Early-stage Non-small Cell Lung Cancer Patients Research Articles

Diagnostic value of microRNA-200 expression in peripheral blood-derived extracellular vesicles in early-stage non-small cell lung cancer

ObjectiveThis study assessed the diagnostic value of microRNA-200 (miR-200) expression in peripheral blood-derived extracellular vesicles (EVs) in early-stage non-small cell lung cancer (NSCLC).MethodsThis study retrospectively analyzed 100 healthy volunteers (the control group) receiving physical examinations, 168 early-stage NSCLC patients (the NSCLC group), and 128 patients with benign lung nodules (the benign group). The basic and clinical data of participants were obtained, including age, sex, smoking history, carbohydrate antigen 242 (CA242), carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), forced expiratory volume in 1 s, maximal voluntary ventilation, forced vital capacity, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and miR-200 expression. The correlation of miR-200 expression in peripheral blood-derived EVs with CA242, CEA, and CA199 was analyzed, and the diagnostic value of peripheral blood-derived EV miR-200 for early-stage NSCLC was assessed. The risk factors of early-stage NSCLC development were also determined.ResultsAge, the percentage of patients with smoking history, CA242, CEA, CA199, IL-6, and TNF-α levels, and miR-200 expression in peripheral blood-derived EVs were significantly higher in the NSCLC group than in the benign and control groups. Lung disease patients with high miR-200 expression in peripheral blood-derived EVs comprised a higher percentage of patients with smoking history and mixed lesions and had higher CA242, CEA, CA199, and TNF-α levels than those with low miR-200 expression in peripheral blood-derived EVs. In lung diseases, miR-200 expression in peripheral blood-derived EVs was significantly and positively correlated with CA242, CEA, and CA199. Peripheral blood-derived EV miR-200 combined with CA242, CEA and CA199 had higher diagnostic value (area under the curve = 0.942) than single detection, along with higher specificity, and high expression of peripheral blood-derived EV miR-200 was an independent risk factor for early-stage NSCLC.ConclusionPeripheral blood-derived EV miR-200 expression in patients with lung diseases is closely correlated with CA242, CEA, and CA199, and high expression of peripheral blood-derived EV miR-200 is an independent risk factor for early-stage NSCLC and is of high clinical diagnostic value for early-stage NSCLC.

Soluble PD-L1 shows no association to relapse and overall survival in early stage non-small cell lung cancer (NSCLC)

BackgroundCancer immune evasion is critical in non-small cell lung cancer (NSCLC) and has been targeted by immunotherapy. High soluble (s)PD-L1 is associated with reduced survival and treatment failure in advanced stages. Here we evaluated the effects of sPD-L1 on T cells, relapse free survival, and overall survival in early stage NSCLC. MethodsIn vitro T cell stimulation was performed in the presence of sPD-L1 to evaluate its immunomodulatory activity. Data from The Cancer Genome Atlas (TCGA) were investigated for PD-L1 splice variants and enzymes involved in proteolytic cleavage (i.e. ADAM10). Plasma from 74 NSCLC (stage IA-IIIB), as well as an additional 73 (control cohort) patients was collected prior to curative surgery. Thereafter sPD-L1 levels from an immunosorbent assay were correlated with patient outcome. ResultsIn vitro sPD-L1 inhibited IFN-γ production and proliferation of T cells and induced a terminal effector CD4 T cell subtype expressing CD27. Data from the TCGA demonstrated that elevated mRNA levels of ADAM10 is a negative predictor of outcome in NSCLC patients. To investigate the clinical relevance of these in vitro and TCGA findings, we quantified sPD-L1 in the plasma of early-stage NSCLC patients. In the first cohort we found significantly higher sPD-L1 levels in relapsing NSCLC patients, with a multivariate analysis revealing high sPD-L1 (>1000 pg/mL) as an independent predictor of survival. However, these findings could not be validated in two independent control cohorts. DiscussionAlthough in vitro and TCGA data support the suppressive effect of sPD-L1 we were unable to translate this in our clinical setting. These results may be due to the small patient number and their heterogeneity as well as the lack of a standardized sPD-L1 ELISA. Our inconclusive results regarding the value of sPD-L1 in early stage NSCLC warrant assay validation and further investigation in larger (neo-)adjuvant trials.

A dual-radiomics model for overall survival prediction in early-stage NSCLC patient using pre-treatment CT images.

Radiation therapy (RT) is one of the primary treatment options for early-stage non-small cell lung cancer (ES-NSCLC). Therefore, accurately predicting the overall survival (OS) rate following radiotherapy is crucial for implementing personalized treatment strategies. This work aims to develop a dual-radiomics (DR) model to (1) predict 3-year OS in ES-NSCLC patients receiving RT using pre-treatment CT images, and (2) provide explanations between feature importanceand model prediction performance. The publicly available TCIA Lung1 dataset with 132 ES-NSCLC patients received RT were studied: 89/43 patients in the under/over 3-year OS group. For each patient, two types of radiomic features were examined: 56 handcrafted radiomic features (HRFs) extracted within gross tumor volume, and 512 image deep features (IDFs) extracted using a pre-trained U-Net encoder. They were combined as inputs to an explainable boosting machine (EBM) model for OS prediction. The EBM's mean absolute scores for HRFs and IDFs were used as feature importance explanations. To evaluate identified feature importance, the DR model was compared with EBM using either (1) key or (2) non-key feature type only. Comparison studies with other models, including supporting vector machine (SVM) and random forest (RF), were also included. The performance was evaluated by the area under the receiver operating characteristic curve (AUCROC), accuracy, sensitivity, and specificity with a 100-fold Monte Carlo cross-validation. The DR model showed highestperformance in predicting 3-year OS (AUCROC=0.81 ± 0.04), and EBM scores suggested that IDFs showed significantly greater importance (normalized mean score=0.0019) than HRFs (score=0.0008). The comparison studies showed that EBM with key feature type (IDFs-only demonstrated comparable AUCROC results (0.81 ± 0.04), while EBM with non-key feature type (HRFs-only) showed limited AUCROC (0.64 ± 0.10). The results suggested that feature importance score identified by EBM is highly correlated with OS prediction performance. Both SVM and RF models were unable to explain key feature type while showing limited overall AUCROC=0.66 ± 0.07 and 0.77 ± 0.06, respectively. Accuracy, sensitivity, and specificity showed a similar trend. In conclusion, a DR model was successfully developed to predict ES-NSCLC OS based on pre-treatment CT images. The results suggested that the feature importance from DR model is highly correlated to the model prediction power.

Predicting Regional Recurrence and Prognosis in Stereotactic Body Radiation Therapy-Treated Clinical Stage I Non-small Cell Lung Cancer Using a Radiomics Model Constructed With Surgical Data

BackgroundRisk stratification of regional recurrence (RR) is clinically important in the design of adjuvant treatment and surveillance strategies in patients with clinical stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). PurposeTo develop a radiomics model predicting occult lymph node metastasis (OLNM) using surgical data and apply it to the prediction of RR in SBRT-treated early-stage NSCLC patients. MethodsPatients with clinical stage I NSCLC who underwent curative surgery with systematic lymph node dissection from January 2013 to December 2018 (the training cohort) and from January 2019 to December 2020 (the validation cohort) were included. A pre-operative CT-based radiomics model, a clinical feature model, and a fusion model predicting OLNM were constructed. The performance of the three models was quantified and compared in the training and validation cohorts. Subsequently, the radiomics model was used to predict RR in a cohort of consecutive SBRT-treated early-stage NSCLC patients from two academic medical centers. ResultsA total of 769 patients were included. Eight CT features were identified in the radiomics model, achieving areas under the curves (AUCs) of 0.85 (95% CI 0.81-0.89) and 0.83 (95% CI 0.80-0.88) in the training and validation cohorts, respectively. Nevertheless, adding clinical features did not improve the performance of the radiomics model. With a median follow-up of 40.0 (95% CI 35.2-44.8) months, 32 of the 213 patients in the SBRT cohort developed RR and those in the high-risk group based on the radiomics model had a higher cumulative incidence of RR (p<0.001) and shorter regional recurrence-free survival (p=0.02), progression-free survival (p=0.004) and overall survival (p=0.006) than those in the low-risk group. ConclusionThe radiomics model based on pathologically confirmed data effectively identified patients with ONLM, which may be useful in the risk stratification among SBRT-treated patients with clinical stage I NSCLC.

Sentinel Lymph Node Mapping in Lung Cancer: A Pilot Study for the Detection of Micrometastases in Stage I Non-Small Cell Lung Cancer.

Lymphadenectomy represents a fundamental step in the staging and treatment of non-small cell lung cancer (NSCLC). To date, the extension of lymphadenectomy in early-stage NSCLC is a debated topic due to its possible complications. The detection of sentinel lymph nodes (SLNs) is a strategy that can improve the selection of patients in which a more extended lymphadenectomy is necessary. This pilot study aimed to refine lymph nodal staging in early-stage NSCLC patients who underwent robotic lung resection through the application of innovative intraoperative sentinel lymph node (SLN) identification and the pathological evaluation using one-step nucleic acid amplification (OSNA). Clinical N0 NSCLC patients planning to undergo robotic lung resection were selected. The day before surgery, all patients underwent radionuclide computed tomography (CT)-guided marking of the primary lung lesion and subsequently Single Photon Emission Computed Tomography (SPECT) to identify tracer migration and, consequently, the area with higher radioactivity. On the day of surgery, the lymph nodal radioactivity was detected intraoperatively using a gamma camera. SLN was defined as the lymph node with the highest numerical value of radioactivity. The OSNA amplification, detecting the mRNA of CK19, was used for the detection of nodal metastases in the lymph nodes, including SLN. From March to July 2021, a total of 8 patients (3 female; 5 male), with a mean age of 66 years (range 48-77), were enrolled in the study. No complications relating to the CT-guided marking or preoperative SPECT were found. An average of 5.3 lymph nodal stations were examined (range 2-8). N2 positivity was found in 3 out of 8 patients (37.5%). Consequently, pathological examination of lymph nodes with OSNA resulted in three upstages from the clinical IB stage to pathological IIIA stage. Moreover, in 1 patient (18%) with nodal upstaging, a positive node was intraoperatively identified as SLN. Comparing this protocol to the usual practice, no difference was found in terms of the operating time, conversion rate, and complication rate. Our preliminary experience suggests that sentinel lymph node detection, in association with the accurate pathological staging of cN0 patients achieved using OSNA, is safe and effective in the identification of metastasis, which is usually undetected by standard diagnostic methods.

Histology-driven hypofractionated radiation therapy schemes for early-stage lung adenocarcinoma and squamous cell carcinoma

Background and PurposeHistology was found to be an important prognostic factor for local tumor control probability (TCP) after stereotactic body radiotherapy (SBRT) of early-stage non-small-cell lung cancer (NSCLC). A histology-driven SBRT approach has not been explored in routine clinical practice and histology-dependent fractionation schemes remain unknown. Here, we analyzed pooled histologic TCP data as a function of biologically effective dose (BED) to determine histology-driven fractionation schemes for SBRT and hypofractionated radiotherapy of two predominant early-stage NSCLC histologic subtypes adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Material and MethodsThe least-χ2 method was used to fit the collected histologic TCP data of 8510 early-stage NSCLC patients to determine parameters for a well-developed radiobiological model per the Hypofractionated Treatment Effects in the Clinic (HyTEC) initiative. ResultsA fit to the histologic TCP data yielded independent radiobiological parameter sets for radiotherapy of early-stage lung ADC and SCC. TCP increases steeply with BED and reaches an asymptotic maximal plateau, allowing us to determine model-independent optimal fractionation schemes of least doses in 1–30 fractions to achieve maximal tumor control for early-stage lung ADC and SCC, e.g., 30, 44, 48, and 51 Gy for ADC, and 32, 48, 54, and 58 Gy for SCC in 1, 3, 4, and 5 fractions, respectively. ConclusionWe presented the first determination of histology-dependent radiobiological parameters and model-independent histology-driven optimal SBRT and hypofractionated radiation therapy schemes for early-stage lung ADC and SCC. SCC requires substantially higher radiation doses to maximize tumor control than ADC, plausibly attributed to tumor genetic diversity and microenvironment. The determined optimal SBRT schemes agree well with clinical practice for early-stage lung ADC. These proposed optimal fractionation schemes provide first insights for histology-based personalized radiotherapy of two predominant early-stage NSCLC subtypes ADC and SCC, which require further validation with large-scale histologic TCP data.

Potential Role of Lymphocyte CD44 in Determining Treatment Selection Between Stereotactic Body Radiation Therapy and Surgery for Early-Stage Non-Small Cell Lung Cancer

Background: Stereotactic body radiotherapy (SBRT) versus surgery for operable early-stage non-small-cell lung cancer (ES-NSCLC) remains highly debated. Herein, we utilized spatial proteomics to identify whether any molecular biomarker(s) associate with the efficacy of either modality, in efforts to optimize treatment selection between surgery or SBRT for this population. Methods: We evaluated biopsy tissue samples from 44 ES-NSCLC patients treated with first-line SBRT (cohort 1) by GeoMx Digital Spatial Profiling (DSP) with a panel of 70 proteins in five spatial molecular compartments: tumor (panCK+), leukocyte (CD45+), lymphocyte (CD3+), macrophage (CD68+), and stroma (α-SMA+). To validate the findings in cohort 1, biopsy samples from 52 ES-NSCLC patients who received SBRT (cohort 2) and 62 ES-NSCLC patients who underwent surgery (cohort 3) were collected and analyzed by multiplex immunofluorescence (mIF). Results: In cohort 1, higher CD44 expression in the lymphocyte compartment was associated with poorer recurrence-free survival (RFS) (DSP: P<0.001; mIF: P<0.001) and higher recurrence rate (DSP: P=0.001; mIF: P=0.004). mIF data from cohort 2 validated these findings (P<0.05 for all). From cohort 3, higher lymphocyte CD44 predicted higher RFS after surgery (P=0.003). Inter-modality comparisons demonstrated that SBRT was associated with significantly higher RFS over surgery in CD44-low patients (P<0.001), but surgery was superior to SBRT in CD44-high cases (P=0.016). Conclusions: Lymphocyte CD44 may not only be a predictor of SBRT efficacy in this population, but also an important biomarker (pending validation by large prospective data) that could better sharpen selection for SBRT vs. surgery in ES-NSCLC.

Trends and Disparities in Curative-Intent Treatment for Early-Stage Non-Small Cell Lung Cancer: A Population-Based Analysis of Surgery and SBRT.

Despite the increasing adoption of stereotactic body radiotherapy (SBRT) as a recommended alternative for early-stage non-small cell lung cancer (NSCLC), population-based research on racial/ethnic disparities in curative-intent treatment accounting for SBRT remains limited. This study investigated trends and disparities in receiving curative-intent surgery and/or SBRT in a diverse, retrospective cohort. Early-stage NSCLC cases (2005-2017) from the Florida cancer registry were linked to individual-level statewide discharge data containing comorbidities and specific treatment information. Joinpoint regression assessed trends in treatment receipt. Multivariable logistic regression examined associations between race/ethnicity and treatment type. Among 64,999 patients with early-stage NSCLC, 71.6% received curative-intent treatment (surgery and/or SBRT): 73.1%, 72.4%, and 60.3% among Hispanic, White, and Black patients, respectively (P < 0.01). SBRT use increased steeply from 2005 to 2007 and then by 7.9% annually from 2007 to 2017 (P < 0.01); curative-intent surgery remained stable from 2005 to 2014 before declining by 6.2% annually during 2014-2017 (P = 0.04). The Black-White disparity in receipt of curative-intent treatment was significant [ORadj, 0.65; 95% confidence interval (CI), 0.60-0.71]. Patients with Charlson comorbidity index (CCI)≥3 had 36% (ORadj, 0.64; 95% CI, 0.60-0.69) lower odds of receiving curative-intent surgery and no significant difference for SBRT (ORadj, 1.06; 95% CI, 0.93-1.20) compared with CCI = 0. Racial disparities in receiving curative-intent treatment for early-stage NSCLC persist despite the availability of SBRT, suggesting the full potential of curative-intent treatment for early-stage NSCLC remains unachieved. Addressing disparities in early-stage NSCLC requires addressing differential treatment patterns and enhancing accessibility to treatments like underutilized SBRT, particularly for high-comorbidity populations such as Black patients.

A PET/CT radiomics model for predicting distant metastasis in early-stage non–small cell lung cancer patients treated with stereotactic body radiotherapy: a multicentric study

ObjectivesStereotactic body radiotherapy (SBRT) is a treatment option for patients with early-stage non-small cell lung cancer (NSCLC) who are unfit for surgery. Some patients may experience distant metastasis. This study aimed to develop and validate a radiomics model for predicting distant metastasis in patients with early-stage NSCLC treated with SBRT.MethodsPatients at five institutions were enrolled in this study. Radiomics features were extracted based on the PET/CT images. After feature selection in the training set (from Tianjin), CT-based and PET-based radiomics signatures were built. Models based on CT and PET signatures were built and validated using external datasets (from Zhejiang, Zhengzhou, Shandong, and Shanghai). An integrated model that included CT and PET radiomic signatures was developed. The performance of the proposed model was evaluated in terms of its discrimination, calibration, and clinical utility. Multivariate logistic regression was used to calculate the probability of distant metastases. The cutoff value was obtained using the receiver operator characteristic curve (ROC), and the patients were divided into high- and low-risk groups. Kaplan-Meier analysis was used to evaluate the distant metastasis-free survival (DMFS) of different risk groups.ResultsIn total, 228 patients were enrolled. The median follow-up time was 31.4 (2.0-111.4) months. The model based on CT radiomics signatures had an area under the curve (AUC) of 0.819 in the training set (n = 139) and 0.786 in the external dataset (n = 89). The PET radiomics model had an AUC of 0.763 for the training set and 0.804 for the external dataset. The model combining CT and PET radiomics had an AUC of 0.835 for the training set and 0.819 for the external dataset. The combined model showed a moderate calibration and a positive net benefit. When the probability of distant metastasis was greater than 0.19, the patient was considered to be at high risk. The DMFS of patients with high- and low-risk was significantly stratified (P < 0.001).ConclusionsThe proposed PET/CT radiomics model can be used to predict distant metastasis in patients with early-stage NSCLC treated with SBRT and provide a reference for clinical decision-making.Plain language summaryIn this study, the model was established by combining CT and PET radiomics signatures in a moderate-quantity training cohort of early-stage NSCLC patients treated with SBRT and was successfully validated in independent cohorts. Physicians could use this easy-to-use model to assess the risk of distant metastasis after SBRT. Identifying subgroups of patients with different risk factors for distant metastasis is useful for guiding personalized treatment approaches.

The Role of Isocitrate Dehydrogenase as a Serum Biomarker in Detecting Non-Small Cell Lung Cancer: A Literature Review

Background: Lung cancer is a significant health problem, ranking as the second most prevalent cancer worldwide and the leading cause of cancer-related mortality. Non-Small Cell Lung Cancer (NSCLC) accounts for a substantial portion of these cases. While histological biopsy is the golden standard for diagnosis of this disease, its invasiveness and associated risks show the need for an alternative approach. This review evaluates the potential of Isocitrate Dehydrogenase (IDH) as a specific serum biomarker for NSCLC detection. Aim: This study aimed to provide an overview of the diagnostic potential of IDH serum and identify gaps of knowledge for further investigations.Methods: A literature search was conducted across 3 databases, namely Pubmed, Science Direct, and Proquest, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.Results: The analysis of 4 studies showed a higher level of IDH in the serum of early-stage NSCLC patients before surgery compared to healthy control. Most investigations reported an AUC above 0.5 and were statistically significant.Conclusion: IDH has promising potential as a biomarker for diagnosing NSCLC. Future investigations should conduct a cohort study type to avoid bias and establish the definitive role of this enzyme as a reliable biomarker for NSCLC.

Computational markers for personalized prediction of outcomes in non-small cell lung cancer patients with brain metastases.

Intracranial progression after curative treatment of early-stage non-small cell lung cancer (NSCLC) occurs from 10 to 50% and is difficult to manage, given the heterogeneity of clinical presentations and the variability of treatments available. The objective of this study was to develop a mechanistic model of intracranial progression to predict survival following a first brain metastasis (BM) event occurring at a time [Formula: see text]. Data included early-stage NSCLC patients treated with a curative intent who had a BM as the first and single relapse site (N = 31). We propose a mechanistic mathematical model able to derive computational markers from primary tumor and BM data at [Formula: see text] and estimate the amount and sizes of (visible and invisible) BMs, as well as their future behavior. These two key computational markers are [Formula: see text], the proliferation rate of a single tumor cell; and [Formula: see text], the per day, per cell, probability to metastasize. The predictive value of these individual computational biomarkers was evaluated. The model was able to correctly describe the number and size of metastases at [Formula: see text] for 20 patients. Parameters [Formula: see text] and [Formula: see text] were significantly associated with overall survival (OS) (HR 1.65 (1.07-2.53) p = 0.0029 and HR 1.95 (1.31-2.91) p = 0.0109, respectively). Adding the computational markers to the clinical ones significantly improved the predictive value of OS (c-index increased from 0.585 (95% CI 0.569-0.602) to 0.713 (95% CI 0.700-0.726), p < 0.0001). We demonstrated that our model was applicable to brain oligoprogressive patients in NSCLC and that the resulting computational markers had predictive potential. This may help lung cancer physicians to guide and personalize the management of NSCLC patients with intracranial oligoprogression.

Robotic Versus Thoracoscopic Sub-lobar Resection for Octogenarians with Clinical Stage IA Non-small Cell Lung Cancer: A Propensity Score-Matched Real-World Study.

Minimally invasive sub-lobectomy is sufficient in treating small early-stage non-small cell lung cancer (NSCLC). However, comparison of the feasibility and oncologic efficacy between robot-assisted thoracoscopic surgery (RATS) and video-assisted thoracoscopic surgery (VATS) in performing sub-lobectomy for early-stage NSCLC patients age 80 years or older is scarce. Octogenarians with clinical stage IA NSCLC (tumor size, ≤2 cm) undergoing minimally invasive wedge resection or segmentectomy at Shanghai Chest Hospital from 2011 to 2020 were retrospectively reviewed from a prospectively maintained database. Propensity score-matching (PSM) with a RATS versus VATS ratio of 1:4 was performed. Perioperative and long-term outcomes were analyzed. The study identified 594 patients (48 RATS and 546 VATS patients), and PSM resulted in 45 cases in the RATS group and 180 cases in the VATS group. The RATS patients experienced less intraoperative bleeding (60 mL [interquartilerange(IQR), 50-100 mL] vs. 80 mL [IQR, 50-100 mL]; P = 0.027) and a shorter postoperative hospital stay (4 days [IQR, 3-5 days] vs. 5 days [IQR, 4-6 days]; P = 0.041) than the VATS patients. The two surgical approaches were comparable concerning other perioperative outcomes and postoperative complications (20.00% vs. 26.11%; P = 0.396). Additionally, during a median follow-up period of 66 months, RATS and VATS achieved comparable 5-year overall survival (90.48% vs. 87.93%; P = 0.891), recurrence-free survival (83.37% vs. 83.18%; P = 0.782), and cumulative incidence of death. Further subgroup comparison also demonstrated comparable long-term outcomes between the two approaches. Finally, multivariate Cox analysis indicated that the surgical approach was not independently correlated with long-term outcomes. The RATS approach shortened the postoperative hospital stay, reduced intraoperative bleeding by a statistically notable but clinically insignificant amount, and achieved long-term outcomes comparable with VATS in performing sub-lobectomy for octogenarians with early-stage small NSCLC.

IL-17A as a new circulating bioindicator for non-small cell lung cancer diagnosis and prognosis.

Lung cancer (LC) is the highest contributor to cancer-associated mortality worldwide. Approximately 85% of all LC incidences involve non-small cell LC (NSCLC). Unfortunately, owing to a significant lack of sensitive and robust bioindicators, most patient diagnoses occur at advanced stages of the disease, thereby resulting in extremely poor patient outcomes. Herein, we elucidated the role of interleukin-17A (IL-17A) among NSCLC patients. Circulating IL-17A content was measured using enzyme-linked immunosorbent assay (ELISA), and its diagnostic and prognostic abilities were assessed using the receiver operating characteristic (ROC) curve and Kaplan-Meier analysis, respectively. Our analysis revealed that circulating IL-17A levels were significantly augmented among NSCLC vs. control samples. Moreover, based on our area under the curve (AUC) analysis, circulating IL-17A levels fared considerably better than the standard bioindicator carcinoembryonic antigen (CEA) in both testing and validation cohorts. Notably, we also revealed that the circulating IL-17A levels were accurately and reliably predicted in early-stage NSCLC patients. Besides, we demonstrated a strong correlation between elevated circulating IL-17A expression and worse prognosis among NSCLC patients. Herein, we demonstrated that circulating IL-17A levels can serve as reliable and potent diagnostic and prognostic bioindicators for NSCLC.

Inhaled medications for chronic obstructive pulmonary disease predict surgical complications and survival in stage I non-small cell lung cancer.

Lung function is routinely assessed prior to surgical resection for non-small cell lung cancer (NSCLC). Further assessment of chronic obstructive pulmonary disease (COPD) using inhaled COPD medications to determine disease severity, a readily available metric of disease burden, may predict postoperative outcomes and overall survival (OS) in lung cancer patients undergoing surgery. We retrospectively evaluated clinical stage I NSCLC patients receiving surgical treatment within the Veterans Health Administration from 2006-2016 to determine the relationship between number and type of inhaled COPD medications (short- and long-acting beta2-agonists, muscarinic antagonists, or corticosteroids prescribed within 1 year before surgery) and postoperative outcomes including OS using multivariable models. We also assessed the relationship between inhaled COPD medications, disease severity [measured by forced expiratory volume in 1 second (FEV1)], and diagnosis of COPD. Among 9,741 veterans undergoing surgery for clinical stage I NSCLC, patients with COPD were more likely to be prescribed inhaled medications than those without COPD [odds ratio (OR) =5.367, 95% confidence interval (CI): 4.886-5.896]. Increased severity of COPD was associated with increased number of prescribed inhaled COPD medications (P<0.0001). The number of inhaled COPD medications was associated with prolonged hospital stay [adjusted OR (aOR) =1.119, 95% CI: 1.076-1.165), more major complications (aOR =1.117, 95% CI: 1.074-1.163), increased 90-day mortality (aOR =1.088, 95% CI: 1.013-1.170), and decreased OS [adjusted hazard ratio (aHR) =1.061, 95% CI: 1.042-1.080]. In patients with FEV1 ≥80% predicted, greater number of prescribed inhaled COPD medications was associated with increased 30-day mortality (aOR =1.265, 95% CI: 1.062-1.505), prolonged hospital stay (aOR =1.130, 95% CI: 1.051-1.216), more major complications (aOR =1.147, 95% CI: 1.064-1.235), and decreased OS (aHR =1.058, 95% CI: 1.022-1.095). When adjusting for other drug classes and covariables, short-acting beta2-agonists were associated with increased 90-day mortality (aOR =1.527, 95% CI: 1.120-2.083) and decreased OS (aHR =1.087, 95% CI: 1.005-1.177). In patients with early-stage NSCLC, inhaled COPD medications prescribed prior to surgery were associated with both short- and long-term outcomes, including in patients with FEV1 ≥80% predicted. Routine assessment of COPD medications may be a simple method to quantify operative risk in early-stage NSCLC patients.

Preoperative splenic area as a prognostic biomarker of early-stage non-small cell lung cancer

BackgroundThe correlation between the preoperative splenic area measured on CT scans and the overall survival (OS) of early-stage non-small cell lung cancer (NSCLC) patients remains unclear.MethodsA retrospective discovery cohort and validation cohort consisting of consecutive NSCLC patients who underwent resection and preoperative CT scans were created. The patients were divided into two groups based on the measurement of their preoperative splenic area: normal and abnormal. The Cox proportional hazard model was used to analyse the correlation between splenic area and OS.ResultsThe discovery and validation cohorts included 2532 patients (1374 (54.27%) males; median (IQR) age 59 (52–66) years) and 608 patients (403 (66.28%) males; age 69 (62–76) years), respectively. Patients with a normal splenic area had a 6% higher 5-year OS (n = 727 (80%)) than patients with an abnormal splenic area (n = 1805 (74%)) (p = 0.007) in the discovery cohort. A similar result was obtained in the validation cohort. In the univariable analysis, the OS hazard ratios (HRs) for the patients with abnormal splenic areas were 1.32 (95% confidence interval (CI): 1.08, 1.61) in the discovery cohort and 1.59 (95% CI: 1.01, 2.50) in the validation cohort. Multivariable analysis demonstrated that abnormal splenic area was independent of shorter OS in the discovery (HR: 1.32, 95% CI: 1.08, 1.63) and validation cohorts (HR: 1.84, 95% CI: 1.12, 3.02).ConclusionPreoperative CT measurements of the splenic area serve as a prognostic indicator for early-stage NSCLC patients, offering a novel metric with potential implications for personalized therapeutic strategies in top-tier oncology research.

Circulating tumor DNA and radiological tumor volume identify patients at risk for relapse with resected, early-stage non-small-cell lung cancer

Predicting relapse and overall survival (OS) in early-stage non-small-cell lung cancer (NSCLC) patients remains challenging. Therefore, we hypothesized that detection of circulating tumor DNA (ctDNA) can identify patients with increased risk of relapse and that integrating radiological tumor volume measurement along with ctDNA detectability improves prediction of outcome. We analyzed 366 serial plasma samples from 85 patients who underwent surgical resections and assessed ctDNA using a next-generation sequencing liquid biopsy assay, and measured tumor volume using a computed tomography-based three-dimensional annotation. Our results showed that patients with detectable ctDNA at baseline or after treatment and patients who did not clear ctDNA after treatment had a significantly worse clinical outcome. Integrating radiological analysis allowed the stratification in risk groups prognostic of clinical outcome as confirmed in an independent cohort of 32 patients. Our findings suggest ctDNA and radiological monitoring could be valuable tools for guiding follow-up care and treatment decisions for early-stage NSCLC patients.

Downregulation of pro-surfactant protein B contributes to the recurrence of early-stage non-small cell lung cancer by activating PGK1-mediated Akt signaling

Recurrence is one of the main causes of treatment failure in early-stage non-small cell lung cancer (NSCLC). However, there are no predictors of the recurrence of early-stage NSCLC, and the molecular mechanism of its recurrence is not clear. In this study, we used clinical sample analysis to demonstrate that low levels of expression of precursor surfactant protein B (pro-SFTPB) in primary NSCLC tissue compared to their adjacent tissues are closely correlated with recurrence and poor prognosis in early-stage NSCLC patients. In vitro and in vivo experiments showed that downregulation of pro-SFTPB expression activates the Akt pathway by upregulating PGK1, which promotes metastasis and tumorigenicity in NSCLC cells. We then demonstrated that pro-SFTPB suppresses the formation of the ADRM1/hRpn2/UCH37 complex by binding to ADRM1, which inhibits PGK1 deubiquitination, thus accelerating ubiquitin-mediated PGK1 degradation. In summary, our findings indicate that low expression of pro-SFTPB in primary NSCLC compared to their adjacent tissue has potential as a predictor of recurrence and poor prognosis in early-stage NSCLC. Mechanistically, downregulation of pro-SFTPB attenuates inhibition of ADRM1-deubiquitinated PGK1, resulting in elevated levels of PGK1 protein; this activates the Akt pathway, ultimately leading to the progression of early-stage NSCLC.

Exploring published and novel pre-treatment CT and PET radiomics to stratify risk of progression among early-stage non-small cell lung cancer patients treated with stereotactic radiation

PurposeDisease progression after definitive stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) occurs in 20–40% of patients. Here, we explored published and novel pre-treatment CT and PET radiomics features to identify patients at risk of progression. Materials/MethodsPublished CT and PET features were identified and explored along with 15 other CT and PET features in 408 consecutively treated early-stage NSCLC patients having CT and PET < 3 months pre-SBRT (training/set-aside validation subsets: n = 286/122). Features were associated with progression-free survival (PFS) using bootstrapped Cox regression (Bonferroni-corrected univariate predictor: p ≤ 0.002) and only non-strongly correlated predictors were retained (|Rs|<0.70) in forward-stepwise multivariate analysis. ResultsTumor diameter and SUVmax were the two most frequently reported features associated with progression/survival (in 6/20 and 10/20 identified studies). These two features and 12 of the 15 additional features (CT: 6; PET: 6) were candidate PFS predictors. A re-fitted model including diameter and SUVmax presented with the best performance (c-index: 0.78; log-rank p-value < 0.0001). A model built with the two best additional features (CTspiculation1 and SUVentropy) had a c-index of 0.75 (log-rank p-value < 0.0001). ConclusionsA re-fitted pre-treatment model using the two most frequently published features – tumor diameter and SUVmax – successfully stratified early-stage NSCLC patients by PFS after receiving SBRT.

Diagnostic Workup, Treatment Patterns, and Clinical Outcomes in Early-Stage IB-IIIA Non-Small-Cell Lung Cancer Patients in Denmark.

Despite recent improvements in early-stage non-small-cell lung cancer (NSCLC), disease relapse remains challenging. Moreover, real-world evidence on long-term follow-up of disease-free survival (DFS) and recurrence patterns in a large, unselected cohort of early-stage NSCLC patients is lacking. This cohort study aimed to assess clinical characteristics, diagnostic workup, treatment, survival, and risk of disease relapse among early-stage NSCLC patients. Adult patients with stage IB, II, or IIIA NSCLC diagnosed and/or treated at Aarhus University Hospital in Denmark from January 2010 to December 2020 were included and followed-up until May 2021. Comprehensive clinical data were collected from electronic medical records of eligible patients and linked to Danish register data. The study population comprised 1341 early-stage NSCLC patients: 22%, 40%, and 38% were diagnosed with stage IB, II, and IIIA disease, respectively. In total, 42% of patients were tested for epidermal growth factor receptor (EGFR), of whom 10% were EGFR-mutation-positive (EGFRm+). Half of all patients received surgery, and nine percent of patients received stereotactic body radiation therapy (SBRT). Disease-free survival 5 years post-diagnosis was 49%, 42%, and 22% for stage IB, II, and stage IIIA patients, respectively. DFS improved over time both for patients treated with surgery and SBRT. However, disease relapse remained a challenge, with approximately 40% of stage IIIA having relapsed 3 years post-diagnosis. This study contributes important knowledge that puts clinical trials on new perioperative treatment modalities for early-stage NSCLC patients into perspective. Our findings cover an essential evidence gap on real-world DFS and recurrence dynamics, confirming that despite an improvement in DFS over time and across different treatment modalities, disease relapse remains a monumental challenge. Therefore, better treatment strategies are needed.

Dissecting Systemic T Cell Responses after Stereotactic Ablative Radiotherapy in NSCLC by Single-Cell RNA and T Cell Receptor Sequencing

There is accumulating evidence that stereotactic ablative radiotherapy (SABR) modulates immune responses to cancer; combining SABR and immunotherapy could promote the abscopal effect, but the precise effects of SABR on patients' systemic T cells is unclear. Here, we investigated SABR-induced systemic T cell response in early-stage non-small cell lung cancer (NSCLC) by single-cell RNA and T cell receptor sequencing. We performed single-cell RNA and T cell receptor sequencing on 29,439 T cells from four pairs of peripheral blood before and after SABR in early-stage NSCLC patients. Cell clustering and dimensionality reduction, SingleR, feature genes score, and TCR profiling analyses were used to investigate the heterogeneity of T cells and their changes following SABR. We identified fourteen T cell subtypes using unsupervised graph-based clustering of uniform manifold approximation and projection. By comparing the gene set scores of CD8_TE and CD8_EM pre- and post-SABR, we found both cytotoxic and inhibitory scores were significantly elevated in CD8_TE (both P < 0.001), while cytotoxic score was significantly increased in CD8_EM (P < 0.001) after SABR. We also found that CD4_TE showed increased cytotoxic scores and decreased Treg scores (P < 0.001 and < 0.05, respectively), while Treg cells showed decreased inhibitory and Treg scores (P < 0.001 and <0.01, respectively) after SABR. The proportion of large TCR clones was higher after SABR, which was accompanied by a decrease in proportion of single clones. When we compared the transcriptomes of CD8_TE cells between the single, small and large clones post-SABR, we found high expression of GZMB and KLRC3 in cells with large clones, and GZMK, IL7R, and SELL in small and single clones. This suggested that T cells after SABR with large clones may have higher cytotoxicity than those with small and single clones. Our study identified systemic T cell activation after SABR at single-cell resolution, providing unprecedented insight into the immune-modulatory role of SABR in early-stage NSCLC.