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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.

Background: Methylation of CpG islands in the promoter and upstream coding regions has been identified as a mechanism for transcriptional inactivation of tumor suppressor genes. The purpose of the current study was to determine the correlation between the aberrant promoter methylation of multiple genes and survival in patients with nonsmall cell lung carcinoma (NSCLC)., Methods: The methylation status of nine genes was determined in 124 surgically resected NSCLC cases using methylation-specific polymerase chain reaction., Results: The methylation frequencies of the genes tested in NSCLC specimens were 52% for E-cadherin (CDH1), 41% for RAS association domain family protein (RASSF1A), 38% for fragile histidine triad (FHIT) and adenomatous polyposis coli (APC), 27% for retinoic acid receptor beta (RARbeta) and H-cadherin (CDH13), 20% for p16INK4A, 0.8% for O6-methylguanine-DNA-methyltransferase (MGMT), and 0% for glutathione S-transferase P1 (GSTP1). The survival of the patients with FHIT methylation-positive tumors was found to be significantly shorter than that for those patients with methylation-negative tumors (P=0.03), even in those patients with International Union Against Cancer TNM Stage I or Stage II disease (P=0.007). In contrast, there were no significant survival differences noted between the methylation-positive and methylation-negative tumors for the other genes tested. In addition, based on multivariate analyses, FHIT methylation-positive status was found to be independently associated with poor survival (P=0.046) and disease stage (P<0.0001)., Conclusions: The results of the current study suggest that methylation of FHIT is a useful biomarker of biologically aggressive disease in patients with NSCLC., (Copyright 2004 American Cancer Society.)

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.

DNA methylation alteration of several genes contributes to human tumorigenesis. Cyclin D2, a member of the D-type cyclins, is implicated in cell cycle regulation and malignant transformation. In our study, we examined the methylation status of the cyclin D2 promoter in small cell lung cancer (SCLC), nonsmall cell lung cancer (NSCLC), breast tumors and tumor cell lines. We observed that aberrant methylation of cyclin D2 was present in 32 of 56 (57%) SCLC cell lines, 7 of 32 (22%) SCLC tumor tissues; 25 of 61 (47%) NSCLC cell lines, 19 of 48 (40%) NSCLC tumor tissues; 18 of 30 (60%) breast tumor cell lines and 19 of 63 (30%) breast tumor tissues. Methylation was more frequent in the tumor cell lines compared to the primary breast and SCLC tumors (p = 0.007 and p = 0.001, respectively). Methylation was rare in the control tissue samples; 0 of 12 peripheral blood lymphocytes; 0 of 12 buccal epithelial cells; 0 of 18 nonmalignant lung tissues and 3 of 28 (11%) nonmalignant breast tissues. Promoter methylation correlated with loss of transcript by reverse transcription PCR (RT-PCR) in 9 of 11 (6 lung, 5 breast) tumor cell lines tested. Two cell lines that were not methylated also lacked expression, suggesting that other mechanisms of inactivation may be involved. Expression was restored by treatment with the demethylating agent, 5 aza 2' deoxycytidine, in all 9 methylated cell lines. Our results confirm earlier reports in breast cancer and indicate that aberrant methylation of cyclin D2 may contribute to the pathogenesis of the 2 major types of lung cancers., (Copyright 2003 Wiley-Liss, Inc.)

Hypertrophic osteoarthropathy is extremely rare in patients with esophageal cancer. We herein describe a 65-year-old Japanese man whose esophageal cancer was diagnosed while examining his symptoms of hypertrophic osteoarthropathy. Esophagectomy and postoperative chemoradiation improved the typical radiologic findings of hypertrophic osteoarthropathy as well as the clinical symptoms. Furthermore, the patient has demonstrated a disease-free survival of more than 3 years.

TMS1 (target of methylation-induced silencing) is a CpG island-associated gene that functions in the regulation of apoptosis and encodes a caspase recruitment domain, a recently described motif found in apoptotic signaling molecules. Recent evidence suggests that silencing of genes in the apoptotic pathway contribute to human carcinogenesis. We examined the DNA methylation status of the TMS1 promoter in lung and breast tumor tissues, tumor cell lines and nonmalignant tissues by methylation-specific polymerase chain reaction (MSP) and its mRNA expression by reverse transcription PCR. Aberrant methylation of TMS1 was present in 70% (40 of 57) of small cell lung cancer (SCLC) cell lines and 41% (13 of 32) of SCLC tumor tissues, 48% (29 of 61) of non small cell lung cancer (NSCLC) cell lines and 40% (28 of 70) of NSCLC tumor tissues and 46% (12 of 26) of breast cancer cell lines and 32% (20 of 63) of breast tumor tissues. Methylation was absent in the peripheral blood lymphocytes and buccal epithelium from healthy volunteers, as well as in nonmalignant lung tissues and was rare in nonmalignant breast tissues 7% (2 of 30). DNA methylation was confirmed by sequence analysis and the methylation status correlated inversely with TMS1 RNA expression in 18 cell lines tested. RNA expression was restored by treatment with the demethylating agent 5-aza-2'-deoxycytidine, in 4 of 4 methylated cell lines that lacked the TMS1 transcript. Our results suggest that methylation of TMS1 may play a role in the pathogenesis of small cell and non small lung and breast cancers., (Copyright 2003 Wiley-Liss, Inc.)

Background and Objectives: We have reported that both lifestyle and family history might be related to multiplicity of carcinoma in the upper aerodigestive tract (UADT). The aim of this study was to elucidate the relationship between the number of carcinomas and risk factors., Methods: A serial histologic evaluation of the entire non-irradiated esophagus was performed in 114 males with esophageal cancer who were divided into three groups (group I: 88 cases with solitary cancer, group II: 11 with double cancers, group III: 15 with three or more cancers). As controls, 228 males with benign diseases were selected., Results: Among group III patients, both the incidence of heavy smoking and that of heavy drinking were 67% and 60%, which were significantly higher than those of group I (28% and 30%) and control subjects (14% and 10%, respectively). Heavy drinkers who were also heavy smokers were observed in 2, 10, 27, and 47% in control subjects, groups I, II, and III, respectively. Regarding family history, 27% of group III had a close relative with UADT or lung cancer, while the incidence was 7% in the control., Conclusions: These findings strongly support the hypothesis that heavy smoking and heavy drinking, as well as a family history of both UADT and lung cancer, might be risk factors for multicentric occurrence of UADT cancer., (Copyright 2003 Wiley-Liss, Inc.)

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.

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%.

Objective: The FDG uptake in lung cancer is considered to reflect the degree of malignancy, while alterations of some tumor suppressor genes are considered to be related to the malignant biological behavior of tumors. The aim of this study is to examine the relationship between FDG-PET and alterations in the tumor suppression genes of lung cancer., Methods: We examined 28 patients with primary lung cancer who underwent FDG-PET before surgery consisting of 17 patients with adenocarcinoma, 10 with squamous cell carcinoma and 1 with large cell carcinoma. The FDG-PET findings were evaluated based on the standardized uptake value (SUV). Alterations in the tumor suppressor genes, Rb, p16, p27 and p53, were evaluated immunohistochemically., Results: The FDG uptake in lung cancer with alteration in each tumor suppressor gene tended to be higher than in those genes without alterations, although the differences were not significant. In 15 tumors with alterations in either tumor suppressor genes, the FDG uptake was 6.83 +/- 3.21. On the other hand, the mean FDG uptake was 1.95 in 2 tumors without alterations in any genes. The difference in the FDG uptake between the 2 groups was statistically significant (p < 0.001)., Conclusions: In conclusion, the presence of abnormalities in the tumor suppressor genes, which results in an accelerated cell proliferation, is thus considered to increase the FDG uptake in lung cancer.

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.

Now that the human genome has been sequenced, we consider that combinations of 3 to 10 million polymorphic loci scattered throughout the genome contribute to individual differences. Genetic polymorphism analysis is useful for the made-to-order medical treatment of patients and the prevention of disease onset in normal healthy individuals. Individually-tailored disease prevention based on findings such as genetic polymorphism analysis results can be grasped by the concept of evidence-based prevention (EBP). In this paper we outline cytochrome P450 (CYP) 1A1 and 2E1 polymorphism-related differences in metabolic activation of carcinogens in relation to the risk of lung cancer, and explain single nucleotide polymorphism (SNP). We also compare the reports to date on SNP types in CYP1A1 and CYP2E1 in relation to the risk of lung cancer with our study results, examine survival rates of lung cancer patients by CYP1A1 or CYP2E1 genotype and discuss the applicability of SNP research to EBP.

Aberrant methylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of lung cancers. There are major smoke exposure, histology, geography and gender-related changes in non-small cell lung cancer (NSCLC). We investigated smoking-related, histologic, geographic and gender differences in the methylation profiles of resected NSCLCs. We examined 514 cases of NSCLC and 84 corresponding nonmalignant lung tissues from 4 countries (USA, Australia, Japan and Taiwan) for the methylation status of 7 genes known to be frequently methylated in lung cancers [p16, RASSF1A (RAS association domain family 1), APC, RARbeta, CDH13, MGMT and GSTP1]. Multivariate analyses were used for data analysis. Adenocarcinoma was the major histologic type in women and never smokers; analyses that involved smoke exposure and gender were limited to this histology. Our major findings are a) methylation status of any single gene was largely independent of methylation status of other genes; b) the rates of methylation of p16 and APC and the mean Methylation Index (MI), a reflection of the overall methylation status, were significantly higher in ever smokers than in never smokers; c) the mean MI of tumors arising in former smokers was significantly lower than the mean of current smokers; d) the methylation rates of APC, CDH13 and RARbeta were significantly higher in adenocarcinomas than in squamous cell carcinomas; e) methylation rates of MGMT and GSTP1 were significantly higher in the USA and Australian cases than in those from Japan and Taiwan; and (f) no significant gender-related differences in methylation patterns were noted. Our findings demonstrate important smoke exposure, histologic type and geography-related differences in the methylation profiles of NSCLC tumors., (Copyright 2002 Wiley-Liss, Inc.)

Unlabelled: Serum copper (Cu), zinc (Zn) the Cu/Zn ratio (Cu/Zn) and selenium (Se) were evaluated in 84 patients with non-small cell lung cancer (NSCLC) before surgery. Serum carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and sialyl Lewis X-i antigen (SLX) levels were also determined in the same cases. The cut-off values of Cu, Zn and Se were established to create two categories with equal numbers of patients. We investigated the clinical and prognostic usefulness of assays of serum trace elements (Cu, Zn, Cu/Zn and Se) and compared levels of serum trace elements and serum tumor markers (CEA, SCC and SLX) in NSCLC patients. Furthermore, we evaluated the usefulness of serum trace elements, when compared with tumor markers, in assessing prognosis for NSCLC., In Conclusion: (1) a preoperative increase in Cu/Zn level predicted tumor progression more effectively than changes in Cu or Zn levels; (2) Se levels seemed to vary with age, but there was no relationship between Se level and disease stage; (3) the measurement of Cu/Zn was useful for assessing both prognosis and extent of the disease in NSCLC patients, similar to the measurement of serum tumor markers such as CEA; and (4) the measurement of the Cu/Zn had prognostic significance, but was inferior to disease stage in predicting outcome. Cu and Zn in serum are storable and the determination of Cu/Zn level is so simple and inexpensive that it can be helpful in determining clinical stages and predicting the prognoses of NSCLC patients.

Angiocentric immunoproliferative lesion (AIL) is the angiocentric and angiodestructive process of lymphoreticular cells with vascular invasion. AIL of the lung is rare. We treated a 57-year-old woman with AIL of the lung in whom chest radiography and computed tomography showed ground-glass opacity in the left lower lobe and lingular segment. Since macroscopical and intraoperative lung biopsy findings could not rule out the possibility of malignancy, including malignant lymphoma, we conducted left pneumonectomy. Immunohistological examination of the tumor showed that infiltrating lymphocytes consistent with AIL. Because tumor markers such as serum LDH and soluble IL-2 receptor increased postoperatively, we conducted systemic chemotherapy, after which elevated serum tumor markers decreased.

Background: Since lung cancer is the major cause of death not only in Japan but in many other industrialized countries, the development of new therapeutic modalities is quite important. In patients with melanoma, immunotherapy with some tumor antigens has been shown to result in tumor regression. However, little is known about specific immune responses and tumor antigens in lung cancer, due to difficulty in establishing appropriate lung cancer cell lines. In order to resolve these difficulties, we tried to establish and characterize lung cancer cell lines as useful tools for the analysis of tumor-specific immune responses in patients with lung cancer., Materials and Methods: We tried to establish lung cancer cell lines from 549 patients with resectable lung cancer and from 21 patients with pleural and pericardial effusions or lymph node metastasis. We characterized the established cell lines after the induction of tumor-specific cytotoxic T lymphocytes (CTLs), and analyzed both the major histocompatibility complex (MHC) class I and class II molecules on their surfaces., Results: We succeeded in establishing 15 lung cancer cell lines from 570 specimens (2.6%). The success rate of the establishment of lung cancer cell lines was significantly higher in patients at such advanced stages as MHC III and IV than in those at MHC stages I and II (p = 0.004). MHC class I molecules were expressed in 12 of 15 cell lines (80%), while MHC class II molecules were found in 3 of 15 cell lines (20%) on their cell surfaces by flow cytometry. A haplotype loss of MHC class I antigens was found in 6 of 15 cell lines (40%). Although CTLs were induced in only two of eight cell lines tried by stimulation with nontransduced autologous tumor cell lines, CTLs were successfully induced in all of eight cell lines tested by stimulation with CD80-transfected autologous tumor cells., Conclusions: These results suggested that the tumor antigens recognized by CTLs could thus exist in the tumor cells derived from many lung cancer patients. It is, therefore, possible that antigen-specific immunotherapies may be potentially effective for patients with lung cancer by adoptive transfer of CTLs, as well as by vaccine therapy using tumor-specific antigens.

Purpose: This study was designed to substantiate the prognostic impact of occult micrometastatic tumor cells in the lymph nodes (LNs) and bone marrow (BM) in stage I non-small-cell lung cancer (NSCLC) patients using cytokeratin (CK) as a micrometastatic marker and the relationship between the micrometastases in the LNs and BM., Patients and Methods: A total of 2,432 hilar and mediastinal LNs were removed during surgery from 115 patients with completely resected stage I NSCLC. The LNs were analyzed for micrometastasis using immunohistochemistry with the biclonal anti-CK antibody AE1/AE3. BM aspirates from 115 patients were immunocytochemically stained with the monoclonal anti-CK antibody CK2., Results: CK-positive (CK+) cells were detected in 42 (1.7%) of 2,432 LNs, in 32 (27.8%) of 115 patients, and in 32 (27.8%) of 115 BM aspirates. There was no relationship between the frequencies of CK+ cells in the LNs and in the BM. The patients with CK+ cells in the LNs had a poor prognosis by both univariate (P =.008) and multivariate analyses (P =.01), whereas the presence of CK+ cells in the BM did not allow prediction of survival (P =.32). The prognostic impact of LNs micrometastasis was independent even after adjusting for the status of BM micrometastasis., Conclusion: The detection of lymph nodal micrometastatic tumor cells provides an accurate assessment of tumor staging and has powerful prognostic implications for completely resected stage I NSCLC patients.

A case report of a slowly progressive adenocarcinoma of the lung, followed by computed tomography is herein discussed. The patient was a 76-year-old woman, who was operated on about four years after a small lung nodule on her left upper lobe was discovered. The tumor was suspected to be either well differentiated adenocarcinoma or atypical adenomatous hyperplasia (AAH) by the findings of chest computed tomography before the operation, and the resected specimen demonstrated well differentiated adenocarcinoma, without lymph node metastasis. This case demonstrates the possibility that some adenocarcinomas with particular histology are slowly progressive, and also there might be the option of lobectomy or segmentectomy for treating such tumors.

We analyzed the outcome of 30 patients who underwent surgery (40 operations) for pulmonary metastases of colorectal cancer. Overall 5-year survival rate was 56%. There were no significant differences in survivals 5 years after the first surgery on the basis of potential prognostic factors: disease free interval, number of pulmonary metastases and size of metastatic lesion. Three patients with recurrent pulmonary metastases after the first resection underwent repeated resections and are alive 23, 58 and 62 months after the first pulmonary metastasectomy, respectively. Pulmonary resection for metastases from colorectal cancer prolonged the survival of patients, even those with bilateral lesions or recurrent metastases. These results confirm that pulmonary resection for metastatic colorectal cancer is a potentially curative therapy.

Two surgical cases of synchronous double esophageal and gastric cancer, both of which revealed a superficial type were investigated. The first case was a 58 years old man, who was found to have an abnormal gastric shadow on mass screening. Gastrointestinal examination revealed a synchronous double cancer of the esophagus (Mt-Lt, m) and stomach (L, m). An endoscopic mucosal resection was performed on the gastric cancer and after 3 weeks a blunt dissection on the esophageal cancer was performed and the gastric tube was reconstructed. The second case was a 65 years old man, who was found to have an ulcerative esophageal tumor (Ut, type 2) and a gastric tumor (M, 0-II c) at the anterior wall of the upper body on gastrointestinal examination for a complaint of hematemesis. A subtotal esophagectomy and a lymph node dissection was performed in which reconstruction was made by using a gastric tube avoiding the gastric cancer lesion. We also reviewed previous reports of 22 cases that had synchronous superficial esophageal and gastric cancer, and discussed the indications and methods of operation.

Thorombospondin-1 (TSP-1) is a 450 kDa extracellular matrix glycoprotein, with anti-angiogenic activity. We analyzed the relationship in TSP-1 expression and Microvessel count (MVC), and also clinical factors, using immunohistochemical methods for non-small cell cancer (NSCLC). Histopathologically, there was inverse correlation between TSP-1 expression and MVC for squamous cell carcinoma, but not for adenocarcinoma cases. Among 199 completely resected cases of NSCLC, the 5-year survival was 77.0% when the expression of TSP-1 was maintained and 55.1% when the expression were reduced, respectively (P=0.0046). When compared with TSP-1 expression in the high MVC subgroup, there was significantly shorter survival time when TSP-1 expression was reduced (P=0.0091), and no significant difference was seen for the low MVC subgroup. Multivariate analysis revealed that expression of TSP-1 is as a prognostic factor of NSCLC. Our present data suggest that TSP-1 might not be a direct anti-angiogenic factor and the TSP-1 expression is a prognostic indicator of NSCLC.

Bochdalek hernia is a type of congenital diaphragmatic hernia that mainly occurs in childhood, but is extremely rare in adults. A case report of Bochdalek hernia in a 17-year-old woman, complaining of left lateral upper abdominal pain is herein reported with a brief review of the literature. The herniated organs into the thoracic cavity in this case were the as stomach, large intestine, spleen and greater omentum which was diagnosed using computed tomography, an upper gastrointestinal double contrast study and irrigography. The patient was successfully treated by video-assisted thorachoscopic surgery (VATS) with a pushback method. The post-operating course was uneventful with minimal pain of the surgical wound. This case demonstrated the efficacy of the VATS repair for Bochdalek hernia.

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.

We assessed the occurrence of atypical adenomatous hyperplasia (AAH) in whole lung lobes with primary cancer lesions. Following surgical resection, tissue specimens were sliced to a thickness of 4 mm (3,641 specimens from 61 cases; mean = 59.7 specimens per case). A total of 119 AAH foci were found and an association was evident in 25 (57%) of 44 adenocarcinomas, 3 (30%) of 10 squamous cell carcinomas, and 2 (29%) of 7 other lung cancers. Histologic evaluation showed that 108 AAH foci were categorized as low-grade and the other 11 as high-grade AAH. These 11 foci of high-grade AAH were present in 7 patients with adenocarcinoma, and in 1 patient there was a synchronous double primary lung adenocarcinoma. High-grade AAH was closely associated with bronchioloalveolar carcinoma (BAC) type adenocarcinoma, and low-grade AAH with non-BAC adenocarcinoma. The mean +/- SD Ki-67 labeling index in high-grade AAH (3.5%+/-2.9%) was significantly higher than for the low-grade index (1.4%+/-1.6%). We propose that foci of high- but not low-grade AAH may be potential precursor lesions of lung adenocarcinoma, especially with the BAC component.

Background: A loss or dysfunction of E-cadherin or catenins, which maintain tissue integrity, is associated with an invasive phenotype of various solid tumors. Therefore, we analyzed the expression of E-cadherin and alpha-catenin, beta-catenin, and gamma-catenin in thymoma tissue specimens to investigate its clinical significance., Methods: The expressions of E-cadherin and alpha-catenin, beta-catenin, and gamma-catenin in thymoma tissues were evaluated in 21 patients, including 9 epithelial predominant type, 5 lymphocytic predominant type, and 7 mixed type patients based on an immunohistochemical analysis using monoclonal antibodies, and the relationship between the expression status and clinicopathologic features was investigated., Results: Reduced expressions were observed in 11 patients (52%) for E-cadherin, 10 (45%) for alpha-catenin, 6 (27%) for beta-catenin, and 10 (45%) for gamma-catenin. Such an expression status (reduced or preserved) of the molecules closely correlated with each other. The expression of E-cadherin was well preserved in 5 of 5 patients with lymphocyte predominant type whereas E-cadherin was reduced in 11 of 17 patients with other histologic subtypes. All of the 9 cortex type thymomas (B1 to 3) showed preserved expression of beta-catenin. There was no significant relationship among the expressions of the molecules and the Masaoka stage classification (I versus others)., Conclusions: The status of expressions for these molecules may affect the degree of lymphoid infiltration while not affecting the degree of invasiveness in thymoma.

Bronchial leiomyoma with atelectasis in the left lower lobe occurred in a 44-year-old woman. The leiomyoma was diagnosed by bronchofiberscopy, and left lower sleeve lobectomy was performed. The histopathology of the tumor revealed a leiomyoma with no evidence of malignancy. An early accurate diagnosis is thought to be important for a more conservative treatment.

Background: The presence of disseminated tumor cells in bone marrow is considered to be a premetastatic state, which is called micrometastasis. To evaluate the relationship between micrometastasis and cellular adhesion molecules in the primary lesion, E-cadherin and beta-catenin were immunohistochemically investigated. Methods. Fifty-eight patients with non-small cell lung cancer who underwent a complete resection were entered into this study. Tumor cells in bone marrow aspirates were detected by immunohistochemistry using cytokeratin (CK) 18. Immunohistochemical studies of E-cadherin and beta-catenin were performed in the corresponding primary tumor., Results: CK-positive cells were detected in the bone marrow aspirates from 27 of 58 patients. A reduced expression of the E-cadherin and beta-catenin was found in 16 (27.6%) and in 22 (37.9%) of 58 patients, respectively. In 26 cases with a reduced expression of E-cadherin and/or beta-catenin, 16 cases had CK-positive cells, whereas 11 of 32 cases with normal expression of both factors had CK-positive cells (P=.0392). The patients with micrometastasis demonstrated an earlier recurrence (P =.0642) and a significantly poorer survival (P =.0437) than those without such cells., Conclusions: Micrometastasis in the bone marrow might be a significant predictor of poor prognosis, and a reduced expression of E-cadherin and beta-catenin are important determinants for the metastatic capability of individual cancer cells.

We immunohistochemically examined 141 surgically resected peripheral lung adenocarcinomas for the expression of Fas, single stranded (ss-) DNA and Ki-67, and statistically evaluated the relationship of these parameters with other clinicopathologic variables, including clinical stage, nodal involvement, and histopathologic subtypes classified according to WHO criteria. Fas expression by cancer cells was characteristically localized in the cytoplasm, and the extent of expression correlated well with the degree of Ki-67 reactivity (p = 0.0004), but not with the degree of apoptic occurrence, as assessed by ss-DNA reactivity. Cancer cells of the bronchioloalveolar carcinoma (BAC) subtype without invasive growth exhibited a significantly lower Fas expression than those of other subtypes (p < 0.0001). Positive expression of Fas was frequently associated with a high incidence of nodal involvement and advanced clinical stage, as compared with cases of negative expression (p = 0.0111 and p = 0.0439, respectively). Multivariate analysis revealed that Fas expression significantly correlated with the histologic subtype, but not with tumor size, nodal involvement, or clinical stage. Survival analysis determined by the log-rank test revealed that clinical stage and Ki-67 reactivity were poor prognostic variables, and Fas expression was not statistically significant. Based on these data, intracytoplasmic expression of Fas in cancer cells may participate in the development of resistance to fas-mediated apoptosis.

Background: The acquisition of immune reaction in the peripheral blood is expected to play a critical role in the prevention of tumor progression. However, the clinical role of the circulating immune response against human cancer remains unclear., Methods: Serum samples from 68 consecutive patients who underwent resection for pulmonary adenocarcinoma were obtained before the operation. The serum levels of interferon gamma and interleukin 4 were measured and the impact on the clinical features was assessed. According to the predominance of the cytokine levels, the patients were classified into 4 groups: interferon gamma only (T(H)1), interleukin 4 only (T(H)2), both (T(H)0), and neither (T(H)X)., Results: In the T(H)1 group, 18 of 22 patients (81.8%) were free from lymph node metastasis, whereas 5 of 7 patients (71.4%) in the T(H)2 group had lymph node involvements. As a result, 62 patients underwent complete resection, with 9 of 19 patients (47.3%) in the T(H)1 group having recurrence, but no relapse of the disease appearing in the T(H)2 group during the observation period. The disease-free interval for the T(H)2 group was significantly longer than that for the T(H)1 group (44.2 mo vs 26.1 mo, P =.03)., Conclusions: Assessing the serum T(H) profile on the basis of the predominance of the serum interferon gamma or interleukin 4 is important to presume the ongoing responses of T cells against the tumor burden.