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Tomoharu Miyashita,
Koichi Miwa,
Masafumi Inokuchi,
Hisatoshi Nakagawara,
Hidehiro Tajima,
Hiroyuki Takamura, Itasu Ninomiya,
Hirohisa Kitagawa,
Sachio Fushida,
Takashi Fujimura,
Takanori Hattori,
Tetsuo Ohta
[show abstract]
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ABSTRACT: Residual mucosa in the gastric stump after pylorus-preserving gastrectomy (PPG) is considered a risk factor for the development of gastric stump carcinoma (GSC). Duodenogastric reflux (DGR) and Helicobacter pylori (H. pylori) infection are suspected to contribute to the development of GSC. The aim of this study was to investigate the prevalence of H. pylori in the residual stomach after PPG for gastric cancer and to assess factors associated with the presence of H. pylori. We investigated 72 patients who had undergone PPG at least 1 year prior to the study and were confirmed to be positive for H. pylori infection on presurgical endoscopic biopsy. The extent of DGR, the prevalence of H. pylori infection based on H. pylori stool antigen (HpSA) tests and the severity of gastritis were analyzed in these post-PPG patients. None of the patients had DGR, as shown by 99mTc-PMT. Of the 72 post-PPG patients, 33 (46%) were positive for HpSA. The prevalence of H. pylori infection was significantly lower after surgery than before surgery. The endoscopic severity of remnant gastritis, as well as histological inflammation and activity, were higher in H. pylori-positive patients than in H. pylori-negative patients. In conclusion, some patients who undergo PPG and are negative for DGR experience spontaneous clearance of H. pylori infection.
Oncology Reports 05/2013; · 1.84 Impact Factor
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Tomoya Tsukada,
Sachio Fushida,
Shinichi Harada,
Shiroh Terai,
Yasumichi Yagi,
Jun Kinoshita,
Katsunobu Oyama,
Hidehiro Tajima, Itasu Ninomiya,
Takashi Fujimura,
Tetsuo Ohta
[show abstract]
[hide abstract]
ABSTRACT: Various treatments have been used for peritoneal dissemination, which is the most common mode of metastasis in gastric cancer, but sufficiently good clinical outcomes have not yet been obtained because of the presence of rich fibrous components and acquired drug resistance. Epithelial-mesenchymal transition (EMT) is one of the major causes of tissue fibrosis and transforming growth factor-β (TGF-β) has a pivotal function in the progression of EMT. Smad proteins play an important role in the TGF-β signalling pathway. The TGF-β/Smad signalling pathway can be modulated by stabilising microtubules with paclitaxel (PTX). Here, we investigated whether paclitaxel can modulate TGF-β/Smad signalling in human peritoneal methothelial cells (HPMCs). To determine the cytostatic concentrations of antineoplastic agents in HPMCs, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was performed using PTX, 5-fluorouracil and cisplatin. The minimum concentration that caused significant inhibition of TGF-β1-induced morphological changes in human peritoneal methothelial cells on pre-treatment with PTX was 5 nM at 48 h (cell viability: 87.1±1.5%, P<0.01). The TGF-β signalling cascade and the status of various fibrous components were evaluated by immunofluorescence staining, real-time quantitative PCR and western blotting. TGF-β signalling induced morphological changes, α-SMA expression and collagen I synthesis in HPMCs and PTX treatment suppressed these EMT-like changes. Moreover, PTX treatment markedly suppressed Smad2 phosphorylation. These data suggest that at a low-dose, PTX can significantly suppress the TGF-β/Smad signalling pathway by inhibiting Smad2 phosphorylation in the human peritoneum and that this can reduce stromal fibrosis.
International Journal of Oncology 04/2013; 42(4):1167-74. · 2.40 Impact Factor
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Tomoharu Miyashita,
Furhawn A Shah,
Koichi Miwa,
Shozo Sasaki,
Koji Nishijima,
Katsunobu Oyama, Itasu Ninomiya,
Sachio Fushida,
Takashi Fujimura,
Takanori Hattori,
John W Harmon,
Tetsuo Ohta
[show abstract]
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ABSTRACT: The incidence of esophageal cancer continues to rise in the Western world. Prior studies have suggested that gastroduodenal content reflux from gastroesophageal reflux disease induces the inflammation-mediated progression from hyperplasia to metaplasia, and to adenocarcinoma. We further investigated the sequential development of esophageal adenocarcinoma (EADC) with the use of an established surgical rat model. The present paper will describe the impact of the inflammation-metaplasia-adenocarcinoma sequence and chemoprevention in surgical rat models. A clinically relevant rat reflux model was used to investigate the cause of carcinogenesis, the sequential development of adenocarcinoma and chemoprevention with the use of a proton pump inhibitor. We found that duodenal reflux plays an important role in the inflammation-induced transformation of esophageal mucosa to adenocarcinoma. We were able to inhibit this transformation with rabeprazole, a proton pump inhibitor. Duodenal reflux promotes inflammation in the esophagus. The inflammation-metaplasia-adenocarcinoma sequence is important in the progression and development of EADC. Carcinogenesis can be prevented with chemoprevention agents such as rabeprazole. These results will need to be validated in clinical trials.
Digestion 01/2013; 87(1):6-11. · 2.05 Impact Factor
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Hidehiro Tajima,
Tetsuo Ohta,
Hiroyuki Shinbashi,
Atsushi Hirose,
Tomoya Tsukada,
Koichi Okamoto,
Shinichi Nakanuma,
Seisho Sakai,
Hiroyuki Furukawa,
Isamu Makino, [......],
Hisatoshi Nakagawara,
Tomoharu Miyashita,
Hideto Fujita,
Hiroyuki Takamura, Itasu Ninomiya,
Hirohisa Kitagawa,
Sachio Fushida,
Takashi Fujimura,
Hisatsugu Mouri,
Koushiro Ohtsubo
[show abstract]
[hide abstract]
ABSTRACT: A 56-year-old female with metastatic gallbladder cancer involving the liver and stenosis of the hilar bile duct was treated with gemcitabine (1,000 mg/m(2)) plus S-1 (60 mg/m(2)). After 9 cycles of therapy, CT showed evidence of stable disease; however, the serum CEA level was increased. Therefore, the chemotherapy regimen was changed to weekly low-dose paclitaxel (60 mg/m(2)). After 12 cycles of therapy, paclitaxel was reduced to 30 mg/m(2) as the patient developed neutropenia. The patient completed 32 cycles of therapy, and the tumor was reduced in size and marked improvement in bile duct stenosis was noted without any impairment in quality of life. The patient succumbed to the disease 25 months after treatment was initiated. Thus, in this case paclitaxel was more effective than gemcitabine plus S-1. Palliative chemotherapy with paclitaxel after failure of gemcitabine and 5-FU was well-tolerated; therefore, it may be an effective treatment for biliary tract cancer (BTC). A phase I study of palliative chemotherapy with weekly low-dose paclitaxel following gemcitabine (plus cisplatin) and 5-FU is currently in progress in patients with unresectable or recurrent BTC.
Oncology letters 12/2012; 4(6):1281-1284. · 0.11 Impact Factor
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Tomoharu Miyashita,
Furhawn A Shah,
John W Harmon,
Guy P Marti,
Daisuke Matsui,
Koichi Okamoto,
Isamu Makino,
Hironori Hayashi,
Katsunobu Oyama,
Hisatoshi Nakagawara,
Hidehiro Tajima,
Hideto Fujita,
Hiroyuki Takamura,
Manabu Murakami, Itasu Ninomiya,
Hirohisa Kitagawa,
Sachio Fushida,
Takashi Fujimura,
Tetsuo Ohta
[show abstract]
[hide abstract]
ABSTRACT: Gastro-duodenal content reflux from gastro-esophageal reflux disease (GERD) induces the inflammation-metaplasia-dysplasia-adenocarcinoma sequence. Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, which are widely used for treating GERD and peptic ulcer-associated acid-secreting diseases. The effect of PPI therapy on esophageal carcinogenesis remains unclear. While some studies suggest PPIs result in a significant reduction in the risk of developing dysplasia and adenocarcinoma in patients with Barrett's esophagus, others suggest that PPIs have no effect. Recent studies have revealed that PPIs can exert anti-inflammatory effects such as anti-oxidant properties and immunomodulatory effects through their interactions with neutrophils, monocytes, endothelial and epithelial cells. In addition, PPIs have the ability to prevent adhesion molecule binding in malignant cells and suppress metastasis. This article reviews the role of PPIs in esophageal carcinogenesis and their use as antitumor agents.
Surgery Today 10/2012; · 1.22 Impact Factor
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ABSTRACT: Distal pancreatectomy (DP) is the most common surgical procedure for treating benign and malignant lesions in the body or tail of the pancreas. Although the mortality rate related to DP has recently been reduced, the postoperative morbidity remains high. The most frequent and dismal complication occurring after DP is the development of postoperative pancreatic fistulas (POPF). Several resection methods and closure techniques for treating remnant pancreas have been developed in an effort to reduce the incidence of complications, especially POPF. However, the optimal procedure has not yet been established. In this review, we summarize the current clinical data and evidence for surgical techniques and perioperative management strategies for preventing POPF after DP. Finally, we introduce our non-closure technique for managing remnant pancreatic stumps.
Surgery Today 10/2012; · 1.22 Impact Factor
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ABSTRACT: The mechanism through which each histological type of carcinoma arises from the esophageal mucosa remains unknown. This study was designed to investigate whether there is an association between the severity of duodeno-esophageal reflux and the histological type of esophageal cancer. A series of 120 male Fischer rats, weighing ∼180 g, were randomized to receive one of the following procedures: duodeno-forestomach reflux (DFR) with reduced exposure to duodenal contents, duodeno-esophageal reflux (DER) with increased exposure to duodenal contents and three control operations (DFR, DER control and sham). The reflux of bile was estimated with (99m) Tc-PMT scintigraphy. All animals were fed a standard diet without carcinogen. The esophageal mucosa was assessed 50 weeks after surgery for carcinoma. The median scanned fraction rate of duodeno-esophageal reflux was significantly lower for the rodents in the DFR group than those in the DER group. Five of 28 rodents in the DFR group and 17 of the 22 rodents in the DER group developed esophageal carcinoma. None of the controls developed carcinoma. The five rodents in the DFR group developed SCC. Of 22 esophageal carcinomas for the DER group, nine were SCC, 12 ADC and one was adenosquamous carcinoma. The fraction of esophageal SCC for the DFR group was significantly higher than that for the DER group, while the fraction of esophageal ADC for the DFR group was significantly lower than that for the DER group. These observations suggest that the severity of duodeno-esophageal reflux in rodents is related to the development of different histological types of esophageal carcinoma.
International Journal of Cancer 09/2012; · 5.44 Impact Factor
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Katsunobu Oyama,
Sachio Fushida,
Jun Kinoshita,
Koichi Okamoto,
Isamu Makino,
Keishi Nakamura,
Hironori Hayashi,
Masafumi Inokuchi,
Hisatoshi Nakagawara,
Hidehiro Tajima,
Hideto Fujita,
Hiroyuki Takamura, Itasu Ninomiya,
Hirohisa Kitagawa,
Takashi Fujimura,
Tetsuo Ohta
[show abstract]
[hide abstract]
ABSTRACT: Cytokeratin 18 (CK18) fragments are released into circulation during epithelial cell death. M30 (reflects caspase-cleaved CK18 fragment) and M65 (reflects total CK18 fragment) enzyme-linked immunosorbent assay (ELISA) detect circulating CK18 fragments released during caspase-dependent or total cell death, respectively; thus, CK18 has the potential of being a biomarker for epithelial cancers. In the present study, we investigated the serum levels of M30 and M65 in patients with gastric cancer, determined correlation of these levels with clinical features, and evaluated the usefulness of these enzymes as diagnostic and prognostic markers. We enrolled 54 gastric cancer patients and 12 healthy volunteers in this study. We measured the serum levels of M30 and M65 by quantitative ELISA. The levels of M30 and M65 in gastric cancer patients were significantly higher than those in healthy volunteers (P = 0.001, P < 0.001). The enzyme levels were elevated with the progress of gastric cancer. The sensitivity and specificity of M30 as a diagnostic marker were 67.5 and 90.9 %, respectively, and those of M65 were 70.1 and 90.9 %, respectively. The serum levels of M30 and M65 in patient with early gastric cancer were elevated in 38.1 and 66.7 %, respectively. Further, increased serum level of M65 is an independent indicator of poor prognosis (P = 0.036). The serum levels of M30 and M65 may be useful biomarkers for gastric cancer as diagnostic markers that can reflect the extent of cancer. Moreover, M65 levels can be used as a prognostic indicator.
Clinical and Experimental Medicine 07/2012; · 1.58 Impact Factor
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Katsuhiro Yoshimoto,
Hidehiro Tajima,
Tetsuo Ohta,
Koichi Okamoto,
Seisho Sakai,
Jun Kinoshita,
Hiroyuki Furukawa,
Isamu Makino,
Hironori Hayashi,
Keishi Nakamura, [......],
Hiroshi Itoh,
Hideto Fujita,
Hiroyuki Takamura, Itasu Ninomiya,
Hirohisa Kitagawa,
Sachio Fushida,
Takashi Fujimura,
Tomohiko Wakayama,
Shoichi Iseki,
Koichi Shimizu
[show abstract]
[hide abstract]
ABSTRACT: Several recent studies have reported that selectins are produced during ischemia-reperfusion injury, and that selectin ligands play an important role in cell binding to the endothelium and in liver metastasis. Portal clamping during pancreaticoduodenectomy with vessel resection for pancreatic head cancer causes hepatic ischemia-reperfusion injury, which might promote liver metastasis. We investigated the liver colonization of pancreatic cancer cells under hepatic ischemia-reperfusion and examined the involvement of E-selectin and its ligands. A human pancreatic cancer cell line (Capan-1) was injected into the spleen of mice after hepatic ischemia-reperfusion (I/R group). In addition, to investigate the effect of an anti-E-selectin antibody on liver colonization in the IR group, mice received an intraperitoneal injection of the anti-E-selectin antibody following hepatic ischemia-reperfusion and tumor inoculation (IR+Ab group). Four weeks later, mice were sacrificed and the number of tumor nodules on the liver was compared to mice without hepatic ischemia-reperfusion (control group). The incidence of liver metastasis in the I/R group was significantly higher (16 of 20, 80%) than that in the control group (6 of 20, 30%) (P<0.01). Moreover, mice in the I/R group had significantly more tumor nodules compared to those in the control group (median, 9.9 vs. 2.7 nodules) (P<0.01). In the I/R+Ab group, only 2 of 5 (40%) mice developed liver metastases. RT-PCR and southern blotting of the liver extracts showed that the expression of IL-1 and E-selectin mRNA after hepatic ischemia-reperfusion was significantly higher than the basal levels. Hepatic ischemia-reperfusion increases liver metastases and E-selectin expression in pancreatic cancer. These results suggest that E-selectin produced due to hepatic ischemia-reperfusion is involved in liver metastasis.
Oncology Reports 07/2012; 28(3):791-6. · 1.84 Impact Factor
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ABSTRACT: We examined the effects of the preferential cyclooxygenase-2 (COX-2) inhibitor celecoxib on tumorigenesis, angiogenesis, apoptosis, vascular endothelial growth factor (VEGF) protein expression and metastasis in HT-29 human colorectal carcinoma cell xenografts in nude mouse rectum. COX-2 mRNA expression was examined in the xenograft and metastatic sites. The antitumor effect of celecoxib in the xenografts was evaluated by measuring the weight of the peri-ano-rectal tumor. The anti-metastatic effect of celecoxib was assessed by quantification of lymph node and lung metastases by amplification of a cancer-related human DNA by TaqMan PCR. The effects of celecoxib on angiogenesis, apoptosis, prostaglandin E2 (PGE2) production and VEGF protein expression in the xenografts were evaluated by means of microvessel density (MVD) counting, terminal deoxynucleotidyl transferase-mediated nick end labeling assay, quantitative enzyme-linked immunosorbent assay and western blotting, respectively. The rectal xenograft model showed lymph node and lung metastases with enhanced expression of COX-2 mRNA in each organ. Celecoxib inhibited rectal xenograft growth in a dose-dependent manner as follows: 150 ppm, 33.0% (p=0.000220); 750 ppm, 46.4% (p=0.0000292); 1500 ppm, 63.4% (p=0.0000109). Celecoxib inhibited lymph node metastasis in a dose-dependent manner as follows: 150 ppm, 86.7% (p=0.0263); 750 ppm, 90.3% (p=0.00638); 1500 ppm, 96.0% (p=0.000894). Celecoxib also inhibited lung metastasis as follows: 750 ppm, 53.3% (p=0.0107); 1500 ppm, 78.3% (p=0.00022). Celecoxib (1500 ppm) significantly inhibited PGE2 production by 68.4% (p=0.000157) and MVD counting by 48.2% (p=1.3x10-12) and induced apoptosis 2.5-fold (p=3.0x10-14) in the rectal xenograft. Celecoxib suppressed VEGF protein expression in the rectal xenograft. These studies demonstrate that celecoxib reduces the growth and metastatic potential of colorectal carcinoma in mice through COX-2 inhibition, anti-angiogenesis and apoptosis induction. The studies using HT-29 human colorectal carcinoma cell xenografts in nude mouse rectum also provide important information that supports that the COX-2 inhibitor celecoxib has a high potential for use as a clinical agent for inhibition of hematological and lymphatic metastases of colorectal cancer.
Oncology Reports 06/2012; 28(3):777-84. · 1.84 Impact Factor
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Hidehiro Tajima,
Tetsuo Ohta,
Hirohisa Kitagawa,
Koichi Okamoto,
Seisho Sakai,
Jun Kinoshita,
Isamu Makino,
Hiroyuki Furukawa,
Hironori Hayashi,
Keishi Nakamura, [......],
Hisatoshi Nakagawara,
Hideto Fujita,
Hiroyuki Takamura, Itasu Ninomiya,
Sachio Fushida,
Takashi Tani,
Takashi Fujimura,
Seiko Kitamura,
Hiroko Ikeda,
Koichi Tsuneyama
[show abstract]
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ABSTRACT: We examined the pathological effects of preoperative neoadjuvant chemotherapy (NAC) and the expression of markers of apoptosis, epithelial-to-mesenchymal transition (EMT) and cancer stem cells in resected pancreatic cancer specimens from patients treated with gemcitabine as NAC. Immunohistochemical expression of the apoptosis marker M30, EMT marker Snail and stem cell marker CD44 in surgically resected pancreatic cancer specimens were compared between patients treated (NAC group n=13) and not treated (control group n=21) with gemcitabine. In the NAC group, the tumor specimens showed tumor cell injury; however, there was no significant reduction of serosal, retroperitoneal, perineural or vascular invasion, lymph node metastasis or tumor size. The expression frequencies of M30 and CD44 were significantly higher in the NAC group (61.5 and 53.8%) compared to the control group (9.5 and 14.3%); however, no significant difference in Snail expression was noted between the two groups (53.8 versus 42.9%). Gemcitabine induced apoptosis of pancreatic cancer cells in vivo; however, it did not reduce the tumor burden. Moreover, the residual cancer tissues were rich in chemoresistant cancer stem cells. By contrast, marked EMT of cancer cells was observed in the specimens from the groups treated and not treated with gemcitabine.
Oncology letters 06/2012; 3(6):1186-1190. · 0.11 Impact Factor
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Masatoshi Shoji, Itasu Ninomiya,
Isamu Makino,
Jun Kinoshita,
Keishi Nakamura,
Katsunobu Oyama,
Hisatoshi Nakagawara,
Hideto Fujita,
Hidehiro Tajima,
Hiroyuki Takamura,
Hirohisa Kitagawa,
Sachio Fushida,
Shinichi Harada,
Takashi Fujimura,
Tetsuo Ohta
[show abstract]
[hide abstract]
ABSTRACT: Histone deacetylase (HDAC) inhibitors have been shown to enhance radiation response in various cancer cell lines. Valproic acid (VPA) has been used in clinical practice for the treatment of epilepsy and other seizure disorders and is also one of the most represented HDAC inhibitors. The aim of this study was to evaluate the radiosensitizing ability of VPA and its mechanisms in four esophageal squamous cell carcinoma (ESCC) cell lines (TE9, TE10, TE11 and TE14). VPA inhibited the viability of all ESCC cells in a dose-dependent manner. The 50% inhibitory concentration (IC50) value of VPA in each cell line was between 1.02-2.15 mM, which is higher than clinically used safe concentrations. VPA induced the hyperacetylation of histones H3 and H4, as well as apoptosis and had a radiosensitizing effect on all four ESCC cell lines at a concentration of 0.5 mM which is equivalent to the therapeutic plasma concentration of anti-epilepsy therapy in humans. The radiosensitization was accompanied by an increase in γH2AX levels, indicating the presence of double-strand breaks (DSBs), and decrease in Rad51 expression, a DSB repair protein. These results suggest that a clinically safe dose of VPA can enhance radiation-induced cytotoxicity in human ESCC cells by chromatin decondensation with histone hyperacetylation and downregulation of Rad51. In conclusion, VPA appears to be a safe and promising radiosensitizer for esophageal cancer radiotherapy.
International Journal of Oncology 06/2012; 40(6):2140-6. · 2.40 Impact Factor
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Koichi Okamoto,
Hidehiro Tajima,
Shinichi Nakanuma,
Seisho Sakai,
Isamu Makino,
Jun Kinoshita,
Hironori Hayashi,
Keishi Nakamura,
Katsunobu Oyama,
Hisatoshi Nakagawara,
Hideto Fujita,
Hiroyuki Takamura, Itasu Ninomiya,
Hirohisa Kitagawa,
Sachio Fushida,
Takashi Fujimura,
Shinichi Harada,
Tomohiko Wakayama,
Shoichi Iseki,
Tetsuo Ohta
[show abstract]
[hide abstract]
ABSTRACT: We previously reported that hepatic stellate cells (HSCs) activated by angiotensin II (AngII) facilitate stromal fibrosis and tumor progression in intrahepatic cholangiocarcinoma (ICC). AngII has been known as a growth factor which can promote epithelial-to-mesenchymal transition (EMT) in renal epithelial cells, alveolar epithelial cells and peritoneal mesothelial cells. However, in the past, the relationship between AngII and stromal cell-derived factor-1 (SDF-1) in the microenvironment around cancer and the role of AngII on EMT of cancer cells has not been reported in detail. SDF-1 and its specific receptor, CXCR4, are now receiving attention as a mechanism of cell progression and metastasis. In this study, we examined whether activated HSCs promote tumor fibrogenesis, tumor progression and distant metastasis by mediating EMT via the AngII/AngII type 1 receptor (AT-1) and the SDF-1/CXCR4 axis. Two human ICC cell lines and a human HSC line, LI-90, express CXCR4. Significantly higher concentration of SDF-1α was released into the supernatant of LI-90 cells to which AngII had been added. SDF-1α increased the proliferative activity of HSCs and enhanced the activation of HSCs as a growth factor. Furthermore, addition of SDF-1α and AngII enhanced the increase of the migratory capability and vimentin expression, reduced E-cadherin expression, and translocated the expression of β-catenin into the nucleus and cytoplasm in ICC cells. Co-culture with HSCs also enhanced the migratory capability of ICC cells. These findings suggest that SDF-1α, released from activated HSCs and AngII, play important roles in cancer progression, tumor fibrogenesis, and migration in autocrine and paracrine fashion by mediating EMT. Our mechanistic findings may provide pivotal insights into the molecular mechanism of the AngII and SDF-1α-initiated signaling pathway that regulates fibrogenesis in cancerous stroma, tumor progression and meta-stasis of tumor cells expressing AT-1 and CXCR4.
International Journal of Oncology 05/2012; 41(2):573-82. · 2.40 Impact Factor
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Tomoya Tsukada,
Sachio Fushida,
Shinichi Harada,
Yasumichi Yagi,
Jun Kinoshita,
Katsunobu Oyama,
Hidehiro Tajima,
Hideto Fujita, Itasu Ninomiya,
Takashi Fujimura,
Tetsuo Ohta
[show abstract]
[hide abstract]
ABSTRACT: Peritoneal dissemination is the most frequent metastatic pattern of scirrhous gastric cancer. However, despite extensive research effort, disease outcomes have not improved sufficiently. Tumor progression and metastasis result from interactions between cancer and various cells in the stroma, including endothelial cells, immune cells and fibroblasts. Fibroblasts have been particularly well studied; they are known to change into carcinoma-associated fibroblasts (CAFs) and produce transforming growth factor β (TGF-β), which mediates cancer-stroma interactions. Here, we investigated whether TGF-β derived from cancer cells in the peritoneal microenvironment activates human peritoneal mesothelial cells (HPMCs), leading to the progression and fibrosis of gastric cancer. We found that activated HPMCs (a-HPMCs) took on a spindle shape formation, decreased the expression of E-cadherin and increased that of α-SMA. Furthermore, a-HPMCs became more invasive and upregulated proliferation of human gastric cancer-derived MKN45 cells following direct cell-cell contact. Notably, MKN45 cells co-cultured with a-HPMCs also acquired anchorage-independent cell growth and decreased expression of E-cadherin in vitro. To measure the effects of the co-culture in vivo, we developed a mouse xenograft model into which different culture products were subcutaneously injected. The largest tumors were observed in mice that had been given MKN45 cells co-cultured with a-HPMCs. Furthermore, these tumors contained HPMC-derived fibrous tissue. Thus, the epithelial-mesenchymal transition (EMT) of HPMCs appears to drive peritoneal dissemination and tumor fibrosis.
International Journal of Oncology 05/2012; 41(2):476-82. · 2.40 Impact Factor
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Hidehiro Tajima,
Tetsuo Ohta,
Hirohisa Kitagawa,
Koichi Okamoto,
Seisho Sakai,
Isamu Makino,
Jun Kinoshita,
Hiroyuki Furukawa,
Keishi Nakamura,
Hironori Hayashi, [......],
Masafumi Inokuchi,
Hisatoshi Nakagawara,
Hideto Fujita,
Hiroyuki Takamura, Itasu Ninomiya,
Sachio Fushida,
Takashi Tani,
Takashi Fujimura,
Hiroko Ikeda,
Seiko Kitamura
[show abstract]
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ABSTRACT: Results of surgery alone for pancreatic cancer are disappointing. We retrospectively evaluated the efficacy and tolerability of neoadjuvant chemotherapy (NAC) with gemcitabine and oral S-1 in patients with potentially resectable pancreatic cancer. A total of 34 patients with pancreatic ductal adenocarcinoma, radiologically diagnosed preoperatively as having potentially resectable tumors, underwent pancreatic resection with lymphadenectomy at Kanazawa University Hospital. NAC was administered to 13 patients (NAC group). The remaining 21 patients were surgically treated without preoperative chemotherapy (control group). Surgical results were compared between these two groups, with follow-up for at least 24 months. No statistically significant differences were found in the clinicopathological background data (tumor location, age, gender, lymph node metastases, tumor stage and tumor size) between the NAC and control groups. Following preoperative chemotherapy, no patients were judged to be unable to undergo laparotomy, i.e., neither distant metastasis nor tumor progression was observed. Radiologically, all 13 NAC group patients had stable disease, whereas, histopathologically, all tumor specimens showed evidence of tumor cells. The treatment effect was judged by Evans grading to be grade IIa in 11 patients and grade IIb in 2 patients. Toxicity was evaluated in 11 patients. Grade III side effects were regarded as hematological toxicity, i.e., leucopenia (7.7%) and thrombocytopenia (15.4%). Moreover, the incidence of perioperative complications did not differ significantly between the NAC and control groups. The one- and three-year overall survival rates of the NAC group with pancreatic head cancer were 88.9 and 55.6%, respectively, superior to 88.9 and 29.6% in the control group (p=0.055). Therefore, NAC with gemcitabine and S-1 is well tolerated and potentially effective against pancreatic head cancer. A phase I study of NAC with gemcitabine and S-1 is under way in patients with resectable pancreatic cancer.
Experimental and therapeutic medicine 05/2012; 3(5):787-792.
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ABSTRACT: We introduce our novel and original idea of placing a feeding catheter gastrostomy (FCG) at esophagectomy with gastric tube
reconstruction through the posterior mediastinal route. The 9-Fr catheter was inserted into the jejunum through the gastric
tube by the creation of submucosal and Witzel tunnels on the gastric antrum. Among the 45 patients who underwent FCG, the
catheter was guided to the anterior abdominal wall through the sub-diaphragm route in 25 patients (group A) or the extra-peritoneal
route with the overlapping of catheter entry by the omentum in 20 patients (group B). There were no cases of spontaneous catheter
prolapse or bowel obstruction. Five out of 45 patients (11.1%), including 4 (16%) in group A and 1 (5%) in group B, showed
mild and transient localized peritonitis after catheter removal. The extra-peritoneal route with omental cover is recommended
for safe indwelling catheterization. FCG is useful for avoiding jejunostomy-related bowel obstruction.
KeywordsEnteral nutrition–Esophagectomy–Gastrostomy
Esophagus 04/2012; 8(3):217-223. · 0.66 Impact Factor
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Tomoya Tsukada,
Sachio Fushida,
Shinichi Harada,
Shiroh Terai,
Yasumichi Yagi,
Jun Kinoshita,
Katsunobu Oyama,
Hidehiro Tajima,
Hideto Fujita, Itasu Ninomiya,
Takashi Fujimura,
Tetsuo Ohta
[show abstract]
[hide abstract]
ABSTRACT: Adiponectin is inversely related to BMI, positively correlates with insulin sensitivity, and has anti-atherogenic effects. In recent years, adiponectin has been well studied in the field of oncology. Adiponectin has been shown to have antiproliferative effects on gastric cancer, and adiponectin expression is inversely correlated with clinical staging of the disease. However, no studies have reported the correlation between serum adiponectin and receptor expression with disease progression.
In this study, we evaluated expression levels of 2 adiponectin receptors--AdipoR1 and AdipoR2--and attempted to correlate their expression with prognosis in gastric cancer patients. AdipoR1 and AdipoR2 expression in gastric cancer cell lines (MKN45, TMK-1, NUGC3, and NUGC4) was evaluated by western blotting analysis, and the antiproliferative potential of adiponectin was examined in vitro. Serum adiponectin levels were evaluated in 100 gastric cancer patients, and the expression of AdipoR1 and AdipoR2 was assessed by immunohistochemical staining.
MKN45 and NUGC3 expressed higher levels of AdipoR1 compared to NUGC4, even though there was no significance in AdipoR2 expression. The antiproliferative effect of adiponectin was confirmed in MKN45 and NUGC3 at 10 μg/ml. No significant associations were observed between serum adiponectin levels and clinicopathological characteristics, but lymphatic metastasis and peritoneal dissemination were significantly higher in the negative AdipoR1 immunostaining group (24/32, p = 0.013 and 9/32, p = 0.042, respectively) compared to the positive AdipoR1 group (lymphatic metastasis, 33/68; peritoneal dissemination, 8/68). On the other hand, AdipoR2 expression was only associated with histopathological type (p = 0.001). In survival analysis, the AdipoR1 positive staining group had significantly longer survival rates than the negative staining group (p = 0.01). However, multivariate analysis indicated that AdipoR1 was not an independent prognostic factor on patient's survival on gastric cancer.
In gastric cancer, adiponectin has the possibility to be involved in cell growth suppression via AdipoR1. The presence of AdipoR1 could be a novel anticancer therapeutic target in gastric cancer.
Journal of Experimental & Clinical Cancer Research 11/2011; 30:107. · 2.15 Impact Factor
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Atsushi Hirose,
Hidehiro Tajima,
Koichi Okamoto,
Isamu Makino,
Jun Kinoshita,
Hironori Hayashi,
Keishi Nakamura,
Katsunobu Oyama,
Hisatoshi Nakagawara,
Masafumi Inokuchi,
Hideto Fujita,
Hiroyuki Takamura, Itasu Ninomiya,
Hirohisa Kitagawa,
Sachio Fushida,
Takashi Tani,
Takashi Fujimura,
Tetsuo Ohta,
Wataru Koda,
Osamu Matsui
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ABSTRACT: A 73-year-old woman visited our hospital for a treatment of pancreatic tumor that increased steadily in size of 6 cm in diameter in 1999 to 13 cm in 2008, while remaining in asymptomatic condition throughout this follow-up time. The tumor was big and flowed from many vessels such as portal and superior mesenteric veins and the celiac and superior mesenteric arteries. These were critical for determining tumor respectability and the risk of massive intra-operative hemorrhage was felt to be considerable. Therefore, preoperative embolization of the tumor-feeding arteries arising from the celiac axis (gastroduodenal, splenic and dorsal pancreatic arteries) was performed on the previous day of operation. Tumor resection with pancreaticoduodenectomy and partial resection of portal vein and reconstruction were performed. We got to SMA with the use of "paraduodenal mesenteric approach", we called, and we finished the operation without a blood transfusion. The final pathology confirmed the diagnosis of serous microcystic adenoma.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2011; 38(12):2451-3.
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Jun Kinoshita,
Sachio Fushida,
Isamu Makino,
Keishi Nakamura,
Katsunobu Oyama,
Hisatoshi Nakagawara,
Hideto Fujita,
Hidehiro Tajima,
Hiroyuki Takamura, Itasu Ninomiya,
Hirohisa Kitagawa,
Takashi Tani,
Masatoshi Miyamoto,
Takashi Fujimura,
Tetsuo Ota
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ABSTRACT: Vascular endothelial growth factor (VEGF) plays an important role in proliferation of cancer cells, angiogenesis and vascular permeability in peritoneal dissemination. In addition, the release of VEGF by tumor cells has been identified as a main factor promoting the intraperitoneal secretion of fluid. Accordingly, recent evidence suggests that targeting VEGF may have the potential to suspend the ascites production resulting from peritoneal metastasis. We previously reported the effects of bevacizumab (BEV) on the growth inhabitation of peritoneal nodules and the reduction of ascites in peritoneal metastatic models. Here we present two cases of women (62 and 42 years old) with refractory peritoneal dissemination of scirrhous gastric cancer and server symptomatic ascites. They required frequent paracenteses for ascites which was resistant to systemic and intraperitoneal chemotherapy of S-1 and taxane. We treated them with intravenous BEV (5-10 mg/kg) with dramatic improvement in their ascites. BEV may have a role in the management of malignant ascites in the patient with refractory gastric cancer which should be confirmed in a larger series of well selected patients.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2011; 38(12):2360-2.
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Katsunobu Oyama,
Sachio Fushida,
Jun Kinoshita,
Isamu Makino,
Keishi Nakamura,
Hironori Hayashi,
Hisatoshi Nakagawara,
Hidehiro Tajima,
Hideto Fujita,
Hiroyuki Takamura, Itasu Ninomiya,
Hirohisa Kitagawa,
Takashi Tani,
Takashi Fujimura,
Tetsuo Ohta
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ABSTRACT: The prognosis of gastric cancer with para-aortic lymph node (PAN) metastasis is poor. We applied triple combination chemotherapy with docetaxel, cisplatin, and S-1 (DCS therapy) as pre-operative chemotherapy and investigated the outcome of the combination of this therapy and gastrectomy with para-aortic lymph node dissection (PAND).
We retrospectively identified 44 patients with pathologically positive PAN who underwent curative surgery at Kanazawa University Hospital between 1990 and 2008. Among the 44 patients, 16 received pre-operative DCS therapy and subsequent surgical resection after two courses of the therapy.
Pre-operative DCS therapy showed high clinical response ratio (68.8%) and disease control ratio (100%). The pathological response ratio of resected specimen was 87.5%. At 2 years after surgery, the overall survival ratio was 93.8% and relapse-free survival was 75.0%. Pre-operative DCS therapy was only independent prognostic factor in multivariate analysis. Grade 3/4 toxicity was observed only in 25.0% of patients who underwent DCS therapy. Surgical complication was observed in 31.3% of patients, and this ratio was equal to that of patients who did not receive DCS therapy.
Multimodal therapy comprising combined pre-operative DCS therapy and gastrectomy with PAND was extremely effective and feasible for advanced gastric cancer with PAN metastasis.
Journal of Surgical Oncology 10/2011; 105(6):535-41. · 2.10 Impact Factor
