[Thymoma Showing Elevating Anti-acetylcholine Receptor Antibody without Clinical Symptoms of Myasthenia Gravis;Report of a Case].

A 46-year-old man was referred to our hospital with a suspicion of pericardial cyst. Chest computed tomography (CT) revealed an anterior mediastinal tumor. He had no symptoms, but laboratory data showed positive titer to acetylcholine receptor antibody (Anti-AchR Ab). Under a clinical diagnosis of thymoma, extended thymectomy was performed. This case may represent subclinical myasthenia gravis, so we suggest extended thymectomy is crucial for thymoma with elevated level of Anti-AchR Ab without any symptoms.

Evaluation of extratumoral lymphatic permeation in non-small cell lung cancer as a means of predicting outcome.

BACKGROUND: Lymphatic permeation (ly) has been described as a potential prognostic factor for non-small cell lung cancer (NSCLC). METHODS: The purpose of this study was to analyze whether evaluation of the presence or absence of ly and its location (ly 0: absent, N=464; ly 1: intratumoral, N=42; ly 2: extratumoral, N=52) provides an appropriate means of predicting the outcome of NSCLC. We investigated the clinical implications of ly in 558 consecutive patients with surgically resected NSCLC. RESULTS: Evaluation according to ly status showed that the recurrence-free survival (RFS) time of the ly 2 patients was significantly shorter than that of the ly 0 patients (P<0.0001), the ly 1 patients (P=0.0028). A significant difference in RFS time was also observed between the ly 0 patients and the ly 1 patients (P=0.0025). RFS time of the ly 0 patients was significantly longer than that of the ly 1 plus ly 2 patients (P<0.0001). We also evaluated the patients with pathological stage I disease (N=378) separately. The RFS time of the ly 2 patients (N=9) was significantly shorter than that of the ly 0 plus ly 1 patients (P<0.0001). In the nine ly 2 patients, six developed a distant metastasis within 1 year. A multivariate analysis revealed that ly status (ly 0 plus ly 1 versus ly 2) was an independent prognostic factor (P=0.0116), demonstrating the significant prognostic value of extratumoral lymphatic permeation in NSCLC. CONCLUSIONS: These results indicate that ly status is a good prognostic marker of poorer outcome in patients with resected NSCLC.

Eg5 expression is closely correlated with the response of advanced non-small cell lung cancer to antimitotic agents combined with platinum chemotherapy.

BACKGROUND: Eg5 is a microtubule motor protein that functions in bipolar spindle assembly. We investigated the relationship between Eg5 expression and the response to chemotherapy of patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Eg5 expression was investigated immunohistochemically in 122 formalin-fixed tumor samples from untreated stage IIIB or IV NSCLC patients. We also investigated cyclin B1 expression, which is involved in the G2/M transition. All patients received antimitotic agents combined with platinum chemotherapy. The response to chemotherapy was compared in relation to Eg5 and cyclin B1 expression and in relation to clinicopathological factors. RESULTS: The response rate to chemotherapy of patients with Eg5-positive tumors was 37%, as opposed to 10% for patients with Eg5-negative tumors, and Eg5 expression was significantly associated with the response to chemotherapy (P=0.002). The response rate of patients with cyclin B1-positive tumors (53%) was higher than that of patients with cyclin B1-negative tumors (23%) (P=0.009), and Eg5 expression was significantly correlated with cyclin B1 expression (P=0.005). A multivariate analysis confirmed Eg5 status to be an independent variable related to response to chemotherapy (P=0.008). CONCLUSIONS: Eg5 expression can predict a response to antimitotic agents combined with platinum chemotherapy among patients with advanced NSCLC.

Differences in clinicopathological and biological features between central-type and peripheral-type squamous cell carcinoma of the lung.

The central type and peripheral type squamous cell carcinoma (SCC) of the lung have different clinicopathological characteristics, but, little is known about their biological characteristics. We investigated differences between the properties and phenotypes of peripheral-type (P-type) and central-type (C-type) SCC by performing an immunohistochemical analysis of each type by tissue microarray analysis with a large panel of antibodies. To examine strictly, we selected 20 P-type SCCs that were pathological stage T1 and limited to more peripherally than the fifth bronchial bifurcation, and 21 C-type SCCs that were pathological stage T1 and limited to a lobar bronchus. The results of the clinicopathological study showed that the patients with P-type SCC were significantly older than the patients with C-type SCC and that squamous metaplasia was predominant in C-type SCC than in P-type SCC. The 36 antibodies revealed different expression patterns of cytokeratin 7 (CK 7) and cytokeratin 19 (CK 19) between C-type and P-type SCC. CK 7 expression was more predominant in P-type SCC than in C-type SCC, and CK 19 expression was more predominant in C-type SCC than in P-type SCC. These results suggest that C-type and P-type SCC have different clinicopathological and biological features.

[A possibility of overcoming local tumor immune tolerance by radiofrequency ablation in combination with intratumoral injection of naïve dendritic cell].

Recently we reported the systemic antitumor efficacy of intratumoral naive dendritic cell injection (IT-DC) in combination with local photodynamic therapy in Clinical Cancer Research 2006. In general, tumor cells secrete several immune suppression cytokines which could induce immune tolerance in a tumor microenvironment. The rationale and advantages of IT DC in combination with conventional antitumor therapy are as follows: (1) dying tumor cells release some tumor antigens, (2) sufficient number of DC recruiting occurs at tumor site, (3) there is naive DC capturing some tumor antigens in vivo, (4) DC activation by inflammatory cytokines are released from dying tumor cells, and (5) DC migration happens in regional lymph nodes and induces adoptive tumor immunity. Conventional antitumor therapy before IT DC could destroy the immune tolerance at a tumor site and induce durable DC vaccination. In this report, we demonstrated the mechanism of (4) and (5) by radiofrequency ablation plus IT DC using mouse tumor model.

Lung cancer patients showing pure ground-glass opacity on computed tomography are good candidates for wedge resection.

Small lung cancers frequently have been detected in mass screening by computed tomography (CT) in recent years. Suitability of limited resection for these small lung cancers remains controversial. One hundred patients who underwent sublobular limited resection (wedge resection or segmentectomy) for lung cancer in our hospital from 1981 to 2002 were analyzed retrospectively. From CT findings, tumors were classified into two groups; pure ground-glass opacity (PGGO) and non-PGGO. Patients included 44 women and 56 men, and ages ranged from 40 to 92 years (mean, 71.0). Histologic types included 76 adenocarcinomas, 21 squamous cell carcinomas, and 3 large cell carcinomas. Clinical stages included 83 stage IA and 17 stage IB. By high-resolution CT, 27 tumors (27%) showed PGGO; at postoperative histopathologic examination, all of these were localized bronchioloalveolar carcinomas. Diameter of tumors showing PGGO was 9.3+/-mm (mean +/- S.D.); that of non-PGGO tumors was 21.2+/-13.7 mm. Overall and lung cancer-specific 5-year survival rates in all patients were 58.0 and 64.8%, respectively. Overall 5-year survival rate with small adenocarcinomas (

Peripheral leukocytes with HLA-DR+/CD8- phenotype are associated with prognosis in patients with lung cancer.

BACKGROUND: We have previously reported that the most significant immunological prognostic factors in patients with lung cancer are the percentages of peripheral HLA-DR+ lymphocytes. PATIENTS AND METHODS: We performed two-color flow cytometric analyses using two combinations of double-staining to identify lymphocyte phenotypes HLA-DR/CD4 and HLA-DR/CD8, and examined the correlation between the expression of these subsets and survival in 51 patients with non-small cell lung cancer. RESULTS: The percentages of HLA-DR+, HLA-DR+/CD4+ (activated helper/inducer T cells) and HLA-DR+/CD8+ (activated cytotoxic/suppressor T cells) did not correlate with survival. However, survival was better when the percentage of HLA-DR+/CD8- was below normal (p = 0.0267). The 4-year survival rate in patients with high and low percentages of peripheral HLA-DR+/CD8- lymphocytes was 26.0% and 53.2%, respectively. CONCLUSION: The subset of HLA-DR+/CD8- lymphocytes powerfully predicts the survival of patients with non-small cell lung cancer.

Significance of expression of TGF-beta in pulmonary metastasis in non-small cell lung cancer tissues.

Recent studies have evaluated the cytokine network involved in the local immune response to tumors. In addition to infiltrating inflammatory cells, tumors also produce cytokines and growth factors that may alter tumor growth and tumor immunogenicity. Ninety-one samples of NSCLC were used in this study. We measured the expression of VEGF, TNF-alpha, TGF-beta, IL-6, IL-8, IL-12, INF-gamma, and MCP-1 in NSCLC tissues, by ELISA. The expression of IL-6 and IL-8 were significantly higher in squamous cell carcinoma than in adenocarcinoma (p=0.016 and p<0.001, respectively). The expression of TGF-beta, MCP-1 and IL-8 were significantly higher in pulmonary metastasis positive than negative cases (p=0.002, p=0.001, and p=0.008, respectively). In multivariate logistic regression analysis, the expression of TGF-beta was an independent risk factor for the occurrence of pulmonary metastasis (p=0.008, 95% CI=1.002-1.011). We confirmed that tumor infiltrating stromal cells were major sources of TGF-beta by immunohistochemical analysis. The expression of VEGF and IL-8 were significantly higher in cases with central necrosis (p=0.006 and p=0.011, respectively). We speculated that TGF-beta expression in tumor infiltrating stromal cells may regulate the occurrence of spontaneous pulmonary metastasis in NSCLC. (Ann Thorac Cardiovasc Surg 2003; 9: 295-300)

Comparison of immunohistochemistry and real-time reverse transcription-polymerase chain reaction to detect expression of carcinoembryonic antigen in lung cancer.

Real-time reverse transcription-polymerase chain reaction (RT-PCR) can detect mRNA of carcinoembryonic antigen (CEA) quantitatively. We compared the serum concentration, localization, and mRNA expression of CEA to determine the relationship between these three factors in patients with lung cancer. Tumors from ten patients who underwent surgery were analyzed. The serum concentration of CEA was measured before initiating therapy using a quantitative latex agglutination reaction. Immunohistochemical staining of pathologic specimens of resected tumors was performed to localize CEA. Real-time RT-PCR to detect mRNA of CEA was performed for isolating RNA from a piece of fresh-frozen tumor. Positivity for CEA production was 20% for serum, 60% for immunohistochemistry, and 80% for real-time RT-PCR. Thus, the percentage of mRNA and protein positivity of CEA in lung cancer was much higher than for the serum CEA concentration. No statistically significant correlation between the serum CEA concentration and the amount of mRNA expression was found (p=0.0932). Real-time RT-PCR is useful to quantify specific mRNA expression from a small piece of tissue.

Chromosomal instability detected by fluorescence in situ hybridization in surgical specimens of non-small cell lung cancer is associated with poor survival.

PURPOSE: Chromosomal instability (CIN) in non-small cell lung cancer (NSCLC) has yet to be well studied. We examined the relationship between CIN detected by fluorescence in situ hybridization and survival in patients with NSCLC. EXPERIMENTAL DESIGN: Touch preparations from 50 surgical specimens of NSCLC were studied. Tumors included 34 adenocarcinomas, 15 squamous cell carcinomas, and 1 large cell carcinoma. The pathologic stage was IA in 14, IB in 17, IIB in 8, IIIA in 9, and IIIB in 2 cases. Enumeration of chromosomes 3, 10, 11, and 17 was used to determine which tumors carried CIN. The association between CIN and survival was also analyzed. RESULTS: Disomy was most common, but tetrasomy and trisomy of the examined chromosomes were seen frequently. Fourteen tumors (28%) showed heterogeneity of all four chromosomes examined and were judged to be carrying CIN. Both univariate and multivariate analyses revealed that two factors, lymph node metastasis and CIN, were significant poor prognostic factors. CONCLUSIONS: CIN in NSCLC detected by fluorescence in situ hybridization is an independent factor predicting a poor prognosis.

cDNA microarray analysis of gene expression in pathologic Stage IA nonsmall cell lung carcinomas.

BACKGROUND: The relationship between altered gene expression and tumor progression in lung carcinoma has yet to be characterized. Gene expression in pathologic Stage IA nonsmall cell lung carcinoma specimens was analyzed using a cDNA microarray. METHODS: Surgical specimens were used for the current study. The pathologic stage was IA (AJCC) in five tumors, IB in two, IIA in one, IIIA in one, and IIIB in one. Seven tumor specimens were adenocarcinomas and three were squamous cell carcinomas. Paired mRNAs from carcinoma cells and normal lung tissue specimens from the same lobe were labeled with different fluorochromes during cDNA probe synthesis in a reverse-transcription reaction. Both synthesized, labeled cDNA probes were mixed and hybridized to the microarray. The signal intensity of each spot was measured by laser scanner and gene expression was quantified as the tumor-to-normal fluorescence ratio (T:N ratio). The gene was overexpressed when the T:N ratio was greater than 2.0 and underexpressed when the ratio was less than 0.5. RESULTS: Overall, 40 (9.4%) of the 425 genes evaluated were overexpressed, and 74 genes (17.4%) were underexpressed. In the 5 Stage IA tumor specimens, 31 (7.3%) genes were overexpressed and 76 (17.9%) were underexpressed. For 30 genes (7.1%), expression was different in Stage IA tumor specimens compared with more advanced tumor specimens. CONCLUSIONS: The cDNA microarray system showed that numerous alterations of gene expression were present in early-stage nonsmall cell lung carcinoma specimens.