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Hiroyuki Kuwano

Publications and source records attributed to Hiroyuki Kuwano.

At least 19 recordsLinked to original sources
PubMed2007

Enforced expression of Bcl-2 partially restores cell numbers but not functions of TCRgammadelta intestinal intraepithelial T lymphocytes in IL-15-deficient mice.

IL-15 knockout (KO) mice have severely reduced numbers of TCRgammadelta intestinal intraepithelial T lymphocytes (i-IEL), suggesting requirements of IL-15 signaling in the development or maintenance of i-IEL. To determine an involvement of survival signals via Bcl-2 in IL-15-mediated homeostasis of TCRgammadelta i-IEL, we introduced a bcl-2 transgene into IL-15 KO mice. In situ apoptosis of TCRgammadelta i-IEL was decreased in Bcl-2 transgenic (Tg) x IL-15 KO mice compared with IL-15 KO mice. The enforced expression of Bcl-2 partially restored the numbers of TCRgammadelta i-IEL in IL-15 KO mice. However, effector functions of TCRgammadelta i-IEL, including cytokine production and cytotoxic activity, were not recovered in Bcl-2 Tg x IL-15 KO mice. Importantly, TCRgammadelta i-IEL in Bcl-2 Tg x IL-15 KO mice expressed a reduced level of eomesodermin, a transcription factor critical for effector functions of NK cells and CD8(+) T cells. Similar to the case of TCRgammadelta i-IEL, enforced expression of Bcl-2 restored the numbers but not the functions of NK cells in IL-15 KO mice. These results suggest that Bcl-2-mediated survival signal is involved in the IL-15-mediated homeostasis of TCRgammadelta i-IEL and NK cells, but other signals from IL-15 are critical for inducing transcription factors, such as eomesodermin for their effector functions.

Animals↗
PubMed2007

Prognostic significance of EpCAM expression in human esophageal cancer.

EpCAM is a 40-kDa epithelial transmembrane glycoprotein that has a well-known role in Ca2+ -independent homophilic cell-cell adhesion. Recently, correlations between EpCAM expression and clinicopathological features have been investigated in various cancers. We examined EpCAM expression in surgical specimens from esophageal cancer patients (n = 138), using real-time RT-PCR, immunohistochemistry and ELISA. The mean expression level of EpCAM mRNA in tumor tissues was significantly higher than that in corresponding normal tissues (P < 0.0001). Immunohistochemically, positive staining for EpCAM was found in 135 (97.8%) of the 138 primary tumor specimens. EpCAM expression was correlated with tumor depth (P = 0.0005), stage (P = 0.0037), blood-vessel invasion (P = 0.0397) and infiltrative growth pattern (P = 0.0015). The survival rates of patients with tumors with high EpCAM expression was significantly higher than those for patients with tumors with low EpCAM expression (P = 0.0213). Furthermore, the serum EpCAM levels of patients with esophageal cancer were significantly higher than those of normal volunteers (P = 0.0221). The survival rates of patients with a high EpCAM level in the peripheral vein were also significantly higher than those for patients with a low serum EpCAM level (P = 0.0291). The serum EpCAM level in the peripheral vein was independently associated with prognosis (P = 0.0074; hazard ratio 7.40). Tumor-specific EpCAM expression and release into the circulation may serve as effective immunotherapy in esophageal cancer patients.

Aged↗
PubMed2006

Expression of carbohydrate antigens in human esophageal squamous cell carcinoma: prognostic application and its diagnostic implications.

BACKGROUND: Tumor markers whose antigenic determinants have been demonstrated to consist of carbohydrates are probably one of the most extensive tools that have been used in routine cancer diagnosis. In this study, the relevance of carbohydrate antigen expression profile was examined in esophageal squamous cell carcinoma together with prognosis in 130 patients. METHODS: The expression of carbohydrate antigens was estimated immunohistochemically by anti-sialyl Lewis a (sialyl Le(a)) and anti-sialyl Lewis x (sialyl Le(x)) monoclonal antibodies, and correlation between their staining and clinicopathological status was examined. In addition, the correlation of both carbohydrate antigens expression was evaluated with microvessel density (MVD). RESULTS: Expressions of sialyl Lewis antigens and MVD were associated with several clinicopathological features that reflect the tumor aggressiveness in esophageal cancer. The 5-year survival rate of patients was found to be associated with expression of sialyl Le(a) and sialyl Le(x) antigens and with MVD; thus, all of them were revealed to be independent prognostic factors. CONCLUSIONS: Combination of these factors offered a better prediction of prognosis of esophageal squamous cell carcinoma. Further, carbohydrate antigens represent a promising target for therapeutic approaches against the disease.

Aged↗
PubMed2006

Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib.

PURPOSE: Non-small cell lung cancers carrying activating mutations in the gene for the epidermal growth factor receptor (EGFR) are highly sensitive to EGFR-specific tyrosine kinase inhibitors. However, most patients who initially respond subsequently experience disease progression while still on treatment. Part of this "acquired resistance" is attributable to a secondary mutation resulting in threonine to methionine at codon 790 (T790M) of EGFR. EXPERIMENTAL DESIGN: We sequenced exons 18 to 21 of the EGFR gene to look for secondary mutations in tumors with acquired resistance to gefitinib in 14 patients with adenocarcinomas. Subcloning or cycleave PCR was used in addition to normal sequencing to increase the sensitivity of the assay. We also looked for T790M in pretreatment samples from 52 patients who were treated with gefitinib. We also looked for secondary KRAS gene mutations because tumors with KRAS mutations are generally resistant to tyrosine kinase inhibitors. RESULTS: Seven of 14 tumors had a secondary T790M mutation. There were no other novel secondary mutations. We detected no T790M mutations in pretreatment specimens from available five tumors among these seven tumors. Patients with T790M tended to be women, never smokers, and carrying deletion mutations, but the T790M was not associated with the duration of gefitinib administration. None of the tumors had an acquired mutation in the KRAS gene. CONCLUSIONS: A secondary T790M mutation of EGFR accounted for half the tumors with acquired resistance to gefitinib in Japanese patients. Other drug-resistant secondary mutations are uncommon in the EGFR gene.

Amino Acid Sequence↗
PubMed2006

Nonendothelial mesenchymal cell-derived MCP-1 is required for FGF-2-mediated therapeutic neovascularization: critical role of the inflammatory/arteriogenic pathway.

OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1) is a C-C chemokine that is known as an inflammatory/arteriogenic factor. Angiogenesis contributes to the inflammatory process; however, the molecular and cellular mechanisms of the links among the inflammatory pathway, arteriogenesis, and angiogenesis have not been well elucidated. METHODS AND RESULTS: Using murine models of fibroblast growth factor-2 (FGF-2)-mediated therapeutic neovascularization, we here show that FGF-2 targets nonendothelial mesenchymal cells (NEMCs) enhancing both angiogenic (vascular endothelial growth factor [VEGF]) and arteriogenic (MCP-1) signals via independent signal transduction pathways. Severe hindlimb ischemia stimulated MCP-1 expression that was strongly enhanced by FGF-2 gene transfer, and a blockade of MCP-1 activity via a dominant negative mutant as well as a deficiency of its functional receptor CCR2 resulted in the diminished recovery of blood flow attributable to adaptive and therapeutic neovascularization. Tumor necrosis factor (TNF)-alpha stimulated MCP-1 expression in all cell types tested, whereas FGF-2-mediated upregulation of MCP-1 was found only in NEMCs but not in others, a finding that was not affected by VEGF in vitro and in vivo. CONCLUSIONS: These results indicate that FGF-2 targets NEMCs independently, enhancing both angiogenic (VEGF) as well as inflammatory/arteriogenic (MCP-1) pathways. Therefore, MCP-1/CCR2 plays a critical role in adaptive and FGF-2-mediated therapeutic neovascularization.

Adaptation, Physiological↗
PubMed2006

Lack of activated Smad2 in transforming growth factor-beta signaling is an unfavorable prognostic factor in patients with esophageal squamous cell carcinoma.

BACKGROUND AND OBJECTIVES: Transforming growth factor-beta (TGF-beta) regulates cell growth in various cells, and inactivation of the TGF-beta-signaling pathway contributes to tumor progression. In this study, we investigated the expression of Smad2 and Smad3, which are specific intracellular mediators of TGF-beta signaling. We also examined the relationship between the expression levels of activated Smad2 by TGF-beta and clinicopathologic characteristics of patients with esophageal squamous cell carcinoma (SCC). METHODS: Immunohistochemical staining with anti-phosphorylated Smad2 (P-Smad2) polyclonal antibody, anti-Smad2 monoclonal antibody, and anti-Smad3 polyclonal antibody was performed on surgical specimens obtained from 80 patients with esophageal SCC. RESULTS: Our data indicated that a low level of P-Smad2, as detected immunohistologically, correlated with lymph node metastasis (P = 0.0002), distant metastasis (P = 0.0338), pathologic stage (P = 0.0093), and poor survival rate (P = 0.0246). All patients without positive Smad2 immunostaining were included among those without positive P-Smad2 immunostaining. There was no significant correlation between expression of Smad2 or Smad3 and clinicopathologic characteristics. CONCLUSIONS: We demonstrated that a lack of Smad2-P appears to be correlated with tumor development and poor prognosis in patients with esophageal SCC.

Adult↗
PubMed2006

Matrilsin expression is a useful marker of submucosal invasion and lymph node metastasis in early stage signet ring cell carcinoma of the stomach.

BACKGROUND: Matrilysin (MMP-7) is considered to play an important role in tumor progression and metastasis. The aim of this study was to examine the MMP-7 expression of early-stage undifferentiated gastric carcinoma, and to investigate differences between gastric signet ring cell (SIG) and other undifferentiated carcinomas (non-SIG). METHODS: Immunohistochemical staining of MMP-7 was performed using specimens from 150 patients with early-stage gastric undifferentiated carcinomas (76 SIG, 74 non-SIG). RESULTS: SIG had a larger proportion of mucosal-confined carcinoma and a lower rate of lymphatic invasion than non-SIG (P < 0.05). The incidence of the positive expression of MMP-7 in submucosal SIG was significantly higher than that of mucosal SIG (P < 0.01). In contrast, MMP-7 expression was frequently found in mucosal non-SIG, suggesting an apparent difference in the invasiveness between mucosal SIG and non-SIG. The larger the size of the mucosal SIG, the more frequently MMP-7 positive expression was demonstrated (P < 0.05). There was a significant correlation between MMP-7 positive expression and lymph node metastasis of early SIG (P < 0.05). CONCLUSION: Early SIG revealed less invasiveness than non-SIG in terms of clinicopathologic features and MMP-7 expression. Preoperative estimation of the MMP-7 expression might be useful as a predictor of submucosal invasion and lymph node metastasis in early SIG.

Adult↗
PubMed2006

Living-related liver transplantation for multiple liver metastases from rectal carcinoid tumor: a case report.

A 42-year-old woman was admitted to our hospital because of multiple liver tumors detected by ultrasonography. Colonoscopy revealed submucosal tumor in the rectum, which was considered the primary lesion. Endoscopic mucosal resection followed by histopathological examination revealed that the tumor was carcinoid. The resected margin of the tumor was positive for malignant cells. Two courses to transcatheter arterial chemotherapy for liver metastasis were ineffective. Accordingly, the rectal tumor and metastatic lymph nodes were surgically resected. One month after the operation, she received liver transplantation (left lateral segment and caudate lobe) from her son. No recurrent lesion has been observed at two years after the liver transplantation. Liver transplantation should be considered as a treatment option even in advanced case of carcinoid metastasis to the liver. We also discuss the literature on liver transplantation for metastatic carcinoid tumor.

Adult↗
PubMed2006

Hepatic adenomatosis associated with hormone replacement therapy and hemosiderosis: a case report.

We have reported a case of hepatic adenomatosis associated with hormone replacement therapy (estrogen and progesterone) and hemosiderosis caused by excessive blood transfusion for the treatment of chronic myeloid leukemia. A 34-year-old woman was found to have several hepatic tumors on a routine medical examination. The general condition was good. Laboratory studies showed iron overload. Abdominal computed tomography and selective hepatic angiography showed several hypervascular tumors in the right lobe of the liver (up to 20 mm in diameter). Since hepatocellular carcinoma could not be ruled out, subsegmental hepatectomy was performed. Histopathological examination of the surgical specimen showed hepatic adenomatosis with hemosiderosis. Both hormone replacement therapy and iron overload could be the cause of hepatic adenomatosis.

Adenoma↗
PubMed2006

IL-15 regulates CD8+ T cell contraction during primary infection.

During the course of acute infection with an intracellular pathogen, Ag-specific T cells proliferate in the expansion phase, and then most of the T cells die by apoptosis in the following contraction phase, but the few that survive become memory cells and persist for a long period of time. Although IL-15 is known to play an important role in long-term maintenance of memory CD8+ T cells, the potential roles of IL-15 in CD8+ T cell contraction are not known. Using an adoptive transfer system of OT-I cells expressing OVA257-264/Kb-specific TCR into control, IL-15 knockout (KO) and IL-15 transgenic (Tg) mice followed by challenge with recombinant Listeria monocytogenes expressing OVA, we found that the survival of CD44+CD62L-CD127- effector OT-I cells during the contraction phase is critically dependent on IL-15. In correlation with the expression level of Bcl-2 in OT-I cells, the number of OT-I cells was markedly reduced in IL-15 KO mice but remained at a high level in IL-15 Tg mice during the contraction phase, compared with control mice. In vivo administration of rIL-15 during the contraction phase in IL-15 KO mice inhibited the contraction of effector OT-I cells accompanied by up-regulation of Bcl-2 expression. Furthermore, enforced expression of Bcl-2 protected the majority of effector OT-I cells from death in IL-15 KO mice after infection. These results suggest that IL-15 plays a critical role in protecting effector CD8+ T cells from apoptosis during the contraction phase following a microbial infection via inducing antiapoptotic molecules.

Adoptive Transfer↗
PubMed2006

Factors predicting long-term responses to splenectomy in patients with idiopathic thrombocytopenic purpura.

BACKGROUND: Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder for which appropriate diagnostic treatments are uncertain. The response to splenectomy varies from 60% to 90%, and the remaining patients relapse and require further treatment. Therefore, it is important to predict the outcome of splenectomy before and after surgery. The objective of this study was to evaluate the efficacy of splenectomy in patients diagnosed with ITP. MATERIALS AND METHODS: From 1988 to 2004, we splenectomized 32 patients with ITP; 17 underwent laparoscopic splenectomy (LS) and 15 underwent conventional open splenectomy (OS). For analysis, patients were separated retrospectively into two groups: the "responding group," those who showed good outcomes with splenectomy, and the "non-responding group," those who did not show good outcomes with splenectomy. Blood samples were examined before and immediately after surgery (day 0) and on postoperative days (POD) 1, 3, 5, and 7. RESULTS: The median follow-up was 8.3 years (range: 1-16 years). The overall 5- and 10-year survival rates after splenectomy were 96.9% (one death). The responding group included 24 patients (75%), and the non-responding group included 7 (21.9%). Platelet counts in the responding group increased gradually until POD 7, and although platelet counts in the non-responding group were almost constant until POD 5, they subsequently decreased until POD 7. Average platelet counts in the responding and non-responding groups were 269 and 124 x 10(9)/l on POD 7, respectively (P < 0.05). The pre- to post-surgery ratio of platelet counts were almost the same as the result of the actual data. Platelet counts during the long-term follow-up for the responding and non-responding groups were related to those noted on discharge. CONCLUSIONS: A high platelet count on POD 7 was associated with a good response to splenectomy, but age at surgery, the time interval between diagnosis and splenectomy, and prior responses to corticosteroid were not. We suggest that long-term outcomes of splenectomy can easily be predicted by platelet counts on POD 7.

Adolescent↗
PubMed2006

Factors associated with the development of reflux esophagitis after Helicobacter pylori eradication.

We investigated whether Helicobacter pylori (HP) eradication increases the incidence of reflux esophagitis (RE) in patients with peptic ulcers. From 2001-2005 consecutive out patients with peptic ulcers and HP received eradication and were followed endoscopically. HP was cured in 119 and RE developed in 33 of the 153 patients. RE developed in 24 of the 119 HP-eradicated patients and 9 of the 34 HP-persistent patients. The estimated RE occurrence rate within 1 year was higher in the HP-eradicated patients than in the HP-persistent patients, but it was reversed at 2 years by the Kaplan-Meier analysis. In 76 patients follow up for > or = 18 months, hiatal hernia, duodenal ulcer, and eradication failure were significantly associated with the increased RE rate by univariate and multivariate analysis. The follow-up period after HP eradication affected the RE occurrence rate, and eradication failure significantly increased the RE development in patients followed up for > or = 18 months.

Adult↗
PubMed2006

Sentinel lymph node mapping with technetium-99m colloidal rhenium sulfide in patients with gastric carcinoma.

BACKGROUND: The objective of this study was to determine, with the use of technetium-99m colloidal rhenium sulfide, whether the concept of sentinel lymph nodes (SLNs) is applicable to gastric cancers. METHODS: Fifty-nine gastric cancer patients underwent radical gastrectomy and SLN mapping with an intraoperative hand-held gamma probe. After surgery, each transected lymph node was measured for radioisotope (RI) activities by a well-type scintillation counter. RESULTS: SLNs were detectable in 57 (96%) of 59 patients. The sensitivity, specificity, and diagnostic accuracy were calculated to be 83.3%, 100%, and 92.9%, respectively. Sensitivity was 100% in the T1 group, 91.6% in the T2 group, and 62.5% in the T3 group. When RI activities were measured with a well-type scintillation counter, every metastatic non-SLN was found to be situated in the same lymphatic basin as the SLNs. CONCLUSION: The SLN concept is applicable to patients with early gastric cancer (T1). SLN mapping is suitable for identifying the lymphatic basin in cases of gastric cancer.

Adenocarcinoma↗
PubMed2006

A novel technique to facilitate laparoscopic repair of large paraesophageal hernias.

BACKGROUND: Laparoscopic repair of large paraesophageal hernias (LPEH) is technically challenging, and requires advanced laparoscopic skills. We have developed a novel technique for facilitating laparoscopic repair of LPEHs safely and easily, using a Nelaton catheter. PATIENTS AND METHODS: Seven patients with LPEHs were operated on through a laparoscopic approach. During surgery, the left lobe of the liver and right diaphragmatic crus were elevated using a suspended thread covered by a Nelaton catheter. RESULTS: All patients were operated on laparoscopically using this technique. No patient required conversion to open method. The median operating time was 205 minutes and the range was from 155 to 295 minutes. No intraoperative or early complications occurred in any patient. Late complications occurred in 2 patients due to a small sliding hernia: a slipped fundoplication in 1 patient, and a gastric ulcer in the other. CONCLUSIONS: In conclusion, laparoscopic repair of LPEH is a challenging procedure that requires wide experience in laparoscopic gastroesophageal surgery. Further refinement for this operation may be necessary.

Aged↗
PubMed2006

The synchronization of chemotherapy to circadian rhythms and irradiation in pre-operative chemoradiation therapy with hyperthermia for local advanced rectal cancer.

PURPOSE: The therapeutic and adverse effects of pre-operative chrono-chemoradiation with local hyperthermia for patients with rectal adenocarcinoma were evaluated. MATERIALS AND METHODS: Pre-operative radiation therapy of a total dose of 40 Gy (n = 10) or 50 Gy (n = 19) on the whole pelvis and hyperthermia once a week during the radiation therapy for 1 h were performed for patients with T2-T4 rectal adenocarcinoma. Chemotherapy consisted of 5-FU (250 mg m-2 per day) and LV (25 mg m-2 per day) administered by continuous infusion in the night for 5 days a week in the second and fourth weeks of radiation. RESULTS: Grade 3+ toxicities were seen only in two patients (6.9%). A significant down staging was seen in 41.4% of all cases and 52.6% of cases with a radiation dose of 50 Gy. Of the patients who had received surgical resection of a tumour, three (11.1%) had no residue pathologically in the specimen and eight (29.6%) had microscopic lesions. CONCLUSIONS: These results yielded a high response rate with minimal toxicities for advanced low-rectal adenocarcinoma. The administration of 5-FU during the sleeping time before irradiation might have an advantage not only as a chronotherapy but also as a radiation sensitizer.

Adenocarcinoma↗
PubMed2006

A phase I radioimmunolocalization trial of humanized monoclonal antibody huA33 in patients with gastric carcinoma.

In order to determine the in vivo characteristics of huA33, an open label dose escalation biopsy-based phase I clinical trial and radioimmunolocalization study were conducted with a complement determinant region-grafted humanized monoclonal antibody against the A33 antigen in patients with gastric carcinoma. Thirteen patients were entered onto one of four dose levels (1.0, 2.0, 5.0 or 10.0 mg/m(2)). Patients with locally advanced (UICC-TNM [International Union Against Cancer-tumor, node, metastasis] stage over 2 but resectable at clinical diagnosis) gastric carcinoma received a single infusion of (131)I-huA33 1 week prior to surgery. Adverse events were monitored, and imaging studies with gamma camera plus ex vivo scintigraphy of the resected specimen, biodistribution study by dosimetry analysis of the biopsied and resected tissues, and immunohistochemical analysis were carried out and evaluated. No dose-limiting toxicity was observed during the trial. Therefore, the maximum tolerated dose was not reached. Although cancer tissues with + intensity and <25% extent by immunostaining in biopsied frozen sections did not show positive imaging or postoperative dosimetry findings, cancers with ++ or +++ intensity or wide (>25%) extent by frozen and paraffin sections in the biopsied specimen showed positive ex vivo tumor images and positive antigen expression in resected gastric cancer specimens, and the biodistribution analysis showed tumor uptake of (131)I-huA33. In conclusion, humanized monoclonal antibody huA33 demonstrated selective localization to gastric cancer that expressed A33 antigen strongly. These excellent targeting characteristics of huA33 indicate potential for targeted therapy of advanced gastric cancer that is refractory to cytotoxic therapy, and could also be exploitable for curatively resected early gastric cancer in an adjuvant setting.

Aged↗
PubMed2006

Expression of Foxp3 in non-small cell lung cancer patients is significantly higher in tumor tissues than in normal tissues, especially in tumors smaller than 30 mm.

Active suppression by CD4+CD25+ T regulatory cells (T regs) plays an important role in the down-regulation of T cell responses to foreign and self-antigens. Thus far, the potential role of T regs in human tumors has been reported. T reg-mediated suppression of antitumor immune responses may partly explain the poor clinical response to vaccine-based immunotherapy for human cancer. The forkhead transcription factor Foxp3 is a critical regulator of T regs development and function. Foxp3 represents a specific marker for the T regs. In this study, we measured the Foxp3 mRNA expression in tumors and in normal tissues from 46 patients with non-small cell lung carcinoma (NSCLC), and tumor tissues showed a significantly higher expression of Foxp3 mRNA than normal tissues. The expression of Foxp3 mRNA and the tumor diameter were inversely proportional. These results suggest that T regs expressing Foxp3 selectively accumulate in tumor tissues of NSCLC and contribute to antitumor immune dysfunction, especially in the early stages.

Adult↗