Primary Non-small Cell Lung Cancer Research Articles

Prise en charge des stades précoces des cancers bronchiques non à petites cellules : radiothérapie en conditions stéréotaxiques

Surgery remains the reference treatment for primary non-small cell lung cancer (NSCLC) T1-T2 N0. However, 20-30 % of patients present a surgical contraindication. For these patients who cannot be operated on, stereotactic radiotherapy (SBRT) has been validated as the alternative of choice by learned medical societies. These two treatments are aimed at different populations, with a recognized role for these tumours local control. Radiotherapy remains less risky for fragile patients, but maybe at the cost of a higher risk of lymph node recurrence. The role of systemic treatment in association with stereotactic radiotherapy remains to be determined, particularly for non-operable T3NO tumours.Several complex clinical situations can be identified depending on the location and size of the tumour, the patient’s history of irradiation and co-morbidities. The treatment of central tumours, re-irradiation, which is becoming increasingly frequent with advances in systemic treatments, and treatment of patients with pulmonary fibrosis represent a real technical challenge, requiring a specialized multi-disciplinary assessment to evaluate the benefit-risk ratio.1877-1203/© 2024 SPLF. Published by Elsevier Masson SAS. All rights reserved

Association of area-level broadband and non-small cell lung cancer diagnosis and guideline-concordant care in the US.

96 Background: Access to broadband is a social determinant of health facilitating connections with healthcare services and other resources and alleviating burdens of travel distance, time, and cost. We used nationwide data to examine the association of zip code-level broadband usage and stage at diagnosis, as well as the receipt of quality care among individuals newly diagnosed with non-small cell lung cancer (NSCLC). Methods: Individuals ≥18 years newly diagnosed with first primary NSCLC between April - December of 2019-2021, were identified from the National Cancer Database (January - March were excluded to match the COVID-19 timeframe in 2020). Broadband usage percentage (the percentage of individuals per zip code with access to fixed broadband at speeds of 25 Mbps/3 Mbps in 2020) were combined with the cohort based on individual’s residential zip code. Multivariable logistic regression models examined associations between broadband usage quartiles and stage at diagnosis, as well as the receipt of guideline-concordant care based on National Comprehensive Cancer Network guidelines, including surgery and radiation, ≥10 lymph nodes sampling, chemotherapy, and neoadjuvant chemoradiation (NACR). Analyses were conducted overall and stratified by metropolitan status and year, adjusting for age group, sex, race and ethnicity, comorbidity, distance to facility, state, and zip code-level social deprivation index (SDI). Results: Cohort included 305,198 individuals newly diagnosed with NSCLC. Individuals living in areas with the highest broadband usage were more likely to be aged 65-74 years, female, non-Hispanic White, with Medicare coverage, living in metropolitan and low SDI areas. In adjusted models, individuals living in areas with the highest broadband usage were more likely to be diagnosed with stage I NSCLC (adjusted odds ratio [AOR] = 1.10, 95% confidence interval [95%CI] = 1.01-1.20) and to receive guideline-concordant NACR (AOR = 1.38, 95%CI = 1.09-1.73) compared with those living in areas with the lowest broadband usage in 2020. When stratified by metropolitan status, associations of broadband and diagnosis and receipt of NACR were only observed among individuals living in non-metropolitan areas with medium-low and medium-high broadband usage, respectively (AOR = 1.15, 95%CI = 1.01-1.32; AOR = 1.80, 95%CI = 1.25-2.58). No significant associations were identified for other care modalities or during 2019 and 2021. Conclusions: Increased access to broadband usage is associated with earlier stage NSCLC diagnosis and receiving guideline-concordant NACR in 2020. Our results suggest that increased broadband access, combined with the expansion of telehealth services during the COVID-19 pandemic, may have improved telehealth utilization throughout 2020, leading to enhanced quality of cancer care, particularly benefiting individuals residing in non-metropolitan areas.

Elevated origin recognition complex subunit 6 expression promotes non-small cell lung cancer cell growth

Exploring novel targets for non-small cell lung cancer (NSCLC) remains of utmost importance. This study focused on ORC6 (origin recognition complex subunit 6), investigating its expression and functional significance within NSCLC. Analysis of the TCGA-lung adenocarcinoma database revealed a notable increase in ORC6 expression in lung adenocarcinoma tissues, correlating with reduced overall survival, advanced disease stages, and other key clinical parameters. Additionally, in patients undergoing surgical resection of NSCLC at a local hospital, ORC6 mRNA and protein levels were elevated in NSCLC tissues while remaining low in adjacent normal tissues. Comprehensive bioinformatics analyses across various cancers suggested that ORC6 might play a significant role in crucial cellular processes, such as mitosis, DNA synthesis and repair, and cell cycle progression. Knocking down ORC6 using virus-delivered shRNA in different NSCLC cells, both primary and immortalized, resulted in a significant hindrance to cell proliferation, cell cycle progression, migration and invasion, accompanied by caspase-apoptosis activation. Similarly, employing CRISPR-sgRNA for ORC6 knockout (KO) exhibited significant anti-NSCLC cell activity. Conversely, increasing ORC6 levels using a viral construct augmented cell proliferation and migration. Silencing or knockout of ORC6 in primary NSCLC cells led to reduced expression of several key cyclins, including Cyclin A2, Cyclin B1, and Cyclin D1, whereas their levels increased in NSCLC cells overexpressing ORC6. In vivo experiments demonstrated that intratumoral injection of ORC6 shRNA adeno-associated virus markedly suppressed the growth of primary NSCLC cell xenografts. Reduced ORC6 levels, downregulated cyclins, and increased apoptosis were evident in ORC6-silenced NSCLC xenograft tissues. In summary, elevated ORC6 expression promotes NSCLC cell growth.

Sex-Based Differences in Lung Cancer Incidence: A Retrospective Analysis of Two Large US-Based Cancer Databases

Background/Objectives: Non-small cell lung cancer (NSCLC) has seen a relative rise in incidence among females versus males in recent years, although males still have a higher overall incidence. However, it is unclear whether this trend is consistent across all populations. Therefore, we retrospectively examined this relationship in two large high-risk clinical cohorts. Methods: First, we analyzed lung cancer incidence among individuals with a smoking history of over 40 pack-years in the National Lung Screening Trial (NLST). Then, we investigated the incidence of second primary NSCLC in patients who underwent lobectomy for previous stage I lung cancer using the Surveillance, Epidemiology, and End Results (SEER) database. We performed both univariate and multivariable time-to-event analyses to investigate the relationship between sex and lung cancer incidence. Results: In the NLST cohort (n = 37,627), females had a higher risk of developing primary NSCLC than males (HR = 1.11 [1.007–1.222], p = 0.035) after adjusting for age and pack-year history. In the SEER cohort (n = 19,327), females again exhibited an increased risk of developing a second primary lung cancer (HR = 1.138 [1.02–1.269], p = 0.021), after adjusting for age, race, grade, and histology. Conclusions: Our analysis reveals that females have a modestly higher lung cancer incidence than males in high-risk populations. These findings underscore the importance of further researching the underlying cellular processes that may cause sex-specific differences in lung cancer incidence.

FLAIR: A Phase II, Open Label, Randomized Study of Osimertinib Plus Bevacizumab Versus Osimertinib in Recurrent or Metastatic Treatment-Naïve NSCLC Patients Harboring EGFR 21L858R Mutation

IntroductionOsimertinib, the 3rd generation EGFR-TKI, has emerged as standard first-line treatment for patients with advanced EGFR mutated nonsmall cell lung cancer (NSCLC). Patients with exon 21 L858R mutation showed lower efficacy with EGFR-TKIs than those with 19Del mutation, even with osimertinib, it remains an unmet medical need to further improve the efficacy in L858R population. We present the rationale and design for FLAIR (NCT04988607), which will investigate the efficacy and safety of osimertinib plus bevacizumab versus osimertinib monotherapy in treatment-naïve recurrent or metastatic NSCLC patients harboring EGFR exon 21 L858R mutation. Materials and MethodsFLAIR is a prospective, multicenter, randomized, open label study. Patients age ≥18 years with primary recurrent or metastatic nonsquamous NSCLC who are treatment-naïve with documented EGFR exon 21 L858R mutation is eligible. Patients will be randomized 1:1 to receive osimertinib 80 mg once daily plus bevacizumab 15mg/kg every 3 weeks or osimertinib monotherapy 80 mg once daily until progression or another discontinuation criterion is met. The primary endpoint is investigator-assessed progression free survival (PFS). Secondary endpoints include: overall survival rate at 24 months, time to treatment failure (TTF), overall response rate (ORR), disease control rate (DCR), duration of response (DoR), central nervous system (CNS) PFS, CNS ORR and safety. ResultsFLAIR has completed the enrollment, and results are expected in the fourth quarter of 2025 (depending on the actual event rate).

Circulating Interleukins as Biomarkers in Non-Small Cell Lung Cancer Patients: A Pilot Study Compared to Normal Individuals.

Identifying biomarkers in non-small cell lung cancer (NSCLC) can improve diagnosis and patient stratification. We evaluated plasmas and sera for interleukins (IL)-11, IL-6, IL-8, IL-17A, and IL-33 as biomarkers in primary NSCLC patients undergoing surgical treatment against normal volunteers. Exhaled-breath condensates (EBCs), a potential source without invasive procedures, were explored in normal individuals. Due to separate recruitment criteria and intrinsic cohort differences, the NSCLC and control cohorts were not well matched for age (median age: 65 vs. 40 years; p < 0.0001) and smoking status (p = 0.0058). Interleukins were first assessed through conventional ELISA. IL-11 was elevated in NSCLC plasma compared to controls (49.71 ± 16.90 vs. 27.67 ± 14.06 pg/mL, respectively, p < 0.0001) but undetectable in sera and EBCs by conventional ELISA. Therefore, high-sensitivity PCR-based IL-11 ELISA was repeated, albeit with concentration discrepancies. IL11 gene and protein upregulation by RT-qPCR and immunohistochemistry, respectively, were validated in NSCLC tumors. The lack of detection sensitivity across IL-6, IL-8, IL-17A, and IL-33 suggests the need for further, precise assays. Surprisingly, biomarker concentrations can be dissimilar across paired plasmas and sera. Our results identified a need to optimize detection limits for biomarker detection and caution against over-reliance on just one form of blood sample for biomarker assessment.

The burden of tuberculosis among patients with non-small cell lung carcinoma in a tertiary care center

BackgroundLung cancer and tuberculosis share similar risk factors, clinical spectrum, radiological features and it is difficult to differentiate but it is important to diagnose both conditions for targeted therapy and better outcome. AimsOur primary objective was to estimate the proportion of TB in primary biopsy proven non-small cell lung carcinoma (NSCLC) cases. Material & methodsThis prospective observational study was conducted in the Departments of Medicine/Pulmonary Medicine/Medical Oncology and Microbiology at the All India Institute of Medical Sciences, New Delhi for a period of 2 years (January 2020–December 2021). Patients with biopsy proven, primary non-small cell lung cancer were recruited and sputum samples were subjected to microbiological investigations to confirm tuberculosis. Comparison was done in two groups of lung cancer patients with confirmed TB (Group A) and without confirmed tuberculosis (Group B). ResultsTotal 75 patients with biopsy proven, primary NSCLC were recruited and 16 % (12/75) were diagnosed with confirmed TB. Adenocarcinoma (36.48 %) and Squamous cell carcinoma (33.44 %) were the two predominant histopathological subtypes of NSCLC. About 57 (76 %) of them were found to be in stage IV of Lung cancer at initial presentation itself (75 % in group A & 74.6 % in group B; p value < 0.80). A majority of patients (11/12 cases; 91 %) of group A were males with a mean age of 59 ± 7.5 years. The upper lobes of the lung were involved in 65 % (49/75) of the cases and showing a mass lesion on imaging (75 % in group A & 65 % in group B; p value < 0.52). Kaplan Meier survival revealed a median survival time of 11 months in subjects with only NSCLC and a median survival time of 4 months in the group with concomitant TB and NSCLC (p value < 0.44).

Prognostic Implications of Selective Dissection of Left Lower Paratracheal Lymph Nodes in Patients with Left-Sided Non-Small Cell Lung Cancer.

This study aimed to examine the clinical implications of selective station 4L lymph node dissection (S4L-LND) on survival in non-small cell lung cancer (NSCLC) and to evaluate its potential advantages. We enrolled patients with primary left-sided NSCLC who underwent upfront video-assisted thoracoscopic surgery with R0 resection including lobectomy and segmentectomy, with or without S4L-LND, at our institution between January 2007 and December 2021. Following 1:1 propensity score matching (PSM), we compared overall survival (OS) and recurrence-free survival (RFS) between patients with and without S4L-LND. The study included 2,601 patients, of whom 1,126 underwent S4L-LND and 1,475 did not. PSM yielded 1,036 patient pairs. Among those who underwent S4L-LND, 87 (7.7%) exhibited S4L-LN involvement. Neither OS (p=0.12) nor RFS (p=0.24) differed significantly between matched patients with and without S4L-LND. In patients with S4L-LN involvement, metastases were more common in the left upper lobe (LUL) than in the left lower lobe (LLL) (3.6% vs. 2.0%, p=0.061). Metastasis became significantly more frequent with more advanced clinical N (cN) stage (cN0, 2.3%; cN1, 5.8%; cN2, 32.6%; p<0.001). Multivariate logistic regression analysis revealed that cN stage and tumor location were independently associated with S4L-LN involvement (p<0.001 for both). OS and RFS did not differ significantly between matched patients with and without S4L-LND. Among participants with S4L-LN involvement, metastases occurred more frequently in the LUL than the LLL, and their incidence increased significantly with more advanced cN stage. Thus, patients with LUL or advanced cN lung cancers may benefit from S4L-LND.

Patients with Pulmonary Artery Reconstruction or Double Sleeve Resection Show Inferior Survival than Patients with Bronchial Sleeve Resection for Non-small Cell Lung Cancer.

Sleeve lobectomy or resection with pulmonary artery reconstruction is a technique that allows for resection of locally advanced central lung carcinoma, preserving lung function, and is associated with lower morbidity and mortality than pneumonectomy. This survey aimed to assess the long-term survival comparing different types of sleeve lobectomy and identify risk factors affecting survival.All consecutive patients who underwent anatomical resection for primary non-small cell lung cancer with bronchial sleeve or pulmonary artery reconstruction in our department between September 2003 and September 2021 were included in this study. Cases with carinal sleeve pneumonectomy were excluded. Data were evaluated retrospectively.Bronchial sleeve resection was performed in 227 patients, double sleeve resection in 67 patients, and 45 cases underwent isolated lobectomy with pulmonary artery reconstruction. The mean follow-up was 33.5 months. The 5-year survival was 58.5% for patients after bronchial sleeve, 43.2% after double sleeve, and 36.8% after resection with vascular reconstruction. The difference in overall survival of these three groups was statistically significant (p=0.012). However, the UICC stage was higher in cases with double sleeve resection or resection with vascular reconstruction (p=0.016). Patients with lymph node metastases showed shorter overall survival (p=0.033). The 5-year survival rate was 60.1% for patients with N0 and 47% for patients with N1 and N2 status. Induction therapy, vascular sleeve resection, and double sleeve resection were independent adverse predictors for overall survival in multivariate analysis.Sleeve lobectomy and resection with vascular reconstruction are safe procedures with good long-term survival. However, double sleeve resection and vascular sleeve resection were adverse predictors of survival, possibly due to a higher UICC stage in these patients.

1224P Evaluation of safety and feasibility of adjuvant chemotherapy in elderly patients with primary non-small cell lung cancer

1224P Evaluation of safety and feasibility of adjuvant chemotherapy in elderly patients with primary non-small cell lung cancer

RILPL2 as a potential biomarker for predicting enhanced Tcell infiltration in non-small cell lung cancer.

Our previous bioinformatics analysis has revealed that Rab-interacting lysosomal protein-like 2 (RILPL2) is associated with tumor immune microenvironment in non-small cell lung cancer (NSCLC). In our study, we collected 140 patients with primary NSCLC to verify the RILPL2 expression and its prognostic value, the relationship between RILPL2 expression and CD4+, CD8+T cell infiltration. A total of 140 patients who had been diagnosed with primary NSCLC (including 66 lung adenocarcinomas and 74 lung squamous cell carcinomas) were enrolled in our study. Immunohistochemical (IHC) staining was performed to analyze the expression of RILPL2, CD4, and CD8 in these patients. Compared with peri-cancer tissues, the RILPL2 expression in NSCLC tissues was significantly lower (P < 0.0001). RILPL2 expression was significantly related to clinical stage (P = 0.019), and low RILPL2 expression indicated higher stage. Low RILPL2 expression predicted worse overall survival (OS) in NSCLC patients (P = 0.017). Correlational analyses revealed that RILPL2 expression was significantly positively correlated with CD4+T cell infiltration in NSCLC (R = 0.294, P < 0.001), LUAD subgroup (R = 0.256, P = 0.038), and LUSC subgroup (R = 0.333, P = 0.004); RILPL2 expression was also significantly positively correlated with CD8+ T cell infiltration in NSCLC (R = 0.263, P = 0.002), LUAD subgroup (R = 0.280, P = 0.023), and LUSC subgroup (R = 0.250, P = 0.031).In conclusion, RILPL2 expression was downregulated in NSCLC; low RILPL2 expression was significantly related to higher stage and worse prognosis; RILPL2 expression was significantly positively correlated with CD4+, CD8+T cell infiltration.

Evaluating predictors of kinase activity of STK11 variants identified in primary human non-small cell lung cancers.

Critical evaluation of computational tools for predicting variant effects is important considering their increased use in disease diagnosis and driving molecular discoveries. In the sixth edition of the Critical Assessment of Genome Interpretation (CAGI) challenge, a dataset of 28 STK11 rare variants (27 missense, 1 single amino acid deletion), identified in primary non-small cell lung cancer biopsies, was experimentally assayed to characterize computational methods from four participating teams and five publicly available tools. Predictors demonstrated a high level of performance on key evaluation metrics, measuring correlation with the assay outputs and separating loss-of-function (LoF) variants from wildtype-like (WT-like) variants. The best participant model, 3Cnet, performed competitively with well-known tools. Unique to this challenge was that the functional data was generated with both biological and technical replicates, thus allowing the assessors to realistically establish maximum predictive performance based on experimental variability. Three out of the five publicly available tools and 3Cnet approached the performance of the assay replicates in separating LoF variants from WT-like variants. Surprisingly, REVEL, an often-used model, achieved a comparable correlation with the real-valued assay output as that seen for the experimental replicates. Performing variant interpretation by combining the new functional evidence with computational and population data evidence led to 16 new variants receiving a clinically actionable classification of likely pathogenic (LP) or likely benign (LB). Overall, the STK11 challenge highlights the utility of variant effect predictors in biomedical sciences and provides encouraging results for driving research in the field of computational genome interpretation.

Preoperative respiratory assessment predicts post-operative survival in stage IA non-small cell lung cancer.

Respiratory impairment can lead to pulmonary complications after surgery; therefore, it should be considered when determining the choice of surgical procedure. Several studies have examined the relationship between preoperative respiratory function and postoperative mortality and morbidity after lung resection; however, there are no indicators for limited surgical procedure selection. The aim of this study was to examine the association between preoperative respiratory function and postoperative early and late complications, recurrence-free survival (RFS), and overall survival (OS) in patients undergoing pulmonary resection for stage I lung cancer. We performed a retrospective analysis of data from 192 patients undergoing pulmonary resection for primary pathological stage IA non-small cell lung cancer (NSCLC) at the Iwakuni Clinical Center in Japan between 2012 and 2015. We reviewed clinicopathological characteristics including preoperative pulmonary function and elucidated the relationship between them and postoperative survival. Obstructive ventilatory impairment was present in 55 patients (28.6%), and restrictive ventilatory impairment was present in 31 patients (16.1%). Seven patients (3.6%) had both ventilatory impairment. Obstructive ventilatory impairment did not affect the 5-year RFS (P=0.08) or OS (P=0.21). However, restrictive ventilatory impairment reduced the 5-year RFS (P=0.002) and OS (P=0.009). The rates of early and late complications were not significantly different based on the preoperative respiratory function. In patients with preoperative restrictive ventilatory impairment in whom lobectomy or segmentectomy cannot be performed, careful consideration is needed for surgical indications.

Treatment Outcomes of Stereotactic Body Radiotherapy for Early-stage Non-small Cell Lung Cancer and Lung Metastasis

Background and rationale: Stereotactic body radiotherapy (SBRT) is a highly precise localized high-dose per fraction radiation treatment used mainly in lung cancer. Despite SBRT's increasing use, no clear predictive factors of outcome exist. Objectives: To report local control rates, patterns of failure, and incidence of treatment-related toxicity, and to determine factors predicting SBRT outcomes for primary and secondary lung tumors at Ramathibodi Hospital using competing risk analysis. Materials and methods: This retrospective study included all patients diagnosed with primary early non-small cell lung cancer (NSCLC) and lung metastasis in our radiosurgery and radiotherapy database registry between January 2009 and September 2018. Results: Fifty-nine patients (98 lung tumors) were studied; primary NSCLC and lung metastasis were 15.3% and 84.7%, respectively. Median follow-up was 16.8 months. The overall 1-year local control rate was 90.8%. The most common pattern of failure was distant failure (46.9%). The incidence of radiation pneumonitis (RP) grade ≥2 was 9.2%, and one of four patients with an ultra-central tumor developed grade 5 pulmonary toxicity. The predictive factor for local failure was the mean biological equivalent dose (BED) of the planning target volume (PTV), and for RP grade ≥2, the tumor's maximal diameter. BED PTV mean &lt;100 Gy had higher local failure than BED PTV mean ≥100 Gy (adjusted subdistribution hazard ratio 8.26; 95% confidence interval (CI) 1.76–38.68, p=0.007). Patients with tumors with maximal diameters ≥5 cm compared with those with maximal diameters &lt;5 cm had more RP grade ≥2 (adjusted subdistribution hazard ratio 5.34; 95% CI 1.52–18.69, p=0.009). The overall 1-year survival rate was 73.5%. Conclusions: Local control of lung tumors using SBRT was high with acceptable toxicity. BED PTV mean was a local control predictor. Large tumors correlated with symptomatic RP grade ≥2. SBRT should be used judiciously for ultra-central lung tumors.

The prognostic value of visceral pleural infiltration in ≤3cm non-small cell lung cancer presenting with ground glass opacity: An inverse probability of treatment weighting study.

Visceral pleural infiltration (VPI) has been identified as an important risk factor in non-small cell lung cancer (NSCLC) for many decades. However, for patients who present with ground glass opacity (GGO), the prognostic value of VPI is still elusive. We aimed to investigate whether the VPI is a significant prognostic factor in surgically resected ≤3cm stage I NSCLC who presented with GGO. Patients with primary NSCLC who underwent surgical resection between December 2009 and December 2018 were collected. Stage I tumors that presented as GGO nodule with a tumor size of less than 3cm were included and divided into two groups based on VPI status (positive and negative). Clinical, pathological, and prognostic data were prospectively collected and retrospectively reviewed. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics. Overall survival (OS) and recurrence-free survival (RFS) were analyzed using the Cox proportional hazards model and Kaplan-Meier method. A total of 2043 patients were included in this study (VPIs were found in 196 patients). After IPTW weighting, all factors between the two groups were balanced. The median follow-up time was 67.3 months. According to the multivariable Cox models, the VPI was not a significant prognostic factor for OS (HR = 2.00, 95% CI, 0.96-4.17; P= 0.063), but was significant for RFS (HR =2.00, 95% CI, 1.12-3.55; P= 0.019). In subgroup analysis, we found VPI was significant for OS (HR=3.17, 95%CI: 1.09-9.26, P=0.035) and RFS (HR=4.07, 95%CI: 1.76-9.40, P=0.001) in patients with a tumor size >1cm and a consolidation to tumor ratio (CTR) >50%. For patients with a tumor size ≤1cm or a CTR ≤50%, the VPI was not significant. VPI may be a significant risk factor for GGOs in NSCLC patients with a tumor size >1cm and a CTR >50%. Further prospective studies conducted across multi-centers with a larger sample size are needed.

Expansion of tumor-infiltrating lymphocytes in non-small cell lung cancer: Clinical potential and efficacy in EGFR mutation subsets

Our study aimed to expand tumor-infiltrating lymphocytes (TILs) from primary non-small cell lung cancers (NSCLCs) and evaluate their reactivity against tumor cells. We expanded TILs from 103 primary NSCLCs using histopathological analysis, flow cytometry, IFN-γ release assays, cell-mediated cytotoxicity assays, and in vivo efficacy tests. TIL expansion was observed in all cases, regardless of EGFR mutation status. There was also an increase in the median CD4+/CD8+ ratio during expansion. In post-rapid expansion protocol (REP) TILs, 13 out of 16 cases, including all three cases with EGFR mutations, exhibited a two-fold or greater increase in IFN-γ secretion. The cytotoxicity assay revealed enhanced tumor cell death in three of the seven cases, two of which had EGFR mutations. In vivo functional testing in a patient-derived xenograft model showed a reduction in tumor volume. The anti-tumor activity of post-REP TILs underscores their potential as a therapeutic option for advanced NSCLC, irrespective of mutation status.

ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages

BackgroundUnderstanding the mechanisms that mediate the interaction between tumor and immune cells may provide therapeutic benefit to patients with cancer. The N6-methyladenosine (m6A) demethylase, ALKBH5 (alkB homolog 5), is overexpressed in non-small cell lung cancer. However, its role in the tumor microenvironment is unknown.MethodsDatasets and tissue samples were used to determine the relationship between ALKBH5 expression and immunotherapy efficacy. Bioinformatic analysis, colorimetric assay to determine m6A RNA methylation, dual luciferase reporter assay, RNA/m6A-modified RNA immunoprecipitation, RNA stability assay, and RNA sequencing were used to investigate the regulatory mechanism of ALKBH5 in non-small cell lung cancer. In vitro and in vivo assays were performed to determine the contribution of ALKBH5 to the development of non-small cell lung cancer.ResultsALKBH5 was upregulated in primary non-small cell lung cancer tissues. ALKBH5 was positively correlated with programmed death-ligand 1 expression and macrophage infiltration and was associated with immunotherapy response. JAK2 was identified as a target of ALKBH5-mediated m6A modification, which activates the JAK2/p-STAT3 pathway to promote non-small cell lung cancer progression. ALKBH5 was found to recruit programmed death-ligand 1-positive tumor-associated macrophages and promote M2 macrophage polarization by inducing the secretion of CCL2 and CXCL10. ALKBH5 and tumor-associated macrophage-secreted IL-6 showed a synergistic effect to activate the JAK2/p-STAT3 pathway in cancer cells.ConclusionsALKBH5 promotes non-small cell lung cancer progression by regulating cancer and tumor-associated macrophage behavior through the JAK2/p-STAT3 pathway and the expression of CCL2 and CXCL10, respectively. These findings suggest that targeting ALKBH5 is a promising strategy of enhancing the anti-tumor immune response in patients with NSCLC and that identifying ALKBH5 status could facilitate prediction of clinical response to anti-PD-L1 immunotherapy.

Computed tomography characteristics of cN0 primary non-small cell lung cancer predict occult lymph node metastasis

Computed tomography characteristics of cN0 primary non-small cell lung cancer predict occult lymph node metastasis

Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single‐cell transcriptomic analysis: Implications for distinct immunotherapy outcomes

AbstractBackgroundImmune checkpoint blockade has emerged as a key strategy to the therapy landscape of non‐small cell lung cancer (NSCLC). However, notable differences in immunotherapeutic outcomes exist between the two primary NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This disparity may stem from the tumor immune microenvironment's heterogeneity at the transcriptome level.MethodsBy integrative analysis of transcriptomic characterization of 38 NSCLC patients by single‐cell RNA sequencing, the present study revealed a distinct tumor microenvironment (TME) between LUAD and LUSC, with relevant results further confirmed in bulk transcriptomic and multiplex immunofluorescence (mIF) validation cohort of neoadjuvant immunotherapy patients.ResultsLUAD exhibited a more active immune microenvironment compared to LUSC. This included highly expression of HLA I/II in cancer cells, reinforced antigen presentation potential of dendritic cells and enhanced cytotoxic activity observed in T/NK cells. In LUSC, cancer cells highly expressed genes belonging to the aldo‐keto reductases, glutathione S‐transferases and aldehyde dehydrogenase family, negatively correlating with immunotherapy outcomes in the validation cohort of our center. Further analysis revealed elevated infiltrated cancer‐associated fibroblasts (CAFs) in LUSC, which was corroborated in The Cancer Genome Atlas cohort. Corresponding increased infiltration of ADH1B+ CAFs in major pathologic response (MPR) patients and the higher presence of FAP+ CAFs in non‐MPR patients were demonstrated by multiplex mIF. Moreover, upregulating immunosuppressive extracellular matrix remodeling was identified in LUSC.ConclusionsThese comprehensive analyses advance the understanding of the differences in TME between LUAD and LUSC, offering insights for patient selection and developing subtype‐specific treatment strategies.

Genetic profiles of oligometastatic non-small cell lung cancer and corresponding brain metastases.

In patients with oligometastatic non-small cell lung cancer, systemic therapy in combination with local ablative treatment of the primary tumor and all metastatic sites is associated with improved prognosis. For patient selection and treatment allocation, further knowledge about the molecular characteristics of the oligometastatic state is necessary. Here, we performed a genetic characterization of primary non-small cell lung cancer and corresponding brain metastases. We retrospectively identified patients with oligometastatic non-small cell lung cancer and synchronous (<3 months) or metachronous (>3 months) brain metastases who underwent surgical resection of both primary tumor and brain metastases. Mutation profiling of formalin-fixed paraffin-embedded tumor cell blocks was performed by targeted next generation sequencing using the oncomine focus assay panel. Sequencing was successful in 46 paired samples. An oncogenic alteration was present in 31 primary tumors (67.4%) and 40 brain metastases (86.9%). The alteration of the primary tumors was preserved in the corresponding brain metastases in 29 out of 31 cases (93.5%). The most prevalent oncogenic driver in both primary tumors and brain metastases was a KRAS mutation (n = 21). In 16 patients (34.8%), the brain metastasis harbored additional oncogenic alterations. The presence of a private genetic alteration in the brain metastasis was an independent predictor of shorter overall survival. In oligometastatic non-small cell lung cancer, brain metastases retain the main genetic alterations of the primary tumors. Patients may profit from targeted inhibition of mutated KRAS. Additional private genetic alterations in the brain metastases are dismal.