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Phototheranostics represents a highly promising paradigm for cancer therapy, although selecting an appropriate optical imager and sensitizer for clinical use remains challenging.Liposomally formulated phospholipid-conjugated indocyanine green, denoted as LP-iDOPE, was developed as phototheranostic nanoparticle and its cancer imaging-mediated photodynamic reaction, defined as the immune response induced by photodynamic and photothermal effects, was evaluated with a near-infrared (NIR)-light emitting diode (LED) light irradiator.Using in vivo NIR fluorescence imaging, we demonstrated that LP-iDOPE was selectively delivered to tumor sites with high accumulation and a long half-life. Following low-intensity NIR-LED light irradiation on the tumor region of LP-iDOPE accumulated, effector CD8Our anti-cancer strategy based on tumor-specific LP-iDOPE accumulation and low-intensity NIR-LED light irradiation to the tumor regions, i.e., photodynamic reaction, represents a promising approach to noninvasive cancer therapy.

Phototheranostics represents a highly promising paradigm for cancer therapy, although selecting an appropriate optical imager for clinical use remains challenging. We evaluated the phototheranostic nanoparticle-related properties of liposomally formulated phospholipid-conjugated indocyanine green, denoted as LP-iDOPE, for cancer diagnosis and treatment using photobiomodulation with a near-infrared (NIR)-light emitting diode (LED) light irradiator. Using in vivo NIR fluorescence imaging, we demonstrated that LP-iDOPE was selectively delivered to tumor sites with high accumulation and a long half-life. Following NIR-LED light irradiation of the tumor region of LP-iDOPE accumulation, effector CD8+ T cells were activated at the secondary lymphoid organs, migrated, and subsequently released cytokines including interferon-γ and tumor necrosis factor-α, resulting in effective tumor regression. Our cancer immunotherapy strategy using LP-iDOPE as a phototheranostic nanoparticle and an NIR-LED light irradiator as a photobiomodulation device represents a promising approach to noninvasive cancer therapy.

Background The optimal mode of surgery for ground-glass opacity dominant peripheral lung cancer defined with thoracic thin-section computed tomography remains unknown. Methods We conducted a single-arm confirmatory trial to evaluate the efficacy and safety of sublobar resection for ground-glass opacity dominant peripheral lung cancer. Lung cancer with maximum tumor diameter 2.0 cm or less and with consolidation tumor ratio 0.25 or less based on thin-section computed tomography were registered. The primary end point was 5-year relapse-free survival. The planned sample size was 330 with the expected 5-year relapse-free survival of 98%, threshold of 95%, 1-sided α of 5%, and power of 90%. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number University Hospital Medical Information Network 000002008. Results Between May 2009 and April 2011, 333 patients were enrolled from 51 institutions. Median age was 62 years (interquartile range, 56-68), and 109 were smokers. Median maximum tumor diameter was 1.20 cm (1.00-1.54). Median maximum tumor diameter of consolidation was 0 (0.00-0.20). The primary end point, 5-year relapse-free survival, was estimated on 314 patients who underwent sublobar resection. Operative modes were 258 wide wedge resections and 56 segmentectomies. Median pathological surgical margin was 15 mm (0-55). The 5-year relapse-free survival was 99.7% (90% confidence interval, 98.3-99.9), which met the primary end point. There was no local relapse. Grade 3 or higher postoperative complications based on Common Terminology Criteria for Adverse Effect v3.0 were observed in 17 patients (5.4%), without any grade 4 or 5. Conclusions Sublobar resection with enough surgical margin offered sufficient local control and relapse-free survival for lung cancer clinically resectable N0 staged by computed tomography with 3 or fewer peripheral lesions 2.0 cm or less amenable to sublobar resection and with a consolidation tumor ratio of 0.25 or less.

We conducted a phase I study of the trans-bronchial injection of α-galactosylceramide (αGalCer)-pulsed antigen presenting cells (APCs) to evaluate their safety, immune responses, and anti-tumor activities. Patients with advanced or recurrent non-small cell lung cancer (NSCLC) refractory to standard treatments were eligible. αGalCer-pulsed APCs were administered intratumorally or intranodally by bronchoscopy. Twenty-one patients were enrolled in this study. No severe adverse events related to the cell therapy were observed during this study in any patient. After αGalCer-pulsed APCs were administrated, increased iNKT cell numbers were observed in PBMCs from eight cases, and IFN-γ producing cells were increased in the peripheral blood of 10 cases. Regarding clinical responses, one case exhibited a partial response and eight were classified as stable disease. In the tumor microenvironment, IFN-γ expression was upregulated after treatment in partial response or stable disease cases and TGF-β was upregulated in progressive disease cases.

Objectives In 2015, we reported the outcomes of patients undergoing intentional limited resection (ILR) for non-small-cell lung cancer (NSCLC) from a retrospective, multi-institutional large database in Japan. Here, we analyse the clinicopathological characteristics of the patients extracted from this database with late recurrence and compare them with those with early recurrence. Methods Of 1538 patients in the database with cT1aN0M0 NSCLC, 92 (6%) had recurrence. In this study, early recurrence was defined as recurrence within 5 years and late recurrence as recurrence beyond 5 years after surgery. We compared the clinicopathological characteristics and post-recurrence survival (PRS) between patients with early and late recurrence. Results Of the 92 patients with recurrence, 21 (23%) had late recurrence. Compared with the early recurrence group, there were significantly more adenocarcinomas and local recurrences in the late recurrence group (P = 0.04 for both). The 3- and 5-year PRS rates were 53 and 24%, respectively, and the median PRS period was 38 months. There were no significant differences in the PRS curves between patients with early and late recurrence (P = 0.12). Only 3 patients (0.2%) had recurrence more than 10 years after ILR. Of the 21 late-recurrence patients, 17 (81%) had tumours with a consolidation/tumour ratio (CTR) >0.25. Conclusions Late recurrence occurred in 21 (23%) of 92 patients with recurrence after ILR for cT1aN0M0 NSCLC. Late recurrence was more likely to involve adenocarcinoma and local recurrence. It is thus considered reasonable to follow patients with a CTR >0.25 for 10 years after ILR.

Background: The International Association for the Study of Lung Cancer, in collaboration with members of the International Mesothelioma Interest Group (IMIG), developed a large international database and TNM‑based system to study malignant pleural mesothelioma (MPM). However, this database has some limitations since it was a retrospective study and it was based predominantly on surgical cases. The Japanese Joint Committee of Lung Cancer Registry (JJCLCR) employs a project of prospective registry database of patients in Japan with MPM in order to clarify MPM’s epidemiology, current management practices, and prognosis and also to investigate the potential capabilities to target the best patients for therapy. Methods: Tumor stage is described using the 7th and 8th versions of IMIG staging system. This prospective cohort study has been conducted from April 1, 2017 to March 31, 2019. Discussion: We will analyze the data in this registry to determine the most recent outcomes and trends related to MPM treatment in Japan. The present prospective study is expected to validate the 8th version of IMIG staging system, and to investigate whether tumor thickness is a reliable T‑descriptor. Trial registration: ClinicalTrials.gov Identifier: UMIN 000024664

We retrospectively investigated whether histological cell type could affect patient prognosis for each stage according to the seventh edition of the TNM classification. Clinical records of 1623 consecutive non-small cell lung cancer patients who underwent surgery between 1990 and 2007 were retrospectively reviewed. Over 92% of these patients had either adenocarcinoma (Ad; n = 1043, 64.3%) or squamous cell carcinoma (Sq; n = 452, 27.9%). The overall 5-year survival rates for patients of all stages with Ad, Sq, large cell carcinoma (La), and adenosquamous cell carcinoma (As) were 67%, 56%, 58%, and 41%, respectively. Ad patients experienced better survival than Sq, As, or La patients (HR: 0.66, P0.0001; HR: 0.38, P = 0.011; HR: 0.69, P = 0.057, respectively). Stage IA Ad patients experienced better survival than stage IA Sq patients (5-year survival; Ad/Sq = 91%/78%, log-rank test, P = 0.001). Such a difference was also observed among seventh-edition TNM stage IB patients (5-year survival; Ad/Sq = 78%/64%, log-rank test, P = 0.048), but not for sixth-edition stage IB patients. Multivariate analysis demonstrated that histological cell type is a significant prognostic factor among stage I ≥ T1b Ad and Sq patients. Survival after complete resection of new stage I ≥ T1b Sq patients is significantly worse than that of Ad patients, which could be partially attributed to stage migration effect in stage IB disease between the sixth and seventh editions of the TNM staging system.

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

A precise preoperative diagnosis of in situ or minimally invasive carcinoma may identify patients who can be treated by limited resection. Although some clinical trials of limited resection for lung cancer have started, it will take a long time before the results will be published. We have already reported a large-scale study of limited resection. We herein report the data for a subclass analysis according to differences in pathology.Data from multiple institutions were collected on 1710 patients who had undergone limited resection (segmentectomy or wedge resection) for cT1N0M0 non-small cell carcinoma. The disease-free survival (DFS) and recurrence-free proportion (RFP) were analyzed. Small cell carcinomas and carcinoid tumors were excluded from this analysis. Adenocarcinomas were sub-classified into four groups using two factors, the ratio of consolidation to the tumor diameter (C/T) and the tumor diameter alone.The median patient age was 64 (20-75) years old. The mean maximal diameter of the tumors was 1.5 ± 0.5 cm. The DFS and RFP at 5 years based on the pathology were 92.2 and 94.7 % in adenocarcinoma (n = 1575), 76.3 and 82.4 % in squamous cell carcinoma (SqCC) (n = 100), and 73.6 and 75.9 % in patients with other tumors (n = 35). The prognosis of adenocarcinoma in both groups A (C/T ≤0.25 and tumor diameter ≤2.0 cm) and B (C/T ≤0.25 and tumor diameter2.0 cm) was good. In SqCC, only segmentectomy was a favorable prognostic factor. In the groups with other pathologies, large cell carcinomas were worse in prognosis (the both DFS and RFP: 46.3 %).Knowing the pathological diagnosis is important to determine the indications for limited resection. Measurement of the tumor diameter and C/T was useful to determine the indications for limited resection for adenocarcinoma. Limited resection for adenocarcinomas is similar with a larger resection, while the technique should be performed with caution in squamous cell carcinoma and other pathologies.

Objectives: We retrospectively investigated whether histological cell type could affect patient prognosis for each stage according to the seventh edition of the TNM classification. Patients and methods: Clinical records of 1623 consecutive non-small cell lung cancer patients who underwent surgery between 1990 and 2007 were retrospectively reviewed. Over 92% of these patients had either adenocarcinoma (Ad; n = 1043, 64.3%) or squamous cell carcinoma (Sq; n = 452, 27.9%). Results: The overall 5-year survival rates for patients of all stages with Ad, Sq, large cell carcinoma (La), and adenosquamous cell carcinoma (As) were 67%, 56%, 58%, and 41%, respectively. Ad patients experienced better survival than Sq, As, or La patients (HR: 0.66, P < 0.0001; HR: 0.38, P = 0.011; HR: 0.69, P = 0.057, respectively). Stage IA Ad patients experienced better survival than stage IA Sq patients (5-year survival; Ad/Sq = 91%/78%, log-rank test, P = 0.001). Such a difference was also observed among seventh-edition TNM stage IB patients (5-year survival; Ad/Sq = 78%/64%, log-rank test, P = 0.048), but not for sixth-edition stage IB patients. Multivariate analysis demonstrated that histological cell type is a significant prognostic factor among stage I ≥ T1b Ad and Sq patients. Conclusions: Survival after complete resection of new stage I ≥ T1b Sq patients is significantly worse than that of Ad patients, which could be partially attributed to stage migration effect in stage IB disease between the sixth and seventh editions of the TNM staging system.

The intravenous administration of α-Galactosylceramide (α-GalCer)-pulsed antigen presenting cells (APCs) is well tolerated and the increased IFN-γ producing cells in the peripheral blood after the treatment appeared to be associated with prolonged survival. An exploratory study protocol was designed with the preoperative administration of α-GalCer-pulsed APCs to clarify the mechanisms of these findings, while especially focusing on the precise tumor site.Patients with operable advanced lung cancer received an intravenous injection of α-GalCer-pulsed APCs before surgery. The resected lung and tumor infiltrating lymphocytes (TILs) as well as peripheral blood mononuclear cells were collected and the invariant NKT (iNKT) cell-specific immune responses were analyzed.Four patients completed the study protocol. We observed a significant increase in iNKT cell numbers in the TILs and augmented IFN-γ production by the α-GalCer-stimulated TILs.The administration of α-GalCer-pulsed APCs successfully induced the dramatic infiltration and activation of iNKT cells in the tumor microenvironment.

Objectives We investigated the ability of a high-resolution bronchovideoscopy system with narrow band imaging (NBI) to detect blood vessel structures in squamous cell carcinoma (SCC) of bronchi, as well as squamous dysplasia. Methods Seventy-nine patients with either abnormal sputum cytology or lung cancer were entered into the study. First, high-resolution bronchovideoscopy with white light was performed. Observations were repeated using NBI light to examine microvascular structures in the bronchial mucosa. Spectral features of the RGB (red/green/blue) sequential videoscope system were changed from a conventional RGB filter to the new NBI filter. The wavelength ranges of the NBI filter were: 400–430 nm (blue), 400–430 nm (green) and 520–560 nm (red). Results The following were clearly observed with NBI with high-resolution bronchovideoscopy: increased vessel growth and complex networks of tortuous vessels of various sizes, in squamous dysplasia; some dotted vessels, in addition to increased vessel growth and complex networks of tortuous vessels, in ASD; several dotted vessels and spiral or screw type tumor vessels of various sizes and grades, in SCC. Capillary blood vessel and/or tumor vessel mean diameters of ASD, CIS, microinvasive and invasive carcinoma were 41.4 ± 9.8 μm, 63.7 ± 8.2 μm, 136.5 ± 29.9 μm and 259.4 ± 29.6 μm, respectively. These results indicated a statistically significant increase of mean vessel diameters in the four groups (P Conclusion NBI with high-resolution bronchovideoscopy was useful for detecting the increased vessel growth and complex networks of tortuous vessels, dotted vessels and spiral or screw type tumor vessels of bronchial mucosa. This may enable detecting the onset of angiogenesis during multi-step carcinogenesis of the lung.

A surgical resection for locally advanced non-small cell lung carcinoma (NSCLC) remains controversial. This study analyzed the clinicopathological profile and surgical outcome of patients with locally advanced NSCLC to identify the predictors of survival.This study retrospectively analyzed clinical data from 86 patients with pathological T3 or T4 primary NSCLC treated at Chiba University Hospital, and evaluated prognostic factors.Sixty-eight of 86 cases were treated with a complete resection, and 18 were evaluated as an incomplete resection. The 5-year overall survival rate of all cases was 45.7%. Univariate analyses of survival were performed to determine the predictors of overall survival in patients with pathological T3 or T4 NSCLC. Age of 70 years or more, tumor length more than 5 cm, lymph node metastases, incomplete resection, and histology of non-adenocarcinoma were significantly associated with an unfavorable prognosis. Multivariate analyses revealed that older age, incomplete resection, and lymph node metastases were independent predictors of shorter survival.A complete resection for selected cases is acceptable in the management of T3 or T4 NSCLC.

Background Pyothorax-associated lymphoma (PAL) is a comparatively rare tumor, and it is difficult to definitively diagnose it preoperatively, especially in patients with only pleural thickening without mass formation. Pleural effusion aspiration cytology is a useful and easy diagnostic method for a large number of chest diseases. However, the cytologic findings of PAL have been rarely described. Here we report on the cytologic findings in a patient with PAL, manifested by pleural thickening without mass formation, and which was diagnosed preoperatively by pleural effusion aspiration cytology. Case A 64-year-old man was admitted to our hospital because of pleural thickening involving an empyema sac located in the left thorax and rapidly increasing pleural effusion. He had a 30-year history of chronic empyema and a 10-year history of diabetes mellitus. Left pleural effusion aspiration cytology showed malignant lymphoma. The patient was admitted to our hospital for PAL treatment. Because of poor respiratory function, he only underwent decortication with complete resection of the thickening pleural peel. However, he was well, without recurrence, 5 years after the operation. The histologic examination revealed that lymphoma cells were located only in the thickening pleural peel. Conclusion This is a very rare case of PAL diagnosed by preoperative aspiration cytology for an increasing pleural effusion. This report demonstrates that pleural effusion aspiration cytology can be valuable for the diagnosis of PAL.

While lymph node metastasis is a major factor associated with poor prognosis in cancer, little is known of its molecular mechanisms. The aim of this study was to identify genes differentially expressed between non-cancerous and cancerous lung tissues, and to investigate the gene expression profiles of 41 primary lung adenocarcinomas to select sets of gene predictors for lymph node metastasis of lung cancer. Gene expression profiles were obtained using oligonucleotide microarrays, and predictor sets constructed by evaluating the statistical significance of expression levels of selected genes. Gene analysis revealed 15 predictor genes for lymph node metastasis of lung adenocarcinoma. Using the most suitable set of genes, it was possible to predict the lymph node metastasis of patients with lung cancer. The prediction scoring system yielded 71.4% accuracy for forecasting lymph node metastasis in 14 independent test cases. Survival was also significantly better in 18 cases that were pathologically LN negative and predicted to be LN negative according to molecular classification, compared with 23 cases that were pathologically LN positive or predicted to be LN positive according to molecular classification. Gene expression analysis combined with statistical analysis successfully distinguished lymph node metastasis. The findings of this study showed that pathological diagnosis combined with molecular classification clearly distinguished patients with good prognoses from patients with poor prognoses.

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.

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.

A 33 year-old man was referred to our center with swelling of the left scrotum. He underwent resection of the left testis,and pathological diagnosis indicated a germ cell tumor of that testis. His past history included lung cancer resection 5 yearsbefore the testicular surgery. Precise pathological reevaluation of the lung cancer using immunohistochemical methodsindicated that the tumor originally diagnosed as lung cancer was a metastasis of the germ cell tumor of the left testis.

Background Sclerosing hemangiomas of the lung are uncommon tumors and are thought to be benign. However, the histogenesis and clinicopathological features of these tumors have not been elucidated. Methods We analyzed the clinicopathological features of 26 sclerosing hemangiomas. The immunoreactivity for Ki-67 and p53 of sclerosing hemangiomas was determined and compared with that of pathological stage 1 pulmonary papillary adenocarcinomas. Results The patients of sclerosing hemangioma were predominantly female. Eighteen patients were detected as a result of routine medical examinations and 15 were nonsmokers. Seven patients underwent tumor enucleation, 10 underwent a wedge resection, and 9 underwent a lobectomy. The mean tumor size was 2.2 cm (range 1 to 5 cm). Pathological findings demonstrated a papillary pattern in 23 cases, sclerotic pattern in 26 cases, hemorrhagic pattern in 22 cases and a solid pattern in 25 cases. Twenty-five cases had an excellent prognosis with no evidence of recurrence following surgery. However, 1 patient who had undergone a wedge resection developed a local recurrence and required an additional wedge resection. The Ki-67 labeling index of sclerosing hemangiomas was significantly lower than that of adenocarcinomas, whereas the Ki-67 labeling index of the recurrent case was 0.4%. No significant immunohistochemical staining for p53 was observed in sclerosing hemangioma cases. Conclusions Sclerosing hemangioma exhibits various histologic findings. Although we experienced one case with a recurrent tumor, sclerosing hemangiomas did not exhibit malignant behavior.

Background In 1999, the World Health Organization classified large cell neuroendocrine carcinoma as a variant of large cell carcinoma and this has been categorized as lying between atypical carcinoid and small cell lung carcinoma in terms of clinical aggressiveness. Methods We analyzed the proliferative activity of stage 1 large cell neuroendocrine carcinoma derived from patients with primary lung cancer who underwent surgical resection and compared the results with stage 1 classic large cell carcinoma cases. The mitotic rate was counted in ten high-power fields of light microscope. Immunohistochemical staining using anti-Ki-67 antibody was performed. The Ki-67 labeling index, expressed as a percentage of positive cells, was determined by light microscopy with random counting of at least 1,000 tumor nuclei. The expression of P53 and Bcl-2 was examined and compared. Results The mitotic rate of large cell neuroendocrine carcinoma cases was significantly higher than that of classic large cell carcinoma cases. The Ki-67 labeling index of stage 1 large cell neuroendocrine carcinoma cases was significantly higher than that of stage 1 classic large cell carcinoma cases. Immunohistochemical expression of P53 in large cell neuroendocrine carcinoma and classic large cell carcinoma was comparable. However, large cell neuroendocrine carcinoma exhibited a significantly higher expression of Bcl-2 than classic large cell carcinoma. The disease specific disease-free survival for patients with stage 1 large cell neuroendocrine carcinoma was significantly lower than that for patients with stage 1 classic large cell carcinoma. Conclusions Large cell neuroendocrine carcinoma appears to be more clinically aggressive than classic large cell carcinoma with these findings indicating that large cell neuroendocrine carcinoma has a higher level of proliferative activity than classic large cell carcinoma.

BACKGROUND Angiogenesis plays a crucial role in tumor growth and metastasis. Recently, some studies have focused on the angiogenesis inhibitor endostatin. However, the biologic role of the precursor of endostatin, collagen XVIII, in human malignancy is unknown. The purpose of the current study was to evaluate whether the expression of collagen XVIII has additional prognostic value for survival in patients with nonsmall cell lung carcinoma (NSCLC). METHODS The authors investigated the expression of collagen XVIII in 221 patients using immunohistochemical methods. To confirm the specificity of the collagen XVIII polyclonal antibody used in the current study and to test the expression of collagen XVIII in human lung carcinoma, Western blot analysis was performed on a panel of human lung carcinoma cell lines. RESULTS Collagen XVIII expression was detected in 162 of 221 patients with NSCLC (73%), primarily in the tumor cell cytoplasm. Low collagen XVIII expression levels were found in 75 tumor specimens, while high collagen XVIII expression levels were noted in 87 tumor specimens. The prevalence of positive collagen XVIII expression was greater in T2–4 tumors than in T1 tumors (P = 0.0235). The prognosis for patients with strongly collagen XVIII–positive NSCLC was significantly worse than the prognosis for patients with collagen XVIII–positive or collagen XVIII–negative NSCLC (P = 0.0010). Multivariate analysis indicated that T status, lymph node status, and the overexpression of collagen XVIII were independent prognostic factors. CONCLUSIONS The results of the current study indicated that the overexpression of collagen XVIII was associated with NSCLC progression and poor outcome. Thus, collagen XVIII expression may serve as a useful prognostic marker in patients with NSCLC. Cancer 2004. © 2004 American Cancer Society.

8561 Background: The optimal mode of surgery for peripheral ground glass opacity (GGO) dominant lung cancer (LC) defined with thoracic thin-section computed tomography (TSCT) remains unknown. Methods: We conducted multi-institutional confirmatory phase III trial to evaluate the efficacy and safety of sublobar resection for peripheral GGO dominant LC. Mode of surgery is basically wedge resection, and segmentectomy is allowed when surgical margin is insufficient ( < 5 mm) or histological invasiveness. LC with maximum tumor diameter (MTD) ≤ 2.0 cm and with consolidation tumor ratio ≤ 0.25 based on TSCT were registered. The primary endpoint was 5-year relapse-free survival (RFS). The planned sample size was 330, with the expected 5-year RFS of 98%, threshold of 95%, one-sided α of 5% and power of 90%. Survival analyses were performed using the Kaplan-Meier method and their confidence intervals were estimated by Greenwood’s formula. Results: Between May 2009 and April 2011, 333 pts were enrolled from 51 institutions. The primary endpoint, RFS was estimated on 314 pts who underwent sublobar resection. Median age was 62 (range 24 - 79) and 104 were smokers. Median MTD on lung window was 1.20 cm (0.53 - 2.00). Median MTD of consolidation was 0 (0.00 - 0.48). Operative modes were 258 wedge resection and 56 segmentectomy. Histological diagnosis were 310 adenocarcinomas, 27 precancerous lesions, and 14 non-neoplastic lesions. Median pathological surgical margin was 15 mm (0 - 55). Grade 2 or higher postoperative complications based on CTCAE v3.0 were observed in 119 (37.9%), and Grade 3 in 17 (5.4%), without any Grade 4 or 5. The 5-year RFS was 99.7% (95% CI, 97.7 - 100.0%), which met the primary endpoint. There was no local relapse. The ratio of FEV1.0 change between preoperative and one year after surgery over preoperative value ranged -37% to +49% with a median of -5%. Conclusions: Sublobar resection, mainly wedge resection, offered sufficient local control and RFS for peripheral GGO dominant LC on TSCT. Sublobar resection should be the first choice of mode of surgery if surgical margin is enough preserved. Clinical trial information: 000002008.

OBJECTIVES: Peripheral small lung tumours (LTs) showing ground-glass opacity (GGO) tend to be treated without preoperative histological diagnosis due to difficulty in obtaining tissue samples. Exclusion of non-neoplastic lesions (NNLs) is essential when considering non-surgical treatment such as stereotactic radiotherapy. Here, we sought to determine preoperative factors associated with NNLs in peripheral LTs using data from a prospective study that investigated the efficacy of lesser pulmonary resection (JCOG0804/WJOG4507L). METHODS: The key eligibility criteria of the study were as follows: (i) peripherally located definitive or suspected LC with maximum diameter ≤2 cm and (ii) radiological non-invasive tumour with consolidation/tumour ratio (CTR) of ≤0.25 based on thin-section computed tomography (CT). Among all the resected LTs, incidences of NNL and precancerous lesions were examined. Also, logistic regression analysis was conducted to investigate the predictors of NNL using maximum tumour dimension (≤1 cm/>1 cm) and CTR (0/>0) as an explanatory variable. RESULTS: Between May 2009 and April 2011, 333 patients were prospectively enrolled from 51 institutions into the study. Among 333 patients, 345 LTs were included in the analysis. There were 314 (91.0%) LCs, 17 (4.9%) precancerous lesions and 14 (4.1%) non-cancerous lesions. Maximum tumour dimension ≤1 cm was identified as a significant predictor of NNLs with logistic regression analysis. There were 10 (8.6%) NNLs in 116 LT ≤1 cm, but 4 (1.7%) NNLs in 229 LTs >1 cm. CONCLUSIONS: NNLs were found in only 4.1% of peripheral LTs with GGO. However, when the tumour diameter was ≤1 cm, 10% were NNLs, necessitating a histological diagnosis when non-surgical treatment was considered.

A precise preoperative diagnosis of 'very early' lung carcinoma may identify patients who can undergo curative surgery with limited resections.Data from a multi-institutional project were collected on 1737 patients who had undergone limited resections (segmentectomy or wedge resection) for T1N0M0 non-small-cell carcinomas. As it was expected, this study was predominantly including ground glass nodules. Computed tomography was used to obtain the ratio of consolidation to the maximal tumour diameter to determine invasive potential of the tumours. Overall and disease-free survivals and recurrence-free proportions were analysed.Median age was 64 years. Mean maximal diameter of the tumours was 1.4±0.5 cm. Overall and recurrence-free survivals after limited lung resection were 94.0 and 91.1% at 5 years, respectively. Recurrence-free proportions were 93.7% at 5 years. Unfavourable prognostic factors in overall survival were lymph node metastasis, interstitial pneumonia, male gender, older age, comorbidities (cardiac disease, diabetes etc.) and consolidation/tumour ratio (C/T)≤0.25. C/T≤0.25 predicted good outcomes especially in cT1aN0M0 disease. In a subclass analysis of cT1N0M0 squamous cell carcinomas, wedge resection was the only unfavourable prognostic factor in both overall and disease-free survivals.If the patient was 75 years old or younger and was judged fit for lobectomy, limited resection for cStage I non-small-cell lung cancer (NSCLC) showed excellent outcomes and was not inferior to the reported results of lobectomy for small-sized NSCLC. The carcinomas with C/T≤0.25 rarely recur and are especially good candidates for limited resection.

Acute respiratory distress syndrome after pulmonary resection for lung cancer frequently has a lethal outcome. Treatment with a combination therapy of neutrophil elastase inhibitor and steroid administration was used to achieve good control, without impairing lung function, in a patient with postoperative acute respiratory distress syndrome. A 74-year-old man was diagnosed with lung cancer and referred to the outpatient department of Chiba University Hospital with double primary lung cancers located in the right upper lobe that were staged at T2N0M0 (stage IB). He underwent right upper lobectomy with hilar and mediastinal lymph node dissection. After 10 postoperative days, he had acute respiratory distress syndrome. He was given a corticosteroid and a neutrophil elastase inhibitor, which resulted in rapid improvement without lung dysfunction.

Background: Chemokines and chemokine receptors not only have significant roles in cancer metastasis and tumorigenesis but also act as antitumour agents. The interaction between the Crk-like adaptor protein (CrkL), which is encoded by the CRKL gene, and non-receptor tyrosine kinase c-ABL is reported to transform many cells into malignant cells. We examined the effects of CC chemokine receptor 7 (CCR7), CCR7 ligands and CrkL and c-ABL in lung adenocarcinoma. Methods: One hundred and twenty patients with lung adenocarcinoma were included in this historical cohort analysis. We examined CCR7 and CCR7 ligands and CrkL and c-ABL mRNA expressions in surgically resected lung adenocarcinoma specimens and evaluated their contribution to prognosis, and the relationship with epidermal growth factor receptor (EGFR) and TP53 mutations. Results: High CCR7 mRNA expressions indicated better prognoses than those of the groups with low CCR7 mRNA expressions (P=0.007, HR=2.00, 95% CI of ratio: 1.22 –3.31). In lung adenocarcinoma, CrkL and c-ABL mRNAs were related to CCR7 mRNA expression (P

Purpose The aim of this retrospective study was to evaluate the relevance of surgery in non-small cell lung cancer (NSCLC) patients with ipsilateral pulmonary metastases. Methods The clinical records of 1,623 consecutive NSCLC patients who underwent surgery between 1990 and 2007 were retrospectively reviewed. Overall, 161 (9.9 %) and 21 (1.3 %) patients had additional nodules in the same lobe as the primary lesion (PM1) and additional nodules in the ipsilateral different lobe (PM2), respectively. Results The 5-year survival rate was 54.4 % in the PM1 patients and 19.3 % in the PM2 patients (log-rank test: p = 0.001). Tumor size B3 cm, N0-1 status and surgical procedures less extensive than bilobectomy were identified as favorable prognostic factors in the PM1 patients. The 5-year survival rate in the PM1-N0-1 patients was 68.7 %, while that in the PM1-N2-3 patients was 29.1 % (p \ 0.0001). Compared to the non-PM1 stage IIIA patients, the stage IIIA patients with PM1 disease (PM1-N1) tended to experience longer survival times (p = 0.06). Squamous cell types and bilobectomy or more extensive procedures were found to be unfavorable factors in the PM2 patients. The survival of the PM2 patients was significantly worse than that of the other T4 patients (p = 0.007). Conclusions PM1 patients with N0-1 disease are good candidates for surgery, whereas PM2 patients do not appear to benefit from surgery.

Analysis of the microRNA (miRNA) expression signature of lung squamous cell carcinoma (lung-SCC) revealed that the expression levels of miR-133a were significantly reduced in cancer tissues compared with normal tissues. In this study, we focused on the functional significance of miR-133a in cancer cell lines derived from lung-SCC and the identification of miR-133a-regulated novel cancer networks in lung-SCC. Restoration of miR-133a expression in PC10 and H157 cell lines resulted in significant inhibition of cell proliferation, suggesting that miR-133a functions as a tumor suppressor. We used genome-wide gene expression analysis to identify the molecular targets of miR-133a regulation. Gene expression data and web-based searching revealed several candidate genes, including transgelin 2 (TAGLN2), actin-related protein2/3 complex, subunit 5, 16kDa (ARPC5), LAG1 homolog, ceramide synthase 2 (LASS2) and glutathione S-transferase pi 1 (GSTP1). ARPC5 and GSTP1 likely represent bona fide targets as their expression is elevated in lung-SCC clinical specimens. Furthermore, transient transfection of miR-133a, repressed ARPC5 and GSTP1 mRNA and protein levels. As cell proliferation was significantly inhibited in lung-SCC cells following RNAi knock down of either gene, ARPC5 and GSTP1 may function as oncogenes in the development of lung-SCC. The identification of a tumor suppressive miRNA and the novel cancer pathways it regulates could provide new insights into potential molecular mechanisms of lung-SCC carcinogenesis.

Background N-methyl-D-aspartate receptors (NMDAR) act as tumor suppressors of digestive malignancies. The expression and genetic methylation patterns of NMDAR2B in non-small cell lung cancer (NSCLC) are unknown. Methods The relationship between gene methylation and expression of NMDAR2B was analyzed in NSCLC cell lines (N = 9) and clinical tissues (N = 216). The cell lines were studied using RT-PCR and 5-aza-2'-deoxycytidine treatment, while the clinical tissues were examined by methylation specific real-time quantitative PCR and immunohistochemistry. Retrospective investigation of patient records was used to determine the clinical significance of NMDAR2B methylation. Results NMDAR2B was silenced in five of the nine cell lines; 5-aza-2'-deoxycytidine treatment restored expression, and was inversely correlated with methylation. Aberrant methylation of NMDAR2B, detected in 61% (131/216) of clinical NSCLC tissues, was inversely correlated with the status of protein expression in 20 randomly examined tumors. Aberrant methylation was not associated with clinical factors such as gender, age, histological type, or TNM stage. However, aberrant methylation was an independent prognostic factor in squamous cell carcinoma cases. Conclusions Aberrant methylation of the NMDAR2B gene is a common event in NSCLC. The prognosis was significantly better for cases of squamous cell carcinoma in which NMDAR2B was methylated. It may have different roles in different histological types.

OBJECTIVES: The prognosis of non-small-cell lung cancer (NSCLC) patients with malignant pleural disease (MPD), characterized by malignant pleural effusion and/or malignant pleural nodules, is reported to be poor, and patients with MPD are generally not subjected to surgery. However, whether or not the primary tumor should be resected, when MPD is first detected at thoracotomy, is controversial. METHODS: The clinical records of 1623 consecutive NSCLC patients, who underwent surgery between 1990 and 2007, were retrospectively reviewed. A hundred patients (6.2%) were classified with pathological stage IV disease according to the seventh edition of the Union for International Cancer Control (UICC) staging system. There were 73 patients with MPD, which included 32 with effusion without nodules (MPE) and 41 with nodules with or without effusion (MPN). Intra- or postoperative pleural chemotherapy was administered to 37 MPD patients. RESULTS: The median survival time, the 3-year survival rate and the 5-year survival rate for MPD patients were 25.9 months, 41.4%, and 23.7%, respectively, which are better outcomes than those for M1b patients (8.7 months, 18% and 18%, respectively) (log-lank test: p = 0.014). Among MPD patients, N0–1 disease was determined to be a favorable prognostic factor (p = 0.01). MPD status (MPE or MPN) was not prognostically significant (p = 0.40). MPE patients with N0–1 disease had a significantly better prognosis with a 5-year survival rate of 63.6% compared to MPE patients with N2–3 disease (p = 0.003). Twenty-seven percent of MPN patients with N0–1 disease achieved 5-year survival, whereas none of the MPD patients with N2–3 disease survived longer than 5 years after surgery. CONCLUSIONS: The prognosis of patients with surgically detected MPD, who underwent resection, was better than that of M1b patients. MPE patients with N0–1 disease may be candidates for resection.

The prognosis for non-small cell lung cancer (NSCLC) with chest wall invasion can vary due to the heterogeneous nature of the cell population. Because NSCLC with large tumors (>7 cm) have been reclassified as T3, the applicability of the new designation must be evaluated. We reviewed 140 patients with chest wall T3 and 28 patients with T3 NSCLC with large tumors, but no chest wall invasion who underwent resection at our institution. Among chest wall T3 patients, elderly T3 patients (≥80 years old) who died within 42 months, patients with either lymph node or pulmonary metastasis, or patients with a large tumor (>7 cm) had poorer prognoses than those who had not. The survival rates for cases with chest wall T3 and cases with a large tumor without chest wall invasion were not significantly different. NSCLC patients with chest wall T3 with lymph node, or pulmonary metastasis, or with a large tumor should be considered for further multimodal treatment with or without resection to enhance their survival time. Elderly patients with chest wall invasion may not be good candidates for resection. A large tumor is so aggressive that re-classification of large tumor cases as T3 is suitable.

We herein report a case of acute respiratory distress syndrome (ARDS) that appeared to be related to a granulocyte colony-stimulating factor (G-CSF)-producing lung cancer. A 77-year-old man with arterial sclerotic obstruction (ASO) underwent reconstructive surgery of the left femoral artery. He developed ARDS on the 5th postoperative day, which resolved following mechanical ventilation with steroid pulse treatment. Four months later, he was admitted with a fever and right arm pain. Chest computed tomography showed a malignant lesion in the right apical lung, and percutaneous needle biopsy demonstrated adenocarcinoma. Laboratory data revealed neutrophilia with elevated serum G-CSF levels. He underwent a right upper lobectomy with chest wall resection, and administration of sivelestat sodium to treat his postoperative pre-acute lung injury state. Pathology revealed a G-CSF-producing pleomorphic carcinoma. Retrospectively, a tumor shadow was noted on chest X-ray at the time of ARDS just after ASO surgery. The relationship between an abnormal G-CSF level and ARDS was considered, and the implications are herein discussed.

Pyothorax-associated lymphoma (PAL) is a comparatively rare tumor, and it is difficult to definitively diagnose it preoperatively, especially in patients with only pleural thickening without mass formation. Pleural effusion aspiration cytology is a useful and easy diagnostic method for a large number of chest diseases. However, the cytologic findings of PAL have been rarely described. Here we report on the cytologic findings in a patient with PAL, manifested by pleural thickening without mass formation, and which was diagnosed preoperatively by pleural effusion aspiration cytology.A 64-year-old man was admitted to our hospital because of pleural thickening involving an empyema sac located in the left thorax and rapidly increasing pleural effusion. He had a 30-year history of chronic empyema and a 10-year history of diabetes mellitus. Left pleural effusion aspiration cytology showed malignant lymphoma. The patient was admitted to our hospital for PAL treatment. Because of poor respiratory function, he only underwent decortication with complete resection of the thickening pleural peel. However, he was well, without recurrence, 5 years after the operation. The histologic examination revealed that lymphoma cells were located only in the thickening pleural peel.This is a very rare case of PAL diagnosed by preoperative aspiration cytology for an increasing pleural effusion. This report demonstrates that pleural effusion aspiration cytology can be valuable for the diagnosis of PAL.

Hypermethylation of promoter CpG islands is a major inactivation mechanism of tumor suppressor genes, some of which are thought to be related to the prognosis of patients with non-small cell lung cancer (NSCLC). Therefore, hypermethylation of the specific genes may be expected to serve as a prognostic biomarker for NSCLC. In this study, the methylation status of 14 genes was analyzed in 44 stage IA NSCLC cases using methylation-specific PCR. Hypermethylation was detected in PTGER2 (70% of cases), DRM/Gremlin (66%), sFRP-2 (57%), IL-12Rbeta2 (48%), Reprimo (41%), APC (39%), CXCL12 (39%), HPP1 (30%), SPARC (30%), sFRP-5 (30%), p16 (25%), RUNX3 (20%), sFRP-1 (20%) and Wif-1 (16%). Patients with p16, sFRP-5, Wif-1 or CXCL12 methylation had a significantly shorter duration of relapse-free survival than their counterparts with an unmethylated gene (p16, P=0.011; sFRP-5, P=0.030, Wif-1, P=0.036; CXCL12, P=0.026). Also, those with methylated HPP1, p16 or Wif-1 had a significantly shorter duration of overall survival (HPP1, P=0.031; p16, P=0.026; Wif-1, P=0.008). Multivariate analysis revealed that p16 methylation in relapse-free survival and Wif-1 methylation in overall survival were the strongest independent prognostic factors (p16, P=0.036; Wif-1, P=0.035). In conclusion, the hypermethylation of the p16 and Wif-1 genes has potential as biomarkers that may be used to predict the prognosis of stage IA NSCLC.

A 32-year-old woman with ocular-typed myasthenia gravis (MG) without thymoma was admitted to the hospital to undergo surgical treatment. Video-assisted thoracoscopic surgery (VATS) extended thymectomy was successfully performed with three small ports using manual manipulators, the Radius Surgical System (RSS). The device may facilitate many degrees of freedom to general thoracic surgery.

Several studies have described p16INK4A and prostaglandin E2 (PGE2) co-alterations in various solid tumors, including non-small cell lung cancer (NSCLC). In this study, we examined the correlation between PGE2 receptor 2 (EP2) expression and p16INK4A methylation in NSCLC, and the association with clinicopathological features and prognostic significance. We retrospectively reviewed 88 NSCLC patients who underwent resection from July 1993 to May 1997. The tumors included 43 adenocarcinomas, 39 squamous cell carcinomas, and 6 large cell carcinomas. EP2 expression was determined by immunostaining, and p16INK4A methylation was analyzed by methylation specific PCR. EP2 was overexpressed in 44% of NSCLC patients, 61% of adenocarcinoma cases, 28% of squamous cell carcinoma cases, and 33% of large cell carcinoma cases. EP2 expression positively correlated with lymph node metastasis (P=0.034), especially in patients with squamous cell carcinoma (P

The aim of this study was to evaluate the molecular influence of chronic obstructive pulmonary diseases (COPD) on the pathogenesis of non-small cell lung cancer (NSCLC).The methylation profiles of 12 genes, and the epidermal growth factor receptor (EGFR) and KRAS mutations were determined for samples from 229 NSCLC patients. In addition, protein expression of EGFR and HER2 in 116 NSCLCs was analyzed based on the presence or absence of COPD.IL-12Rbeta2 and Wif-1 methylation and HER2 overexpression were more frequent events in the COPD group. Eighty nonmalignant lung tissues had no correlation with any molecular changes between the COPD and the non-COPD group. EGFR mutation was significantly higher in the non-COPD group, while EGFR expression was inversely correlated with %FEV1.0. In the COPD group, unmethylated SPARC and sFRP-2 genes or a negative CpG island methylator phenotype (CIMP) was a negative prognostic factor, while methylation of p16(INK4A) and WNT antagonist genes was a negative prognostic factor in the non-COPD group.Novel characteristics of COPD-related NSCLC were identified by examination of methylation profiles and alterations of EGFR signaling. In consideration of the high sensitivity to smoking in patients with COPD, NSCLC with COPD might be a distinct population of smoke-related NSCLC, the genetic profile of which is quite different from non-COPD NSCLC.

Objectives The prognosis for patients with large-cell neuroendocrine carcinoma is generally very poor. In this study, we describe the clinical features of recurrent tumors of large-cell neuroendocrine carcinoma and discuss the role of adjuvant chemotherapy and management of recurrence in patients with large-cell neuroendocrine carcinoma. Methods We retrospectively analyzed clinical data from 79 patients and evaluated the prognosis of patients with platinum-based adjuvant chemotherapy, recurrence patterns, patient response to chemotherapy or radiation therapy, and prognosis in patients who experienced relapse. Results Of 72 patients, 36 had confirmed recurrent tumors upon follow-up examinations. Of those with recurrent tumors, 33 patients (91.7%) had their first recurrent tumors within 3 years. Patients who underwent platinum-based adjuvant chemotherapy had a significantly lower rate of tumor recurrence and a higher rate of disease-free survival than those who had non–platinum-based adjuvant chemotherapy or no adjuvant chemotherapy. Multivariate analyses revealed that platinum-based adjuvant chemotherapy, pathologic stage, and the presence of second cancer are independent prognostic factors. Three patients with limited resection of the primary tumor had poor prognosis with recurrence. Postoperatively, 11 of the 36 patients without recurrence (30.6%) had metachronous second primary cancers, of which 4 patients had more than 1 site. Conclusions Patients with large-cell neuroendocrine carcinoma had frequent recurrence following resection of the primary tumor, and those without recurrence often developed metachronous second primary cancers. Platinum-based adjuvant chemotherapy after surgery may be useful for preventing recurrence in patients with large-cell neuroendocrine carcinoma.