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We report 3 cases of surgical resection for lung metastasis more than 15 years after initial surgery for breast cancer. Case 1: A 77-year-old woman was referred to our hospital because of a lung nodule in the left lower lobe detected in a computed tomography (CT) scan. She had undergone breast preservation therapy for breast cancer 15 years before the first visit. Left lower lobectomy was performed via video-assisted thoracoscopic surgery (VATS). The pathological diagnosis was lung metastasis of breast cancer, based on positive immunohistochemical staining of estrogen receptor (ER) and gross cystic disease fluid protein 15 (GCDFP-15). Case 2: An 88-year-old woman had undergone a mastectomy for breast cancer 23 years previously. A CT scan revealed a nodule in the upper lobe of the left lung. A wedge resection of the left upper lobe was performed. Because immunostainings for progesterone receptor (PgR) and GCDFP-15 were positive, the pathological diagnosis was metastasis of breast cancer. Case 3: A 78-year-old woman had undergone right mastectomy for the breast cancer 29 years previously. The patient was referred to our hospital because of a nodule in the right lung in a CT scan. Thoracoscopic right upper lobectomy was performed. The pathological diagnosis was lung metastasis of the breast cancer, with immunohistochemical positivity to ER, PgR, and focally to GCDFP-15. A differential diagnosis between primary lung cancer and metastasis of breast cancer on the basis of the findings of a CT scan is often difficult. It is important to obtain the previous clinical information about the breast cancer before VATS, even in patients with a long disease-free interval of more than 15 years.

Objectives: Whether or not the preoperative exercise capacity, as assessed by 6-min walk test, influences the survival of patients undergoing thoracoscopic lobectomy for lung cancer is unclear. We therefore investigated the prognostic value of the 6-min walk distance in this population., Materials and Methods: This prospective cohort study was conducted between 2005 and 2013. We studied 224 consecutive subjects with stage I-II non-small cell lung cancer who underwent thoracoscopic lobectomy. Survival was calculated by the Kaplan-Meier method. The log-rank test was used to assess the survival rate. Cox proportional hazards models were used to estimate the risk of 5-year all-cause mortality based on the preoperative 6-min walk distance with adjustment for other prognostic factors, including the age, performance status, postoperative cardiopulmonary complication, and pathological stage., Results: The median follow-up period was 60.8 months. During this period, 38 deaths were recorded. The 5-year overall survival rate of the subjects with a preoperative 6-min walk distance of <400 m were significantly lower than those with a 6-min walk distance of ≥400 m (65.3% vs. 88.0%; p < 0.001). A multivariate analysis showed that the 6-min walk distance was significantly associated with the overall survival after adjusting for the age and pathologic stage (hazard ratio, 2.40; 95% confidence interval, 1.20-4.79), but it did not provide additional prognostic value beyond the performance status., Conclusion: The preoperative 6-min walk distance may be useful as an additional prognostic factor for patients at an increased risk of mortality after thoracoscopic lobectomy for stage I-II non-small cell lung cancer., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Case 1: A 81-year-old man was admitted to our hospital because of a mass shadow on chest x-ray examination. Chest computed tomography (CT) showed a 1.5 cm nodule in the middle lobe of the right lung. We suspected a primary lung cancer and performed video-assisted right middle lobectomy. Histopathological examination showed a white, elastic, hard and solid 30 × 10 × 10 mm nodule with infiltration of small-to-medium-sized lymphocytes that were positive for CD20 and CD79a, and negative for CD10 and Cyclin D1 in immunohistochemical staining. We diagnosed mucosa-associated lymphoid tissue (MALT) lymphoma. Case 2: A 67-year-old woman was admitted to our hospital because of a mass shadow in the right upper lobe on chest x-ray and chest CT. As the lesion had not grow in 1 year, the patient strongly wanted it resected, therefore we performed wedge resetion of the right upper lobe via video-assisted thoracic surgery. Histopathological examination showed a white, elastic, hard and solid 25 × 25 × 16 mm nodule with infiltration of small-to-medium-sized lymphocytes that had positive staining of CD20 and CD79a, and negative staining of CD10 and Cyclin D1. We diagnosed MALT lymphoma. Primary lung MALT lymphoma shows a variety of shadows on chest CT, similar to lung cancer and other inflammatory diseases. Local therapies such as surgery and radiation therapy are effective against early stage MALT lymphoma, but there is no consensus of a standard surgery.

Objective: The study objective was to investigate the prognostic impact of programmed death-ligand 1 expression in correlation with human leukocyte antigen class I expression on tumor cells in early-stage adenocarcinoma of the lung, because both programmed death-ligand 1 and human leukocyte antigen class I molecules play important roles in cancer immunity., Methods: Ninety-four patients with completely resected pathologic stage I lung adenocarcinoma were retrospectively reviewed. Programmed death-ligand 1 expression on tumor cells was evaluated with immunohistochemistry in correlation with several clinicopathologic and molecular features, including human leukocyte antigen class I expression on tumor cells., Results: Fifteen patients (16.0%) had tumor with positive programmed death-ligand 1 expression (percentage of tumor cells expressing programmed death-ligand 1, ≥5%), and the incidence was significantly higher in poorly differentiated tumors. There was no significant correlation between human leukocyte antigen class I expression and programmed death-ligand 1 expression. Programmed death-ligand 1 positivity was a significant factor to predict a poor survival (5-year survival, 66.7% vs 85.9%; P = .049), which was enhanced in tumors with normal human leukocyte antigen class I expression (P = .029) but was not evident in tumors with reduced human leukocyte antigen class I expression (P = .552)., Conclusions: The prognostic impact of programmed death-ligand 1 expression on tumor cells in early-stage lung adenocarcinoma may be distinct according to concurrent human leukocyte antigen class I expression., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

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., (© 2016 S. Karger AG, Basel.)

We herein report a very rare case of adenoid cystic carcinoma of the peripheral lungs. A 77-year-old female visited a family physician for aortitis syndrome, diabetes mellitus and hyperlipidemia. A follow-up chest computed tomography scan for aortitis syndrome revealed a nodule in the middle lobe of the right lung. Although a transbronchial lung biopsy was attempted, a definitive diagnosis could not be made. Because the possibility of lung malignancy could not be ruled out, thoracoscopic wedge resection of the middle lobe was performed. The intraoperative pathological diagnosis revealed carcinoma of the lungs and we performed middle lobectomy under complete video-assisted thoracoscopic surgery. A histopathological examination demonstrated an adenoid cystic carcinoma with a characteristic cribriform structure.

Background: Regulatory T-cells (Tregs) have a pivotal role not only in abrogating autoimmune disease, but also in tumor immune escape. The purpose of the present study was to evaluate the clinical significance of the relative expression of forkhead/winged helix transcription factor (FOXP3) and micrometastasis in the regional lymph nodes (RLNs) of patients with stage I non-small cell lung cancer (NSCLC)., Materials and Methods: The RLNs in 131 patients who underwent complete surgical resection for stage I NSCLC were collected at the time of surgery. The relative expression levels of FOXP3 and cytokeratin 19 (CK19) in RLNs were determined by quantitative RT-PCR., Results: The pathological stage was diagnosed as stage IA in 97 patients (74.0%) and stage IB in 34 patients (26.0%). The relative expression levels of FOXP3 and CK19 in the RLNs were 0.062±0.0083% and 0.025±0.056%, respectively. The relative expression of FOXP3 tended to increase with increasing relative expression of CK19. The five-year overall survival rate of the patients with low expression of FOXP3 was better (90.3%) than that of patients with high expression (79.3%) (p=0.0419). A multivariate analysis using the significant variables (gender, age, histology and FOXP3 expression) showed that the FOXP3 expression in RLNs was a significant independent prognostic factor., Conclusion: The expression of CK19 tended to be positively correlated with the expression of FOXP3. High expression of FOXP3 in RLNs was a significant unfavorable prognostic factor in patients with stage I NSCLC., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: Locally advanced lung cancer, such as T3/4 tumors, is considered to have a significantly worse prognosis than lower-stage disease, and the treatment of these tumors is difficult. Nevertheless, the information regarding the optimal treatment of T3/4 lung cancers after an operation is still limited. This study evaluated the prognostic factors for the postoperative outcome in patients with T3/4 lung cancers., Methods: The results of the surgical treatments were retrospectively analyzed for 212 patients with pathological T3 and 197 patients with T4 disease., Results: The global 5-year survival rate was 30.7% in this series. The 5-year overall survival (OS) rate in patients with T3 disease was 36.1%, while that in patients with T4 disease was 24.8%. The prognosis in females, those with N0-1 disease and those who underwent a complete resection was better than that of the other patients in both the T3 and T4 subgroups. The examination of the OS according to a time series showed that the rate was higher in more recent versus less recent years. From the standpoint of pulmonary metastasis (PM), the 5-year OS rates in T4 patients with PM and without PM were 38.6 and 17.4%, respectively. Multivariate analyses demonstrated that female gender, T3 disease, N0-1 disease and postoperative treatment were significant favorable prognostic predictors for OS., Conclusions: These findings suggest that surgical resection remains an important treatment option, especially in cases having the aforementioned factors.

Background: Regulatory T cells (Tregs) are potent immunosuppressive cells that play a crucial role in tumor immune escape. The purpose of the present study was to evaluate the prognostic significance of the frequency of CD4+CD25+Foxp3+ Tregs in the regional lymph node lymphocytes (RLNL) and peripheral blood lymphocytes (PBL) in patients who underwent surgical resection of non-small cell lung cancer (NSCLC)., Methods: The RLNL and PBL in 158 NSCLC patients who underwent complete surgical resection were collected at the time of surgery. The proportions of CD4+CD25+Foxp3+ cells in the RLNL and PBL were determined by flow cytometry., Results: The average proportions of Tregs in the RLNL and PBL were 1.28% and 0.76%, respectively. The proportion of Tregs in the RLNL was significantly higher than that in the PBL (p < 0.0001). The 5-year overall survival rates of the patients according to the proportion of Tregs in the RLNL were 84.4% and 63.5% in the lower and higher groups, respectively. A significant difference was observed in the survival rate between the higher and lower groups (p = 0.0056). Among the patients with stage I disease, the 5-year survival rate (91.4%) was significantly higher in patients with the lower proportion of Tregs in RLNL that in the higher group (72.1%) (p = 0.0147)., Conclusions: The higher proportion of Tregs in the RLNL was a significant unfavorable prognostic factor, even in patients with node-negative NSCLC. The information about the proportion of Tregs in the RLNL might improve the discriminatory power for assessing the risk of the recurrence of NSCLC., (Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.)

Purpose: Information regarding the treatment of pleural lavage cytology (PLC)-positive patients is still limited. This study evaluated the efficacy of intrapleural chemotherapy (IPC) in PLC-positive patients., Methods: Three hundred eighty-six of the 567 lung cancer patients who underwent surgery had undergone PLC after thoracotomy, following by a complete resection were evaluated. IPC was performed after surgery, and cisplatin or adriamycin was injected intrapleurally through the thoracic tube., Results: The pathological diagnosis showed that 17 patients (4.4 %) were positive for (or suspected to have) malignancy in their PLC. The univariate and multivariate analysis showed that only pleural invasion was a significant predictor of a PLC-positive status. The 5-year overall survival in PLC-positive patients was 38 % and that in PLC-negative patients was 84 %. Both the univariate (p < 0.01) and multivariate (p = 0.045) analyses showed that the status of PLC was significantly associated with the overall survival. Eight of the 17 PLC-positive patients underwent IPC. The 2-year OS rate in the patients treated with IPC was 88 % and that of those without IPC was 44 (p = 0.04)., Conclusion: IPC improved the postoperative survival in PLC-positive NSCLC patients, and a further prospective evaluation regarding this therapy is warranted.

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.

Background: OPN is a multifunctional glycophosphoprotein originally described as a secreted protein from malignant epithelial cells. This study focused on the clinical significance of preoperative serum level of OPN in NSCLC patients who underwent a complete resection., Patients and Methods: The serum OPN level was assayed in 244 patients who underwent a complete resection of NSCLC by commercially available sandwich enzyme-linked immunosorbent assay kits. The patients were considered as a higher group, when the serum OPN levels exceeded 81.3 ng/mL., Results: The patients included 166 male and 78 female subjects. The histologic types included 172 adenocarcinomas, 49 squamous cell carcinomas, and 23 other types of carcinoma. The serum level of OPN in male patients (92.6 ng/mL) was significantly higher than that of female patients (76.9 ng/mL). The OPN level of squamous cell carcinoma was significantly higher than that of adenocarcinoma. The OPN level was significantly elevated in patients with the pleural invasion or microvascular invasion than those without the invasion. The 5-year survival rate after surgery in the lower OPN group (82.0%) was a significant favorable prognosis than that in the higher OPN group (63.7%) (P < .0001). The 5-year survival rates in the lower OPN group at stage I NSCLC (88.1%) was significantly better than that in the higher OPN group (80.5%) (P = .0321)., Conclusion: The preoperative serum OPN level was a useful predictor of an unfavorable prognosis, and it was found to be an independent prognostic determinant of outcome in patients who underwent surgery for NSCLC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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.

A history of an increase in pulmonary mass was presented in the right upper lobe of a 72-year-old male. The bronchial brushing cytology specimens contained many sheet-like or three-dimensional clusters of malignant cells having small to medium-sized, uniform oval to round, and hyperchromatic nuclei, inconspicuous nucleoli, and scanty cytoplasm, admixed with mitotic figures. A coarsely granular chromatin pattern was predominantly noted. We first interpreted it as suspicious of malignancy, such as atypical carcinoid. A right upper lobectomy was performed, and gross examination revealed a centrally cavity-formed tumor lesion, containing asymmetrically thinned wall and looking grayish to whitish, partly adjacent to the bronchiolar wall. On microscopic examination, the tumor was predominantly composed of a solid proliferation of atypical epithelial cells without apparent glandular or squamous differentiation, often arranged in an alveolar growth pattern with peripheral palisading. Immunohistochemically, these atypical cells are negative for all three neuroendocrine markers and thyroid transcription factor 1, whereas positive for 34βE12, p63 and S-100 protein. Therefore, we finally made a diagnosis of basaloid carcinoma with cavity formation. We should be aware that, owing to its characteristic features, cytopathologists might be able to raise basaloid carcinoma of the lung as one of differential diagnoses, based on careful cytological examination., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.dianosticpathology.diagnomx.eu/vs/1519986488570234

Background: The post-surgical follow-up strategy in non-small cell lung cancer (NSCLC) is still controversial. Data on factors that affect the interval between surgery and recurrence or predict survival after recurrence in NSCLC patients are still limited., Methods: From a group of 775 NSCLC patients who consecutively underwent curative surgery, 133 patients showing recurrence were retrospectively analyzed., Results: Recurrence was most often seen in smokers and patients with advanced stage disease. In patients experiencing relapse, the 1- and 2-year recurrence rates were 58% and 84%, respectively. A multivariate analysis showed that patients who underwent limited surgery, had non-adenocarcinoma disease, or had metastatic lymph node involvement showed early recurrence (p-values: <0.01, 0.04, and 0.04, respectively). Among all relapsed patients, the 2-year overall survival rate after recurrence was 37%. A multivariate analysis demonstrated that patients with lymph node metastasis at the time of surgery and patients who experienced early recurrence were significantly more likely to have a shorter survival time after recurrence (hazard ratio, 1.73; p=0.03; hazard ratio, 2.56; p<0.001, respectively)., Conclusions: Patients who are node-positive, show non-adenocarcinoma disease, and/or undergo limited surgery should receive careful follow-up during the first year after surgery for NSCLC. The present data provide additional information about postoperative recurrence in NSCLC patients., (Copyright © 2012 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

The difficulty in the induction and preparation of a large number of autologous tumor-specific cytotoxic T lymphocytes (CTL) from individual patients is one of major problems in their application to adoptive immunotherapy. The present study tried to establish the useful antitumor effectors by using γδ T cells through tumor-specific TCRαβ genes transduction, and evaluated the efficacy of their adoptive transfer in a non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice model. The TCRαβ gene was cloned from the HLA-B15-restricted CTL clone specific of the Kita-Kyushu Lung Cancer antigen-1 (KK-LC-1). The cloned TCRαβ as well as the CD8 gene were transduced into γδ T cells induced from peripheral blood lymphocytes (PBL). Cytotoxic T lymphocyte activity was examined using a standard 4 h (51) Cr release assay. Mice with a xenotransplanted tumor were treated with an injection of effector cells. Successful transduction of TCRαβ was confirmed by the staining of KK-LC-1-specific tetramers. The γδ T cells transduced with TCRαβ and CD8 showed CTL activity against the KK-LC-1-positive lung cancer cell line in a HLA B15-restricted manner. Adoptive transfer of the effector cells in a mice model resulted in marked growth suppression of KK-LC-1- and HLA-B15-positive xenotransplanted tumors. Co-transducing TCRαβ and CD8 into γδ T cells yielded the same antigen-specific activity as an original CTL in vitro and in vivo. The TCRαβ gene transduction into γδ T cells is a promising strategy for developing new adoptive immunotherapy., (© 2012 Japanese Cancer Association.)

Purpose: The purpose of this study was to assess the toxicity and efficacy of re-irradiation plus regional hyperthermia for recurrent NSCLC and to identify the predictors of long-term survival., Methods and Materials: A total of 33 patients with recurrent NSCLC treated with re-irradiation plus regional hyperthermia were retrospectively analyzed. The median total dose of initial radiotherapy and re-irradiation were 70 Gy and 50 Gy, respectively. A median of 5 hyperthermia treatments using an 8-MHz radiofrequency-capacitive device were applied during re-irradiation in all patients., Results: Toxicity of Grade 3 was seen in 3 (9%) patients, and no Grade 4 or 5 toxicity was observed. The median overall survival, local control, and disease progression-free survival times after re-irradiation were 18.1, 12.1, and 6.7 months, respectively. Eight patients achieved a long-term survival (more than 3 years after re-irradiation), and 4 of them underwent a third round of irradiation for re-recurrent tumors. Univariate analyses showed that a smaller tumor size (<4 cm) and the absence of distant metastases were significant predictors for a better overall survival. The absence of distant metastases was also found to be a significant predictor for better disease progression-free survival in the univariate analyses. In the subset analyses of 23 patients treated with hyperthermia using electrodes of 30 cm in diameter, the use of a higher radiofrequency-output power tended to be associated with a better prognosis in terms of the local control rate., Conclusions: Re-irradiation plus regional hyperthermia for recurrent NSCLC appears feasible, with acceptable toxicity, and may be a promising treatment that can result in the long-term survival of patients without distant metastasis and larger recurrent tumors., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

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.

We assessed the prognostic value of the 'Zone-classification' which has been proposed by the Japanese Association for Lung Cancer (JALC) for mediastinal nodal metastases in non-small cell lung cancer (NSCLC). Among 357 NSCLC patients who underwent curative surgery, 46 patients with pathological (p) N2 disease were divided into two groups as follows: 32 patients in whom the nearer zone was involved were classified as the pN2a-1 group, and 14 patients in whom the further mediastinal node station was involved were classified as the pN2a-2 group. The proportions of patients with non-adenocarcinoma histology, with multiple station metastases with the involvement of four or more nodes, and who underwent pneumonectomy, were higher in the pN2a-2 group. The 'Zone-classification' proved to be a significant prognostic factor in a univariate analysis (the 5-year overall survival rate, 7.1% for pN2a-2 versus 21.9% for pN2a-1; P < 0.01). A multivariate analysis confirmed that pN2a-2 sub-classification (hazard ratio 2.77; P = 0.03) and undergoing pneumonectomy (hazard ratio 4.86; P < 0.01) were independent and significant factors in predicting a poor prognosis. In pN2 NSCLC patients, the involved mediastinal zone according to the primary tumour site was important in prediction of survival.

Purpose: This study retrospectively investigated the clinical significance of surgical treatment for stage IV non-small-cell lung cancer (NSCLC)., Subjects: There were 36 patients who underwent surgical resection for stage IV NSCLC between 1999 and 2008., Results: The patients included 22 males and 14 females. All patients had either synchronous distant metastasis or pleural dissemination. The mean age of the patients was 65.8 years (range, 18 to 90 years). The histological types included 29 adenocarcinomas, 5 squamous-cell carcinomas and 2 large-cell carcinomas. The organs of metastasis were bone in 5 patients, brain in 4, adrenal gland in 4, axillary lymph nodes in 3, liver in 2, and 1 patient had a contralateral pulmonary metastasis. The number of metastases was one site in 13, two sites in 3, three sites in 1, and five sites in 2 patients. The patients with bone metastasis were treated with radiation, and the patients with brain metastasis underwent stereotaxic radiosurgery. The patients with either adrenal metastasis, axillary lymph node metastasis, or contralateral lung metastasis underwent surgical resection. Among the patients with distant metastasis, the 5-year survival rate was 30.1 %. There were 17 patients with pleural dissemination. The 5-year survival rate in these patients was 25.3%. The overall 5-year survival rate after surgery in the patients with stage IV disease was 26.8%., Conclusion: Selected patients who can undergo surgical resection for the primary tumor and effective local therapy for metastatic lesions still have a chance to obtain long-term survival. Surgical treatment for NSCLC with oligometastatic disease can be considered as one arm of multidisciplinary treatment., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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.)

Pulmonary hamartoma is the most common tumor in benign lung neoplasm. We reviewed the clinical characteristics of 9 patients who had undergone surgical resection for pulmonary hamartoma between 2000 and 2009. There were 1 male and 8 female patients. The age of the patients ranged from 42 to 77 years old (mean 59). Calcification was not observed by computed tomography scan except in 1 patient. Although transbronchial lung biopsy (TBLB) was performed in 5 patients, no definitive diagnosis was obtained. Six patients underwent 18F-fluorodeoxyglucose (FDG)-positron emission tomography, and none of them showed any accumulation of FDG except for 1 patient. Concerning the operative procedures, a sleeve lobectomy was performed in 1 patient, a segmentectomy in 1, a lobectomy in 2, a partial resection of the lung in 3, and a nucleation in 2 patients. The postoperative courses were uneventful, and no findings of recurrence were observed in any of the patients after surgery. As a preoperative diagnosis of pulmonary hamartoma is often difficult in TBLB, it is necessary to perform surgical resection in the differential diagnosis of lung cancer or metastatic lung tumor, unless there are typical findings of pulmonary hamartoma in clinical imaging.

The purpose of this study was to evaluate the efficacy and toxicity of the postoperative radiotherapy in patients with incompletely resected NSCLC, and to investigate whether the histological subtype is a prognostic factor. Forty-one incompletely resected NSCLC patients who underwent postoperative radiotherapy were retrospectively analyzed. The microscopic residual tumor (R1 group) was recognized in 23 patients, and the macroscopic residual tumor (R2 group) in 18. The postoperative pathological stages were I (n = 3), II (n = 8), IIIA (n = 17), and IIIB (n = 13). The histology included squamous cell carcinoma (n = 23), adenocarcinoma (n = 14) or other types (n = 4). The first site of disease progression was distant metastases alone for 3 (13%) of 23 with squamous cell carcinoma, and for 9 (64%) of 14 with adenocarcinoma (p < 0.01). The 5-year overall, local control, disease-free, and distant metastasis-free survival rates were 56%, 63%, 37% and 49%. Univariate analyses showed that squamous cell carcinoma histology, N0-1 stage and the R1 group were significant predictors for better disease-free and distant metastasis-free survival. Multivariate showed that squamous cell carcinoma and N0-1 stage were significant predictors for better distant metastasis-free survival. Toxicity was generally mild; Grade 3 toxicities occurred in 3 patients (neutropenia, radiation pneumonia and esophageal stenosis), and no acute and late toxicities of Grade 4 to 5 were observed. In conclusion, postoperative radiotherapy for incompletely resected NSCLC could achieve a relatively high local control rate without severe toxicity. However, different treatment strategies for non-squamous cell carcinoma should be considered, because of the higher risk for the distant metastases.

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.

Purpose: This study investigated whether the number of involved lymph nodes is associated with the prognosis in patients that underwent surgery for pathological stage (p-stage) III/N2 NSCLC., Subjects: This study evaluated 121 patients with p-stage III/N2 NSCLC., Results: The histological types included 65 adenocarcinomas, 39 squamous cell carcinomas and 17 others. The average number of dissected lymph nodes was 23.8 (range: 6-55). The average number of involved lymph nodes was 5.9 (range: 1-23). The 5-year survival rate of the patients was 51.0% for single lymph node positive, 58.9% for 2 lymph nodes positive, 34.2% for 3 lymph nodes positive, and 30.0% for 4 lymph nodes positive, and 20.4% for more than 5 lymph nodes positive. The patients with either single or 2 lymph nodes positive had a significantly more favorable prognosis than the patients with more than 5 lymph nodes positive. A multivariate analysis revealed that the number of involved lymph nodes was a significant independent prognostic factor., Conclusion: Surgery appears to be preferable as a one arm of multimodality therapy in p-stage III/N2 patients with single or 2 involved lymph nodes. The optimal incorporation of surgery into the multimodality approach therefore requires further clinical investigation.

Purpose: This study investigated the preoperative serum levels of CYFRA 21-1 and CEA as prognostic factors in patients with stage I non-small cell lung cancer., Subjects: This study evaluated 341 patients who had undergone a complete resection for stage I NSCLC between 2002 and 2008., Results: The patients included 193 males and 148 females. The mean age of the patients was 69.2 years (range: 19-88). The histological types included 264 adenocarcinomas, 56 squamous cell carcinomas, 11 large cell carcinomas, and 10 other types of carcinoma. A pneumonectomy was performed in 2 patients, a bilobectomy in 7, a lobectomy in 255, a segmentectomy in 46, and partial resection of the lung in 31 patients. The positive rates for CYFRA 21-1 in the adenocarcinoma and squamous cell carcinoma patients were 33.3% and 76.8%, respectively. The positive rates for CEA in adenocarcinoma and squamous cell carcinoma patients were 23.8% and 26.8%, respectively. The 5-year survival rate after surgery in the normal CYFRA 21-1 group and the high CYFRA 21-1 groups were 92.8% and 75.4%, respectively, in the patients with stage I NSCLC. There was a significant difference between the 2 groups (p<0.0001). The 5-year survival rate according to the serum level of CEA in the patients with stage I NSCLC were 88.3% for the normal group and 76.3% for the high group. In a multivariate analysis using the variables found to be significant prognostic factors in univariate analysis, a high CYFRA 21-1 level was found to be a significant independent prognostic factor (95% confidence interval 1.213-5.442, p=0.014)., Conclusion: A high preoperative CYFRA 21-1 level was a significant independent prognostic factor in patients with stage I NSCLC. The patients with a high CYFRA 21-1 level should carefully followed-up to rule out occult metastasis. Further clinical studies will be necessary to evaluate the efficacy of adjuvant therapy for the patients selected according to this criterion., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

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.)

This study evaluated 325 patients who had undergone pleural lavage cytology (PLC) immediately after thoracotomy following a complete resection for non-small cell lung cancer (NSCLC) between 2004 and 2008. The number of patients with negative and positive findings in PLC was 309 and 13, respectively. The proportion of T1 in the PLC-positive group was significantly smaller than that of the PLC-negative group. The pathologic examinations revealed that the parietal pleural invasion was significantly more severe in the PLC-positive group than in the PLC-negative group. Pathologic lymphovascular invasion was also significantly more prominent in the PLC-positive group than in the PLC-negative group. The 5-year survival rate after surgery in the PLC-positive group and PLC-negative group was 54.7% and 79.0%, respectively. The positive finding in PLC showed a tendency of an unfavorable prognosis for NSCLC patents following complete resection. Further clinical studies will be necessary to evaluate the efficacy of adjuvant therapy for PLC-positive patients.

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.)

Aim: The development of a bronchopleural fistula (BPF) after lung resection is a life-threatening complication, and thoracic surgeons should always consider the risk of BPF in their patients. We herein describe our experiences with BPF after major lung resection and describe the results of our management of the cases seen during the past 31 years., Patients and Methods: Between August 1979 and May 2010, 19 patients (1.3%) who underwent lung tumor resection developed a BPF. Their clinical records, associated risk factors, and outcomes, were retrospectively reviewed., Results: There were 14 patients who developed the BPF on the right side, and 5 who developed it on the left. All but one patient with BPF were male. There were prior and postoperative complicating diseases in 9 and 11 out of the 19 cases of BPF, respectively. The closure, using various techniques, was successful in 8 patients, while the repair failed in the other 11 patients, who subsequently developed further fatal complications. This gives a mortality rate of 57.9%. BPF occurred more frequently before 1994, in males, in those with stage T3-4 disease and/or metastasis to the lymph nodes, and in those who underwent a pneumonectomy. The incidence of BPF was higher in the patients who received preoperative chemotherapy and/or radiotherapy than in those who did not, although no significant influence of postoperative treatment was identified. The outcome was more favorable in those with left-sided tumor than in those whose tumors were on the right side. No significant correlation was identified between the outcome and concurrent disease, day of onset, preoperative treatment, postoperative treatment, preoperative chemotherapy, postoperative chemotherapy, preoperative radiotherapy, or the presence of a prior complicating disease. Interestingly, the existence of concurrent disease after the development of BPF, perioperative complications, and the development of an infection were significantly related to a poorer outcome., Conclusion: BPF continues to have high morbidity and mortality rates. Thoracic surgeons should pay special attention to the risk factors that affect the development and successful treatment of a BPF. Establishment of standard treatments and guidelines for the prevention and proper treatment of BPF are needed.

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.)

Recurrent breast cancer (BC) tends to show an aggressive behavior and the number of cases of long-term survival is limited. Two rare cases of recurrent breast cancer were treated with a multidisciplinary approach. The outcome of the two cases indicated an excellent survival period of more than 13 years after recurrence. These findings suggest that patients who experience a recurrence after tumor resection have a chance of achieving long-term survival when treated with aggressive therapy, even in the presence of extensive metastases involving multiple organs.

Background: The purpose of this study was to clarify the role and clinical significance of lymphangiogenesis/micrometastases and adhesion molecules in resected stage I non-small cell lung cancer (NSCLC)., Methods: Immunohistochemical (IHC) staining was used to analyze the protein expression of vascular endothelial growth factor-C (VEGF-C), VEGF, E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin in paraffin-embedded tumor samples from 117 well-characterized stage I NSCLC patients and to compare the protein expression, clinical variables and survival outcome. As a micrometastatic parameter in lymph nodes (LNs), cytokeratin (CK) staining was performed., Results: The positive expression of VEGF-C and VEGF were detected in 54 (48.7%) and 86 (73.5%), respectively. We identified micrometastatic tumor cells in pathological N0 LNs in 34 (29.1%) of 117 patients. E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin were identified in 70 (59.8%), 41 (35.0%), 83 (70.9%), and 61 (52.1%) specimens, respectively. The VEGF-C expression was found more frequently in squamous cell carcinoma (SQ) and in the tumors with negative expression of beta-catenin than counter features. The VEGF expression was found more frequently in the tumors with a negative expression of E-cadherin. Micrometastasis was found more frequently in a pathological T2 status and in the tumors with a negative expression of alpha-catenin. Beta-catenin and gamma-catenin expressions were found less and more frequently in SQ, respectively. A univariate and multivariate survival analysis demonstrated that old age, pathological T2 status, and micrometastasis were independently associated with an increased risk of poor survival in the patients who underwent a surgical resection of stage I NSCLC., Conclusions: Complicated relationships exist between lymphangiogenesis/micrometastases and adhesion molecules with a specific histology. The detection of lymph nodal micrometastasis by CK may therefore be a useful marker for predicting a poor prognosis in patients who undergo a complete resection of stage I NSCLC., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

To evaluate the optimum treatment strategy for metastatic adrenal tumors derived from non-small cell lung cancer (NSCLC), we retrospectively analyzed 17 consecutive cases (8 resection cases: 4 synchronous and 4 metachronous: 9 non-resection cases: 3 synchronous and 6 metachronous) who received surgical resection for NSCLC. The patients included 12 males and 5 females with a mean age of 63.9 years. Of these, 9, 3, 2, 2, and 1 patient (s) were diagnosed as having adenocarcinoma, squamous cell carcinoma, pleomorphic carcinoma, large cell carcinoma, and adenosquamous cell carcinoma, respectively. The mean interval after lung resection and treatment of metachronous adrenal metastasis was 9.9 months. The mean time to progression from treatment of metachronous adrenal metastasis to disease progression was 8.9 months. A survival analysis showed no significant prognostic difference between the patient age, gender, pathological stage, synchronous/metachronous classification, CEA, and site of metastases. However, patients who received an adrenalectomy had a more favorable prognosis. The 2-year survival of patients following resection versus those who did not undergo a resection for adrenal metastasis was 62.5 and 22.8%, respectively. These data indicate that metastatic adrenal tumors should be resected if the patient can tolerate surgery after appropriate selection.

Background: DeltaNp63 is an isoform of the p53 homolog p63, which lacks an amino-terminal transactivation domain. The aim of this study was to detect the deltaNp63 expression in the squamous carcinoma component of adenosquamous carcinoma and evaluate its usefulness as a specific squamous carcinoma marker., Patients and Methods: Immunohistochemistry was used to analyze the protein expression of deltaNp63 and high molecular weight cytokeratin in paraffin-embedded tumor samples from 17 patients with well-characterized adenosquamous carcinoma., Results: Of 17 cases, 13 (76.5%) and 14 (82.4%) cases showed positive staining for deltaNp63 and HMWCK in the tumor cells, respectively. It was easy to discriminate the squamous carcinoma and adenocarcinoma components in all tumors. Interestingly, positive expression of deltaNp63 was detected in one case with a negative expression of HMWCK., Conclusion: These findings indicated that the deltaNp63 status was useful for distinguishing squamous carcinoma from adenocarcinoma in formalin-postfixed adenosquamous carcinoma specimens.

Background: adenosquamous carcinoma (ADSQ) of non-small cell lung cancer (NSCLC) is a rare disease and the biological behavior and clinicopathological characteristics have not yet been thoroughly described., Method: This study reviewed the patient charts of 11 (1.6%) ADSQ cases among 779 patients with primary lung cancer who underwent a lung resection. The characteristics and clinicopathological factors were evaluated retrospectively., Results: Six of the 11 patients with ADSQ were male and five were female. The mean age was 67.3 years' olds. Three patients had pathological stage IA, one patient each had stage IB and IIA, five patients had stage IIIA, and one patient stage IIIB. Five patients had coexistent double cancer including 2 gastric, 1 rectal, 1 prostate and 1 bladder cancer. ADSQ was found less frequently in males than squamous cell carcinoma (SQ). ADSQ was found more frequently in older patients, with advanced stage, advanced T status, and lymph node metastases than adenocarcinoma (AD). The proportion with coexistent double cancer of AD, SQ, and ADSQ were 21.1, 17.6, and 45.5%, respectively. ADSQ had a significantly correlation with double cancer (ADSQ vs. non- ADSQ p = 0.03). A multivariate analysis showed no significant prognostic difference between the patients with ADSQ and non- ADSQ., Conclusions: In this study, cases with ADSQ showed no significantly prognostic difference in comparison to AD and SQ. However, surgeons must be cautious of any coexistent double cancer because approximately half of all patients with ADSQ of the lung have double cancer.

Induction of angiogenic responses by multiple factors, a crucial step in tumor growth and metastasis, is not completely understood. Recently, involvement of the cytoskeletal actin-binding proteins in angiogenesis has been suggested as a target for anti-neovascular cancer therapy in vitro. In this study, the expression of filamin A (FLNA) and vascular endothelial growth factor (VEGF) in paraffin-embedded tumor samples from patients with well-characterized lung tumors was immunohistochemically analyzed and compared with clinical variables and survival outcome. A positive expression of FLNA and VEGF was detected in the cytoplasm of tumor cells in 66 (48.2%) and 69 (50.4%) of the 137 patients with lung cancer, respectively (p<0.0001). A significant difference was observed between FLNA expression and VEGF expression. Although our findings do not suggest that the expression of FLNA alone plays an independent prognostic role, the angiogenesis pathway mediated by FLNA appears to be responsible for controlling the growth of lung tumors.

Background: Recently, pemetrexed (PEM), a new generation antifolate, has been used for the treatment of patients with advanced non-squamous cell carcinoma (SQ) of non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). However, no useful markers for selecting appropriate candidates exist at present., Materials and Methods: Tumor specimens were collected from 5 lung non-SQ and 8 MPM patients who underwent surgery and received PEM. Real-time PCR and immunohistochemical (IHC) staining of the primary tumor were used to analyze the mRNA and protein expressions of thymidylate synthase (TS)/dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), and to compare the expression status and clinical outcomes., Results: TS, DHFR, and GARFT mRNA levels had a median value of 2.39, 1.70, and 1.40 in non-SQ samples of NSCLC patients. The TS and DHFR protein levels had a mean total score of 2 and 4 in non-SQ of NSCLC patients. TS, DHFR, and GARFT mRNA levels had a median value of 5.55, 3.73, and 3.52 in MPM patients. TS and DHFR protein levels had a mean total expression score of 1 and 3 in MPM patients. No significant correlation was identified between the expression levels of TS/DPD/GARFT mRNA and clinical response for the non-SQ of NSCLC and MPM patients treated with PEM., Conclusion: TS, DHFR, and GARFT mRNA and protein expression may not be useful markers for predicting clinical response in Japanese patients with non-SQ of NSCLC and MPM. Further investigations are necessary in order to develop biomarkers to determine the clinical benefits of PEM treatment.

Background: Adjuvant chemotherapy is required following the resection of aggressive NSCLC. It is therefore necessary to identify factors that accurately predict prognosis., Materials and Methods: Tumor specimens were collected from 107 patients who underwent a complete resection for NSCLC from 1994-2000 in this Department. The expression of E-cadherin, dysadherin, and cytokeratin in stage I NSCLC specimens was analyzed by immunohistochemistry., Results: Seventeen percent of tumors showed reduced E-cadherin immunostaining. Twenty-nine per cent of tumors showed dysadherin expression in over 50% of the cancer cells. Positive expression of cytokeratin was identified in 30 (28.0%) patients. The incidence of positive expression of dysadherin in females and elderly patients was higher than that in other patients. Cytokeratin immunoreactive tumor cells in lymph nodes were identified in 34 (28.0%) out of 107 patients. The incidence of positive expression of cytokeratin in T1 tumors was higher than that in T2 tumors. There was a significant inverse correlation between the expression of E-cadherin and dysadherin. The increased expression of cytokeratin was significantly associated with recurrence. Logistic regression models indicated that cytokeratin expression was an independent predictor of recurrence. The increased expression of dysadherin and cytokeratin had a significant impact on patient survival. Furthermore, tumors with an increased expression of dysadherin and a reduced expression of E-cadherin showed the worst prognosis., Conclusion: The detection of dysadherin in tumors and cytokeratin in the lymph nodes may be a potential significant indicator of a poor prognosis for patients who undergo complete resection of stage I NSCLC.

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: Adjuvant chemotherapy improves the prognosis of patients with non-small cell lung cancer (NSCLC) after a complete resection despite unacceptable toxicity and low compliance., Methods: A total of 67 patients were enrolled in a multi-institutional study. The patients received chemotherapy with carboplatin (CBDCA) area under the curve of 3 and paclitaxel (PTX) 90 mg/m(2) every 2 weeks for six cycles after surgery., Results: Fifty patients (74.6%) completed all cycles of therapy. The presence of grade 3 and 4 toxicities of neutropenia were 13.4, and 3.0%, respectively. Non-haematological adverse effects were infrequent and no treatment-related death was registered. The estimated disease-free survival and overall survival at 2 years were 89.0% and 88.8%, respectively., Conclusion: A bi-weekly schedule of CBDCA and PTX as adjuvant chemotherapy showed an acceptable toxicity and favourable feasibility in Japanese NSCLC patients after complete tumor resection. Consequently, it is desirable to validate this regimen in a future randomized clinical trial.

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: This study analysed the humoral immune response in asbestos exposed lung cancer patients to identify new surrogate markers of the carcinogenic risk in populations exposed to asbestos., Methods and Results: A serological analysis identified five distinct antigens reactive with IgG derived from a lung cancer patient with high asbestos exposure. In one of the isolated antigens, quantitative RT-PCR indicated that annexin A2 (AnxA2) was overexpressed in lung cancer tissues and normal lung from patients with high asbestos exposure. Antibody against AnxA2 was detected in 9/15 (60%) of lung cancer patients with high asbestos exposure; however, in only 1/12 (8%) of lung cancer patients with low asbestos exposure. AnxA2 was also overexpressed in malignant mesothelioma cells, and the antibody was also positive in 8/15 (53%) of patients with malignant mesothelioma., Conclusion: The antibody titer against AnxA2 may be a potentially useful new diagnostic surrogate marker for asbestos-related lung cancer and malignant mesothelioma.

Purpose: A surgical resection is a potentially curative treatment for non-small cell lung cancer (NSCLC). This study investigated the time trends of the surgical outcome in patients with NSCLC., Methods: This study clinicopathologically evaluated 1487 patients who had undergone a resection for NSCLC between 1979 and 2008 during the five periods of 1979-1988, 1989-1993, 1994-1998, 1999-2003, and 2004-2008., Results: The number of patients who underwent a resection during the five respective periods increased: 167, 261, 248, 382, and 429. The percentage of pathologic stage IA lung cancers was 16.2, 21.5, 23.0, 38.5, and 52.0% in each period, respectively, and it has risen rapidly in recent years. The percentage of adenocarcinoma has also progressively increased during each period: 49.1, 52.1, 54.7, 62.8, and 69.7%, respectively. The diameter of the tumors resected during each period was 36, 37, 38, 33, and 26 mm, respectively, showing that the tumor tended to be diagnosed at an increasingly smaller size. The postoperative 5-year survival rates during the five periods improved markedly: 34.1, 44.0, 44.9, 65.4, and 76.5%, respectively. Patients with pathologic stage IA lung cancer also exhibited increasingly higher 5-year survival rates during the five periods: 70.0, 71.2, 80.4, 89.2, and 88.7%, respectively., Conclusion: The prognosis of NSCLC patients has remarkably improved in recent years. The increase in the number of patients with adenocarcinoma in the early stage is thought to have strongly contributed to the favorable results. Thus, early diagnosis remains a key factor for improving the survival of lung cancer patients after surgical treatment.