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Background: Smoking participates in pathogenesis of lung cancer. Long non-coding RNAs (lncRNAs) play some specific roles during development of lung cancers. Objective: To investigate effects of smoking on lncRNA alterations in lung cancer. Methods: There are 522 lung adenocarcinoma (LUAD) and 504 lung squamous cell carcinoma (LUSC) participants. Clinical and lncRNA genetic data were downloaded from The Cancer Genome Atlas (TCGA) database. LncRNA alterations were analyzed in lung cancer patients. Smoking category and packs were evaluated. Correlations between smoking and LncRNA alterations were analyzed. Kaplan-Meier analysis was performed to determine overall survival and disease free survival. Results: There are more non-smokers in LUSC than in LUAD. In both LUAD and LUSC, smoking could increase total mutation counts and fraction of copy number alterations. Smoking index positively correlated with total mutations in LUAD, but not in LUSC. Smoking could trigger lncRNA alterations both in LUAD and LUSC. Smoking regulated different lncRNA between male and female. EXOC3-AS1 and LINC00603 alterations were positively correlated with smoking index in male LUAD smokers. In female LUAD smokers, smoking index was positively correlated with SNHG15, TP53TG1 and LINC01600 and negatively with LINC00609 and PTCSC3. In both male and female LUSC patients, smoking increased or decreased several lncRNA alterations. DGCR5 alteration increased in male LUSC than in female LUSC patients. In female LUSC patients, LOH12CR2 alteration was positively correlated with smoking index. Conclusions: Smoking promoted LUAD and LUSC development by affecting different lncRNA alterations in different genders.

Background Lipusu is the first commercialized liposomal formulation of paclitaxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma (LSCC) in a small‐scale study. Here, we conducted a multicenter, randomized, phase 3 study to compare the efficacy and safety of cisplatin plus Lipusu (LP) versus cisplatin plus gemcitabine (GP) as first‐line treatment in locally advanced or metastatic LSCC. Methods Patients enrolled were aged between 18 to 75 years, had locally advanced (clinical stage IIIB, ineligible for concurrent chemoradiation or surgery) or metastatic (Stage IV) LSCC, had no previous systemic chemotherapy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors (version 1.1) before administration of the trial drug. The primary endpoint was progression‐free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles. To explore the possible predictive value of plasma cytokines for LP treatment, plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45‐Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology. The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses. Results The median duration of follow‐up was 15.4 months. 237 patients in the LP group and 253 patients in the GP group were included in the per protocol set (PPS). In the PPS, the median PFS was 5.2 months versus 5.5 months in the LP and GP group (hazard ratio [HR]: 1.03, P = 0.742) respectively. The median OS was 14.6 months versus 12.5 months in the LP and GP group (HR: 0.83, P = 0.215). The ORR (41.8% versus 45.9%, P = 0.412) and DCR (90.3% versus 88.1%, P = 0.443) were also similar between the LP and GP group. A significantly lower proportion of patients in the LP group experienced adverse events (AEs) leading to treatment interruptions (10.9% versus 26.4%, P < 0.001) or treatment termination (14.3% versus 23.1%, P = 0.011). The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR, and 15 cytokines were associated with improved PFS, with 14 cytokines, including TNF‐α, IFN‐γ, IL‐6, and IL‐8, demonstrating an overlapping trend. Conclusion The LP regimen demonstrated similar PFS, OS, ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles. The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen., Cisplatin plus Lipusu (LP) regimen has comparable efficacy and more favorable toxicity profiles compared with cisplatin plus gemcitabine (GP) regimen for patients with advanced LSCC. The study also demonstrated that LP had a significant impact on the levels of plasma cytokines and a spectrum of cytokines were associated with clinical benefit in patients who received LP. Thus, our results provided a new option for patients with advanced LSCC.

Background: At present, only a small fraction of patients with cancer benefit from treatment with immune checkpoint inhibitors, the reasons for which are not fully understood. Monitoring molecular and immunologic changes during treatment with immune checkpoint inhibitors would help to identify potential biomarkers and mechanisms associated with resistance and guide subsequent treatment. Methods: The authors report on a patient previously treated for lung squamous cell carcinoma who received atezolizumab-based therapy for 24 months. Results & Conclusion: Analysis of samples before and after atezolizumab treatment suggested that genetic mutations in EGFR exon 20 insertion, phosphatase and PTEN and NOTCH1 as well as changes in tumor immune microenvironment may be associated with acquired resistance to immune checkpoint inhibitor therapy.

EML4-ALK rearrangement is common in lung adenocarcinoma. The ALK inhibitors remarkably inhibit lung adenocarcinoma and reveal long-term beneficial effects in several patients. Advanced genetic testing technology reveals that EML4-ALK rearrangement has been observed in patients with lung squamous cell carcinoma. In the present study, we report a case of a 53-year-old patient with EML4-ALK rearranged in lung squamous carcinoma; PET/CT scan revealed brain and multiple bone metastases. First-line ALK-TKI combined with local stereotactic body radiation therapy indicated progression-free survival of 9 months. After progressive disease, treatment was switched to lorlatinib, with little efficacy and a total overall survival of 11 months. The emergence of drug resistance revealed that the genetic test result was EML4-ALK fusion (V3a/b variants), indicating a poor prognosis. In this study, we analyzed the treatment efficacy of ALK inhibitors and provided a research basis for the treatment of EML4-ALK rearranged in lung squamous cell carcinoma patients.

The definitive efficacy of anaplastic lymphoma kinase (ALK) inhibitors in ALK positive lung squamous cell carcinoma (sqCC) patients remain unclear. Here, we report a case in which brigatinib had a therapeutic effect on ALK‐positive lung squamous cell carcinoma. The patient in this report was diagnosed with ALK‐positive lung squamous cell carcinoma with brain metastases, and received brigatinib after failure of first‐line chemotherapy. Response duration was approximately 11 months, with tolerable side effects. In conclusion, a good clinical effect was achieved in a patient with ALK positive lung squamous cell carcinoma who received treatment with an ALK inhibitor., Our case was first report to determine the excellent antitumor effect of Brigatinib on ALK positive lung SqCC. PFS was more than 11 months, and the side effects were tolerable.

Background So far, few have concerned miR-497-5p in lung squamous cell carcinoma (LUSC). Methods MiR-497-5p expression in LUSC was measured by qRT-PCR. Its impacts on tumor-related cell behaviors were investigated by CCK8 assay, scratch healing assay, flow cytometry and Transwell invasion methods. In addition, interaction between miR-497-5p and CDCA4 in LUSC was also elucidated through rescue experiment, western blot, dual-luciferase, and bioinformatics analysis. Results Low level of miR-497-5p was confirmed in LUSC tissue and cells. Overexpressed miR-497-5p markedly inhibited cancer progression. miR-497-5p restrained CDCA4 expression. Rescue assay showed that overexpressing miR-497-5p eliminated effect of overexpressed CDCA4. Conclusion By targeting CDCA4, miR-497-5p restrained development of LUSC.

Background. Lung squamous cell carcinoma (LUSC) is one of the most common types of lung carcinoma and has specific clinicopathologic characteristics. In this study, we screened novel molecular biomarkers relevant to the prognosis of LUSC to explore new diagnostic and treatment approaches for this disease. Methods. We downloaded GSE73402 from the Gene Expression Omnibus (GEO) database. GSE73402 contains 62 samples, which could be classified as four subtypes according to their pathology and stages. Via weighted gene coexpression network analysis (WGCNA), the main module was identified and was further analyzed using differentially expressed genes (DEGs) analysis. Then, by protein-protein interaction (PPI) network and Gene Expression Profiling Interactive Analysis (GEPIA), hub genes were screened for potential biomarkers of LUSC. Results. Via WGCNA, the yellow module containing 349 genes was identified, and it is strongly related to the subtype of CIS (carcinoma in situ). DEGs analysis detected 180 genes that expressed differentially between the subtype of CIS and subtype of early-stage carcinoma (Stage I and Stage II). A PPI network of DEGs was constructed, and the top 20 genes with the highest correlations were selected for GEPIA database to explore their effect on LUSC survival prognosis. Finally, ITGA5, TUBB3, SCNN1B, and SERPINE1 were screened as hub genes in LUSC. Conclusions. ITGA5, TUBB3, SCNN1B, and SERPINE1 may have great diagnostic and prognostic significance for LUSC and have great potential to be new treatment targets for LUSC.

Background Lung squamous cell carcinoma (LUSC), one of the main pathological types of lung cancer, has led to consequential socioeconomic burden. Ferroptosis is an iron‐dependent form of cell death process with potentials for therapeutic target in various kinds of tumors. However, whether ferroptosis‐related genes (FRGs) are associated with the prognosis of LUSC patients is still unclear. The aim of this study was to establish a FRGs‐based signature which could stratify patients with LUSC. Methods The RNA sequencing profiles and corresponding clinical data of LUSC patients were retrieved from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) dataset. A FRG‐based signature was developed using the TCGA‐LUSC cohort and validated in the GEO cohort. Gene set enrichment analysis (GSEA) and analysis of immune cell characteristics were conducted to assess the relationship between FRGs and biological function or immune status. A nomogram based on selected clinical factors and the risk scores which were generated from the FRG‐based signature was developed using the TCGA cohort and validated in the GEO cohort. Results A set of 16 FRGs, significantly associated with overall survival (OS) in the TCGA cohort, was identified and could classify LUSC patients into two risk groups. Kaplan–Meier analysis illustrated that the survival rate of the high‐risk group was significantly lower than the low‐risk group. Assessment and external validation of the signature showed that the survival predictive performance of this signature was adequate. Additionally, multiple pathways and functions were enriched through GSEA and the analysis of immune cell characteristics showed significantly different abundances of immune cells among the two risk groups. Finally, a nomogram integrating the FRG‐based signature and selected clinical factors was also developed and assessed in both the TCGA and GEO cohort. Conclusion This study indicated the association between the FRGs and prognosis of patients with LUSC. Targeting ferroptosis may serve as a novel potential therapeutic alternative for LUSC., We developed a nomogram to predict the overall survival of lung squamous cell carcinoma patients using the risk score calculated from the ferroptosis‐related gene‐based signature and the T stage. The nomogram showed satisfactory discrimination power, calibration, and clinical usefulness in both the TCGA and GEO cohort.

Since the treatment of lung squamous cell carcinoma (SCC) was limited due to a lack of appropriate biomarkers and novel target agents. Immune checkpoint inhibitors can offer an effective treatment for patients with advanced non-small cell lung cancer. Here, we described the cases of two patients with SCC who showed a good response following treatment with tislelizumab. We encountered two patients with unresectable lung SCC who were treated with immunotherapy and chemotherapy. One patient had negatively programmed death-ligand 1 expression, and the primary lesion becomes a thick wall cavity after the tislelizumab combined with chemotherapy. Another patient was diagnosed with advanced lung SCC with negative programmed death-ligand 1 expression. After the treatment, the fluorine-18-fluorodeoxyglucose PET/computed tomography indicated that no abnormal increase in radioactivity uptake and tend to complete remission. We found a significant response or even complete response in unresectable SCC treated with tislelizumab combined with chemotherapy. Our cases added evidence of the feasibility and efficacy of tislelizumab combined with chemotherapy in unresectable lung SCC.

Zhenwen Chen,1,2,&ast; Ning Zhao,1,&ast; Qi Wang,1 Yanfeng Xi,3 Xiaoai Tian,2 Huiwen Wu,1 Yirong Xu1,2 1Department of Pathology, Fenyang College of Shanxi Medical University, Fenyang, 032200, Shanxi Province, People’s Republic of China; 2Department of Pathology, Shanxi Fenyang Hospital, Fenyang, Shanxi Province, People’s Republic of China; 3Department of Pathology, Shanxi Cancer Hospital (Shanxi Institute of Oncology), Taiyuan, Shanxi Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huiwen Wu; Yirong XuDepartment of Pathology, Fenyang College of Shanxi Medical University, No. 16 Xueyuan Road, Fenyang, 032200, Shanxi Province, People’s Republic of ChinaTel +86 151 3588 2981Email yirongxu@163.comPurpose: To investigate PD-L1 protein expression and gene amplification in lung squamous cell carcinoma (LUSC) and analyse their correlation with the clinicopathological characteristics and prognosis of LUSC patients.Patients and Methods: Tissue samples from 164 LUSC patients were collected. PD-L1 protein was detected by immunochemistry (IHC), and PD-L1 gene amplification was investigated by fluorescence in situ hybridization in LUSC patients.Results: The positive expression rate of PD-L1 in LUSC was 47.6% (78/164), and the amplification rate of PD-L1 was 6.7% (11/164); both rates were higher than those of paratumor tissue. Both PD-L1 positive expression and gene amplification were correlated with clinical stage and lymph node metastasis (P< 0.05). PD-L1 protein expression, PD-L1 gene amplification, late stage, lymph node metastasis and distant metastasis were significantly correlated with the prognosis of patients. Among these factors, late stage, lymph node metastasis, PD-L1 protein expression and PD-L1 gene amplification were independent prognostic factors for LUSC.Conclusion: Positive PD-L1 protein expression and gene amplification are involved in the malignant progression and metastasis of LUSC. Both PD-L1 protein expression and gene amplification are associated with poor prognosis.Keywords: PD-L1 protein expression, PD-L1 gene amplification, lung squamous cell carcinoma, prognosis

Programmed cell death ligend-1 (PD-L1) expression by immunohistochemistry (IHC) assays is a predictive marker of anti-PD-1/PD-L1 therapy response. With the popularity of anti-PD-1/PD-L1 inhibitor drugs, quantitative assessment of PD-L1 expression becomes a new labor for pathologists. Manually counting the PD-L1 positive stained tumor cells is an obviously subjective and time-consuming process. In this paper, we developed a new computer aided Automated Tumor Proportion Scoring System (ATPSS) to determine the comparability of image analysis with pathologist scores. A three-stage process was performed using both image processing and deep learning techniques to mimic the actual diagnostic flow of the pathologists. We conducted a multi-reader multi-case study to evaluate the agreement between pathologists and ATPSS. Fifty-one surgically resected lung squamous cell carcinoma were prepared and stained using the Dako PD-L1 (22C3) assay, and six pathologists with different experience levels were involved in this study. The TPS predicted by the proposed model had high and statistically significant correlation with sub-specialty pathologists’ scores with Mean Absolute Error (MAE) of 8.65 (95% confidence interval (CI): 6.42–10.90) and Pearson Correlation Coefficient (PCC) of 0.9436 ($$p < 0.001$$ p < 0.001 ), and the performance on PD-L1 positive cases achieved by our method surpassed that of non-subspecialty and trainee pathologists. Those experimental results indicate that the proposed automated system can be a powerful tool to improve the PD-L1 TPS assessment of pathologists.

CUGBP Elav‐like family member 2(CELF2) plays crucial roles in the development and activation of T cell. However, the impacts of CELF2 on tumour‐infiltrating immune cells (TIICs) and clinical outcomes of tumours remain unclear. In this study, we found that elevated CELF2 expression was markedly correlated with prolonged survival in multiple tumours, particularly in breast and lung cancers. Notably, CELF2 only impacted the prognosis of triple‐negative breast cancer (TNBC) with lymph node metastasis. Further investigation showed CELF2 expression was positively correlated with the infiltration abundance of dendritic cells (DCs), CD8+ T cells and neutrophils in breast invasive carcinoma (BRCA) and DCs in lung squamous cell carcinoma (LUSC). CELF2 also had strong correlations with markers of diverse TIICs such as T cells, tumour‐associated macrophages and DCs in BRCA and LUSC. Importantly, CELF2 was significantly associated with plenty of immune checkpoint molecules (ICMs) and outperformed five prevalent biomarkers including PD‐1, PD‐L1, CTLA‐4, CD8 and tumour mutation burden in predicting immunotherapeutic responses. Immunohistochemistry also revealed lower protein levels of CELF2 in TNBC and LUSC compared to normal tissues, and patients with high expression showed significantly prolonged prognosis. In conclusion, we demonstrated that increased CELF2 expression was closely related to better prognosis and superior TIIC infiltration and ICM expression, particularly in BRCA and LUSC. CELF2 also performed well in evaluating the immunotherapeutic efficacy, suggesting CELF2 might be a promising biomarker.

Propose: Autophagy plays a complicated role in cancer progression. This study aims at assessing the function of ATG5-induced autophagy in progression of lung squamous cell carcinoma and its upstream mechanism. Method: TCGA database of lung squamous cell carcinoma was analyzed to explore the differentially expressed miRNAs and mRNAs and relative prognosis. RT-PCR and Western blot were performed to evaluate autophagy relative gene expression level in human lung squamous cell carcinoma cell Lines. Autophagy flux was observed using transmission electron microscopy and immunofluorescence. Meanwhile, binding relationship of potential target miRNA and mRNAs were also confirmed using Dual-luciferase reporter gene assay. Lung metastatic model was established to evaluated the effect of targeting protein and miRNA. Result: High level expression of ATG5 was detected in LUSC patients. Relative experiments confirmed that ATG5 silencing could decrease the autophagy flux in LUSC. In addition, our research revealed that there is a binding sites between hsa-mir-30a-5p and 3′-UTR of ATG5. Mimic miR-30a-5p suppresses ATG5-mediated autophagy in lung squamous cell carcinoma cells. The in vivo experiments confirmed that miR-30a-5p could attenuate lung squamous cell carcinoma progression through the autophagy pathway. Conclusion: Accordingly, the in vivo and in vitro study in our research have demonstrated that miR-30a-5p inhibits lung squamous cell carcinoma progression via ATG5-mediated autophagy.

Tao Lu,1,&ast; Longfeng Zhang,2,&ast; Mingqiu Chen,3 Xiaobin Zheng,2 Kan Jiang,2 Xinlong Zheng,2 Chao Li,4 Weijin Xiao,4 Qian Miao,2 Shanshan Yang,2 Gen Lin2 1Department of Radiology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, People’s Republic of China; 2Department of Thoracic Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, People’s Republic of China; 3Department of Thoracic Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, People’s Republic of China; 4Department of Pathology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Gen LinDepartment of Thoracic Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, People’s Republic of ChinaEmail fjzllg133@fjzlhospital.comBackground: Predictive markers for guidance and monitoring of immunotherapy in lung squamous cell carcinoma (LSCC) are an interesting topic but have yet to be fully explored. A primary characteristic of LSCC is tumor necrosis that results in extensive immune suppression in patients. We sought to assess whether tumor necrosis or cavity on baseline CT could effectively predict the efficacy of immune checkpoint inhibitors (ICIs) in advanced LSCC.Methods: Advanced LSCC cases undergoing pre-treatment chest CT imaging and receiving ICIs were retrospectively collected. All CT images were reviewed by an independent chest radiologist blinded to any previous diagnosis to confirm morphological alterations in necrosis or cavity. We performed Logistic regression and developed Cox proportional hazards models to assess the predictive performance of baseline necrosis or cavity characteristics in advanced LSCC. Survival estimates were observed using Kaplan–Meier curves.Results: Ninety-three patients were eligible for analysis, predominantly consisting of patients with ECOG performance status of 0 or 1 (97.8%), male patients (95.7%), and heavy smokers (92.5%). Intrapulmonic necrosis or cavity on CT scan was present in 52.7% of all patients. Generally, the objective response rate (ORR) in patients with necrosis or cavity to ICI treatment was significantly worse versus those without (30.6% vs 54.5%, p = 0.020), with the subgroup ORRs as follows: ICI monotherapy (necrosis vs non-necrosis: 10.0% vs 36.8%, p =0.047) and ICI combination therapy (44.8% vs 68.0%, p =0.088). Multivariable analysis identified intrapulmonic necrosis or cavity at baseline as a major risk factor for advanced LSCC (HR 4.042, 95% CI1.149– 10.908, p = 0.006). Multivariate Cox analysis showed that baseline necrosis or cavity and ICI monotherapy were unfavorable factors for progression-free survival (HR 1.729; 95% CI1.203– 2.484, p =0.003).Conclusion: LSCC patients with intrapulmonic cavity or necrosis on baseline CT scan may respond poorly to anti-PD-(L)1-treatment, monotherapy and combination therapy alike.Keywords: lung squamous cell carcinoma, immune-checkpoint inhibitor, predictive marker, necrosis, cavity

Background Lung squamous cell carcinoma (LUSC), one of the main types of lung cancer, has caused a huge social burden. There has been no significant progress in its therapy in recent years, Resulting in a poor prognosis. This study aims to develop a glycolysis‐related gene signature to predict patients’ survival with LUSC and explore new therapeutic targets. Methods We obtained the mRNA expression and clinical information of 550 patients with LUSC from the Cancer Genome Atlas (TCGA) database. Glycolysis genes were identified by Gene Set Enrichment Analysis (GSEA). The glycolysis‐related gene signature was established using the Cox regression analysis. Results We developed five glycolysis‐related genes signature (HKDC1, AGL, ALDH7A1, SLC16A3, and MIOX) to calculate each patient's risk score. According to the risk score, patients were divided into high‐ and low‐risk groups and exhibited significant differences in overall survival (OS) between the two groups. The ROC curves showed that the AUC was 0.707 for the training cohort and 0.651 for the validation cohort. Additionally, the risk score was confirmed as an independent risk factor for LUSC patients by Cox regression analysis. Conclusion We built a gene signature to clarify the connection between glycolysis and LUSC. This model performs well in evaluating patients’ survival with LUSC and provides new biomarkers for targeted therapy., We established a glycolysis‐related gene signature to calculate the risk score for patients with lung squamous cell carcinoma. The risk score divided patients into high‐ and low‐risk groups, and there was a significant difference in survival between the two groups. In addition, the risk score was confirmed as an independent predictor of patients.

Non-small-cell lung cancer (NSCLC) causes significant mortality each year. After successful resection of disease stage IB (>4 cm) to IIIA (per AJCC 7), adjuvant platinum-based chemotherapy improves median overall survival and is the standard of care, but many patients still experience recurrence of disease. An adjuvant regimen with greater efficacy could substantially improve outcomes. Pembrolizumab, a programmed cell death-1 inhibitor, has become an important option in the treatment of metastatic NSCLC. ALCHEMIST is a clinical trial platform of the National Cancer Institute that includes biomarker analysis for resected NSCLC and supports therapeutic trials including A081801 (ACCIO), a three-arm study that will evaluate both concurrent chemotherapy plus pembrolizumab and sequential chemotherapy followed by pembrolizumab to standard of care adjuvant platinum-based chemotherapy. Clinical trial registration: NCT04267848 (ClinicalTrials.gov), Tweetable abstract Non-small-cell lung cancer adjuvant platinum-based therapy is standard of care (SOC). Including pembrolizumab may improve efficacy. A081801 (ACCIO) is a three-arm study: SOC versus sequential chemotherapy–pembrolizumab versus concurrent chemotherapy + pembrolizumab.

Background MicroRNAs (miRNAs) are involved in the oncogenesis, development and transformation of lung squamous cell carcinoma (LUSC). miR-665 is clinically significant and acts as a pivotal function in some cancers. Nevertheless, the effects and the potential mechanisms of miR-665 in human LUSC are still unknown. Methods To analyse the clinical significant of miR-665 in human LUSC, quantitative real-time PCR (qRT-PCR) was use to measure miR-665 expression in LUSC specimen tissues and cell lines. Tripartite motif 8 (TRIM8) was verified a target of miR-665 by performing bioinformatic prediction and luciferase reporter assay. The expression levels of TRIM8 were examined through qRT-PCR and Western blotting in LUSC specimen tissues. CCK8 assay was fulfilled for analyzing the function in LUSC cell proliferation. Flow cytometry was used to detect cell and apoptosis. TRIM8 silencing and overexpression further verified the biological effects as those caused by miR-665. Results Here we reported that miR-665 expression was upregulated in LUSC specimen tissues and cell lines. High miR-665 levels were related to differentiation, tumor size and TNM stage. miR-665 mimics facilitated LUSC cell growth and cell cycle G1-S transition and repressed apoptosis. miR-665 inhibitor suppressed cell proliferation and G1-S transition and promoted apoptosis. miR-665 expression was negatively correlated with TRIM8 mRNA expression in LUSC. Luciferase reporter assay confirmed that TRIM8 was a direct target gene of miR-665. miR-665 mimics downregulated the TRIM8 levels, and miR-665 inhibitor upregulated the TRIM8 levels in LUSC cells. Particularly, silencing TRIM8 led to the similar effects of miR-665 mimics in LUSC cells. Overexpression of TRIM8 inhibited LUSC cell proliferation in vitro and in vivo. Furthermore, miR-665 promoted LUSC cell proliferation through facilitating the Wnt5a/β-catenin signaling pathway and restrained apoptosis via inhibiting Caspase-3 signaling pathway, whereas TRIM8 suppressed cell growth by repressing the Wnt5a/β-catenin signaling pathway and induced apoptosis through activating Caspase-3 signaling pathway. Conclusions The current study demonstrates that miR-665 facilitates LUSC cell proliferation and cell cycle transition by regulation of the Wnt5a/β-Catenin signaling pathway and represses cell apoptosis via modulation of Caspase-3 signaling pathway by directly targeting TRIM8. These findings suggest that miR-665 might be a potential new target for LUSC therapy.

Background Lung squamous cell carcinoma (LSCC) is a form of cancer that is associated with high rates of relapse, poor responsiveness to therapy, and a relatively poor prognosis. The relationship between long non-coding RNA (lncRNA) expression and LSCC patient prognosis remains to be established. Methods In the present study, we discovered that lncRNAs were differentially expressed in LSCC tumor tissues relative to normal control tissues, and we explored the prognostic relevance of these lncRNA expression patterns using data from the Cancer Genome Atlas (TCGA). Results These multidimensional data were analyzed in order to identify lncRNA signatures that were associated with LSCC patient survival outcomes. Kaplan-Meier survival curves revealed prognostic capabilities for three of these lncRNAs (LINC02555, APCDD1L-DT and OTX2-AS1). A Cox regression analysis revealed this three-lncRNA signature to be significantly associated with patient survival. Further GO and KEGG analyses revealed that the predicted target genes of these three lncRNAs were also potentially involved in cancer-associated pathways. Conclusions Together these results thus indicate that this novel three-lncRNA signature can be used to predict LSCC patient prognosis.

Pulmonary tuberculosis (TB) and lung cancer are both common diseases with poor prognosis and high mortality worldwide. The coexistence of the two diseases has rarely been reported while their relationship has been noted. Here we describe a patient diagnosed with both TB and squamous cell carcinoma in a single lesion. The patient had a cough for four months and polypnea for two months, with a smoking history of over 40 years. Chest computed tomography (CT) showed a lobular mass in the right hilar region, which was diagnosed as TB by transbronchial lung biopsy. The symptoms and CT findings indicated the possibility of lung cancer. So, the patient underwent a further lung biopsy at the periphery of the mass, which was confirmed as squamous cell carcinoma. This case illuminated that when the mass with cancer-like morphologic features and location instead of typical TB, even the initial pathological result shows TB, coexistence of the diseases should be considered.

Background & Objective: Diagnosis and discrimination of lung adenocarcinoma (LUAD) from lung squamous cell carcinoma (LUSC) is critical to select the appropriate treatment regimen as recently targeted therapies require accurate subtyping of nonsmall-cell lung carcinoma (NSCLCs). There are currently several biomarkers that could be used for differentiation between LUAD and LUSC, but they have less sensitivity, specificity, and clinical applicability. The aim of this study was to assess the diagnostic and prognostic values of CLCA2, SPATS2, ST6GALNAC1, and Adipophilin tissue expression in the tissues retrieved from LUAD and LUSC patients using immunohistochemistry. Methods: The current study was performed on the samples retrieved from sixty primary lung masses that were diagnosed as LUAD and LUSC. Immunohistochemistry was performed by using a panel of CLCA2, SPATS2, and ST6GALNAC1. We assessed the diagnostic roles of the studied markers in the discrimination between LUAD and LUSC and their prognostic values. Results: SPATS2 and CLCA2 were expressed higher in LUSC than LUAD. ST6GALNAC1 and Adipophilin showed higher expression in LUAD than LUSC (P

Lung squamous cell carcinoma (LUSC) represents a major subtype of non-small cell lung cancer with limited treatment options. Previous studies have elucidated the complex genetic landscape of LUSC and revealed multiple altered genes and pathways. However, in stark contrast to lung adenocarcinoma, few targetable driver mutations have been established so far and targeted therapies for LUSC remain unsuccessful. Immunotherapy has revolutionized LUSC treatment and is currently approved as the new standard of care. To gain a better understanding of the LUSC biology, improved modeling systems are urgently needed. Preclinical models, particularly those mimicking human disease with an intact tumor immune microenvironment, are an invaluable tool to study cancer development and evaluate new therapeutic targets. Here, we discuss recent advances in LUSC preclinical models, with a focus on genetically engineered mouse models (GEMMs) and organoids, in the context of evolving precision medicine and immunotherapy.

Aim: To build a valid prognostic model based on immune-related genes for lung squamous cell carcinoma (LUSC). Materials & methods: Differential expression of immune-related genes between LUSC and normal specimens from TCGA dataset and underlying molecular mechanisms were systematically analyzed. Constructing and validating the high-risk and low-risk groups for LUSC survival. Results: The immune-related gene-based prognostic index (IRGPI) could predict the overall survival in patients with different clinicopathological characteristics. Functional enrichment analysis of differential expression of immune-related gene signature indicated distinctive molecular pathways between high-risk and low-risk groups. Conclusion: Analysis of IRGs in LUSC enable us to stratify patients into distinct risk groups, which may help to screen LUSC patients at risk and decision making on follow-up therapeutic intervention.

Objective To report the treatment of a long‐term survival case of stage IV lung squamous cell carcinoma (LSCC) patient with multiorgan metastases, including intrapulmonary, brain, liver, bone, and multiple lymph nodes. Methods and results A 72‐year‐old male patient with stage IV LSCC achieved a total survival of 85 months with comprehensive treatment of chemotherapy, radiotherapy, targeted, and immunotherapy. Conclusion Full‐course management, multidisciplinary diagnosis and treatment, and rational application of multiple treatment measures can improve the quality of life of the patient with advanced lung cancer and prolong their survival.

Background: Several previous researchers have investigated the prognostic value of serum tumor markers, especially carcinoembryonic antigen (CEA). Only a limited number of studies reported the usefulness of serum tumor markers for lung squamous cell carcinoma (SQ). We aimed to examine the significance of serum tumor markers for lung SQ. Methods: Eighty-five lung SQ patients who underwent surgery and followed more than 5-year were included. The ratios of 5-year survivors to all patients in groups with several clinicopathologic factors, including tumor markers, were compared. We also compared the clinicopathologic factors between central type and peripheral type SQ. Results: The majority of patients were male gender and current/ former smokers. Age, pN status, cytokeratin-19 fragment (CYFRA 21-1), squamous cell carcinoma antigen (SCC), and comorbid interstitial pneumonia (IP) were associated with the ratio of 5-year survivors significantly. When patients were compared based on tumor location, high p-stage and CYFRA 21-1 were related to central type SQ. Conclusion: Both SCC and CYFRA 21-1 appeared to be useful prognostic markers for patients with lung SQ. Furthermore, CYFRA 21-1 was related to central type SQ.

Rationale: Platinum-based chemotherapy is one of treatment mainstay for patients with advanced lung squamous cell carcinoma (LUSC) but it is still a "one-size fits all" approach. Here, we aimed to investigate the predictive and monitoring role of circulating cell-free DNA (cfDNA) profiling for the outcome of first-line chemotherapy in patients with advanced LUSC. Methods: Peripheral blood samples of 155 patients from a phase IV trial and 42 cases from an external real-world cohort were prospectively collected. We generated a copy number variations-based classifier via machine learning algorithm to integrate molecular profiling of cfDNA, named RESPONSE SCORE (RS) to predict the treatment outcome. To monitor the treatment efficacy, cfDNA samples collected at different time points were subjected to an ultra-deep sequencing platform. Results: The results showed that patients with high RS showed substantially higher objective response rate than those with low RS in training set (P < 0.001), validation set (P < 0.001) and real-world cohort (P = 0.019). Furthermore, a significant difference was observed in both progression-free survival (training set, P < 0.001; validation set: P < 0.001; real-world cohort: P = 0.019) and overall survival (training set, P < 0.001; validation set: P = 0.037) between high and low RS group. Notably, variant allele frequency (VAF) calculated from an ultra-deep sequencing platform significantly reduced in patients experienced a complete or partial response after 2 cycles of chemotherapy (P < 0.001), while it significantly increased in these of non-responder (P < 0.001). Moreover, VAF undetectable after 2 cycles of chemotherapy was correlated with markedly better objective response rate (P < 0.001) and progression-free survival (P < 0.001) than those with detectable VAF. Conclusions: These findings indicated that the RS, a circulating cfDNA sequencing-based stratification index, could help to guide first-line chemotherapy in advanced LUSC. The change of VAF is valuable to monitor the treatment response.

Pulmonary artery pseudoaneurysm is a rare but fatal condition. It has been associated with lung cancer, abscesses, and radiation therapy. Identification in patients with hemoptysis is critical, and timely interventional therapy is warranted.

Introduction Heterogeneity of non-small cell lung carcinoma (NSCLC) among patients is currently not well studied. Pathologic markers and staging systems have not been a precise predictor of the prognosis of an individual patient. Hence, we hypothesize to develop a transcript-based signature to categorize stage IIIA-NSCLC in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), plus identify markers that could indicate the prognosis of the disease. Methods Human Transcriptome Array 2.0 (HTA) and NanoString nCounter® platform were used for high-throughput gene-expression profiling. Initially, we profiled stage IIIA-NSCLC through HTA and validated through NanoString. Additionally, two metastatic markers SPP1 and CDH2 were validated in 47 NSCLC stage IIIA samples through real-time PCR. Results We observed distinct gene clusters in LUAD and LUSC with down-regulation of six genes and up-regulation of 57 genes through HTA. Ninety-six transcripts were randomly selected after analyzing HTA data and validated on the NanoString platform. We found 40 differentially expressed transcripts that categorized NSCLC into LUAD and LUSC. SPP1 is significantly overexpressed (4.311±1.27 fold in LUAD and 13.41±3.82 fold in LUSC compared to control), and the CDH2 transcript was significantly overexpressed (11.53 ± 4.027-fold compared to control) only in LUSC. Discussion These markers enable us to categorize stage IIIA NSCLC into LUAD and LUSC plus these markers may be helpful to understand the pathophysiology of NSCLC. However, more data required to make these findings useful in general clinical practice.

The efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in lung squamous cell carcinoma is said to be low. Thus far, only four cases of osimertinib in lung squamous cell carcinoma have been published. We experienced a case of EGFR mutant lung squamous cell carcinoma in which fifth-line treatment with osimertinib was effective after T790M EGFR mutation turned positive. Osimertinib was resumed after sixth-line chemotherapy was ineffective, showing efficacy again. Osimertinib may be a promising treatment option for EGFR mutant lung squamous cell carcinoma. This is the first report to show its effect in a case of rechallenge after intervening chemotherapy. It may therefore be important to evaluate EGFR in never-smoker lung squamous cell carcinoma patients.

Background The aim of the study was to investigate 3D texture analysis (3D‐TA) in noncontrast enhanced computed tomography (CT) (NCECT) to differentiate squamous cell carcinoma (SCC) from adenocarcinoma (AC), and the correlation with immunohistochemical markers. Methods A total of 70 patients confirmed with SCC (n = 29) and AC (n = 41) were enrolled in this retrospective study. 3D‐TA was utilized to calculate TA parameters of all the tumor lesions based on NCECT images, and all the patients were divided into the training and the test groups. The TA parameters were selected by dimensionality reduction, and the model was established to differentiate SCC from AC according to the training group. The ROC curve was used to evaluate the diagnostic efficiency of the model in both the training and the test groups. Spearman correlation were used to assess the correlation between the selected feature parameters and immunohistochemical markers (P63, P40, and TTF‐1). Results Five TA parameters, including volume count, relative deviation, Haralick correlation, gray‐level nonuniformity and run length nonuniformity, were obtained to differentiate SCC from AC by multistep dimensionality reduction. The new model combined with all five TA parameters yielded a high diagnostic performance to differentiate SCC from AC (AUC 0.803) in test group, with a specificity of 89% and a sensitivity of 77%. There was weak correlation between the five texture feature parameters and P63 as well as P40 in all patients (P, The model created by five selected textural feature parameters can differentiate solid SCC from AC without contrast media. The selected five texture feature parameters are correlated to the immunohistochemical markers P63 and P40.

Cancer tissue is composed of both a cancer cell component and a stromal component. The aim of this study was to investigate if the component ratio predicts a prognosis for lung squamous cell carcinoma (SqCC) patients by using a machine learning method.A total of 135 peripheral SqCC cases (tumor size: 3-5 cm) were enrolled in this study. The areas of the cancer cell component, the necrotic component, and the stromal component were accurately measured via a machine learning method. Each case was divided into the following three subtypes: 1) predominant cancer cell, 2) predominant necrosis, and 3) predominant stroma. The study examined if a particular subtype had prognostic significance.The number of cases per subtype of predominant cancer cell, predominant necrosis, and predominant stroma was 59, 6, and 70, respectively. Patients with the predominant stroma subtype had a significantly shorter recurrence free survival (RFS) than did those with the predominant cancer cell subtype (5-yr RFS: 42.3 % vs. 84.3 %,p0.01). Also, in pathological stage I patients, the 5-year RFS rate for the predominant stroma subtype was significantly shorter (5-yr RFS: 64.3 % vs. 88.4 %, p0.01). In the multivariate analysis of p-stage I patients, the predominant stroma subtype was confirmed to be an independent prognostic factor for RFS (p0.01).Using machine learning, the study confirmed that the predominant stroma subtype was an independent factor for RFS, suggesting that the ratio of the stromal component correlates with the malignant potential of SqCC.

Background The aim of this paper is to identify the differentially expressed lncRNAs (DELs) that could serve as markers for the prognosis of early-stage (stage I–II) lung squamous cell carcinoma (SCC). Methods lncRNAs expression data and corresponding clinical information for 395 patients with stage I–II lung SCC were obtained from The Cancer Genome Atlas (TCGA). Univariate Cox regression analysis and LASSO regression were used to screen key lncRNAs, which were then were subjected to a multivariate Cox regression analysis. Furthermore, based on the results of multivariate analysis, lncRNAs with statistical significance were utilized to establish a risk assessment model. Also, a prognostic nomogram based on the risk assessment model was built. These two tools were evaluated by receiver operating characteristic (ROC) curve. Additionally, Kaplan-Meier (KM) survival curves for potential prognostic lncRNAs and clinical factors were performed. Results A total of 5 key lncRNAs (AC015712.4, LINC02301, AGAP11, AC099850.3, and AC008915.1) were screened to construct the risk assessment model, and the area under the ROC curves (AUC) showed the model had a general performance. The risk level of the model was identified as an independent prognostic factor for stage I–II lung SCC. A nomogram combining the lncRNA-based risk assessment model, age, and T stage was constructed to predict 3- and 5-year overall survival (OS) in patients with stage I–II lung SCC. The results of ROC and calibration curves demonstrated that the nomogram was reliable in predicting OS rate. Besides, KM survival curves showed OS time was significantly corrected with the expression of AC015712.4, age, and T stage. Conclusions In the present study, a risk assessment model and a nomogram based on five lncRNAs were constructed to predict OS time for early-stage lung SCC, which may contribute to the management of lung SCC.

Background Treatment of human lung squamous cell carcinoma (LUSC) using current targeted therapies is limited because of their diverse somatic mutations without any specific dominant driver mutations. These mutational diversities preventing the use of common targeted therapies or the combination of available therapeutic modalities would require a preclinical animal model of this tumor to acquire improved clinical responses. Patient-derived xenograft (PDX) models have been recognized as a potentially useful preclinical model for personalized precision medicine. However, whether the use of LUSC PDX models would be appropriate enough for clinical application is still controversial. Methods In the process of developing PDX models from Korean patients with LUSC, the authors investigated the factors influencing the successful initial engraftment of tumors in NOD scid gamma mice and the retainability of the pathological and genomic characteristics of the parental patient tumors in PDX tumors. Conclusions The authors have developed 62 LUSC PDX models that retained the pathological and genomic features of parental patient tumors, which could be used in preclinical and co-clinical studies. Trial registration Tumor samples were obtained from 139 patients with LUSC between November 2014 and January 2019. All the patients provided signed informed consents. This study was approved by the institutional review board (IRB) of Samsung Medical Center (2018-03-110)