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A standard treatment for patients with early-stage non-small cell lung cancer (NSCLC) who undergo surgery, and subsequently develop local failure or intrathoracic oligo-recurrence, has not yet been established. The present study aimed to assess the feasibility of stereotactic body radiotherapy (SBRT) for this subgroup of patients. Consequently, a retrospective analysis was conducted of patients with NSCLC recurrence who were treated with SBRT, and previously underwent curative surgical resection between October 2011 and October 2016. Post-SBRT survival [overall survival (OS); progression-free survival (PFS); and local control (LC)] and toxicity were analyzed. Prognostic factors for OS were identified using univariate and multivariate analysis. A total of 52 patients and 59 tumors were analyzed. The median follow-up time was 25 months (35 months for surviving patients), and median OS following salvage SBRT was 32 months. The 1- and 3-year OS rates were 84.4 and 67.8%, respectively. 1- and 3-year PFS rates were 80.8 and 58.7%, respectively. Only 4 patients (7.7%) developed local failure. Median LC was 71 months and 1- and 3-year LC rate were 97.9 and 94.9%, respectively. A total of 4 patients experienced grade 3 or higher adverse events (AEs) and two experienced grade 5 AEs (pneumonitis and hemoptysis). Central tumor location and the possibility of re-operation were independent prognostic factors for OS. The present study indicated that post-operative salvage SBRT is a promising therapeutic option for patients with NSCLC with locoregional or intrathoracic oligo-recurrence. We regard toxicity was also acceptable. However, further research is required on the appropriate selection of subjects, and stratification of the analysis by certain risk factors would increase the accuracy of the conclusions., (Copyright: © Aoki et al.)

Purpose: The azygoesophageal recess (AER) is known as a possible cause of bulla formation in patients with spontaneous pneumothorax. However, there has been little focus on the depth of the AER. We evaluated the relationship between the depth of the AER and pneumothorax development., Methods: We conducted a retrospective study of 80 spontaneous pneumothorax patients who underwent surgery at our institution. We evaluated the depth of the AER on preoperative computed tomography scans., Results: Ruptured bullae at the AER were found in 12 patients (52.2%) with secondary spontaneous pneumothorax (SSP) and 8 patients (14.0%) with primary spontaneous pneumothorax (PSP) (p < 0.001). In patients with ruptured bullae at the AER, 10 SSP patients (83.3%) had a deep AER while only 2 PSP patients (25%) had a deep AER (p = 0.015)., Conclusions: A deep AER was more frequently associated with SSP than with PSP. A deep AER may contributes to bulla formation and rupture in SSP patients.

A patient with pleuroparenchymal fibroelastosis (PPFE) was successfully treated with living-donor lobar lung transplantation. A 27-year-old woman with a 3-month history of dyspnea received a diagnosis of PPFE. Her chest wall was extremely flattened over time, and her respiratory condition progressively deteriorated. She underwent semielective bilateral living-donor lobar lung transplantation. Her chest wall rigidity, which was secondary to PPFE, required intensive pulmonary rehabilitation postoperatively. By 6 months after transplantation, the flattening of her chest wall was reversed. Living-donor lobar lung transplantation was a life-saving procedure for this patient and improved the chest wall deformity of PPFE., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We experienced an uncommon presentation of Kikuchi-Fujimoto disease (KFD) with sole mediastinal lymphadenopathy in senior age, which was histologically diagnosed by thoracoscopic biopsy leading to appropriate therapy. A 69-year-old man was admitted due to intermittent high fever, general malaise, and appetite loss lasting over 3 months along with 10-kg weight loss in 6 months. Chest computed tomography (CT) showed isolated mediastinal lymphadenopathy, and malignant diseases including malignant lymphoma or metastatic carcinoma, tuberculous lymphadenitis, and sarcoidosis were considered. Therefore thoracoscopic biopsy should be performed for the correct diagnosis, even in uncommon portion of lymph node swelling and age for KFD.

A 36-year-old woman underwent proton beam therapy for encapsulated type B1 thymoma for curative intent at 66 GyE. Radiographically partial response was achieved. Although the tumor size had been stable since that time, she developed systemic myasthenia gravis 10 years after the proton therapy. Extended thymectomy was performed. There were no adhesions between the tumor and the pericardium, and there were no adhesions also between the tumor and the sternum, probably due to the favor of Bragg peak effect. Extensive hyalinization with small foci of viable tumor cells showing degenerated type A-like morphology was observed in the resected tumor. Whether the viable cells represented recurrence with degenerative changes or de novo tumor formation was unable to be determined, and whether the viable cells were responsible for the onset of myasthenia gravis remained unclear.

Objectives: The outcome of surgical treatment for secondary spontaneous pneumothorax (SSP) has rarely been investigated., Methods: We retrospectively reviewed 183 patients who underwent surgery for SSP. We categorized the patients into three groups according to underlying diseases: Group A (chronic obstructive pulmonary disease), Group B (interstitial pneumonia [IP]) and Group C (others). We defined treatment success as surgery without hospital mortality, postoperative complications, death within 6 months or ipsilateral recurrence of pneumothorax within 2 years. We assessed the risk factors for unsuccessful treatment using a Cox regression hazard model., Results: There were 123 patients in Group A, 20 in Group B and 40 in Group C. The hospital mortality rates were 2, 15 and 0% in Groups A, B and C, respectively. The hospital mortality, morbidity and pneumothorax recurrence rates in the IP group were higher than in the other groups. The 5-year overall survival rates were 78, 32 and 84% in Groups A, B and C, respectively; the prognosis of the IP group was significantly poorer. The treatment success rates were 86, 45 and 83% in Groups A, B and C, respectively. SSPs caused by IP and SSPs requiring open surgery were identified as the risk factors for unsuccessful treatment., Conclusions: Surgery for SSP caused by underlying diseases other than IP yielded favourable results. However, a careful examination of surgical indication and a realistic disclosure for informed consent are required for patients with SSP caused by IP, because of the high treatment failure rate., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Introduction: Two strategies for selecting neoantigens as targets for non-small cell lung cancer vaccines were compared: (1) an "off-the-shelf" approach starting with shared mutations extracted from global databases and (2) a personalized pipeline using whole-exome sequencing data on each patient's tumor., Methods: The Catalogue of Somatic Mutations in Cancer database was used to create a list of shared missense mutations occurring in more than 1% of patients. These mutations were then assessed for predicted binding affinity to HLA alleles of 15 lung cancer patients, and potential neoantigens (pNeoAgs) for each patient were selected on this basis. In the personalized approach, pNeoAgs were selected from missense mutations detected by whole-exome sequencing of the patient's own samples., Results: The list of shared mutations included 22 missense mutations for adenocarcinoma and 18 for squamous cell carcinoma (SCC), resulting in a median of 10 off-the-shelf pNeoAgs for each adenocarcinoma (range 5-13) and 9 (range 5-12) for each SCC. In contrast, a median of 59 missense mutations were identified by whole-exome sequencing (range 33-899) in adenocarcinoma and 164.5 (range 26-232) in SCC. This resulted in a median of 46 pNeoAgs (range 13-659) for adenocarcinoma and 95.5 (range 10-145) for SCC in the personalized set. We found that only one or two off-the-shelf pNeoAgs were included in the set of personalized pNeoAgs-and then in only three patients, with no overlap seen in the remaining 12 patients., Conclusions: Use of an off-the-shelf pipeline is feasible but may not be satisfactory for most patients with non-small cell lung cancer. We recommend identifying personal mutations by comprehensive genome sequencing for developing neoantigen-targeted cancer immunotherapies., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: We investigated the role of the 2011 International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) classification in predicting occult lymph node metastasis in clinically mediastinal node-negative lung adenocarcinoma., Methods: We reviewed lung adenocarcinoma patients who had clinically N2-negative status, were evaluated by preoperative positron emission tomography combined with computed tomography (PET/CT) and had undergone lobectomy or pneumonectomy at Memorial Sloan Kettering Cancer Center (n = 297). Tumours were classified according to the 2011 IASLC/ATS/ERS classification. The associations between occult lymph node metastasis and clinicopathological variables were analysed using Fisher's exact test and logistic regression analysis., Results: Thirty-two (11%) cN0-1 patients had occult mediastinal lymph node metastasis (pN2) whereas 25% of cN1 patients had pN2 disease. Increased micropapillary pattern was associated with increased risk of pN2 disease (P = 0.001). On univariate analysis, high maximum standard uptake value of the primary tumour on PET/CT (P = 0.019) and the presence of micropapillary (P = 0.014) and solid pattern (P = 0.014) were associated with occult pN2 disease. On multivariable analysis, micropapillary pattern was positively associated with risk of pN2 disease (odds ratio = 3.41; 95% confidence intervals = 1.42-8.19; P = 0.006)., Conclusions: The presence of micropapillary pattern is an independent predictor of occult mediastinal lymph node metastasis. Our observations have potential therapeutic implications for management of early-stage lung adenocarcinoma., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: The Glasgow Prognostic Score (GPS), which is calculated with C-reactive protein (CRP) and albumin (Alb) values, is a prognostic indicator for various types of cancers. However, its role in lung cancer still remains unclear, and its optimal cut-off values are controversial. Here, we evaluated the significance of the GPS and adjusted GPS (a-GPS) using our institution's cut-off values in patients undergoing resection for primary lung cancer., Methods: We analysed 1043 lung cancer patients who underwent resection between 1998 and 2012. The overall survival (OS) probabilities of the GPS subgroups were estimated using the Kaplan-Meier method and were compared using the log-rank test. The prognostic significance of the GPS and the a-GPS was assessed by the Cox proportional hazards model with clinicopathological variables and inflammation markers, such as the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR). The GPS was calculated based on cut-off values of 1.0 mg/dl for CRP and 3.5 g/dl for Alb, as previously reported. The a-GPS was calculated based on cut-off values 0.3 mg/dl for CRP and 3.9 g/dl for Alb, which are the standard thresholds used by our institution., Results: The GPS and the a-GPS were correlated with preoperative factors, such as age, sex, smoking status, the NLR and the PLR, and oncological factors, including the pathological stage, histological type and level of lymphovascular invasion. The 5-year OS rates were 82, 55 and 55% with GPS 0, 1 and 2 (1 vs 0: P < 0.01; 2 vs 1: P = 0.66), respectively, and 88, 67 and 59% with a-GPS 0, 1 and 2 (1 vs 0: P < 0.01; 2 vs 1: P = 0.04), respectively. Multivariable analysis revealed that the GPS [1 vs 0, hazard ratio (HR): 1.63, 2 vs 0, HR: 1.44] and the a-GPS (1 vs 0, HR: 2.00, 2 vs 0, HR: 2.10) were independent prognostic factors. The a-GPS classification showed a clearer prognostic distribution than the GPS classification., Conclusions: The GPS is a useful prognostic indicator of the OS in lung cancer surgery. The optimal cut-off values for GPS estimation may need to be re-evaluated., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Currently, non-small cell lung carcinomas are primarily classified by light microscopy. However, recent studies have shown that poorly differentiated tumors are more accurately classified by immunohistochemistry. In this study, we investigated the use of immunohistochemical analysis in reclassifying lung carcinomas that were originally diagnosed as squamous cell carcinoma. Tumor slides and blocks were available for histologic evaluation, and tissue microarrays were constructed from 480 patients with resected lung carcinomas originally diagnosed as squamous cell carcinoma between 1999 and 2009. Immunohistochemical analyses for p40, p63, thyroid transcription factor-1 (TTF-1; clones SPT24 and 8G7G3/1), napsin A, chromogranin A, synaptophysin, and CD56 were performed. Staining intensity (weak, moderate, or strong) and distribution (focal or diffuse) were also recorded. Of all, 449 (93.5%) patients were confirmed as having squamous cell carcinomas; the cases were mostly diffusely positive for p40 and negative for TTF-1 (8G7G3/1). Twenty cases (4.2%) were reclassified as adenocarcinoma, as they were positive for TTF-1 (8G7G3/1 or SPT24) with either no or focal p40 expression, and all of them were poorly differentiated with squamoid morphology. In addition, 1 case was reclassified as adenosquamous carcinoma, 4 cases as large cell carcinoma, 4 cases as large cell neuroendocrine carcinoma, and 2 cases as small cell carcinoma. In poorly differentiated non-small cell lung carcinomas, an accurate distinction between squamous cell carcinoma and adenocarcinoma cannot be reliably determined by morphology alone and requires immunohistochemical analysis, even in resected specimens. Our findings suggest that TTF-1 8G7G3/1 may be better suited as the primary antibody in differentiating adenocarcinoma from squamous cell carcinoma.

Background: Currently, tumor-node-metastasis stage and histologic type are the established prognostic factors for malignant pleural mesothelioma, whereas no prognostic markers have been established for clinical practice. We investigated the prognostic value of CD10, a metalloproteinase that can promote cancer aggressiveness through enzymatic degradation and intracellular signaling crosstalk, in malignant pleural mesothelioma., Methods: CD10 immunostaining was performed for 176 cases of malignant pleural mesothelioma (epithelioid, 148; biphasic, 14; sarcomatoid, 14), and its expression was dichotomized as negative (no staining) or positive (any staining). Epithelioid tumors were classified as pleomorphic subtype when cytologic pleomorphism was ≥10 % of the tumor. Overall survival (OS) was analyzed by log-rank tests and Cox proportional hazard models., Results: Tumoral CD10 expression was identified in 42 % of epithelioid non-pleomorphic tumors, 57 % of epithelioid pleomorphic tumors, 79 % of biphasic tumors, and 93 % of sarcomatoid tumors (p < 0.001). Positive CD10 expression was correlated with higher mitotic count (p = 0.002). Overall survival for patients with positive CD10 expression was significantly shorter than that for patients with negative CD10 expression in all patients (p = 0.001) and in patients with epithelioid tumor (p = 0.04). On multivariate analysis, CD10 expression was an independent prognostic factor for all patients (hazard ratio 1.48; p = 0.019)., Conclusions: Tumoral CD10 expression correlated with aggressive histologic types and higher mitotic activity and is an independent prognostic factor for patients with malignant pleural mesothelioma.

Aims: The IASLC/ATS/ERS classification of lung adenocarcinoma provides a prognostically significant histological subclassification. The aim of this study was to investigate the accuracy, limitations and interobserver agreement of frozen sections for predicting histological subtype., Methods and Results: Frozen section and permanent section slides from 361 resected stage I lung adenocarcinomas ≤ 3 cm in size were reviewed for predominant histological subtype and the presence or absence of lepidic, acinar, papillary, micropapillary and solid patterns. Fifty cases were additionally reviewed by three pathologists to determine interobserver agreement. To test the accuracy of frozen section in judging degree of invasion, five pathologists reviewed frozen section slides from 35 cases with a predominantly lepidic pattern. There was moderate agreement on predominant histological subtype between frozen sections and final diagnosis (κ = 0.565). Frozen sections had high specificity for micropapillary and solid patterns (94% and 96%, respectively), but sensitivity was low (37% and 69%, respectively). The interobserver agreement was satisfactory (κ > 0.6, except for the acinar pattern)., Conclusions: Frozen section can provide information on the presence of aggressive histological patterns-micropapillary and solid-with high specificity but low sensitivity. It was difficult to predict the predominant pattern on the basis of frozen sections, mostly because of sampling issues., (© 2014 John Wiley & Sons Ltd.)

We report a case of tracheal resection and reconstruction for a squamous cell carcinoma of the trachea that was found in an 82-year-old male patient who had underwent right lower lobectomy for an adenosquamous cell carcinoma 3.5 years before. He noticed bloody sputum. Chest computed tomography (CT) revealed a 15 mm tumor in the anterior wall of the trachea. A transbronchial biopsy for the tracheal tumor showed a squamous cell carcinoma. Under right thoracotomy, we resected the tumor with 3 tracheal rings. Histologically a squamous cell carcinoma was diagnozed. As there was intraepithelial spread of cancer cells in the oral margin, the tracheal tumor was suspected to be a primary tracheal tumor rather than a metastasis from lung cancer. After the surgery, combination therapies of an external radiation therapy for 50 Gy and brachytherapy 2 times for totally 8 Gy were performed as a postoperative adjuvant therapy. He does not have any signs of recurrence in 1 year and 6 months after the surgery.

Objectives: The optimal strategy for pleural dissemination of advanced thymoma remains controversial, while a potential benefit from macroscopic clearance of disseminations has been reported. In this study, we review our mid-term results of surgical resection of pleural disseminations of invasive thymoma., Methods: Data from patients with pleural dissemination synchronously or metachronously to primary invasive thymoma who underwent surgical resection from 1991 to 2012 at our institute were retrospectively reviewed., Results: Of 136 thymoma patients who underwent surgery during the study period, 13 consecutive patients with pleural dissemination (synchronous: 7, metachronous: 6) with a median age of 49 years (range: 27-78 years) at the time of dissemination resection were identified. No patients presented with haematogenous metastases. Operative procedures included the thorough resection of visible disseminated nodules in 11 patients and extrapleural pneumonectomy (EPP) in 2 patients. The median number of resected nodules was 6 (range: 1-52). The median follow-up was 948 days (range: 38-4025 days). One patient died of postoperative bleeding, but there were no tumour-related deaths during the study period. Pleural recurrence was found in 9 cases, including 2 EPP cases, and among them, 3 underwent repeated resection. The overall survival and the recurrence-free survival ratio at 5 years was 92.3 and 33.3%, respectively. Five patients, including 2 repeated resection cases, remained tumour-free at the final observation., Conclusions: Resection of pleural dissemination of invasive thymoma can be performed in selected patients and may offer optimal local control as part of a multimodal strategy., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Purpose: Growing number of elderly lung cancer patients reflecting a lengthening life span has become a serious problem. Purpose of this study was to elucidate the short and long-term outcome of the surgery for octogenarians, and to evaluate the role of lung cancer surgery for this high age group., Methods: The patients with lung cancer aged 80 years or more who underwent the surgery at our institute from January 1998 through December 2012 were retrospectively analyzed by chart review, and the operative mortality, morbidity and the long-term survival were assessed., Results: Out of a total of 1107 patients with primary lung cancer who received surgery during the study period, 94 were octogenarians (8.5%). Sixty-nine patients (73.4%) had preoperative co-morbidity including hypertension in 50 (53.2%), coincidence of other malignancy in 35 (37.2%), anti-coagulant therapy in 29 (30.9%). Twenty-six patients (27.7%) had major or minor postoperative morbidity, and one (1.1%) died due to bronchopleural fistula. Overall-5-year survival rate was 57.5%. Univariative and multivariative analysis using Cox proportional hazard model revealed that male gender and non-adenocarcinoma histology were significant risk factors for poor prognosis., Conclusion: Gender and histology should be taken into account in preoperative evaluation of indication for lung cancer in octogenarians.

Purpose: The early and long-term outcomes of bony chest wall reconstruction with expanded polytetrafluoroethylene (Gore-Tex) soft tissue patch remain a concern. No clinical study has reported the shrinkage of Gore-Tex following reconstruction to date., Methods: Thirty-seven patients who underwent bony chest wall reconstruction from 1994 to 2012 were retrospectively reviewed. Postoperative chest computed tomography images of 17 patients were examined, and shrinkage of reconstruction materials was measured and compared., Results: Gore-Tex was used for reconstruction in 18 patients, autologous materials were used in 14, Marlex mesh was used in four, and Medifit felt was used in one. No surgery-related deaths were observed. Twenty patients experienced early postoperative complications. Four patients experienced local infection. One patient with Marlex-mesh experienced empyema 33 days postoperatively. Chest drainage time in the Gore-Tex patients was significantly lower than in patients with other types of prosthetic reconstruction. No dislocation or dehiscence was found. Shrinkage of Gore-Tex was absent in 4 patients and acceptable in seven patients. No granulation formation was evident around the Gore-Tex, No significant difference in shrinkage was seen between the different materials used., Conclusion: Chest wall reconstruction with Gore-Tex was feasible with favorable early and long-term results.

Introduction: For lung squamous cell carcinomas, there are no pathological findings that have been universally accepted as prognostic factors, with the exception of pathological stage. Tumor budding and nuclear grade have been recognized as a poor prognostic factor in other carcinomas. In this study, we investigated whether pathological findings could determine prognosis in lung squamous cell carcinomas., Methods: All available tumor slides from patients with surgically resected, solitary lung squamous cell carcinomas (1999-2009) were reviewed (n = 485; stage I/II/III, 281/136/68). Tumors were evaluated for differentiation, subtypes (keratinizing, nonkeratinizing, basaloid pattern, papillary growth, and clear cell feature), tumor nest size (tumor budding and single cell invasion), and nuclear grade (nuclear diameter and mitosis). Overall survival (OS) was estimated using the Kaplan-Meier method (stratified by pathological stage), and group differences were investigated using the stratified log-rank test and the Cox proportional hazards model., Results: OS was significantly decreased in patients with versus without single cell invasion (p = 0.002 for the entire tumor and p = 0.001 for tumor edge), with large versus small nuclei (p = 0.011), and with high versus low grade tumor budding (p < 0.001 for maximum and p = 0.007 for total). In multivariate analyses, single cell invasion (hazard ratio [HR], 1.47-1.49), nuclear diameter (HR, 1.09-1.33), and tumor budding (HR, 1.04) were independent prognostic factors of OS. However, histologic subtyping including keratinizing, nonkeratinizing, basaloid, and clear cell subtypes did not show prognostic significance., Conclusions: Pathological factors can help stratify prognosis in patients with lung squamous cell carcinomas.

Purpose: Limited resection is an increasingly utilized option for treatment of clinical stage IA lung adenocarcinoma (ADC) ≤2 cm (T1aN0M0), yet there are no validated predictive factors for postoperative recurrence. We investigated the prognostic value of preoperative consolidation/tumor (C/T) ratio [on computed tomography (CT) scan] and maximum standardized uptake value (SUVmax) on (18)F-fluorodeoxyglucose-positron emission tomography (PET) scan., Methods: We retrospectively reviewed 962 consecutive patients who underwent limited resection for lung cancer at Memorial Sloan-Kettering between 2000 and 2008. Patients with available CT and PET scans were included in the analysis. C/T ratio of 25 % (in accordance with the Japan Clinical Oncology Group 0201) and SUVmax of 2.2 (cohort median) were used as cutoffs. Cumulative incidence of recurrence (CIR) was assessed., Results: A total of 181 patients met the study inclusion criteria. Patients with a low C/T ratio (n = 15) had a significantly lower 5-year recurrence rate compared with patients with a high C/T ratio (n = 166) (5-year CIR, 0 vs. 33 %; p = 0.015), as did patients with low SUVmax (n = 86) compared with patients with high SUVmax (n = 95; 5-year CIR, 18 vs. 40 %; p = 0.002). Furthermore, within the high C/T ratio group, SUVmax further stratified risk of recurrence [5-year CIR, 22 % (low) vs. 40 % (high); p = 0.018]., Conclusions: With the expected increase in diagnoses of small lung ADC as a result of more widespread use of CT screening, C/T ratio and SUVmax are widely available markers that can be used to stratify the risk of recurrence among cT1aN0M0 patients after limited resection.

Background: We sought to analyze the prognostic significance of the new International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) lung adenocarcinoma (ADC) classification for patients undergoing resection for small (≤2cm) lung ADC and to investigate whether histologic subtyping can predict recurrence after limited resection (LR) vs lobectomy (LO)., Methods: Comprehensive histologic subtyping was performed according to the IASLC/ATS/ERS classification on all consecutive patients who underwent LR or LO for small lung ADC between 1995 and 2009 at Memorial Sloan-Kettering Cancer Center. Clinical characteristics and pathologic data were retrospectively evaluated for 734 consecutive patients (LR: 258; LO: 476). Cumulative incidence of recurrence (CIR) was calculated using competing risks analysis and compared across groups using Grey's test. All statistical tests were two-sided., Results: Application of IASLC/ATS/ERS lung ADC histologic subtyping to predict recurrence demonstrates that, in the LR group but not in the LO group, micropapillary (MIP) component of 5% or greater was associated with an increased risk of recurrence, compared with MIP component of less than 5% (LR: 5-year CIR = 34.2%, 95% confidence interval [CI] = 23.5% to 49.7% vs 5-year CIR = 12.4%, 95% CI = 6.9% to 22.1%, P < .001; LO: 5-year CIR = 19.1%, 95% CI = 12.0% to 30.5% vs 15-year CIR = 12.9%, 95% CI = 7.6% to 21.9%, P = .13). In the LR group, among patients with tumors with an MIP component of 5% or greater, most recurrences (63.4%) were locoregional; MIP component of 5% or greater was statistically significantly associated with increased risk of local recurrence when the surgical margin was less than 1cm (5-year CIR = 32.0%, 95% CI = 18.6% to 46.0% for MIP ≥ 5% vs 5-year CIR = 7.6%, 95% CI = 2.3% to 15.6% for MIP < 5%; P = .007) but not when surgical margin was 1cm or greater (5-year CIR = 13.0%, 95% CI = 4.1% to 22.1% for MIP ≥ 5% vs 5-year CIR = 3.4%, 95% CI = 0% to 7.7% for MIP < 5%; P = .10)., Conclusions: Application of the IASLC/ATS/ERS classification identifies the presence of an MIP component of 5% or greater as independently associated with the risk of recurrence in patients treated with LR.

Background: In the current study, the authors investigated whether thyroid transcription factor-1 (TTF-1) expression is correlated with the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification and whether it stratifies patients with stage I lung adenocarcinoma with respect to disease recurrence., Methods: Patients with stage I lung adenocarcinoma were classified according to the IASLC/ATS/ERS classification. Tissue microarrays were constructed and immunostaining for TTF-1 was performed. A total of 452 cases were available for analysis. Tumors were dichotomized based on the intensity of nuclear TTF-1 expression as negative (score of 0) or positive (score of 1-3). The cumulative incidence of recurrence (CIR) was used to estimate disease recurrence probabilities., Results: TTF-1 expression was identified in 92% of patients, including 100% of patients with minimally invasive or lepidic-predominant adenocarcinoma, 94% of patients with acinar-predominant adenocarcinoma, 98% of patients with papillary-predominant adenocarcinoma, 93% of patients with micropapillary-predominant adenocarcinoma, 86% of patients with solid-predominant adenocarcinoma, 67% of patients with colloid-predominant adenocarcinoma, and 47% of patients with invasive mucinous carcinoma. The CIR for patients with negative TTF-1 expression (n = 34 patients; 5-year CIR, 40%) was significantly higher than that for patients with positive TTF-1 expression (n = 418 patients; 5-year CIR, 15%) (P < .001). Among the patients with intermediate-grade tumors, the CIR for patients with negative TTF-1 expression (n = 16 patients; 5-year CIR, 45%) was significantly higher than that for patients with positive TTF-1 expression (n = 313 patients; 5-year CIR, 14%) (P < .001). On multivariate analysis, negative TTF-1 expression was found to be significantly correlated with an increased risk of disease recurrence (hazards ratio, 2.55; P = .009)., Conclusions: TTF-1 expression was found to be an independent predictor of disease recurrence, stratifying intermediate-grade tumors into 2 prognostic subsets, and it correlates with the IASLC/ATS/ERS classification., (Copyright © 2012 American Cancer Society.)

Purpose: Mounting evidence suggests that tumor-infiltrating immune cells have prognostic value for patients with solid organ malignancies. Our aim was to investigate the prognostic significance of the immune microenvironment in patients with stage I lung adenocarcinoma (ADC)., Patients and Methods: Using tissue microarray and immunohistochemistry, we investigated eight types of tumor-infiltrating immune cells in the tumor nest and tumor-associated stroma as well as tumor expression of five cytokines in a uniform cohort of 956 patients with stage I lung ADC (478 each in training and validation cohorts)., Results: Although a high density of stromal forkhead box P3 (FoxP3) -positive cells was associated with shorter recurrence-free probability (RFP; P = .043), the relative proportion of stromal FoxP3 to CD3 was a stronger predictor of recurrence (5-year RFP, 85% for high v 77% for low ratio; P = .004). High expression of tumor interleukin-12 receptor β2 (IL-12Rβ2) was associated with better outcome (5-year RFP, 90% for high v 80% for low expression; P = .026), whereas high expression of tumor IL-7R was associated with worse outcome (5-year RFP, 76% for high v 86% for low expression; P = .001). In multivariate analysis, these immune markers were independently associated with recurrence. Although IL-7R remained significant for poor overall survival, all the markers remained prognostic for recurrence in patients with stages IA and IB disease as well as for patients with tumors ≤ 2 cm., Conclusion: Our investigation confirms the biologic and prognostic significance of the tumor immune microenvironment for patients with stage I lung ADC and provides support for its use to stratify clinical outcome and immunotherapeutic interventions.

Background: We have recently proposed to reclassify the pleomorphic subtype of epithelioid malignant pleural mesothelioma (MPM) as nonepithelioid (biphasic/sarcomatoid) histology because of its similarly poor prognosis. We sought to investigate whether preoperative maximum standardized uptake value (SUVmax) on F-fluorodeoxyglucose (FDG) positron emission tomography (PET) correlates with histologic subtype in MPM., Methods: Clinical data were collected for 78 patients with MPM who underwent preoperative FDG-PET. We retrospectively classified the epithelioid tumors into five subtypes: trabecular, tubulopapillary, micropapillary, solid, and pleomorphic. Tumors were categorized by SUVmax into two groups: low (<10.0) and high (≥10.0)., Results: The median overall survival of epithelioid tumors with high SUVmax (n = 12) was significantly shorter (7.1 months) than that of epithelioid tumors with low SUVmax (n = 54, 18.9 months, p < 0.001) and comparable to nonepithelioid tumors (n = 12, 7.2 months). Epithelioid tumors with pleomorphic subtype (n = 9) had marginally higher SUVmax (mean ± SD: 10.6 ± 5.9) than epithelioid nonpleomorphic subtype (n = 57, 6.5 ± 3.2, p = 0.050), and were comparable to that of nonepithelioid tumors (n = 12, 9.1 ± 4.8). Among the epithelioid tumors with high SUVmax (n = 12), 50% (n = 6) showed pleomorphic subtype. In contrast, among epithelioid tumors with low SUVmax (n = 54), 6% (n = 3) showed epithelioid pleomorphic subtypes (p = 0.001). A positive correlation between mitotic count and SUVmax was observed (r = 0.30, p = 0.010)., Conclusions: Pleomorphic subtype of epithelioid MPM showed higher SUVmax than the epithelioid nonpleomorphic subtype and was similar to nonepithelioid histology. Preoperative SUVmax on FDG-PET in epithelioid MPM can indicate patients with pleomorphic subtype with poor prognosis, supporting their reclassification as nonepithelioid.

Purpose: Mesothelin (MSLN) is a tumor-associated antigen, being investigated as a biomarker and therapeutic target in malignant pleural mesothelioma (MPM). The biologic function of MSLN overexpression in MPM is unknown. We hypothesized that MSLN may promote tumor invasion in MPM, a tumor characterized primarily by regional aggressiveness and rare distant metastases., Experimental Design: Human and murine MPM cells with MSLN forced expression and short hairpin RNA knockdown were examined for proliferation, invasion, and matrix metalloproteinase (MMP) secretion. The influence of MSLN overexpression on MPM cell invasion was assessed in an orthotopic mouse model and in patient samples., Results: MSLN expression promotes MPM cell invasion and MMP secretion in both human and murine MPM cells. In an orthotopic MPM mouse model characterized by our laboratory, MPM cells with MSLN overexpression preferentially localized to the tumor invading edge, colocalized with MMP-9 expression, and promoted decreased survival without an increase in tumor burden progression. In a tissue microarray from epithelioid MPM patients (n = 139, 729 cores), MSLN overexpression correlated with higher MMP-9 expression at individual core level. Among stage III MPM patients (n = 72), high MSLN expression was observed in 26% of T2 tumors and 51% of T3 tumors., Conclusions: Our data provide evidence elucidating a biologic role for MSLN as a factor promoting tumor invasion and MMP-9 expression in MSLN expressing MPM. As regional invasion is the characteristic feature in MSLN expressing solid cancers (MPM, pancreas, and ovarian), our observations add rationale to studies investigating MSLN as a therapeutic target., (©2012 AACR.)

Background: Previous studies have shown the sex differences in lung cancer and the associations between estrogen-related genes and non-small cell lung cancer. In the present study, we assumed the existence of shared candidate genes that are common in lung and breast cancers, and examined whether women with a family history of breast cancer are at increased risk of lung cancer compared with men, especially adenocarcinoma, in a case-only study., Methods: This case-only study was conducted based on the Lung Cancer Database Project at the National Cancer Center Hospital East. A total of 1566 patients with newly diagnosed primary lung cancer were consecutively recruited between 1999 and 2003. Information on their family history of cancer and smoking habit was obtained from a self-administered questionnaire. To assess an interactions between two factors, odds ratios for interaction (ORis) and 95% confidence intervals (CIs) were calculated by case-only contingency table., Results: A statistically significant ORi was observed between a family history of breast cancer in first-degree relatives (parent and siblings, not including children) and the sex of a patient (ORi: 2.22, 95% CI: 1.02-4.81). A stratified analysis by histologic subtypes showed a statistically significant ORi only for adenocarcinoma (ORi: 3.27, 95% CI: 1.19-8.98). No other family history of cancer, such as stomach, colon and lung cancer, showed a statistically significant ORi., Conclusion: This study suggests the possibility of gene-sex interaction in lung cancer.

Background: Postoperative infections have been a major issue in lung cancer surgery. We changed our perioperative prophylactic antibiotic policy to a single dose of cefazolin before and after surgery in July 2002., Objective: To identify the risk factors of postoperative pneumonia and empyema in lung cancer patients undergoing surgical resection., Methods: From July 1992 through September 2003, 2105 patients underwent primary lung cancer resection at our division. We reviewed 1855 eligible patients for possible risk factors of pneumonia and empyema., Results: Postoperative respiratory infections developed in 69 (3.7%) patients. There were 58 (3.1%) pneumonia cases and 18 (1.0%) cases of empyema. The mortality rate was 0.8% (15 patients). Nine (0.5%) patients died from postoperative respiratory infections. Multivariate analysis showed age 75 years or older, forced expiratory volume in 1 second as a percentage of forced vital capacity (FEV1%) less than 70%, advanced pathologic stage, and induction therapy to be independent risk factors of pneumonia. For postoperative empyema, advanced age was the significant factor. Twelve of 18 patients (67%) with empyema were complicated with bronchopleural fistula. The infection incidence rate did not change significantly after we modified our prophylactic antibiotic policy to a single dose of cefazolin before and after surgery., Conclusions: Lung cancer patients with advanced age, low FEV1%, advanced pathologic stage, or induction therapy had a risk for pneumonia after lung cancer surgery. Postoperative empyema was associated with advanced age.

Study Objectives: To clarify the possibility of a hereditary predisposition to lung cancer, we investigated the association between a family history of lung cancer and subsequent risk of lung cancer in a large-scale, population-based cohort study., Design: We investigated 102,255 middle-aged and older Japanese subjects (48,834 men and 53,421 women) with 13-year follow-up. A total of 791 cases of lung cancer were newly diagnosed during the follow-up period., Results: A family history of lung cancer in a first-degree relative was associated with a significantly increased risk of lung cancer (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.31 to 2.88). The association was stronger in women than in men (HR, 2.65; 95% CI, 1.40 to 5.01 and HR, 1.69; 95% CI, 1.03 to 2.78, respectively), and in never-smokers than in current smokers (HR, 2.48; 95% CI, 1.27 to 4.84 and HR, 1.73; 95% CI, 0.99 to 3.00, respectively). In addition, family history was more strongly associated with the risk of squamous cell carcinoma than with other histologic types (HR, 2.79; 95% CI, 1.37 to 5.68), while no clear increase in risk was observed in adenocarcinoma and small cell carcinoma. A family history of overall cancer was not associated with an increased risk of lung cancer., Conclusions: These results suggest that those with a family history of lung cancer are more likely to acquire lung cancer themselves.

The latest World Health Organization (WHO) classification divides adenocarcinoma mainly into adenocarcinoma mixed subtypes, acinar adenocarcinoma, papillary adenocarcinoma, bronchioloalveolar carcinoma, and solid adenocarcinoma with mucin production, and it mentions several variants, including fetal adenocarcinoma, mucinous ("colloid") adenocarcinoma, mucinous cystadenocarcinoma, signet-ring adenocarcinoma, and clear cell adenocarcinoma. In general, the mucin-producing adenocarcinoma of the lung comprises signet-ring cell carcinoma (SRCC), solid adenocarcinoma with mucin production (SA), and mucinous bronchioloalveolar carcinoma (m-BAC), mucinous ("colloid") adenocarcinomas and/or mucinous cystadenocarcinoma, and mucoepidermoid carcinoma. As SRCC, SA, and m-BAC exhibit distinct clinical features, it is important to identify differences in their immunohistochemical characteristics to better understand their histogenesis. In this study we analysed SRCC, SA, m-BAC, normal lung, and foregut-related secretory tissue for immunohistochemical differences using tissue microarrays. SRCC and SA showed high expression of MUC1 (97.4% and 100%, respectively), cytokeratin (CK) 7 (both 100%), and thyroid transcription factor-1 (TTF-1) (81.1% and 100%, respectively). They also showed low expression of MUC5AC (25.5% and 21.1%, respectively) and MUC6 (18.3% and 10.5%, respectively), whereas m-BAC showed high expression of MUC5AC (97.5%), MUC6 (75.0%), and CK7 (94.7%), but low expression of MUC1 (57.5%), and TTF-1 (27.5%). Hierarchical clustering showed that the immunophenotypes of SRCC and SA belong to the same category as alveolar lining cells, whereas m-BAC clustered onto another branch with gastric foveolar cells and bronchial goblet cells. These immunohistochemical findings support the results of our previous clinicopathological analysis of SRCC of the lung showing that SRCC occurs anatomically in the peripheral portion of the lung rather than in the bronchial gland-bearing portion., (Copyright 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

To elucidate additional phenotypic differences between large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), we performed tissue microarray (TMA) analysis of surgically resected LCNEC and SCLC specimens. Immunostaining with 48 antibodies was scored based on staining intensity and the percentage of cells that stained positively. Four proteins were identified as significantly expressed in LCNEC as compared with SCLC: cytokeratin (CK)7, 113 vs 49 (P < .0301); CK18, 171 vs 60 (P < .0008); E-cadherin, 77 vs 9 (P < .0073); and beta-catenin, 191 vs 120 (P < .0286). Immunostaining of cross-sections containing LCNEC and SCLC components revealed significant expression of CK7, CK18 and beta-catenin in the LCNEC component compared with the SCLC component in 2 of 3 cases. Our results indicate that significant expression of CK7, CK18, E-cadherin, and beta-catenin is more characteristic of LCNEC than of SCLC, and these findings provide further support that these tumor types are separate entities morphologically and immunophenotypically, if not biologically.

Aims: Immunohistochemical prognostic factors of pulmonary metastatic colorectal cancer lesions have not been well investigated. The study was conducted to identify the immunohistochemical prognostic factors of metastasized colorectal cancer., Methods: We immunohistochemically investigated the expression of insulin-like growth factor-1 receptor (IGF1-R), E-cadherin, beta-catenin, and p53 using a tissue microarray in the surgical specimens of 86 metastatic lesions., Results: The univariate analysis revealed E-cadherin and membrane beta-catenin positive to be prognostic factors. IGF1-R and p53 were not significantly associated with the patient's survival. In multivariate analysis, the reduced expression of E-cadherin, aerogenous spread with floating cancer cell clusters and vascular invasion were independent prognostic factors., Conclusions: The reduced expression of E-cadherin in the pulmonary metastatic lesions was an independent predictor of poor survival after pulmonary metastasectomy.

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

Purpose: Gefitinib (IRESSA; AstraZeneca, Osaka, Japan) shows excellent antitumor activity against advanced non-small-cell lung cancer, especially for the treatment of adenocarcinoma. However, the predictive factors for the response to gefitinib are still controversial. The aim of this study was to identify the clinicopathological and immunohistochemical features that are favorable to the use of gefitinib in adenocarcinoma patients., Experimental Design: Between June 2002 and October 2003, 36 adenocarcinoma patients who experienced a relapse after surgical resection were treated with gefitinib at our hospital. The histologic patterns of the tumors were divided into four distinctive subtypes according to the revised World Health Organization histologic classification, and the dominant histologic subtype for the maximum cut surface of each resected specimen was documented. Association between the response to gefitinib and the clinicopathological features or immunohistochemical expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR, or c-erbB-2 were then investigated., Results: A significant association between the response to gefitinib and dominant papillary subtype findings was observed (P = 0.0021); the survival time of papillary subtype patients was also significantly prolonged compared with that of non-papillary subtype patients (P = 0.03). No other clinicopathological features or the expression of EGFR, phosphorylated EGFR, or c-erbB-2 were associated with the response to gefitinib., Conclusions: The results of the present study indicate that dominant papillary subtype findings of lung adenocarcinomas can be an important predictor of the response to gefitinib. Thus, this type of adenocarcinoma might be susceptible to postoperative adjuvant treatment with gefitinib.

The clinical and histologic profiles of primary lung carcinomas with signet-ring cell carcinoma (SRCC) components were analyzed. The SRCC components were seen in 39 cases (1.5%) of 2640 cases of surgically resected primary lung carcinomas. The patients' mean age was 54.6 years (range, 32-76 years), and the male-to-female ratio was 1.16:1.00. Twenty-six patients (66.7%) were smokers. The SRCC component was seen as part of an adenocarcinoma in 36 cases (acinar, 27 cases; mixed bronchioloalveolar and acinar, 9 cases) and as part of an adenosquamous cell carcinoma in 2 cases; one lesion consisted of only SRCC cells. The morphologic appearance of cancer nests containing SRCC was classified into three patterns: solid, tubuloacinar, and discohesive. Each case was composed of a varying proportion of these three patterns. The carcinomas with SRCC components were divided into two groups, according to those in which the SRCC component occupied <50% of the lesion (L-SRCC; n = 20) and those in which the SRCC component occupied > or = 50% of the lesion (H-SRCC; n = 19). The frequencies of blood vessel invasion, lymph vessel invasion, and lymph node metastasis were significantly higher in the H-SRCC group than in 1634 adenocarcinoma, and adenosquamous cell carcinomas (non-SRCC). The 5-year survival rates of patients non-SRCC, with l-SRCC, or with H-SRCC were 52.7%, 50%, and 28.4%, respectively. The 5-year survival rate of patients with H-SRCC and of patients without SRCC were significantly different. Based on these clinicopathologic characteristics, we classified primary lung carcinomas with SRCC components into the following two groups: 1) SRCC, in which the SRCC component occupies >or = 50% of the lesion, and 2) signet-ring feature, in which the SRCC components occupies <50% of the lesion.

A 50-year-old male underwent a left nephrectomy for clear cell type renal cell carcinoma (RCC) in February 1978. A right pulmonary metastasis was resected in February 1994. At that time, chest computed tomography revealed the presence of three small nodules in the left lung, but these were followed up as inflammatory lesions. In January 2002, a right pleural metastasis, which showed rapid growth, was detected and it was resected in June of the same year. A gradual growth was observed in the left lung nodules, and the patient underwent wedge resection of the left lung in March 2003, 25 years after nephrectomy. These nodules were diagnosed as metastatic RCC. Currently, the patient is doing well with no signs of recurrence, 8 months after the third metastasectomy.

The relationship between the cell features of central type early lung cancer and the degree of invasion to the bronchial wall was investigated. Bronchial brushing specimens were obtained from 19 cases of central type early lung cancer preoperatively and the resected specimens were pathologically examined. The cell features were classified into three types: Type I: low grade atypia without increased nuclear chromatin, Type II: moderate grade atypia with increased chromatin and Type III: high grade atypia with irregular shaped nucleus and increased chromatin. The expression of Type I cells was significant in cases of carcinoma in situ or microinvasion and Type II and III cells were observed more frequently in cases with extramuscular bronchial wall invasion. The cell features as well as endoscopic findings can provide a basis for the more precise staging of early stage lung cancer and the determination of therapeutic strategy.