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Biomedical subjects

Soji Ozawa

Publications and source records attributed to Soji Ozawa.

At least 19 recordsLinked to original sources
PubMed2006

Role of steroid administration to reduce inflammation after thoracotomy in a rat surgical stress model.

BACKGROUND: Unilateral lung surgical insult can lead to bilateral pulmonary inflammation after transthoracic esophagectomy for esophageal cancer. An inflammatory response of the cytokine network induced by surgical stress followed by neutrophil sequestration is the major mechanism involved in these complications. We examined modulation of the inflammatory cytokine and neutrophil sequestration by preoperative steroid administration in a rat thoracotomy model. METHODS: Adult male rats were subjected to right thoracotomy with pulmonary compression in the surgical stress model. In the another surgical stress model, 10 mg/kg of methylprednisolone (MP) was administered 1 h before the operation intraperitoneally, and peri-operative biological effects of steroid administration to neutrophil sequestration and cytokine-induced neutrophil chemoattractant (CINC) as an inflammatory cytokine were examined. Sham-operated animals were subjected to intubation only. RESULTS: Surgical insult to the unilateral lung increased local CINC concentration followed by an increase in neutrophil sequestration, wet-to-dry weight ratio in bilateral lungs and systemic CINC concentration. Pre-treatment with methylprednisolone reduced CINC concentration as well as neutrophil sequestration and wet-to-dry weight ratio of both lungs. CONCLUSIONS: These data suggest that inflammatory changes induced by the unilateral operative procedure occur in both lungs through local inflammatory response. Pre-operative methylprednisolone administration down-regulates cytokine release and neutrophil sequestration, preventing lung edema, and possibly may act as a prophylactic treatment against acute lung injury caused by a so-called "second attack" theory.

Animals↗
PubMed2006

Anti-high-mobility group box chromosomal protein 1 antibodies improve survival of rats with sepsis.

BACKGROUND: High-mobility group box chromosomal protein 1 (HMGB1) has recently been shown to be an important late mediator of endotoxin shock, intraabdominal sepsis, and acute lung injury, and a promising therapeutic target of severe sepsis. We sought to investigate the effect of antibodies to HMGB1 on severe sepsis in a rat cecal ligation and puncture (CLP) model. METHODS: Adult male Sprague-Dawley rats underwent CLP and then were randomly divided into two groups: treatment with anti-HMGB1 polyclonal antibodies, and non-immune IgG-treated controls. The serum HMGB1 concentrations were measured at ten time points (preoperatively, and postoperatively at 4, 8, 20, 32, and 48 h and at 3, 4, 5, and 6 days). Hematoxylin-eosin staining, elastica-Masson staining, and immunohistochemical staining for HMGB1 were performed on the cecum and the lung to assess pathological changes 24 h after the CLP procedure. RESULTS: Treatment with anti-HMGB1 antibodies significantly increased survival [55% (anti-HMGB1) vs. 9% (controls); P< 0.01]. The serum HMGB1 concentrations at postoperative hours 20 and 32 of the anti-HMGB1 antibody-treated animals were significantly lower than those of the controls (P < 0.05). Treatment with anti-HMGB1 antibodies markedly diminished the pathological changes and the number of HMGB1-positive cells in the cecum and the lung. CONCLUSIONS: The present study demonstrates that anti-HMGB1 antibodies are effective in the treatment of severe sepsis in a rat model, thereby supporting the relevance of HMGB1 eradication therapy for severe sepsis.

Animals↗
PubMed2006

Antiangiogenic agent SU6668 suppresses the tumor growth of xenografted A-431 cells.

SU6668 is an antiangiogenic agent that acts as a tyrosine kinase inhibitor for the vascular endothelial growth factor (VEGF) receptor. We treated xenografted A-431, a human squamous cell carcinoma cell line, with SU6668 to investigate the efficacy of tumor dormant therapy using angiogenesis inhibitors for patients with squamous cell carcinoma. A-431 cells were transplanted into severe combined immunodeficient (SCID) mice. The treatment group was given SU6668 at a dose of 200 mg/kg orally twice a day for 3 weeks; the control group was given only the vehicle in the same manner and intervals. SU6668 suppressed tumor growth of A-431 cells in the xenograft model. Furthermore, tumor volume and the number of vessels were significantly reduced in the treatment group compared with those of the control. No significant differences in body weight were found between the treatment and control groups, and no toxic reactions occurred during the experiment. We concluded that this agent was safe, efficient and potentially useful for the treatment of patients with squamous cell carcinoma.

Angiogenesis Inhibitors↗
PubMed2005

New endoscopic treatments for gastroesophageal reflux disease.

This article reviews the available endoscopic treatments for gastroesophageal reflux disease (GERD). Plicating gastric folds methods, like Bard's EndoCinch method (Endoscopic Gastroplication, ELGP method), NDO Surgical's Full-thickness Plicator method, and Wilson-Cook Medical's Endoscopic Suturing Device (ESD) method, are used to form new plications in the cardia. Alternatively, thermal tissue remodeling/neurolysis methods, like Curon Medical's Stretta System, can be used to denature the muscular layer of the lower esophageal sphincter (LES) region. Finally, bulking injection methods, like Boston Scientific's Enteryx Procedure and Medtronic's Gatekeeper Reflux Repair System, can be used to insert a foreign body into the LES region. All six methods resulted in the improvement of symptoms and acid reflux, but only the bulking injection methods caused an improvement of the manometric findings. Nevertheless, the improvement of symptoms and acid reflux seems to be much more important than the improvement of the manometric findings. The overall discontinuation of proton-pump inhibitor (PPI) use was about 70%. Thus, endoscopic treatments for GERD are still in the development phase. The efficacy, safety, durability, cost-effectiveness, indications, and possible combination with other treatments must be thoroughly assessed in randomized controlled trials. If the usefulness of endoscopic treatment is confirmed, however, a new minimally invasive treatment strategy for GERD will have been established.

Endoscopy, Gastrointestinal↗
PubMed2005

Expression of basic fibroblast growth factor is associated with a good outcome in patients with squamous cell carcinoma of the esophagus.

Angiogenesis is an essential step in tumor growth and metastasis, but rather than being controlled by means of a simple mechanism, the control of tumor angiogenesis may be mediated by several angiogenic factors. We investigated the expression of basic fibroblast growth factor (b-FGF) and platelet-derived endothelial cell growth factor (PD-ECGF) in squamous cell carcinoma of the esophagus in order to clarify the mechanism of angiogenesis. Expression of b-FGF and PD-ECGF was immunohistochemically investigated in tissue specimens from the tumors of 79 patients with squamous cell carcinoma of the esophagus who underwent curative esophagectomy without preoperative chemotherapy or radiation therapy, and the relationship between expression of b-FGF/PD-ECGF, microvessel density (MVD), and clinicopathological background factors was assessed. Tumor cells that expressed b-FGF were found in 41 patients (51.9%), and tumor cells that expressed PD-ECGF were found in 57 patients (72.2%). Although the mean vascular density (47.9/mm(2)) of b-FGF-positive tumors was significantly lower than that (67.2/mm(2)) of b-FGF-negative tumors (p=0.014), the difference between the 56.0/mm2 in PD-ECGF-positive tumors and 60.3/mm2 in PD-ECGF-negative tumors was not significant. Although the survival rate of patients with b-FGF-positive tumors was significantly higher than those with b-FGF-negative tumors (p=0.033), there was no significant difference between the survival rates of patients with PD-ECGF-positive and -negative tumors (p=0.580). Expression of b-FGF may be associated with promotion of angiogenesis and a good prognostic factor in squamous cell carcinoma of the esophagus.

Adult↗
PubMed2005

TSU-68 (SU6668) inhibits local tumor growth and liver metastasis of human colon cancer xenografts via anti-angiogenesis.

A number of receptor tyrosine kinases (RTKs) are involved in angiogenesis. TSU-68 (SU-6668) was developed as an inhibitor of RTKs involved in VEGF, bFGF and PDGF signaling, which then inhibits endothelial cell proliferation. We investigated the antitumor effects of TSU-68 against human colon cancer xenografts in male SCID mice and its anti-angiogenic activity using a dorsal air-sac (DAS) assay. TSU-68 was administered orally at a dose of 200 mg/kg twice daily. Mice bearing human colon carcinoma, HT-29, or WiDr xenografts were treated for 16 days. To determine the effect on hepatic metastasis, cell suspensions of HT-29 or WAV-I were injected into the spleen of mice on day 0, and mice treated for 28 days starting from day 1. For the DAS assay, HT-29, WiDr or WAV-I cells suspended in PBS at 2 x 10(7) cells/Millipore chamber were implanted subcutaneously into SCID mice, which were then treated from day 0 to 5, On day 6, the anti-angiogenic effects were assessed. Results indicated that TSU-68 significantly inhibited the growth of subcutaneous tumors. In the hepatic metastasis model, liver weights of the TSU-68-treated group were significantly reduced, compared to those of control mice. In the DAS assay, the angiogenic indices of the treated groups were significantly decreased for HT-29, WiDr and WAV-I tumors, with T/C ratios of 13.4, 50 and 35.3%, respectively. As TSU-68 significantly inhibited tumor growth and liver metastasis formation of human colon cancer xenografts, probably through anti-angiogenic activity, this agent may be useful for the treatment of colon cancer.

Administration, Oral↗
PubMed2004

Loss of p16INK4a expression is associated with vascular endothelial growth factor expression in squamous cell carcinoma of the esophagus.

Vascular endothelial growth factor (VEGF) expression has been suggested to correlate with intratumoral microvessel density, tumor advancement and prognosis in esophageal squamous cell carcinoma (ESCC). Previous studies have showed that disruption of cell cycle regulator p16 is related to oncogenesis and tumor progression in ESCC. We hypothesized that VEGF expression in ESCC is reflected by abnormalities in the p16(INK4a) gene. To clarify the regulatory role of p16(INK4a) in VEGF expression in vitro, we transferred the p16(INK4a) gene into a p16(INK4a)-deleted ESCC cell line and observed changes in VEGF expression. Furthermore, we immunohistochemically assessed the expression of the cell cycle regulators (p16, p53 and RB) and VEGF in 90 surgically resected specimens of ESCC. Introduction of p16(INK4a) cDNA by the p16 expression vector significantly suppressed cell proliferation in the p16(INK4a)-deleted cell line TE8 (p < 0.0001). VEGF secretion by TE8 cells transfected with the p16(INK4a) vector was significantly suppressed as compared to non-transfected TE8 cells (p < 0.0001) and TE8 cells transfected with a control vector (p = 0.0015). The immunohistochemical studies of ESCC primary tumor specimens showed that loss of p16 expression was significantly correlated with VEGF-positive expression (p = 0.0004). The cumulative postoperative survival rate in the group with p16-positive and VEGF-negative expression was significantly higher than in the other groups. Neither p53 nor RB expression had any impact on outcome. Aberrant p53 expression tended to be associated with VEGF expression, but the trend did not reach statistical significance. Our study demonstrated that VEGF expression was correlated with p16 expression in ESCC. Our results suggest that p16 may have a regulatory role in VEGF expression in ESCC.

Aged↗
PubMed2004

Significance of metastasis detected by molecular techniques in sentinel nodes of patients with gastrointestinal cancer.

The clinical significance of micrometastasis in sentinel nodes (SNs) may differ in various organs. In particular, the prognostic value of SN micrometastases detected by reverse transcriptase-polymerase chain reaction (RT-PCR) is still controversial. We investigated the diagnostic and therapeutic significance of nodal molecular metastasis detected by nested RT-PCR for cytokeratin (CK) 19 mRNA in gastrointestinal cancer. In 51 cases with GI tract cancer treated by standard curative resection, SNs were identified by a radio-guided method. In 10 of 51 patients, 25 SNs and 3 non-SNs were histologically negative and RT-PCR positive. Three non-SNs with positive CK19 mRNA were randomly sampled from the same basin where histologically positive SNs were identified. Immunohistochemical analysis of six additional step sections obtained at 30- micro m intervals with use of an anticytokeratin antibody showed clearly recognizable histological metastases in 4 of 25 histologically negative/RT-PCR-positive SNs (16%). In one case of esophageal squamous cell carcinoma with nodal micrometastasis identified by CK19 RT-PCR, extranodal local recurrence in the SN basin (left supraclavicular basin) was observed 6 months postoperatively. These findings suggest that nodal micrometastasis detected by nested RT-PCR has some clinical significance in GI cancer. Molecular assessment of the SN may be a valuable tool to complement routine histological examination for GI cancers.

Esophageal Neoplasms↗
PubMed2004

Metachronous gastric carcinoma from a gastric tube after radical surgery for esophageal carcinoma.

BACKGROUND: Cases of metachronous gastric carcinoma arising from a gastric tube used for reconstruction have been increasing in long-term survivors of esophageal cancer in recent years. We investigated the characteristics of gastric tube carcinoma to determine the most appropriate approach to managing it. METHODS: Between 1980 and 1997, 508 patients underwent radical esophagectomy for esophageal carcinoma at Keio University Hospital. Reconstruction was performed with a gastric tube in 414 (81.5%) of them, and 8 of them developed a metachronous carcinoma in the gastric tube. The clinical and pathologic characteristics of the gastric tube carcinomas were evaluated in this study. RESULTS: Gastric cancer was detected during follow-up endoscopic examinations or in an upper gastrointestinal series in seven patients. All of the cancers were diagnosed as adenocarcinoma histopathologically. Endoscopic mucosal resection was performed in two patients, partial resection of the residual stomach was performed in three patients. One patient was treated by endoscopic mucosal resection as palliative therapy, since he had severe pulmonary emphysema. Total resection of the gastric tube was attempted in 2 advanced cases but was unsuccessful because of direct invasion of other organ by the cancer. The 5 patients who underwent curative resection are alive with no subsequent recurrence. CONCLUSIONS: Since early diagnosis permits less invasive treatment and curative treatment is difficult in advanced cases, strict postoperative examinations are important after radical esophagectomy to ensure early detection of metachronous gastric carcinoma arising from gastric tubes used for reconstruction.

Adenocarcinoma↗
PubMed2004

[Endoscopic treatment for gastroesophageal reflux disease].

The endoscopic treatment as a minimally invasive method to gastroesophageal reflux disease (GERD) came to be tried in addition to medication and laparoscopic antireflux surgery. Clinical trials, such as the Endoluminal Gastroplication method, the Full Thickness Plicator method, the Stretta method, the Enteryx method, and the Gatekeeper method, are advancing in the United States and Europe. It is necessary to consider the efficacy, safety, durability, cost effectiveness, an indication, etc. using data from a randomized controlled trial with sufficient observation period. If the usefulness of endoscopic treatment is confirmed in the future, the new minimally invasive strategy over GERD will be established.

Endoscopy, Digestive System↗
PubMed2003

Cell-cycle regulators and the Ki-67 labeling index can predict the response to chemoradiotherapy and the survival of patients with locally advanced squamous cell carcinoma of the esophagus.

BACKGROUND: We investigated whether aberrant p53 and p16 expression, the Ki-67 labeling index (LI), and int-2/cyclin D1 gene amplification predict the response to chemoradiotherapy (CRT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: p53 and p16 expression status, the Ki-67 LI, and int-2/cyclin D1 amplification were assessed by immunohistochemical staining and slot blot analysis in pretreatment endoscopic biopsy specimens of 41 patients with T4 or M1 Lym (distant lymph node metastasis) ESCC. All patients received a course of chemotherapy (5-fluorouracil and cisplatin) with radiotherapy. RESULTS: The CRT therapeutic response rate was 71%, and resection after CRT was successful in 15 of the cases in which the CRT effect was significant. The cumulative survival rate after CRT in the p53-negative patients was significantly higher than in the p53-positive patients (P =.037). The mean Ki-67 LI in the CRT response cases was significantly higher than in the CRT no-response cases (P =.023). Multivariate regression analysis revealed high Ki-67 LI to be an independent variable linked to a pathologic complete response to CRT (P =.033). The cumulative survival rate after CRT in the group that was p53-negative and int-2/cyclin D1 amplification-positive was significantly higher than in the other groups (P =.008). CONCLUSIONS: Evaluating predictive factors in pretreatment endoscopic biopsy specimens may allow selection of more suitable multimodal treatment for ESCC patients and improve their quality of life.

Adenocarcinoma↗
PubMed2003

[Current status and future perspectives of sentinel node navigation surgery for esophageal cancer].

Esophageal cancer is a particularly aggressive malignancy because of the high incidence and widespread distribution of lymph node metastases. However, the sentinel node (SN) concept appears to be applicable even for esophageal cancer, according to recent reports. A dye-guided method is not applicable for esophageal cancer because of its anatomic site. It is impossible to trace the flow of blue dye within a certain observation time without destruction of the lymphatic network. SNs in esophageal cancer are multiple and their distribution is widely spread from the cervical to the abdominal area. Therefore the lymphoscintigram in the radio-guided method is essential to identify the SNs in esophageal cancer. Recently chemoradiotherapy has attracted attention as a multidisciplinary curative treatment for cT1N0 esophageal cancer. In this approach, control of invisible micrometases is essential. Lymphoscintigrams revealing the distribution of SNs in each individual case are useful to plan the field of irradiation. Selective and modified lymphadenectomy for clinical N0 esophageal cancer should become feasible and clinically useful. Individualized selective lymphadenectomy for cN0 esophageal cancer located in the esophagogastric junction including Barrett's carcinoma based on SN status would be a reasonable surgical approach.

Esophageal Neoplasms↗
PubMed2002

Clinical significance of telomerase activity in peripheral blood of patients with esophageal squamous cell carcinoma.

BACKGROUND: The presence of tumor cells in the blood stream is considered evidence of a high risk of distant organ metastasis. We examined the usefulness of telomerase activity in peripheral blood polymorphonuclear cells as an indicator of distant metastasis in patients with esophageal squamous cell carcinoma. METHODS: Telomerase activity was measured in the peripheral blood mononuclear cell and polymorphonuclear cell fractions obtained from blood samples of healthy volunteers mixed with squamous cell carcinoma cell lines, and cell distribution was analyzed by flow cytometry. Then telomerase activity of forty-two polymorphonuclear cell fractions obtained from esophageal squamous cell carcinoma patients was measured. RESULTS: Telomerase activity was detected in polymorphonuclear cell fractions and cell distribution analysis revealed the presence of esophageal squamous cell carcinoma cells. Organ metastasis was detected in 7 (78%) of the 9 patients with telomerase-positive polymorphonuclear cell fractions as opposed to only five (15%) of the 33 with telomerase-negative cases, and there was a significant positive correlation between telomerase activity and organ metastasis (p < 0.0008). CONCLUSIONS: Measurement of telomerase activity in the polymorphonuclear cell fractions is useful for identifying a high risk group for distant organ metastasis in patients with esophageal squamous cell carcinoma.

Aged↗
PubMed2002

Intraoperative lymphatic mapping and sentinel lymph node sampling in esophageal and gastric cancer.

Recent studies for SN mapping of esophageal and gastric carcinoma show that the SN concept is valid even for upper GI cancers with multidirectional and complicated lymphatic flow. The relatively high incidence of anatomic skip metastasis can be attributed to aberrant distribution of SNs. An individualized and minimally invasive surgical approach can be applicable to management of esophageal and gastric carcinoma based on SN status. Although there are several issues to be resolved, this novel procedure has the potential for great benefit to improve quality control in the treatment of upper GI cancer. Well-designed clinical trials of lymphatic mapping for upper GI cancer will be essential to determine whether this technique is widely applicable in the management of these tumors.

Esophageal Neoplasms↗
PubMed2002

[Molecular alterations in esophageal cancer].

The clinicopathological characteristics of esophageal cancer have gradually been clarified using molecular biologic methods developed over the past 20 years. For example, amplification of the c-erb B gene is a prognostic factor and predictive of lymph node involvement, while the amplification of the cyclin D1 gene is also a prognostic factor and predictive of distant organ metastasis. Alteration of the p16 gene is also a prognostic factor and predicts lymph node involvement. As telomerase activity is almost a unique phenomenon of cancer cells, highly sensitive detection of esophageal cancer cells in the peripheral blood can be performed. Recently, such new methods as comparative genomic hybridization analysis and cDNA microarray analysis have been used to determine meaningful genetic changes. For therapeutic purposes, although tailor-made therapy has been proposed for several years, the validity of these approaches should be confirmed in a well-designed clinical trial. As molecular targeted therapies, tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR) and monoclonal antibodies against EGFR are being studied in clinical trials in Western countries. A clinical trial of p53 gene therapy against esophageal cancer is also promising.

Cyclin D1↗