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Purpose: Anaplastic lymphoma kinase (ALK) fusion genes represent novel oncogenes for non–small cell lung cancers (NSCLC). Several ALK inhibitors have been developed, and are now being evaluated in ALK-positive NSCLC. The feasibility of detecting ALK fusion genes in samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was determined. The clinicopathologic characteristics of ALK-positive lung cancer were also analyzed.Experimental Design: From April 2008 to July 2009, NSCLC cases with hilar/mediastinal lymph node metastases detected by EBUS-TBNA were enrolled. Positive expression of ALK fusion protein was determined using immunohistochemistry, and ALK gene rearrangements were further examined to verify the translocation between ALK and partner genes using fluorescent in situ hybridization and reverse transcription-PCR. Direct sequencing of PCR products was performed to identify ALK fusion variants.Results: One hundred and nine cases were eligible for the analysis using re-sliced samples. Screening of these specimens with immunohistochemistry revealed ALK positivity in seven cases (6.4%), all of which possessed echinoderm microtubule–associated protein-like 4–ALK fusion genes as detected by fluorescent in situ hybridization and reverse transcription-PCR. All ALK-positive cases had an adenocarcinoma histology and possessed no EGFR mutations. Compared with ALK-negative cases, ALK-positive cases were more likely to have smaller primary tumors (P < 0.05), to occur at a younger age (P < 0.05), and to occur in never/light smokers (smoking index < 400; P < 0.01). Mucin production was frequently observed in ALK-positive adenocarcinomas (29.4%; P < 0.01).Conclusions: EBUS-TBNA is a practical and feasible method for obtaining tissue from mediastinal and hilar lymph nodes that can be subjected to multimodal analysis of ALK fusion genes in NSCLC. Clin Cancer Res; 16(20); 4938–45. ©2010 AACR.

Background The aim of this study was to describe the characteristics and outcomes of patients with non-small cell lung cancer undergoing salvage surgery after chemoradiotherapy, conventional external beam, stereotactic body radiotherapy, and ion beam radiotherapy. Methods We retrospectively evaluated patients who underwent salvage surgery between 2010 and 2016. Data on perioperative morbidity and mortality and patient outcomes were analyzed. Results In total, 156 patients were included; of those, 110 were categorized into category 1, chemoradiotherapy or conventional external beam; and 46 into category 2, stereotactic body radiotherapy or ion beam radiotherapy. Three-year overall survival (OS) and recurrence-free survival (RFS) in category 1 were 67.3% and 49.8%, respectively. In category 1, pathological nodal stage was an independent prognosticator of both OS (hazard ratio [HR] = 3.53, 95% confidence interval [CI], 1.05-11.83) and RFS (HR = 4.32, 95% CI, 1.32-14.14). In category 2, 3-year OS and RFS were 57.7% and 46.4%, respectively. Age 70 years and greater at initial treatment was the only independent prognosticator of OS (HR = 5.61; 95% CI, 1.44-21.87), whereas age at initial treatment (HR = 6.13; 95% CI, 1.38-27.12) and pathological nodal metastasis (HR = 3.84; 95% CI, 1.40-10.57) were independent prognosticators for RFS. Overall 30- and 90-day mortality were 0% and 0.9% in category 1 and 0% and 4.3% in category 2, respectively. Conclusions Patients who undergo salvage surgery can have reasonable outcomes, and salvage surgery can be considered in selected patients.

Purpose The efficacy of sublobar resection of primary lung cancer have been proven in recent years. However, sublobar resection for highly invasive lung cancer increases local recurrence. We developed and validated multiple machine learning models predicting pathological invasiveness of lung cancer based on preoperative [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) and computed tomography (CT) radiomic features. Methods Overall, 873 patients who underwent lobectomy or segmentectomy for primary lung cancer were enrolled. Radiomics features were extracted from preoperative PET/CT images with the PyRadiomics package. Seven machine learning models and an ensemble of all models (ENS) were evaluated after 100 iterations. In addition, the probability of highly invasive lung cancer was calculated in a nested cross-validation to assess the calibration plot and clinical usefulness and to compare to consolidation tumour ratio (CTR) on CT images, one of the generally used diagnostic criteria. Results In the training set, when PET and CT features were combined, all models achieved an area under the curve (AUC) of ≥ 0.880. In the test set, ENS showed the highest mean AUC of 0.880 and smallest standard deviation of 0.0165, and when the cutoff was 0.5, accuracy of 0.804, F1 of 0.851, precision of 0.821, and recall of 0.885. In the nested cross-validation, the AUC of 0.882 (95% CI: 0.860–0.905) showed a high discriminative ability, and the calibration plot indicated consistency with a Brier score of 0.131. A decision curve analysis showed that the ENS was valid with a threshold probability ranging from 3 to 98%. Accuracy showed an improvement of more than 8% over the CTR. Conclusion The machine learning model based on preoperative [18F]FDG PET/CT images was able to predict pathological highly invasive lung cancer with high discriminative ability and stability. The calibration plot showed good consistency, suggesting its usefulness in quantitative risk assessment.

The efficacy of sublobar resection of primary lung cancer have been proven in recent years. However, sublobar resection for highly invasive lung cancer increases local recurrence. We developed and validated multiple machine learning models predicting pathological invasiveness of lung cancer based on preoperative [Overall, 873 patients who underwent lobectomy or segmentectomy for primary lung cancer were enrolled. Radiomics features were extracted from preoperative PET/CT images with the PyRadiomics package. Seven machine learning models and an ensemble of all models (ENS) were evaluated after 100 iterations. In addition, the probability of highly invasive lung cancer was calculated in a nested cross-validation to assess the calibration plot and clinical usefulness and to compare to consolidation tumour ratio (CTR) on CT images, one of the generally used diagnostic criteria.In the training set, when PET and CT features were combined, all models achieved an area under the curve (AUC) of ≥ 0.880. In the test set, ENS showed the highest mean AUC of 0.880 and smallest standard deviation of 0.0165, and when the cutoff was 0.5, accuracy of 0.804, F1 of 0.851, precision of 0.821, and recall of 0.885. In the nested cross-validation, the AUC of 0.882 (95% CI: 0.860-0.905) showed a high discriminative ability, and the calibration plot indicated consistency with a Brier score of 0.131. A decision curve analysis showed that the ENS was valid with a threshold probability ranging from 3 to 98%. Accuracy showed an improvement of more than 8% over the CTR.The machine learning model based on preoperative [

Although the incidence of metachronous second primary lung cancer (MSPLC) after curative resection for primary lung cancer may be increasing, appropriate treatment and the outcome are unclear yet. We reviewed the literature and conducted a retrospective chart review of the patients who underwent surgery for MSPLC in our institute. We had 27 surgical cases for MSPLC during 2017 and 2018. The interval from the previous surgery was 59.4±35.2 months. Comparing to the patients who were underwent surgery for first primary lung cancer in the same period, the patients with MSPLC showed significantly older age and lower respiratory function. More than 90% of resected MSPLC were stage 0 orⅠand we selected limited surgery for more than 90% of the MSPLC patients. Maybe due to limited surgery, time for surgical procedure and postoperative complication were significantly less than first primary lung cancer cases. No death or recurrence were observed until one year after surgery for MSPLC. For performing feasible limited surgery to early-stage MSPLC cases, continuous computed tomography surveillance in the late phase after the first primary lung cancer surgery should be important.

Randomized controlled trial of adjuvant chemoimmunotherapy for lung cancer indicated a significant advantage in patients receiving immunotherapy. Herein we report the final results and immunological analysis with a median follow-up of 59.6 months. Patients with post-surgical lung cancer were randomly designated to receive either chemoimmunotherapy (group A, immunotherapy arm) or chemotherapy (group B, control arm). The immunotherapy comprised the adoptive transfer of autologous activated killer T cells and dendritic cells (AKT–DC). The 2- and 5-year overall survival (OS) rates were 96.0 and 69.4% in group A and 64.7 and 45.1% in group B, respectively. Multivariate analysis results revealed that the hazard ratio was 0.439. The 2- and 5-year recurrence-free survival rates were 70.0 and 57.9% in group A and 43.1 and 31.4% in group B, respectively. Subgroup analysis for the OS between treatment groups indicated that younger patients (≤ 55 years: HR 0.098), males (HR 0.474), patients with adenocarcinoma (HR 0.479), patients with stage III cancer (HR 0.399), and those who did not receive preoperative chemotherapy (HR 0.483) had lower HRs than those in the other groups. Immunological analysis of cell surface markers in regional lymph nodes of subjects receiving immunotherapy indicated that the CD8+/CD4+ T-cell ratio was elevated in survivors. Patients with non-small-cell lung cancer benefited from adoptive cellular immunotherapy as an adjuvant to surgery. Patients with stage III cancer, those with adenocarcinoma, and those not receiving preoperative chemotherapy were good candidates. Lastly, cytotoxic T cells were important for a favorable chemoimmunotherapy outcome.

Objectives Thoracoscopic surgery for lung metastasectomy remains controversial. The study aimed at determining the efficacy of thoracoscopic surgery for lung metastasectomy. Methods This was a multi-institutional, retrospective study that included 1047 patients who underwent lung metastasectomy for colorectal cancer between 1999 and 2014. Prognostic factors of overall survival were compared between the thoracoscopic and open thoracotomy groups using the multivariate Cox proportional hazard model. The propensity score, calculated using the preoperative covariates, included the era of lung surgery as a covariate. A stepwise backward elimination method, with a probability level of 0.15, was used to select the most powerful sets of outcome predictors. The difference between the radiological tumour number and the resected tumour number (delta_num) was also evaluated. Results The c -statistics and the P -value of the Hosmer-Lemeshow Chi-square of the propensity score model were 0.7149 and 0.1579, respectively. After adjusting for the propensity score, the thoracoscopy group had a better survival rate than the open group (stratified log-rank test: P = 0.0353). After adjusting for the propensity score, the most powerful predictive model for overall survival was that which combined thoracoscopy [hazard ratio (HR): 0.468, 95% CI: 0.262-0.838, P = 0.011] and anatomical resection (HR: 1.49, 95% CI: 1.134-1.953, P = 0.004). Before adjusting for the propensity score, the delta_num was significantly greater in the open group than in the thoracoscopy group (thoracoscopy: 0.06, open: 0.33, P = 0.001); however, after adjustment, there was no difference in the delta_num (thoracoscopy: 0.04, open: 0.19, P = 0.114). Conclusions Thoracoscopic metastasectomy showed better overall survival than the open approach in this analysis. The thoracoscopic approach may be an acceptable option for resection of pulmonary metastases in terms of tumour identification and survival outcome in the current era.

Background Pulmonary carcinoma patients with low pulmonary function cannot be treated surgically because of the high risk of complications. Diaphragmatic eventration is a disease characterized by diaphragmatic paralysis and dyspnea. Here, we report a surgical case of multiple pulmonary carcinomas with contralateral diaphragmatic eventration. Case presentation The patient was a 75-year-old woman with multiple metachronous right lung carcinomas complicated by left diaphragmatic eventration. When she was 70 years old, a right upper lobectomy and right S6b wedge resection were performed for double lung carcinomas. Five years later, two new lung tumors in her right lower lobe and left diaphragmatic eventration were identified, but resection was thought to be impossible because of her low pulmonary function. We performed video-assisted thoracoscopic surgery (VATS) plication with carbon dioxide (CO2) insufflation for the left diaphragmatic eventration, and her pulmonary function improved. Subsequently, we performed a right S6 wedge resection and right S9 segmentectomy for the double lung tumors with no complications. The tumors were diagnosed as double primary carcinomas. Conclusions Our case presented with low pulmonary function and right multiple lung carcinomas with left diaphragmatic eventration. VATS plication for the left diaphragmatic eventration achieved improvement in her pulmonary function, and right pulmonary resection for the lung carcinomas was performed. VATS plication can expand the choice of treatments in such cases.

It is not uncommon for patients with lung cancer to receive supportive care alone. However, the clinical characteristics of these patients have not been fully studied. We conducted a retrospective study to identify the clinical characteristics of definitive lung cancer patients treated with supportive care alone. We retrospectively analyzed the percentage of and reasons for definitive lung cancer patients treated with supportive care alone at a regional cancer center. We also investigated the histological diagnostic approaches, palliative therapy types, primary treatment locations after hospital consultation, and places of death. A total of 1,223 patients were histologically diagnosed as having lung cancer between 2011 and 2014. Of these, 160 (13%) patients were treated with supportive care alone. The primary reason for treatment with supportive care alone was a poor performance status (PS) in almost half of the patients. Overall, 40% of the patients received supportive care at home, and 17% were admitted to a palliative care unit (PCU). Death occurred at home for 17% of the patients and in the PCU for 42% of the patients. This study revealed that 13% of histologically proven lung cancer patients were treated with supportive care alone, mostly because of a poor PS. Only 40% of these patients received home care, suggesting the need for a more accessible home care system for patients and their families.

Solitary splenic metastasis is an extremely rare event. We herein report a surgical case of a solitary splenic metastasis from lung cancer. A 78-year-old man presented with abdominal pain. Abdominal computed tomography (CT) showed splenic rupture. Coil embolization to the splenic artery was performed, and the patient’s condition improved. Chest CT showed a 5-cm lung mass in the right upper lobe, suggesting lung cancer with splenic metastasis. Transbronchial aspiration cytology showed squamous cell carcinoma of the lung. We diagnosed the patient with lung cancer (cT2bN0M1b [spleen only] stage IVA) and performed splenectomy and right upper lobectomy separately. Both lesions were squamous cell carcinoma and positive for p40. Thus, primary lung squamous cell carcinoma and solitary splenic metastasis were diagnosed. The patient was still alive without recurrence 15 months postoperatively. We herein report a rare case of lung squamous cell carcinoma with solitary splenic metastasis and review the literature.

Tumor-associated macrophages influence tumor progression and resistance to immune checkpoint therapy. Chemokine signaling is a key regulator of macrophage accumulation and activity. Here, we report that the chemokine receptor-binding protein FROUNT modulates tumor-associated macrophage responses and is an important regulator of tumor progression. By screening 131,200 compounds, we identified the anti-alcoholism drug disulfiram (DSF) as a potent inhibitor of FROUNT that interferes with FROUNT-chemokine receptor interaction by directly binding to FROUNT. Both DSF-treatment and FROUNT-deficiency markedly reduced tumor progression and decreased the tumor-promoting activity of macrophages. Studies using clinical specimens and FROUNT-GFP reporter mice showed that FROUNT was highly expressed in macrophages, and myeloid-specific deletion of FROUNT impaired tumor growth. Low FROUNT expression in patients with lung adenocarcinoma was correlated with better clinical outcomes. Moreover, co-treatment of DSF with an immune checkpoint antibody synergistically inhibited tumor growth. Together, inhibition of FROUNT by DSF presents a strategy for macrophage-targeted cancer therapy.

Background Integrated positron emission tomography (PET) with computed tomography (CT) is a useful modality to investigate lymph node metastases for non-small cell lung cancer, but is less sensitive for normal-sized lymph nodes. We sometimes encounter cases with radiologically normal lymph nodes and unsuspected mediastinal metastases detected by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). However, few studies have investigated staging in patients with radiologically normal mediastina, and the accuracy of EBUS-TBNA staging for radiologically normal mediastina and hila is unclear. Methods This study was a retrospective, single-institution review of a prospectively maintained database at Chiba Cancer Center between May 1, 2008, and September 1, 2013. We analyzed 113 non-small cell lung cancer patients with both CT-negative and PET/CT-negative lymph nodes (N0) in preoperative nodal staging performed by EBUS-TBNA. After preoperative staging was performed, patients with either N0 or N1 clinical staging underwent surgery. Final N factors were determined by mediastinal lymphadenectomy. Results In our study, the overall rate of N2 disease was 17.6% (20 of 113). For nodal staging by EBUS-TBNA, the sensitivity, specificity, negative predictive value, and diagnostic accuracy were 35.0% (7 of 20), 100% (93 of 93), 87.7% (93 of 106), and 88.4% (100 of 113), respectively. There were no severe complications from EBUS-TBNA staging. Conclusions The overall rate of unsuspected N2 was not low. EBUS-TBNA was accurate and feasible for preoperative mediastinal nodal staging of non-small cell lung cancer with both CT-negative and PET/CT-negative lymph nodes. The sensitivity of EBUS-TBNA for radiologically normal mediastina and hila was low. Further investigations are required.

The brain is a frequent site of metastases from non-small-cell lung cancer (NSCLC). We analyzed the frequency of brain metastases (BMs) from NSCLC in the era of magnetic resonance images, and evaluated the correlation between epidermal growth factor receptor (EGFR) mutations and BMs among East Asian patients. Frequency, number, and size of BMs, and survival of 1,127 NSCLC patients were retrospectively reviewed. Mutation status of EGFR was evaluated in all cases, and its association with BMs was statistically evaluated. EGFR mutations were found for 331 cases (29.4 %). BM was the cause of primary symptoms for 52 patients (4.6 %), and found before initiation of treatment for 102 other patients (9.1 %); In addition to these 154 patients, 107 patients (9.5 %) developed BMs, giving a total of 261 patients (23.2 %) who developed BMs from 1,127 with NSCLC. BM frequency was higher among EGFR-mutated cases (31.4 %) than EGFR-wild cases (19.7 %; odds ratio: 1.86; 95 % confidence interval (CI) 1.39–2.49; P

Background Brain metastases (BM) are a common in patients with lung cancer. Although whole-brain radiation therapy (WBRT) is the standard therapy, it may have a risk of decline in cognitive function of patients. In this study, we evaluated the efficacy of gefitinib alone without radiation therapy for the treatment of patients with BM from lung adenocarcinoma. Materials and methods Eligible patients had BM from lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Gefitinib was given at 250mg orally once a day until tumor progression or unacceptable toxicity. Results Forty-one patients were enrolled. The response rate was 87.8%. No patient experienced grade ≥4 toxicity. The median progression-free survival time was 14.5 months (95% CI, 10.2–18.3 months), and the median overall survival time was 21.9 months (95% CI, 18.5–30.3 months). In compared with L858R, exon 19 deletion was associated with better outcome of patients after treatment with gefitinib in both progression-free ( p =0.003) and overall survival ( p =0.025). Conclusion Favorable response of BM to gefitinib even without irradiation was demonstrated. Exon 19 deletion was both a predictive and prognostic marker of patients with BM treated by gefitinib.

We report a case of four synchronous lung cancers, each with a different epidermal growth factor receptor (EGFR) mutation in the tyrosine kinase domain. Bilateral double lung cancer was diagnosed clinically, and a left upper lobectomy and partial left S6 resection were performed. Right S1 segmental resection was performed later. Pathological examination revealed three lung adenocarcinomas in the left lung (S1 + 2, S3, and S6) and one in the right. Three different mutations of EGFR were identified with the polymerase chain reaction and direct sequencing of DNA from the three left lung tumors. The EGFR mutation on the right also differed from that of the left lung tumors.

Background Anaplastic lymphoma kinase (ALK) fusion gene-positive lung cancer accounts for 4–5% of non-small cell lung carcinoma. A clinical trial of the specific inhibitor of ALK fusion-type tyrosine kinase is currently under way. Methods ALK fusion gene products were analyzed immunohistochemically with the materials obtained by surgery or by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). The echinoderm microtubule-associated protein-like 4(EML4)-ALK or kinesin family member 5B (KIF5B)-ALK translocation was confirmed by the reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). After eligibility criteria were met and informed consent was obtained, 3 patients were enrolled for the Pfizer Study of Crizotinib (PF02341066), Clinical Trial A8081001, conducted at Seoul National University. Results Out of 404 cases, there were 14 of EML4-ALK non-small cell carcinoma (NSCLC) and one KIF5B-ALK NSCLC case (8 men, 7 women; mean age, 61.9 years, range 48–82). Except for 2 light smokers, all patients were non-smokers. All cases were of adenocarcinoma with papillary or acinar subtypes. Three were of stage IA, 5 of stage IIIA, 1 of stage IIIB and 6 of stage IV. Ten patients underwent thoracotomy, 3 received chemotherapy and 2 only best supportive care (BSC). One BSC and 2 chemotherapy cases were enrolled for the clinical trial. Patients with advanced stages who received chemotherapy or best supportive care were younger (54.0 ± 6.3) than those who were surgically treated (65.8 ± 10.1) (p The powerful effect of ALK inhibitor on EML4-ALK NSCLC was observed. Soon after its administration, almost all the multiple bone and lymph node metastases quickly disappeared. Nausea, diarrhea and the persistence of a light image were the main side effects, but they diminished within a few months. Conclusion ALK-fusion gene was found in 3.7% (15/404) NSCLC cases and advanced disease with this fusion gene was correlated with younger generation. The ALK inhibitor presented in this study is effective in EML4-ALK NSCLC cases. A further study will be necessary to evaluate the clinical effectiveness of this drug.

Background and objective: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has typically been performed using the 22gauge (G) dedicated TBNA needle. Recently a new 21G TBNA needle has been introduced. The efficacy of using a larger gauge biopsy needle during EBUS-TBNA has not been reported. The purpose of this study was to compare the diagnostic yield and utility of 21G and 22G needles during EBUS-TBNA. Methods: EBUS-TBNA was performed using both 21G and 22G needles. Cytological and histological findings were recorded for each samples obtained by an independent cytologist and pathologist. The cellularity and blood contamination were evaluated in the cytological samples. The quality of the histological core was evaluated by the amount of blood clots versus the actual tissue. Each factor was compared within two slides from the two different size needles. The diagnostic yield and the differences of the cytology and histology were analysed. Results: The evaluation of 45 lesions by EBUS-TBNA revealed that tumour cells were equally detected by both 21G and 22G needles. Two patients of adenocarcinoma were histologically diagnosed only by the 21G needle. Although histological structure was better preserved in five lesions collected by the 21G needle, there was more blood contamination with the 21G needle (P

症例は60歳代，男性．前医にて直腸癌に対し手術を施行．原発巣診断時に指摘されていた右肺下葉小結節影の増大傾向を認め，CTガイド下生検により直腸癌肺転移と診断された．当科での肺部分切除術の術後経過観察中，胸部CTにて右肺下葉背側の胸膜直下および肋骨，胸壁筋層にかけて異常影を認め，FDG-PETで同部位に集積を認めた．再発と診断し，右肺部分切除および胸壁合併切除を施行した．病理所見では，肺組織内，肋骨およびその周辺軟部組織内に腫瘍を認めたが，胸膜は保たれており，CTガイド下生検による腫瘍のインプラントが疑われた．CTガイド下生検施行後は，その後のインプラントの可能性も念頭に置いた注意深い経過観察が必要であると考える．

Interleukin-12 receptor beta2 (IL-12Rbeta2) knock-out mice develop lung adenocarcinoma, and epigenetic silencing by CpG methylation leads to loss of this gene in B-cell malignancies. The aim of this study was to determine whether IL-12Rbeta2 methylation is a common feature in human lung cancer.We examined mRNA expression of IL-12Rbeta2 in lung cancer cell lines, and normal bronchial, and tracheal epithelial cells using RT-PCR, and we examined the methylation status of IL-12Rbeta2 in primary lung cancers.Loss of expression was found in 10 of 13 (77%) NSCLC cell lines, and 2 of 5 (40%) SCLC cell lines compared with normal bronchial or tracheal cells. Treatment of 11 expression-negative cell lines with a demethylating agent restored expression in all cases. Aberrant methylation status of IL-12Rbeta2 gene was reversely concordant with its mRNA expression. IL-12Rbeta2 methylation was detected in 96 of 230 primary NSCLCs (42%) and 3 of 6 primary SCLCs (50%). IL-12Rbeta2 methylation correlated with poorer prognosis in lung adenocarcinomas (hazard ratio = 2.33, P = 0.0059).We conclude that epigenetic silencing of IL-12Rbeta2 is a frequent event in lung cancers. Aberrant methylation of this gene seems to be a useful predictor of long-term outcome for adenocarcinoma of the lung.

BACKGROUND. Patients who have pathologic N2 (pN2) nonsmall cell lung cancer (pN2 NSCLC) represent a heterogeneous group with regard to prognosis and treatment. Molecular features of NSCLC seem to be of interest. For the current study, to select an appropriate therapeutic strategy for each patient, patients with N2 NSCLC were stratified into homogenous subgroups according to the expression profiles of cell cycle-related markers. METHODS. The expression levels of retinoblastoma protein (pRb), cyclin D1, p16, p53, and p21 proteins and values of the Ki-67 labeling index were evaluated in 61 primary surgically resected tumor specimens from patients with pN2 NSCLC using immunohistochemistry. The prognostic impact of these markers on overall survival was analyzed in both univariate and multivariate analyses. RESULTS. In univariate analysis, p21, p16, and Ki-67 were correlated significantly with survival. In multivariate analysis, only p21 and p16 influenced survival. Indeed, the group of patients with pN2 NSCLC who were positive for p21 and p16 had the most favorable overall survival (P = .001) and were correlated significantly with the clinical lymph node (cN) status (cN2 disease; P = .008). Moreover, no significant difference in survival was observed between patients with cN0/cN1 disease and patients with cN2 disease within the group (P = .4333). CONCLUSIONS. Loss of control of cell-cycle checkpoints is a common occurrence in pN2 NSCLC. Functional cooperation between different cell-cycle regulators constitutes another level of regulation in cell growth control and tumor suppression. Preoperative patients with pN2 NSCLC, even those with cN2 disease, who have positive p21 and p16 protein expression in their primary tumors are expected to have a favorable postoperative prognosis and may be candidates for primary resection. Cancer 2007. © 2007 American Cancer Society.

A diagnosis of sarcoidosis should be substantiated by pathological means in order to thoroughly exclude other diseases. The role of real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of sarcoidosis has not been reported. The purpose of the present study is to evaluate the diagnostic yield of EBUS-TBNA in demonstrating the pathological features of sarcoidosis. In total, 65 patients with suspected sarcoidosis, with enlarged hilar or mediastinal lymph nodes on computed tomography, were included in the study. Patients with a suspected or known malignancy or previously established diagnosis of sarcoidosis were excluded. Convex probe endobronchial ultrasonography integrated with a separate working channel was used for EBUS-TBNA. Surgical methods were performed in those in whom no granulomas were detected by EBUS-TBNA. Patients were followed up clinically. EBUS-TBNA was performed on a total of 77 lymph node stations in 65 patients. A final diagnosis of sarcoidosis was made for 61 (93.8%) of the patients. The remaining four patients were diagnosed as having Wegener9s granulomatosis (n = 1) or indefinite (n = 3). In patients with a final diagnosis of sarcoidosis, EBUS-TBNA demonstrated noncaseating epithelioid cell granulomas in 56 (91.8%) of the patients. No complications were reported. Endobronchial ultrasound-guided transbronchial needle aspiration proved to be a safe procedure with a high yield for the diagnoses of sarcoidosis.

We herein report two cases of thymomas diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). In both cases, the tumor was adjacent to the central airway. Therefore, we attempted to perform EBUS-TBNA in order to obtain specimens for a histopathological examination, which resulted in a diagnosis of thymoma. In one case, surgical resection was conducted and the histological evaluation of the resected specimen confirmed thymoma type AB, consistent with the histology from the EBUS-TBNA specimen. As a safe and minimally invasive procedure, EBUS-TBNA may be considered for the diagnosis of mediastinal tumors, including thymoma.

Primary intrapulmonary thymomas (PITs), which are intrapulmonary tumors without an associated mediastinal component, are very rare. The diagnosis of a PIT can be difficult. Here, we report two cases of resected PITs that were difficult to differentiate from other lung tumors. The patients, of a 62-year-old man and a 64-year-old woman, had no significant symptoms and were both referred to our hospital due to the presence of an abnormal shadow on chest computed tomography (CT). The patients underwent (18)F-fluorodeoxyglucose positron emission tomography-CT (FDG-PET/CT) and subsequently tumor excision. A PIT was confirmed histopathologically in the surgical specimens from both patients. In one case, the tumor consisted of a type A thymoma without abnormal FDG uptake. In the other case, the tumor consisted of a type B2 thymoma presenting with weak FDG uptake. This report thus documents two cases of PITs with different histopathologic and FDG-PET/CT findings. Thoracoscopic surgery is essential in the differential diagnosis between PITs and other lung tumors.

RRAD, a small Ras-related GTPase, is highly expressed in human skeletal muscle, lung, and heart. Although loss of expression of RRAD in breast cancer cells has been reported and it may act as an oncogene, the mechanism of silencing is unknown. We examined (1) mRNA expression of RRAD in lung and breast cancer cell lines using RT-PCR and (2) methylation status of lung and breast cancers. Loss of RRAD expression was found in 14 of 20 (70%) NSCLC cell lines, 11 of 11 (100%) SCLC cell lines, and 8 of 10 (80%) breast cancer cell lines; expression was not affected in normal bronchial and mammary epithelial cells. Treatment of 23 expression-negative cell lines with a demethylating agent restored expression in all cases. We developed a methylation-specific assay from the analysis of bisulfite sequencing of the 5′ region of RRAD in expression-negative and positive cell lines, which resulted in good concordance between methylation and expression. Primary lung and breast cancers showed hypermethylation in 89 of 214 (42%) and 39 of 63 (62%) cases, respectively. RRAD hypermethylation correlated with smoking history and poorer prognosis in lung adenocarcinomas. We conclude that epigenetic silencing of RRAD is a frequent event in lung and breast cancers, and analysis of it may provide novel opportunities for prognosis and therapy of these cancers.

Background Patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) have a very poor prognosis, but the benefit of adjuvant chemotherapy for these patients has not been established. We performed a prospective analysis of adjuvant chemotherapy for patients with completely resected pulmonary LCNECs to assess the effect of adjuvant chemotherapy. Methods The adjuvant mixture consisted of cisplatin and VP-16 and was administered after surgery to 15 patients with LCNECs from 2000 to 2005. We compared patient survival with historical data for LCNEC patients treated without platinum-based adjuvant chemotherapy after surgery. Results There were no differences in age, gender, surgical methods, and staging between the adjuvant chemotherapy group and the control group. Median follow-up was 33 months for the adjuvant group and 42 months for the control group. Of the 15 patients in the adjuvant chemotherapy group, 2 patients had disease recurrence and 1 died of interstitial pneumonia. The overall survival rate at 2 and 5 years of patients with adjuvant chemotherapy was 88.9%. The overall survival rate between patients with adjuvant chemotherapy and the historical control group was significantly different. Conclusions Adjuvant chemotherapy consisting of cisplatin and VP-16 after surgery appears promising for the improvement of the prognosis for patients with completely resected LCNECs, and it should be evaluated further in larger multi-institutional trials.

Purpose: Human Vα24 natural killer T (Vα24 NKT) cells bearing an invariant Vα24JαQ antigen receptor are activated by a glicolipid ligand α-galactosylceramide (αGalCer; KRN7000) in a CD1d-dependent manner. The human Vα24 NKT cells activated with αGalCer and interleukin-2 have been shown to produce large amounts of cytokines, such as IFN-γ, and also exerting a potent killing activity against various tumor cell lines. We did a phase I study with autologous activated Vα24 NKT cell therapy.Experimental Design: Patients with advanced or recurrent non–small cell lung cancer received i.v. injections of activated Vα24 NKT cells (level 1: 1 × 107/m2 and level 2: 5 × 107/m2) to test the safety, feasibility, and clinical response of this therapeutic strategy. Immunomonitoring was also done in all cases.Results: Six patients were enrolled in this study. No severe adverse events were observed during this study in any patients. After the first and second injection of activated Vα24 NKT cells, an increased number of peripheral blood Vα24 NKT cells was observed in two of three cases receiving a level 2 dose of activated Vα24 NKT cells. The number of IFN-γ-producing cells in peripheral blood mononuclear cells increased after the administration of activated Vα24 NKT cells in all three cases receiving the level 2 dose. No patient was found to meet the criteria for either a partial or a complete response.Conclusions: The clinical trial with activated Vα24 NKT cell administration was well tolerated and carried out safely with minor adverse events even in patients with advanced diseases.

Purpose. The characteristics of tumor extension determine whether pneumonectomy or lobectomy with bronchoplasty should be performed for central lung cancer. We investigated how the characteristics of tumor extension determined the operative methods and the surgical outcomes. Methods. We conducted a retrospective chart review of 151 patients with positive bronchoscopic findings who underwent lung cancer operations between January 1995 and March 2002. Twenty-five patients underwent pneumonectomy, 88 underwent lobectomy/segmentectomy (Lob/Seg), and 38 underwent Lob/Seg with bronchoplasty. Results. Pathologic staging was higher in the pneumonectomy group than in the Lob/Seg groups, with or without bronchoplasty (P = 0.002). Interlobar extension and hilar lymph node involvement were more frequent, and mucosal invasion was less frequent, in the pneumonectomy group than in the Lob/Seg with bronchoplasty group. The frequencies of all specific pulmonary complications and 30-day mortality were similar among the three groups. The 5-year overall survival rates were 23.7%, 51.5%, and 72.8% for the pneumonectomy, Lob/Seg, and Lob/Seg with bronchoplasty groups, respectively (P = 0.0004). There was a significant difference in survival between patients with mucosal and those with submucosal types of lung cancer (P = 0.0114). Conclusions. Lob/Seg with bronchoplasty was feasible without a higher risk of operative complications or poorer long-term survival. The nature of tumor extension was important in the selection of operative methods and in predicting survival.

The transforming growth factor β (TGFβ)-signalling pathway is deregulated in many cancers. We examined the role of gene silencing via aberrant methylation of DRM/Gremlin and HPP1, which inhibit TGFβ signalling, and RUNX3, which facilitates TGFβ-signalling, of all genes that are thought to be tumour suppressors, are aberrantly expressed, and are thus thought to have important role in human cancers. We examined DRM/Gremlin mRNA expression in 44 cell lines and the promoter methylation status of DRM/Gremlin, HPP1, and RUNX3 in 44 cell lines and 511 primary tumours. The loss of DRM/Gremlin mRNA expression in human cancer cell lines is associated with DNA methylation, and treatment with the methylation inhibitor-reactivated mRNA expression (n=13). Methylation percentages of the three genes ranged from 0–83% in adult tumours and 0–50% in paediatric tumours. Methylation of DRM/Gremlin was more frequent in lung tumours in smokers, and methylation of all three genes was inversely correlated with prognosis in patients with bladder or prostate cancer. Our results provide strong evidence that these TGFβ-related genes are frequently deregulated through aberrant methylation in many human malignancies.

The molecular mechanisms for frequent epidermal growth factor receptor (EGFR, a tyrosine kinase [TK]) and HER2 (the preferred coreceptor of EGFR) overexpression in lung cancer are poorly understood. Recent studies have shown the mutations of the TK domain in EGFR and HER2 to be present in lung cancer. The purpose of this study was to investigate the relationship between mutation status and expression of EGFR and HER2 in lung cancer. Immunostaining took place for EGFR and HER2, and mutational analyses for EGFR, HER2, and KRAS (a signaling protein) were conducted using 130 resected lung cancer specimens. Thirty-seven EGFR mutations (28%) and 8 HER2 mutations (6%), both of the TK domains, and 5 KRAS (4%) mutations were found, whereas 73 (56%) EGFR and 47 (36%) HER2 overexpressions were found. EGFR overexpression was seen more frequently in tumors with EGFR mutation (28/37, 76%) than in tumors without EGFR mutations (45/93, 48%; P = .0059). No correlation was found between HER2 mutation and HER2 expression. Multivariate regression revealed that EGFR mutation, adenocarcinoma histology, and HER2 expression were associated with EGFR expression, whereas female sex, EGFR mutation, and EGFR expression were associated with HER2 expression. In conclusion, EGFR and HER2 overexpression is frequent in lung cancer, and EGFR overexpression correlates with the EGFR TK domain mutations.

Objective: Descending necrotizing mediastinitis (DNM) is a severe infection spreading from the cervical region to the mediastinal connective tissue. The mortality rate was reported as 40% until the 1980s. Since DNM is uncommon, few reports of large series of patients with DNM (i.e. more than 10 cases) have been published. The present aim was to evaluate our treatment strategy for DNM by retrospective chart review. Methods: Retrospective chart review was performed in 10 patients with DNM between 1991 and 2003. The mean age was 53.8G23.3 years (median 58, range 16–82). The causes of DNM were primary peritonsillar or parapharyngeal abscess in 5 patients, post-extraction odontogenic abscess in 3, cervical abscess of post-tracheostomy in 1, and unknown in 1 patient. In nine cases, the abscess extended from the cervical region to the lower mediastinum. Immediately after the diagnosis of DNM, broad-spectrum antibiotics were administered empirically, and surgical treatments consisting of cervical drainage, thoracotomy with radical surgical debridement of the mediastinum and excision of necrotic tissue, decortication, and irrigation were performed in all cases. Post-operatively, mediastinopleural irrigation with saline was performed once or twice a day until a culture of pleural effusion became negative. Results: The mean duration of chest tube retention was 26.7G17.0 days, and the mean hospital stay was 62.3G33.9 days. Five patients suffered from severe complications including septic shock, acute respiratory distress syndrome, disseminated intravascular coagulation, and pan-peritonitis due to duodenal perforation. The outcome was favorable in 8 patients. Of those with severe complications, two patients, who were older than 75 and had diabetes, died of multiple organ failure due to septic shock. Therefore, the mortality rate was 20%. Conclusion: Our treatment strategy for severe DNM was efficacious for early treatment and reduced the mortality rate. Early detection of DNM, and immediate thoracotomy and irrigation of the mediastinum and thoracic cavity, are recommended. Q 2005 Elsevier B.V. All rights reserved.

Autofluorescence bronchoscopy is an important tool for the early detection of preinvasive bronchial lesions. However, autofluorescence bronchoscopy has difficulty distinguishing between preinvasive lesions and other benign epithelial changes. A new autofluorescence imaging bronchovideoscope system (AFI) comprises three signals, including an autofluorescence (460-690 nm) on excitation blue light (395-445 nm) and two different bands of reflected light: G' (550 nm) and R' (610 nm). We hypothesized that color analyses of these three wave lengths would improve our ability to differentiate between inflammation and preinvasive lesions. In order to prove this hypothesis and to evaluate the efficacy of AFI for detecting preinvasive lesions, we conducted a prospective study. A total of 32 patients with suspected or known lung cancer were entered into this study. Conventional white light bronchovideoscopy (WLB) and light induced fluorescence endoscopy (LIFE) were performed prior to using AFI. WLB and LIFE detected 62 lesions, including lung cancers (n=2), squamous dysplasias (n=30), and bronchitis (n=30). By utilizing AFI, 24 dysplasias and 2 cancer lesions were magenta in color, while 25 bronchitis lesions were blue. The sensitivities of detecting dysplasia by LIFE and AFI were 96.7% and 80%, respectively. The specificity of AFI (83.3%) was significantly higher than that of LIFE (36.6%) (p=0.0005). We conclude that AFI appears to represent a significant advance in distinguishing preinvasive and malignant lesions from bronchitis or hyperplasia under circumstances where LIFE would identify these all as abnormal lesions.

BACKGROUND Tumor cells of lung cancer exhibit genetic abnormalities as well as high proliferative activity. The purpose of this study was to evaluate the relationship of genetic abnormalities and smoking status, histological type, and tumor proliferative activity in resected samples of stage I non-small cell lung cancer (NSCLC). METHODS We evaluated 126 samples of stage I NSCLC from patients who underwent complete resection between 1988 and 1993. Loss of heterozygosity (LOH) was assessed using primers that amplified polymorphic microsatellite markers at D3S1300, D3S643, D3S1317, D9S171, IFNA, D13S153, and TP53. Expression of Ki-67 nuclear antigen was examined using immunohistochemical methods to assess tumor proliferative activity. RESULTS The Fractional Regional Loss index (FRL) was significantly higher in squamous cell carcinoma samples than in adenocarcinoma samples (p < 0.0001). In smokers, Ki-67 labeling index (LI) in high-FRL cases was significantly higher than in low-FRL cases (p < 0.0001). CONCLUSION The frequency of LOH at 3 p, 9 p, 13 q, and 17 p was related to proliferative activity in smokers with stage I non-small cell lung cancer.

Neurogenic benign tumors arising from the trachea and bronchus are relatively rare. We experienced three cases of neurofibroma of the bronchus which were successfully treated by transbronchial electrical snaring and Nd-YAG laser abrasion. The first was a 67-year-old man with right lung cancer, who was pointed out to have a neurofibroma in the left main bronchus. The second was a 34-year-old man with an obstruction in the right main bronchus due to neurofibroma. The third was a 66-year-old woman with a complete obstruction in the left main bronchus due to schwannoma. All patients were successfully treated to remove the tumors and obtain a patency of the bronchus by transbronchial electrical snaring and Nd-YAG laser abrasion. We also review 23 reported cases of endobronchial neurogenic tumors and discuss the efficacy of endoscopic treatments for endobronchial neurogenic tumors.

Deregulation of cell cycle inhibition contributes to human carcinogenesis. Reprimo (for stop/repress) is a newly identified mediator of the p53-mediated cell cycle arrest at the G2 phase. Loss of Reprimo expression due to promoter methylation was recently identified in pancreatic cancer. We examined Reprimo expression by reverse transcription PCR (RT-PCR) and aberrant methylation of Reprimo by methylation specific PCR (MSP) in lung cancer cell lines (n=35) and primary tumors (n=167). We also correlated the p53 gene status with Reprimo methylation in cell lines. Aberrant methylation of Reprimo was present in 32% (six of 19) of non-small cell lung cancer (NSCLC) cell lines, 6% (one of 16) of small cell lung cancer (SCLC) cell lines, and 31% (51 of 167) of primary tumors. Methylation was absent in normal lymphocytes and was rare in corresponding nonmalignant lung tissues (7%; four of 57). Overall concordance between loss of expression and aberrant methylation of Reprimo was 94% (33 of 35) in cell lines. Reprimo expression was restored after treatment with the demethylating agent 5-aza-2'-deoxycytidine in all five-cell lines tested that lacked Reprimo expression. There was no significant correlation between p53 gene status and Reprimo methylation in cell lines. These data indicate that Reprimo methylation is frequent in lung cancers and occurs independently of p53 status. Methylation of Reprimo may play a role in the pathogenesis of lung cancers.

目的. XVIII型コラーゲンは, 血管新生抑制因子の一つであるエンドスタチンの前駆物質であり, 血管および上皮基底膜を構成する細胞外マトリックス蛋白の構成成分である. 本研究は非小細胞肺癌におけるXVIII型コラーゲン発現の予後因子としての重要性を明らかにすることを目的とした. 対象と方法. 1994～2000年に切除された非小細胞肺癌306例を対象とした. 男女比は215:91, 年齢は31～85歳 (平均64.8±9.8歳). 扁平上皮癌114例, 腺癌179例, 大細胞癌13例. 術後病期I期130例, II期47例, III期113例, IV期16例であった. 抗XVIII型コラーゲン抗体にて免疫染色を行い, 臨床的因子 (年齢, 性別, 組織型, T因子, N因子, 術後病期) との相関ならびに予後を統計学的に解析した. 結果. 抗XVIII型コラーゲン抗体による切除標本の染色結果は, 陰性92例, 陽性119例ならびに強陽性95例であった. 全体の5年生存率は陰性例70.4%, 陽性例56.5%ならびに強陽性例40.3%で, 強陽性群, 陽性群ではいずれも陰性例に比べ有意に予後不良であった (P

Pulmonary artery sarcoma (PAS) is a rare tumor that is often detected at an advanced stage, when disease is so widespread that a radical surgical procedure is no longer indicated. Therefore, less invasive biopsy techniques are required to establish a definitive preoperative diagnosis. Endobronchial ultrasound (EBUS) is useful for producing real-time images of both lymph nodes and the interior of pulmonary arteries adjacent to the bronchi. We report a case with masslike lesions in the pulmonary artery that were observed by EBUS and from which tissue was obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to establish a diagnosis of PAS.