Diagnosis Of Non-small Cell Lung Cancer Research Articles

Real-world treatment patterns and outcomes in US patients (pts) with advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy (PBC) and anti–PD-(L)1 treatment.

8627 Background: Effective treatment options for advanced or metastatic NSCLC are limited, especially for pts who progress after treatment with PBC and an anti–programmed cell death 1 protein (PD-1) or ligand 1 (PD-L1) regimen. Examining real-world treatment patterns and long-term outcomes, we report on progression-free survival (PFS) and overall survival (OS) in pts with NSCLC who previously received PBC and anti–PD-(L)1 regimens. Methods: This study used the nationwide Flatiron Health electronic health record–derived deidentified database. Pts included in the analysis were ≥18 years old with an initial diagnosis of advanced or metastatic NSCLC and an ECOG PS of 0 or 1 who had received prior PBC and anti–PD-(L)1 therapy in 1 (in combination) or 2 (in sequence) lines and had initiated ≥1 subsequent line of treatment between 2018 and 2023; the start date of subsequent treatment (defined as the index regimen) was the index date. Pts were followed up until death or last available data through Mar 31, 2023. Pt characteristics, treatment patterns, and outcomes were analyzed for the overall pt group and according to initial treatment cohort (cohort 1: first-line [1L] PBC plus anti–PD-(L)1; cohort 2a: 1L PBC and second-line [2L] anti–PD-(L)1; or cohort 2b: 1L anti-PD-(L)1 and 2L PBC). PFS and OS were estimated using Kaplan-Meier methods. Results: Of 1793 pts, most were in cohort 1 (73.5%), with fewer pts in cohorts 2a (22.5%) and 2b (4.1%). The majority of pts in cohort 2b had PD-L1 ≥50% (n = 57, 78.1%), while the percentage was lower in cohorts 1 (n = 262, 19.9%) and 2a (n = 72, 17.9%). Most pts (n = 1626, 90.7%) had stage IV disease. Median time from advanced diagnosis to index date was 10.5 months (range, 1.1-103.8); median follow-up from index date was 7.8 months (range, 0.0-65.0). A broad range of treatments were used after PBC and anti–PD-(L)1 regimens; among all pts, the most common were docetaxel + ramucirumab and docetaxel monotherapy. Among all pts, median PFS and OS from the time of starting these index regimens were 5.29 and 11.20 months, respectively; PFS and OS were similar across cohorts. Conclusions: A broad range of subsequent treatments were used following PBC and anti–PD-(L)1 regimens, most commonly docetaxel with or without ramucirumab. Short median PFS and OS underscore a significant unmet need among pts previously treated with PBC and anti–PD-(L)1. [Table: see text]

Real-world KRAS testing and treatment utilization among patients with metastatic non-small cell lung cancer.

e20593 Background: About 30% of patients with non-small cell lung cancer (NSCLC) have been reported to harbor gene mutations of Kirsten rat sarcoma oncogene homologue (KRAS). KRAS testing is recommended at metastatic NSCLC (mNSCLC) diagnosis and targeted treatment has shown better outcomes among KRAS-positive patients. This study aimed to understand KRAS testing rates among mNSCLC patients and utilization of targeted treatment among KRAS G12C positive patients treated in the community oncology setting. Methods: A random sample of 836 mNSCLC patients from the Integra Connect PrecisionQ de-identified database was included in this retrospective observational analysis, with additional information supplemented by chart curation. The database contains ~80% community oncology and ~20% academic practices with over 3 million cancer patients across 500 sites of care. Eligible patients were those aged ≥18 years, diagnosed with mNSCLC, and who initiated treatment in the second line (2L) setting between 01-May-2021 and 01-Jan-2024. KRAS testing rates and utilization of targeted treatment use were assessed and presented for this study. Results: The median (IQR) age of 836 mNSCLC patients was 68 (62,75) years; 52.9% were female; 73.8% identified as White, 11.7% as African American, 1.9% as Asian, and 12.6% as Other. Testing for KRAS was reported in 749 (89.6%) of the mNSCLC patients any time during the evaluation period, with most of them (738/749) tested before 2L treatment initiation; 186/749 (24.8%) of those patients were positive, and 74 were KRAS G12C positive. Of the KRAS G12C positive patients, 53/74 (71.6%) reported a targeted KRAS treatment in the 2L or greater setting. Conclusions: In this real-world setting, the testing rates for KRAS are almost 90%, with about 70% of the mutated patients receiving a targeted treatment. However, there is still a proportion of patients who did not receive KRAS testing or targeted treatment in this real-world setting. Appropriate and timely testing and utilization of the targeted treatment is necessary for better patient outcomes. [Table: see text]

Dissecting racial/ethnic disparities in non-small cell lung cancer staging at diagnosis: Intra-ethnic and geographic differences.

1575 Background: Lung cancer outcomes significantly rely on accurate and early detection. This population-based study aims to identify factors contributing to disparities in the stage of non-small cell lung cancer (NSCLC) diagnoses, focusing on Hispanic ethnic subgroups. Methods: Incident cases diagnosed from 2005–2018 were extracted from the Florida State Cancer Registry. Stage was categorized as resectable (Stage I-IIIA) or nonresectable (Stage IIIB/IIIC/IV) NSCLC. Multivariable logistic regression models were used to assess the association between race/ethnicity and stage at diagnosis, adjusted for socioeconomic, smoking status, and clinical factors. Regional stratification involved separate analyses for heavily Hispanic South Florida and the rest of Florida. Results: Among 157,034 NSCLC patients, with a racial distribution of 81.0% White, 8.3% Black, and 9.2% Hispanic, 43.2% were diagnosed at a resectable stage. Age-adjusted models showed Black patients had 22% higher odds (odds ratio [OR]=1.22; 95% CI: 1.21-1.23) and Hispanic patients had 11% higher odds (OR=1.11; 95% CI: 1.10-1.12) of non-resectable stage across all subgroups diagnoses compared to White patients. However, after further adjustment, higher odds were significant only for NHB (ORadj=1.12; 95% CI: 1.11-1.14) and Central American Hispanics (ORadj=1.41; 95% CI: 1.35-1.47). Regional differences were significant, with Hispanic patients in South Florida showing more favorable staging outcomes than Whites (ORadj=0.95; 95% CI: 0.94-0.97), while in the rest of Florida, Hispanic patients were at a disadvantage (ORadj=1.09; 95% CI: 1.07-1.10). Conclusions: Pronounced NSCLC staging disparities are manifest in Black and Hispanic populations, coupled with striking regional variations among Florida's Hispanic groups which underscores the necessity for targeted research to dissect and address the underlying causes of these inequities in the cancer care continuum.

A phase IV study of ApricityCARE program for cancer adverse events rapid evaluation to improve treatment outcomes of ethnic/racial minority patients with non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICI).

TPS1642 Background: ICI have changed the treatment landscape of NSCLC, with many now FDA approved in not just advanced, but even early-stage disease. With the increase in ICI use, the incidence of immune-related adverse effects (irAEs) has also risen, occurring in up to 16% of ICI-treated patients. Prompt recognition and timely management are necessary to avert potential poor outcomes from direct toxicity and/or early treatment discontinuation. However, existing barriers to access care that disproportionately impact racial and ethnic minority patients may amplify challenges in early, effective management of irAEs. Using technology-enabled health interventions in a culturally competent manner can improve access to health care resources and reduce health disparities. These platforms need to be optimized at the technology and health literacy level of underserved minority communities and adapted to meet the community's needs. Methods: We have designed a multi-center phase IV clinical trial to 1) assess factors related to suboptimal and optimal use of the ApricityCARE, a virtual first-response clinical support (or coverage) to provide 24/7 symptom monitoring and side effect management and 2) determine the impact of the program on ICI toxicity management for NSCLC patients receiving ICIs in a highly diverse community. Eligible patients are those with a confirmed diagnosis of NSCLC who self-identify as a member of an ethnic minority or underserved population, prescribed for any treatment regimen that includes an ICI. The study entails a 50-patient run-in phase with two focus group discussions, stratified on a Likert-type scale based on the frequency of utilization, to determine factors impacting usability of the ApricityCare program. This data will inform optimal implementation of ApricityCare for the randomized phase of the study, where 230 patients will be assigned 1:1 to use of ApricityCare versus standard of care. The run-in phase of the study is currently accruing at Columbia University, and is planned to open at NYU, Mount Sinai, and Montefiore (NCT05812274). Clinical trial information: NCT05812274 .

Results from METIS (EF-25), an international, multicenter phase III randomized study evaluating the efficacy and safety of tumor treating fields (TTFields) therapy in NSCLC patients with brain metastases.

2008 Background: For non-small cell lung cancer (NSCLC) with brain metastases (BM) stereotactic radiosurgery (SRS) is the current preferred therapy. Due to frequent intracranial failures, there is a high unmet need for salvage therapies. Whole brain radiotherapy (WBRT) reduces intracranial failure but used less frequently due to cognitive consequences. Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell division and have shown improved survival and safety in patients with glioblastoma and metastatic NSCLC. Phase 3 METIS trial [NCT02831959] aimed to evaluate the efficacy and safety of TTFields therapy in NSCLC patients with BM treated with SRS, specifically in terms of lengthening time to intracranial progression without cognitive decline. Methods: Mutation negative (M-) NSCLC patients with 1–10 BM were randomized 1:1 to receive stereotactic radiosurgery (SRS) followed by Tumor Treating Fields (TTFields; 150 kHz) therapy with best supportive care (BSC) or SRS followed by BSC. Patients with Karnofsky Performance Status (KPS) ≥70, newly diagnosed with one inoperable or 2–10 supra-/infratentorial brain metastases suitable for SRS and receiving optimal extracranial disease therapy were included. Exclusions were prior WBRT and single operable or recurrent brain metastases. Primary endpoint was time to first intracranial progression (RANO-BM) based on cumulative risk. Patients were followed every two months until second intracranial progression. Cognition and patient quality of life (QoL) were evaluated. Results: Between July 2016 and September 2022, 298 patients were randomized. Baseline characteristics were balanced: median age was 63.5 (range 37-84) years, 37.6% females, majority of patients had a KPS ≥ 80, median time from initial NSCLC diagnosis was 1.8 months (range: 0.2-55.7), 77% had adenocarcinoma. Median treatment duration of TTFields was 16 weeks, with a median usage time of 67%. Primary endpoint, time to intracranial progression from SRS, was significantly prolonged with SRS followed by TTFields therapy with BSC vs. TTFields plus BSC arm (median of 21.9 vs. 11.3 months); HR=0.67 [0.48-0.93], p=0.02. TTFields-related AEs were mainly dermatological, and Grade ≤2. TTFields therapy also improved deterioration-free survival of global health status, physical functioning, and fatigue according to QoL, and did not negatively impact cognition. Conclusions: METIS study met its primary endpoint, demonstrating that TTFields therapy following SRS in mutation negative NSCLC patients with BM, significantly prolongs time to intracranial progression and could postpone WBRT, without QoL and cognition decline. Clinical trial information: NCT02831959 .

Association between antibiotic use and mortality among older persons receiving first-line immune checkpoint inhibitors for non-small cell lung cancer (NSCLC).

e14607 Background: There is biologic plausibility that antibiotics (ABX) may reduce the effectiveness of cancer therapy, most notably immune checkpoint inhibitors (ICI). As ABX are commonly prescribed to older persons and more than a third of US persons with cancer are eligible for ICIs, use of ABX has important population health implications. We assess the association between ABX use and mortality among persons with NSCLC who receive first-line (1L) treatment. Methods: Using SEER-Medicare, we assembled a cohort of persons ≥66 years with NSCLC who received 1L treatment with platinum-based chemotherapy (PLT) or ICI (PLT without ICI, PLT with ICI, and ICI monotherapy) within one year of cancer diagnosis between 2017-2019. We assessed overall ABX exposure from 1 month to 1 year prior to treatment initiation and by ABX class. Primary outcome was all cause deaths within three years of treatment initiation or until 12/31/2020. Multivariable Cox proportional hazard models adjusting for individual-level characteristics (demographics, time-to-treatment, comorbidities, healthcare use, SEER registry, and neighborhood socioeconomic status) and landmark analyses of 1-6 months after cancer treatment were used to assess the association between ABX exposure and mortality. Results: Among 4,182 persons (mean age 75 years, 85% white, 68% chemo-immunotherapy within 2 months of NSCLC diagnosis), 63%, 18%, and 18% received PLT, PLT+ICI, and ICI, respectively. ICI+/-PLT increased in prevalence from 20% of treatments (2017) to 55% (2019). The mean age of persons who received ICI alone (78 years old) was higher than PLT or PLT+ICI. Prior to 1L treatment, 22% and 72% of persons received ABX within 30 days and 1 year prior to cancer treatment, respectively. The three most common ABX classes were fluoroquinolones (48%), penicillins (21%), and macrolides (18%). The cohort was followed for 3,274 person-years and included 2,958 deaths within 1 year and 4,144 deaths within 3 years of follow-up. Compared with persons who did not receive ABX within 3 months of cancer treatment, ABX use was associated with higher risk of death within 3 years for ICI alone [HR 1.24 (1.05-1.46) but not for PLT alone or PLT+ICI. Fluoroquinolones were associated with an elevated risk of mortality among persons who received ICI alone HR 1.41(95%CI: 1.1-1.8) and PLT alone HR 1.18 (95%CI: 1.05-1.32) but not PLT+ICI. Our findings were similar across definitions of ABX exposure (30 days to 1 year prior to treatment) and analytic landmarks after treatment initiation. Conclusions: Among patients with NSCLC who received 1L treatment, we identified an association between ABX exposure prior to treatment and increased mortality among persons who received ICI monotherapy but not PLT+ICI. As ICIs expand to more cancer types and earlier stages, ABX use may have a significant impact on outcomes and population health.

Budget impact model of LungFlag, a predictive risk model for lung cancer screening.

10534 Background: Lung cancer screening (LCS) programs using low-dose computed tomography (LDCT) for early detection reduce mortality and have been widely recommended. LungFlag is a machine-learning risk prediction model that uses patient-level data to identify individuals at high risk of developing non-small cell lung cancer (NSCLC), prompting their physician to recommend screening with LDCT. Methods: A budget impact model was developed to estimate the costs associated with adoption of LungFlag as an adjunct to existing US Preventive Services Task Force (USPSTF) screening guidelines for a hypothetical US commercial health plan population of 1 million beneficiaries. The model calculates the total expected annual costs of screening for NSCLC with LDCT in scenarios with and without LungFlag, including healthcare resource utilization for detecting NSCLC and treatment of patients diagnosed with NSCLC. Incremental costs were evaluated over a 5-year period. Results: Among 36,803 USPSTF-eligible persons, we assumed that 4600 (12.5%) had already initiated LCS, leaving 32,203 persons who were candidates for pre-screening with LungFlag. The model estimated that 17 additional NSCLC diagnoses per year would be detected by screening when using LungFlag, with most in stage 1. Over 5 years, LungFlag was estimated to result in 33 fewer patients with stage 3 or stage 4 NSCLC at diagnosis and 22 fewer NSCLC-related deaths. Use of LungFlag increased annual costs during the first 2 years and provided cost savings from Year 4 onwards (Table). Cost savings from LungFlag were attributable to reductions in the costs of advanced NSCLC treatment. Conclusions: In a population of 1 million commercial health plan beneficiaries, the adoption of LungFlag as an adjunct to existing screening guidelines for USPSTF-eligible patients was estimated to prevent 22 additional NSCLC-related deaths, with a cost savings of $2.87 million over 5 years from a US commercial payer perspective. [Table: see text]

Novel approach to implementing natural language processing for clinical staging of non-small-cell lung cancer.

e13624 Background: Cancer staging is instrumental in driving clinical management and trial enrollment, but staging data are generally unreliable and unstructured in the electronic health record (EHR). Advances in natural language processing (NLP) may facilitate clinical staging and documentation [1], but challenges to real-world implementation include (1) automatically identifying appropriate patients and reports from the EHR and (2) developing an unbiased dataset for training and validation [2]. We describe our institution’s novel approach to overcome these barriers while building an in-house NLP pipeline for clinical tumor staging of non-small-cell lung cancer (NSCLC). Methods: We identified patients by searching our EHR (Epic) for a molecular analysis test ordered specifically for pathological diagnoses of NSCLC at our institution. We used the test order date as the diagnosis proxy date (DPD). For each patient, we extracted imaging reports up to 16 weeks before and 6 weeks after the DPD. To derive primary tumor size, we analyzed the CT Chest or PET/CT report closest to the DPD using an oncology-trained NLP text extraction and labeling tool (John Snow Labs). We cleaned all extracted tumor size entities and identified the largest measurement linked to the lungs. We compared primary tumor measurements from the NLP pipeline to those in a preexisting, manually compiled cancer registry (CNEXT). We manually analyzed discrepancies through chart review. Results: 542 patients with a DPD between 11/2016 - 9/2023 were processed through the NLP pipeline. Of 443 patients with valid values in both the pipeline and CNEXT, 53% (234) were exact matches, and 20% (90) had a close match (within 0-5mm), yielding a 73% accuracy rate for values within 5mm. When mismatched values were manually reviewed, several cases in CNEXT were found to have a DPD differing by more than 3 months and tumor sizes derived from external reports. When these cases were excluded, 320 of the remaining 349 patients had valid values in both the pipeline and the updated manual review. In this refined population, 66% (213) were exact matches, and 15% (48) had a close match, yielding an 82% accuracy rate for values within 5mm. Conclusions: To our knowledge, this is the first report of a pathology-based method to automatically and reliably identify patients with NSCLC and their relevant imaging reports directly from the EHR. We used a prebuilt NLP tool to derive primary tumor sizes with relatively high accuracy and found that adding flags for timeline discrepancies and external reports can further improve validity. As we near completion of analogous pipelines for node and metastasis staging, we will develop methodology to identify subgroups of patients that can be clinically staged with near-perfect accuracy, ultimately aiming to substantially limit manual staging of uncomplicated cases. 1. Puts 2023. 2. Wang 2022.

Pulmonary Hypertension and Survival among Non-Small Cell Lung Cancer Patients: A Retrospective Cohort Study in the U.S. Military Health System.

Background: Lung cancer is one of the most lethal cancers with survival being closely related to stage and influenced by comorbid illness. The survival implications of pulmonary hypertension (PH) on patients with non-small cell lung cancer (NSCLC) have only been evaluated in small cohorts, with limited long-term follow-up. Methods: We conducted a retrospective cohort study of 7946 patients with NSCLC diagnosed in the MHS. This study evaluated the survival impact of PH in patients diagnosed with NSCLC in the MHS. Patients were classified as having and not having PH. We stratified PH into those diagnosed before the diagnosis of NSCLC and those diagnosed after NSCLC diagnosis. Results: Relative to patients without PH, patients with PH diagnosed before NSCLC had an increased risk of death (HR = 1.15 [95% CI, 1.02-1.29]). The increased risk of death was more obvious for patients with PH diagnosed after NSCLC compared with those without PH (HR = 2.74 [95% CI, 2.51-2.99]). The results were similar when stratified by patient demographics. Conclusions: In the MHS, PH is associated with worsened NSCLC survival, regardless of when it is diagnosed. When PH is diagnosed after NSCLC, it is associated with a marked reduction in survival, and this finding may suggest a potential role for monitoring pulmonary pressures in NSCLC patients. Furthermore, as specific PH therapy exists, some NSCLC patients with PH may be candidates for therapy.

Three-year follow-up study reveals improved survival rate in NSCLC patients underwent guideline-concordant diagnosis and treatment.

No studies in China have assessed the guideline-concordance level of the first-course of non-small cell lung cancer (NSCLC) diagnosis and treatment and its relationship with survival. This study comprehensively assesses the current status of guideline-concordant diagnosis (GCD) and guideline-concordant treatment (GCT) of NSCLC in China and explores its impact on survival. First course diagnosis and treatment data for NSCLC patients in Liaoning, China in 2017 and 2018 (n=1828) were used and classified by whether they underwent GCD and GCT according to Chinese Society of Clinical Oncology (CSCO) guidelines. Pearson's chi-squared test was used to determine unadjusted associations between categorical variables of interest. Logistic models were constructed to identify variables associated with GCD and GCT. Kaplan-Meier analysis and log-rank tests were used to estimate and compare 3-year survival rates. Multivariate Cox proportional risk models were constructed to assess the risk of cancer mortality associated with guideline-concordant diagnosis and treatment. Of the 1828 patients we studied, 48.1% underwent GCD, and 70.1% underwent GCT. The proportions of patients who underwent both GCD and GCT, GCD alone, GCT alone and neither GCD nor GCT were 36.7%, 11.4%, 33.5% and 18.4%, respectively. Patients in advanced stage and non-oncology hospitals were significantly less likely to undergo GCD and GCT. Compared with those who underwent neither GCD nor GCT, patients who underwent both GCD and GCT, GCD alone and GCT alone had 35.2%, 26.7% and 35.7% higher 3-year survival rates; the adjusted lung cancer mortality risk significantly decreased by 29% (adjusted hazard ratio[aHR], 0.71; 95% CI, 0.53-0.95), 29% (aHR, 0.71; 95% CI, 0.50-1.00) and 32% (aHR, 0.68; 95% CI, 0.51-0.90). The 3-year risk of death is expected to be reduced by 29% if patients with NSCLC undergo both GCD and GCT. There is a need to establish an oncology diagnosis and treatment data management platform in China to monitor, evaluate, and promote the use of clinical practice guidelines in healthcare settings.

Prognostic and predictive value of interstitial lung abnormalities and EGFR mutation status in patients with non-small cell lung cancer

BackgroundTo determine the predictive value of interstitial lung abnormalities (ILA) for epidermal growth factor receptor (EGFR) mutation status and assess the prognostic significance of EGFR and ILA in patients with non-small cell lung cancer (NSCLC).MethodsWe reviewed 797 consecutive patients with a histologically proven diagnosis of primary NSCLC from January 2013 to October 2018. Of these, 109 patients with NSCLC were found to have concomitant ILA. Multivariate logistic regression analysis was used to identify the significant clinical and computed tomography (CT) findings in predicting EGFR mutations. Cox proportional hazard models were used to identify significant prognostic factors.ResultsEGFR mutations were identified in 22 of 109 tumors (20.2%). Multivariate analysis showed that the models incorporating clinical, tumor CT and ILA CT features yielded areas under the receiver operating characteristic curve (AUC) values of 0.749, 0.838, and 0.849, respectively. When combining the three models, the independent predictive factors for EGFR mutations were non-fibrotic ILA, female sex, and small tumor size, with an AUC value of 0.920 (95% confidence interval[CI]: 0.861–0.978, p < 0.001). In the multivariate Cox model, EGFR mutations (hazard ratio = 0.169, 95% CI = 0.042–0.675, p = 0.012; 692 days vs. 301 days) were independently associated with extended overall survival compared to the wild-type.ConclusionNon-fibrotic ILA independently predicts the presence of EGFR mutations, and the presence of EGFR mutations rather than non-fibrotic ILA serves as an independent good prognostic factor for patients with NSCLC.

Preoperative evaluation of visceral pleural invasion in peripheral lung cancer utilizing deep learning technology.

This study aimed to assess the efficiency of artificial intelligence (AI) in the detection of visceral pleural invasion (VPI) of lung cancer using high-resolution computed tomography (HRCT) images, which is challenging for experts because of its significance in T-classification and lymph node metastasis prediction. This retrospective analysis was conducted on preoperative HRCT images of 472 patients with stage I non-small cell lung cancer (NSCLC), focusing on lesions adjacent to the pleura to predict VPI. YOLOv4.0 was utilized for tumor localization, and EfficientNetv2 was applied for VPI prediction with HRCT images meticulously annotated for AI model training and validation. Of the 472 lung cancer cases (500 CT images) studied, the AI algorithm successfully identified tumors, with YOLOv4.0 accurately localizing tumors in 98% of the test images. In the EfficientNet v2-M analysis, the receiver operating characteristic curve exhibited an area under the curve of 0.78. It demonstrated powerful diagnostic performance with a sensitivity, specificity, and precision of 76.4% in VPI prediction. AI is a promising tool for improving the diagnostic accuracy of VPI for NSCLC. Furthermore, incorporating AI into the diagnostic workflow is advocated because of its potential to improve the accuracy of preoperative diagnosis and patient outcomes in NSCLC.

Silencing of circRPPH1 Inhibits the Progression of Non-Small-Cell Lung Cancer Through miR-326/ERBB4 Signal Axis.

Circular RNAs (circRNAs) play critical roles in the recurrence and progression of non-small-cell lung cancer (NSCLC). This study aimed to investigate the function and underlying mechanism of a novel circRNA (circRPPH1) in NSCLC. Localization of circRPPH1 was determined via FISH assay, while cell proliferation was assessed via CCK8 and colony formation assay. Cell migration and invasion were studied using transwell assay, while binding sites between miR-326 and circRPPH1 or ERBB4 were verified by luciferase reporter, RIP, and RNA pull-down assays. Moreover, xenograft assay was performed to verify the in vivo roles of circRPPH1. Results indicated that circRPPH1 was highly expressed in NSCLC tissues and cells, where circRPPH1 levels were predictive of poor prognosis. The malignant behavior of NSCLC cells was exacerbated by overexpressing circRPPH1, while opposite effects were observed when it was knocked down. Direct interaction between miR-326 and circRPPH1 or ERBB4 was confirmed in NSCLC cells, while rescue experiment results showed that circRPPH1 exerted an oncogenic role via miR-326-ERBB4 signal axis. Moreover, in vitro, growth of NSCLC cells was significantly attenuated following circRPPH1 depletion. The study concluded that circRPPH1 was involved in promoting NSCLC progression via the miR-326/ERBB4 axis, which provided a novel potential target for the diagnosis or treatment of NSCLC.

Hypersensitive detection of CYFRA21-1 by SERS dual antibody sandwich method

PurposeAs an important reference index for the early diagnosis of non-small cell lung cancer (NSCLC), CYFRA21-1 still lacks the detection of low equipment cost, wide linear range and high sensitivity. Surface-enhanced Raman scattering (SERS) is a vibration spectrum technology based on the surface plasma of precious metal nanoparticles, which has been effectively applied to the detection of tumor markers. The combination of SERS technology and sensors has great potential in the ultrasensitive detection of tumor markers. The purpose of this study was to develop a sensitive method using SERS to quantitatively detect CYFRA21-1 for early diagnosis of NSCLC. MethodsA double-antibody sandwich immunoassay based on SERS was designed and tested to implement the ultrasensitive detection of CYFRA21-1 in the serum of NSCLC patients. ResultsGold @Ag nanorods (Au @Ag NRs) with higher Raman signals were prepared and used as probes, while magnetic graphene oxide was used as a magnetic substrate. The immunized probe, immune substrate and CYFRA21-1 standard substance in the buffer system formed a double-antibody sandwich structure. The standard curve displayed a liner range from 1pg mL−1 to 10 ng mL−1, and the detection limit (LOD) is 0.8943pg mL−1. The Raman intensity exhibited a wide linear relationship with the logarithm of CYFRA21-1 concentration. ConclusionOur study successfully established a double-antibody sandwich immunoassay based on SERS. This method demonstrated high specificity and sensitivity for detecting CYFRA21-1 protein content in serum. It has the potential to be applied for early detection of lung cancer biomarkers.

Circ_0006949 as a potential non-invasive diagnosis biomarker promotes the proliferation of NSCLC cells via miR-4673/GLUL axis

The 5-year survival for non-small cell lung cancer (NSCLC) remains <20 %, primarily due to the early symptoms of lung cancer are inconspicuous. Prompt identification and medical intervention could serve as effective strategies for mitigating the death rate. We therefore set out to identify biomarkers to help diagnose NSCLC. CircRNA microarray and qRT-PCR reveal that sputum circ_0006949 is a potential biomarker for the early diagnosis and therapy of NSCLC, which can enhance the proliferation and clone formation, regulate the cell cycle, and accelerate the migration and invasion of NSCLC cells. Circ_0006949 and miR-4673 are predominantly co-localized in the cytoplasm of NSCLC cell lines and tissues; it upregulates GLUL by adsorption of miR-4673 through competing endogenous RNAs mechanism. The circ_0006949/miR-4673/GLUL axis exerts pro-cancer effects in vitro and in vivo. Circ_0006949 can boost GLUL catalytic activity, and they are highly expressed in NSCLC tissues and correlate with poor prognosis. In summary, circ_0006949 is a potential biomarker for the early diagnosis and therapy of NSCLC. This novel sputum circRNA is statistically more predictive than conventional serum markers for NSCLC diagnosis. Non-invasive detection of patients with early-stage NSCLC using sputum has shown good potential for routine diagnosis and possible screening.

Association between postoperative radiotherapy for young-onset nonsmall cell lung cancer and risk of second primary malignancies: comparative study.

The most common form of therapy for nonsmall cell lung cancer (NSCLC) in early stage is surgery-based combination therapy, including radiotherapy and immunotherapy. However, postoperative radiotherapy (PORT) of cancer is correlated with increasing risk of second primary malignancy (SPM), especially young-onset cancer cases. The authors aimed to quantify the risks of SPM associated with PORT treatment for young‑onset NSCLC in early stage. The authors screened for SPM that developed over 5 years since the diagnosis of NSCLC. Using the data from the Surveillance, Epidemiology, and End Results database, PORT-correlated risks were estimated with multivariate Logistic regression analysis. Moreover, Fine-Gray's competing risk regression analysis was used to calculate the cumulative incidence of SPMs. Among the 30308 young-onset NSCLC patients in early stage undergoing surgery, a total of 3728 patients have received PORT. Logistic regression analyses showed that PORT showed substantial correlation with elevated risks of second solid malignancies [relative risks (RR)=1.31; 95% CI: 1.17-1.46], lung cancer (RR=1.23; 95% CI: 1.07-1.42), breast cancer (RR=1.74; 95% CI: 1.16-2.74), and colon and rectum cancers (RR=1.37; 95% CI: 1.07-2.06) as well as a negligible risk of second hematologic malignancies (RR=1.15; 95% CI: 0.82-1.67). The cumulative incidence of SPMs revealed similar findings. Higher RR was obtained in NSCLC patients aged 60-69 years (RR=1.33), in white race (RR=1.36), diagnosed in 1975-2000 (RR=1.23) and 2001-2015 (RR=1.40), or diagnosed with lung adenocarcinoma (RR=1.55). PORT for young-onset NSCLC in early stage was correlated with elevated risks of SPMs (lung cancer, breast cancer, as well as colon and rectum cancers), supporting the need for long-term surveillance of these patients.

Endobronchial Ultrasound Guided Transbronchial Needle Aspiration and Next Generation Sequencing Yields

PurposeThe use of endobronchial ultrasound (EBUS) is standard practice for lung cancer diagnosis and staging. Next generation sequencing (NGS) for detection of genetic alterations is recommended in advanced, non-squamous, non-small-cell lung cancer (NSCLC). Existing protocols for NGS testing are minimal and reported yields vary. This study aimed to determine the yield of EBUS samples obtained for NGS using a sampling protocol at our institution and assess predictive factors to form collection protocols.MethodsWe reviewed EBUS bronchoscopies from 2016 to 2021 with non-squamous NSCLC diagnoses. For target lesions suspected to be malignant, the sampling protocol was: (a) two slides for on-site evaluation, (b) three to five fine needle aspirations rinsed into saline for immunohistochemical staining and in-house molecular markers, and (c) additional three to five rinses for NGS. Sufficiency for NGS processing was determined by the pathology department.ResultsTwo hundred and seventy-eight non-squamous NSCLC samples were obtained by EBUS (205 adenocarcinoma; 73 not otherwise specified). EBUS was performed under general anesthesia in 75.5% of cases. The overall sample adequacy for NGS testing was 57.5%. Higher adequacy rates were observed when protocol was adhered to 66.0% versus 37.2% (p < 0.001). There was no statistically significant difference based on the size of the lesion or location of the sample.ConclusionWhen a protocol of three to five dedicated needle rinses for NGS was followed, we nearly doubled our sample adequacy rate for NSG as compared to standard care. Studies are needed to determine the ideal collection and processing modality to preserve tissue samples for genetic sequencing.

Advancing Nonsmall Cell Lung Cancer Diagnosis Accuracy via Dual Detection Fluorescent Nanoprobes.

Among the primary threats to human health worldwide, nonsmall cell lung cancer (NSCLC) remains a significant factor and is a leading cause of cancer-related deaths. Due to subtle early symptoms, NSCLC patients are diagnosed at advanced stages, resulting in low survival rates. Herein, novel Au-Se bond nanoprobes (NPs) designed for the specific detection of Calpain-2 (CAPN2) and Human Neutrophil Elastase (HNE), pivotal biomarkers in NSCLC, were developed. The NPs demonstrated exceptional specificity and sensitivity toward CAPN2 and HNE, enabling dual-color fluorescence imaging to distinguish between NSCLC cells and normal lung cells effectively. The NPs' performance was consistent across a wide pH range (6.2 to 8.0), and it exhibited remarkable resistance to biological thiol interference, indicating its robustness in complex physiological environments. These findings suggest the nanoprobe is a promising tool for early NSCLC diagnosis, offering a novel approach for enhancing the accuracy of cancer detection.

Response to lorlatinib rechallenge in a case of ALK-rearranged metastatic NSCLC with a resistance mutation to second generation TKIs.

Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have been developed for the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged non-small cell lung cancer (NSCLC), with the newer generation agents brigatinib, alectinib and lorlatinib showing prolonged responses. With the increasing number of target therapies available, the optimal sequence is yet to be defined, as resistance profiles may evolve over time and in response to sequential ALK inhibitors. Therefore, ALK-targeted strategies may be personalized based upon the presence of specific ALK resistance mutations. Here, we report on the case of a patient who has been treated with a sequence of three ALK TKIs after receiving diagnosis of ALK-rearranged metastatic NSCLC in 2015 and gained further benefit upon lorlatinib rechallenge after the acquisition of the G1202R resistance mutation to second generation TKIs. In this case, the first ALK resistance mutation detected after progression on first line TKI, the I1171N, is a common resistance mutation after alectinib and confers sensitivity to brigatinib, that the patient received afterwards with a long-term disease stability. The second ALK resistance mutation detected after a chemotherapy interval, the G1202R, is the most common resistance mutation after second generation ALK TKIs and has been associated with sensitivity to third generation TKIs, such as lorlatinib. This case of a patient with EML4-ALK-rearranged NSCLC shows that sequential treatment with next-generation ALK TKIs, including rechallenge, can induce profound remissions, even in heavily pretreated patients, and that ALK-targeted strategies may be personalized by considering the presence of distinct ALK resistance mutations.

CircIARS: a potential plasma biomarker for diagnosing non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the most prevalent cancers in the world, and early diagnosis can effectively improve patient survival. Here, differentially expressed circIARS genes are screened from the sequencing results, and their molecular characteristics are examined by Sanger sequencing, RNase R assay, agarose gel electrophoresis (AGE), and fluorescence in situ hybridization (FISH). Real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) is performed to detect the expression level of circIARS. The diagnostic value of the signature is analyzed using a subject operating characteristic (ROC) curve. Moreover, plasma is collected from postsurgical, chemotherapy, and relapse patients to investigate the prognostic value of circIARS in NSCLC. The expression of circIARS is greater in both the plasma and tissues of NSCLC patients than in those of healthy individuals, and could be used to distinguish NSCLC patients from patients with benign pulmonary disease (BPD), small cell lung cancer (SCLC) patients, and healthy individuals. The expression level of circIARS relatively decreases after antitumor therapy, such as chemotherapy, and relatively increases after recurrence. ROC analysis reveals that circIARS has better detection efficiency than traditional markers. In addition, circIARS expression level is strongly correlated with several clinicopathological parameters. Finally, we tentatively predict the downstream miRNAs or RBP that might bind to circIARS. Plasma circIARS is significantly greater in NSCLC patients and has good stability and specificity as a diagnostic marker, which could aid in the adjuvant diagnosis and dynamic monitoring of NSCLC.