Publications by authors named "Likun Hou"

49 Publications

Excimer laser atherectomy combined with drug-coated balloon versus drug-eluting balloon angioplasty for the treatment of infrapopliteal arterial revascularization in ischemic diabetic foot: 24-month outcomes.

Lasers Med Sci 2021 Oct 13. Epub 2021 Oct 13.

Department of Vascular Surgery, Tianjin First Central Hospital, Tianjin, 300192, People's Republic of China.

There are few studies on excimer laser (308 nm) atherectomy in the treatment of infrapopliteal artery disease. The purpose of this retrospective clinical study was to assess the efficacy and safety of excimer laser atherectomy (ELA) in combination with adjuvant drug-coated balloon angioplasty (DCB) compared to DCB for infrapopliteal arterial revascularization in patients with ischemic diabetic foot. From September 2018 to February 2019, a total of 79 patients with diabetic foot were treated for infrapopliteal arterial revascularization at Tianjin First Central Hospital (Tianjin, China). In this project, 35 patients were treated with ELA combined with DCB angioplasty, and 44 patients were treated with DCB angioplasty. The patients' baseline characteristics were similar between the 2 groups. The primary efficacy endpoints through 24 months were clinically driven target lesion revascularization (CD-TLR), wound healing rate, major amputation rate, and target vessel patency rate. The primary safety endpoint through 24 months was all-cause mortality. The primary efficacy results at 24 months of ELA + DCB versus DCB were CD-TLR of 14.3% versus 34.1% (p = 0.044), wound healing rate of 88.6% versus 65.9% (p = 0.019), target vessel patency rate of 80.0% versus 52.3% (p = 0.010), and major amputations rate of 5.7% versus 22.7% (p = 0.036). The safety signal at 24 months of all-cause mortality rate was 2.9% for ELA + DCB group and 4.5% for DCB group (p = 0.957). ELA combined with DCB angioplasty is more effective than DCB in the treatment of infrapopliteal artery disease in patients with ischemic diabetic foot, which can improve the wound healing rate and target vessel patency rate. There was no statistical difference in the safety results between the two groups.
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http://dx.doi.org/10.1007/s10103-021-03393-zDOI Listing
October 2021

Improving differential diagnosis of pulmonary large cell neuroendocrine carcinoma and small cell lung cancer via a transcriptomic, biological pathway-based machine learning model.

Transl Oncol 2021 Dec 14;14(12):101222. Epub 2021 Sep 14.

Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, PR China. Electronic address:

Background: Accurately differentiating between pulmonary large cell neuroendocrine carcinomas (LCNEC) and small cell lung cancer (SCLC) is crucial to make appropriate therapeutic decisions. Here, a classifier was constructed based on transcriptome data to improve the diagnostic accuracy for LCNEC and SCLC.

Methods: 13,959 genes mapped to 186 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were included. Gene Set Variation Analysis (GSVA) algorithm was used to enrich and score each KEGG pathway from RNA-sequencing data of each sample. A prediction model based on GSVA score was constructed and trained via ridge regression based on RNA-sequencing datasets from 3 published studies. It was validated by another independent RNA-sequencing dataset. Clinical feasibility was tested by comparing model predicated result using RNA-sequencing data derived from hard-to-diagnose samples of lung neuroendocrine cancer to conventional histology-based diagnosis.

Results: This model achieved a ROC-AUC of 0.949 and a concordance rate of 0.75 for the entire prediction efficiency. Of the 27 borderline samples, 17/27 (63.0%) were predicted as LCNEC, 7/27 were predicted as SCLC, and the remainder was NSCLC. Only 8 cases (29.6%) with LCNEC were diagnosed by pathologists, which was significantly lower than the results predicted by the model. Furthermore, cases with predicted LCNEC by the model had a significant longer disease-free survival than those where the model predicted SCLC (P = 0.0043).

Conclusion: This model was able to give an accurate prediction of LCNEC and SCLC. It may assist clinicians to make the optimal decision for patients with pulmonary neuroendocrine tumors in choosing appropriate treatment.
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http://dx.doi.org/10.1016/j.tranon.2021.101222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450252PMC
December 2021

Risk-score model to predict prognosis of malignant airway obstruction after interventional bronchoscopy.

Transl Lung Cancer Res 2021 Jul;10(7):3173-3190

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.

Background: Interventional bronchoscopy exhibits substantial effects for patients with malignant airway obstruction (MAO), while little information is available regarding the potential prognostic factors for these patients.

Methods: Between October 31, 2016, and July 31, 2019, a total of 150 patients undergoing interventional bronchoscopy and histologically-confirmed MAO were collected, in which 112 eligible participants formed the cohort for survival study. External validation cohort from another independent institution comprised 33 MAO patients with therapeutic bronchoscopy. The least absolute shrinkage and selection operator regression (LASSO) was applied to the model development dataset for selecting features correlated with MAO survival for inclusion in the Cox regression from which we elaborated the risk score system. A nomogram algorithm was also utilized.

Results: In our study, we observed a significant decline of stenosis rate after interventional bronchoscopy from 71.7%±2.1% to 36.6%±2.7% (P<0.001) and interventional bronchoscopy dilated airway effectively. Patients in our study undergoing interventional bronchoscopy had a median survival time of 614.000 days (95% CI: 269.876-958.124). Patients receiving distinct therapeutic methods of interventional bronchoscopy had different prognosis (P=0.022), and patients receiving treatment of electrocoagulation in combination with stenting and electrosurgical snare had worse survival than those receiving other options. Multivariate Cox analysis revealed that nonsmoking status, adenoid cystic carcinoma, and low preoperative stenosis length, as independent predictive factors for better overall survival (OS) of MAO patients. Then, the nomogram based on Cox regression and risk score system based on results from LASSO regression were elaborated respectively. Importantly, this risk score system was proved to have better performance than the nomogram and other single biomarkers such as traditional staging system (area under the curve 0.855 0.392-0.739). Survival curves showed that patients with the higher risk-score had poorer prognosis than those with lower risk-score (third quantile of OS: 126.000 days, 95% CI: 73.588-178.412 532.000 days, 95% CI: 0.000-1,110.372; P<0.001).

Conclusions: Nonsmoking status, adenoid cystic carcinoma, and low preoperative stenosis length, were independent predictive factors for better OS of MAO patients. We proposed a nomogram and risk score system for survival prediction of MAO patients undergoing interventional bronchoscopy with good performance.
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http://dx.doi.org/10.21037/tlcr-21-301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350098PMC
July 2021

Proposal for Rib invasion as an independent T descriptor for non-small cell lung cancer: A propensity-score matching analysis.

Lung Cancer 2021 09 21;159:27-33. Epub 2021 Jul 21.

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. Electronic address:

Introduction: To evaluate the prognosis between patients with non-small cell lung cancer (NSCLC) invading difference depth of chest wall and estimate the impact of rib invasion on the pathological T classifications (pT).

Methods: We retrospectively evaluated 521 patients with resected pT3-4 NSCLC. Propensity-score matching (PSM) balanced the known confounders of the prognosis, resulting in two sets (rib invasion vs the pT3 and pT4 group). Recurrence-free survival (RFS) and Overall survival (OS) was assessed by Cox regression and Kaplan-Meier methods. Time-dependent receiver operating characteristic (ROC) curves were used to assess the additional benefit for survival prediction after reclassifying rib invasion cases.

Results: Chest wall invasion occurred in 171 patients (62 rib invasion, 51 parietal pleural invasion [PL3] and 58 soft tissue invasion). Rib invasion was found to be an independent prognostic factor for both RFS (p = 0.006) and OS (p < 0.001) of pT3-4 NSCLC. The survival of rib invasion group was the worst (RFS: 13.1%; OS: 19.8%), followed by PL3 (RFS: 34.2%, P = 0.001; OS: 48.8%; p < 0.001) and the soft tissue invasion group (RFS: 40.6%, p = 0.001; OS: 57.7%, p < 0.001). Besides, the prognosis of rib invasion group was also found to be worse than those of pT3 (RFS: p < 0.001; OS: p < 0.001) and pT4 group (RFS: p = 0.002; OS: p < 0.001). After PSM, the 5-year RFS rate of rib invasion group were still lower than that of pT3 and pT4 group (p < 0.001); the 5-year OS rate of rib invasion was similar with that of pT4 group (p = 0.066) but lower than that of pT3 group (p = 0.014). The time-dependent ROC curves demonstrated that reclassifying rib invasion as pT4 disease provided an additional benefit for survival prediction (p < 0.001).

Conclusion: The rib invasion group had a worse prognosis than the PL3 and pT3 groups. The prognostic impact of rib invasion should be further validated as a pT4 disease in the TNM classification.
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http://dx.doi.org/10.1016/j.lungcan.2021.07.010DOI Listing
September 2021

Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer.

Nat Commun 2021 05 5;12(1):2540. Epub 2021 May 5.

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Lung cancer is a highly heterogeneous disease. Cancer cells and cells within the tumor microenvironment together determine disease progression, as well as response to or escape from treatment. To map the cell type-specific transcriptome landscape of cancer cells and their tumor microenvironment in advanced non-small cell lung cancer (NSCLC), we analyze 42 tissue biopsy samples from stage III/IV NSCLC patients by single cell RNA sequencing and present the large scale, single cell resolution profiles of advanced NSCLCs. In addition to cell types described in previous single cell studies of early stage lung cancer, we are able to identify rare cell types in tumors such as follicular dendritic cells and T helper 17 cells. Tumors from different patients display large heterogeneity in cellular composition, chromosomal structure, developmental trajectory, intercellular signaling network and phenotype dominance. Our study also reveals a correlation of tumor heterogeneity with tumor associated neutrophils, which might help to shed light on their function in NSCLC.
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http://dx.doi.org/10.1038/s41467-021-22801-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100173PMC
May 2021

A machine learning-based prediction of the micropapillary/solid growth pattern in invasive lung adenocarcinoma with radiomics.

Transl Lung Cancer Res 2021 Feb;10(2):955-964

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Background: Micropapillary/solid (MP/S) growth patterns of lung adenocarcinoma are vital for making clinical decisions regarding surgical intervention. This study aimed to predict the presence of a MP/S component in lung adenocarcinoma using radiomics analysis.

Methods: Between January 2011 and December 2013, patients undergoing curative invasive lung adenocarcinoma resection were included. Using the "PyRadiomics" package, we extracted 90 radiomics features from the preoperative computed tomography (CT) images. Subsequently, four prediction models were built by utilizing conventional machine learning approaches fitting into radiomics analysis: a generalized linear model (GLM), Naïve Bayes, support vector machine (SVM), and random forest classifiers. The models' accuracy was assessed using a receiver operating curve (ROC) analysis, and the models' stability was validated both internally and externally.

Results: A total of 268 patients were included as a primary cohort, and 36.6% (98/268) of them had lung adenocarcinoma with an MP/S component. Patients with an MP/S component had a higher rate of lymph node metastasis (18.4% versus 5.3%) and worse recurrence-free and overall survival. Five radiomics features were selected for model building, and in the internal validation, the four models achieved comparable performance of MP/S prediction in terms of area under the curve (AUC): GLM, 0.74 [95% confidence interval (CI): 0.65-0.83]; Naïve Bayes, 0.75 (95% CI: 0.65-0.85); SVM, 0.73 (95% CI: 0.61-0.83); and random forest, 0.72 (95% CI: 0.63-0.81). External validation was performed using a test cohort with 193 patients, and the AUC values were 0.70, 0.72, 0.73, and 0.69 for Naïve Bayes, SVM, random forest, and GLM, respectively.

Conclusions: Radiomics-based machine learning approach is a very strong tool for preoperatively predicting the presence of MP/S growth patterns in lung adenocarcinoma, and can help customize treatment and surveillance strategies.
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http://dx.doi.org/10.21037/tlcr-21-44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947386PMC
February 2021

Comprehensive genomic profiling of combined small cell lung cancer.

Transl Lung Cancer Res 2021 Feb;10(2):636-650

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Background: Combined small cell lung cancer (CSCLC) is an uncommon and heterogeneous subtype of small cell lung cancer (SCLC). However, there is limited data concerning the different molecular changes and clinical features in CSCLC compared to pure SCLC.

Methods: The clinical and pathological characteristics of pure SCLC and CSCLC patients were analyzed. Immunohistochemistry and microdissection were performed to isolate the CSCLC components. Further molecular analysis was carried out by next-generation sequencing (NGS) in 12 CSCLC and 30 pure SCLC.

Results: There were no significant differences in clinical features between CSCLC and pure SCLC. Overall survival (OS) of CSCLC patients was worse than pure SCLC (P=0.005). NGS results indicated that and were the most frequently mutated genes in both CSCLC (83.33% and 66.67%) and pure SCLC (80.00% and 63.33%) groups. However, less than 10% common mutations were found in both CSCLC and pure SCLC. When analyzing the data of SCLC and non-small cell lung cancer (NSCLC) components of CSCLC, more than 50% common mutations, and identical genes with mutations were detected. Moreover, there were also common biological processes and signaling pathways identified in CSCLC and pure SCLC, in addition to SCLC and NSCLC components.

Conclusions: There were no significant differences in terms of clinical features between CSCLC and pure SCLC. However, the prognosis for CSCLC was worse than pure SCLC. NGS analysis suggested that CSCLC components might derive from the same pluripotent single clone with common initial molecular alterations and subsequent acquisitions of other genetic mutations.
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http://dx.doi.org/10.21037/tlcr-20-1099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947408PMC
February 2021

Characterization of evolution trajectory and immune profiling of brain metastasis in lung adenocarcinoma.

NPJ Precis Oncol 2021 Feb 12;5(1). Epub 2021 Feb 12.

Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, 200433, Shanghai, China.

Characterizing the evolutionary trajectory and immune profiling of brain metastasis (BM) may provide insights in the development of novel therapeutic strategies. Here, we performed whole-exome sequencing and multiplex immunofluorescence (MIF) of 40 samples from 12 lung adenocarcinoma (LUAD) patients with BM and compared to their paired primary tumors. We observed significantly higher intertumor heterogeneity between paired primary tumors and BMs, with only a median of 8.3% of genetic mutations identified as shared. Phylogenetic analysis revealed that BM-competent clones genetically diverged from their primary tumors at relatively early stage, suggesting that the parallel progression model is dominant. In cases with synchronous lymph node metastasis (LNM), phylogenetic analysis suggested that BM is a later event than LNM. MIF analysis found that BMs exhibited significantly lower CD8 T cell infiltration (P = 0.048), and elevated CD4Foxp3 T cell infiltration (P = 0.036) and PD-1 expression (P = 0.047) in comparison to the matched primary tumors, indicating an immunosuppressive microenvironment in BMs. The current study revealed the discrepancy of mutational landscape as well as tumor immune microenvironment between BM and its primary tumor - such findings shall help us better understand the unique biological features of BM and develop innovative strategies accordingly for our patients with LUAD.
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http://dx.doi.org/10.1038/s41698-021-00151-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881241PMC
February 2021

Efficacy of immune-checkpoint inhibitors in advanced non-small cell lung cancer patients with different metastases.

Ann Transl Med 2021 Jan;9(1):34

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Background: To investigate the significance of metastatic sites and their numbers to the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC).

Methods: A total of 232 patients who received ICI monotherapy or ICI-based combination therapy were retrospectively identified from January 2016 to February 2019. Six metastatic sites (brain, liver, bone, adrenal gland, contralateral lung, pleura) were included to analyze their significance to ICI efficacy. To explore the association between liver metastasis (LM) and tumor T cell infiltration, 46 patients with available tumor specimens were tested for PD-L1 expression, CD8+ tumor infiltrating lymphocytes (TILs) density. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier curves.

Results: More metastatic organs involved were associated with significantly worse PFS (0-1 organ: 5.7 months, 2-3 organs: 3.5 months, ≥4 organs: 2.7 months, P<0.001) and lower ORR (36% 29.8% 18.2%, P<0.001). Patients with brain metastasis (BM) had shorter PFS and OS than those without (P=0.002, P=0.021; respectively). Notably, patients with LM had the shortest PFS (2.3 months, P=0.005) and numerically shortest OS (9.8 months, P=0.238) compared with those with other organ metastases. Multivariate analysis revealed that LM was independently associated with inferior PFS (P<0.001). Immunostaining showed that patients with LM tended to have lower proportions of PD-L1+CD8+TIL+ tumors compared with those without LM (0% 30.8%, P=0.088). Interestingly, ICI-based combination therapy could effectively control LM with improved intrahepatic PFS (P=0.056) and ORR (41.7% 6.7%, P=0.030).

Conclusions: More metastatic organs involved were associated with poorer response to ICIs. LM was a negative predictive factor for patients treated with ICI monotherapy and the combination strategy might effectively control LM.
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http://dx.doi.org/10.21037/atm-20-1471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859789PMC
January 2021

Epidermal growth factor receptor tyrosine kinase inhibitor remodels tumor microenvironment by upregulating LAG-3 in advanced non-small-cell lung cancer.

Lung Cancer 2021 03 14;153:143-149. Epub 2021 Jan 14.

Department of Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China. Electronic address:

Introduction: Previous clinical investigations have demonstrated that patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation have moderate responses to programmed cell death-1 and it's ligand-1 (PD-1/PD-L1) inhibitors, while some patients who failed EGFR-tyrosine kinase inhibitor (TKI) therapy could benefit from immunotherapy. As a result, we have explored alterations in the tumor immune microenvironment (TIME) before and after EGFR-TKI treatment to detect the chances and proper timing of immunotherapy among patients.

Methods: We identified 16 paired tissue samples pre- and post-EGFR-TKI treatment. Sections 4 μm thick were utilized to evaluate CD8, PD-L1, PD-1, LAG-3, and TIM-3 expressions by multiplexed fluorescent immunohistochemical staining. Five to ten representative original multispectral images of each sample were employed in the analysis.

Results: Patients with positive CD8 + T-cell infiltration accounted for 37.5 % at baseline. Positive expression of PD-L1, PD1, LAG-3, and TIM-3 cells were observed in seven (43.8 %), four (25 %), one (6.25 %) and five (31.25 %) of the patients, respectively. PD-1 expression and infiltration of CD8PD-1-exhausted T cells increased significantly in patients with EGFR L858R mutation compared to patients with EGFR 19DEL. Patients who acquired T790 M after TKI treatment had less infiltrations of CD8PD-1 T cells and CD8TIM-3 T cells in the TIME at baseline. Positive expression of checkpoint proteins-including PD-1, TIM-3, and LAG-3-significantly correlated with shorter progression-free survival. LAG-3 was significantly upregulated after TKI treatment (p = 0.003), while other checkpoint proteins remained stationary.

Conclusion: The present study is the first work to report LAG-3 upregulation after EGFR-TKI failure in advanced NSCLC, which proposed novel insights for rational use of LAG-3 inhibitors in advanced NSCLC patients with EGFR mutation.
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http://dx.doi.org/10.1016/j.lungcan.2021.01.010DOI Listing
March 2021

Primary Invasive Mucinous Adenocarcinoma of the Lung: Prognostic Value of CT Imaging Features Combined with Clinical Factors.

Korean J Radiol 2021 04 19;22(4):652-662. Epub 2020 Nov 19.

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Objective: To investigate the association between CT imaging features and survival outcomes in patients with primary invasive mucinous adenocarcinoma (IMA).

Materials And Methods: Preoperative CT image findings were consecutively evaluated in 317 patients with resected IMA from January 2011 to December 2015. The association between CT features and long-term survival were assessed by univariate analysis. The independent prognostic factors were identified by the multivariate Cox regression analyses. The survival comparison of IMA patients was investigated using the Kaplan-Meier method and propensity scores. Furthermore, the prognostic impact of CT features was assessed based on different imaging subtypes, and the results were adjusted using the Bonferroni method.

Results: The median follow-up time was 52.8 months; the 5-year disease-free survival (DFS) and overall survival rates of resected IMAs were 68.5% and 77.6%, respectively. The univariate analyses of all IMA patients demonstrated that 15 CT imaging features, in addition to the clinicopathologic characteristics, significantly correlated with the recurrence or death of IMA patients. The multivariable analysis revealed that five of them, including imaging subtype ( = 0.002), spiculation ( < 0.001), tumor density ( = 0.008), air bronchogram ( < 0.001), emphysema ( < 0.001), and location ( = 0.029) were independent prognostic factors. The subgroup analysis demonstrated that pneumonic-type IMA had a significantly worse prognosis than solitary-type IMA. Moreover, for solitary-type IMAs, the most independent CT imaging biomarkers were air bronchogram and emphysema with an adjusted p value less than 0.05; for pneumonic-type IMA, the tumors with mixed consolidation and ground-glass opacity were associated with a longer DFS (adjusted = 0.012).

Conclusion: CT imaging features characteristic of IMA may provide prognostic information and individual risk assessment in addition to the recognized clinical predictors.
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http://dx.doi.org/10.3348/kjr.2020.0454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005341PMC
April 2021

Mutational Landscape and Evolutionary Pattern of Liver and Brain Metastasis in Lung Adenocarcinoma.

J Thorac Oncol 2021 02 12;16(2):237-249. Epub 2020 Nov 12.

Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, People's Republic of China. Electronic address:

Introduction: A comprehensive genomic analysis of paired primary tumors and their metastatic lesions may provide new insights into the biology of metastatic processes and therefore guide the development of novel strategies for intervention. To date, our knowledge of the genetic divergence and phylogenetic relationships among diverse metastatic lesions from cancer remains limited.

Methods: We performed whole-exome sequencing in 84 tissue and blood samples from 26 patients with lung adenocarcinoma having liver metastases (LiM) or brain metastases (BrM) before any systemic therapy, with the goal to molecularly characterize the metastatic process. Mutational landscape and evolutionary patterns were compared between paired primary lesions (primary lesion of LiM or BrM) and metastases (metastatic site of LiM or BrM).

Results: We found that common driver mutations, including TP53 and EGFR, were highly consistent between paired primary and metastatic tumors. Although tumor mutational burden was comparable among groups, the LiM group had significantly higher mutational and copy number variational similarity than the BrM group between paired primary lesions and metastases (p = 0.019 and p = 0.035, respectively). Phylogenetic analysis further revealed that LiM-competent disseminations had a higher level of genetic similarity to their paired primary lesions and were genetically diverged from their primary tumors at a relatively later stage than those of BrM. These results suggest that LiM favorably followed the linear progression model, whereas BrM was more consistent with the parallel progression model.

Conclusions: This study suggests that the mutational landscape and evolutionary pattern was distinctly different between the LiM and BrM of lung adenocarcinoma.
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http://dx.doi.org/10.1016/j.jtho.2020.10.128DOI Listing
February 2021

Prognostic impact of tumour spread through air space in radiological subsolid and pure solid lung adenocarcinoma.

Eur J Cardiothorac Surg 2021 04;59(3):624-632

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Objectives: The aim of the study was to investigate the relationship between ground-glass opacity (GGO) and tumour spread through air space (STAS), as well as their joint influence on the prognosis of stage I lung adenocarcinoma.

Methods: A total of 620 consecutive patients with surgically resected lung adenocarcinoma between January 2011 and December 2012 were reviewed retrospectively. The relevance of STAS and GGO was analysed by logistic regression, and their prognostic significance was investigated via the Kaplan-Meier method and Cox regression models. Furthermore, to determine the magnitude of the prognostic impact of GGO and STAS, we respectively performed survival analysis in subgroups according to the presence of STAS and GGO.

Results: Of all 620 cases, 26.7% were positive for STAS, and 32.9% had a GGO component. STAS was present in 10.8% of part-solid lesions and 34.9% of pure solid nodules (P < 0.001). Lepidic-predominant histologic subtype, GGO component and pathological T stage exhibited significant relevance to the presence of STAS. For the whole population, STAS and GGO component were each revealed as independent predictors for overall survival and recurrence-free survival (each with P < 0.001). Interestingly, in the GGO-present subgroup, STAS failed to significantly stratify prognosis. However, in the STAS-positive subgroup, the presence of a GGO component was independently associated with favourable oncological results.

Conclusions: STAS is associated with a GGO component, and each factor was a significant predictor for the prognosis of stage I lung adenocarcinoma. Moreover, the favourable prognostic impact of a GGO component was greater than the adverse prognostic influence of STAS, indicating that GGO is a more reliable prognostic predictor in stage I lung adenocarcinoma.
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http://dx.doi.org/10.1093/ejcts/ezaa361DOI Listing
April 2021

Evaluation of liquid based cytology in detection of EGFR mutation in NSCLC by large samples.

J Thorac Dis 2020 Sep;12(9):4941-4949

Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Background: Cytology samples are the main resources to detect driver oncogene alterations for advanced lung cancer patients. To explore the value of liquid-based cytology in the detection of epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC), we analyzed data from a large cohort of EGFR mutation-positive patients.

Methods: We analyzed the clinicopathological characteristics of 8,029 NSCLC cases tested for EGFR mutation by liquid-based cytology specimens and 1,934 NSCLC cases tested by formalin-fixed and paraffine-embedded (FFPE) samples in the Shanghai Pulmonary Hospital from September 2015 to December 2019. Before detection, we evaluated the number of tumor cells in the liquid-based cytology slide, and samples with more than 50 tumor cells and visible sediment were selected for DNA extraction after centrifugation.

Results: The positive rate of EGFR mutation in liquid-based cytology-tested cases was 47.18%, higher than the 41.37% tested through FFPE sample (P<0.01). Accordingly, the mutation rate of EGFR in adenocarcinoma (AC) and NSCLC was higher than that of the FFPE sample (60.01% . 54.15%, P<0.01; 30.54% 21.99%, P<0.01). The positive rate of EGFR mutation in pleural effusion was 62.67%, which was the highest rate among liquid-based cytology sample t (P<0.01).

Conclusions: Using quality control and standard procedure, it was found that liquid-based cytology specimen testing is a convenient and reliable method of EGFR detection, as validated by analysis of a large cohort. EGFR mutation detection should also be carried out in NSCLC patients diagnosed by cytology more than in AC patients.
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http://dx.doi.org/10.21037/jtd-20-2750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578468PMC
September 2020

Using droplet digital PCR in the detection of Mycobacterium tuberculosis DNA in FFPE samples.

Int J Infect Dis 2020 Oct 30;99:77-83. Epub 2020 Jul 30.

Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, PR China. Electronic address:

Background: Droplet digital PCR (ddPCR) is a technology that has higher sensitivity than real-time PCR for the identification of trace DNA. However, the use of ddPCR for the detection of Mycobacterium tuberculosis DNA in pathological samples has not been fully studied.

Methods: A total of 65 formalin-fixed and paraffin-embedded (FFPE) specimens were included in this study. Twenty samples with definite results for tuberculosis (TB) were used to establish the ddPCR system for TB detection. ddPCR was then conducted to detect TB DNA in the 45 patients who were classified as 'possible TB' (real-time PCR results in the gray area, Ziehl-Neelsen staining-negative, and hematoxylin and eosin staining showing morphology suspicious for TB). The clinical treatment and disease outcomes were followed to assess the accuracy of ddPCR in the detection of TB DNA.

Results: Among the 45 possible TB samples, 26 were ddPCR-positive, 12 were ddPCR-negative, and seven were in the gray area. ddPCR improved the positive rate of 57.8% (26/45) for the samples that were in the gray area by real-time PCR. Moreover, several patients received anti-TB therapy, and the effective ratio of therapy for the ddPCR-positive, ddPCR-negative, and ddPCR-gray area cases was 61.9% (13/21), 50.0% (2/4), and 33.3% (1/3), respectively.

Conclusions: ddPCR is more sensitive for detecting mild TB via FFPE samples than real-time PCR. The ddPCR method is of additional value in the diagnosis of TB from pathological samples.
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http://dx.doi.org/10.1016/j.ijid.2020.07.045DOI Listing
October 2020

Single-cell transcriptome and antigen-immunoglobin analysis reveals the diversity of B cells in non-small cell lung cancer.

Genome Biol 2020 06 24;21(1):152. Epub 2020 Jun 24.

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.

Background: Malignant transformation and progression of cancer are driven by the co-evolution of cancer cells and their dysregulated tumor microenvironment (TME). Recent studies on immunotherapy demonstrate the efficacy in reverting the anti-tumoral function of T cells, highlighting the therapeutic potential in targeting certain cell types in TME. However, the functions of other immune cell types remain largely unexplored.

Results: We conduct a single-cell RNA-seq analysis of cells isolated from tumor tissue samples of non-small cell lung cancer (NSCLC) patients, and identify subtypes of tumor-infiltrated B cells and their diverse functions in the progression of NSCLC. Flow cytometry and immunohistochemistry experiments on two independent cohorts confirm the co-existence of the two major subtypes of B cells, namely the naïve-like and plasma-like B cells. The naïve-like B cells are decreased in advanced NSCLC, and their lower level is associated with poor prognosis. Co-culture of isolated naïve-like B cells from NSCLC patients with two lung cancer cell lines demonstrate that the naïve-like B cells suppress the growth of lung cancer cells by secreting four factors negatively regulating the cell growth. We also demonstrate that the plasma-like B cells inhibit cancer cell growth in the early stage of NSCLC, but promote cell growth in the advanced stage of NSCLC. The roles of the plasma-like B cell produced immunoglobulins, and their interacting proteins in the progression of NSCLC are further validated by proteomics data.

Conclusion: Our analysis reveals versatile functions of tumor-infiltrating B cells and their potential clinical implications in NSCLC.
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http://dx.doi.org/10.1186/s13059-020-02064-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315523PMC
June 2020

Hsa-miR-217 Inhibits the Proliferation, Migration, and Invasion in Non-small Cell Lung Cancer Cells Via Targeting SIRT1 and P53/KAI1 Signaling

Balkan Med J 2020 06 9;37(1):208-214. Epub 2020 Apr 9.

Tongji University School of Medicine, Shanghai, China

Background: Brain metastasis is a major cause of cancer death in patients with lung cancer. Sirtuin 1 and hsa-miR-217 have been identified to mediate the development of non-small cell lung cancer.

Aims: To investigate the roles of hsa-miR-217, its target sirtuin 1, and the P53/KAI1 axis in the brain metastasis from non-small cell lung cancer.

Study Design: Cell culture study.

Methods: Human pulmonary adenocarcinoma brain metastasis cell line PC-14/B were incubated and treated with constructed lentiviral plasmids expressing miR-217 and/or sirtuin 1. BEAS-2B cell line was used as a control. The targeted regulation of miR-217 to sirtuin 1was examined using a dual-luciferase reporter assay. Cell proliferation, migration, invasion, and related protein expression were detected to examine the effect of the miR-217/sirtuin 1 expression on metastasis.

Results: PC-14/B cells expressed higher sirtuin 1 and lower P53 and KAI1 compared with BEAS-2B control cells (p<0.05). Sirtuin 1 was a direct target of miR-217. MiR-217 expression suppressed PC-14/B cell invasion (p=0.004), migration (p=0.001), and proliferation (p<0.05), whereas sirtuin 1 overexpression reversed all processes. sirtuin 1 expression inhibited P53, KAI1/CD82, matrix metalloproteinase-9, and β-catenin but upregulated E-cadherin protein. MiR-217 overexpression induced reverse changes.

Conclusion: Hsa-miR-217 and its target sirtuin 1 acted as metastasis suppressor and promoter gene in non-small cell lung cancer, respectively. The hsa-miR-217/sirtuin 1/P53/KAI1 metastasis regulatory pathway showed novel and crucial roles in brain metastasis from non-small cell lung cancer. This axis might be a potential target for the treatment of brain metastasis of lung cancer.
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http://dx.doi.org/10.4274/balkanmedj.galenos.2020.2019.9.91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285661PMC
June 2020

Characterization of PD-L1 protein expression and CD8 tumor-infiltrating lymphocyte density, and their associations with clinical outcome in small-cell lung cancer.

Transl Lung Cancer Res 2019 Dec;8(6):748-759

Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai 200433, China.

Background: This study aimed to characterize programmed death ligand-1 (PD-L1) expression and CD8 tumor-infiltrating lymphocytes (TILs) density, and their impact on survival in patients with surgically resected small-cell lung cancer (SCLC).

Methods: Fifty-six patients with surgically resected SCLC were included. PD-L1 protein expression and CD8 TILs were tested by immunohistochemistry. A meta-analysis of 15 articles with 1,505 patients that investigated the prevalence and prognostic significance of PD-L1 expression in SCLC was conducted.

Results: Twenty-two (39.3%) patients had positive PD-L1 protein expression and 42 (75.0%) had high CD8 TILs density. PD-L1 expression level was not associated with CD8 TILs density (P=0.528). No any association between clinicopathological features and PD-L1 expression level or CD8 TILs density was observed. Positive PD-L1 expression [hazard ratio (HR) =0.374, P=0.002] and high CD8 TILs density (HR =0.429, P=0.008) were independently associated with significantly longer overall survival (OS), which remain the statistical significance in multivariate analyses (P=0.007, P=0.002; respectively). Meta-analysis showed that the prevalence of positive PD-L1 expression was 0.35 [95% confidence interval (CI), 0.22-0.48] and positive PD-L1 expression was correlated with markedly longer OS (HR =0.61; 95% CI, 0.31-0.91) in patients with SCLC.

Conclusions: The prevalence of PD-L1 expression in surgically resected SCLC is lower than that published for NSCLC. There was no association between PD-L1 expression or CD8 TILs density and clinicopathological parameters. PD-L1 expression and CD8 TILs density was independently correlated with better outcome in patients with SCLC.
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http://dx.doi.org/10.21037/tlcr.2019.10.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976348PMC
December 2019

Comparison of the SuperARMS and ARMS for detecting EGFR mutations in liquid-based cytology specimens from NSCLC patients.

Diagn Pathol 2020 Jan 31;15(1). Epub 2020 Jan 31.

Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 200433, Shanghai, People's Republic of China.

Background: Non-surgical cytological specimens are adequate not only for accurate histological subtyping but also for molecular profiling. A modified amplification refractory mutation system polymerase chain reaction (ARMS PCR), known as SuperARMS PCR, was improved by optimizing the primers designation, which provides a higher sensitivity and specificity approach for free plasma DNA detection. It is unclear whether SuperARMS PCR detects epidermal growth factor receptor (EGFR) mutations in cytology samples. The aim of this study was to compare the EGFR mutations detected by ARMS PCR and SuperARMS PCR in cytology samples derived from advanced non-small cell lung cancer (NSCLC) patients.

Methods: From March 2016 to March 2018, a total of 234 cytological samples were obtained from primary or metastatic lesions of NSCLC, including 144 fine-needle aspirations (FNAs), 36 endobroncheal ultrasonography (EBUS) FNAs, 36 transbronchial needle aspirations (TBNAs) and 18 pleural effusion (PLEs). EGFR mutations were simultaneously detected using an ADx-ARMS EGFR kit (Amoy Diagnostics CO., ltd., Xiamen, China) and an ADx-SuperARMS EGFR kit (Amoy Diagnostics CO., ltd., Xiamen, China). Digital droplet PCR (ddPCR) and next-generation sequencing (NGS) were further used to verify the EGFR mutant inconsistent samples.

Results: All of the 234 patients with advanced or recurrent NSCLC were diagnosed and assessed by two cytopathologists, and their EGFR mutation statuses were successfully detected by ARMS and SuperARMS. Importantly, the SuperARMS and ARMS methods showed a highly concordant result of 94.0% (220/234) (95%CI: 85.0, 95.0%). The positive rate of the SuperARMS was higher than the ARMS in the cytology samples for EGFR detection (46.2% vs. 40.2%). The specific EGFR mutation sites in 16 samples (6.8%) were not completely consistent between the SuperARMS and ARMS. A total of 14 patients showed EGFR mutations when detected by SuperARMS, but by ARMS there were EGFR wild-type. Two patients were detected as having one more EGFR mutation site by SuperARMS than by ARMS. ddPCR and NGS were used to further confirm the EGFR mutations in these inconsistent samples. Eight samples had the same mutation results as the SuperARMS, and 6 samples were not verified because the remaining DNA was insufficient. A total of 78 EGFR mutation patients received Tyrosine Kinase Inhibitor (TKI) treatment. The overall objective response rate (ORR) was 88.5% (69/78) for EGFR TKI treatment.

Conclusion: SuperARMS showed a high sensitivity and specificity for EGFR detection and thus, is expected to become a routine test in the clinic to be used as a widely available, easy-to-operate and sensitive method for EGFR mutation detection in liquid-based cytology samples.
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http://dx.doi.org/10.1186/s13000-019-0910-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995041PMC
January 2020

Cell Block as a Surrogate for Programmed Death-Ligand 1 Staining Testing in Patients of Non-Small Cell Lung Cancer.

J Cancer 2020 1;11(3):551-558. Epub 2020 Jan 1.

Department of Medicine, Division of Medical Oncology, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO, USA.

Programmed death-ligand 1 (PD-L1) staining is used in clinical practice to guide the proper use of immune checkpoint inhibitors. This study aimed to investigate the accuracy of PD-L1 staining of non-small cell lung cancer (NSCLC) cytological cell block samples. Paired cytological cell block and surgical resection samples were consecutively collected from January 2016 to February 2017 in Shanghai Pulmonary Hospital, Tongji University. Two trial-validated PD-L1 assays (28-8 and SP142) were used to quantify PD-L1 expression. A total of 112 pairs of specimens were collected, including 68(60.7%) adenocarcinomas and 28(25.0%) squamous cell carcinomas. Based on a tumor proportion score (TPS) cutoff of 1% for the 28-8 and SP142 assays, PD-L1 expression was positive in 78.6% and 58.9% of surgical samples respectively, while PD-L1 expression was positive in 67.9% and 25.0% of cytological cell block samples. Based on staining by each antibody, fair to substantial concordance of PD-L1 expression was observed for cytological cell block specimens as compared to surgical resection (𝛋 ranges from 0.377 to 0.686). However, as the tumor cells in the cell block specimen increased, the consistency of PD-L1 expression increased. The concordance of PD-L1 expression in cell blocks with abundant cellularity was nearly perfect with various cutoffs (28-8: tumor cells over 400; SP142: tumor cells over 500). Cytological cell block specimens may serve as a surrogate for PD-L1 staining in patients of NSCLC when more than 400-500 cancer cells were contained (over 400 cancer cells for 28-8, over 500 cancer cells for SP142).
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http://dx.doi.org/10.7150/jca.35810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959032PMC
January 2020

Genomic landscape and its correlations with tumor mutational burden, PD-L1 expression, and immune cells infiltration in Chinese lung squamous cell carcinoma.

J Hematol Oncol 2019 07 12;12(1):75. Epub 2019 Jul 12.

Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Zheng Min Road, Shanghai, 200433, China.

Introduction: To depict the genomic landscape of Chinese early-stage lung squamous cell carcinoma (LUSC) and investigate its correlation with tumor mutation burden (TMB), PD-L1 expression, and immune infiltrates.

Methods: Whole-exome sequencing was performed on 189 surgically resected LUSC. TMB was defined as the sum of nonsynonymous single nucleotide and indel variants. CD8 tumor-infiltrating lymphocyte (TIL) density and PD-L1 expression were evaluated by immunohistochemistry. Six immune infiltrates were estimated using an online database.

Results: The median TMB was 9.43 mutations per megabase. Positive PD-L1 expression and CD8 TILs density were identified in 24.3% and 78.8%. PIK3CA amplification was associated with significantly higher TMB (P = 0.036). Frequent genetic alterations had no impact on PD-L1 expression but PIK3CA amplification and KEAP1 mutation were independently associated with significantly lower CD8 TIL density (P < 0.001, P = 0.005, respectively). Low TMB and high CD8 TIL density were independently associated with longer disease-free survival (DFS) while none of them could individually predict the overall survival (OS). Combination of TMB and PD-L1 expression or TMB and CD8 TIL density could stratify total populations into two groups with distinct prognosis. Classifying tumor-immune microenvironment based on PD-L1 expression and CD8 TIL density showed discrepant genomic alterations but similar TMB, clinical features, and OS. Notably, patients with different smoking status had distinct prognostic factors.

Conclusion: The combination of TMB, PD-L1 expression, immune infiltrates, and smoking status showed the feasibility to subgroup stratification in Chinese patients with early-stage LUSC, which might be helpful for future design of personalized immunotherapy trials in LUSC.
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http://dx.doi.org/10.1186/s13045-019-0762-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625041PMC
July 2019

MicroRNA-510 Plays Oncogenic Roles in Non-Small Cell Lung Cancer by Directly Targeting SRC Kinase Signaling Inhibitor 1.

Oncol Res 2019 Aug 14;27(8):879-887. Epub 2019 Apr 14.

Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P.R. China.

An increasing number of studies have demonstrated that microRNAs (miRNAs) may play key roles in various cancer carcinogenesis and progression, including non-small cell lung cancer (NSCLC). However, the expressions, roles, and mechanisms of miR-510 in NSCLC have, up to now, been largely undefined. In vivo assay showed that miR-510 was upregulated in NSCLC tissues compared with that in adjacent nontumor lung tissues. miR-510 expression was significantly correlated with TNM stage and lymph node metastasis. In vitro assay indicated that expressions of miR-510 were also increased in NSCLC cell lines. Downregulation of miR-510 suppressed NSCLC cell proliferation and invasion in vitro. We identified SRC kinase signaling inhibitor 1 (SRCIN1) as a direct target gene of miR-510 in NSCLC. Expression of SRCIN1 was downregulated in lung cancer cells and negatively correlated with miR-510 expression in tumor tissues. Downregulation of SRCIN1, leading to inhibition of miR-510 expression, reversed cell proliferation and invasion in NSCLC cells. These results showed that miR-510 acted as an oncogenic miRNA in NSCLC, partly by targeting SRCIN1, suggesting that miR-510 can be a potential approach for the treatment of patients with malignant lung cancer.
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http://dx.doi.org/10.3727/096504018X15451308507747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848405PMC
August 2019

PD-L1 expression and its effect on clinical outcomes of EGFR-mutant NSCLC patients treated with EGFR-TKIs.

Cancer Biol Med 2018 Nov;15(4):434-442

Department of General and Oncological Pulmonology, University Clinical Hospital Norbert Barlicki, Medical University of Lodz, Lodz 50243, Poland.

Objective: Epidermal growth factor receptor (EGFR) activation was reported to upregulate programmed death-ligand 1 (PD-L1) expression in lung cancer cells and subsequently contribute to immune escape, indicating its critical role in EGFR-driven lung tumors. This study characterized PD-L1 expression in patients with surgically resected EGFR-mutant non-small cell lung cancer (NSCLC). The effect of PD-L1 expression on clinical outcomes was also investigated in advanced EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKIs).

Methods: In total, 73 patients with surgically resected NSCLC and EGFR mutations were identified. PD-L1 expression and CD8+ tumor-infiltrating lymphocyte (TIL) density were assessed by immunohistochemistry. A literature review of publications that assessed the predictive and prognostic value of PD-L1 expression in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs was performed.

Results: Nineteen (26.0%) patients were positive for PD-L1 expression, which was significantly associated with concomitant KRAS mutation ( = 0.020) and marginally associated with higher CD8+ TILs density ( = 0.056). Positive PD-L1 expression was associated with markedly inferior overall survival (OS) in multivariate analysis ( = 0.032). The combination of PD-L1 and CD8+ TILs expression could be used to stratify the population into three groups with distinct prognoses. A meta-analysis of six publications showed that positive PD-L1 expression was not associated with OS [hazard ratio (HR) = 0.90; 95% confidence interval (CI), 0.42-1.38] or progression-free survival (HR = 1.03; 95 CI, 0.73-1.33) in advanced EGFR-mutant NSCLC patients receiving EGFR-TKIs.

Conclusions: PD-L1 expression tended to correlate with CD8+ TIL expression, concomitant KRAS mutation, and poor survival in surgically resected EGFR-mutant NSCLC. PD-L1 expression was neither the predictive nor the prognostic factor in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2018.0223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372913PMC
November 2018

Heterogeneity of PD-L1 Expression Among the Different Histological Components and Metastatic Lymph Nodes in Patients With Resected Lung Adenosquamous Carcinoma.

Clin Lung Cancer 2018 07 31;19(4):e421-e430. Epub 2018 Mar 31.

Division of Medical Oncology, Department of Medicine, University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO, USA.

Introduction: Programmed death-ligand 1 (PD-L1) expression using immunohistochemistry is approved by the US Food and Drug Administration to guide treatment with anti-programmed death-1/PD-L1 monoantibodies. However, intratumoral heterogeneity of PD-L1 expression and the accordance between primary and metastatic lesions remains unresolved.

Materials And Methods: PD-L1 expression was evaluated in tumor cells and tumor-infiltrating lymphocytes (TILs) of surgically resected lung adenosquamous carcinoma. Discrepancy of PD-L1 expression and cluster of differentiation 8-positive TILs of different histologic components was investigated. PD-L1 expression was also compared between primary tumor and nodal metastases.

Results: The study included a total of 72 lung adenosquamous carcinomas. Fifteen patients (20.8%) and 25 patients (34.7%) were positive for PD-L1 expression in adenomatous and squamous components respectively, with a cutoff value of 5%. We found that 57.8% of cases showed consistent PD-L1 expression in tumor cells in the different histological components at a cutoff of 1%, and 48.1% of cases were likewise consistent at a cutoff of 5%. In paired squamous components of metastatic nodes and primary lesions, 90% and 80% of cases of PD-L1 expression were consistent, at cutoffs of 1% and 5%, respectively. For the adenomatous component of tumor/metastasis pairs, 77.8% of cases at the 1% cutoff and 74.1% of cases at the 5% cutoff were consistent, partially attributed to the difference of predominant histologic patterns.

Conclusion: PD-L1 expression showed discrepancy in different histological components within a tumor and consistency in paired histological type between tumor and metastases. Different pathological features might contribute to the heterogeneous PD-L1 expression in patients with non-small-cell lung cancer.
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http://dx.doi.org/10.1016/j.cllc.2018.02.008DOI Listing
July 2018

Distinct clinicopathologic features, genomic characteristics and survival of central and peripheral pulmonary large cell neuroendocrine carcinoma: From different origin cells?

Lung Cancer 2018 02 15;116:30-37. Epub 2017 Dec 15.

Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address:

Background: Pulmonary large cell neuroendocrine carcinoma (LCNEC) represents a rare entity in lung cancer with dismal prognosis. In the present study, we investigated whether there are significant differences between central and peripheral tumors of LCNEC, in terms of clinicopathologic features, genomic profiles, and survival.

Methods And Materials: A total of 126 cases of LCNEC were included. The tumors with invasion of the segmental and/or lobar bronchus were classified as central LCNEC and those without as peripheral LCNEC. EGFR/BRAF/Kras mutations and ALK/ROS1 translocations were detected. Overall survival (OS) was evaluated by the Kaplan-Meier plots.

Results: The majority of LCNEC proved to be of the peripheral type (64.3%, 81/126). Central tumors were associated with smoking habit (p = 0.047), higher TNM-stage (p = 0.014) and larger tumor size (p < 0.001). Expression of neuroendocrine markers (CD56, CGA, and SYN) was not significantly different by tumor location but central tumors had higher serum levels of NSE (p = 0.004). Peripheral tumors had a higher incidence of EGFR mutations (18.8% vs. 0%, p = 0.023). ROS1 translocation was detected in 1 patient with peripheral LCNEC. RB1 protein was more frequently expressed in peripheral tumor than central tumor. The median OS was 3.71 years in the entire cohort. Peripheral tumors had better survival compared with central tumors (median OS: 4.04 vs. 1.51 years, p < 0.001). Multivariate analyses demonstrated tumor location (hazard ratio [HR], 6.07, 95% confidence interval [CI], 1.57-23.44, p = 0.009), resection status (HR, 6.58, 95% CI, 1.92-22.51, p = 0.003) and EGFR mutational status (HR, 0.18, 95% CI, 0.04-0.75, p = 0.018) were independent prognostic factors for OS.

Conclusion: Primary tumor location of LCNEC, divided into central and peripheral type, has distinct clinicopathologic features, genomic characteristics and survival. These differences are likely due to differences in the origin cells and pathogenesis of these tumors.
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http://dx.doi.org/10.1016/j.lungcan.2017.12.009DOI Listing
February 2018

MicroRNA-125a-3p downregulation correlates with tumorigenesis and poor prognosis in patients with non-small cell lung cancer.

Oncol Lett 2017 Oct 24;14(4):4441-4448. Epub 2017 Aug 24.

Department of Nuclear Medicine, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China.

MicroRNA (miR)-125a-3p is derived from the 3'-end of pre-miR-125a, which is associated with several types of cancer, such as gastric and prostate cancer, and glioma. The aim of the present study was to identify the prognostic significance of miR-125a-3p expression levels in patients with NSCLC. The gene expression omnibus database was used to analyze miR-125a-3p expression in NSCLC , and 148 NSCLC samples and 30 adjacent normal lung tissue specimens were analyzed for the expression of miR-125a-3p by qPCR. The results showed that the expression levels of miR-125a-3p in the adjacent normal tissues was higher than the expression level in the NSCLC tissues. There were several clinical parameters demonstrated to be associated with miR-125a-3p expression, such as lymph node metastasis, tumor node metastasis classification of malignant tumor stage and tumor diameter. Furthermore, high expression levels of miR-125a-3p with chemotherapy prolonged the overall survival rate and disease free survival rate compared with untreated patients with low expression of miR-125a-3p. Thus, miR-125a-3p is a significant prognostic biomarker for patients with NSCLC, from which a novel therapeutic strategy to combat NSCLC may be derived.
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http://dx.doi.org/10.3892/ol.2017.6809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649526PMC
October 2017

Element-based prognostics of occupational pneumoconiosis using micro-proton-induced X-ray emission analysis.

Am J Physiol Lung Cell Mol Physiol 2017 Dec 14;313(6):L1154-L1163. Epub 2017 Sep 14.

Department of Pneumoconiosis, Occupational Disease Clinical Research Centre, Department of Radiotherapy, Central Laboratory, Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China;

Pneumoconiosis is an occupational disease accompanied by long-term lung impairment, for which prediction of prognosis is poorly understood because of the complexity of the inhaled particles. Micro-proton-induced X-ray emission (micro-PIXE) analysis, which is advantageous for high-sensitivity, two-dimensional element mapping of lung tissues, was used to investigate element-based predictive factors of prognosis in Chinese patients with welder's and coal miner's pneumoconiosis. Chest radiographs and lung function tests showed that most of the coal miners deteriorated, whereas symptoms in some welders were alleviated after 5 yr, as determined by comparing percent vital capacity (%VC) and forced expiratory volume in the 1st second over forced vital capacity (FEV1.0/FVC) to values taken at the initial diagnosis. Micro-PIXE analysis suggested that the most abundant particulates in welder's pneumoconiosis were Fe, Mn, and Ti (metallic oxide),which were accompanied by particulates containing Si, Al, and Ca (aluminum silicate) or only Si (SiO); the most abundant particulates in coal miner's pneumoconiosis were composed of C, Si, Al, K, and Ti, which were accompanied by particulates containing Ca or Fe. Particulates containing Al, Si, S, K, Ca, and Ti (orthoclase and anorthite) were correlated with severity of fibrosis. Multivariable linear regression suggested that long-term FEV1.0/FVC decrease was independently associated with Si and smoking index, whereas %VC decrease was associated with Si and Ti. A risk index comprised of these factors was developed to predict the prognosis of pneumoconiosis. Micro-PIXE analysis is feasible for the evaluation of elemental composition and dust exposure, especially for patients whose exposure is mixed or uncertain.
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http://dx.doi.org/10.1152/ajplung.00009.2017DOI Listing
December 2017

LAG-3 Protein Expression in Non-Small Cell Lung Cancer and Its Relationship with PD-1/PD-L1 and Tumor-Infiltrating Lymphocytes.

J Thorac Oncol 2017 05 26;12(5):814-823. Epub 2017 Jan 26.

Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Electronic address:

Introduction: Immunotherapy targeting the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) checkpoint has shown promising efficacy in patients with NSCLC. Lymphocyte activating 3 gene (LAG-3) is another important checkpoint, and its role in NSCLC is still not clear. In this study we investigated lymphocyte activing 3 (LAG-3) protein expression; its correlation with PD-1, PD-L1, and tumor-infiltrating lymphocytes (TILs); and its association with survival in NSCLC.

Methods: The expression of LAG-3 (EPR4392 [Abcam, Cambridge, MA]) protein was assessed in 55 NSCLC cell lines by immunohistochemistry. LAG-3, PD-1 (NAT 105 [Cell Marque, Rocklin, CA]), and PD-L1 (22C3 [Dako, Carpenteria, CA]) protein expression was evaluated by immunohistochemistry, and TIL abundance was scored in 139 surgically resected specimens from patients with NSCLC. We also verified results in samples from 62 patients with untreated NSCLC and detected a correlation between LAG-3 expression and EGFR and KRAS mutation and echinoderm microtubule associated protein like 4 gene (EML4)-anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement.

Results: LAG-3 was not expressed on any of the 55 NSCLC cell lines. However, LAG-3 was expressed on the TILs in 36 patients with NSCLC (25.9%). Sixty patient samples (43.2%) were positive for PD-1 on the TILs, and 25 (18.0%) were positive for PD-L1 on tumor cells. Neither LAG-3 nor PD-1 was expressed on the tumor cells. LAG-3 was overexpressed on the TILs in nonadenocarcinoma compared with in adenocarcinoma (p = 0.031). LAG-3 expression on TILs was significantly correlated with that of PD-1 on TILs (p < 0.001) and PD-L1 on tumor cells (p = 0.041) but not with TIL percentage (p = 0.244). With the logistic regression model, the ORs for LAG-3 were 0.320 (95% confidence interval [CI]: 0.110-0.929) and 4.364 (95% CI: 1.898-10.031) when nonadenocarcinoma was compared with adenocarcinoma and TILs that were negative for PD-1 were compared with those positive for PD-1. Recurrence-free survival was significantly different in patients whose TILs were LAG-3-negative as opposed to LAG-3-positive (1.91 years [95% CI: 0.76-3.06] versus 0.87 years [95% CI: 0.27-1.47] [p = 0.025]). Likewise, LAG-3 status of TILs (negative versus positive) did significantly affect overall survival (OS) (3.04 years [95% CI: 2.76-3.32] versus 1.08 years [95% CI: 0.42-1.74] [p = 0.039]). Using Kaplan-Meier analysis, we found that patients with both PD-L1-negative tumor cells and LAG-3-negative TILs have longer recurrence-free survival than patients who are either PD-L1- or LAG-3-positive or both PD-L1- and LAG-3-positive (2.09 years [95% CI: 0.90-3.28] versus 1.42 years [95% CI: 0.46-2.34] versus 0.67 years [95% CI: 0.00-1.45] [p = 0.007]). In the verification stage, high expression of LAG-3 was also significantly correlated with higher expression of PD-1 on TILs (p = 0.016) and PD-L1 on tumor cells (p = 0.014). There was no correlation between LAG-3 expression and EGFR (p = 0.325) and KRAS mutation (p = 1.000) and ALK fusion (p = 0.562).

Conclusions: LAG-3 is expressed on TILs in tumor tissues of some patients with NSCLC. Its expression was higher in nonadenocarcinoma and correlated with PD-1/PD-L1 expression. LAG-3 positivity or both LAG-3 and PD-L1 positivity was correlated with early postoperative recurrence. LAG-3 was related to poor prognosis.
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http://dx.doi.org/10.1016/j.jtho.2017.01.019DOI Listing
May 2017

Incidence and physiological mechanism of carboplatin-induced electrolyte abnormality among patients with non-small cell lung cancer.

Oncotarget 2017 Mar;8(11):18417-18423

Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.

To clarify the association between carboplatin and electrolyte abnormality, a pooled-analysis was performed with the adverse event reports of non-small cell lung cancer patients. A total of 19901 adverse events were retrieved from the FDA Adverse Event Reporting System (FAERS). Pooled reporting odds ratios (RORs) and 95% CIs suggested that carboplatin was significantly associated with hyponatremia (pooled ROR = 1.57, 95% CI 1.18-2.09, P = 1.99×10-3) and hypokalemia (pooled ROR = 2.37, 95% CI 1.80-3.10, P = 5.24×10-10) as compared to other therapies. In addition, we found that dehydration was frequently concurrent with carboplatin therapy (pooled ROR = 2.01, 95% CI 1.52-2.66, P = 8.37×10-7), which may prompt excessive water ingestion and decrease serum electrolyte concentrations. This information has not been mentioned in the FDA-approved drug label and could help explain the physiological mechanism of carboplatin-induced electrolyte abnormality. In conclusion, the above results will facilitate clinical management and prompt intervention of life-threatening electrolyte imbalance in the course of cancer treatment.
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http://dx.doi.org/10.18632/oncotarget.12813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392339PMC
March 2017

Two-gene signature improves the discriminatory power of IASLC/ATS/ERS classification to predict the survival of patients with early-stage lung adenocarcinoma.

Onco Targets Ther 2016 25;9:4583-91. Epub 2016 Jul 25.

Central Lab, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.

Background: In this study, we investigated the contribution of a gene expression-based signature (composed of BAG1, BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, IL11, LCK, RND3, SH3BGR) to survival prediction for early-stage lung adenocarcinoma categorized by the new International Association for the Study of Lung Cancer (IASLC)/the American Thoracic Society (ATS)/the European Respiratory Society (ERS) classification. We also aimed to verify whether gene signature improves the risk discrimination of IASLC/ATS/ERS classification in early-stage lung adenocarcinoma.

Patients And Methods: Total RNA was extracted from 93 patients with pathologically confirmed TNM stage Ia and Ib lung adenocarcinoma. The mRNA expression levels of ten genes in the signature (BAG1, BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, IL11, LCK, RND3, and SH3BGR) were detected using real-time polymerase chain reaction. Each patient was categorized according to the new IASLC/ATS/ERS classification by accessing hematoxylin-eosin-stained slides. The corresponding Kaplan-Meier survival analysis by the log-rank statistic, multivariate Cox proportional hazards modeling, and c-index calculation were conducted using the programming language R (Version 2.15.1) with the "risksetROC" package.

Results: The multivariate analysis demonstrated that the risk factor of the ten-gene expression signature can significantly improve the discriminatory value of TNM staging in survival prediction, but not the value of the IASLC/ATS/ERS classification. Further analysis suggested that only BRCA1 and ERBB3 in the signature were independent risk factors after adjusting for the IASLC/ATS/ERS classification by Cox regression. A new algorithm of the two-gene expression signature containing BRCA1 and ERBB3 was generated. Adding the two-gene signature into the IASLC/ATS/ERS classification model further improved the discriminatory c-statistic from 0.728 to 0.756.

Conclusion: The two-gene signature composed of BRCA1 and ERBB3 was an independent risk factor of the IASLC/ATS/ERS classification, which can be used to improve the discriminatory power of prognosis prediction of the IASLC/ATS/ERS classification in early-stage lung adenocarcinoma. The two-gene signature combination with the IASLC/ATS/ERS classification might contribute to better patient stratification for adjuvant chemoradiotherapy or targeted therapy after the surgery.
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http://dx.doi.org/10.2147/OTT.S107272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966694PMC
August 2016
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