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Multiple primary lung cancer (MPLC) is an increasingly prevalent subtype of lung cancer. According to recent genomic studies, the different lesions of a single MPLC patient exhibit functional similarities that may reflect evolutionary convergence. We perform whole-exome sequencing for a unique cohort of MPLC patients with multiple samples from each lesion found. Using our own and other relevant public data, evolutionary tree reconstruction reveals that cancer driver gene mutations occurred at the early trunk, indicating evolutionary contingency rather than adaptive convergence. Additionally, tumors from the same MPLC patient are as genetically diverse as those from different patients, while within-tumor genetic heterogeneity is significantly lower. Furthermore, the aberrant molecular functions enriched in mutated genes for a sample show a strong overlap with other samples from the same tumor, but not with samples from other tumors or other patients. Overall, there is no evidence of adaptive convergence during the evolution of MPLC. Most importantly, the similar between-tumor diversity and between-patient diversity suggest that personalized therapies may not adequately account for the genetic diversity among different tumors in an MPLC patient. To fully exploit the strategic value of precision medicine, targeted therapies should be designed and delivered on a per-lesion basis., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest to disclose., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Radiation Pneumonitis (RP) is one of the most common and severe complication in patients receiving thoracic radiotherapy. The release of cytokines contribute to activating the RP process. Macrophages also play an important role in the pathogenesis of RP. The differential activation of macrophages is regulated by microRNA (miRNA). Exosomes containing miRNAs are one of the important ways to mediate cellular communication. However, the exosomes mediate communication between tumor cells and macrophages during the pathogenesis of RP remains understudied. In this study, we isolated and characterized the exosomes secreted by lung cancer cells after irradiation. Co-culture of exosomes with macrophages revealed that exosomes could induce macrophage proliferation activation and M2 polarization. miRNA array was used to analyze the differential expression of miRNAs in exosomes, and it was found that miR-4655-5p was stably and highly expressed in exosomes. The function of miR-4655-5p in macrophages was confirmed by overexpression/inhibition of miR-4655-5p expression in macrophages. The targeting association between miR-4655-5p and MID1 was determined by bioinformatics prediction followed by a confirmatory dual luciferase reporter assay. We showed that miR-4655-5p regulate the macrophage proliferation and inflammatory response by forming a negative regulatory loop that alters MID1 activity and its downstream PP2Ac. Overall, our results indicated that exosomal miR-4655-5p secreted by lung cancer cells after irradiation promoted the proliferation and M2 polarization of macrophages. It can be speculated that exosomes play an immunomodulatory role in the pathogenesis of RP and provided a new target for the prevention and treatment of RP., Competing Interests: Conflicts of Interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The purpose of this study was to distinguish pneumonic-type mucinous adenocarcinoma (PTMA) from lobar pneumonia (LP) by pre-treatment CT radiological and clinical or radiological parameters., Methods: A total of 199 patients (patients diagnosed with LP = 138, patients diagnosed with PTMA = 61) were retrospectively evaluated and assigned to either the training cohort ( n = 140) or the validation cohort ( n = 59). Radiomics features were extracted from chest CT plain images. Multivariate logistic regression analysis was conducted to develop a radiomics model and a nomogram model, and their clinical utility was assessed. The performance of the constructed models was assessed with the receiver operating characteristic (ROC) curve and the area under the curve (AUC). The clinical application value of the models was comprehensively evaluated using decision curve analysis (DCA)., Results: The radiomics signature, consisting of 14 selected radiomics features, showed excellent performance in distinguishing between PTMA and LP, with an AUC of 0.90 (95% CI, 0.83-0.96) in the training cohort and 0.88 (95% CI, 0.79-0.97) in the validation cohort. A nomogram model was developed based on the radiomics signature and clinical features. It had a powerful discriminative ability, with the highest AUC values of 0.94 (95% CI, 0.90-0.98) and 0.91 (95% CI, 0.84-0.99) in the training cohort and validation cohort, respectively, which were significantly superior to the clinical model alone. There were no significant differences in calibration curves from Hosmer-Lemeshow tests between training and validation cohorts ( p = 0.183 and p = 0.218), which indicated the good performance of the nomogram model. DCA indicated that the nomogram model exhibited better performance than the clinical model., Conclusions: The nomogram model based on radiomics signatures of CT images and clinical risk factors could help to differentiate PTMA from LP, which can provide appropriate therapy decision support for clinicians, especially in situations where differential diagnosis is difficult., Competing Interests: Author J-TZ was employed by GE Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ji, Liu, Chen, Gu, Chen, Guo, Ning, Zhang and Li.)

Background: Immune-checkpoint inhibitors (ICIs) remain ineffective in a large group of non-small cell lung cancer (NSCLC) patients. Mucosal-associated invariant T (MAIT) cells, a population of unconventional innate-like T lymphocytes abundant in the human body, play important roles in human malignancies. Little is known about the immune characteristics of MAIT cells in NSCLC and correlation with prognosis and response rate of ICIs treatment., Methods: To investigate the distribution, activation status, and function of MAIT cells in NSCLC patients and their correlations with anti-PD-1 immunotherapy, MAIT cells in peripheral blood, tumor and paratumor samples from NSCLC patients with or without anti-PD-1 immunotherapy were analyzed using flow cytometry and single-cell RNA-sequencing., Results: MAIT cells were enriched in the tumor lesions of NSCLC patients migrating from peripheral blood via the CCR6-CCL20 axis. Both peripheral and tumor-infiltrating MAIT cells displayed an exhausted phenotype with upregulated PD-1, TIM-3, and IL-17A while less IFN-γ. Anti-PD-1 therapy reversed the function of circulating MAIT cells with higher expression of IFN-γ and granzyme B. Subcluster MAIT-17s (defined as cells highly expressing exhausted and Th17-related genes) mainly infiltrated in the non-responsive tissues, while the subcluster MAIT-IFNGRs (cells expressing genes related to cytotoxic function) were mainly enriched in responsive tissues. Moreover, we found predictive value of circulating MAIT cells for anti-PD-1 immunotherapy in NSCLC patients., Conclusions: MAIT cells shifted to an exhausted tumor-promoting phenotype in NSCLC patients and the circulating MAIT subset could be a predictor for patients who respond to anti-PD-1 immunotherapy., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Synchronous multiple primary lung cancers associated with small non-dominant nodules are commonly encountered. However, the incidence, follow-up, and treatment of small non-dominant tumors have been but little studied. We explored the prevalence and management of small non-dominant tumors and factors associated with interval growth., Methods: This observational, consecutive, retrospective single-center study enrolled patients diagnosed with synchronous multiple primary lung cancers and small non-dominant tumors (≤ 6 mm in diameter) who underwent resection of the dominant tumor. The incidence, follow-up, and management of small non-dominant tumors and predictors of nodule growth were analyzed., Results: There were 88 patients (12% of all lung cancer patients) with pathological diagnoses of synchronous multiple primary lung cancers. A total of 131 (18%) patients were clinically diagnosed with at least one small (≤ 6 mm in diameter) multiple primary lung cancer non-dominant tumor. 94 patients with 125 small-nodule non-dominant tumors clinically diagnosed as multiple primary lung cancers were followed-up for at least 6 months. A total of 29 (29/125, 23.2%) evidenced small pulmonary nodules (≤ 6 mm in diameter) that exhibited interval growth on follow-up computed tomography (CT). On multivariate analysis, a part-solid nodule (compared to a pGGN) (OR 1.23; 95% CI 1.08-1.40) or a solid nodule (compared to a pGGN) (OR 3.50; 95% CI 1.94-6.30) predicted small nodule interval growth., Conclusion: We found a relatively high incidence of multiple primary lung cancers with small non-dominant tumors exhibiting interval growth on follow-up CT, suggesting that resection of non-dominant tumors at the time of dominant tumor resection, especially when the nodules are part-solid or solid, is the optimal treatment., (© 2022. The Author(s).)

Objectives: Uniportal video-assisted thoracoscopic surgery (UniVATS) is widely used as a minimally invasive thoracic operation. The goal of our study was to analyse the effect of long-term experience with the UniVATS lobectomy on the learning curve., Methods: The learning curves were quantitatively evaluated by the unadjusted cumulative sum, and they were segmented using joinpoint linear regression analysis. The variables were compared between subgroups using trend analysis, and linear regression analysis was applied to correlate clinical characteristics at different stages of the learning curve with the duration of the operation., Results: The learning curve for the UniVATS lobectomy can be divided into 3 phases of proficiency at ∼200-300 procedures, with a fourth phase as the number of procedures increases. The 1st-52nd, 52nd-156th, 156th-244th and 244th-538th procedures comprised the preliminary learning stage, preliminary proficiency stage, proficiency stage and advanced proficiency stage, respectively. Surgical outcomes and their variability between stages improved with increasing case numbers, with the most significant addition of an auxiliary operating port and conversions. In multivariable analysis, as stages progressed, influences other than surgical experience increased the operative time, with male and extensive pleural adhesions in the preliminary proficiency stage; male and incomplete pulmonary fissures in the proficiency stage; and male, extensive pleural adhesions and incomplete pulmonary fissures in the advanced proficiency stage., Conclusions: As the number of procedures increases, there may be 4 different proficiency stages in the UniVATS lobectomy learning curve. The surgeon enters the fourth stage at approximately the 244th procedure. Moreover, at stage 4, the perioperative indicators tend to stabilize, and influences other than surgical experience become more significant., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD3) is a crucial oncogene in human lung cancer, whereas protein kinase C δ (PKCδ) acts as a tumor suppressor. In this study, we aimed to explore the regulation by PLOD3 on the expression of YAP1 to affect the progression of non-small cell lung cancer (NSCLC) via the PKCδ/CDK1/LIMD1 signaling pathway. We found that PLOD3, CDK1, and YAP1 were highly expressed, while LIMD1 was poorly expressed in NSCLC tissues. Mechanistic investigation demonstrated that silencing PLOD3 promoted the cleavage of PKCδ in a caspase-dependent manner to generate a catalytically active fragment cleaved PKCδ, enhanced phosphorylation levels of CDK1, and LIMD1 but suppressed nuclear translocation of YAP1. Furthermore, functional experimental results suggested that loss of PLOD3 led to increased phosphorylation levels of CDK1 and LIMD1 and downregulated YAP1, thereby suppressing the proliferation, colony formation, cell cycle entry, and resistance to apoptosis of NSCLC cells in vitro and inhibiting tumor growth in vivo. Taken together, these results show that PLOD3 silencing activates the PKCδ/CDK1/LIMD1 signaling pathway to prevent the progression of NSCLC, thus providing novel insight into molecular targets for treating NSCLC., (© 2022. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.)

Purpose: Currently, formalin-fixed paraffin-embedded (FFPE) tissue specimens are the conventional material for gene testing for non-small cell lung cancer (NSCLC) patients. In our study, we aimed to develop a quick gene testing procedure using fresh core needle biopsy samples from NSCLC patients. Methods: In total, 77 fresh NSCLC samples obtained from core needle biopsy were evaluated by frozen section examination. If the NSCLC diagnosis and adequate tumor cell counts were confirmed by histopathology, the fresh tissues were used to extract DNA and subsequent gene testing by ARMS-PCR. Meanwhile, the paired FFPE core needle biopsy samples from 30 NSCLC patients also underwent gene testing. Results: In total, 77 fresh samples showed an EGFR mutation rate of 61.0%, higher than the levels in the Asian. Following a comparison of gene testing results with fresh tissues and paired FFPE tissues from the 30 patients, no significant difference in the DNA concentration extracted from fresh tissues and FFPE tissues was found. However, DNA purity was significantly higher in fresh tissues than that in FFPE tissues. Gene testing detected the same gene mutations in 93.3% of cases in fresh tissues and paired FFPE tissues. The gene testing procedure using fresh biopsy samples greatly shortens the waiting time of patients. Conclusion: The multi-gene mutation testing using fresh core needle biopsy samples from NSCLC patients is a reasonable, achievable, and quick approach. Fresh tissues may serve as a potential alternative to FFPE tissues for gene testing in NSCLC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yao, Wei, Cheng, Huang, Zong, Meng, Li, Han, Xu, Wang, Jing, Li, Cao, Ni, Sun, Yang and Ye.)

Objective: To investigate the differences in efficacy between drug-eluting beads transbronchial arterial chemoembolization (DEB-BACE) combined with systemic chemotherapy and systemic chemotherapy alone for unresectable lung squamous cell carcinoma. Methods: Totally 60 cases of unresectable lung squamous cell carcinoma undergoing systemic chemotherapy in Yancheng Third People Hospital were retrospectively selected as the research object. According to patients' wishes, they were divided into chemotherapy-only group (group A) and combined treatment group (group B). Group A received gemcitabine combined with cisplatin chemotherapy. DEB-BACE was applied in the first half, and systemic chemotherapy was administered in the second half (starting 3 d after BACE). The first half and the second half of the chemotherapy dose were 1/2 of the drug dose in the chemotherapy alone group. The short-term efficacy, incidence of toxic side effects, peripheral blood T lymphocyte subsets, serum vascular endothelial growth factor (VEGF) levels, and survival time were compared between the two groups. Results: After 2 cycles of treatment, the total effective rates of group A and group B were 50.0% (15/30) and 76.7% (23/30) ( P< 0.05), the incidence of nausea and vomiting (63.3% vs 20.0%), decreased appetite (76.7% vs 43.3%), hair loss (86.7% vs 40.0%), and bone marrow suppression (40.0% vs 10.0%) in group A were higher than in group B (all P< 0.05). After 2 cycles of treatment, the levels of CD3(+), CD4(+)and CD4(+)/CD8(+)in the two groups were higher than before treatment (group A: 47.7%±6.6% vs 52.3%±7.7%, 31.5%±4.9% vs 34.7%±5.8%, 1.05±0.24 vs 1.18±0.32; group B: 49.2%±7.0% vs 62.0%±14.0%,29.2%±5.5% vs 42.2%±7.3%, 1.07±0.26 vs 1.39±0.42; all P< 0.05), while the level of CD8(+)was lower than before treatment (group A: 30.4%±5.4% vs 24.5%±4.8%; group B: 29.5%±4.1% vs 21.1%±4.5%; all P< 0.05). The CD3(+), CD4(+), and CD4(+)/CD8(+) levels in group A were lower than those in group B ( P< 0.05), while CD8(+)level was higher than in group B ( P< 0.05). After 2 cycles of treatment, the VEGF levels in the two groups were lower than before treatment (group A: (423±85) vs (352±64) ng/L; group B: (404±114) vs (296±66) ng/L; P< 0.05), and the VEGF level in group A was higher than that in group B ( P< 0.05). The 1-year survival rates of groups A and B were 54.9% and 77.9%, and the 2-year survival rates were 17.2% and 41.7% (Log rank χ(2)=4.750, P= 0.029). Conclusion: DEB-BACE combined with systemic chemotherapy is superior to systemic chemotherapy in the treatment of unresectable lung squamous cell carcinoma. It can reduce toxic and side effects, improve immune function and prolong survival time, which is worthy of clinical application.

Objective: To identify imaging markers that reflect the epidermal growth factor receptor (EGFR) mutation status by comparing computed tomography (CT) imaging-based histogram features between bone metastases with and without EGFR mutation in patients with primary lung adenocarcinoma., Materials and Methods: This retrospective study included 57 patients, with pathologically confirmed bone metastasis of primary lung adenocarcinoma. EGFR mutation status of bone metastases was confirmed by gene detection. The CT imaging of the metastatic bone lesions which were obtained between June 2014 and December 2017 were collected and analyzed. A total of 42 CT imaging-based histogram features were automatically extracted. Feature selection was conducted using Student's t-test, Mann-Whitney U test, single-factor logistic regression analysis and Spearman correlation analysis. A receiver operating characteristic (ROC) curve was plotted to compare the effectiveness of features in distinguishing between EGFR(+) and EGFR(-) groups. DeLong's test was used to analyze the differences between the area under the curve (AUC) values., Results: Three histogram features, namely range, skewness, and quantile 0.975 were significantly associated with EGFR mutation status. After combining these three features and combining range and skewness, we obtained the same AUC values, sensitivity and specificity. Meanwhile, the highest AUC value was achieved (AUC 0.783), which also had a higher sensitivity (0.708) and specificity (0.788). The differences between AUC values of the three features and their various combinations were statistically insignificant., Conclusion: CT imaging-based histogram features of bone metastases with and without EGFR mutation in patients with primary lung adenocarcinoma were identified, and they may contribute to diagnosis and prediction of EGFR mutation status.

This study evaluated the efficacy and toxicity of erlotinib and celecoxib (EC) for treating Chinese patients with advanced non-small cell lung cancer (ANSCLC) and epidermal growth factor receptor (EGFR) wild type.Totally, 75 subjects with ANSCLC and EGFR wild type were included. They all underwent EC treatment. The outcome measurements consisted of progression-free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), stable disease (SD), progress disease (PD), and disease control rate (DCR). Additionally, adverse events were also documented.Two-year CR, PR, SD, PD, and DCR were 4.0%, 6.7%, 42.6%, 46.7%, and 53.3% respectively. The median PFS was 3.4 months, the median OS was 10.0 months. Additionally, acceptable toxicities were recorded in this study.The results showed that EC may be efficacious for patients with ANSCLC and EGFR wild type only, and acceptable toxicity among the Chinese Han population.

Purpose: To better understand the gene mutational status and heterogeneity between primary and metastatic CRC (mCRC) using a sensitive sequencing method., Methods: The mutational status of EGFR, KRAS, NRAS, PIK3CA, ERBB2, BRAF, KIT, and PDGFRA was analyzed in 65 patients, with 147 samples of primary and paired live or lung metastatic CRC, using next-generation sequencing (NGS), quantitative RT-PCR (qPCR), and Sanger sequencing., Results: Fifteen cases (15/22, 68.2%) of lung mCRC and thirteen cases (13/20, 65%) of liver mCRC harboured the same mutation profiles of KRAS, NRAS, or BRAF in the primary lesions. To all detected genes, 11 cases (11/22, 50%) of lung mCRC and 11 cases (11/20, 55%) of liver mCRC showed different mutational genes in the primary tumours. KRAS and BRAF mutations were more frequent in lung metastatic lesions (p = 0.004 and 0.003, respectively). The gene mutations in KRAS, NRAS, BRAF, and PIK3CA in the lung metastatic sites were more frequent than those in the liver metastatic sites (86.7 vs. 44%, respectively, p = 0.000). Some new mutations were not covered in the qPCR ranges but were detected by NGS., Conclusion: The study demonstrated that the discordance of gene mutational status between paired primary and metastatic tumours is rather high when detected by NGS. Evaluating the mutational status of both the primary and metastatic tumours should be considered in clinical mutation testing.

Background: Non-small-cell lung cancer (NSCLC) is characterized by abnormalities of numerous signaling proteins that play pivotal roles in cancer development and progression. Many of these proteins have been reported to be correlated with clinical outcomes of NSCLC. However, none of them could provide adequate accuracy of prognosis prediction in clinical application., Methods: A total of 384 resected NSCLC specimens from two hospitals in Beijing (BJ) and Chongqing (CQ) were collected. Using immunohistochemistry (IHC) staining on stored formalin-fixed paraffin-embedded (FFPE) surgical samples, we examined the expression levels of 75 critical proteins on BJ samples. Random forest algorithm (RFA) and support vector machines (SVM) computation were applied to identify protein signatures on 2/3 randomly assigned BJ samples. The identified signatures were tested on the remaining BJ samples, and were further validated with CQ independent cohort., Results: A 6-protein signature for adenocarcinoma (ADC) and a 5-protein signature for squamous cell carcinoma (SCC) were identified from training sets and tested in testing sets. In independent validation with CQ cohort, patients can also be divided into high- and low-risk groups with significantly different median overall survivals by Kaplan-Meier analysis, both in ADC (31 months vs. 87 months, HR 2.81; P <  0.001) and SCC patients (27 months vs. not reached, HR 9.97; P <  0.001). Cox regression analysis showed that both signatures are independent prognostic indicators and outperformed TNM staging (ADC: adjusted HR 3.07 vs. 2.43, SCC: adjusted HR 7.84 vs. 2.24). Particularly, we found that only the ADC patients in high-risk group significantly benefited from adjuvant chemotherapy (P = 0.018)., Conclusions: Both ADC and SCC protein signatures could effectively stratify the prognosis of NSCLC patients, and may support patient selection for adjuvant chemotherapy.

Objective: To determine whether the specific genotype of exon 19 deletion has a better survival outcome than that of exon 21 substitution in advanced lung adenocarcinoma with EGFR mutant patients that were treated with EGFR-TKIs as second-line therapy after first-line chemotherapy., Methods: Between April 1, 2010 and December 31, 2012, the detailed clinical information of 128 patients was screened from the hospital information database of the First Affiliated Hospital and the Third Affiliated Hospital of Kunming Medical University by inclusion/exclusion criteria. Then, a telephone follow-up and a review of all patients' image data were done to obtain the survival information of all patients. After that, all patients' data were processed by IBM(®) SPSS(®) version 19.0., Results: There were correlations between EGFR mutation status, gross tumor type and PFS or OS according to the Kaplan-Meier survival analyses and log-rank tests. The exon 19 deletions had significantly better survival outcomes in comparison to exon 21 substitutions (median PFS: 8.1 vs. 6.8 months, P = 0.002; median OS: 17.6 vs. 12.5 months, P = 0.000). Stratification analyses of PFS and OS revealed that exon 19 deletions had a survival superior to exon 21 substitutions., Conclusion: Compared with L858R mutation, the genotype of exon 19 deletion had a better survival outcome in terms of PFS and OS in patients with advanced lung adenocarcinoma treated with EGFR-TKIs as second-line therapy after first-line chemotherapy.

HoxB7 is involved in cell migration and metastasis in many malignant tumors. But, the role of HoxB7 in lung adenocarcinoma has not been elucidated. In the present study, we aimed to clarify the function of HoxB7 in the progression of lung adenocarcinoma. The protein expression of HoxB7 was examined by immunohistochemical assay in human lung adenocarcinoma tissues, and lentivirus-mediated HoxB7 shRNA (Lv-shHoxB7) was transfected into lung adenocarcinoma cells to evaluate cell proliferation and invasive potential indicated by MTT and Transwell assays. As a result, the protein expression level of HoxB7 was increased in lung adenocarcinoma tissues compared with the adjacent non-tumor tissues (56.25% vs 31.25%, P=0.014), and was positively correlated with the lymph node metastasis in patients with lung adenocarcinoma (P=0.036). Moreover, knockdown of HoxB7 decreased the proliferation and invasion of lung adenocarcinoma cells followed by decreased expression of TGF-β/SMAD3, vascular endothelial growth factor A (VEGFA) and matrix metalloproteinase-2 (MMP-2). Taken together, our findings demonstrate that increased expression of HoxB7 is associated with tumor metastasis in patients with lung adenocarcinoma and HoxB7 may be implicated in promoting the development of lung adenocarcinoma through activation of the TGF-β/SMAD3 signaling.

Increased expression of pituitary tumor-transforming gene 1 (PTTG1) is expressed in many tumors and regulates tumor growth and progression. However, the precise function of PTTG1 in the tumorigenesis of lung adenocarcinoma (LAC) is not defined yet. Here, we examined the expression of PTTG1 in human LAC tissues by immunohistochemical assay using a tissue microarray procedure. A loss-of-function experiment was carried out to investigate the effects of lentiviral vector-mediated PTTG1 shRNA (shPTTG1) on cell growth and invasive potential in LAC cell lines (A549 and LETPα-2), assessed by MTT and Transwell assays. As a consequence, we found that the expression of PTTG1 protein was markedly upregulated in LAC tissues compared with the adjacent non-cancerous tissues (ANCT) (54.0% vs. 28.0%, P = 0.008), and was positively associated with the lymphatic invasion of the tumor (P = 0.01). Moreover, knockdown of PTTG1 expression inhibited tumor proliferation and invasion of LAC cells, companied by the decreased expression of CyclinD1 and MMP-2 and increased expression of p-TGFβ1 and p-SMAD3. Collectively, our findings indicate that high expression of PTTG1 is correlated with the tumor metastasis of LAC patients, and knockdown of PTTG1 suppresses the growth and invasion of LAC cells through upregulation of the TGFβ1/SMAD3 signaling, suggesting that PTTG1 may be a potential target for developing an effective immunotherapeutic strategy for LAC., (© The Author(s) 2015.)

Skin metastasis from internal organ malignancy has a 5% to about 10% incidence, and zosteriform metastasis is much rarer. We present the case of a 51-year-old male smoker initially given a diagnosis of right lower lung adenocarcinoma T2N3M0 who developed new-onset zosteriform skin metastasis over the right-side T3∼T5 dermatomes documented by skin biopsy specimen. The probable mechanism for this band-distributed skin metastasis is the retrograde flow of lymph after obstruction by cancer cells. Such a phenomenon may be demonstrated by lymphoscintigraphy.

Cancer patients frequently develop autoantibodies. To test the hypothesis that the appearance of autoantibodies precedes the clinical diagnosis of cancer, we applied an immunoproteomic approach to compare autoantibody profiles before and after appearance of malignances. Proteins from A549 cells, a lung adenocarcinoma cell line, were separated by two dimensional electrophoresis and then immunoblotted with serum samples from 8 individuals who were eventually diagnosed with lung cancer. Compared with autoantibody profiles from 3 years prior to the appearance of malignances, 21 immunoreactive spots newly appeared or presented with stronger staining intensity when clinical diagnoses were made. Among them, 10 matched spots on 2-DE gels were identified by mass spectrometry analysis as 5 proteins. With immunoprecipitation analysis, the antigenicity of protein cathepsin D was confirmed, and notably, in lung cancer sera, the occurrences of autoantibodies against the specific forms of cathepsin D differed significantly from the control groups (p<0.05). Our findings suggest that harnessing immunity may have utility for early cancer marker discovery, and that comparing autoantibodies to specific forms of cathepsin D may be a promising early marker of lung cancer., (Copyright © 2012. Published by Elsevier Inc.)

Exposures to carcinogenic polycyclic aromatic hydrocarbons (PAHs) have been linked to human lung cancer. The purpose of this study was to assess lung cancer risk caused by inhalation exposure to nano/ultrafine particle-bound PAHs at the population level in Taiwan appraised with recent published data. A human respiratory tract model was linked with a physiologically based pharmacokinetic model to estimate deposition fraction and internal organic-specific PAHs doses. A probabilistic risk assessment framework was developed to estimate potential lung cancer risk. We reanalyzed particle size distribution, total-PAHs, particle-bound benzo(a)pyrene (B[a]P) and PM concentrations. A dose-response profile describing the relationships between external B[a]P concentration and lung cancer risk response was constructed based on population attributable fraction (PAF). We found that 90% probability lung cancer risks ranged from 10(-5) to 10(-4) for traffic-related nano and ultrafine particle-bound PAHs, indicating a potential lung cancer risk. The particle size-specific PAF-based excess annual lung cancer incidence rate due to PAHs exposure was estimated to be less than 1 per 100,000 population, indicating a mild risk factor for lung cancer. We concluded that probabilistic risk assessment linked PAF for limiting cumulative PAHs emissions to reduce lung cancer risk plays a prominent role in future government risk assessment program., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Activating mutations in Ras proteins are present in about 30% of human cancers. Despite tremendous progress in the study of Ras oncogenes, many aspects of the molecular mechanisms underlying Ras-induced tumorigenesis remain unknown. Through proteomics analysis, we previously found that the protein Gankyrin, a known oncoprotein in hepatocellular carcinoma, was upregulated during Ras-mediated transformation, although the functional consequences of this were not clear. Here we present evidence that Gankyrin plays an essential role in Ras-initiated tumorigenesis in mouse and human cells. We found that the increased Gankyrin present following Ras activation increased the interaction between the RhoA GTPase and its GDP dissociation inhibitor RhoGDI, which resulted in inhibition of the RhoA effector kinase Rho-associated coiled coil-containing protein kinase (ROCK). Importantly, Gankyrin-mediated ROCK inhibition led to prolonged Akt activation, a critical step in activated Ras-induced transformation and tumorigenesis. In addition, we found that Gankyrin is highly expressed in human lung cancers that have Ras mutations and that increased Gankyrin expression is required for the constitutive activation of Akt and tumorigenesis in these lung cancers. Our findings suggest that Gankyrin is a key regulator of Ras-mediated activation of Akt through inhibition of the downstream RhoA/ROCK pathway and thus plays an essential role in Ras-induced tumorigenesis.

Thirty-two cases of so-called sclerosing hemangioma of the lung observed by light microscopy were further studied by electron microscopy and/or immunohistochemistry. Three histologic patterns were seen: hemangioma-like, papillary, and solid. The only significant component representing the nature of the lesion is characteristic round cells within the stroma in all these patterns, whereas the surface cells lining the papillary projections or cystic spaces are normal or are hyperplastic bronchioloalveolar cells with a few neuroendocrine cells. Immunohistochemical findings showed that the "stromal cells" (tumor cells) were positive for neuroendocrine markers, namely, chromogranin A (19 of 22 cases), neuron-specific enolase (24 of 24), synaptophysin (six of 10), adrenocorticotropic hormone (14 of 15), growth hormone (14 of 15), calcitonin (11 of 15), and gastrin (11 of 14). Besides, some tumor cells were positive for epithelial membrane antigen (four of four), carcinoembryonic antigen (one of four), and vimentin (one of one). All tumor cells were negative for polyclonal antikeratin antibody (25 cases), AE1 (one case), and AE3 (one case). However, in contrast to the "stromal cells," the surface cells of the cystic spaces stained positively for keratin (25 of 25 cases), AE1 (one of one), AE3 (one of one), epithelial membrance antigen (four of four), and carcinoembryonic antigen (four of four); only a few of them expressed neruoendocrine markers. Both surface and tumor cells were negative for factor VIII-related antigen (25 cases), CD31 (one case), and alpha1-antitrypsin (25 cases). Ten cases further studied by electron microscopy and six examined by ultrastructural morphometry showed that the surface cells were mainly type 2 pneumocytes containing many lamellar bodies in the cytoplasm. Lying among them, neuroendocrine cells were occasionally seen. The stromal tumor cells had no lamellar body, but dense core granules (neurosecretory granules) and microtubules. In six cases, 92.3% (345 of 374) of tumor cells contained neurosecretory granules, which were pleomorphic and 73 to 1056 nm in diameter (mean, 302 nm). Two to 193 (mean, 12) neurosecretory granules were found in each tumor cell. Both immunohistochemical findings and ultrastructural evidence indicate that so-called sclerosing hemangioma of the lung is a benign lesion composed of neoplastic neuroendocrine cells with areas of sclerosis. A suggested name for this tumor is benign neuroendocrine tumor of the lung. The differentiation between this tumor and papillary adenoma, bronchioloalveolar carcinoma, or carcinoid tumor of the lung is discussed.

31 cases of the so-called sclerosing hemangiomas of the lung were studied by light microscope, immunohistochemical and electron microscopy. This tumor is benign and has 3 histologic patterns: papillary, hemangioma-like and solid type. Characteristic morphology being uniform round tumor cells, lying within the stroma in different patterns and regarded as the major component of sclerosing hemangioma, expressing neuroendocrine markers which include chromagranin A, neuron-specific enolase, ACTH, growth hormone, calcitonin and gastrin. Only a few tumor cells were positive for epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA), all the tumor cells were negative for keratin (Polyclonal, Z622) stain. However, in contrast to the round tumor cells, the cells lining papillary projections or cystic spaces, which presented as normal or hyperplastic alveolar cells, stained positive for keratin, EMA and CEA but negative for neuroendocrine markers. Both the surface cells and tumor cells were negative for Factor VIII-related antigen and alpha 1-AT. Therefore, pulmonary sclerosing hemangioma was regarded to be a benign tumor originating from the neuroendocrine cells of the lung and we suggest that it be renamed as benign neuroendocrine tumor of the lung (LBNET). This viewpoint has not been previously reported in the literature.

30 cases of resected pulmonary neuroendocrine carcinoma (NEC) collected from September 1983 to February 1992 were confirmed by microscopy, electron microscopy and immunohistochemical observations. Of the 30 cases, 8 were typical carcinoid (TC), 15 atypical carcinoid (AC), 5 small cell lung carcinoma (SCLC) and 2 cases of giant cell neuroendocrine carcinoma (LCNEC), which have never been reported in the literature. This series of pulmonary NEC exhibited their specific morphology under light microscope. Electron microscopic examination found the common feature of neuroendocrine granules in the cytoplasm of carcinoma cells. Immunohistochemical studies with neuroendocrine cell markers for NEC gave positive results. The morphological features and differential diagnosis of the various NEC under light microscope and electron microscope were compared and are discussed. Complimental devise to the classification of NECs of the lung is suggested.

For the purpose of providing more accurate histological typing of lung carcinoma, it is necessary to classify carcinomas of the lung by electron microscopy. One hundred and fifty cases of resected lung carcinoma were examined under electron microscope. The results of ultrastructural typing of lung carcinoma were as follows: 1. carcinomas showed differentiated features of glandular and squamous epithelium, including squamous cell carcinoma (28 cases), adenocarcinoma (35 cases), and adenosquamous carcinoma (29 cases). Among them, some cases were associated with neuroendocrine differentiation. In addition, solid mucinous cell carcinoma (4 cases) and adenoid cystic carcinoma (2 cases) were seen. 2. Carcinomas showed differentiated features of bronchioloalveolar epithelium, subdividing into clara cell (9 cases), type II pneumocyte (3 cases), mucinous cell (5 cases) and mixed type (4 cases). 3. Carcinomas showed differentiated features of neuroendocrine cell (Kulchitsky cell), including well differentiated (carcinoid, 13 cases), intermediately differentiated (atypical carcinoid, 12 cases), and poorly differentiated (small cell carcinoma, 6 cases). Among them, some cases were associated with squamous differentiation. The ultrastructural classification was compared with histological classification of lung carcinomas and the differences between them are discussed.

Human lung giant cell carcinoma cell strains were implanted into the lungs of nude mice via an intrabronchial procedure. Tumorigenicity, invasion and metastasis of the xenografts, and their morphological features, including the findings by light and electronic microscopy and immunohistochemistry were investigated. Dissemination of xenografts within the airway (2/8), invasion to diaphragm (5/8), and development of bloody hydrothorax (5/8), were discovered. Metastasis via lymphatic and blood vessel routes as well as seeding metastasis occurred in all the tumor-bearing animals. The morphological features of xenografts were consistent with those of the parental giant cell carcinoma. These results indicate that lung cancer cell strains grow autonomously and the behavior of invasion and metastasis of the xenografts imitates more closely the clinical manifestation of lung cancer than their subcutaneous counterparts. Since microenvironment influences the biological behavior of the transplants, this model seemed to be more ideal for further investigation experimentally.

Thirteen cases (10.5%) of squamous cell carcinoma of the lung with neuroendocrine differentiation were identified ultrastructurally in 124 cases of resected pulmonary carcinoma. In addition to the features of epidermoid differentiation, i.e. presence of tonofilaments and desmosones, a small amount of cancer cells containing neurosecretory granules were found in all the 13 cases. Ultrastructures indicated that both epidermoid and neuroendocrine differentiations were present simultaneously in individual cancer cell. Immunohistochemical staining for NSE was performed in 12 cases. Positive reaction was obtained in all but one (91.7%). NSE positive cancer cells distributed focally or in single cell scattered in the cancer cell nests. The results suggest that biphasic differentiation of pulmonary squamous cell carcinoma diagnosed by light microscopy may not originate from different cells of different derms, but may be derived from a common stem cell of the bronchial epithelium which possesses the ability of multipotential differentiation.

Twenty-two cases of neuroendocrine tumor comprising neurosecretory granules were identified ultrastructurally in 124 cases of resected pulmonary carcinoma. Among these, 10 cases of atypical carcinoid of the lung were examined by LM, EM and immunohistochemical staining for NSE. The diagnosis of atypical carcinoid is difficult by LM alone. Therefore light microscopic observation is required in combination with electron microscopic findings for obtaining an accurate diagnosis of atypical carcinoid of the lung. Based on the data observed in these 10 cases, the diagnostic criteria of atypical carcinoid of lung are as follows: Microscopically: Increased cellularity with organoid architecture and rosette formation. Patchy necrosis at the center of cancer nests. Pleomorphism and irregularity of nuclei with hyperchromatism. Presence of abundant mitotic figures. NSE is positive immunohistochemically. Ultrastructurally: Various amount of neurosecretory granules found in cancer cells. Rich organelles, such as mitochondria, RER and ribosomes found in cytoplasm. Presence of basal lamina and desmosomes.