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Y Okugawa,
K Tanaka,
Y Inoue,
M Kawamura,
A Kawamoto,
J Hiro,
S Saigusa,
Y Toiyama,
M Ohi,
K Uchida,
Y Mohri, M Kusunoki
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ABSTRACT: Background:Brain-derived neutrophic factor (BDNF) is a member of the neutrophin family that is known to activate the high-affinity tropomyosin-related receptor kinase B (TrkB). This study aimed to clarify the clinical and biological significance of the BDNF/TrkB pathway in gastric cancer.Methods:We analysed BDNF and TrkB expression in gastric cancer samples by real-time reverse transcription PCR and immunohistochemistry. To investigate the biological role of BDNF/TrkB axis, recombinant human BDNF (rhBDNF) and the Trk antagonist K252a were used for in vitro and in vivo analysis.Results:The BDNF expression at the invasive front of primary tumours was significantly elevated compared with that in the tumour core and adjacent normal mucosa. Increased BDNF expression at the invasive front was significantly correlated with factors reflecting disease progression, and poor prognosis. Increased co-expression of the BDNF/TrkB axis was significantly correlated with poor prognosis. Gastric cancer cells expressed BDNF, and administration of rhBDNF promoted proliferation, migration, invasion, and inhibition of anoikis. These effects were generally inhibited by K252a. In an in vivo assay, BDNF(+)/TrkB(+) gastric cancer cells injected into nude mice established peritoneal dissemination, whereas K252a inhibited tumour growth.Conclusion:The BDNF/TrkB pathway might be deeply involved in gastric cancer disease progression.British Journal of Cancer advance online publication, 22 November 2012; doi:10.1038/bjc.2012.499 www.bjcancer.com.
British Journal of Cancer 11/2012; · 5.04 Impact Factor
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N J Shimwell,
D G Ward,
Y Mohri,
T Mohri,
L Pallan,
M Teng,
Y C Miki, M Kusunoki,
O Tucker,
W Wei,
J Morse,
P J Johnson
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ABSTRACT: Background:There is a need for sensitive and specific blood-borne markers for the detection of gastric cancer. Raised serum macrophage inhibitory factor (MIF) levels have been proposed as a marker for gastric cancer diagnosis but, to date, studies have only encompassed patients from high-incidence areas.Methods:We have compared the serum concentration of MIF in a large cohort of UK and Japanese gastric cancer patients, together with appropriate control subjects (age and gender matched). Carcinoembryonic antigen and H. pylori IgG were also measured, as was DJ-1, a novel candidate protein biomarker identified by analysis of gastric cancer cell line secretomes.Results:Marked elevations of the serum concentration of MIF and DJ-1 were seen in Japanese patients with gastric cancer compared with Japanese controls, a trend not seen in the UK cohort. These results could not be accounted for by differences in age, disease stage or H. pylori status.Conclusion:In regions of high, but not low incidence of gastric cancer, both MIF and DJ-1 have elevated serum concentrations in gastric cancer patients, compared with controls. This suggests that differing mechanisms of disease pathogenesis may be at play in high- and low-incidence regions.
British Journal of Cancer 09/2012; 107(9):1595-601. · 5.04 Impact Factor
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ABSTRACT: To evaluate the relationship between vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) levels in gastric cancer tissue and clinicopathological features and to determine whether these factors were correlated with survival.
We analysed tissue samples from 58 patients with gastric cancer and used 24 normal gastric mucosae as controls. Tissue levels of VEGF and HGF were measured in tissue extracts by enzyme-linked immunosorbent assay.
HGF and VEGF levels were significantly higher in gastric cancer tissue than in matched normal gastric mucosa. VEGF levels were significantly increased in cancer tissue from cases involving lymphatic invasion. HGF levels were significantly increased according to the disease stage. Patients with high levels of VEGF or HGF showed significantly worse survival rates than patients with low levels. Using multivariate analysis, a high level of VEGF or HGF was an independent factor predicting poor survival.
Intratumoral levels of HGF and VEGF are an important prognostic determinant in gastric cancer. The current findings suggest that high concentrations of HGF and VEGF may induce aggressive tumour growth and metastasis.
Clinical Oncology 11/2011; 24(9):610-6. · 2.07 Impact Factor
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Takemitsu Takemitsu,
Hideo Wada,
Tsuyoshi Hatada,
Yukinari Ohmori,
Ken Ishikura,
Taichi Takeda,
Takashi Sugiyama,
Norikazu Yamada,
Kazuo Maruyama,
Naoyuki Katayama,
Shiji Isaji,
Hideto Shimpo, Masato Kusunoki,
Tsutomu Nobori
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ABSTRACT: There are three different diagnostic score systems for disseminated intravascular coagulation (DIC) established by the Japanese Ministry Health and Welfare (JMHW), the International Society on Thrombosis and Haemostasis (ISTH) and the Japanese Association for Acute Medicine (JAAM). The JMHW criteria are still used in Japan. In the present study, all three diagnostic criteria were used to prospectively evaluate 413 patients with different underlying diseases of DIC who were treated at the Mie University Hospital (JMHW, n= 166; ISTH, n=143; JAAM, n=291). The odds ratio (95% confidence interval) for death was 1.88 (1.22 - 2.90) in JMHW, 2.55 (1.65 - 3.95) in ISHT and 1.99 (1.19 - 3.32) in JAAM. The platelet count, prothrombin time, fibrin and fibrinogen degradation products and fibrinogen were significantly important for diagnosis of DIC by all three diagnostic criteria. Haemostatic molecular markers were significantly high in all patients and were useful for the diagnosis of DIC. The JAAM diagnostic criteria displayed a high sensitivity for DIC and the ISTH overt-DIC diagnostic criteria displayed a high specificity for DIC. All three diagnostic criteria for DIC were related to a poor patient outcome.
Thrombosis and Haemostasis 10/2010; 105(1):40-4. · 5.04 Impact Factor
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ABSTRACT: The mechanism of distant recurrence in rectal cancer after preoperative chemoradiotherapy (CRT) has yet to be fully elucidated. Further improvements in survival rates cannot be achieved without decreasing distant recurrence after preoperative CRT. Recently, it was reported that hypoxic conditions were correlated with cancer stem cell generation. Therefore, we investigated the correlation between the expression of CD133 and hypoxia inducible factor-1α (HIF-1α), and their association with clinical outcome.
Fifty-two patients with rectal cancer underwent preoperative CRT. Residual cancer cells after CRT were obtained from formalin-fixed paraffin-embedded specimens using micro-dissection. The expression levels of CD133 (PROM1) and HIF-1α genes were measured using real-time reverse transcription polymerase chain reaction. The correlation between expression and irradiation was evaluated using colon cancer cell lines. Immunohistochemical staining of these proteins after CRT was also investigated.
We observed a significant inverse correlation between the gene expression of CD133 (PROM1) and HIF-1α genes in residual cancer cells after CRT. Elevated CD133 gene expression was associated with distant recurrence and poor recurrence-free survival. Elevated HIF-1α gene expression was associated with poor overall survival. In vitro, the change in gene expression levels after irradiation showed inverse patterns. Immunohistochemical analyses showed that residual cancer cells strongly expressed CD133 and lacked HIF-1α expression.
Our results suggest that CD133 and HIF-1α expression is associated with tumour re-growth and distant recurrence after CRT. These results may assist in clarifying the development of future cancer therapeutics in rectal cancer patients undergoing preoperative CRT.
Clinical Oncology 10/2010; 23(5):323-32. · 2.07 Impact Factor
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ABSTRACT: Interleukin-6 (IL-6) binds both the membrane and soluble forms of the IL-6 receptor (sIL-6R), which induces a complex with gp130, and proliferation of tumour cells. The aim of this study is to clarify the relationship between tumoral sIL-6R expression and disease progression in colorectal cancer patients.
We measured tissue concentrations of sIL-6R in tumour and normal mucosa from 161 colorectal cancer patients undergoing surgery, and in supernatants from colon cancer cell lines. The expression of IL-6, IL-6R and gp130 was evaluated by immunohistochemical analysis.
Loss of tumour expression of sIL-6R as defined by sIL-6R Ca/N ratio <1.0 was significantly associated with factors reflecting disease progression, and was an independent prognostic factor not only in all the patients in this study, but also in the patients with curative intent. Colon cancer cell lines produced sIL-6R in vitro, and the production of sIL-6R in cancer cell lines was stimulated by cytokine stimulation. Immunohistochemistry revealed that loss of tumour expression of sIL-6R was significantly inversely correlated with intense IL-6 expression in the cytoplasm of cancer cells. In addition, tumoral IL-1beta expression was significantly correlated with sIL-6R expression.
Loss of tumour expression of sIL-6R is associated with colorectal cancer disease progression.
British Journal of Cancer 09/2010; 103(6):787-95. · 5.04 Impact Factor
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ABSTRACT: To establish a causal relationship between the gene expression profiles of angiogenetic molecular markers, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1), in rectal cancer and the local responsiveness to neoadjuvant chemoradiotherapy and subsequent disease recurrence.
We examined the pre-treatment tumour biopsies (n=40) obtained from patients with rectal adenocarcinoma (clinical International Union Against Cancer stage ll/III) who were scheduled to receive neoadjuvant 5-fluorouracil-based chemoradiotherapy for EGFR, VEGF and HIF-1 expression by quantitative real-time polymerase chain reaction.
Responders (patients with significant tumour regression, i.e. pathological grades 2/3) showed significantly lower VEGF, HIF-1 and EGFR gene expression levels than the non-responders (patients with insignificant tumour regression, i.e. pathological grades 0/1) in the pre-treatment tumour biopsies. The elevated expression level of each gene could predict patients with a low response to chemoradiation. During the median follow-up of all patients (41 months; 95% confidence interval 28-60 months), 6/40 (15%) developed disease recurrence. Although local responsiveness to neoadjuvant chemoradiotherapy was associated with neither local nor systemic disease recurrence, lymph node metastasis and an elevated VEGF gene expression level were independent predictors of systemic disease recurrence. The 3-year disease-free survival rates of the patients with lower VEGF or EGFR expression levels were significantly lower than those of patients with higher VEGF or EGFR expression levels.
Analysing VEGF expression levels in rectal cancer may be of benefit in estimating the effects of neoadjuvant chemoradiotherapy and in predicting systemic recurrence after rectal cancer surgery.
Clinical Oncology 05/2010; 22(4):272-80. · 2.07 Impact Factor
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British Journal of Cancer 10/2009; 101(9):1648-9; author reply 1650. · 5.04 Impact Factor
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European Journal of Pediatric Surgery 07/2009; 20(2):121-3. · 0.81 Impact Factor
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ABSTRACT: Proteomic methods have the potential to meet the urgent need for better cancer biomarkers. We have used a range of proteomic analyses of serum and tissue from gastric cancer patients and relevant controls to discover biomarkers for gastric cancer.
Surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI) and antibody arrays were used to compare protein expression in 21 pairs of gastric cancer tissue and adjacent normal mucosa and serum from 51 gastric cancer patients and 29 patients with benign gastric diseases. Expression differences were confirmed by enzyme-linked immunosorbent assay.
Tissue analysis shows human neutrophil peptides 1-3 (HNPs 1-3) elevated 10-fold (P=0.001) in gastric cancer relative to adjacent normal mucosa. Macrophage migration inhibitory factor (MIF) was increased five-fold (P=1.84 x 10(-7)) in the serum of gastric cancer patients relative to individuals with benign gastric disease. The large increase in MIF concentration in serum gives an area under the receiver operating characteristic curve of 0.85.
Proteomic analyses of serum and tissue indicate that HNPs 1-3 and MIF have potential as biomarkers for gastric cancer. In particular MIF may be useful, either alone or in combination with other markers, for diagnosing and monitoring gastric cancer.
British Journal of Cancer 07/2009; 101(2):295-302. · 5.04 Impact Factor
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Clinical Oncology 03/2009; 21(4):362-3. · 2.07 Impact Factor
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ABSTRACT: HsMAD2 and BubR1 are crucial components of a functional mitotic checkpoint. Recently, impaired mitotic checkpoints or decreased expression of mitotic checkpoint genes have been associated with sensitivity to certain anticancer drugs. The current study aimed to evaluate the association of hsMAD2 and BubR1 with sensitivity to various anticancer drugs in oesophageal squamous cell carcinoma (ESCC) cell lines. We also investigated responses to 5-fluorouracil and cisplatin-based radiochemotherapy in ESCC patients.
HsMAD2 and BubR1 mRNA levels in six ESCC cell lines and 21 ESCC patients were determined by real-time reverse transcription polymerase chain reaction. Responses to 5-fluorouracil, cisplatin, paclitaxel and docetaxel in human oesophageal cancer cell lines, TE1 and TE2, were evaluated by WST-8 colorimetric assay. HsMAD2 and BubR1 levels were compared with clinicopathological characteristics and responses to radiochemotherapy.
TE1, with lower hsMAD2 and BubR1, showed greater sensitivity to paclitaxel and docetaxel compared with TE2, with higher hsMAD2 and BubR1. HsMAD2 and BubR1 were significantly higher in cancer tissue than in adjacent normal tissue (P < 0.01). Tumoral hsMAD2 and BubR1 were significantly decreased after radiochemotherapy (P < 0.01). There was a significantly strong positive association between hsMAD2 and BubR1 in cancer tissue (P < 0.01). Neither clinicopathological characteristics nor the response to radiochemotherapy was associated with hsMAD2 or BubR1.
The mitotic checkpoint genes, hsMAD2 and BubR1, were co-ordinately overexpressed in ESCC. Low hsMAD2 and BubR1 was associated with sensitivity to paclitaxel and docetaxel. Decreased hsMAD2 and BubR1 after radiochemotherapy may indicate the potential efficacy of taxanes as second-line chemotherapy for recurrent and metastatic oesophageal cancer.
Clinical Oncology 08/2008; 20(8):639-46. · 2.07 Impact Factor
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ABSTRACT: It has recently been recognized that there is a close relationship between spinal cord tethering (SCT) and congenital anorectal malformation (ARM).
We evaluated spinal MRI examinations of 28 patients with ARM (14 boys and 14 girls) aged 5 months to 9 years. All patients diagnosed with SCT subsequently underwent operation. Patients were divided into high and low type ARM groups. We reviewed the relationship between SCT and ARM, and evaluated the untethering surgery.
We evaluated 14 boys (high, 9; low, 5) and 14 girls (high, 4; low, 10). Of these 28 patients, 13 had SCT on MRI. Five out of 13 patients with high type ARM and 8 out of 15 patients with low type ARM had SCT. Seven out of 10 girls with low type ARM had SCT. Ten of these 13 patients with SCT experienced bowel/urological/orthopedic symptoms. SCT symptoms progressed prior to operation in the 2 patients who underwent untethering surgery a few years after their initial MRI examination. Postoperatively, orthopedic symptoms disappeared completely in all patients, but other symptoms did not.
Based on the results of this study, we recommend routine MRI examination of patients with ARM and early untethering surgery in cases with SCT.
European Journal of Pediatric Surgery 01/2008; 17(6):408-11. · 0.81 Impact Factor
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ABSTRACT: The optimum duration of antimicrobial prophylaxis in elective gastric cancer surgery is still open to question. This multicentre randomized clinical trial compared a single-dose with a multiple-dose regimen of antimicrobial prophylaxis for prevention of surgical-site infection.
Between May 2001 and December 2004, 501 patients undergoing elective surgery for gastric cancer in ten centres were allocated randomly to single- or multiple-dose antimicrobial prophylaxis. The primary outcome measure was the incidence of surgical-site infection, analysed by intention to treat.
Some 243 patients who received a single dose and 243 who received multiple doses of antibiotics were included in the final analysis. The surgical-site infection rate was 9.5 per cent (23 of 243) and 8.6 per cent (21 of 243) respectively (difference 0.9 (95 per cent confidence interval - 4.3 to 5.9) per cent). Antimicrobial prophylaxis had no major adverse effects.
The incidence of surgical-site infection in elective gastric cancer surgery was similar with both antibiotic prophylaxis regimens.
British Journal of Surgery 07/2007; 94(6):683-8. · 4.61 Impact Factor
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ABSTRACT: IFL [irinotecan (CPT-11), 5-fluorouracil (5-FU), and folinic acid] is one of the treatments for metastatic colorectal cancer. We evaluated cytotoxic effects of a sequentially administered a combination of 5-FU with CPT-11 in human p53 mutant colon cancer. Sequential combination of 5-FU and CPT-11 in human colon cancer SW480 cells using a WST-8 colorimetric assay was studied. Cytotoxicity and cell cycle distribution for each drug were evaluated using an apoptosis assay and flow cytometry. Potential mechanisms of sequence-dependent cytotoxic effects were investigated using microarrays. Cytotoxicity of 5-FU (10, 100, 1000 microM) combined with subsequent use of CPT-11 (1 microM) was significantly greater than the reverse sequence of CPT-11 followed by 5-FU (p < 0.05). Following 24 hrs treatment with 5-FU (0.1-100 microM), no significant apoptosis was observed. In contrast, apoptosis was significantly induced after 24 hrs treatment with CPT-11 (1 and 10 microM). Flow cytometric analysis showed no significant difference in cell cycle distribution between different drug concentrations. We demonstrated up-regulation of 85 genes and down-regulation of 21 genes correlating with sequence-dependent cytotoxicities of 5-FU and CPT-11. The superiority of 5-FU-CPT-11 sequence was proven for p53 mutant colon cancer, SW480. Treatment with 5-FU followed by CPT-11 administration may be the optimal sequence for IFL treatment of metastatic colon cancers.
Journal of experimental & clinical cancer research: CR 06/2007; 26(2):241-51. · 1.50 Impact Factor
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ABSTRACT: The inflammatory reaction is known to be controlled in neonates. We clarified the characteristics of cytokine profile in neonatal patients and assess its clinical significance. Serum levels of interleukin (IL)-6 and IL-1 receptor antagonist (ra) were determined in 152 pediatric patients and 33 each of maternal and cord bloods. Supernatant IL-1ra levels of cultured monocytes and granulocytes stimulated with IL-1beta or LPS, and IL-1ra mRNA expression of granulocytes were assayed in 15 each of cord and healthy adult bloods. Although surgical stress in neonates was heavier than that in infants, there was no difference in the occurrence of postoperative morbidity and mortality. In neonates, the perioperative serum level of IL-1ra was significantly raised, and the postoperative IL-6 response was well controlled. The serum concentration of IL-1ra in cord blood was not different from that in maternal blood, whereas, the serum concentration of IL-6 in cord blood was significantly reduced than that in maternal blood. In granulocytes, significantly more IL-1ra was produced from cord than from adult blood. An IL-1ra predominant immune status in neonates may be a naturally acquired adaptation system and play a crucial role in attenuating acute inflammatory reaction in a vulnerable host defense.
Pediatric Surgery International 04/2007; 23(3):249-55. · 1.25 Impact Factor
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ABSTRACT: It is still debated whether perioperative blood transfusion alters the incidence of disease recurrence or otherwise affects the prognosis after curative resection of malignant tumours. We conducted a prospective observational study of patients with colorectal cancer to provide data on the effect of blood transfusion and the related perioperative cytokine response on long-term prognosis.
Perioperative blood samples were obtained from 117 patients with colorectal cancer undergoing potentially curative resection. Factors associated with perioperative blood transfusion were assessed, and their relationship with early postoperative systemic responses of tumour growth factors and long-term prognosis were evaluated.
Independent factors associated with perioperative blood transfusion were preoperative anaemia, operative blood loss and the development of postoperative infectious complication. The patients receiving transfusions were subdivided according to the independent factors. Group A comprised 19 patients who received blood transfusions because of preoperative anaemia and Group B comprised 16 patients who received blood transfusions because of excessive operative blood loss. Group B patients showed exaggerated postoperative systemic induction of interleukin (IL)-6 and IL-6-triggered tumour growth factors, such as hepatocyte growth factor and vascular cell adhesion molecule-1. Intraoperative blood transfusion under intense surgical stress was associated with poor prognosis, whereas preoperative blood transfusion for correcting anaemia or intraoperative blood transfusion under less invasive surgery was not associated with survival. Multivariate analysis using the Cox proportional hazards method showed that a significant independent risk was demonstrated for blood transfusion, T stage, lymph-node metastasis and perioperative peak levels of IL-6.
Blood transfusion and intense surgical stress might synergistically affect the long-term prognosis after curative resection of colorectal cancer. Postoperative exaggerated systemic inductions of IL-6 may indicate the critical situation that could lead to disease recurrence.
Clinical Oncology 03/2006; 18(1):60-6. · 2.07 Impact Factor
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Clinical Oncology 06/2005; 17(3):200-1. · 2.07 Impact Factor
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ABSTRACT: Although conventional tumor markers including carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9) have been used in gastric cancer patients, clinically useful markers of early gastric cancer have not been identified. The present study was designed to clarify the clinical significance of the circulating level of hepatocyte growth factor (HGF) as a tumor marker, especially in early-stage gastric cancer patients.
Preoperative serum HGF levels were measured with an enzyme-linked immunosorbent assay in 30 early-stage and 42 advanced-stage gastric cancer patients.
The mean value of serum HGF in 72 patients was significantly higher than that in the normal subjects. There was a significant increase in serum HGF levels in both advanced-stage and early-stage patients compared with normal subjects. The positivity rates of HGF in early disease cases were higher than those of CEA and CA19-9. The serum HGF level was significantly higher in patients with vessel invasion than in those without invasion. In smaller early gastric cancers, serum HGF elevation was associated with lymphatic invasion.
The serum HGF level may be a clinically significant tumor marker in patients with early-stage, as well as advanced-stage, gastric cancer. HGF elevation in early-stage patients may help us to predict the risk of lymph node metastasis of early gastric tumors, even of smaller tumor size. HGF may be a useful indicator for appropriate lymphadenectomy in early gastric cancer.
Scandinavian Journal of Gastroenterology 08/2004; 39(8):754-60. · 2.02 Impact Factor
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ABSTRACT: Monocyte chemoattractant protein-1 (MCP-1) has been shown to act as a chemokine in the recruitment of monocyte/macrophages during inflammation states. It acts as an important factor in the cytokine network, which regulates tumor proliferation, whereas the association between serum MCP-1 level and gastric cancer has not yet been clarified.
The serum concentration of MCP-1 in 76 gastric cancer patients and in 45 normal controls was determined using an immunoradiometric assay. The concentration of MCP-1 in the 47 cancer tissue samples was also determined.
The serum concentration of MCP-1 in patients with advanced carcinoma was significantly lower than that in controls. The serum concentration of MCP-1 in patients with advanced carcinoma was significantly lower than that in patients with early carcinoma. The serum concentration of MCP-1 was associated with clinicopathological factors including lymph node metastasis, serosal invasion and histological differentiation of the tumor. In patients who underwent palliative surgery, the serum MCP-1 level significantly decreased postoperatively, whereas in patients who underwent curative surgery the serum MCP-1 level tended to increase. The 4-year survival rate in patients whose serum MCP-1 levels were lower than or equal to the median value was significantly lower than that in patients whose MCP-1 levels were higher than the median value. The tissue concentration of MCP-1 in the cancer tended to decrease in accordance with disease progression.
The serum level of MCP-1 decreased in accord with disease progression, which reflects local consumption in gastric cancer. Serum MCP-1 may be a useful marker that reflects the host's local resistance to the tumor.
Scandinavian Journal of Gastroenterology 08/2002; 37(7):830-3. · 2.02 Impact Factor
