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Background: The purpose of the present study was to clarify the prognostic significance of human leukocyte antigen (HLA) class I expression in patients with non-small-cell lung cancer who underwent complete surgical resection., Patients and Methods: The expression of HLA class I molecules was evaluated in 403 resected NSCLC specimens using immunohistochemistry. The results were scored as the percentage of stained tumor cells and were categorized into three groups: 0%-24% (decreased), 25%-79% (heterogeneous), and 80% or more (normal)., Results: The expression of HLA class I was evaluated in 124 tumors in the normal expression group, 181 tumors in the heterogeneous expression group, and 98 tumors in the decreased expression group. The 5-year survival rate of all patients after surgery according to the HLA class I expression in the normal, heterogeneous, and decreased groups was 76.6%, 65.9%, and 76.1%, respectively. The prognosis was significantly better in the normal expression group than in the heterogeneous group. Normal HLA class I expression also correlated with favorable survival in patients with stage I disease., Conclusions: The normal expression of HLA class I was associated with a favorable prognosis compared with the heterogeneous expression group, but no significant difference was observed between the normal expression and decreased expression groups., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aim: The purpose of this study was to investigate the clinical significance of expression of cancer/testis (CT) antigen and down-regulation of HLA class-I in patients with stage I non-small cell lung cancer (NSCLC), which underwent complete surgical resection., Patients and Methods: The expression of HLA class-I molecules was evaluated in 136 resected NSCLC specimens by immunohistochemistry. The results were scored as the percentage of stained tumor cells and categorized into two groups: 0-79%, reduced expression; and >80%, normal expression. The expression of CT antigen was performed by reverse transcription-polymerase chain reaction (RT-PCR)., Results: The expression of HLA class-I was normal in 49 tumors (36%), and there was reduced expression in 87 tumors (64%). The expression of Melanoma antigen (MAGE)-A3, MAGE-A4, and Kita-Kyushu lung cancer antigen-1 (KK-LC-1) was positive in 34 (25.0%), 22 (16.2%), and 42 (30.9%) patients, respectively. There was no significant difference in the proportion of HLA class-I expression associated with the expression of any of the CT antigens. Among the patients with positive expression of at least one of the CT antigens, the 5-year survival rate of the patients with the normal expression of HLA class-I was 87.5%; however, it was 63.4% in patients with the reduced expression of HLA class-I (p=0.0477)., Conclusion: Reduced expression of HLA class-I was an unfavorable prognostic factor in patients with positive expression of CT antigen, and represents an important hurdle to antigen-based cancer immunotherapy.

Objectives: Immune therapy targeting cancer/testis (CT) antigens improve the survival in several types of solid tumours. The expression of CT antigens is related to poor survival in non-small-cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) mutation is the best predictive factor for the sensitivity to tyrosine kinase inhibitors in lung adenocarcinoma. The aim of this study was to elucidate the correlation between the expression of CT antigens and clinicopathological factors, including the EGFR mutation, and to analyse the prognosis in lung adenocarcinoma., Methods: Data were collected from a total of 281 lung adenocarcinoma patients who underwent surgery. Among them, 125 cases, whose specimens were too small to extract sufficient DNA and/or RNA, and 2 cases with the coexistence of another histological lung cancer were excluded. A total of 154 patients were reviewed. The expression of CT antigens (melanoma-associated antigen gene [MAGE]-A4 and KK-LC-1) and the EGFR-activating mutation (L858R point mutation in exon 21 and inframe deletion in exon 19) was evaluated by using polymerase chain reaction amplification., Results: The expression of MAGE-A4 and KK-LC-1 was detected in 14 (9%) and 54 patients (35%) with adenocarcinoma. The EGFR-activating mutation was found in 64 patients (42%). Univariate and multivariate analyses demonstrated that tumours expressing at least one CT antigen were associated with no EGFR mutation (odds ratio = 0.3; 95% confidence interval, 0.14-0.71; P < 0.01). A survival analysis was performed in 135 patients who underwent complete resection and the 5-year overall survival rate was 71.1% in those with any expression of CT antigens and 83.2% in those without expression of the genes (P < 0.04)., Conclusion: Two different therapeutic targets, EGFR-activating mutation and CT antigen, have a negative relationship with each other.

We evaluated the tumour shape as a potential prognostic indicator in lung adenocarcinoma patients. Among 994 patients who underwent curative surgery, 78 cases of adenocarcinoma (N0M0) with tumours ≥ 31 mm in diameter were reviewed. The patients were divided into two groups based on the ratio between the longest and the smallest axis length. The patients who had tumours whose ratios were > 0.5 were defined as the globular shape group (GL) and the others, whose ratio was 0.5 or less, were defined as the ellipse shape group (EL). The 78 patients were divided into two subgroups (57 in the GL and 21 in the EL). The tumour shape was related to the prognosis, and the 5-year overall survival (OS) rate in the GL was 51.5%, and that in the EL was 85.5% (P = 0.018). The 5-year disease-free survival rate of the GL was 46.6% and that of the EL patients was 85.0% (P = 0.04). The multivariate analysis showed that the shape of the tumour and the presence of pleural invasion were the independent and significant factors predicting the OS (P = 0.04 and P < 0.01, respectively). In adenocarcinoma patients, the shape of the tumour is related to the postoperative survival.

Background: The incidence of breast cancer has been increasing in Japan over the past three decades, and it is the currently the most common malignancy in Japan. This study investigated the temporal trends of the surgical outcomes in patients with breast cancer., Methods: We evaluated 543 consecutive patients who underwent breast-cancer resection between 1980 and 2009. The temporal trends in the surgical outcome and clinicopathological features were evaluated separately for the periods covering 1980 to 1989, 1990 to 1999, and 2000 to 2009., Results: The number of patients who underwent resection during these three respective periods were 133, 176, and 234, respectively. All patients were women. The percentage of patients at stages 0 or 1 was 63.2%, 58.5%, and 43.6%, respectively, during the three periods. The mean diameter of tumors in each period was 38, 29, and 30 mm, respectively. The percentage of tumors with positive ER expression was 62.5%, 64.3%, and 69.7%, respectively. In terms of surgical procedures, the use of Halsted's radical mastectomy decreased during each period: from 40.6% of cases to 8.5% and then to 0.4%, while the proportion of breast-conserving therapies increased, from 0% to 12.5%, and finally to 35.9%. The postoperative 10-year survival rates during the three periods were 75.9%, 83.5%, and 84.9%, respectively. The 10-year survival rates of patients with stage II disease during the three periods were 66.2%, 75.7%, and 90.7%, respectively. The prognosis of stage III disease in the three periods also showed a tendency toward improvement, increasing from 37.8% to 64.2%, and finally to 84.5%., Conclusion: The survival of patients with stage II and III disease has improved during the past 30 years. Along with the recent advances in drug therapy, the surgical treatment has become less invasive, often because of drug therapy-related modifications.

Objective: To assess the frequency of osteosclerotic changes on CT that appeared after treatment with gefitinib in patients with lung adenocarcinoma and the relationship between the osteosclerotic changes and the response to the therapy., Materials and Methods: Our study included 41 patients with lung adenocarcinoma who underwent chest CT both before (CTpre) and after (CTpost) starting treatment with gefitinib. The presence or absence of bone metastases was assessed on the CTpre, and the interval bony change after the therapy was classified as lytic, sclerotic, or no changes on the CTpost. The relationship between treatment results of primary lung cancer and interval bony changes was evaluated., Results: Osteosclerotic lesions were identified in 11 patients (27%) on CTpost; in 6 of 11 patients osteosclerotic lesions newly appeared where the CTpre showed no bone metastasis before the gefitinib therapy. There were significant differences in the therapeutic response of the primary cancers (P < 0.001) and in the survival rate (P < 0.01) in patients with osteosclerotic changes versus those without osteosclerotic changes., Conclusion: Osteosclerotic changes on CT, observed after gefitinib treatment in patients with lung adenocarcinomas, may be an indicator of a good therapeutic response.

Background: The purpose of the current study was to clarify the clinical role of insulin-like growth factor receptor-1 (IGF1R) in NSCLC., Patients and Methods: Tumor specimens were collected from 285 patients who underwent complete resection for adenocarcinoma (AD, n = 182), squamous cell carcinoma (SCC, n = 77), and other histologic types of cancer (n = 26) of the lung. The expression of IGF1R and Ki-67 was evaluated by immunohistochemical (IHC) analysis., Results: Positive expression of IGF1R was detected in 87 (30.5%) of 285 cases, of which 43 (23.6%) of 182 cases were AD, 36 (46.8%) of 77 cases were SCC, and 8 (30.8%) of 26 cases were other histologic types (SCC vs. AD, p < .001; SCC vs. non-SCC, p < .001). Positive IGF1R expression was also identified in 20 (44.4%) and 67 (27.9%) of the patients with and without recurrence, respectively (p = .027). Multivariate logistic regression models indicated that positive staining for IGF1R expression was an independent factor in AD associated with tumor recurrence (p = .040) but not in NSCLC, SCC, and other types of cancer. A positive IGF1R expression tended to demonstrate a poor disease-free survival (DFS) in NSCLC according to the Kaplan-Meier DFS curves (p = .053). The tumors showing a positive expression of IGF1R were observed more frequently in tumors with a positive expression of Ki-67 than in the tumors with a negative expression of Ki-67 (p = .010)., Conclusion: IGF1R expression was associated with reduced DFS correlating with postoperative recurrence. In addition, a significant relationship was also observed between IGF1R and Ki-67 expression in NSCLC. However, in subgroup analysis, a significant correlation was not observed. IGF1R expression predicts postoperative recurrence in patients with AD, but not in those with non-AD of NSCLC., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim: The human epidermal growth factor receptor HER-2/neu (HER2) gene is a proto-oncogene involved in the signal transduction pathways leading to cell growth and differentiation. The present study focused on the clinical significance of the expression of HER2 in non-small cell lung cancer (NSCLC)., Patients and Methods: Consecutive specimens of 159 adenocarcinomas and 77 squamous cell carcinomas, from patients who had been treated by complete resection of NSCLC in our department between 2003 and 2005, were studied. The HER2 expression was evaluated by immunohistochemical staining with score of membranous staining being 0=none, 1=weak, 2=10-30% cells, 3≥30% cells stained., Results: The staining scores in adenocarcinoma were 0 in 121 patients (76.1%), 1 in 16 (10.0%), 2 in 17 (10.7%), and 3 in 5 patients (3.1%). The HER2 expression scores in squamous cell carcinoma were 0 in 74 patients (96.1%), 1 in 1 (1.2%), 2 in 1 (1.2%), and 3 in 1 patient (1.2%). The postoperative 5-year survival rate of patients with adenocarcinoma according to the expression of HER2 scores 0, 1, 2 and 3 was 75.3%, 77.8%, 76.5% and 20.0%, respectively. Patients with adenocarcinoma with score 3 staining had a significantly unfavorable prognosis compared to those with staining scores of 0-2 (p=0.0216)., Conclusion: HER2 overexpression (score 3) in adenocaricinoma was a significantly unfavorable prognostic factor. Since the number of NSCLC patients with HER2 overexpression was small, further investigations will be necessary to clarify the efficacy of molecular targeted therapy for this subgroup.

Primary lung cancer is an extremely rare neoplasm in young adults. We report a case of a primary lung adenocarcinoma in an 18-year-old man who presented for examination of a solitary nodule located in the right lower lobe of the lung. A right lower lobectomy was performed with an incomplete resection because of pleural dissemination (pT4N2M0 stage IIIB adenocarcinoma). Intrathoracic chemotherapy (cisplatin, 50 mg/body) was administered initially, followed by systemic chemotherapy (carboplatin + paclitaxel). A bronchopleural fistula occurred 2 months postoperatively and was successfully treated with conservative therapy, including thoracic drainage, intrathoracic fibrin glue administration, and transbronchial superglue administration. Thereafter, a total of five courses of systemic chemotherapy with minor changes in the administration regimen were performed. The patient was alive and with no evidence of recurrence at his 5-year follow-up.

Background: Individualized treatment is an attractive challenge that may allow for more effective and safer treatment of human disease. Activating mutations in the epidermal growth factor receptor (EGFR) gene in lung adenocarcinoma are associated with a dramatic clinical response to EGFR-tyrosine kinase inhibitors (TKIs). However, patients often experience a relapse after treatment with EGFR-TKIs, even when the tumors are initially highly sensitive. However, the "whole picture" regarding acquired resistance remains unclear., Methods: Tumor specimens were collected from 11 lung adenocarcinoma patients before and after treatment with gefitinib. The status of the EGFR and K-ras genes were investigated by PCR-based analyses. Immunohistochemistry and real-time PCR assays were used to evaluate the MET gene in terms of its tyrosine phosphorylation and amplification, respectively. The expression of HGF, PTEN, and EGR-1, and changes in the epithelial-mesenchymal transition (EMT) status including the expression of E-cadherin and gamma-catenin as epithelial markers, and vimentin and fibronectin as mesenchymal markers, were evaluated by immunohistochemistry., Results: Seven (64%) of the gefitinib refractory tumors exhibited a secondary threonine-to-methionine mutation at codon 790 in EGFR (T790M). All of the tumors had wild type K-ras gene expression. No MET amplification was detected in any of the samples, nor was there phosphorylation of MET detected in any of the resistant samples. Neither MET gene amplification, nor the overexpression of HGF was observed in samples without the T790M mutation. A strong expression of HGF was detected in 6 of 8 specimens with the T790M mutation. Three (38%) of 8 cases showed a loss of PTEN in samples with the T790M mutation. A loss of EGR-1 was detected in 2 (29%) of 7 cases, including one tumor without PTEN. Four (57%) of 7 cases showed positive expression of phosphorylated Akt (p-Akt). A change in the EMT status between pre-and post-treatment was observed in 4 (44%) of 9 cases. In all examined samples cases, some alterations of gene or proteins were observed., Conclusions: The current results showed that these alterations in gene or protein expression can account for all resistant mechanisms. This phenomenon suggests the existence of complicated relationships among acquired resistance-related genes., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The incidence of multiple primary lung adenocarcinoma (MPLA) is increasing, and it is important to distinguish MPLA from intrapulmonary metastasis (IPM) in order to determine the therapeutic strategy. However, there is no reliable method to differentiate between the two. The purpose of this study was to distinguish MPLA from IPM based on the gene status of EGFR and K-ras and the morphological Noguchi classification system. Sixty-eight tumors from 34 cases of clinical MPLA were evaluated. Of them, 11 cases (32.4%) were diagnosed as biological MPLA (bMPLA) by EGFR/K-ras mutation analyses, and 12 cases (35.3%) by morphological analysis. In all, 23 of the 34 cases (67.6%) were diagnosed as bMPLA. The remaining 11 cases were diagnosed as biological IPM (bIPM). The 5-year survival rates of bMPLA and bIPM were 90.9% and 63.6%, respectively (p=0.04). These findings suggest that the combination method including gene mutation and morphological analysis can guide treatment decisions and that there is a need for systemic chemotherapy, and surveillance monitoring.

Background: Not all patients with lung cancer require postoperative adjuvant chemotherapy after a complete resection. However, no useful markers for either selecting appropriate candidates or for predicting clinical recurrence exist., Methods: Tumor specimens were collected from 183 consecutive patients who underwent a complete resection for lung adenocarcinoma from 2003 to 2007 in our department. We analyzed the thymidylate synthase (TS) and dihydrofolate reductase (DHFR) expressions in the primary lung adenocarcinoma by immunohistochemisty., Results: The strong expression of TS and DHFR was identified in 39 (21.3%) and 120 (65.6%) patients, respectively. The strong TS expression was identified in 11 (39.3%) of 28 patients and 28 (18.1%) of 155 patients in patients with and without recurrence, respectively (p=0.012). The strong DHFR expression was also identified in 23 (82.1%) and 97 (62.6%) of the patients with and without recurrence, respectively (p=0.045). Logistic regression models indicated the strong TS expression to be an independent factor for tumor recurrence. The strong TS and DHFR expression was associated with a poorer disease-free survival (DFS) according to the survival analysis. A multivariate analysis demonstrated the strong TS expression to be independently associated with an increased risk for poor DFS., Conclusions: The strong TS expression may be a useful marker for predicting postoperative recurrence in patients with lung adenocarcinoma following surgery., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: The purpose of this study was to clarify the role and clinical significance of metastasis associated in colon cancer 1 in resected stage I non-small cell lung cancers., Methods: Tumor specimens were collected from 146 consecutive patients who underwent a complete resection for stage I lung adenocarcinoma from 1998 to 2007 at the University of Occupational and Environmental Health. We analyzed the expression of metastasis associated in colon cancer 1 mRNA of primary lung adenocarcinomas by real-time reverse transcriptase-polymerase chain reaction., Results: The average postoperative observation period was 49.4 months. Thirteen (8.9%) of 146 patients had recurrences after surgery. Overexpression of metastasis associated in colon cancer 1 mRNA was identified in 62 patients (42.5%). Metastasis associated in colon cancer 1 was overexpressed in 9 (69.2%) of 13 patients and 53 (39.9%) of 133 patients with and without recurrence, respectively (P = .004). The median metastasis associated in colon cancer 1 copy number was 3.0 and 1.4 in patients with and without tumor recurrence, respectively. Metastasis associated in colon cancer 1 overexpression was associated with poorer disease-free survival according to the survival analysis (P = .033)., Conclusions: Metastasis associated in colon cancer 1 gene overexpression may be a useful marker for predicting postoperative recurrence in patients with lung adenocarcinoma after surgery., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Purpose: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (EGFR-TKI) demonstrates a dramatic clinical response for the lung adenocarcinoma patients harboring a somatic mutation of EGFR. Such EGFR mutations are frequently found in adenocarcinoma with a strong expression of estrogen receptor (ER) beta, which has been shown to correlate with a favorable prognosis for the patients with EGFR mutations. The aim of this study is to elucidate the correlation between expression of ER beta and the therapeutic effect of EGFR-TKI in adenocarcinoma of the lung., Patients and Methods: Forty-three patients who were treated with EGFR-TKI for adenocarcinoma of the lung were evaluated. The expression of ER beta and the EGFR mutation were evaluated by immunohistochemistry and the polymerase chain reaction, respectively. Patients divided into two groups by the nuclear expression of ER beta. The clinical response and survival data were compared between the two groups., Result: Strong (S) and weak (W) expression of ER beta was observed in 21 and 22 patients, respectively. EGFR mutations were detected in 30 (69.8%) cases. The S group had more frequent EGFR mutations than the W group (85.7%, 54.5%, p=0.045). The S group had better response rate (p=0.006) and longer progression-free survival (PFS; p=0.001) than the W group. Even in a limited analysis in the patients with EGFR mutations, the S group had tended to have a better response rate (77.8%, 41.7%, p=0.063), and significant longer PFS (p=0.012) than the W group., Conclusion: A strong expression of ER beta predicts a good clinical outcome for patients with adenocarcinoma of the lung after treatment with EGFR-TKI. This suggests that the expression status of ER beta can be a candidate surrogate marker for EGFR-TKI treatment of patients with adenocarcinoma of the lung. Further investigation will be necessary to identify biomarkers using a larger cohort of patients in a prospective study., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: It was recently reported that a limited pulmonary resection (segmentectomy or wedge resection) was not inferior to a lobectomy in the management of peripheral small-sized adenocarcinoma (tumor ≦ 20 mm) of the lung., Methods: We retrospectively analyzed patients undergoing a lobectomy (n = 114) and a limited resection (n = 35) for peripheral small-sized adenocarcinoma of the lung during a 7-year period from April 2001 to March 2008. Our criteria for the limited resection of lung cancer were as follows: (1) adenocarcinoma of 10 mm or less in diameter and (2) adenocarcinoma of 11-20 mm in diameter, in which the ratio of the ground glass opacity is 50% or more, without pleural indentation on computed tomography. Additionally, the frozen sections of the tumors were intraoperatively diagnosed as Noguchi type A or B. The survival and clinical outcomes were analyzed., Results: The 5-year survival rates of the lobectomy group and limited resection groups were 89.2% and 100%, respectively. No recurrence was seen in the limited resection group., Conclusions: Our results suggest that our criteria for limited resection were adequate for the management of small-sized adenocarcinoma of the lung., (Copyright © 2010 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

Introduction: The identification of activating mutations in the epidermal growth factor receptor (EGFR) gene is one of the most intriguing recent discoveries in the field of lung cancer research, and they are more commonly found in adenocarcinoma occurring in females, never/light smokers, and East Asian patients. Why such certain patients are susceptible to the development of EGFR-mutant tumors is currently unknown., Methods: This study evaluated the medical records of 437 patients with adenocarcinoma of the lung who underwent a surgical resection. The genetic status of the EGFR gene was investigated by polymerase chain reaction-based analyses. The serological typing of histocompatibility leukocyte antigen (HLA) class I was performed using a microcytotoxicity test of lymphocytes or polymerase chain reaction-sequence-specific oligonucleotides, and the correlation between the EGFR mutation and HLA alleles was analyzed., Results: An EGFR mutation was found more frequently in females and never/former smokers than their counterpart. In females, the incidences of EGFR mutation were 61.0% and 41.7% in HLA-A2 (+) and A2 (-) patients with adenocarcinoma of the lung, respectively (p = 0.008). The EGFR mutation was found more frequently in female patients with HLA-A2. However, no significant correlation was identified between the frequencies of other HLA alleles and EGFR mutations in the same patients group., Conclusions: EGFR: mutations are associated with HLA-A2 in female patients with adenocarcinoma of the lung. Further research was needed to elucidate the other relevant factors in the histogenesis of lung cancer with an EGFR mutation.

Background: The epithelial to mesenchymal transition (EMT) may well play a part in determining the sensitivity to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). However to date, no study has investigated the association between the EMT status and acquired resistance using cancer specimens., Patients and Methods: Immunohistochemical (IHC) staining was used to analyse the protein expression of epithelial and mesenchymal markers in tumour samples from lung adenocarcinoma patients. Mutations in the EGFR and K-ras gene were also examined., Results: All patients showed a positive expression of epithelial markers in sensitive tumours. Tumour in 4 (44.4%) out of 9 patients showed down-regulation of epithelial markers or up-regulation of mesenchymal markers. The change in the EMT status between pre-and post-treatment was shown in 2 cases each with and without the T790M mutation., Conclusion: EMT plays a role in approximately half of the cases of resistance to EGFR-TKI, independent of T790M mutation.

Background: The mutation and amplification of oncogenic genes are associated with carcinogenesis and tumor growth. The purpose of this study was to clarify the role of the epidermal growth factor receptor (EGFR), K-ras, MET, and hepatocyte growth factor (HGF) status in lung adenocarcinoma., Methods: Tumor specimens were collected from 183 patients who underwent a complete resection for adenocarcinoma of the lung from 2003 to 2007 in our department. The genetic status of the EGFR and K-ras genes were investigated by polymerase chain reaction (PCR)-based analyses. Immunohistochemistry and real time PCR assays were used to evaluate the MET gene regarding to tyrosine phosphorylation and amplification, respectively. HGF status was evaluated by immunohistochemistry., Results: The mutations of EGFR and K-ras were detected in 64 (35%) and 17 patients (9%), respectively. The tyrosine 1234/1235 phosphorylation of MET (p-MET 1234/1235) and MET amplification was identified in 12 (7%) and 8 (4%) specimens, respectively. Positive expression of HGF was identified in 104 specimens (57%). An EGFR mutation was found significantly more frequently in females and in tumors with wild type of K-ras and without MET amplification. A p-MET 1234/1235 was found significantly more frequently in the tumors with a positive expression of HGF. A multivariate survival analysis demonstrated that the wild type of K-ras, negative p-MET 1234/1235, and positive HGF expression were independently associated with an increased risk of poor survival., Conclusions: The occurrence of MET amplification and EGFR/ K-ras mutations might be mutually exclusive suggesting several distinct mechanisms in the development of lung adenocarcinoma. The wild type of K-ras, negative p-MET 1234/1235, and positive expression of HGF may be a useful marker for predicting poor prognosis of patients who underwent surgical resection of lung adenocarcinoma.

The purpose of the present study was to identify a novel tumor-specific antigen capable of inducing a specific cellular immune response in lung cancer patients. The co-culture of regional lymph node lymphocytes and the CD80-transfected autologous lung adenocarcinoma cell line H1224L resulted in a successful induction of bulk cytotoxic T lymphocytes (CTL). CTL clone L7/8 was established by the limiting dilution method from these bulk CTLs and lysed H1224L but not autologous Epstein-Barr virus-transformed B cells or K562. The CTL clone also recognized allogeneic lung cancer cell lines in an HLA-A*31012-restricted manner. Using the CTL clone, an antigen-coding gene was identified using the cDNA expression cloning technique, which encodes ribosomal protein L19 (RPL19). Finally, a 9 mer antigenic peptide was identified by means of construction of mini-genes. RPL19 was overexpressed in the lung cancer tissue from patient H1224. All of the normal tissues examined expressed lower levels of RPL19 mRNA than that of the lung cancer tissue. RPL19 was also found to be overexpressed in 12 of 30 (40%) non-small-cell lung cancer tissues by immunohistochemical staining. The expression level of RPL19 in tumor cell lines correlated positively with the production of interferon (IFN)-gammaby CTL clone L7/8 in response to such cell lines. In addition, the suppression of RPL19 expression by transfection with small interfering RNA resulted in the suppression of cyclinD1, D3 synthesis, and the growth inhibition of lung cancer cell lines overexpressing RPL19. Therefore, this growth suppression could be ascribed to the inhibition of the cell cycle. These results may indicate that RPL19 is a novel overexpressed antigen which may therefore be a useful candidate as a target for specific immunotherapy.

Purpose: A sleeve lobectomy for lung cancer is a procedure intended both for the maintenance of lung function and for radical treatment. We investigated the clinico-pathological features and treatment responses of lung cancer patients who underwent sleeve lobectomy in our department., Subjects: Among the 984 patients with non-small cell lung cancer who underwent resection in our department between 1994 and 2007, the subjects were 24 patients in whom a sleeve lobectomy was performed., Results: There were 18 male and 6 female patients, with a mean age of 65 years. The histological type was diagnosed as squamous cell carcinoma in 14 patients, and adenocarcinoma in 10. Patients with either mucoepidermoid carcinoma (n=1) or carcinoid tumor (n=1) were excluded. The pathological stage was evaluated as IA, IB, II, IIIA, IIIB, and IV in 4, 1, 8, 8, 2, and 1 patient, respectively. Regarding post-operative complications, 4 patients required sputum aspiration with a bronchoscope from the 2nd to 7th post-operative day due to sputum retention. The 5-year survival rate in patients who underwent sleeve lobectomy was 70.0%. According to the pathological nodal status, the 5-year survival rates of N0, N1, and N2 were 100.0%, 87.5%, and 41.7%, respectively. The 5-year survival rates in squamous cell carcinoma and adenocarcinoma were 83.0% and 45.7%, respectively., Conclusion: Sleeve lobectomy facilitated the maintenance of residual lung function without serious perioperative complications. This finding suggests that patients with direct tumor invasion to the bronchus might be good candidates for a sleeve lobectomy, but not those with extra-nodal invasion., (Copyright 2009 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

In this study, we evaluated the results of surgical treatment in young adults and compared the clinico-pathological features between young and elderly patients. We reviewed the clinical records of 1185 lung cancer patients who underwent surgery in our department. A total of 20 (1.7%) primary lung cancer patients (14 men and 6 women) < or =40 years of age were retrieved. The age range was from 26 to 40 years. Histological type included 10 adenocarcinomas (50%), 3 large cell carcinomas (15%), 3 carcinoids (15%), 2 squamous cell carcinomas (10%), and 2 others. The surgical procedure included 7 (35%) pneumonectomies, 11 (55.0%) lobectomies, and 1 (5%) partial resection. The proportion of pneumonectomies was significantly higher than among elderly patients. Clinical stage was underestimated in 7 of 20 patients, and among these, mediastinal lymph node metastases were revealed by pathological examination in 6 patients. Postoperative 5-year survival rates were 50.2%, 50.4%, and 43.8% in patients < or =40, 41-70, and > or =71 years old, respectively. There were no significant differences in survival rates between younger group and elderly groups. This study suggests that surgical resection is also recommended as the first-line treatment for younger patients with lung cancer.

We previously reported the humoral immune response of tumor-infiltrating B lymphocytes in a lung cancer patient and 22 genes coding tumor-associated antigens identified using the serological identification of antigens by recombinant expression cloning method. In this study, we investigated one of these genes, designated University of Occupational and Environmental Health-Lung cancer antigen-1 (UOEH-LC-1), which has an extracellular domain. Quantitative reverse transcription-PCR revealed that UOEH-LC-1 was expressed ubiquitously in the normal tissues tested. However, it was overexpressed in 5 of 11 (45.5%) lung cancer cell lines and also in 9 of 15 (60%) lung cancer tissues compared with the paired normal lung tissues. A sequence analysis revealed that UOEH-LC-1 has a transmembrane domain. Flow cytometry analysis using a polyclonal antibody against UOEH-LC-1 revealed positive staining on lung cancer cell lines that were positive for expression of mRNA of UOEH-LC-1. Phage plaque assay showed the specific reactivity of anti-UOEH-LC-1 antibody against UOEH-LC-1 protein derived from the antigen encoding phage. By immunohistochemical staining with the anti-UOEH-LC-1 antibody, 7 of 28 (25.0%) lung cancer specimens showed positive staining on the cell surface. The administration of anti-UOEH-LC-1 antibody inhibited the growth of the UOEH-LC-1-positive tumors that were xenotransplanted into severe combined immunodeficiency mice. Complement-dependent cytotoxicity was one of the mechanisms to suppress the tumor growth. These results suggest that the antibody against UOEH-LC-1 therefore seems to have a promising therapeutic potential as a treatment for lung cancer.

The purpose of our present study is to identify a tumor-specific antigen capable of inducing a specific cellular immune response in lung cancer patients. We established a lung adenocarcinoma cell line, designated as F1121L, and induced tumor-specific CTL clone H1 from regional lymph node lymphocytes of patient F1121. CTL clone H1 lysed autologous tumor cells in an HLA-B*1507-restricted manner, but not autologous EBV-B, phytohemagglutinin-blast cells, and K562. The CTL clone also recognized allogeneic HLA-B*1501- or 1507-positive lung cancer cell lines in the HLA-restricted manner. Using the CTL clone, we identified an antigen-coding gene by cDNA expression cloning technique. The gene consisted of 556 bp, including an open reading frame consisted of 113 amino acids, designated as Kita-kyushu lung cancer antigen 1 (KK-LC-1). A 9-mer peptide (KK-LC-1(76-84); RQKRILVNL) was identified as an epitope peptide. The genomic DNA of this antigen was located in chromosome Xq22. A reverse transcription-PCR analysis revealed that the mRNA of this gene was only expressed in the testis among normal tissues. It was expressed in 9 of 18 (50%) allogeneic non-small-cell lung cancer cell lines and in 40 of 100 (40%) non-small-cell lung cancer tissues. We thus identified a new tumor antigen-coding gene categorized as a cancer/germline gene by an autologous lung cancer and CTL system. The new cancer/germline gene was located in Xq22, which is apparently different from the locations of previously reported cancer/germline genes.

A case of pulmonary collision tumor is herein reported. An abnormal shadow was discovered in the right lung of a 53-year-old man. A right upper lobectomy with a mediastinal lymph node dissection was performed. Based on the findings of a postoperative pathologic examination, this tumor was considered to be a collision tumor of large cell carcinoma and adenocarcinoma, as the distribution of each tumor was clearly separated. This case is the first report of a primary pulmonary collision tumor consisting of large cell carcinoma and adenocarcinoma.

A 56-year patient was diagnosed adenocarcinoma of the right lung and underwent lower lobectomy. Pleural dissemination was observed, and the pathological stage was T4N0M0. Systemic chemotherapy was performed with paclitaxel and vinorelbine after the surgery. Because multiple pulmonary and liver metastases were appeared 1 year after the surgery, the second line chemotherapy (CDDP and 5FU) was performed. The response of the chemotherapy was not observed, and thus the patient was enrolled in the clinical trial of MAGE-A3 peptide vaccine with OK-432. The peptide (300 mg) was injected subcutaneously at the upper thigh or upper arm a total of 6 times over 2 months (days 1, 8, 15, 22, 36, and 50) with OK432. During two courses of the vaccinations, the tumor markers (CA19-9 and CEA) decreased markedly. Furthermore, the tumor size of the lung and liver metastases decreased to 30% of their pre-treatment size. The delayed type hypersensitive reaction became positive after the first course of vaccinations. The precursor CTL for the peptide in the peripheral blood had increased after the vaccination. MAGE-A3 peptide vaccination with OK-432 has a potential to induce immunological response and clinical response in advanced lung cancer patients.

Background/Objectives: CD44 is often expressed in various types of tumor cells and involved in a number of biological behaviors of malignancy. The present study focused on the clinical significance of the expression of CD44st and CD44v6 in non-small cell lung cancer (NSCLC). Methods: The cohort consisted of 261 consecutive patients who had undergone complete resection of NSCLC. CD44 expression was evaluated in surgical specimens by immunohistochemical staining. Serum CD44 levels were determined using a sandwich ELISA (enzyme-linked immunosorbent assay). Results: In the immunohistochemical analysis, significant correlations were observed between CD44 expression and clinicopathological factors such as the T factor, N factor, pathological stage, and histological type. The 5-year survival rates according to CD44v6 expression were 65.8 and 80.6% in the higher and lower expression groups, respectively (p = 0.0053). According to ELISA, the group with higher expression of serum CD44v6 also showed a significantly more unfavorable prognosis than the lower expression group (p = 0.014). According to multivariate analysis using these significant variables, serum CD44v6 level was found to be an independent prognostic factor (p = 0.048). Conclusions: CD44v6 overexpression and higher serum CD44v6 levels were found to be significantly unfavorable prognostic factors. [ABSTRACT FROM AUTHOR]

Abstract: Cancer/testis antigens (CT antigens) are thought to be suitable targets for antigen-specific immunotherapy, because of the cancer-specific expression except for the testis among various normal tissues and no-expression of HLA class I in the testis. In the present study, the expressions of CT antigens (MAGE-A3, MAGE-A4, NY-ESO-1 and KK-LC-1) in non-small cell lung cancer (NSCLC) were analyzed by RT-PCR. The subjects were 239 patients with NSCLC who underwent surgery from 2001 to 2005 in our department. The expression rates of MAGE-A3, MAGE-A4, NY-ESO-1 and KK-LC-1 were 23.8%, 20.1%, 10.5% and 32.6% in patients with NSCLC, respectively. MAGE-A4 was expressed more frequently in male (25.3%) than in female (10.6%) (p <0.01). The positive proportion of MAGE-A4 was higher in stages II–IV (30.6%) than in stage I (12.8%) (p <0.01). Both of MAGE-A3 and MAGE-A4 were expressed more frequently in squamous cell carcinoma than in adenocarcinoma (p <0.01). Such tendency was not observed among NY-ESO-1 and KK-LC-1 expression. KK-LC-1 was expressed in 32.1% of patients with adenocarcinoma and in 36.5% of patients with squamous cell carcinoma. Patients with positive MAGE-A4 expression showed significantly poorer overall survival than those without MAGE-A4 expression (p =0.013), and such effect on survival was also observed, when the analysis was limited to patients at stage I (p =0.0037). Expression of MAGE-A3, NY-ESO-1 or KK-LC-1 did not affect survival of patients with NSCLC significantly, however, expression of at least one of such CT antigens negatively affect survival of patients with NSCLC (p =0.045). [Copyright &y& Elsevier]

Abstract: Background: Some types of somatic mutation of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) are associated with a significant clinical response to a tyrosine kinase inhibitor (TKI). However, most of the patients with this type of sensitive mutations in their tumor show acquired resistance during the TKI treatment. Methods: The mutations in exons 19–21 of the EGFR gene were examined in both the pre-treatment and the post-treatment gefitinib resistant tumors in 10 patients with lung adenocarcinoma. Eight patients were recurrent cases after surgery, and two patients were non-surgical cases whose tumor specimens were obtained from the metastatic lymph node and endobronchially invading tumor. Results: In 10 patients, 5 patients had a deletion in exon 19 and another 5 did L858R mutation in exon 21 of EGFR in gefitinib pre-treatment tumors. The mutation status did not change in the gefitinib-resistant tumors. In 7 of 10 patients, the gefitinib-resistant tumors had a secondary T790M mutation, which was not detected in the gefitinib pre-treatment tumors. In one patient, only one of the 4 gefitinib-resistant tumors showed the T790M mutation. Neither other novel secondary mutations of EGFR nor the K-ras were observed in their gefitinib-resistant tumors. Neither MET gene amplification nor HGF were observed in their gefitinib-resistant tumors without T790M mutation. Conclusions: The T790M mutation in the EGFR is relatively common in the patients with acquired resistance to gefitinib. However, mechanisms other than T790M, MET, and HGF status are involved in resistance to gefitinib. [Copyright &y& Elsevier]

Abstract: Background: This study prospectively assessed the efficacy of gefitinib and the survival benefit for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. Method: Patients with either recurrent disease after undergoing surgery or advanced NSCLC disease (IIIB or IV) which demonstrated EGFR mutations were eligible for this study. EGFR mutations in exons 19–21 were examined. The patients with EGFR mutations were enrolled in this study after obtaining their informed consent a second time, and they were thereafter treated with gefitinib. Results: EGFR mutations were detected in 20 of 48 patients with NSCLC, and 19 patients were enrolled onto this study and treated with gefitinib. Seven patients had an exon 19 deletion, 10 had L858R, 1 had both, and 1 had an exon 19 deletion and G796A. The overall response rate was 63.2%, and the disease control rate was 89.5%. In patients with an exon 19 del and L858R, the response rates were 71.4% and 60.0%, respectively. The median progression-free survival time was 7.1 months, and the median survival time was 20.0 months. No life-threatening toxicity was observed. Four of five acquired resistant tumors showed an acquired T790M mutation. Conclusions: EGFR mutations in exons 19 or 21 are considered to be a good predictor of the efficacy of gefitinib. [Copyright &y& Elsevier]