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Biomedical subjects

I Yoshino

Publications and source records attributed to I Yoshino.

At least 19 recordsLinked to original sources
PubMed2006

A case of an inflammatory myofibroblastic tumor in the lung which expressed TPM3-ALK gene fusion.

We herein describe a 4-year-old boy who after being treated for pneumonia showed an abnormal shadow at the hilus of the right lung on chest X-rays with continued inflammatory findings in his laboratory data. CT and MR investigations suggested the existence of a neoplasm at that site. An open biopsy was thus performed for a definite diagnosis. The histological findings and the expression of TPM3-ALK fusion gene confirmed a diagnosis of an inflammatory myofibroblastic tumor. A right upper and middle lobectomy including the tumor was thus performed for a complete resection. In addition to the histological diagnosis, the detection of the tumor specific fusion gene provided objective evidence in making a diagnosis.

Anaplastic Lymphoma Kinase↗
PubMed2005

Essential role of Shp2-binding sites on FRS2alpha for corticogenesis and for FGF2-dependent proliferation of neural progenitor cells.

Mammalian corticogenesis occurs through a complex process that includes neurogenesis, in which neural progenitor cells proliferate, differentiate, and migrate. It has been reported recently that neurogenesis occurs in the subventricular zone (SVZ), a region previously thought to be the primary site of gliogenesis. It has been recognized that in the SVZ, intermediate progenitor cells, derived from radial glial cells that are multipotent neural stem cells, produce only neurons. However, the molecular mechanisms underlying the regulation of neural stem cells and intermediate progenitor cells as well as their contribution to overall corticogenesis remain unknown. The docking protein FRS2alpha is a major mediator of signaling by means of FGFs and neurotrophins. FRS2alpha mediates many of its pleiotropic cellular responses by recruiting the adaptor protein Grb2 and the protein tyrosine phosphatase Shp2 upon ligand stimulation. Here, we report that targeted disruption of Shp2-binding sites in FRS2alpha leads to severe impairment in cerebral cortex development in mutant mice. The defect in corticogenesis appears to be due at least in part to abnormalities in intermediate progenitor cells. Genetic evidence is provided that FRS2alpha plays critical roles in the maintenance of intermediate progenitor cells and in neurogenesis in the cerebral cortex. Moreover, FGF2-responsive neurospheres, which are cell aggregates derived from neural stem/progenitor cells (NSPCs), from FRS2alpha mutant mice were smaller than those of WT mice. However, mutant NSPCs were able to self-renew, demonstrating that Shp2-binding sites on FRS2alpha play an important role in NSPC proliferation but are dispensable for NSPC self-renewing capacity after FGF2 stimulation.

Animals↗
PubMed2004

Tyrosine phosphorylation sites on FRS2alpha responsible for Shp2 recruitment are critical for induction of lens and retina.

Early development of the lens and retina depends upon reciprocal inductive interactions between the embryonic surface ectoderm and the underlying neuroepithelium of the optic vesicle. FGF signaling has been implicated in this signal exchange. The docking protein FRS2alpha is a major mediator of FGF signaling by providing a link between FGF receptors (FGFRs) and a variety of intracellular signaling pathways. After FGF stimulation, tyrosine-phosphorylated FRS2alpha recruits four molecules of the adaptor protein Grb2 and two molecules of the protein tyrosine phosphatase Shp2, resulting in activation of the Ras/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3 kinase/Akt signaling pathways. In this report, we explore the role of signaling pathways downstream of FRS2alpha in eye development by analyzing the phenotypes of mice that carry point mutations in either the Grb2-(Frs2alpha(4F)) or the Shp2-binding sites (Frs2alpha(2F)) of FRS2alpha. Although Frs2alpha(4F/4F) mice exhibited normal early eye development, all Frs2alpha(2F/2F) embryos were defective in eye development and showed anophthalmia or microphthalmia. Consistent with the critical role of FRS2alpha in FGF signaling, the level of activated extracellular signal-regulated kinase in Frs2alpha(2F/2F) embryos was significantly lower than that observed in wild-type embryos. Furthermore, expression of Pax6 and Six3, molecular markers for lens induction, were decreased in the Frs2alpha(2F/2F) presumptive lens ectoderm. Similarly, the expression of Chx10 and Bmp4, genes required for retinal precursor proliferation and for lens development, respectively, was also decreased in the optic vesicles of Frs2alpha(2F/2F) mice. These experiments demonstrate that intracellular signals that depend on specific tyrosine residues in FRS2alpha lie upstream of gene products critical for induction of lens and retina.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Airway-directed gene transfer of interleukin-10 using recombinant Sendai virus effectively prevents post-transplant fibrous airway obliteration in mice.

Bronchiolitis obliterans (BO) after lung transplantation prevents a satisfactory prognosis, and recent studies suggested that interleukin-10 (IL-10) gene transfer to distant organs could inhibit BO in rodent models. Although delivery of the therapeutic gene to a local airway would be favored to minimize systemic effects, current limitations include lower gene transfer efficiency to airway epithelium. As recombinant Sendai virus (SeV) can produce dramatically efficient gene transfer to airway epithelium, we determined if SeV-mediated IL-10 gene transfer to the local airway would inhibit bronchial fibrous obliteration in murine tracheal allografts. Administration of cyclosporine A (CsA) significantly promoted not only recovery of the injured airway epithelium but also SeV-mediated IL-10 expression (CsA- versus CsA+ =228+/-78 versus 3627+/-1372 pg/graft with 5 x 10(7) pfu), thereby suggesting the requirement of epithelia for efficient gene transfer. Even at the highest expression, no significant leakage of IL-10 was evident in the systemic circulation, and the induction of interferon-gamma was completely diminished on day 7 by IL-10 gene transfer. As a result, luminal loss was significantly prevented in allografts treated with SeV-IL-10 (luminal opening, all control groups: 0% respectively, and SeV-IL-10 5 x 10(7) pfu: 25.7+/-10.5%), an effect that was enhanced by short-term CsA treatment (SeV-IL-10 5 x 10(7) pfu with CsA: 63.7+/-12.7%). We propose that SeV is a useful vector that can target airway epithelium to prevent BO avoiding putative systemic effect.

Animals↗
PubMed2001

Unique minithoracotomy assisted by videothoracoscopy facilitates a maximal view even with a minimal wound for resection of primary lung cancer.

Resection for primary lung cancer with an unique minithoracotomy and use of videothoracoscopy is described. Through an incision of approximately 10 cm at an ausculatory triangle, the 5th intercostal thoracotomy is done following dissection of muscles. At the anterior and posterior portion of the 6th rib, the 6th intercostal vessels and nerve were dissected and the rib was resected. This approach makes feasible opening of a thoracic window without injury to the nerve and removal of the rib. Thoracoscopy is introduced through a midaxillary wound of 2 cm. We report nine patients in whom we achieved resection for primary lung cancer by using this approach. This technique facilitates a standard operation for lung cancer and an almost painless postoperative state.

Adult↗
PubMed2001

Heterogeneous distribution of P53 immunoreactivity in human lung adenocarcinoma correlates with MDM2 protein expression, rather than with P53 gene mutation.

Although the tumor suppressor p53 protein (P53) immunoreactivity and its gene (p53) mutation were reported to be significant prognostic indicators for human lung adenocarcinomas, little is known regarding the relationship between the heterogeneous distribution of P53 and its genetic status in each tumor focus and the clinicopathological significance. To determine how P53 is heterogeneously stabilized in patients, we compared P53 expression to both the p53 allelic mutation in exon 2 approximately 9 by polymerase chain reaction-single strand conformation polymorphism using microdissected DNA fractions, and the immunohistochemical MDM2 expression. Of the 48 positive to P53 in 118 lung adenocarcinomas examined, 10 with heterogeneous P53 expression were closely examined. The higher P53 expression foci in 7 of 10 cases were less differentiated, histologically in respective cases, and were frequently associated with fibrous stroma. Two had genetic mutations in exon 7 of the p53 gene in both the high and low P53 expression foci of cancer tissue indicating no apparent correlation between heterogeneous P53 expression and the occurrence of gene mutation. Immunohistochemical expression of MDM2 was significantly lower in high P53 expression areas (p < 0.05, the mean labeling indices of high and low P53 expression areas being 4.2 +/- 5.4% and 13.6 +/- 12.2%, respectively). In addition, among all the 118 cases examined, MDM2 expression was significantly suppressed in cases of p53 gene mutation, simultaneously with P53 overexpression, as compared with cases without both the p53 mutation and expression (p < 0.001). These findings suggest that the heterogeneous stabilization of P53 in human lung adenocarcinomas could be partly due to suppressed MDM2 expression. The overexpression of non-mutated P53 may afford a protective mechanism in human lung adenocarcinomas.

Adenocarcinoma↗
PubMed2001

Expression of tumor-associated antigen RCAS1 correlates significantly with poor prognosis in nonsmall cell lung carcinoma.

BACKGROUND: RCAS1 is a recently discovered antigen molecule expressed on the membrane of cancer cells, and it acts as a ligand for a putative receptor present on immune cells such as T, B and NK cells. It has been suggested that RCAS1 expression is related to the escape of tumors from immune surveillance. In this study, the relation between RCAS1 expression and various clinicopathologic variables, including patient prognosis, was investigated in lung carcinoma through immunohistochemical analysis. METHODS: One hundred two surgically resected nonsmall cell lung carcinoma cases were examined histopathologically by means of the monoclonal antibody 22-1-1, which is specific for RCAS1. The correlation between RCAS1 expression and the clinicopathologic features of patients was evaluated. Moreover, the correlation between RCAS1 expression and the survival of patients was analyzed by the Kaplan-Meier method log-rank test, and multivariate analysis was performed by using the Cox proportional hazard model. RESULTS: The samples of 48 of the 102 lung carcinoma patients (47.1%) were positive for RCAS1. There were significant correlations between RCAS1 expression and either pathologic staging (P = 0.0003) or tumor differentiation (P = 0.0308). The survival time for the RCAS1-positive group was significantly shorter than that for RCAS1-negative group (P < 0.0001). Moreover, multivariate analysis for overall survival revealed that RCAS1 expression was a significantly independent prognostic factor in nonsmall cell lung carcinoma patients. CONCLUSION: These results suggested that RCAS1 expression may play an important role in the immune escape mechanism and that RCAS1 expression may be a good indicator of poor prognosis in patients with nonsmall cell lung carcinoma.

Adult↗
PubMed2001

Lung cancer in patients younger than 40 years of age.

BACKGROUND AND OBJECTIVES: We investigated whether the clinicopathologic characteristics and prognosis of lung cancer in younger patients differ from those of older patients. METHODS: Among 2,763 lung cancer patients treated during the period from April of 1972 to April of 1997, we retrospectively investigated the clinical features and prognosis of 53 patients under 40 years of age (young group) and compared them with the findings of 1,886 patients with 60 years of age or older (elderly group). RESULTS: The proportion of female patients in the younger group was significantly higher than that in the elderly group (39.6% vs. 24.1%). The young group had a significantly higher proportion of adenocarcinoma (75.5% vs. 44.8%) and stage III-IV disease (73.6% vs. 59.2%) and a significantly lower proportion of squamous cell carcinoma (3.8% vs. 32.1%). Regarding the selection of therapy, in the young group, a significantly lower proportion of patients underwent surgical therapy (35.8% vs. 41.5%) and a significantly higher proportion of those (37.7% vs. 16.4%) received chemotherapy. The overall survival between the young and elderly groups was not significantly different. Moreover, the 5-year survival rate of the patients undergoing a surgical resection was 56.1% in the young group and 44.8% in the elderly group (P = 0.0615). CONCLUSIONS: This study suggests that the prognosis of young patients with lung cancer is at least equivalent to that of older patients; therefore, they should be managed according to the general therapeutic guidelines.

Adult↗
PubMed2001

Analysis of MAGE-3 derived synthetic peptide as a human lung cancer antigen recognized by cytotoxic T lymphocytes.

BACKGROUND: The human MAGE-3 gene was originally discovered in melanoma cells that encode tumor antigens, and has been reported to be expressed in various types of tumors, including lung cancer, but not in normal tissues other than testis or placenta. Our aim in this study was to clarify whether HLA-A2 restricted MAGE-3 peptide (FLWGPRALV) could be a lung cancer antigen recognized by cytotoxic T lymphocytes (CTL). METHODS: MAGE-3-derived peptide-specific CTL were induced from the peripheral blood mononuclear cells (PBMC) of HLA-A0201-positive healthy donors and the regional lymph node lymphocytes (RLNL) of HLA-A2-positive patients with lung cancer by multiple stimulations with peptide-pulsed HLA-A0201-positive antigen-presenting cells. RESULTS: Lymphocytes stimulated with MAGE-3 peptide exhibited specific lysis of Epstein-Barr virus-transformed B cells (EBV-B) pulsed with MAGE-3 peptide, but not with control peptide derived from influenza matrix protein, erbB-2, or wild type p53. Specific activity for MAGE-3-presenting targets was found after the second stimulation, and increased depending on the number of stimulations. The peptide-specific activity was inhibited by the addition of monoclonal antibodies against MHC class I and HLA-A2. Such CTL also recognized tumor cell lines expressing both HLA-A2 and MAGE-3 in an MHC class I-restricted manner, but did not recognize tumor cell lines that did not express HLA-A2 or MAGE-3. CONCLUSION: These results suggested the MAGE-3 peptide could be a potential target of specific immunotherapy for HLA-A2 patients with lung cancer.

Antibodies, Monoclonal↗
PubMed2001

High vascularity in the peripheral region of non-small cell lung cancer tissue is associated with tumor progression.

OBJECTIVES: We attempted to determine if the degree of angiogenesis can serve as a prognostic factor in the case of completely resected non-small cell lung cancer patients, with special reference to the center and the periphery of the tumor tissue. METHOD: For 255 Japanese patients who underwent completely resected non-small cell lung cancer (NSCLC), micro vessel density (MVD) was assessed by visual quantification of microvessels immunostained with anti-CD34 monoclonal antibody in 5 m section. Vascular endothelial growth factor (VEGF) was also immunostained on the same paraffin block specimen. RESULTS: MVD at the center (MVD-c) and that at the periphery (MVD-p) were frequently different in each individual although a weak positive correlation was observed (r=0.499, P<0.0001). One hundred and one patients with high MVD-p, but not the 107 patients with high MVD-c, showed a significantly higher proportion of advanced stage, larger tumor size and nodal metastasis as compared with MVD. The 5 year survival rate and median survival time for the high MVD-p group were significantly lower than that of low the MVD-p group (43.0%/31 months vs 48.6%/54 months, P=0.0256). As to the relationship among vascular endothelial growth factor (VEGF) and MVD, expression of VEGF was not associated with the degree of MVD. However, patients with high grade MVD-p showed an unfavorable prognosis in cases of high expression of VEGF. CONCLUSION: High MVD-p is associated with advancement of NSCLC, and it was particularly apparent in conjunction with high VEGF expression.

Adult↗
PubMed2001

Successful induction of tumor-specific cytotoxic T lymphocytes from patients with non-small cell lung cancer using CD80-transfected autologous tumor cells.

Cytotoxic T lymphocytes (CTL) against human lung cancer cells are difficult to induce by a conventional method using tumor cell stimulation probably due to an insufficiency of tumor antigens (TA) or costimulatory molecules such as CD80. We, therefore, investigated the potential of CD80-transfected tumor cells as stimulators of the in vitro induction of autologous tumor-specific CTL from regional lymph node lymphocytes in patients with lung cancer. Five non-small cell lung cancer cell lines (two adenocarcinomas, 1 squamous cell carcinoma, 1 large cell carcinoma and 1 adenosquamous cell carcinoma) were established from surgical specimens and were successfully transduced with a plasmid constructed with expression vector pBj and human CD80 cDNA, using a lipofection method. CD80-transfected tumor cells (CD80-AT) significantly augmented the proliferation of autologous lymphocytes from all cases as compared with non-transfected tumor cells (AT). AT-stimulated lymphocytes from 4 out of 5 cases did not show any cytotoxicity against AT; however, lymphocytes stimulated with CD80-AT exhibited substantial cytotoxicity against parental AT in all 5 cases tested. AT-stimulated lymphocytes derived from only one out of 5 cases showed major histocompatibility complex (MHC)-class I-restricted cytokine production in response to AT, while the MHC-class I-restricted responses were found in CD80-AT-stimulated lymphocytes from 4 out of 5 cases. These results indicate that CD80 on tumor cells could be a beneficial costimulatory molecule to elicit CTL against lung cancer, and also show that TA recognized by CTL was frequently expressed on lung cancer cells.

Adenocarcinoma↗
PubMed2001

Clinicopathological and molecular evidence indicating the independence of bronchioloalveolar components from other subtypes of human peripheral lung adenocarcinoma.

Although human lung adenocarcinoma has diverse histological subtypes, the correlation between histological subtypes and occurrence of the p53 gene mutation has been given less attention. We investigated 145 surgically resected lung adenocarcinomas to search for the incidence of p53 mutations and for record data on survival in each histological subtype, according to the new WHO criteria (1999). The frequency of p53 mutation in bronchioloalveolar carcinoma (BAC; 0% in 17 cases) and BAC with invasive growth component (BAC-invasive; 11% in 27 cases), which is conventionally categorized as the mixed subtype in WHO typing, were apparently significantly lower than in other types (non-BAC including acinar, papillary, solid, or mixed histology with these subtypes; 48% in 101 cases; P < 0.01). Multivariate analysis revealed that the histological subtype including BAC-invasive was a strong, independent, and significant prognostic factor (P < 0.03), as were tumor size and pathological stage (P < 0.001 and 0.002, respectively) for overall survival. However, the occurrence of p53 mutation itself was seen to be significant only in case of the univariate analysis. Therefore, histological subtyping may be a better prognostic indicator than is p53 mutation. These findings suggest that the WHO classification with the BAC and BAC-invasive from other histological subtypes may prove useful to predict the outcome for surgically treated patients with lung adenocarcinoma.

Adenocarcinoma↗
PubMed2001

Survival of non-small cell lung cancer patients with postoperative recurrence at distant organs.

BACKGROUND: Recurrence after complete resection of non-small cell lung cancer (NSCLC) is often observed. However, its influence on the prognosis of patients with recurrence is still unclear. PATIENTS AND METHODS: Of 468 consecutive patients with NSCLC undergoing complete resection during 10 years, 118 experienced recurrence at distant organs. In such patients, the influence of the following variables on post-recurrent survival was analyzed; sex, age at recurrence, disease-free interval, cell type, pathological (p-) stage at operation, adjuvant therapy (thoracic radiation and/or chemotherapy), site of recurrence, and treatment against recurrence. To identify independent factors, multivariate analysis was performed for variables which were considered to be influential in univariate analysis. RESULTS: Mean post-recurrent survival time was 418 days, and survival rate at 2-years was 15.7%. Multivariate analysis revealed that female, early p-stage, younger age at recurrence, metastasectomy and intra-pulmonary metastasis were the significant favorable factors in patients with distant metastases. Adjuvant therapy and bone metastasis were marginally significant unfavorable factors. Chemotherapy for recurrence tended to prolong survival. Length of disease-free survival and post-recurrent survival exhibited a positive relationship with p-stage. Seven out of 16 patients who underwent metastasectomy survived more than 1000 days after recurrence. CONCLUSIONS: Patients even with recurrence in distant organs could expect for long survival if they are in the early p-stage of primary cancer or a resectable recurrent disease.

Adenocarcinoma↗
PubMed2001

Asymptomatic atresia of the lobar bronchus of the lung: a case report.

A 64-year old woman presented with an asymptomatic occlusion of the intermediate bronchus associated with a peripheral mass occupying the entire middle and lower lobes. As malignancy was suspected, inferior bilobectomy was done. There was a complete atelectasis of both lobes, with massive parenchymal necrosis. Pathological examinations suggested a tuberculous granuloma in the bronchus and parenchyma although tuberculous bacilli were not found. This case was unusual as congenital anomaly, and was suspected as bronchial tuberculosis.

Bronchi↗
PubMed2000

The influence of enhanced postoperative inflammation by the intrapleural administration of streptococcal preparation (OK-432) on the prognosis of completely resected non-small-cell lung cancer.

BACKGROUND AND OBJECTIVES: It is not clear whether postoperative inflammation affects the prognosis of malignant disease. METHODS: We retrospectively reviewed the patients with non-small-cell lung cancer who underwent a complete resection at the National Kyushu Cancer Center from 1989 to 1996. For the treatment of prolonged air leakage after a pulmonary lobectomy, 25 patients received an intrapleural injection of OK-432, a lyophilized preparation of the heat- and penicillin-treated Su-strain of the Streptococcus pyogenes group A3. All patients were males who were older than 50 years of age. As a control, we selected 164 male patients who were older than 50 years of age and not given OK-432 during the same period. RESULTS: The administration of OK-432 in most patients was performed on the 4th day after the operation. Pleural drainage could be terminated in a mean of 5.5 days after the intrapleural administration of OK-432. In the control group, the serum C-reactive protein (CRP) level reached a peak on day 4 after the operation and returned to almost a normal level on day 14 after the operation. In the OK-432 group, the peak CRP level, which was significantly higher than that in the control group, was observed on day 7 after the operation and the elevated CRP level was maintained until 28 days after the operation. The mean level of CRP in the OK-432 group was significantly higher than that in the control on days 7, 14, and 28 after the operation. No significant difference was observed in the disease-free survivals between the two groups. CONCLUSIONS: Based on the above findings, postoperative prolonged inflammation does not seem to affect the progression of subclinically residual tumor cells.

Aged↗
PubMed2000

Adoptive immunotherapy using specific cytotoxic T lymphocytes against human lung-cancer-engrafted severe combined immunodeficiency mice.

OBJECTIVE: We studied the ability of human lung-cancer-specific cytotoxic T lymphocytes to suppress the growth of human lung adenocarcinoma (PC-9) engrafted in severe combined immunodeficiency mice. METHODS: PC-9-specific cytotoxic T lymphocytes were generated by multiple stimulation with irradiated PC-9 cells of regional lymph node lymphocytes from lung cancer patients expressing the same human leukocyte antigen-A locus haplotype as PC-9 following expansion due to the administration of immobilized anti cluster of differentiation 3 mAb and interleukin-2. Cytotoxic T lymphocytes showed specific cytotoxicity against PC-9 cells in vitro. Severe combined immunodeficiency mice with a subcutaneous graft of PC-9 were treated with a PC-9-specific cytotoxic T lymphocyte by i.v. injection and/or with interleukin-2 by s.c. injection. RESULTS: Cytotoxic T lymphocyte treatment suppressed PC-9 graft growth significantly an effect, significantly enhanced when combined with interleukin-2 injection. To evaluate the in vivo specificity of anti-PC-9 cytotoxic T lymphocytes, each mouse was subcutaneously inoculated in the right flank with PC-9, and in the left flank with A549 or Sq-1. Cytotoxic T lymphocytes plus interleukin-2 treatment was found to suppress PC-9 growth selectively, but not A549 or Sq-1 growth. CONCLUSIONS: These results provide sufficient rationale for conducting further clinical trials on immunotherapy using cytotoxic T lymphocyte for lung cancer patients.

Adenocarcinoma↗
PubMed2000

Aggressive surgical treatment of multiple primary lung cancers.

A case of triple primary lung cancers--squamous cell carcinoma, adenocarcinoma and large-cell carcinoma--is presented. Surgical treatment comprised, respectively, left pneumonectomy, partial resection of the right upper lobe and completion right upper lobectomy. The postoperative courses were uneventful and the patient remains well, with no sign of recurrence, 20 months after the third operation.

Adenocarcinoma↗