Early Non-small Cell Lung Cancer Patients Research Articles

Effect of SBRT plus immunotherapy on immune status and survival quality of NSCLC patients: A study of combined radiotherapy and immunotherapy.

non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancer populations. Stereotactic radiotherapy (SBRT) is mainly suitable for early NSCLC patients who are not suitable for surgery or refuse surgery. To analyze the effects of stereotactic radiotherapy (SBRT) plus immunotherapy for non-small cell lung cancer (NSCLC) patients on their immune status and survival quality. NSCLC patients admitted to our hospital from 2019-2022 were divided into 61 cases in control group (SBRT) and 60 cases in observation group (SBRT plus immunotherapy) by the randomized numerical table method to compare the efficacy, the level of tumor markers in the serum, the level and activity of the immune cells in the peripheral blood and the Kahlil's functional status (KPS) scores. The observation group had a higher efficacy rate than that of the control group (P< 0.05). There was no statistical difference between the two groups in serum tumor marker content, immune cell level and activity in peripheral blood and KPS score before treatment (P> 0.05). After treatment, serum tumor markers were lower than those in control group, and immune cell level, NK cell-related activity and KPS score were higher than those in control group (P< 0.05). SBRT plus immunotherapy can reduce the level of various tumor markers, improve the immune status and quality of survival for NSCLC patients.

Preoperative small airway dysfunction is associated with skeletal muscle loss in early-stage non-small cell lung cancer

Postoperative skeletal muscle loss (SM loss) was reported to be associated with a poor prognosis in early-stage non-small cell lung cancer (NSCLC). Small airway dysfunction (SAD) is a common but neglected respiratory abnormality. Little information is known about the association between preoperative SAD and postoperative SM loss in early-stage NSCLC. Therefore, this study aimed to investigate the correlation between preoperative SAD and SM loss after surgery in early-stage NSCLC patients. There were 348 NSCLC patients with stages I-IIIA in this study from January 2017 to December 2020. All CT images were contrast-enhanced scans, and the skeletal muscle index (SMI) was measured using CT images. A 10.0% decrease in SMI over 12 months was determined as the cut-off value to define excessive SM loss. Logistic regression analyses were used to examine the relationship between SAD and SM loss. This study included 348 subjects who underwent pulmonary operation (159 males and 189 females; mean age: 57.5±8.8 years). 152 (43.7%) patients were identified as having SAD before surgery, and 179 patients (51.4%) were identified as having SM loss after 1 year. Moreover, a higher incidence of SAD was found in the SM loss group compared with that in the non-SM loss group (52.0% vs. 34.9%, p=0.001). The patients with SAD were older, had larger tumor size, and had lower albumin levels. Furthermore, there were significant correlations between the lung function parameters manifesting SAD and the percentage change in SMI (for the forced expiratory flow when 75% of forced vital capacity has been exhaled (FEF75%), Pearson r=-0.107, p=0.046; for FEF50%, r=-0.142, p=0.008; and for FEF25-75%, r=-0.124, p=0.021; respectively). However, no significant correlations were found between SMI and the lung function parameters reflecting proximal airway obstruction (p>0.05). Logistic regression analysis revealed that preoperative SAD (HR, 2.465; 95% CI, 1.256-4.838; p=0.009) was independent risk factor for postoperative SM loss in early-stage NSCLC. In addition, multivariable analysis revealed that SAD (HR, 1.816; 95% CI, 1.025-3.216, P=0.041) were associated with postoperative complications. Preoperative SAD is significantly associated with postoperative complications and SM loss in early NSCLC patients. Our results suggest that preoperative assessment of SAD may be useful for risk stratification of surgical candidates with potential for targeted interventions.

Location of CD39+ T cell subpopulations within tumors predict differential outcomes in non-small cell lung cancer

PurposeAn improved mechanistic understanding of immunosuppressive pathways in non-small cell lung cancer (NSCLC) is important to develop novel diagnostic and therapeutic approaches. Here, we investigate the prognostic significance of the...

Analysis of Diagnostic Value of CTC and CTDNA in Early Lung Cancer.

This paper is the exploration and analysis of the diagnostic value of circulating tumor cells (CTC) and circulating tumor deoxyribonucleic acid (ctDNA) in early non-small cell lung cancer (NSCLC).A total of 125 NSCLC patients that hospitalized from March 2019 to December 2020 were selected, of which 64 subjects with stage I-II were listed as the early-stage group, and 61 patients with stage III-IV were classified as the intermediate-advanced group; In addition, 47 patients with benign pulmonary nodules hospitalized within same period were selected as a group of benign pulmonary nodules, and 50 healthy subjects were enrolled as a control group. The levels of CTC and ctDNA, serum tumor markers carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratin 21-1 (CYFRA21-1) and gastrin-releasing peptide precursor (pro-GRP) were detected. The diagnostic value of CTC and ctDNA in early NSCLC patients was analyzed by ROC curve. The area under the curve of CTC count for early-stage lung cancer was 0. 949 (P=0. 000, 95%CI: 0. 918-0. 980), and ctDNA was 0. 914 (P=0. 000, 95%CI: 0. 866~0. 963). There were significant differences in CTC count and ctDNA among subjects in each group (P<0. 05). CTC count and ctDNA of the early and intermediate-advanced group were remarkably higher than those of the control group and group of benign pulmonary nodules (P<0. 05), and CTC count and ctDNA of patients in the middle-late group were critically higher than those in the early-stage group (P<0. 05). There were significant differences in serum CEA, NSE, CYFRA21-1 and pro-GRP levels among all groups (P<0. 05). The results showed that CTC and ctDNA in NSCLC patients were significantly positively correlated with CEA, NSE, CYFRA21-1 and pro-GRP (P<0. 05). Peripheral blood CTC and ctDNA levels are significantly increased in NSCLC patients. They are positively correlated with serum tumor markers CEA, NSE, CYFRA21-1 and pro-GRP levels, and are related to tumor progression. CTC and ctDNA have high value in the clinical diagnosis of early NSCLC.

Prognostic value of postoperative ctDNA detection in patients with early non-small cell lung cancer: a systematic review and meta-analysis.

Circulating tumor DNA (ctDNA) has emerged as a potential biomarker for monitoring early non-small cell lung cancer (ENSCLC), particularly after radical surgery. However, the prognostic value of postoperative ctDNA is still being investigated due to the small sample size and heterogeneity of patients with ENSCLC in current trials. Moreover, the potential clinical utility of ctDNA assessment for administering adjuvant therapy (AT) in patients with ENSCLC is also an important area of active research. We aimed to identify the prognostic value of postoperative ctDNA detection in ENSCLC patients with stages I-III. This study type is a systematic review and meta-analysis. We conducted a search in the Cochrane Library, Embase, PubMed, and ScienceDirect for prospective or retrospective investigations involving patients with ENSCLC, gathering outcomes based on predefined end points. The literature review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the Newcastle-Ottawa scale was employed to carry out a quality evaluation of the included studies. The primary end point of the study was to evaluate the association of ctDNA status in two time points (within 1 month after surgery and long-term postoperative monitoring with more than 3 months) with relapse-free survival (RFS) and overall survival (OS). In addition, the study investigated the role of ctDNA in predicting the response to AT. The secondary end points of the study were to determine the impact of ctDNA on RFS and OS in different subgroups of ENSCLC patients based on pathological subtypes and TNM staging. In total, 2149 studies were screened, and 11 studies met the inclusion criteria for the analysis. The presence of ctDNA within 1 month after surgery as well as long-term postoperative ctDNA were both associated with poorer RFS [hazard ratio (HR) = 4.43; 95% CI: 3.23-6.07 and HR = 7.99; 95% CI: 3.28-19.44, respectively] and worse OS (HR = 5.07; 95% CI: 2.80-9.19 and HR = 7.49; 95% CI: 3.42-16.43, respectively). Most subgroup analyses yielded similar results. Moreover, ctDNA-positive patients could acquire survival benefits from AT (HR = 0.30; 95% CI: 0.16-0.54), while ctDNA-negative patients that received AT did not show significant improvement in RFS (HR = 1.18; 95% CI: 0.67-2.09). The postoperative ctDNA assessment is a promising approach to stratify the risk of relapse and death in ENSCLC patients. Our data suggest that patients with negative ctDNA in the postoperative setting may not benefit from AT, which warrants further investigation. This finding, if validated in prospective trials with a larger sample size, could aid in better-individualized treatment for patients and avoid potential side effects of AT. This study was designed in accordance with PRISMA and registered with PROSPERO (CRD42022311615).

EP01.01-008 Expression of PD-L1 mRNA and Its Epigenetic Regulators: MicroRNA-17, -93 and -142 in Early Stages NSCLC Patients’ Plasma

One of the leading treatment options for advanced non-small cell lung cancer (NSCLC) patients is immunotherapy based on immune checkpoint inhibitors, including programmed death ligand 1 (PD-L1) inhibitors. PD-L1 molecule expressed on tumor cells causes PD-1+ tumor infiltrating lymphocytes (TILs) exhaustion and thus escape from immune surveillance. Blockade of the PD-1/PD-L1 pathway by monoclonal antibodies enables restoration of the anti-tumor response. PD-L1 expression is regulated by epigenetic factors, e.g.: microRNAs (miRNAs).

Evaluation of response to stereotactic body radiation therapy for nonsmall cell lung cancer: PET response criteria in solid tumors versus response evaluation criteria in solid tumors.

Recommendations for surveillance after stereotactic body radiation therapy (SBRT) for early-stage nonsmall cell lung cancer (NSCLC) are not well defined. Recently, PET response criteria in solid tumors (PERCIST) have been proposed as a new standardized method to assess radiotherapeutic response both quantitatively and metabolically. The aim of this study was to evaluate therapeutic response following SBRT in early-stage NSCLC patients by comparing PERCIST with the currently widely used RECIST. Forty-nine patients with early-stage NSCLC who had been prescribed SBRT were studied. Responses of lesion were evaluated using CT and 18F-FDG PET according to the RECIST and PERCIST methods. PET-CT scans were obtained before SBRT and 3-6 months after SBRT. Associations between overall survival (OS) and clinicopathologic results (histology, tumor location, tumor size, lymphatic invasion, clinical stage, and radiotherapeutic responses in RECIST and PERCIST) were statistically analyzed. The median patient follow-up was 30 months. Thirteen patients had stage IA, 9 stage IB, 10 stage IIA, and 17 stage IIB biopsy-proven NSCLC. Three-year OS was 79.6%. CT scans indicated three regional recurrences. PET-CT/chest indicated three regional recurrences and distant metastasis. Significant differences were observed in response classification between RECIST and PERCIST (Wilcoxon signed-rank test, P = 0.0041). Univariate analysis showed that clinical stage, RECIST, and PERCIST were significant factors associated with OS, whereas by multivariate analysis PERCIST was the only predictor of OS. SMD, PMD/PMR, and CMR in PERCIST criteria were indicative of a 9.900-fold increase in the risk of OS in early NSCLC patients [risk ratio, 9.900 (95% CI, 1.040-21.591); P = 0.001]. RECIST based on the anatomic size reduction rate did not demonstrate the correlation between radiotherapeutic response and prognosis in patients with early-stage NSCLC receiving SBRT. However, PERCIST was shown as the strongest independent predictor of outcomes. PERCIST might be considered more suitable for the evaluation of NSCLC tumor response to SBRT than RECIST.

Systemic Immune Dysregulation Correlates With Clinical Features of Early Non-Small Cell Lung Cancer.

BackgroundSystemic immune dysregulation correlates with cancer progression. However, the clinical implications of systemic immune dysregulation in early non-small cell lung cancer (NSCLC) remain unclear.MethodsUsing a panel of 9 markers to identify 12 parameters in the peripheral blood of 326 patients (34 in the discovery group and 292 in the validation group), we investigated systemic immune dysregulation in early NSCLC. Then, we analyzed the impact of surgery on the systemic immune state of these patients. Finally, we analyzed correlations between systemic immune dysregulation and the clinical features of early NSCLC.ResultsWe found striking systemic immune dysregulation in the peripheral blood of early NSCLC patients. This dysregulation was characterized by a significant decrease in total lymphocytes, T cells, quiescent T cells, CD4+ T cells, and NKT cells. We also observed increased proportions of activated lymphocytes and activated T cells. Systemic immune dysregulation was increased after surgery. Furthermore, systemic immune dysregulation was correlated with multiple clinical features, such as sex, age, smoking history, pathological type, tumor stage, surgical approach, tumor differentiation, and epidermal growth factor receptor (EGFR) mutation. Finally, we observed that systemic immune dysregulation was correlated with complications and systemic inflammatory response syndrome (SIRS) in early NSCLC patients.ConclusionsOur results reveal systemic immune dysregulation occurring in early NSCLC and demonstrate the correlation between these dysregulations and clinical features. Our findings suggest that systemic immune dysregulation is involved in cancer development and may be a promising candidate for high-risk screening and treatment strategies for early NSCLC.

Revealing the subtyping of non-small cell lung cancer based on genomic evolutionary patterns by multi-region sequencing.

Accurately classifying patients with non‐small cell lung cancer (NSCLC) from the perspective of tumor evolution has not been systematically studied to date. Here, we reconstructed phylogenetic relationships of somatic mutations in 100 early NSCLC patients (327 lesions) through reanalyzing the TRACERx data. Based on the genomic evolutionary patterns presented on the phylogenetic trees, we grouped NSCLC patients into three evolutionary subtypes. The phylogenetic trees among three subtypes exhibited distinct branching structures, with one subtype representing branched evolution and another reflecting the early accumulation of genomic variation. However, in the evolutionary pattern of the third subtype, some mutations experienced selective sweeps and were gradually replaced by multiple newly formed subclonal populations. The subtype patients with poor prognosis had higher intra‐tumor heterogeneity and subclonal diversity. We combined genomic heterogeneity with clinical phenotypes analysis and found that subclonal expansion results in the progression and deterioration of the tumor. The molecular mechanisms of subtype‐specific Early Driver Feature (EDF) genes differed across the evolutionary subtypes, reflecting the characteristics of the subtype itself. In summary, our study provided new insights on the stratification of NSCLC patients based on genomic evolution that can be valuable for us to understand the development of pulmonary tumor profoundly.

Immune microenvironment composition in non-small cell lung cancer and its association with survival.

ObjectivesIn non‐small cell lung cancer (NSCLC), the immune system and possibly its composition affect survival. In this in silico study, the immune infiltrate composition in NSCLC patients was evaluated.MethodsGene expression data of tumors from early NSCLC patients were obtained from Gene Expression Omnibus (GEO). With CIBERSORT, 22 immune cell fractions were estimated.ResultsThe immune infiltrate of 1430 pretreatment NSCLC patients contained mostly plasma cells, macrophages and CD8 T cells. Higher fractions of resting mast and CD4 T‐helper cells were associated with longer overall survival (OS) (HR = 0.95, P < 0.01; HR = 0.98, = 0.04, respectively) and higher fractions of M2 macrophages and active dendritic cells with shorter survival (HR = 1.02, P = 0.03; HR = 1.03, P = 0.05, respectively). Adenocarcinoma patients with survival data (n = 587) showed higher fractions of resting mast and resting CD4 T cells, and lower M0 macrophages than squamous cell carcinoma (n = 254), which were associated with OS (HR = 0.95, P = 0.04; HR = 0.97, P = 0.01; HR = 1.03, P = 0.01, respectively). Fractions of memory B cells, naïve CD4 T cells and neutrophils had different associations with survival depending on the subtype. Smokers had had higher fractions of regulatory T cell, follicular helper T cell, neutrophil and M2 macrophage, which were associated with shorter survival (HR = 1.3, P < 0.01; HR = 1.13, P = 0.02; HR = 1.09, P = 0.03; HR = 1.04, P = 0.02, respectively).ConclusionPretreatment differences in immune cell composition in NSCLC are associated with survival and depend on smoking status and histological subtype. Smokers' immune composition is associated with lower survival.

TMPRSS4: A Novel Tumor Prognostic Indicator for the Stratification of Stage IA Tumors and a Liquid Biopsy Biomarker for NSCLC Patients.

Relapse rates in surgically resected non-small-cell lung cancer (NSCLC) patients are between 30% and 45% within five years of diagnosis, which shows the clinical need to identify those patients at high risk of recurrence. The eighth TNM staging system recently refined the classification of NSCLC patients and their associated prognosis, but molecular biomarkers could improve the heterogeneous outcomes found within each stage. Here, using two independent cohorts (MDA and CIMA-CUN) and the eighth TNM classification, we show that TMPRSS4 protein expression is an independent prognostic factor in NSCLC, particularly for patients at stage I: relapse-free survival (RFS) HR, 2.42 (95% CI, 1.47–3.99), p < 0.001; overall survival (OS) HR, 1.99 (95% CI, 1.25–3.16), p = 0.004). In stage IA, high levels of this protein remained associated with worse prognosis (p = 0.002 for RFS and p = 0.001 for OS). As TMPRSS4 expression is epigenetically regulated, methylation status could be used in circulating tumor DNA from liquid biopsies to monitor patients. We developed a digital droplet PCR (ddPCR) method to quantify absolute copy numbers of methylated and unmethylated CpGs within the TMPRSS4 and SHOX2 (as control) promoters in plasma and bronchoalveolar lavage (BAL) samples. In case-control studies, we demonstrated that TMPRSS4 hypomethylation can be used as a diagnostic tool in early stages, with an AUROC of 0.72 (p = 0.008; 91% specificity and 52% sensitivity) for BAL and 0.73 (p = 0.015; 65% specificity and 90% sensitivity) for plasma, in early stages. In conclusion, TMPRSS4 protein expression can be used to stratify patients at high risk of relapse/death in very early stages NSCLC patients. Moreover, analysis of TMPRSS4 methylation status by ddPCR in blood and BAL is feasible and could serve as a non-invasive biomarker to monitor surgically resected patients.

1446P - Immunological impact of surgery in NSCLC patients

BackgroundImmune checkpoint inhibitors (ICI) improve survival in patients with advanced non-small cell lung cancer (NSCLC) and have become one of standard therapy. It was demonstrated that nivolumab therapy for resectable NSCLC patients prior to surgery resulted in major pathological responses in 40% of the patients. On the other hand, adjuvant nivolumab therapy for melanoma resulted in longer recurrence-free survivals. Thus, it is still uncertain which host immunological status is appropriate for ICI therapy, before or after surgery. In this study, we examined the peripheral blood, and tumor tissues to elucidate immunological impact of surgery in NSCLC patients. MethodsThe present study comprised of 20 surgically resectable early (stage I, II, or IIIA) NSCLC patients in Saitama Medical University International Medical Center. Peripheral blood samples were collected before and after surgical resection of NSCLC. PBMCs were analyzed with LSR FortessaTM. ResultsInterestingly, more effector memory (EM) CCR7-CD45RA- CD8+ T cells and CD62Llow CD4+ T cells were observed in early stage NSCLC patients, compared with stage IV NSCLC patients. Significant decrease of the percentages of EM CD8+ T cells (P=0.0045) and CD62Llow CD4+ T cells (P<0.0001) were detected after surgical removal of cancer. In contrast, central memory (CM) CCR7+CD45RA- CD8+ T cells significantly increased (P=0.0037). It is likely that the decrease of EM CD8+ T cells and CD62Llow CD4+ T cells reflected conversion of EM T cells to CM T cells due to disappearance of cancer antigens, because the decrease was not observed in the patients of incomplete resection. PD-1 expression on both CD8+ and CD4+ T cells was up-regulated after surgery. The percentages of myeloid derived suppressor cells (MDSC) (P<0.0001) increased and natural killer cells (NK) decreased (P=0.0001). ConclusionsAfter surgical removal of lung cancer, EM type T cells were converted to CM type T cells. It seems that surgery may have negative influence for innate immunity. Because PD-1 blockade therapy only activates primed effector T cells, the immunological status before surgery seems more appropriate for ICI therapy. Legal entity responsible for the studySaitama Medical University International Medical Center. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Somatic Alteration Burden Involving Non-Cancer Genes Predicts Prognosis in Early-Stage Non-Small Cell Lung Cancer.

The burden of somatic mutations and neoantigens has been associated with improved survival in cancer treated with immunotherapies, especially non-small cell lung cancer (NSCLC). However, there is uncertainty about their effect on outcome in early-stage untreated cases. We posited that the burden of mutations in a specific set of genes may also contribute to the prognosis of early NSCLC patients. From a small cohort of 36 NSCLC cases, we were able to identify somatic mutations and copy number alterations in 865 genes that contributed to patient overall survival. Simply, the number of altered genes (NAG) among these 865 genes was associated with longer disease-free survival (hazard ratio (HR) = 0.153, p = 1.48 × 10−4). The gene expression signature distinguishing patients with high/low NAG was also prognostic in three independent datasets. Patients with a high NAG could be further stratified based on the presence of immunogenic mutations, revealing a further subgroup of stage I NSCLC with even better prognosis (85% with >5 years survival), and associated with cytotoxic T-cell expression. Importantly, 95% of the highly-altered genes lacked direct relation to cancer, but were implicated in pathways regulating cell proliferation, motility and immune response.

Unique Protein Profiles of Extracellular Vesicles as Diagnostic Biomarkers for Early and Advanced Non-Small Cell Lung Cancer.

Extracellular vesicles (EVs) mediate intercellular communication via transferring proteins and other biological molecules and have been recently investigated as biomarkers of disease. Sensitive and specific biomarkers are required for lung cancer diagnosis and prognosis. The present study screens for abnormal EV proteins in non-small cell lung cancer (NSCLC) using a quantitative proteomics strategy involving LC-MS/MS to identify ideal biomarkers for NSCLC diagnosis. EVs are enriched from the sera of early and advanced NSCLC patients and healthy controls and from cell culture supernatants of lung adenocarcinoma and bronchial epithelial cell lines. In the sera and supernatants, 279 and 632 differentially expressed proteins, respectively, are associated with signaling pathways including extracellular membrane-receptor interaction, focal adhesion, and regulation of the actin cytoskeleton. Thirty-two EV proteins are identified at the intersection of differentially expressed proteins between the NSCLC groups and cell lines. Based on bioinformatics analysis, in silico immunohistochemical, and PRM verification, fibronectin is selected for following in vitro studies and validation with an independent cohort. Fibronectin on EVs is estimated to perform well in the diagnosis of NSCLC patients based on AUC, showing great potential for clinical use and demonstrating the efficacy of this method for EV-associated biomarker screening.

Preliminary Study on the Biological Markers for I-IIb Stage Non-small Cell Lung Cancer Based on a Serum-peptidomics

背景与目的非小细胞肺癌是发病率最高的一种肺恶性肿瘤，早发现、早诊断、早治疗是其治疗原则，因其发病隐匿，缺乏早期筛查的特异性标志物，多数患者就诊时已处于晚期阶段，导致其5年生存率较低，预后不理想。探索一种敏感的生物学标志物，是目前肺癌诊疗的重点。本文基于差异多肽组学技术，旨在筛选Ⅰ期-Ⅱb期非小细胞肺癌的血清生物标志物。方法利用纳升超高效液相色谱联合四级杆轨道阱质谱技术，比较和筛选正常健康人群、肺部良性病变患者、非小细胞肺癌患者血清中的差异多肽片段，通过对目标肽段的鉴别和定量分析，探寻非小细胞肺癌早期诊断的肿瘤生物标志物。结果通过与人类蛋白质组数据库进行比对，共鉴定到545个多肽，分别来自118个蛋白。将各组样本中肽段的谱图数进行比较，共筛选出201个差异多肽，经定量分析发现峰面积的变异系数（coefficient of variation, CV）≤30%的目标肽段共计7个，其中在各组间呈趋势变化的有2条肽段，分别是肺癌组中表达下调的肽段QGAKIPKPEASFSPR和肺癌组中表达上调的肽段CDDYRLC，它们分别来自于中间α球蛋白抑制因子H4蛋白（ITIH4）和基质γ-羧基谷氨酸蛋白（MGP）。结论将血清多肽组学用于筛选肿瘤标志物的研究，可为非小细胞肺癌的早期诊断提供新线索，其中ITIH4与MGP蛋白水解的特异性肽段是潜在早期非小细胞肺癌患者的血清标志物。

Inoperable early-stage primary and early recurrent non-small cell lung cancer: outcomes of a mono-institutional experience using a moderate hypofractionated schedule

Patients with medically inoperable early-stage non-small cell lung cancer (NSCLC) may beneficiate of a hypofractionated radiation therapy in order to intensificate the treatment and to reduce the number of hospital access. From 2007 to 2015, 27 patients with early-stage primary or limited loco-regional recurrent (T2a > 4cm, T2b N0 or T1-2 N1M0) NSCLC were treated. All patients were medically inoperable or refused surgery and were treated with 60Gy in 20 fractions, 5 times per week. Thirteen (48.1%) presented limited recurrence after surgery and 14 (51.9%) primary disease. Median follow-up was 34months. Twelve patients achieved a CR (44.4%) and 8 a PR (29.6%) with a tumour response rate of 74%. Median overall survival (OS) and 2-year OS were 34months and 63.0%, respectively. Median and 2-year loco-regional progression-free survival (LR-PFS) were 31months and 51.4%, respectively. Survival outcomes were statistically favourable in patients with partial or complete response with respect to patients with stable or progressive disease, whereas stage (N0 vs N1) and primary or relapse/recurrent disease not. No cases of acute toxicity > grade 2 were observed. Seven patients (25.9%) presented grade 2 late toxicities. Sixty Gy in 20 fractions is well tolerated and achieves good clinical outcomes in early primary or recurrent NSCLC patients. A greater number of patients and a longer follow-up are necessary to confirm the results obtained with our treatment.

Exosomal miR-126 as a circulating biomarker in non-small-cell lung cancer regulating cancer progression

Lung cancer is one of the leading causes of cancer-related deaths. It is diagnosed mostly at the locally advanced or metastatic stage. Recently, micro RNAs (miRs) and their distribution in circulation have been implicated in physiological and pathological processes. In this study, miR-126 was evaluated in serum, exosome and exosome-free serum fractions in non-small cell lung cancer (NSCLC) patients at early and advanced stages, and compared with healthy controls. Down-regulation of miR-126 was found in serum of advanced stage NSCLC patients. In healthy controls, circulating miR-126 was equally distributed between exosomes and exosome-free serum fractions. Conversely, in both early and advanced stage NSCLC patients, miR-126 was mainly present in exosomes. Different fractions of miR-126 in circulation may reflect different conditions during tumour formation. Incubation of exosomes from early and advanced NSCLC patients induced blood vessel formation and malignant transformation in human bronchial epithelial cells. On the other hand, exosome-enriched miR-126 from normal endothelial cells inhibited cell growth and induces loss of malignancy of NSCLC cells. These findings suggest a role of exo-miRs in the modulation of the NSCLC microenvironmental niche. Exosome-delivered miRs thus hold a substantial promise as a diagnostics biomarker as well as a personalized therapeutic modality.

Patient reported outcomes following video assisted thoracoscopic (VATS) resection or stereotactic ablative body radiotherapy (SABR) for treatment of non-small cell lung cancer: protocol for an observational pilot study (LiLAC).

Lung cancer is increasingly a disease of the elderly and frail population with a median age of 70 years at diagnosis. Therefore, consideration of the impact of interventions on health-related quality of life (HRQOL) and not only absolute survival is especially important. For non-small cell lung cancer (NSCLC), video-assisted thoracoscopic surgery (VATS) has been gaining popularity over the last few decades, replacing traditional open lobectomies. For high-risk patients who are not deemed suitable for surgery, stereotactic ablative body radiotherapy (SABR) provides a potentially curative alternative. However, little is known about how VATS and SABR affect HRQOL measured using patient reported outcome measures (PROMs). The LiLAC study (Life after Lung Cancer) aims to explore HRQOL following intervention with VATS or SABR using validated PROMs and to pilot the use of an online questionnaire system (QTool) in this setting. We hope the results will aid both patients and clinicians in decision making and improve the management of post-intervention problems. In total, 300 patients (150 VATS and 150 SABR) patients will be recruited over the study period. Patients will be approached prior to intervention and asked to complete baseline HRQOL questionnaires. They will be given access to the QTool online system and then in the 12 months following intervention will be asked to complete questionnaires (paper or online) at 4-time points. Answers will available for patients and clinicians to view throughout the study period. Clinical information (age, gender, co-morbidity, current medications and smoking status along with treatment-specific information) will also be collected. Primary outcome will be to detect changes of PROs (HRQOL and patient satisfaction) after VATS lung resections or SABR in early stage lung cancer patients. Secondary outcomes include correlation of patient's clinical data with HRQOL results to identify predictors of poor outcomes and exploration of patient and clinician views on the usefulness of QOL measurements. (I) This first study will primarily compare multiple patients reported outcomes for 12 months after VATS lobectomy and SABR in early stages NSCLC patients. We will explore the acceptability of an online assessment of the HRQOL in NSCLC patients. (II) The study is also focused on the patients' opinion during the shared decision-making process, which has rarely been investigated in surgical lung cancer patients. (III) This is not a randomised trial. As a consequence, inherent cohort selection bias and unknown or unaccounted confounders correlated with the outcome of interest may influence the results of the comparison between the treatment groups. (IV) LILAC is not looking at a direct comparison, but to depict the trajectory of recovery post-treatments and preservation or improvement of the HRQOL. This study has received ethical approval from NRES Yorkshire and the Humber- Leeds East Research Ethics Committee (REC Ref: 16/YH/0407). Results of this study will be shared with participating hospitals and made available to the academic community through submission for publication in international peer-reviewed journals and presentation at relevant national and international conferences. ClinicalTrials.gov Identifier: NCT02882750.

Prospective evaluation of anxiety, depression and quality of life in medically inoperable early stage non-small cell lung cancer patients treated with stereotactic ablative radiotherapy.

The aim of this prospective study was to evaluate the level of anxiety, depression, and quality of life (QoL) in medically inoperable patients with early stage non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR). Prolonged survival is equally important as maintaining high QoL and good psychological functioning during the treatment of lung cancer. Nowadays available SABR has markedly changed clinical care and outcomes in the group of medically inoperable patients. To our knowledge, analysis of QoL and psychological state has not been performed in Polish patients with early NSCLC treated with SABR. Research group consisted of medically inoperable, early NSCLC (T1-2aN0M0) patients qualified to SABR. Patients were asked to complete Polish versions of the European Organization for Research and Treatment of Cancer Quality of Life - Core Questionnaire (EORTC QLQ-C30) with the Lung Cancer Questionnaire (LC13) and Hospital Anxiety and Depression Scale (HAD). These questionnaires were repeated 2 weeks and then 3 months after treatment completion. We enrolled 51 patients who met the inclusion criteria. SABR did not deteriorate QoL and psychological functioning. On the contrary, clinically meaningful improvement was observed in emotional functioning, level of insomnia, anxiety and depression. Significantly worse improvement was shown in patients with chronic obstructive pulmonary disease (COPD). Our results confirm that SABR is well tolerated and does not have a deleterious effect on QoL and psychological state. Results of our study indicate the importance of additional psychological care in the group of patients with COPD.

The associations of TERT-CLPTM1L variants and TERT mRNA expression with the prognosis of early stage non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related death in the world. Several genome-wide association studies (GWAS) have identified TERT-CLPTM1L as plausible causative locus for lung cancer development. This study aimed to investigate the associations of genetic variations in TERT-CLPTM1L and the expression level of TERT with the survival of early stage non-small cell lung cancer (NSCLC) patients. We selected three single-nucleotide polymorphisms of TERT-CLPTM1L (rs2853669, rs2736108 and rs31490) and genotyped in 140 early stage NSCLC patients by TaqMan assay. Associations between these variations and survival outcome of early stage NSCLC patients were further investigated. We also used TCGA data to evaluate the associations of TERT messenger RNA (mRNA) expression and survival outcome of early stage NSCLC patients. Survival analysis showed that, compared with early NSCLC patients carrying TERT rs2853669 TT+TC genotypes, patients with rs2853669 CC genotype had significantly longer median survival time (MST=102.2 vs 52.4 months; log-rank P=0.028) and lower death risk [hazard ratio (HR) with 95% confidence interval (CI))=0.38(0.17-0.82), P=0.014]. Early NSCLC patients carrying TERT rs2736108 AA genotype had significantly shorter MST (MST=29.0 vs 63.3 months; log-rank P=0.020) and increased death risk [HR (95% CI)=2.22(1.01-5.80), P=0.046], when compared with patients carrying rs2736108 GG genotypes. TCGA data revealed that early NSCLC patients with higher expression level of TERT mRNA in lung tumor tissues had a longer MST and decreased death risk than those with low expression level of TERT mRNA [MST=54.4 vs 49.0 months; log-rank P=0.041; adjusted HR (95% CI)=0.68(0.50-0.94)]. These findings may add potential evidence to understand the prognostic value of TERT and provide a new prospect of individualized prevention and treatment for early stage NSCLC.