Biomedical subjects

Takeshi Hanagiri

Publications and source records attributed to Takeshi Hanagiri.

33 records · Page 2Linked to original sources

PubMed2004

Correlation between tumor regression and T cell responses in melanoma patients vaccinated with a MAGE antigen.

The cancer-germline gene MAGE-3 codes for tumor-specific antigens recognized on many tumors by T lymphocytes. A MAGE-3 antigen presented by HLA-A1 has been used in several vaccination trials on metastatic melanoma patients. Only a small minority of patients have shown evidence of tumor regression. Attempts to correlate the tumor rejections with the cytotoxic T lymphocyte (CTL) response against the vaccine have been hampered by the low level of these responses. In noncancerous individuals, the frequency of the T cell precursors against antigen MAGE-3.A1 is approximately 4 x 10(-7) CD8 T cells. The diversity of the T cell receptor repertoire of these anti-MAGE-3.A1 precursors was analyzed in one individual. The results indicate that it is very likely that the repertoire comprises >100 clonotypes. On this basis, it is possible to use not only the frequency of CTL precursors in the blood but also the presence of dominant clonotypes to ascertain in patients the existence of anti-MAGE-3.A1 responses as low as 10(-6) of CD8. With this approach, we observed a correlation between tumor regression and anti-MAGE-3.A1 CTL responses in patients vaccinated with a recombinant virus encoding the antigen and also in patients vaccinated with peptide-pulsed dendritic cells. In contrast, for patients showing tumor regression after vaccination with peptide alone, CTL responses were almost never observed. It is possible that even those CTL responses that are below our present detection level can trigger a sequence of events that leads to tumor regression.

Amino Acid Sequence↗

PubMed2004

Simultaneous cellular and humoral immune response against mutated p53 in a patient with lung cancer.

We recently identified several Ags recognized by tumor-infiltrating B lymphocyte-derived Ab using SCID mice and a xenografted non-small cell lung cancer system. One of these identified Ags was mutated p53 with a point mutation resulting in the alteration of codon 158 from Arg to Leu. The aim of this study was to ascertain whether cellular immunity against mutated p53 exists in the same patient together with humoral immunity. Two different nona peptides (mutated p53(150) and p53(155) peptides), including a mutated amino acid derived from p53, were synthesized according to the binding motif of HLA class I of the established cancer cell line A904L from the patient. Mediastinal lymph node lymphocytes of the patient were stimulated weekly with the peptides. The mutated p53(155) peptide-stimulated lymphocytes showed specific cytotoxicity against both autologous EBV-transformed B cells pulsed with mutated p53(155) peptide and A904L. The mutated p53(155) peptide-specific CTL clone in an HLA-Cw*0702 restriction was established and analyzed for its TCR usage. Clonotypic PCR using CDR3-specific primers was applied to the tumor tissue containing the tumor-infiltrating lymphocytes. The specific amplification of PCR was found in the tumor tissue. These results demonstrated that not only B lymphocytes producing specific Ab against the p53 protein, but also CTL against mutated p53, expressed in autologous lung cancer cells exist in the tumor tissue. This approach may allow us to better understand the mechanisms of T and B cell immunity against the same tumor Ag in cancer patients.

Amino Acid Sequence↗

PubMed2004

Carinal resection after induction bronchial arterial infusion for locally advanced non-small cell lung cancer.

We herein describe 3 cases of a carinal resection after induction bronchial arterial infusion (BAI) for locally advanced non-small cell lung cancer (NSCLC). Case 1 was a 44-year-old man with T1N2M0 adenocarcinoma. After undergoing Nd-YAG laser treatment (5079 J) and BAI [cis-diamminedichloro platinum (CDDP) 100 mg/body], a right sleeve upper lobectomy with a carinal resection and reconstruction (Montage type) was performed. Case 2 was a 67-year-old man with T4N1M0 squamous cell carcinoma. After BAI (CDDP 120 mg/body), an operation (same as case 1) was performed. Case 3 was a 72-year-old man with T4N2M0 squamous cell carcinoma. After BAI (CDDP 120 mg/body), a right sleeve peumonectomy was performed. There was neither BAI-related intraoperative nor postoperative complications. BAI with CDDP was thus found to be a useful and effective therapeutic modality for locally advanced NSCLC invading the carina.

Adult↗

PubMed2003

Survival and prognostic factors of surgically resected T4 non-small cell lung cancer.

BACKGROUND: Category T4 nonsmall cell lung cancer (NSCLC) encompasses heterogenous subgroups. We retrospectively analyzed the survival of patients with surgically resected T4 NSCLC to evaluate the evidence for prognostic implications according to the subgroups of T4 category, nodal status, and resection completeness. METHODS: Seventy-six patients with T4N0-2M0 NSCLC were divided into three subgroups within the T4 category: 24 patients with the tumor invading the mediastinal organs (mediastinal group), 16 with a malignant pleural effusion or dissemination (pleural group), and 36 with satellite tumor nodules within the ipsilateral primary tumor lobe (satellite group). Complete resection was possible in 47 patients (61.8%). The pathologic N statuses were N0 in 28, N1 in 13, and N2 in 35 patients. RESULTS: The overall survival of the 76 patients was 19.1% at 5 years. The overall 5-year survivals according to the three subgroups of the T4 category were as follows: mediastinal group, 18.2%; pleural group, 0%; and satellite group, 26.7% (mediastinal/satellite versus pleural, p = 0.037). Factors significantly influencing the overall 5-year survival were the pathologic N status (N2 versus N0-1, p = 0.022) and the completeness of resection (complete versus incomplete, p = 0.0001). A multivariate survival analysis demonstrated that the pathologic N status and the completeness of resection were significant independent predictors of a poorer prognosis even after adjusting for the subgroup of the T4 category. CONCLUSIONS: Resectable T4N0-1 NSCLC that is not due to pleural disease deserves consideration of aggressive surgical resection with expected 5-year survival of about 20%.

Adult↗

PubMed2003

Pleomorphic carcinoma: report of a case with massive pleural effusion and asbestos particles.

Pleomorphic (spindle/giant cell) carcinoma (PC) is one subset of large cell carcinoma. It is well known that PC patients have a poor survival rate. This report describes a 68-year-old man with PC. The patient's tumor had a massive pleural effusion. A left lower lobectomy and partial resection of the left diaphragm, peritoneum, and parietal pleura were performed to remove the tumor. Numerous asbestos particles were found in the left lower lobe. This is the first reported case of PC which may have been caused by asbestos particles. Further investigation is needed into whether asbestos exposure causes PC.

Aged↗

PubMed2003

Genetic alteration in carcinoid tumors of the lung.

Surgically resected specimens of 13 carcinoid tumors of the lung including nine typical carcinoids and four atypical carcinoids, and eight salivary gland type carcinomas (six mucoepidermoid carcinomas and two adenoid cystic carcinomas) were analyzed regarding p53 expression, loss of heterozygosity (LOH) in chromosome 3p, 9p, and K-ras mutation. The overexpression of p53 was identified in four atypical carcinoid tumors, one mucoepidermoid carcinoma, and one adenoid cystic carcinoma, however, none of typical carcinoids showed p53 immunoreactivity. LOH in 3p14 was demonstrated in three of seven informative cases in all tumors. LOH in 9p was demonstrated in two of five informative cases in all tumors. Two of three cases with LOH at 3p14 had a poor prognosis, one of which also had LOH at 9p. No mutation of the K-ras gene was observed in any of these tumors. These data thus indicate that p53 overexpression might distinguish atypical carcinoid tumors from typical tumors and might therefore be useful as an adjunct modality in the differential diagnosis of pulmonary carcinoid tumors. The presence of LOH at 3p14 or 9p may thus help to identify lung cancer patients with a poor prognosis.

Carcinoid Tumor↗

PubMed2002

Tumor-infiltrating B lymphocytes as a potential source of identifying tumor antigen in human lung cancer.

Functional studies using freshly isolated tumor-infiltrating B lymphocytes(TIB) are difficult to perform and interpret. Here we document a novel function of TIB using fresh human lung cancer tissues engrafted in SCID mice; they are at activated state and produce tumor-specific antibodies in tumor microenvironment: (a) TIB engrafted in SCID mice produced human IgG; (b) IgG derived from TIB highly bound intracellular and membrane-bound antigens of autologous cancer cells; and (c) less recognition of autoantigens expressed on normal lymphocytes by IgG derived from TIB compared with IgG from the serum of the patient. On the basis of the novel findings presented in this study, we modified the original serological analysis of antigens by recombinant cDNA expression cloning design in a patient with lung cancer who expressed unusually favorable clinical evolution and analyzed humoral immunity against identified mutated p53 antigen. This study provides the first demonstration that antibodies derived from TIB recognize tumor antigens by serological analysis of antigens by recombinant cDNA expression cloning methodology and circulating anti-p53 antibodies in sera derived from TIB in tumor microenvironment. Our approach using TIB may allow the identification of key antigens in the humoral cancer-related immune system.

Animals↗

PubMed2002

Establishment of an immortalized T-cell line from lung cancer tissue: phenotypic and functional analyses.

BACKGROUND: In order to investigate host defense against solid tumors, valuable information could be provided by ex-vivo analyses of functional immune cells in tumor tissues. However, available sources of fresh tumor-infiltrating T cells (TIL) are usually very limited, and it is often difficult to establish TIL lines. In this study, we analyzed the phenotypic and functional characteristics of TIL, using an immortalized cell line prepared by cotransfection of human c-myc and c-Ha-ras. METHODS: A human T-cell line was established by cotransfecting c-Ha-ras and c-myc oncogenes to T lymphocytes freshly isolated from human lung large-cell carcinoma tissue. The phenotypes were assessed by flow cytometry. T-cell receptor (TCR) V alpha- and beta-usage was analyzed by polymerase chain reaction (PCR) and Southern blot. Cytotoxic activity against autologous and allogeneic tumor cell lines was examined by standard 51Cr-release cytotoxicity assays. Cytokine production by the established T-cell line, 904-T1, in response to stimulation by autologous tumor cells was assayed by using an enzyme-linked immunosorbent assay. RESULTS: 904-T1 (CD3+, CD8+, CD56+, CD16-, CD161-, TCR V alpha 9, 13, and V beta 1, 5) displayed a broad range of MHC-nonrestricted tumoricidal activity against various human tumor cell lines, but did not lyse autologous B cells transformed by Epstein-Barr virus. The cytotoxicity of 904-T1 was not mediated by a T-cell antigen receptor or by Fas-ligand, but by perforin-based cytolytic pathways, and was enhanced by interleukin (IL)-12. 904-T1 cells produced large amounts of interferon (IFN)-gamma, but not tumor necrosis factor (TNF)-alpha or IL-4 in response to autologous tumor cells, and produced high levels of IFN-gamma and TNF-alpha, and a substantial level of IL-4 following stimulation with anti-CD3 monoclonal antibody. CONCLUSIONS: Our results suggest that 904-T1 cells were natural killer T (NKT)-like cells with regard to their non-specific killing, cytokine repertoire, and sensitivity to IL-12, although the repertoire of the TCR variable region was not compatible with that of NKT cells.

Adenocarcinoma↗

PubMed2002

Cytolytic T-cell responses of cancer patients vaccinated with a MAGE antigen.

'Cancer-germline' genes such as the MAGE gene family are expressed in many tumors and in male germline cells but not in normal tissues. They encode shared tumor-specific antigens, which have been used in therapeutic vaccination trials of metastatic melanoma patients. To establish whether there is a correlation between tumoral regressions and T-cell responses against the vaccine antigen, we evaluated the responses of patients vaccinated with a MAGE-3 antigenic peptide or a recombinant virus coding for the peptide. Blood lymphocytes were stimulated with antigenic peptide followed by detection with tetramer, T-cell cloning, and TCR analysis. In 4/9 regressor patients and in 1/14 progressors we found a low level, usually monoclonal cytolytic T lymphocyte response against the MAGE-3 peptide.

Antigens, Neoplasm↗

PubMedDate not supplied

Molecular genetic tumor markers in non-small cell lung cancer.

Not only serum tumor markers, such as carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and carbohydrate antigen (CA) 125, but also serum growth factors have been examined to evaluate tumor stages and to predict the recurrence and metastasis in patients with non-small cell lung cancer (NSCLC) (1-5). In recent years, the analysis of the genome and proteome has advanced remarkably. An array of molecular genetic tumor markers (MGTMs) have been identified based on the biological characterization of tumors, such as tumor development, growth, invasion and metastasis. Molecular genetic tumor marker research has also entered a new era, since comprehensive gene profile analysis using cDNA microarrays and comprehensive protein expression analysis using proteomics technology have been developed. On the other hand, the frequency of lung cancer patients with which various tumor markers are associated is increasing in Japan (6-8). This paper reviews MGTMs characteristic of lung cancer and clarifies the clinical usefulness and applications of MGTM for cancer treatment.

Biomarkers, Tumor↗

PubMedDate not supplied

Expression of deltaNp63 in squamous cell carcinoma of the esophagus.

BACKGROUND: The p63 gene is present as two isoforms, namely TAp63 and deltaNp63. The biological role of deltaNp63 in the progression of esophageal cancer is still controversial. PATIENTS AND METHODS: The expression of deltaNp63, as well as that of p63, was immunohistochemically examined in 61 resected specimens of squamous cell carcinoma of the esophagus. RESULTS: The incidences of a positive deltaNp63 expression were 32 and 64% in carcinomas with and without adventitial invasion, respectively, and 37 and 65% in those with and without lymph node metastasis, respectively (p<0.05). The prognosis was significantly better in the positive deltaNp63 group than in the negative group (p<0.01). However, a multivariate analysis revealed deltaNp63 not to be an independent prognostic factor. Regarding p63, diminished expression was more frequently observed in advanced carcinomas, however, there were no statistically significant differences. CONCLUSION: The impaired deltaNp63 reflects the progression of squamous cell carcinoma of the esophagus.

Adult↗

PubMedDate not supplied

P53R2, p53 inducible ribonucleotide reductase gene, correlated with tumor progression of non-small cell lung cancer.

p53R2 plays a crucial role in supplying dNTPs for DNA repair. The expression of p53R2 is induced by DNA-damaging agents in a p53-dependent manner and p53R2 translocates to the nucleus upon DNA damage. Immunohistochemistry was used to analyze the protein expression of p53R2 in paraffin-embedded tumor samples from 130 well-characterized non-small cell lung cancer (NSCLC) patients and the expression level of p53R2, clinical variables and survival outcome were compared. A positive expression of p53R2 was detected in the cytoplasm of tumor cells in 61 of the 130 patients (46.2%) with NSCLC. The positive ratio was significantly higher in the patients with pathological stage II/III, pathological T3-4 and pathological N1-3 than in those with stage I, T1-2 and N0, respectively. No significant difference was observed between the p53R2 expression and the gender, age at operation, histological type or p53 expression. Though our findings do not support that the p53R2 immunocytochemical marker alone plays an important prognostic role in NSCLC, the DNA repair pathway mediated by p53R2 may be responsible for controlling the growth of lung cancer.

Adult↗

PubMedDate not supplied

Expression of FHIT in esophageal epithelium and carcinoma: reference to drinking, smoking and multicentric carcinogenesis.

BACKGROUND: Both alcohol consumption and cigarette smoking are risk factors for esophageal cancer. The purpose of this study was to clarify whether the fragile histidine triad (FHIT) is their target gene in esophageal carcinogenesis as well as in multicentric carcinogenesis. PATIENTS AND METHODS: The expression of FHIT was immunohistochemically examined in the squamous cell carcinoma as well as in the normal esophageal epithelium of 55 cases with esophageal cancer. RESULTS: The median drinking indices (DIs) were 546 and 1092 (p<0.01) in cases with positive FHIT expression and those with a diminished expression in the esophageal epithelium, respectively. Furthermore, the incidences of intra-esophageal multiple cancer were 44% and 13%, respectively (p<0.05). Regarding the expression in cancer lesions, the median DIs were 280 and 721 in positive and diminished cases, respectively (p=0.081). CONCLUSION: A loss of FHIT expression is associated not only with alcohol-induced esophageal carcinogenesis, but also with multicentric carcinogenesis.

Acid Anhydride Hydrolases↗

PubMedDate not supplied

Effect of IgG produced by tumor-infiltrating B lymphocytes on lung tumor growth.

BACKGROUND: Tumor-infiltrating B lymphocytes (TIB) are often observed in lung cancer. The role of TIB in tumor growth has not been well investigated. MATERIALS AND METHODS: Forty-four surgically-resected human lung cancer tissues were xenotransplanted into SCID mice. Their blood was collected and the volume of the transplanted tumors was measured regularly. The correlations between the IgG titer in the sera and the growth of the transplanted tumors according to the clinicopathological variables were examined. RESULTS: Human IgG production from TIB was observed in the all xenotransplanted mice. Twenty-seven out of the 44 tumors regressed gradually. The average serum human IgG level of the tumor regressors (n = 10) was significantly higher than that of the progressors (n = 9) in squamous cell carcinoma (p = 0.02), while there was no significant difference in the other histological groups. CONCLUSION: IgG produced by TIB might play a crucial role in preventing tumor growth in squamous cell carcinoma.

Animals↗

PubMedDate not supplied

Antigens recognized by IgG derived from tumor-infiltrating B lymphocytes in human lung cancer.

BACKGROUND: Lung cancer tissues are often infiltrated by B lymphocytes, but it is not clear whether these infiltrations represent tumor-specific immune response or a nonspecific reaction. MATERIALS AND METHODS: The serological analysis of recombinant cDNA expression libraries (SEREX) were previously modified using a severe combined immunodeficient (SCID) mice model engrafted with fresh human lung cancer. Here, a panel of antigens recognized by tumor-infiltrating B lymphocytes (TIB) in human lung cancer were characterized. RESULTS: The modified SEREX analysis identified 22 distinct antigens in a large cell carcinoma of the lung. Sequence analysis and real time-PCR analysis showed that 55% of isolated antigens were overexpressed in tumor tissues and 9% had mutation. CONCLUSION: The results of this study indicate that the humoral immune response of TIB in lung cancer patients can be detected in the xenotransplanted SCID mouse model and our modification shows high sensitivity and specificity for identification of tumor antigens.

Animals↗