Search

Mice have served as an excellent model to understand the etiology of lung cancer for years. However, data regarding dual-stage carcinogenesis of lung squamous cell carcinoma (SCC) remain elusive. Therefore, we aim to develop pre-malignant (PM) and malignant (M) lung SCC in vivo using N-nitroso-tris-chloroethylurea (NTCU). BALB/C mice were allotted into two main groups; PM and M groups which received treatment for 15 and 30 weeks, respectively. Then, the mice in each main group were allotted into three groups; control, vehicle, and cancer (n = 6), which received normal saline, 70% acetone, and 0.04 M NTCU by skin painting, respectively. Histopathologically, we discovered a mix of hyperplasia, metaplasia, and dysplasia lesions in the PM group and intracellular bridge; an SCC feature in the M group. The M group was positive for cytokeratin 5/6 protein which confirmed the lung SCC subtype. We also found significantly higher (P < 0.05) epithelium thickness in the cancer groups as compared to the vehicle and control groups at both the PM and M. Overall, this study discovered that NTCU is capable of developing PM and M lung SCC in mice model at appropriate weeks and the vehicle group was suggested to be adequate as control group for future research., (© 2021. The Author(s).)

Rationale: At present, the prognosis of patients with giant lung squamous cell carcinoma (LSCC) is poor, and there is no safe and effective treatment for elderly patients with large LSCC., Patient Concerns: Here, we reported a 77-year-old man admitted to the hospital with cough for 3 months and significant chest pain. Computed tomography (CT) imaging showed a large mass in the left lung with pleural effusion., Diagnoses: Chest CT scan revealed a 12.5 cm × 7.3 cm mass in the left upper lobe adjacent to the pulmonary vein, with left pleural effusion. Pulmonary tumor markers were significantly elevated, and CT-guided percutaneous lung mass biopsy specimens showed LSCC., Interventions: After diagnosis, the patient was treated with sintilimab combined with endostar and nab-paclitaxel. After 2 cycles of treatment, the lung mass in the patient shrank rapidly and the clinical symptoms were relieved., Outcomes: The patient's tumor dramatically shrank, and the pleural effusion was decreased after 4 cycles of treatment without any adverse effects. Meanwhile, the high-level tumor marker resumed normal., Lessons: Sintilimab combined with endostar and nab-paclitaxel may be a good treatment option for lung squamous cell cancer, especially for that in elderly patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Dysregulation of the long non-coding RNA prostate androgen regulated transcript 1 (lncRNA PART1) is involved in the tumorigenesis of various cancers. However, little is known about its function and molecular mechanism in the development of lung squamous cell carcinoma (LSCC). In this study, we examined the expression of PART1 in LSCC clinical tissue samples and cell lines, and gain- and loss-of-function experiments were performed to explore the function of PART1 in LSCC proliferation, invasion and migration. We found that PART1 was overexpressed in both LSCC tissues and cell lines. Functional studies revealed that PART1 knockdown significantly suppressed cell proliferation, invasion and migration but enhanced apoptosis in LSCC cells, whereas overexpression of PART1 showed the opposite results. Mechanistically, we identified that PART1 acted as a sponge of miR-185-5p, and sineoculis homeobox homolog 1 (Six1) was a direct downstream target of miR-185-5p. Moreover, restoration of miR-185-5p or silencing of Six1 partially abolished the oncogenic effect of PART1 in LSCC cells. Clinically, The areas under the receiver operating characteristic (ROC) curve of PART1, miR-185-5p, and Six1 were 0.7857, 0.7332, 0.8112, respectively. Notably, high PART1, low miR-185-5p, and high Six1 expressions were significantly associated with severe clinical parameters and were the independent risk factors for poor prognosis of LSCC patients. Thus, we concluded that the PART1/miR-185-5p/Six1 axis might serve as a novel biomarker for the diagnosis and treatment of LSCC.

Background: Skeletal muscle depletion (sarcopenia) is associated with poor prognosis in patients with lung cancer. We analyzed changes in skeletal muscle area using serial computed tomography (CT) until the death of patients with advanced squamous cell lung cancer (SQCLC)., Methods: This retrospective study comprised 70 consecutive patients who underwent palliative chemotherapy for SQCLC. The cross-sectional area of the skeletal muscle at the level of the first lumbar vertebra (L1) was measured using chest CT. An artificial intelligence algorithm was developed and used for the serial assessment of the muscle area. Sarcopenia was defined as an L1 skeletal muscle index <46 cm 2 /m 2 in men and < 29 cm 2 /m 2 in women., Results: The median age was 69 years; 62 patients (89%) had metastatic disease at the time of initial diagnosis. Sarcopenia was present in 58 patients (82.9%) at baseline; all patients experienced net muscle loss over the disease trajectory. The median overall survival was 8.7 (95% confidence interval 5.9-11.5) months. The mean percentage loss of skeletal muscle between the first and last CT was 16.5 ± 11.0%. Skeletal muscle loss accelerated over time and was the highest in the last 3 months of life (p < 0.001). Patients losing skeletal muscle rapidly (upper tertile, >3.24 cm 2 /month) had shorter overall survival than patients losing skeletal muscle slowly (median, 5.7 vs. 12.0 months, p < 0.001)., Conclusions: Patients with advanced SQCLC lose a significant amount of skeletal muscle until death. The rate of muscle area reduction is faster at the end of life., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Accessible biomarkers are needed for immunotherapy in advanced non-small-cell lung cancer (NSCLC). We previously described a multivariate risk prediction model, the iSEND, which categorises advanced NSCLC patients treated with nivolumab into Good, Intermediate or Poor groups. This model was developed by using only clinical and analytical variables (sex, ECOG-performance status, neutrophil-to-lymphocyte ratio [NLR] and post-treatment delta NLR)., Methods: An international database of 439 patients who received post-platinum PD-1/L1 monotherapies was collected for validation. Performance of the iSEND to different PD-L1 groups was compared by using time-dependent positive predictive value (PPV) for their mortality events., Results: Median follow-up was 18.2 months (95% CI: 15.9-19.6). The overall survival of the iSEND Good (HR = 0.31, 95% CI: 0.22-0.43, p < 0.0001) was superior to the iSEND Poor. Time-dependent PPV for mortality of iSEND Poor was superior to PD-L1 = 0% group at 12 (75 vs. 53%, p = 0.01) and 18 months (85 vs. 46%, p = 0.03). However, female gender did not independently associate with better outcome in the validation cohort., Conclusion: The iSEND model is associated with the outcome of post-platinum PD-1/L1 monotherapy in advanced NSCLC patients. The iSEND Poor demonstrated a superior performance to PD-L1 = 0% in negative prognostication. Prospective investigation and modelling with other significant parameters in a larger cohort are warranted.

Introduction: Median age at diagnosis of lung cancer is 70 years. Its presentation in patients 40 or younger is uncommon and it has been proposed that maybe it is a different disease due to its clinical characteristics and genetic makeup. There are a limited number of studies in this population and they report different clinic-pathological characteristics in comparison with older patients., Methods: We described the incidence of lung cancer patients diagnosed at age 40 or younger at the Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima-Peru; from 2009 to 2017 and evaluated the characteristic of NSCLC. Epidemiologic and clinic-pathological data was collected from clinical files. Analysis was carried out using SPSSvs19 software., Results: We identified 3823 patients with lung cancer seen at INEN during the study period. Among these, 166 (4.3%) patients were 40 years or younger, and 137/166 (82.5%) were NSCLC. Median age at diagnosis was 36 years (range 14-40 years) and 59.1% of patients were female. A smoking history was present in 14.4% of patients. Frequent symptoms at diagnosis were cough (62.0%), chest pain (51.8%) and dyspnea (40.9%). Adenocarcinoma was the most common histological type (63.3%). Most patients had advanced disease at diagnosis (84.7%). The median overall survival was 8.2 months., Conclusions: The proportion of young patients with lung cancer in our population is higher than that reported in the most recent literature. Lung cancer in the young is mostly sporadic, more frequent in women, usually adenocarcinoma type and it presents with advanced disease, resulting in a very poor survival.

Objective: Long noncoding RNA (lncRNA) family with sequence similarity 201-member A (FAM201A) is a novel lncRNA promoting the development of various cancers. However, the biological function of FAM201A on the metastasis of lung squamous cell carcinoma (LSCC) remains unknown. The aim of this study was to explore the molecular mechanism of FAM201A and its target protein in advanced LSCC., Patients and Methods: Quantitative Polymerase Chain Reaction (qPCR) was applied to evaluate FAM201A expression in lung cancer tissues. The impact of high FAM201A expression on the overall survival in patients with lung cancer was tested using the log-rank test. The relevance between aberrant FAM201A and clinicopathological characteristics in patients with lung cancer was analyzed using the Chi-square tests. Cell proliferation was assayed using the Cell Counting Kit-8 (CCK-8) and a transwell assay, and the mice xenograft models were applied to determine the promoting effects of FAM201A on LSCC in vitro and in vivo. The underlying regulatory mechanism was explored through RNA transfection, qPCR, and Western blotting. The correlation between ATP-binding cassette transporter E1 (ABCE1) and FAM201A expression was verified using Spearman's correlation coefficient., Results: FAM201A is aberrantly elevated in tissues from patients with non-small cell lung cancer. High levels of FAM201A expression were more likely to present in patients with squamous type, M1 stage, and inferior overall survival. Differential expression was found between non-metastatic and metastatic squamous carcinoma, but not in adenocarcinoma. FAM201A knockdown inhibits cell proliferation, migration, and invasion of LSCC cells in vitro, and represses tumor growth in vivo. Furthermore, ABCE1 in LSCC cells was downregulated by silencing FAM201A. The tissue level of ABCE1 was positively correlated with FAM201A expression in patients with LSCC., Conclusions: FAM201A may markedly induce migration and invasion of LSCC, resulting in the M1 stage and poor survival. These findings suggest the FAM201A-ABCE1 axis as a novel therapeutic target in LSCC.

Background: Lung cancer is a common comorbidity of idiopathic pulmonary fibrosis (IPF) and has poor outcomes. The incidence and clinical factors related to development of lung cancer in idiopathic pulmonary fibrosis (IPF) are unclear. The aim of this study was to elucidate the cumulative incidence, risk factors, and clinical characteristics of lung cancer in IPF., Methods: In this retrospective study, we analyzed clinical data for 938 patients who were diagnosed with IPF without lung cancer between 1998 and 2013. Demographic, physiologic, radiographic, and histologic characteristics were reviewed. Cumulative incidence of lung cancer and survival were estimated by the Kaplan-Meier method. Risk factors of lung cancer development were determined by Cox proportional hazard analysis., Results: Among 938 IPF patients without lung cancer at initial diagnosis, lung cancer developed in 135 (14.5%) during the follow-up period. The cumulative incidences of lung cancer were 1.1% at 1 year, 8.7% at 3, 15.9% at 5, and 31.1% at 10 years. Risk factors of lung cancer were male gender, current smoking at IPF diagnosis, and rapid annual decline of 10% or more in forced vital capacity (FVC). Patients who developed lung cancer were mostly elderly men with smoking history. Squamous cell carcinoma followed by adenocarcinoma was the most common histologic type. Lung cancer was frequently located in areas abutting or within fibrosis. Survival was significantly worse in patients with lung cancer compared to patients with IPF alone., Conclusion: Lung cancer frequently developed in patients with IPF and was common in current-smoking men with rapid decline of FVC.

MicroRNAs (miRNAs) are involved in various crucial biological processes including regulation of cell differentiation, proliferation, and migration, and are closely associated with tumor development. This study aimed to investigate miR-130b expression levels in lung cancer patient tissues. Two Gene Expression Omnibus (GEO) databases, including GSE48414 and GSE74190, and two The Cancer Genome Atlas (TCGA) databases including TCGA LUAD and TCGA LUSC, were accessed to obtain information for differential expression analysis and clinical-pathological correlation analysis. The results showed that miR-130b expression levels were significantly increased in lung cancer compared to normal tissues. Data also demonstrated that confounding factors such as tumor clinical stages and tumor invasion depth markedly affected miR-130b expression levels in cancer patients. A total of 169 target genes modified by miR-130b expression were identified by using 4 online websites for target gene prediction. Further enrichment analysis indicated that these 169 target genes were significantly enriched in several cancer-related biological processes and signaling pathways, including wound healing, cell proliferation, Wnt signaling, Ras signaling, and mTOR signaling. It was also of interest to examine the seven sites on the promoter region of miR-130b encoding gene in lung cancer patients and then compare methylation at these loci with miR-130b expression. The correlation analysis between encoding gene methylation and miR-130b expression in TCGA datasets revealed that decreased methylation in the promoter region was significantly associated with elevated miR-130b expression. This phenomenon was markedly dependent upon smoking history and clinical-pathological features. In conclusion, data indicated alterations in the methylation of DNA promoter region of miR-130b encoding gene were associated with disturbances in miR-130b expression in lung cancer patients suggesting that the DNA methylation process and miR-130b expression may serve as biomarkers for detection of lung cancer.

Objective Although lung squamous cell carcinoma (SCC) accounts for 20-30% of lung cancer cases, new treatment options are limited. The CA031 study showed that nanoparticle albumin-bound-paclitaxel (nab-PTX) plus carboplatin produced a significantly higher overall response rate (41%) than solvent-based paclitaxel plus carboplatin in patients with lung SCC. However, the safety and efficacy of combination chemotherapy of nab-PTX and carboplatin has not yet been established for patients with concurrent lung SCC and idiopathic interstitial pneumonias (IIPs). The aim of this study was to assess the safety and efficacy profiles of nab-PTX and carboplatin in patients with lung SCC and concurrent IIPs. Methods Eight patients with inoperable-stage lung SCC and IIPs were treated with nab-PTX plus carboplatin in a first-line setting between June 2013 and December 2016. One of the eight was a woman, and the median age was 77 (range=72-80) years. Their clinical outcomes, including chemotherapy-associated acute exacerbation of IIPs, were retrospectively investigated. Results The overall response rate was 50%, the median progression-free survival time was 5.6 months, and the median overall survival time was 8.1 months. No patients experienced chemotherapy-related exacerbation of IIPs in the first-line treatment with nab-PTX plus carboplatin. However, IIPs worsened in two of four patients who received second-line chemotherapy. Conclusion Combination chemotherapy of nab-PTX and carboplatin may be an effective and safe treatment option for patients with inoperable lung SCC with IIPs. To confirm this, a large-scale prospective study is needed.

Background: Gemcitabine plus cisplatin (GP) is commonly used to treat lung squamous cell carcinoma (SCC); however, it is not clear which subgroup of lung SCC patients could benefit most from GP treatment. We explored the predictive factors in lung SCC patient cohorts., Methods: Seventy-eight lung SCC patients treated with a first-line GP regimen were enrolled in this retrospective cohort study. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Classification tree models were used to explore the risk factors for PFS and OS in these patients., Results: The median PFS and OS in SCC patients treated with a GP regimen were 6.0 and 13.6 months, respectively. Three terminal subgroups were formed for both PFS and OS. The subgroup with a body mass index (BMI) > 23.94 kg/m 2 and aged ≤ 54.5 had the longest PFS (9.0 months); the subgroup with a BMI < 23.94  kg/m 2 and aged ≤ 54.5 had the shortest PFS (4.05 months). Patients with an objective response (partial or complete response) to treatment had the longest OS (20.0 months), while patients with a BMI ≤ 26.92 kg/m 2 and stable or progressive disease as the best response had the shortest OS (11.2 months)., Conclusions: BMI and age may be predictors of PFS in lung SCC patients who receive GP treatment. BMI and best response to GP treatment predicts OS in such patients. Patients' clinical pathological characteristics may be used to predict the therapeutic efficacy of chemotherapy and survival., (© 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

In the absence of screening, most patients with lung cancer are not diagnosed until later stages, when the prognosis is poor. The most common symptoms are cough and dyspnea, but the most specific symptom is hemoptysis. Digital clubbing, though rare, is highly predictive of lung cancer. Symptoms can be caused by the local tumor, intrathoracic spread, distant metastases, or paraneoplastic syndromes. Clinicians should suspect lung cancer in symptomatic patients with risk factors. The initial study should be chest x-ray, but if results are negative and suspicion remains, the clinician should obtain a computed tomography scan with contrast. The diagnostic evaluation for suspected lung cancer includes tissue diagnosis, staging, and determination of functional capacity, which are completed simultaneously. Tissue samples should be obtained using the least invasive method possible. Management is based on the individual tumor histology, molecular testing results, staging, and performance status. The management plan is determined by a multidisciplinary team consisting of a pulmonology subspecialist, medical oncology subspecialist, radiation oncology subspecialist, and thoracic surgeon. The family physician should remain involved with the patient to ensure that patient priorities are supported and, if necessary, to arrange for end-of-life care., (Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.)

Purpose: Older patients with lung cancer are a heterogeneous population making treatment decisions complex. This study aims to evaluate the value of geriatric assessment (GA) as well as the evolution of functional status (FS) in older patients with lung cancer, and to identify predictors associated with functional decline and overall survival (OS)., Methods: At baseline, GA was performed in patients ≥70 years with newly diagnosed lung cancer. FS measured by activities of daily living (ADL) and instrumental activities of daily living (IADL) was reassessed at follow-up to define functional decline and OS was collected. Predictors for functional decline and OS were determined., Results: Two hundred and forty-five patients were included in this study. At baseline, GA deficiencies were present in all domains and ADL and IADL were impaired in 51 and 63% of patients, respectively. At follow-up, functional decline in ADL was observed in 23% and in IADL in 45% of patients. In multivariable analysis, radiotherapy was predictive for ADL decline. No other predictors for ADL or IADL decline were identified. Stage and baseline performance status were predictive for OS., Conclusions: Older patients with lung cancer present with multiple deficiencies covering all geriatric domains. During treatment, functional decline is observed in almost half of the patients. None of the specific domains of the GA were predictive for functional decline or survival, probably because of the high impact of the aggressiveness of this tumor type leading to a poor prognosis.

Rationale: Metastatic cardiac tumor (MCT) is rare in clinical practice. MCT presenting initially as atrial fibrillation (AF) is even rarer., Patient Concerns: We report a 47-year-old woman with no previous medical history presented with intermittent palpitation for 3 days., Diagnoses: The electrocardiography showed AF with rapid ventricular rate. The transthoracic echocardiography showed a 4 × 4 cm mass occupying the left atrium (LA). The contrast enhanced computed tomography (CT) showed a left lower lung mass with invasion to the LA and left upper pulmonary vein (PV). The chest CT guided biopsy revealed poorly differentiated squamous cell carcinoma. Further workup including bone scan showed no significant findings. The diagnosis of lung squamous cell carcinoma with cardiac invasion was made., Interventions: She went on to received palliative chemotherapy., Outcomes: She is being followed up regularly at the outpatient department., Lessons: Tumor invasion of the LA and PV was thought to be the cause of the AF. This condition is rare, but clinically important. Physicians should be alert that MCT could be an important differential diagnosis in patients presenting with unexplained AF.

Case Presentation: A woman in her 50s with no significant medical history presented with low-grade fever and cough of 3 days' duration, which was productive of blood-streaked sputum. She was an active smoker, with a 30 pack-year history of smoking. She denied chest pain, chronic cough, exertional dyspnea, or constitutional symptoms., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: Improving the early detection and chemoprevention of lung cancer are key to improving outcomes. The pathobiology of early squamous lung cancer is poorly understood. We have shown that amplification of sex-determining region Y-box 2 (SOX2) is an early and consistent event in the pathogenesis of this disease, but its functional oncogenic potential remains uncertain. We tested the impact of deregulated SOX2 expression in a novel organotypic system that recreates the molecular and microenvironmental context in which squamous carcinogenesis occurs., Objectives: (1) To develop an in vitro model of bronchial dysplasia that recapitulates key molecular and phenotypic characteristics of the human disease; (2) to test the hypothesis that SOX2 deregulation is a key early event in the pathogenesis of bronchial dysplasia; and (3) to use the model for studies on pathogenesis and chemoprevention., Methods: We engineered the inducible activation of oncogenes in immortalized bronchial epithelial cells. We used three-dimensional tissue culture to build an organotypic model of bronchial dysplasia., Measurements and Main Results: We recapitulated human bronchial dysplasia in vitro. SOX2 deregulation drives dysplasia, and loss of tumor promoter 53 is a cooperating genetic event that potentiates the dysplastic phenotype. Deregulated SOX2 alters critical genes implicated in hallmarks of cancer progression. Targeted inhibition of AKT prevents the initiation of the dysplastic phenotype., Conclusions: In the appropriate genetic and microenvironmental context, acute deregulation of SOX2 drives bronchial dysplasia. This confirms its oncogenic potential in human cells and affords novel insights into the impact of SOX2 deregulation. This model can be used to test therapeutic agents aimed at chemoprevention.

Background: Atrial fibrillation and atrial flutter are atrial tachycardias associated with embolic strokes. To date, there have only been a few reports highlighting the incidence of these atrial tachycardias due to mechanical compression of myocardial structures and the pulmonary vasculature in certain mediastinal masses and cysts., Case: We present a case of a 75-year-old gentleman who is a nonsmoker with a history of hypertension who presents with an acute embolic stroke due to atrial flutter likely from mechanical compression from an underlying squamous cell carcinoma of the lung., Conclusion: This case represents, to the best of our knowledge, a rare case of squamous cell carcinoma of the lung in a nonsmoker likely leading to mechanical compression and a resultant atrial tachycardia with an embolic stroke.

Objective: To investigate the clinical features, diagnosis, and treatment status of elderly patients with chronic obstructive pulmonary disease (COPD) complicated with lung cancer., Patients and Methods: This was a retrospective study of 206 patients aged >60 years with COPD and newly diagnosed lung cancer at the Tianjin Chest Hospital Respiratory Centre between September 2008 and September 2013. Lung function, radiology, and clinical data were retrieved., Results: Among all patients, 57% (117/206) were hospitalized due to acute COPD aggravation, 47% (96/206) had COPD grade III or IV, 95% (195/206), showed diffusion dysfunction in pulmonary function examination, 90% (185/206) had a history of smoking, and 26% (54/206) were treated with inhaled corticosteroids for COPD treatment. Ninety-eight patients suffered from squamous carcinoma, 73 from adenocarcinoma, and 35 from small-cell carcinoma. Clinical staging was I in 36 patients, II in 47 patients, III in 78 patients, and IV in 45 patients. Initial treatments were surgery in 59 patients, chemotherapy in 30 patients, and no treatment in 117 patients. Multivariate analysis showed that age (P<0.001), COPD grades (P=0.01), clinical staging (P<0.001), and pulmonary diffusion function (P=0.007) were independent factors associated with patients with COPD being given treatments for lung cancer., Conclusion: Younger patients with lower COPD grades, earlier lung cancer stage, and better pulmonary diffusion function are more likely to receive treatments.

Purpose: The purpose of this study is to investigate the prognostic significance of SOX2 gene amplification and expression in patients with American Joint Committee on Cancer stage III lung squamous cell carcinoma (SCC) who underwent surgery followed by adjuvant radiotherapy., Materials and Methods: Pathological specimens were obtained from 33 patients with stage III lung SCC treated with surgery followed by adjuvant radiotherapy between 1996 and 2008. SOX2 gene amplification and protein expression were analyzed using fluorescent in situ hybridization and immunohistochemistry, respectively. Patients were divided into two groups according to their SOX2 gene amplification and protein expression status. Kaplan-Meier estimates and a Cox proportional hazards model were used to identify the prognostic factors affecting patient survival., Results: The median follow-up period for surviving patients was 58 months (range, 5 to 102 months). SOX2 gene amplification was observed in 22 patients and protein overexpression in 26 patients. SOX2 overexpression showed significant association with SOX2 gene amplification (p=0.002). In multivariate analysis, SOX2 overexpression was a significant prognostic factor for overall survival (OS) (hazard ratios [HR], 0.1; 95% confidence interval [CI], 0.002 to 0.5; p=0.005) and disease-free survival (DFS) (HR, 0.15; 95% CI, 0.04 to 0.65; p=0.01). Age (HR, 0.33; 95% CI, 0.11 to 0.98; p=0.046) and total radiation dose (HR, 0.13; 95% CI, 0.02 to 0.7; p=0.02) were the independent prognostic factors for OS and DFS. Patients with SOX2 amplification did not show a longer OS (p=0.95) and DFS (p=0.48)., Conclusion: Our data suggested that SOX2 overexpression could be used as a positive prognostic factor in patients with stage III lung SCC receiving adjuvant radiotherapy.

Cigarette smoking has reached epidemic proportions within many regions of the world and remains the highest risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Squamous cell lung cancer is commonly detected in heavy smokers, where the risk of developing lung cancer is not solely defined by tobacco consumption. Although therapies that target common driver mutations in adenocarcinomas are showing some promise, they are proving ineffective in smoking-related squamous cell lung cancer. Since COPD is characterized by an excessive inflammatory and oxidative stress response, this review details how aberrant innate, adaptive and systemic inflammatory processes can contribute to lung cancer susceptibility in COPD. Activated leukocytes release increasing levels of proteases and free radicals as COPD progresses and tertiary lymphoid aggregates accumulate with increasing severity. Reactive oxygen species promote formation of reactive carbonyls that are not only tumourigenic through initiating DNA damage, but can directly alter the function of regulatory proteins involved in host immunity and tumour suppressor functions. Systemic inflammation is also markedly increased during infective exacerbations in COPD and the interplay between tumour-promoting serum amyloid A (SAA) and IL-17A is discussed. SAA is also an endogenous allosteric modifier of FPR2 expressed on immune and epithelial cells, and the therapeutic potential of targeting this receptor is proposed as a novel strategy for COPD-lung cancer overlap., (© 2015 The British Pharmacological Society.)

Background: While respiratory bronchiolitis (RB) is a frequent histopathological finding in smoker's lungs, RB-associated interstitial lung disease (RB-ILD) remains a rare disease., Objectives: We analyzed how the histological finding of RB was associated with clinical information in a series of 684 consecutive surgical lung biopsies., Methods: Retrospective analysis with delineation of clinical manifestations, smoking habits, pulmonary function test, and blood gas analysis in patients with RB in surgical lung biopsy. In 240 of these biopsies, RB was diagnosed, and in 146 of these cases a full clinical dataset was available., Results: The final diagnosis of these 146 patients was consistent with RB-ILD (n = 18), pulmonary Langerhans cell histiocytosis (n = 7), various ILD (n = 9), spontaneous pneumothorax (n = 43), traumatic pneumothorax (n = 5), lung cancer (n = 41), various benign lung tumors (n = 8), and chronic pulmonary effusion (n = 15). Smoking history was positive in 93% of patients, 72% revealed centrilobular emphysema in their biopsy, and 58% described dyspnea as the main symptom. Amongst these diagnoses there were significant differences in age and smoking habits, but only small distinctions in pulmonary function test and blood gas analysis. Out of the patients with RB-ILD, 17% developed lung cancer in the later course., Conclusion: RB is strongly related to smoking, emphysema, and dyspnea and frequently associated with lung cancer. RB-ILD is a rare disease that may represent a considerable risk for lung cancer. Pulmonary function testing and blood gas analysis do not differ between RB-associated diseases. The finding of RB should prompt further diagnostic workup, and in case of RB-ILD, entail regular screening for lung cancer., (© 2015 S. Karger AG, Basel.)

Aim: Despite the increasing adoption of parenchymal-sparing procedures, pneumonectomy is still necessary in several pleural and pulmonary (benign or malignant) diseases. We reviewed clinical data of a large cohort of patients treated by pneumonectomy with the aim of better define its impact on early and long-term results., Methods: Clinical and pathological characteristics of all consecutive patients treated by pneumonectomy between January 2005 and May 2012 were retrospectively reviewed. Thirty- and 90-day mortality, as well as long-term survival was assessed. Factors associated to long-term survival were analyzed by univariate and multivariate analyses. Evaluation of quality of life was carried out by a standard questionnaire (SF-12) administrated by phone to patients surviving beyond 1 year., Results: A total of 398 patients (293 men; mean age 61 ± 10.9 years) were operated on in the study period. Indication was malignancy in 380 patients (350 primary lung cancers). Thirty-day mortality was 9 % (right: 12.6 % vs. left: 6.3 %, p = 0.013), significantly correlating with age (p = 0.021), comorbidities (p = 0.034), PS > 1 (p = 0.018), preoperative dyspnea (p = 0.0013), and FEV1 (p = 0.0071). Overall 1-, 3-, 5-, and 7-year survival rates were 76.6, 46.6, 34.4, and 29.2 %. In case of primary lung cancer, these figures were 76.8, 46.4, 34.5, and 29.7 %. At univariate analysis, a less favorable survival was associated to PS > 1 (p = 0.0078), right side (p = 0.044), occurrence of postoperative complications (p = 0.00079), and T3-4 status (p = 0.013). At multivariate analysis, PS > 1, right side, and occurrence of postoperative complications were identified as independent worse prognostic factors. SF12 physical score was 39.1 ± 9.0 and was correlated to the presence of preoperative symptoms (p = 0.013). Mental score was 50.68 ± 9.63 and was correlated to preoperative FEV1/FVC ratio (p = 0.023) and side of disease (p = 0.023)., Conclusion: In current practice, pneumonectomy is still performed for malignancy, sometimes after induction treatment. High postoperative morbidity and mortality are observed; however, at a farer interval time point, long-term survival with preserved quality of life can be observed.

Background: Whereas the epidemiological association between lung cancer and chronic obstructive pulmonary disease (COPD), a chronic inflammatory respiratory disease, is well known, limited studies have examined the association between lung cancer and non-cystic fibrosis bronchiectasis, a representative chronic airway inflammatory disease. This study evaluated the association between bronchiectasis and lung cancer in patients with COPD., Methods: A matched case-control study was conducted in a referral hospital in South Korea. Among COPD patients with moderate to very severe airflow limitation (forced expiratory volume in one second/forced vital capacity <0.7 and forced expiratory volume in one second ≤70% [% predicted]) who underwent chest computed tomography (CT) between January 1, 2010 and May 30, 2013, patients with lung cancer and controls matched for age, sex, and smoking history were selected. The risk of lung cancer was assessed according to the presence of underlying bronchiectasis confirmed by chest CT., Results: The study enrolled 99 cases and 198 controls. Combined bronchiectasis on chest CT was inversely associated with the risk of lung cancer compared with controls (odds ratio [OR] 0.25, 95% confidence interval [CI] 0.12-0.52, P<0.001). Significant associations were found in patients with squamous cell carcinoma (OR 0.11, 95% CI 0.03-0.49, P=0.001) and history of smoking (OR 0.27, 95% CI 0.12-0.57, P<0.001). However, the severity and location of bronchiectasis were not associated with the risk of lung cancer., Conclusion: Interestingly, the concomitant presence of bronchiectasis in COPD patients was associated with a lower risk of lung cancer.

Whether the Hippo pathway contributes to cell lineage transition under pathological conditions, especially tumorigenesis, remains largely unknown. Here we show that YAP, the major effector of the Hippo pathway, displays a distinct activation pattern in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC); YAP is initially activated by LKB1 loss in lung ADC, which upregulates ZEB2 expression and represses DNp63 transcription in a default manner. During transdifferentiation, YAP is inactivated, which in turn relieves ZEB2-mediated default repression of DNp63 and triggers squamous differentiation reprogramming. Disruption of the YAP barrier for phenotypic transition significantly accelerates squamous transdifferentiation, whereas constitutive YAP activation conversely inhibits this transition. More importantly, ectopic DNp63 expression rescues the inhibitory effect of YAP on squamous transdifferentiation. These findings have established YAP as an essential barrier for lung cancer cell fate conversion and provided a mechanism for regulating cancer plasticity, which might hold important implication for YAP-targeted therapies.

Lung cancer is one of the leading malignancies worldwide, but the regulatory mechanism of its growth and metastasis is still poorly understood. We investigated the possible expression of immunoglobulin G (IgG) genes in squamous cell carcinomas and adenocarcinomas of the lung and related cancer cell lines. Abundant mRNA of IgG and essential enzymes for IgG synthesis, recombination activation genes 1, 2 (RAG1, 2) and activation-induced cytidine deaminase (AID) were detected in the cancer cells but not in adjacent normal lung tissue or normal lung epithelial cell line. The extents of IgG expression in 86 lung cancers were found to associate with clinical stage, pathological grade and lymph node metastasis. We found that knockdown of IgG with siRNA resulted in decreases of cellular proliferation, migration and attachment for cultured lung cancer cells. Metastasis-associated gene 1 (MTA1) appeared to be co-expressed with IgG in lung cancer cells. Statistical analysis showed that the rate of IgG expression was significantly correlated to that of MTA1 and to lymph node metastases. Inhibition of MTA1 gene expression with siRNA also led to decreases of cellular migration and attachment for cultured lung cancer cells. These evidences suggested that inhibition of cancer migration and attachment induced by IgG down-regulation might be achieved through MTA1 regulatory pathway. Our findings suggest that lung cancer-produced IgG is likely to play an important role in cancer growth and metastasis with significant clinical implications.

Background: Cancer-associated stromal cells interact with carcinoma cells and thus participate in tumor growth. Our aim was to characterize the ultrastructure and contractile properties of stromal cells in collagen gel cultured from lung cancer of various histological types and from tumor-free lung., Methods: Cells cultured from lung cancer (13 adenocarcinomas, six squamous cell carcinomas, one adenosquamous carcinoma, and one pleomorphic carcinoma) and tumor-free lung were analyzed by transmission electron microscopy and three-dimensional collagen gel contraction assays. The expression of α-smooth muscle actin (α-SMA), a recognized myofibroblast marker, was examined by immunoelectron microscopy from individual cells and by Western blotting from the whole cultured cell population., Results: According to their ultrastructure, the cell lines were composed of fibroblastic and myofibroblastic cells. In electron microscopy, cells of lung cancer exhibited more myofibroblastic features displaying higher amounts of actin belts (p = 0.057) and α-SMA labeling (p = 0.010) than cells from tumor-free lung. Myofibroblasts cultured from lung cancer of smokers expressed less α-SMA labeling (p = 0.013) than counterparts from nonsmokers. Western blotting revealed that cancer-associated fibroblasts expressed more α-SMA (p = 0.006) than cells from tumor-free lung, whereas cells from tumor-free central lung of smokers showed less α-SMA (p = 0.039) than counterparts from nonsmokers. Cells cultured from cancer contracted more in collagen gel than those from tumor-free lung. The contractile capacity in collagen gel correlated with the frequency of extracellular component of fibronexus by transmission electron microscopy., Conclusions: Lung cancer-associated myofibroblasts are different both ultrastructurally and functionally when compared with cells cultured from tumor-free lung. Smoking altered myofibroblastic phenotype, regardless of their origin.

Background and Objective: The invasive tumor front (ITF) refers to cells or invasive nests in the junctional region of a tumor and its host. The ITF contains the most invasive cells of a tumor, and has a high prognostic value in carcinoma. The aim of this study is to investigate the epithelial-mesenchymal transformation phenotype in ITF cells of lung squamous cell carcinoma (SCC), and analyze the relationship between clinicopathological features and clinical outcomes of patients., Methods: Semiquantitative immunohistochemistry was used to examine the expression of epithelial markers (E-cadherin and β-catenin) and mesenchymal marker (vimentin) in 104 lung SCC tumor tissues., Results: A decrease in E-cadherin expression in ITF cells was observed in 56 of 104 (53.8%) tumors from patients. This result was markedly lower than that of non-ITF cells, which eventually developed metastatic tumors and were also associated with death (P=0.04). Vimentin expression was observed in 44 of 104 (42.3%) ITF cells, which was much higher than that of non-ITF cells. The downregulation of E-cadherin and overexpression of vimentin were associated with tumor invasive pattern, lymphatic metastasis, and poor prognosis (P<0.01). The expression of β-catenin was 67.3% (70/104) in ITF cells. Moreover, ITF cells showed more nuclear and plasma-positive cells, which were closely associated with metastasis (P<0.01)., Conclusions: The loss in expression of E-cadherin/β-catenin and overexpression of vimentin in ITF cells may be associated with poor prognosis of lung SCC patients.

Among the most common features of highly invasive tumors, such as lung adenocarcinomas (AD) and squamous cell carcinomas (SqCC), is the massive degradation of the extracellular matrix. The remarkable qualitative and quantitative modifications of hyaluronidases (HAases), hyaluronan synthases (HAS), E-cadherin adhesion molecules, and the transforming growth factor β (TGF-β) may favor invasion, cellular motility, and proliferation. We examined HAase proteins (Hyal), HAS, E-cadherin, and TGF-β profiles in lung AD subtypes and SqCC obtained from smokers and non-smokers. Fifty-six patients, median age 64 years, who underwent lobectomy for AD (N = 31) and SqCC (N = 25) were included in the study. HAS-1, -2 and -3, and Hyal-1 and -3 were significantly more expressed by tumor cells than normal and stroma cells (P < 0.01). When stratified according to histologic types, HAS-3 and Hyal-1 immunoreactivity was significantly increased in tumor cells of AD (P = 0.01) and stroma of SqCC (P = 0.002), respectively. Tobacco history in patients with AD was significantly associated with increased HAS-3 immunoreactivity in tumor cells (P < 0.01). Stroma cells of SqCC from non-smokers presented a significant association with HAS-3 (P < 0.01). Hyal, HAS, E-cadherin, and TGF-β modulate a different tumor-induced invasive pathway in lung AD subgroups and SqCC. HAases in resected AD and SqCC were strongly related to the prognosis. Therefore, our findings suggest that strategies aimed at preventing high HAS-3 and Hyal-1 synthesis, or local responses to low TGF-β and E-cadherin, may have a greater impact in lung cancer prognosis.

Background and Purpose: Insulin-like growth factor 1 (IGF1) promotes cell cycle progression and inhibition of apoptosis and may have a role in carcinogenesis and cancer promotion. Growth hormone (GH) stimulates IGF1 production in liver and other tissues. The aim of our study was to evaluate differences between healthy subjects and patients with lung cancer in the GH-IGF1 axis function., Patients and Methods: In 11 healthy male patients (mean age ± standard error [SE], 43.6 ± 1.7), and 9 male patients with non-small-cell lung cancer (mean age ± SE, 51.0 ± 2.4), GH, total IGF1, melatonin, and interleukin (IL)-2 serum levels were measured in blood samples collected every 4 hours for 24 hours., Results: A clear circadian rhythm was present for melatonin and GH serum levels in the group of healthy subjects and for melatonin in the group of patients with cancer. The midline estimating statistic of rhythm (MESOR) of GH was higher in patients with lung cancer (P < .001), the MESOR of IGF1 was higher in healthy subjects (P < .001), the MESOR of melatonin was not different between subjects (P = .383), and the MESOR of IL-2 was higher in patients with cancer (P = .02). The GH/IGF1 ratio was higher in patients with lung cancer (P = .006). Linear regressions across the stages of cancer showed a significant increasing slope for IL-2 (P < .001), GH (P < .001), and the GH/IGF1 ratio (P < .001), a decreasing slope for IGF1 (P < .001), but no significant trend for melatonin (P = .430)., Conclusion: There is evidence that in patients with lung cancer there is a severe alteration of GH-IGF1 axis function, with loss of circadian rhythmicity of hormone secretion, which may play a role in the progression of neoplastic disease and must be considered in defining the therapeutic approach., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Lung is one of the main sites of metastatic tumors, but collision neoplasms consisting of a primary lung cancer and metastatic breast carcinoma have never been so far reported. We describe here 2 cases of primary non-small cell lung cancers (squamous cell and adenocarcinoma, respectively) colliding with metastatic breast carcinomas (ductal and lobular carcinomas, respectively). Clinico-pathologic features characterizing this challenging diagnosis and the important therapeutic implications are discussed., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Although lung cancer is the leading cause of cancer deaths worldwide, reliable markers allowing prediction of patient survival at the time of initial diagnosis are still lacking. Copy number alterations (CNAs) in tumor tissue DNA have been associated with tumorigenesis and malignant progression. We aimed at identification of gene-level CNAs with prognostic value for survival in pulmonary squamous cell carcinoma (SCC)., Methods: The CNA status of a panel of 44 genes was analyzed by high-resolution array comparative genomic hybridization (CGH) in 49 SCC samples. Overall survival information (median follow-up, 40 months) for the patients was collected and used to assess outcome correlations with gene CNAs., Results: Survival analysis showed that both CDKN2B loss and PTCH1 loss were associated with poor survival (both P < .001, log-rank test). Multivariate Cox analysis, including CDKN2B loss and PTCH1 loss as well as age, sex, cigarette smoking status, tumor size, tumor differentiation, and TNM stage showed that CDKN2B loss (hazard ratio [HR], 17.88; 95% confidence interval [CI], 4.40-72.67; P < .001) and PTCH1 loss (HR, 10.81; 95% CI, 1.92-60.98; P = .007) were independent prognostic factors for poor survival. In addition the PTCH1 loss was more frequently found in moderately or poorly differentiated tumors than in well-differentiated tumors (P = .007)., Conclusion: These findings suggest that 2 genes of loss, CDKN2B and PTCH1, are associated with poor overall survival in patients with SCC of the lung and may be useful as prognostic markers., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We report a case of a 54-year-old man with T4N0M0 non-small cell lung cancer directly invading the thoracic wall and aortic arch. He underwent neoadjuvant chemotherapy followed by en bloc resection of the tumor, lung, chest wall and aortic arch. Perfusion was maintained through femoral-femoral cardiopulmonary bypass, with permanent bypass to the arch vessels to avoid separate extracorporeal cerebral circulation. Total reconstructions of the chest wall and aortic arch were completed without the need for cardiac arrest. The final pathological diagnosis was squamous cell carcinoma, T4N0M0. The patient was discharged without major complications and has been free of disease for 20 months postoperatively., (© Georg Thieme Verlag KG Stuttgart · New York.)

Lung cancer and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality worldwide. They share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by the incidence of these diseases in only a fraction of smokers. COPD is also a major independent risk factor for lung carcinoma, among long-term smokers. Smokers with COPD also have a higher risk of developing a specific histological subtype of non-small cell lung cancer termed squamous cell carcinoma. For these reasons the focus of this review is on the potential pathogenic molecular links between tobacco smoking-related COPD and squamous cell carcinoma. We believe that we need to promote more studies on the molecular and cellular pathobiology of smokers with premalignant bronchial lesions of the squamous cell lung carcinoma compared with a control group of smokers with and without COPD to unravel the complex molecular interactions between COPD and early squamous cell lung carcinoma. These studies should also look at younger healthy smokers in combination with risk models of lung cancer and COPD. Overall these studies may allow the discovery of new molecular targets of the early carcinogenesis process that in the foreseeable future may render the early diagnosis and treatment, and may be even the prevention, of invasive squamous cell lung carcinoma a reality., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objectives: To assess risk of lung cancer (LC) in patients with preinvasive bronchial lesions and to identify factors associated with higher risk., Methods: 124 patients with one or more preinvasive bronchial lesions and normal chest computed tomography (CT) (mean age 66.7 years, 121 males and 3 females), followed-up by white light and autofluorescence bronchoscopy (AFB) every 4-6 mo and chest CT every 6-12 mo, end points were development of carcinoma in situ (CIS) or LC., Results: Among 124 patients with 240 preinvasive bronchial lesions, 20 CIS or LC lesions were detected during follow-up in 20 (16%) patients, 7 were detected as new endobronchial lesions, 10 as new peripheral lesions and 3 as local progression from severe dysplasia to CIS. Median time to progression from the same site or development of CIS/LC elsewhere was 24 months (range: 6-54 mo). The Cumulative risk of development of CIS/LC was 7% at one year, 20% at three years and 44% at 5 years. Among detected lung cancers, 80% were stage 0 or stage I and underwent treatment with curative intent. Diagnosis of new SD during follow-up (p=0.0001), chronic obstructive pulmonary disease (COPD) (p=0.001) or smoking index >52 pack-year (p=0.042) was associated with higher risk. Even after controlling for other risk factors, COPD was associated with risk for lung cancer. Baseline lesion grade was not predictive of patient outcome (p=0.146)., Conclusion: Patients with preinvasive bronchial lesions, especially those with new SD during follow-up, COPD or smoking >52 pack-year are at high risk of LC, AFB and CT follow-up facilitated early detection and treatment with curative intent., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objectives: We investigated the capabilities of an endo-cytoscopy system (ECS) that enables microscopic imaging of the tracheobronchial tree during bronchoscopy, including normal bronchial epithelium, dysplastic mucosa and squamous cell carcinoma., Methods: The newly developed ECS has a 3.2 mm diameter that can be passed through the 4.2 mm working channel of a mother endoscope for insertion of the ECS. It has a high magnification of 570× on a 17 in. video monitor. Twenty-two patients (7 squamous cell carcinoma, 11 squamous dysplasia and 4 after PDT therapies) were underwent white light, NBI light and AFI bronchoscopy. Both abnormal areas of interest and normal bronchial mucosa were stained with 0.5% methylene blue and examined with ECS at high magnification (570×). Histological examinations using haematoxylin and eosin staining were made of biopsied specimens. Analyzed ECS images were compared with the corresponding histological examinations., Results: In normal bronchial mucosa, ciliated columnar epithelial cells were visible. In bronchial squamous dysplasia, superficial cells with abundant cytoplasm were arranged regularly. In squamous cell carcinoma, large, polymorphic tumor cells showed increased cellular densities with irregular stratified patterns. These ECS images corresponded well with the light-microscopic examination of conventional histology., Conclusion: ECS was useful for the discrimination between normal bronchial epithelial cells and dysplastic cells or malignant cells during bronchoscopy in real time. This novel technology has an excellent potential to provide in vivo diagnosis during bronchoscopic examinations., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The epidemiological relationship between squamous cell lung cancer (SCC) and chronic obstructive pulmonary disease (COPD), both smoking-related diseases, suggests that they have also a genetic basis. We compared 35 SCC patients with and without COPD with whole-genome gene expression profiles of laser microdissected tissue. Validation of differential expression was performed for 25 genes using quantitative (q)RT-PCR. Subsequently, we performed array-based CGH on the same tumor samples. We found that 374 probes were differentially expressed in SCC from patients with and without COPD. Forty-four probes were derived from genes with mitochondrial functions and 34 probes were located on 5q. All these probes showed a lower expression level in SCC from non-COPD patients. For a random selection of 25 mitochondrial and 5q genes, we confirmed the differential expression by qRT-PCR. Loss of 3p, 5q and 9p was observed, via array-CGH, to be more frequent in SCC from non-COPD patients as compared to SCC from COPD patients. Combination of chromosomal aberrations and the location of the differentially expressed genes showed significant association for loss of the 5q31.2-31.3 region and reduced expression of the 5q genes. In conclusion, a more frequent loss of 5q and a low expression of genes located on 5q in SCC tumors of non-COPD patients compared to tumors from COPD patients was identified suggesting that different oncogenetic pathways are operational in patients with and without COPD., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: Pathological examination of lung cancer often reveals a more advanced stage than clinical stage. The objective of this study was to evaluate whether the association between clinical and pathologic stages depends on tumor histology., Methods: This retrospective study enrolled patients who had undergone major lung resections and systemic lymph node dissections (1990-2004). In total, 483 patients had adenocarcinoma and 225 had squamous cell carcinoma., Results: Clinical and pathologic N-status were significantly different in patients with adenocarcinoma (p<0.0001) but not in those with squamous cell carcinoma. Patients with adenocarcinoma were more likely to be upstaged from clinical N0 disease to pathologic N2 disease than those with squamous cell carcinoma (p = 0.04). Of those patients with adenocarcinoma, surgical procedure, clinical N-status, metastatic pathologic N2 stations and curability were significant prognostic factors. It is of interest, however, that a similar statistically significant difference could not be shown in patients with squamous cell carcinoma. Furthermore, multivariate analysis demonstrated that clinically detectable N2 disease and multiple pathologic N2 stations significantly affected the poorer prognosis in adenocarcinoma. Adenocarcinoma patients with clinically undetectable N2 disease had significantly better 5-year survival than those with clinically detectable N2 disease (p<0.0001), although this was not the case for patients with squamous cell carcinoma (p = 0.81)., Conclusion: In adenocarcinoma patients with pathologic N2 disease, clinical N-status and metastatic pathologic N2 stations were significant prognostic factors. A similar difference was not found in patients with squamous cell carcinoma. Adenocarcinoma and squamous cell carcinoma appear to have different tendencies for lymph node metastasis., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Mina53, a novel target gene product of c-Myc, is overexpressed in various malignancies. We previously demonstrated that Mina53 is overexpressed in lung cancer patients from the early clinical stages. In this paper, the association between disease prognosis and Mina53 expression in lung cancer patients is analyzed; we found that overexpression of Mina53 in lung cancer patients is associated with favorable prognosis. Statistical analysis using the Kaplan-Meier method showed that patients with negative staining for Mina53 had significantly shorter survival than patients with positive staining for Mina53, especially in stage I or with squamous cell carcinoma. Because the major cause of death in lung cancer patients after surgery is distant metastasis, the effect on cancer cell invasiveness was analyzed for the mechanisms involved in the association with favorable outcome. Overexpression of Mina53 in H226B, a lung squamous cell carcinoma cell line, inhibited cancer cell invasion. Transfection with mina53 shRNA increased the number of invading cells. These results suggest that Mina53 immunostaining is a useful prognostic marker--especially in the early stage of lung cancer--and that Mina53 negative patients should be managed particularly carefully after surgery., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

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 microm, 63.7+/-8.2 microm, 136.5+/-29.9 microm and 259.4+/-29.6 microm, respectively. These results indicated a statistically significant increase of mean vessel diameters in the four groups (P<0.0001)., 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., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

The natural chronologic evolution of a lung cancer manifesting as a pure ground-glass opacity (GGO) nodule on CT scans still remains to be elucidated. Therefore, it is sometimes difficult to determine proper follow-up examinations, particularly in case of GGO nodule growing slowly on serial CT scans. In the current case, we demonstrate serial morphologic (CT) and metabolic ((18)F-FDG PET) imaging findings in a case of adenocarcinoma, where stepwise progression from a focal pure GGO nodule (presumed atypical adenomatous hyperplasia [AAH] or bronchioloalveolar carcinoma [BAC]) eventually to an invasive adenocarcinoma was clearly depicted for more than 10-year follow-up period. This case seems to be useful for the prediction of tumor growth pattern and aggressiveness of malignant pure GGO nodules. In addition, the evolving process of this case may suggest a guideline for planning an appropriate follow-up examination and management in such cases., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

The aim of the present study was to investigate the relationship between FDG uptake and clinical stage for non-small cell lung cancer. The patients who were histologically or cytologically proven to be adenocarcinoma (AC) or squamous cell carcinoma (SCC) lung cancer and conducted FDG PET/CT staging were retrospectively reviewed. The FDG uptake was quantified as the maximum standardized uptake value (SUVmax). And the T-N-M status was determined mainly by FDG PET-CT imaging according to the 1997 update of the international staging system for lung cancer. From December 2003 to November 2007, 266 cases (194 men and 72 women; age range 31-90 years, median 62 years) were analyzed, which included 161 AC and 105 SCC patients. The present study showed that both size (3.23+/-1.68cm vs 2.63+/-1.33cm, P=0.004) and SUVmax (9.82+/-5.08 vs 8.43+/-4.21, P=0.016) were significantly greater for SCC compared to AC. There was positive correlation between the SUVmax and size for both SCC and AC (r=0.651, 0.632, respectively; both P=0.000). Significant difference is found among different stages in SUVmax for AC (F=11.693, P=0.000) but not for SCC (F=1.514, P=0.216). After controlling the size factor, a significant correlation was found between tumor stage and FDG uptake value for AC (r=0.323, P=0.000), but not for SCC (r=0.113, P=0.252). In conclusion, this observation showed that tumor size and histologic subtype had influences upon FDG uptake in non-small cell lung cancer. It demonstrated significant correlation between clinical stage and SUVmax for AC, but not for SCC., (Crown Copyright 2009. Published by Elsevier Ireland Ltd. All rights reserved.)

To evaluate the combination of transbronchial biopsy (TBB) using endobronchial ultrasonography with a guide sheath (EBUS-GS) and positron emission tomography with fluorodeoxyglucose (FDG-PET) for the diagnosis of small peripheral pulmonary lesions (PPLs) < or = 30 mm in mean diameter. A total of 74 PPLs (69.2%) were diagnosed by TBB using EBUS-GS with X-ray fluoroscopy. Diagnostic yield by FDG-PET was 78.5% for the 107 PPLs examined. Diagnostic yield with the combination of TBB using EBUS-GS and FDG-PET (90.7%) was significantly higher compared with that for each procedure alone. A significant increment in diagnostic yield with this combination was seen for PPLs >20mm and < or = 30 mm and for malignant lesions. Combination of TBB using EBUS-GS and FDG-PET is useful for the diagnosis of small PPLs., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

The prospect of establishing serum metabolomic profiles offers great clinical significance for its potential to detect human lung cancers at clinically asymptomatic stages. Patients with suspicious serum metabolomic profiles may undergo advanced radiological tests that are too expensive to be employed as screening tools for the mass population. As the first step to establishing such profiles, this study investigates correlations between tissue and serum metabolomic profiles for squamous cell carcinoma (SCC) and adenocarcinoma (AC) in the lungs of humans. Tissue and serum paired samples from 14 patients (five SCCs and nine ACs), and seven serum samples from healthy controls were analyzed with high-resolution magic angle spinning proton magnetic resonance spectroscopy (HRMAS (1)HMRS). Tissue samples were subjected to quantitative histological pathology analyses after MRS. Based on pathology results, tissue metabolomic profiles for the evaluated cancer types were established using principal component and canonical analyses on measurable metabolites. The parameters used to construct tissue cancer profiles were then tested with serum spectroscopic results for their ability to differentiate between cancer types and identify cancer from controls. In addition, serum spectroscopic results were also analyzed independent of tissue data. Our results strongly indicate the potential of serum MR spectroscopy to achieve the task of differentiating between the tested human lung cancer types and from controls., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Introduction: In clinical practice, peripheral small-sized lung cancers with positive mediastinal lymph nodes are sometimes detected. To understand the characteristics of these aggressive tumors, we reviewed the clinicopathological features of small-sized non-small cell lung cancer patients with mediastinal lymph node metastasis resected in our institution., Methods: We studied 360 patients with small-sized lung lesions with a maximum diameter of 2 cm or less. The clinicopathological characteristics of each patient were reviewed and compared among the subgroups, which were stratified according to pathological nodal status., Results: 21 patients (5.8%) had a positive mediastinal lymph node. Among them, 17 patients had lung lesions larger than 1.5 cm. No mediastinal nodal involvement was found in patients with squamous cell carcinomas. In contrast, mediastinal nodal involvement was significantly common in patients with poorly differentiated carcinoma (P=0.004) and high serum carcinoembryonic antigen levels detected during preoperative evaluation (P=0.006). None of the 14 patients with upper lobe tumor had a positive subcarinal lymph node. Lower lobe tumors frequently developed extensive multiple-level involvement, which included the upper mediastinum. Radiographic evaluation of pN2 patients using computed tomography revealed a total absence of ground-glass opacity, or the presence of a small area of ground-glass opacity., Conclusions: Most small-sized non-small cell lung cancer cases with mediastinal lymph node metastasis were invasive adenocarcinoma with poor differentiation, which usually showed a solid shadow without ground-glass opacity on computed tomography.

Parathyroid hormone-related protein (PTHrP) is the causative factor of the paraneoplastic syndrome humoral hypercalcemia of malignancy (HHM) and it also contributes to osteolytic metastases, both of which are common complications of squamous carcinomas of the lung. Inhibition of autocrine epidermal growth factor receptor (EGFR) signaling has been shown to reduce plasma calcium and PTHrP concentrations in two lung squamous cell carcinoma xenograft models of HHM. The purpose of this study was to investigate the mechanism by which EGFR is activated and stimulates PTHrP gene expression in lung squamous carcinoma cell lines. Amphiregulin (AREG) was the only EGFR ligand that could be consistently detected in conditioned media from the SCC lines, and reduction of its expression either by siRNA or by precipitating antibody reduced PTHrP mRNA expression as effectively as EGFR-targeted inhibition. Using siRNA knockdown or inhibitors to upstream regulators of AREG shedding including TACE, Src/Lck, and G(i/o), also reduced PTHrP mRNA expression. We determined that blockade of autocrine AREG-EGFR signaling does not affect PTHrP mRNA stability. Of the three PTHrP promoters (P1, P2, and P3), P1 mRNA could be reduced by nearly 100% with an EGFR inhibitor, and both epidermal growth factor and AREG stimulated P1 mRNA by approximately 5-fold. Finally, ectopic expression of EGFR in a receptor-low but AREG-expressing cell line increased PTHrP mRNA levels in vitro, and induced the capability to cause HHM and rapid osteolytic growth in vivo. Taken together, we provide evidence that AREG stimulation of EGFR results in high levels of PTHrP gene expression, contributing to cancer-associated bone pathology.