirmed by the results of the activity assays. These data strongly indicate that a combination chemotherapy of TXT and S-1 is effective against gastric carcinomas and is therefore a good candidate as a standard chemotherapeutic strategy in treating these tumors.

DNA methylation of genes linked to retinoid signaling in squamous cell carcinoma of the esophagus: DNA methylation of CRBP1 and TIG1 is associated with tumor stage.

Hypermethylation of CpG islands is associated with the silencing of various tumor suppressor genes. Retinoic acid receptor-beta (RAR-beta), cellular retinol-binding protein 1 (CRBP1), and tazarotene-induced gene 1 (TIG1) have been linked to retinoic acid signaling. Little is known about the involvement of these three genes in esophageal squamous cell carcinoma (ESCC). In this study, we investigated the methylation status of these genes and analyzed the role of methylation of their DNA in ESCC. Methylation-specific polymerase chain reaction (PCR) was performed to study the methylation of CpG islands in 28 ESCC (stages I, II, and III) and 10 samples of corresponding non-neoplastic mucosa. The mRNA expression levels of the three genes were measured by quantitative reverse transcription-PCR. DNA hypermethylation of RAR-beta was found in seven (25.0%) of the 28 ESCC, of CRBP1 in five (17.9%), and of TIG1 in five (17.9%). DNA methylation of RAR-beta was identified in one of 10 samples of corresponding non-neoplastic mucosa (10.0%), whereas no DNA methylation of CRBP1 or TIG1 was detected. In total, at least one of the three genes was hypermethylated in 12 (42.9%) ESCC. Reduced expression of RAR-beta, CRBP1, and TIG1 was found in 14 (50.0%), 15 (53.6%), and 13 (46.4%) ESCC, respectively. DNA methylation of each gene was significantly associated with reduced expression of the respective mRNA. No correlation was found between the DNA methylation status of RAR-beta and clinicopathological factors such as depth of invasion, lymph node metastasis, or tumor stage. In contrast, DNA methylation of both CRBP1 and TIG1 was observed only in stage III ESCC. These results show that inactivation of the retinoic acid signaling-associated genes RAR-beta, CRBP1, and TIG1 by DNA methylation occurs frequently in ESCC.

[Weekly paclitaxel therapy is useful for gastric carcinoma as second-line chemotherapy].

The patient was a 58-year-old man who suffered from non-resectable gastric cancer, staged intraoperatively for peritoneal dissemination and paraaorta lymph node metastasis at another hospital in December 2002. He was initially treated with TS-1 as an outpatient. However, he was readmitted on March 4, 2003 for hematuria, general fatigue, jaundice and dyspnea. He was diagnosed with gastric cancer duodenum invasion, obstructive jaundice and lymphangitis carcinomatosa, and began weekly TXL as second-line chemotherapy on March 26. TXL (70 mg/ m2) was infused once a week for 3 weeks followed by a 1-week interval as one cycle. One week after the first infusion therapy, the jaundice and dyspnea were greatly improved. CT scan showed the lymphangitis carcinomatosa had disappeared and paraaorta lymph node metastasis was reduced to 60% after one cycle of the treatment. The toxic events were leukopenia (grade 1) and alopecia (grade 1).

Adult intussusception due to lymphangioma of the colon.

We present herein a case report of adult intussusception due to lymphangioma of the colon. On May 27, 2000, a 39-year-old woman with right lower abdominal pain was admitted to our hospital. Preoperative imaging studies, by ultrasonography, computed tomography (CT), and barium enema examination, showed right colon intussusception with a multilocular cystic tumor as a leading point. Emergency operation was performed. During the operation, normograde ileocecal intussusception with a 9 x 6-cm soft submucosal tumor of the cecum was recognized. Ileocecal resection was performed, and the patient's postoperative course was uneventful. Pathological diagnosis of the resected specimen was a cystic type lymphangioma of the cecum. Recently, lymphangioma of the colon has been diagnosed more frequently by colonoscopy and endoscopic ultrasonography. However, only a few cases of colon intussusception due to lymphangioma have been reported in the literature to date. Large lymphangioma of the colon is rare, but it should be taken into consideration that it is one of the organic lesions that causes adult intussusception.