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PurposeCirculating tumor DNA (ctDNA) testing has become a promising tool to guide first-line (1L) targeted treatment for advanced non-small cell lung cancer (aNSCLC). This study aims to estimate the clinical validity (CV) and clinical utility (CU) of ctDNA-based next-generation sequencing (NGS) for oncogenic driver mutations to inform 1L treatment decisions in aNSCLC through a systematic literature review and meta-analysis.MethodsA systematic literature search was conducted in PubMed/MEDLINE and Embase to identify randomized control trials or observational studies reporting CV/CU on ctDNA testing in patients with aNSCLC. Meta-analyses were performed using bivariate random-effects models to estimate pooled sensitivity and specificity. Progression-free/overall survival (PFS/OS) was summarized for CU studies.ResultsA total of 20 studies were identified: 17 CV only, 2 CU only, and 1 both, and 13 studies were included for the meta-analysis on multi-gene detection. The overall sensitivity and specificity for ctDNA detection of any mutation were 0.69 (95% CI 0.63-0.74) and 0.99 (95% CI 0.97-1.00), respectively. However, sensitivity varied greatly by driver gene, ranging from 0.29 (95% CI 0.13-0.53) for ROS1 to 0.77 (95% CI 0.63-0.86) for KRAS. Two studies that compared PFS with ctDNA versus tissue-based testing followed by 1L targeted therapy found no significant differences. One study reported OS curves on ctDNA-matched and tissue-matched therapies but no hazard ratios were provided.ConclusionsctDNA testing demonstrated an overall acceptable diagnostic accuracy in patients with aNSCLC, however, sensitivity varied greatly by driver mutation. Further research is needed, especially for uncommon driver mutations, to better understand the CU of ctDNA testing in guiding targeted treatments for aNSCLC.

Therapeutic antibodies designed to target three immune checkpoint proteins have been applied in the treatment of various malignancies, including small and non-small cell lung cancers, melanoma, renal cell carcinoma, and others. These treatments combat cancers by reactivating cytotoxic T cells. Nevertheless, this mode of action was found to be associated with a broad range of immune-related adverse events (irAEs), including pneumonitis, sarcoidosis, myocarditis, nephritis, colitis, and hepatitis. Depending on their severity, these irAEs often necessitate the suspension or discontinuation of treatment and, in rare instances, may lead to fatalities. We analyzed over nineteen million reports and identified over eighty thousand adverse event reports from patients treated with immune checkpoint inhibitors submitted to the Food and Drug Administration's Adverse Event Reporting System MedWatch. Reports concerning pembrolizumab, nivolumab, cemiplimab, avelumab, durvalumab, atezolizumab, and ipilimumab revealed a statistically significant association between the irAEs and concurrent infectious diseases for five out of seven treatments. Furthermore, the association trend was preserved across all three types of checkpoint inhibitors and each of the five individual therapeutic agent cohorts, while the remaining two showed the same trend, but an increased confidence interval, due to an insufficient number of records.

BackgroundThe Affordable Care Act expanded Medicaid coverage for people with low income in the United States. Expanded insurance coverage could promote more timely access to cancer treatment, which could improve overall survival (OS), yet the long-term effects of Medicaid expansion (ME) remain unknown. We evaluated whether ME was associated with improved timely treatment initiation (TTI) and 3-year OS among patients with breast, cervical, colon, and lung cancers who were affected by the policy.MethodsMedicaid-insured or uninsured patients aged 40-64 with stage I-III breast, cervical, colon, or non-small cell lung cancer within the National Cancer Database (NCDB). A difference-in-differences (DID) approach was used to compare changes in TTI (within 60 days) and 3-year OS between patients in ME states versus nonexpansion (NE) states before (2010-2013) and after (2015-2018) ME. Adjusted DID estimates for TTI and 3-year OS were calculated using multivariable linear regression and Cox proportional hazards regression models, respectively.ResultsME was associated with a relative increase in TTI within 60 days for breast (DID = 4.6; p

Chest wall pain syndromes can emerge following local therapies for lung cancer and can adversely affect patients quality-of-life. This can occur after lung surgery, radiation therapy, or percutaneous image-guided thermal ablation. This review describes the multifactorial pathophysiology of chest wall pain syndromes that develop following surgical and non-surgical local therapies for lung cancer and summarizes evidence-based management strategies for inflammatory, neuropathic, myofascial, and osseous pain. It discusses a step-wise approach to treating chest wall pain that begins with non-opioid oral analgesics and includes additional pharmacologic treatments as clinically indicated, such as anticonvulsants, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, and various topical treatments. For myofascial pain, physical medicine techniques, such as acupuncture, trigger point injections, deep tissue massage, and intercostal myofascial release can also offer pain relief. For severe or refractory cases, opioid analgesics, intercostal nerve blocks, or intercostal nerve ablations may be indicated. Fortunately, palliation of treatment-related chest wall pain syndromes can be managed by most clinical providers, regardless of the type of local therapy utilized for a patients lung cancer treatment. In cases where a patients pain fails to respond to initial medical management, clinicians can consider referring to a pain specialist who can tailor a more specific pharmacologic approach or perform a procedural intervention to relieve pain.

Myristoylation is a type of protein acylation by which the fatty acid myristate is added to the N-terminus of target proteins, a process mediated by N-myristoyltransferases (NMT). Myristoylation is emerging as a promising cancer therapeutic target; however, the molecular determinants of sensitivity to NMT inhibition or the mechanism by which it induces cancer cell death are not completely understood. We report that NMTs are a novel therapeutic target in lung carcinoma cells with LKB1 and/or KEAP1 mutations in a KRAS-mutant background. Inhibition of myristoylation decreases cell viability in vitro and tumor growth in vivo. Inhibition of myristoylation causes mitochondrial ferrous iron overload, oxidative stress, elevated protein poly (ADP)-ribosylation, and death by parthanatos. Furthermore, NMT inhibitors sensitized lung carcinoma cells to platinum-based chemotherapy. Unexpectedly, the mitochondrial transporter translocase of inner mitochondrial membrane 17 homolog A (TIM17A) is a critical target of myristoylation inhibitors in these cells. TIM17A silencing recapitulated the effects of NMT inhibition at inducing mitochondrial ferrous iron overload and parthanatos. Furthermore, sensitivity of lung carcinoma cells to myristoylation inhibition correlated with their dependency on TIM17A. This study reveals the unexpected connection between protein myristoylation, the mitochondrial import machinery, and iron homeostasis. It also uncovers myristoylation inhibitors as novel inducers of parthanatos in cancer, and the novel axis NMT-TIM17A as a potential therapeutic target in highly aggressive lung carcinomas.SignificanceKRAS-mutant lung carcinomas with LKB1 and/or KEAP1 co-mutations have intrinsic therapeutic resistance. We show that these tumors are sensitive to NMT inhibitors, which slow tumor growth in vivo and sensitize cells to platinum-based chemotherapy in vitro. Inhibition of myristoylation causes death by parthanatos and thus has the potential to kill apoptosis and ferroptosis-resistant cancer cells. Our findings warrant investigation of NMT as a therapeutic target in highly aggressive lung carcinomas.

Accurate diagnosis of lung cancer is important for treatment decision-making. Tumor biopsy and histologic examination are the standard for determining histologic lung cancer subtypes. Liquid biopsy, particularly cell-free DNA (cfDNA), has recently shown promising results in cancer detection and classification. In this study, we investigate the potential of cfDNA methylome for the noninvasive classification of lung cancer histologic subtypes. We focused on the two most prevalent lung cancer subtypes, lung adenocarcinoma and lung squamous cell carcinoma. Using a fragment-based marker discovery approach, we identified robust subtype-specific methylation markers from tumor samples. These markers were successfully validated in independent cohorts and associated with subtype-specific transcriptional activity. Leveraging these markers, we constructed a subtype classification model using cfDNA methylation profiles, achieving an AUC of 0.808 in cross-validation and an AUC of 0.747 in the independent validation. Tumor copy-number alterations inferred from cfDNA methylome analysis revealed potential for treatment selection. In summary, our study demonstrates the potential of cfDNA methylome analysis for noninvasive lung cancer subtyping, offering insights for cancer monitoring and early detection.SignificanceThis study explores the use of cfDNA methylomes for the classification of lung cancer subtypes, vital for effective treatment. By identifying specific methylation markers in tumor tissues, we developed a robust classification model achieving high accuracy for noninvasive subtype detection. This cfDNA methylome approach offers promising avenues for early detection and monitoring.

Immunohistochemistry (IHC) is used to guide treatment decisions in multiple cancer types. For treatment with checkpoint inhibitors, programmed death ligand 1 (PD-L1) IHC is used as a companion diagnostic. However, the scoring of PD-L1 is complicated by its expression in cancer and immune cells. Separation of cancer and noncancer regions is needed to calculate tumor proportion scores (TPS) of PD-L1, which is based on the percentage of PD-L1-positive cancer cells. Evaluation of PD-L1 expression requires highly experienced pathologists and is often challenging and time-consuming. Here, we used a multi-institutional cohort of 77 lung cancer cases stained centrally with the PD-L1 22C3 clone. We developed a 4-step pipeline for measuring TPS that includes the coregistration of hematoxylin and eosin, PD-L1, and negative control (NC) digital slides for exclusion of necrosis, segmentation of cancer regions, and quantification of PD-L1+ cells. As cancer segmentation is a challenging step for TPS generation, we trained DeepLab V3 in the Visiopharm software package to outline cancer regions in PD-L1 and NC images and evaluated the model performance by mean intersection over union (mIoU) against manual outlines. Only 14 cases were required to accomplish a mIoU of 0.82 for cancer segmentation in hematoxylin-stained NC cases. For PD-L1-stained slides, a model trained on PD-L1 tiles augmented by registered NC tiles achieved a mIoU of 0.79. In segmented cancer regions from whole slide images, the digital TPS achieved an accuracy of 75% against the manual TPS scores from the pathology report. Major reasons for algorithmic inaccuracies include the inclusion of immune cells in cancer outlines and poor nuclear segmentation of cancer cells. Our transparent and stepwise approach and performance metrics can be applied to any IHC assay to provide pathologists with important insights on when to apply and how to evaluate commercial automated IHC scoring systems.

Genome-derived microRNAs (miRNAs or miRs) govern posttranscriptional gene regulation and play important roles in various cellular processes and disease progression. While chemo-engineered miRNA mimics or biosimilars made in vitro are widely available and used, miRNA agents produced in vivo are emerging to closely recapitulate natural miRNA species for research. Our recent work has demonstrated the success of high-yield, in vivo production of recombinant miRNAs by using human tRNA (htRNA) fused precursor miRNA (pre-miR) carriers. In this study, we aim to compare the production of bioengineered RNA (BioRNA) molecules with glycyl versus leucyl htRNA fused hsa-pre-miR-34a carriers, namely, BioRNAGly and BioRNALeu, respectively, and perform the initial functional assessment. We designed, cloned, overexpressed, and purified a total of 48 new BioRNA/miRNAs, and overall expression levels, final yields, and purities were revealed to be comparable between BioRNAGly and BioRNALeu molecules. Meanwhile, the two versions of BioRNA/miRNAs showed similar activities to inhibit non-small cell lung cancer cell viability. Interestingly, functional analyses using model BioRNA/miR-7-5p demonstrated that BioRNAGly/miR-7-5p exhibited greater efficiency to regulate a known target gene expression (EGFR) than BioRNALeu/miR-7-5p, consistent with miR-7-5p levels released in cells. Moreover, BioRNAGly/miR-7-5p showed comparable or slightly greater activities to modulate MRP1 and VDAC1 expression, compared with miRCURY LNA miR-7-5p mimic. Computational modeling illustrated overall comparable 3D structures for exemplary BioRNA/miRNAs with noticeable differences in htRNA species and payload miRNAs. These findings support the utility of hybrid htRNA/hsa-pre-miR-34a as reliable carriers for RNA molecular bioengineering, and the resultant BioRNAs serve as functional biologic RNAs for research and development.

Small cell lung cancer (SCLC) is a deadly neuroendocrine malignancy, notorious for its rapid tumor growth, early metastasis, and relatively cold immune environment. Only standard chemotherapies and a few immune checkpoint inhibitors have been approved for SCLC treatment, revealing an urgent need for novel therapeutic approaches. Moreover, SCLC has been recently recognized as a malignancy with high intratumoral and intertumoral heterogeneity, which explains the modest response rate in some patients and the early relapse. Molecular subtypes defined by the expression of lineage-specific transcription factors (ASCL1, NEUROD1, POU2F3, and, in some studies, YAP1) or immune-related genes display different degrees of neuroendocrine differentiation, immune cell infiltration, and response to treatment. Despite the complexity of this malignancy, a few biomarkers and targets have been identified and many promising drugs are currently undergoing clinical trials. In this review, we integrate the current progress on the genomic landscape of this shapeshifting malignancy, the characteristics and treatment vulnerabilities of each subtype, and promising drugs in clinical phases.

In 2020, California passed a flavored tobacco sales restriction (FTSR), but the tobacco companies filed a referendum, and the ban will not be implemented unless approved by voters in November 2022. This study examined the percentage of the California population covered by a city FTSR and identified groups more likely to be covered. Mean demographics as well as tobacco use and control measures were compared for California cities with (n = 93) and without (n = 389) a FTSR, and t tests were used to examine the differences. We calculated adjusted odds ratios using logistic regression models. City FTSR policies covered 20.7% of the California population. Adjusted predictors of having a FTSR included the American Lung Association tobacco control score (odds ratio [OR] = 1.27, 95% confidence interval [CI]: [1.17, 1.38]), voting democratic (OR = 1.06, 95% CI: [1.02, 1.10]). and having a lower adult smoking prevalence (OR = 0.84, 95% CI: [0.72, 0.99]). A state-level policy would cover all populations in California.

Background and purposeMotion management is essential to reduce normal tissue exposure and maintain adequate tumor dose in lung stereotactic body radiation therapy (SBRT). Lung SBRT using an articulated robotic arm allows dynamic tracking during radiation dose delivery. Two stereoscopic X-ray tracking modes are available - fiducial-based and fiducial-free tracking. Although X-ray detection of implanted fiducials is robust, the implantation procedure is invasive and inapplicable to some patients and tumor locations. Fiducial-free tracking relies on tumor contrast, which challenges the existing tracking algorithms for small (e.g., 15 mm) and tumor locations (with/without thoracic anatomy overlapping).ResultsOn X-ray views that conventional methods failed to track the lung tumor, Deep Match achieved robust performance as evidenced by >80 % 3 mm-Hit (detection within 3 mm superior/inferior margin from ground truth) for 70 % of patients and

The presence of toxic metals in tobacco smoke is well documented. However, few studies have quantified trace metals in secondhand smoke (SHS) and thirdhand smoke (THS). Their presence in indoor air can contribute to nonsmokers’ exposures and health effects. In this study, emission and deposition rates of toxic trace metals were determined, and their airborne concentration in typical indoor scenarios was predicted. PM2.5 was collected on Teflon-coated filters at various times following a smoking event in a room-sized chamber over a 43 h period. The concentration of 28 trace metals was determined by extraction and analysis using inductively coupled plasma-triple quadrupole-mass spectrometry (ICP-QQQ-MS). Emission and indoor deposition rates of cadmium, arsenic, chromium, manganese, beryllium and selenium were determined, and used to predict concentrations expected in a smokers’ home and a smoking bar. In most of the considered scenarios, average indoor concentrations of Cd, As, and Cr exceeded their corresponding cancer risk thresholds and, in some cases, also noncancer reference exposure levels, more than 3 h after smoking ended. The fraction of cadmium that remained airborne was significantly higher than those of other metal traces and that of PM2.5, suggesting an association of Cd traces with small particles.

Patients with primary tumor progression after stereotactic body radiation therapy (SBRT) for stage I non-small cell lung cancer (NSCLC) have a second chance at complete tumor eradication with salvage local therapies, including lung resection, repeat course of SBRT, and percutaneous ablative therapies. In this paper, we presented our institutions initial experience with percutaneous high-dose-rate (HDR) brachyablation for a relapsed stage I NSCLC that had been treated with SBRT 4.3 years earlier. Lung tumor measuring approximately 5 cm in maximum tumor dimension at the time of relapse was histopathologically confirmed to be persistent squamous cell carcinoma, and successfully treated with a single fraction of 24 Gy with HDR brachyablation. Treatment was delivered via two percutaneous catheters inserted under CT-guidance, and treated in less than 20 minutes. The patient was discharged home later the same day without the need for a chest tube, and has been monitored with serial surveillance scans every 3 to 6 months without evidence of further lung cancer progression or complications at 2.8 years post-HDR brachyablation procedure and 7.8 years after initial SBRT.

Immune checkpoint blockade (ICB) with PD-1/PD-L1 inhibition has revolutionized the treatment of non-small cell lung cancer (NSCLC). Durable responses, however, are observed only in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment (TME) can lead to deficient T cell recruitment and ICB resistance. We evaluate intratumoral (IT) vaccination with CXCL9- and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a strategy to overcome resistance. IT CXCL9/10-DC leads to enhanced T cell infiltration and activation in the TME and tumor inhibition in murine NSCLC models. The antitumor efficacy of IT CXCL9/10-DC is dependent on CD4+ and CD8+ T cells, as well as CXCR3-dependent T cell trafficking from the lymph node. IT CXCL9/10-DC, in combination with ICB, overcomes resistance and establishes systemic tumor-specific immunity in murine models. These studies provide a mechanistic understanding of CXCL9/10-DC-mediated host immune activation and support clinical translation of IT CXCL9/10-DC to augment ICB efficacy in NSCLC.

OBJECTIVE: To investigate current screening behaviors among high-risk individuals and analyse the factors that influence them. METHODS: A cross-sectional of 1652 high-risk individuals were recruited in Fujian Province, China from February to October 2022. Socio-demographic characteristics of participants were collected and other survey measures included a lung cancer and lung cancer screening knowledge questionnaire and a stage of adoption algorithm. Standardized measures on surveys were comprised of the: Lung Cancer Screening Health Belief Scales, Cataldo Lung Cancer Stigma Scale, Generalized Anxiety Disorder Scale-7, Patient Health Questionnaire-9, and the Patient Trust in the Medical Profession Scale. Factors associated with screening behavior were identified using binary logistic regression analysis. RESULTS: Lung cancer screening behavior stages were largely reported as Stage 1 and Stage 2 (64.4%). The facilitators of lung cancer screening included urban residence (OR = 1.717, 95% CI: 1.224-2.408), holding administrative positions (OR = 16.601, 95% CI: 2.118-130.126), previous lung cancer screening behavior (OR = 10.331, 95% CI: 7.463-14.302), media exposure focused on lung cancer screening (OR = 1.868, 95% CI: 1.344-2.596), a high level of knowledge about lung cancer and lung cancer screening (OR = 1.256, 95% CI: 1.185-1.332), perceived risk of lung cancer (OR = 1.123, 95% CI: 1.029-1.225) and lung cancer screening health beliefs (OR = 1.090, 95% CI: 1.067-1.113). A barrier to lung cancer screening was found to be social influence (influence of friends or family) (OR = 0.669, 95% CI: 0.465-0.964). CONCLUSIONS: This study found a low participation rate in lung cancer screening and identified eight factors that affected lung cancer screening behaviors among high-risk individuals. Findings suggest targeted lung cancer screening programs should be developed based on identified influencing factors in order to effectively promote awareness and uptake of lung cancer screening.

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

AimsTo investigate the trajectory, influencing factors and dynamic relationships between fear of cancer recurrence (FCR) and quality of life (QOL) in lung cancer patients.DesignProspective longitudinal study.MethodsLongitudinal data from 310 lung cancer patients across three hospitals in China were assessed at 1, 3, 6 and 12 months postoperatively (T1 -T4 ). Descriptive statistics characterised patient demographics, clinical characteristics, levels of FCR and QOL. A linear mixed-effects model was employed to analyse FCR trajectories, identify influencing factors on these trajectories, and predict the impact of FCR on QOL.ResultsFCR changed significantly over time, with a slight decrease during T1 -T2 , an increase at T3 and gradual decline at T4 . Higher fear levels were associated with female sex, suburban or rural residency, being a family breadwinner, presence of comorbidities and negative coping behaviours, and low family resilience. QOL negatively correlated with FCR, and FCR predicted lower QOL.ConclusionsAt 3 and 6 months postoperatively, lung cancer patients, especially women, suburban or rural residents, family breadwinners, those with comorbidities, negative coping behaviours and low family resilience, reported high levels of FCR. Healthcare providers should pay special attention to lung cancer patients especially during the period of 3-6 months post-surgery and offer tailored interventions to improve their QOL.Implications for the profession and patient careUnderstanding the FCR trajectories, its influencing factors and its negative impacts on QOL can guide the development of targeted interventions to reduce fear and enhance well-being in patients with cancer.ImpactIdentifying the trajectories and influencing factors of fear of lung cancer recurrence in patients at different time points informs future research on targeted interventions to improve QOL.Reporting methodThe study adhered to the guidelines outlined in the Statement on Reporting Observational Longitudinal Research.

A healthy breath is mainly composed of water, carbon dioxide, molecular nitrogen, and oxygen and it contains many species, in small quantities, which are related to the ambient atmosphere and the metabolism. The breath of a person affected by lung cancer presents a concentration of 1-propanol higher than usual. In this context, the development of specific sensors to detect 1-propanol from breath is of high interest. The amount of propanol usually detected on the breath is of few ppb; this small quantity is a handicap for a reliable diagnostic. This limitation can be overcome if the sensor is equipped with a pre-concentrator. Our studies aim to provide an efficient material playing this role. This will contribute to the development of reliable and easy to use lung cancer detectors. For this, we investigate the properties of a few hydrophobic porous materials (chabazite, silicalite-1, and dealuminated faujasite). Hydrophobic structures are used to avoid saturation of materials by the water present in the exhaled breath. Our experimental and simulation results suggest that silicalite −1 (MFI) is the most suitable structure to be used as a pre-concentrator. [ABSTRACT FROM AUTHOR]