Biomedical subjects

Masaichi Ohira

Publications and source records attributed to Masaichi Ohira.

At least 19 recordsLinked to original sources

PubMed2006

Antitumor effect of trastuzumab for pancreatic cancer with high HER-2 expression and enhancement of effect by combined therapy with gemcitabine.

PURPOSE: The purpose of the present study was to evaluate whether trastuzumab has antitumor effect against pancreatic cancer and whether this effect is concordant with levels of HER-2, which is reportedly overexpressed in pancreatic cancer. We also investigated whether the effect is potentiated in combined therapy with gemcitabine. EXPERIMENTAL DESIGN: Using immunohistochemistry and FACScan, we analyzed HER-2 expression in 16 pancreatic cancer cell lines. The in vitro antiproliferative effect of trastuzumab, alone and in combination with gemcitabine, was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The in vitro antibody-dependent cell-mediated cytotoxicity of trastuzumab was investigated by (51)Cr release assay. The in vivo antitumor effect of trastuzumab, alone and in combination with gemcitabine, was evaluated in nude mouse xenograft growth. The survival benefit was evaluated in a Capan-1 orthotopic implanted nude mouse model. RESULTS: HER-2 expression of 2+ or more was observed in 10 and of 3+ in 2 of the 16 cell lines. No in vitro growth-inhibitory effect of trastuzumab was found in any cell line, but trastuzumab induced antibody-dependent cell-mediated cytotoxicity in proportion to HER-2 expression level. Trastuzumab inhibited tumor growth in Capan-1 (HER-2: 3+) xenografts and prolonged survival in the orthotopic model. These effects were increased by combined therapy with gemcitabine. In contrast, trastuzumab exhibited no antitumor effect against PANC-1 (HER-2: 1+) or SW1990 (HER-2: 2+) xenografts. CONCLUSIONS: The antitumor effect of trastuzumab in pancreatic cancer with high HER-2 expression was shown in vitro and in vivo. Clinical application of trastuzumab is expected in pancreatic cancer with 3+ HER-2 expression.

Animals↗

PubMed2006

Synergic antiproliferative effect of DNA methyltransferase inhibitor in combination with anticancer drugs in gastric carcinoma.

Epigenetic alterations of DNA methylation play an important role in the regulation of gene expression associated with chemosensitivity of gastric carcinomas. With the aim of improving the chemotherapeutic efficacy of gastric carcinoma, the effect of DNA methyltransferase inhibitor, 5-aza-CdR, on the chemosensitivity of five anticancer drugs was investigated. Human gastric cancer cell lines, OCUM-2M and MKN-74, and five anticancer drugs, 5-FU, PTX, OXA, SN38, and GEM, were used. In both gastric cancer cell lines, a synergistic antiproliferative effect by a combination of 5-aza-CdR at 5 microM was found in SN38 and GEM. 5-Aza-CdR at 5 microM increased apoptosis induced by SN38 and GEM in both cell lines. 5-Aza-CdR increases the expression of DAPK-2 and DAPK-3, RASSF1, and THBS1 genes in both OCUM-2M and MKN-74 cells, but not that of hMLH1, p16, MGMT, E-cadherin, and p53 genes. These findings suggest that 5-aza-CdR is a promising chemotherapeutical agent for gastric carcinomas, in combination with the anticancer drugs SN38 and GEM, in apoptosis signaling. The upregulation of DAPK-2 and DAPK-3, RASSF1, and THBS1 genes by 5-aza-CdR might be associated with the synergistic effect.

Antineoplastic Agents↗

PubMed2006

A synergic inhibitory-effect of combination with selective cyclooxygenase-2 inhibitor and S-1 on the peritoneal metastasis for scirrhous gastric cancer cells.

An inhibitory-effect of a selective cyclooxygenase-2 (COX-2) inhibitor on peritoneal metastasis of scirrhous gastric carcinoma was investigated in vivo. Peritoneal metastasis had developed after intraperitoneal inoculation of scirrhous gastric cancer cells, OCUM-2MD3, in nude mice. COX-2 inhibitor and/or S-1 were administered orally in nude mice with peritoneal metastasis. Oral administration of COX-2 inhibitor and S-1 significantly prolonged survival rates of these nude mice, compared with either alone. These findings suggested that combining S-1 and COX-2 inhibitor administration obtain a synergistic inhibitory-effect on the peritoneal metastasis of scirrhous gastric carcinoma.

Adenocarcinoma, Scirrhous↗

PubMed2006

Synchronous adenocarcinomas of the ileum and transverse colon detected by capsule endoscopy: report of a case.

A 77-year-old woman was admitted to our hospital with anemia and anorexia. Neither gastrointestinal endoscopy nor computed tomography showed by abnormal findings; however, a capsule endoscopy, performed to detect obscure gastrointestinal bleeding, revealed a tumor in the ileum. When we tried to take biopsies of the ileal tumor by push enteroscopy via the anus, we found another tumor in the transverse colon. On exploration, tumors were identified in the ileum and the transverse colon. Thus, we resected the ileum and transverse colon with regional lymph node dissection. Histologic sections from both the ileum and colon revealed moderately differentiated adenocarcinomas with no lymph node metastasis.

Adenocarcinoma↗

PubMed2006

Frequent p16 CpG island hypermethylation in primary remnant gastric cancer suggesting an independent carcinogenic pathway.

Cancer found in the post-operative remnant stomach includes both newly developed cancer after surgery for benign-disease (PRC) and metachronous multiple cancer (MRC). Differences in the carcinogenic pathway between PRC and MRC have been suspected from clinical studies. However, no study has demonstrated the difference in molecular alteration between these diseases. P16 is inactivated predominantly by epigenetic change, rather than genetic alteration. We analyzed the methylation status and protein expression of the p16 gene in cancers of the remnant stomach. Eleven lesions of PRC, 24 lesions of MRC and corresponding non-cancerous tissue, as well as 13 primary gastric cancer (PC) lesions were examined. DNA was extracted by the micro-dissection method from paraffin-embedded surgical specimens. The methylation status of the promoter CpG island of the p16 gene was examined by using a methylation-specific polymerase chain reaction technique. To detect protein expression, immunohistochemical staining was employed. p16 promoter hypermethylation was observed more often in remnant gastric cancer than in PC. A significantly more frequent hypermethylation in the p16 gene was found in PRC (64%) than in MRC (21%) or PC (23%). Moreover, a significant correlation was found between p16 promoter hypermethylation and diminishment of protein expression in cancers of the remnant stomach. Silencing of the p16 gene by methylation of its promoter CpG island was suggested as a unique molecular mechanism in the carcinogenesis of PRC compared with MRC or PC.

Aged↗

PubMed2006

[A case of advanced gastric cancer with malignant ascites responding to weekly paclitaxel therapy].

A 54-year-old woman with scirrhous gastric cancer in the upper third area was admitted to our hospital. She was diagnosed with advanced gastric cancer that was inoperable due to peritoneal metastasis, so weekly paclitaxel (PTX) therapy was carried out. After 2 courses, malignant ascites completely disappeared and bilateral hydronephrosis improved. After 4 courses, no ascites or hydronephrosis were seen. Only neutropenia (grade 2) and alopecia (grade 1) were observed as adverse events during the therapy, but no major adverse events were noted. We also investigated the concentration of paclitaxel in ascites. Two hours after intravenous injection of PTX, the concentration of PTX in ascites rose over the reported cytotoxic dose of PTX, and this available concentration was maintained after 48 hours. Weekly paclitaxel therapy is suggested to be one of the safe and useful treatments for advanced gastric cancer with malignant ascites.

Adenocarcinoma, Scirrhous↗

PubMed2005

Clinicopathologic and biological significance of kallikrein 6 overexpression in human gastric cancer.

PURPOSE: Human kallikrein genes (KLK) have been reported to be involved in human malignancies and several KLKs are promising biomarkers of prostate, ovarian, testicular, and breast cancers. Herein, we investigated the clinicopathologic and biological significance of KLK6 gene expression in human gastric cancer. PATIENTS AND METHODS: Using real-time reverse transcription-PCR, we analyzed the KLK6 expression status with respect to various clinicopathologic variables in 66 patients with gastric cancer. In addition, we established a KLK6 stably suppressed gastric cancer cell line (MKN28) using small interfering RNA-mediated gene silencing, and investigated its effects on the cell proliferation rate, cell cycle, and invasiveness. RESULTS: The KLK6 gene expression in cancerous tissue (0.37 +/- 0.53) was significantly (P < 0.000001) higher than that in noncancerous tissue (0.026 +/- 0.060). Elevated KLK6 expression was significantly associated with lymphatic invasion (P = 0.03). Furthermore, patients with a high KLK6 expression had a significantly poorer survival rate than those with a low KLK6 expression (P = 0.03). Therefore, we showed that KLK6 gene silencing with KLK6 small interfering RNA effectively suppressed the cell proliferation rate (P = 0.002), cell population in the S phase (P < 0.01), and invasiveness (P < 0.01) in comparison to mock-transfected cells. CONCLUSIONS: The KLK6 gene is markedly overexpressed in gastric cancer tissue and its expression status may be a powerful prognostic indicator for patients with gastric cancer. Our findings also suggest that KLK6 may possibly be a novel target for gastric cancer therapy by gene-silencing procedures.

Biomarkers, Tumor↗

PubMed2005

Frequent microsatellite instability in primary esophageal carcinoma associated with extraesophageal primary carcinoma.

Patients with esophageal squamous cell carcinoma (ESCC) frequently develop other primary cancers, such as gastric cancer and head and neck cancer. Details of carcinogenesis in patients with multiple primaries that include esophageal carcinoma with other primary carcinoma (ECOPC) remain uncertain. We examined microsatellite instability (MSI) status, frameshift mutation in target genes of MSI, mismatch repair protein expression and hypermethylation of the hMLH1 promoter region in ECOPC patients to better understand the underlying carcinogenic processes. High frequency MSI (MSI-H) was found in 15 (44.1%) of 34 patients with ECOPC, but in only 6 (14.3%) of 42 patients with esophageal cancer alone (p < 0.01). Frameshift mutations in TGFbetaRII, BAX, MSH3 and MSH6 genes respectively were present in 4, 1, 2 and 2 of 34 ECOPC patients. Immunohistochemical study showed that 12 (80.0%) of 15 MSI-H tumors showed loss of expression of either hMLH1 or hMSH2. In addition, 6 of 9 tumors (66.7%) that showed reduced hMLH1 expression also had hypermethylation of the hMLH1 promoter region. Our findings suggested that carcinogenesis in ECOPC was closely associated with the MSI pathway because of mismatch repair protein deficiency.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Somatic mutations of epidermal growth factor receptor in colorectal carcinoma.

PURPOSE: Somatic mutations of the epidermal growth factor receptor (EGFR) gene may predict the sensitivity of non-small cell lung carcinoma to gefitinib. However, no mutations have been reported for colorectal carcinoma. We therefore analyzed EGFR mutations in colorectal adenocarcinomas by the combined use of laser microdissection and sequencing of genomic DNA. EXPERIMENTAL DESIGN: We examined 11 representative colorectal adenocarcinoma cell lines and 33 clinical samples of colorectal carcinoma. In the clinical cases, we carefully dissected only carcinoma cells from frozen sections by laser microdissection. After DNA extraction and PCR, we examined EGFR mutations by sequencing genomic DNA. RESULTS: None of 11 colorectal carcinoma cell lines exhibited somatic mutations, but 4 of 33 clinical tumors (12%) exhibited mutations in the EGFR kinase domain. This may be the first report of somatic mutations in colorectal adenocarcinoma. CONCLUSIONS: Our findings suggest that a distinct minority of colorectal adenocarcinomas exhibit somatic mutations of EGFR, and these tumors may be susceptible to gefitinib treatment.

Base Sequence↗

PubMed2005

Up regulation of ICAM-1 gene expression inhibits tumour growth and liver metastasis in colorectal carcinoma.

We have previously reported that decreased intercellular adhesion molecule-1 (ICAM-1) expression in cancer cells is associated with liver metastasis of colorectal cancer. In this study, we have investigated the effect of ICAM-1 gene transfection into the human colorectal cancer cell line LM-H3 on cell adhesiveness and cytotoxicity of peripheral blood mononuclear cells (PBMC) to cancer cells. Furthermore, we have investigated the effects of this gene transfer on subcutaneous tumour and liver metastases of LM-H3 in nude mice. More PBMC adhered to ICAM-1 transfected LM-H3 cells, LM-H3/ICAM-1, than to non-transfected LM-H3 cells and control LM-H3/Vector. Lysis of LM-H3/ICAM-1 cells by PBMC was significantly increased compared with LM-H3/Vector. Liver metastases with LM-H3/ICAM-1 cells were fewer in number and smaller than metastases with LM-H3/Vector. Intra-tumoural injection of ICAM-1 adenoviral vector significantly inhibited the growth of subcutaneous LM-H3 tumour. In conclusion ICAM-1 gene transfection using adenovirus vector might be an effective therapy for liver metastasis of colorectal carcinoma.

Adenoviridae↗

PubMed2005

[A case of gastric cancer with peritoneal recurrence which developed during adjuvant administration of TS-1 showing complete response by weekly docetaxel regimen].

A 62-year old man had undergone total gastrectomy for Borrmann type 4 gastric cancer. No peritoneal dissemination was observed at the laparotomy. Pathological examination revealed that the tumor involved the subserosal layer, and that the lymph node metastasis extended to the left gastric nodes. Vascular and lymphatic involvement was also observed. One hundred mg/body of TS-1, an oral 5-fluorouracil (5-FU) anticancer agent, which consisted of tegafur (a prodrug of 5-FU), and two modulators (gimeracil and oteracil potassium) was given from the 16th post-operative day. A course of TS-1 consisted of consecutive administration for 4 weeks followed by 2 weeks rest. The patient complained of abdominal fullness after administration of the second course of TS-1. Computed tomography (CT) revealed massive ascites. The serum carcinoembryonic antigen (CEA) titer was elevated to 13.5 ng/ml. From these findings, the occurrence of peritoneal dissemination was suspected. Weekly docetaxel of 30 mg/m2 (40 mg/body) was given for 3 weeks followed by a week cessation. At the start of the 6th course, the serum CEA was normalized, and CT scan detected the disappearance of ascites without any new lesion. Administration of docetaxel was continued until the 10th course then stopped without relapse of the disease. No dose reduction or postponement of administration were required. The patient has survived without disease one year after cessation of the treatment. Weekly docetaxel is a safe and effective regimen for gastric cancer worth using for a second-line therapy after failure of the 5-FU-based regimen.

Adenocarcinoma↗

PubMed2005

Plasminogen activator inhibitor-1 (PAI-1) gene transfection inhibits the liver metastasis of pancreatic cancer by preventing angiogenesis.

Plasminogen activator inhibitor-1 (PAI-1) is a unique type of serine protease inhibitor and one of the key regulators of tumor invasion and metastasis. The purpose of this study was to elucidate the effect of PAI-1 gene transfection on liver metastasis and its mechanism by using the human high liver metastasis pancreatic cancer cell line, SW1990. PAI-1-transfected SW1990 (SW/PAI-1) produced a significantly higher level of PAI-1 in supernatant than parental cells. While no difference was observed for the production of u-PA and u-PA activity in the supernatant, cell proliferation of SW/PAI-1 was slightly suppressed on the 7th day of incubation compared to parental cells. Cellular invasion, in vivo tumorigenesis in xenograft and liver metastasis were significantly suppressed in SW/PAI-1 cells compared to parental cells. The angiogenesis of xenograft by detecting microvascular density and the production of metastasis-related factors, such as VEGF and TGF-beta1, were also decreased in SW/PAI-1 cells. These findings suggested that PAI-1 gene transfection might have the ability to prevent the liver metastasis of pancreatic cancer by modulating angiogenesis.

Animals↗

PubMed2005

[Experience of radiofrequency ablation therapy for hepatocellular carcinoma].

There are various therapeutic options for hepatocellular carcinoma. Radiofrequency ablation (RFA) was introduced to Japan in 1998, and has become popular in percutaneous local treatment for HCC as a treatment with the advantage of both percutaneous ethanol injection therapy and percutaneous microwave coagulation therapy. In this study, we investigated the efficacy and complication of RFA for HCC. Seventeen patients underwent percutaneous or open RFA with a Cool-tip needle (Radionics Co. Ltd) from April 2001 to May 2005. All tumors were solitary and the average diameter of 17 tumors was 2.24 cm. Fifteen tumors were completely ablated, but two weren't. Local recurrence occurred in only one patient and the rate of local recurrence was 6.7%. Mild complication occurred in some patients, but critical complication did not occur in any patients. In this study, it was considered that RFA could be performed safely and was a good treatment for HCC with high efficacy. After investigating the long-term results and indication of RFA, it was suggested that RFA might be reestablished as an effective treatment for HCC.

Aged↗

PubMed2004

Intraductal papillary-mucinous adenoma developed in the ventral pancreas in a patient with pancreas divisum.

A 34-year-old man was admitted to our hospital with the chief complaints of back pain and epigastralgia. The physical examinations on admission disclosed no abdominal tumor. The serum concentration of total bilirubin was 1.4 mg/dl. The serum elastase-1 level was elevated to 526 ng/dl. Computed tomography showed a cystic lesion, 1 cm in diameter, in the head of the pancreas, without dilatation of the main pancreatic duct. Endoscopic retrograde cholangiopancreatography via the papilla of Vater and the accessory papilla revealed an enlarged ventral pancreatic duct and pancreas divisum. The preoperative diagnosis was mucin-producing pancreatic tumor in the ventral pancreas of a patient with pancreas divisum. A pylorus-preserving pancreatoduodenectomy was performed. The gross findings of the cut surface of the resected specimen disclosed mural nodules in the dilated duct of the ventral pancreas. A histological examination of the mural nodules in the ventral pancreas revealed mucin and intraductal papillary adenoma. Benign tumors associated with pancreas divisum are rare; to the best of our knowledge, only three cases have been reported. Although in these three patients the tumor developed in the dorsal pancreas, the tumor developed in the ventral pancreas in our patient.

Adenoma↗

PubMed2004

Carcinoid tumor of the kidney presenting as a large abdominal mass: report of a case.

Carcinoid tumors are known to occur frequently in the gastrointestinal tract and they can develop in nearly every organ system. However, a carcinoid tumor of the kidney is an extremely rare entity and only 38 cases have been reported in the English literature. We herein describe the 39th case of primary renal carcinoid tumor, found in a young Japanese woman 2 months after delivery. The pathologic similarities of our case with those of previously reported cases are briefly reviewed together with some aspects of clinical features and prognostic factors of this rare disease.

Adult↗

PubMed2004

Differences in dihydropyrimidine dehydrogenase activities between gastric and colorectal cancer.

We studied the relation between clinicopathological factors and dihydropyrimidine dehydrogenase (DPD) activity in gastric and colorectal carcinomas. Specimens obtained by surgery from 27 gastric and 17 colorectal carcinomas and their normal mucosa were examined. The levels of DPD activity in the gastric carcinomas and their normal mucosa were significantly higher than those in colorectal carcinomas and their normal counterparts, respectively (both P's < 0.0001). The gastric carcinomas had significantly higher DPD activities than their normal mucosa (P = 0.028), but the colorectal carcinomas did not. Among the clinicopathological factors, which included invasion/metastatic status and staging, the only effect was that of the histological differences of gastric cancer on DPD activity. That is, the level of DPD activity of the histologically undifferentiated gastric carcinoma was significantly higher than that of the differentiated type. No prognostic predictive values of DPD were recognized in either gastric and colorectal cancer. In conclusion, the higher DPD activity in gastric cancer than colorectal cancer may be due to the higher DPD activity in the background mucosa of origin, and the higher population of undifferentiated type of histological classification, compared to the colorectal counterparts.

Biomarkers, Tumor↗

PubMed2004

A possible case of Werner syndrome presenting with multiple cancers.

The treatment of a man with six metachronous primary cancers is described. The primary lesions were in the soft palate, both edges of the tongue, the hard palate, the esophagus, and the right ureter. Pathologically, all of the first five tumors in the head and neck and esophagus were proven to be squamous cell carcinoma with various grades of differentiation, and the last one was transitional cell carcinoma. The cancers were found in the early clinical stage, and were completely controlled one by one except for the ureteral tumor under treatment. His characteristic medical history and physical findings, i.e. bilateral cataracts, short stature, baldness, diabetes mellitus, high-pitched voice, and multiple malignancies, met the clinical criteria for possible Werner syndrome, a genetic premature aging disorder, though the possibility of phenocopy of this syndrome has not been ruled out. We have followed him carefully because he might be vulnerable to malignant tumor formation.

Aged↗

PubMed2004

Inhibition and mechanism of action of a protease inhibitor in human pancreatic cancer cells.

OBJECTIVES: Tumor-associated trypsinogen (TAT), urokinase-type plasminogen activator (u-PA), matrix metalloproteinase-2 (MMP-2), and MMP-9 each play a dominant role in the degradation of extracellular matrix (ECM) during the invasion process of pancreatic cancer. Transforming growth factor beta1 (TGF-beta1) is a multifunctional poly-peptide that regulates cell growth and differentiation, ECM deposition, cellular adhesion properties, angiogenesis, and also immune functions. We previously reported that TGF-beta1 up-regulated vascular endothelial growth factor (VEGF) production and protease production of MMP-2 and of u-PA in the highly metastatic pancreatic cancer cell lines SW1990 and CAPAN-2. In this study, we examined the inhibitor effects of a protease inhibitor, gabexate mesilate (GM), on cell invasion, cell proliferation, growth factor production, and ECM degradation. We also examined the effect of GM on the production of growth factor and ECM degradation by these cell proteases and enzymatic activities. RESULTS: GM down-regulated the invasiveness and liver metastasis potential of SW1990 and CAPAN-2 cells, but it did not affect the proliferation of these cells. GM inhibited not only the enzymatic activities of TAT and u-PA but also the production of MMP-2, and u-PA, all of which have been known to be secondarily down-regulated by TGF-beta1. CONCLUSIONS: These findings suggested that GM has very good potential for use in the treatment against invasion and metastasis of pancreatic cancer.

Adenocarcinoma↗