The role of amino acid metabolism alterations in pancreatic cancer: From mechanism to application

The incidence of pancreatic cancer is increasing in both developed and developing Nations. In recent years, various research evidence suggested that reprogrammed metabolism may play a key role in pancreatic cancer tumorigenesis and development. Therefore, it has great potential as a diagnostic, prognostic and therapeutic target. Amino acid metabolism is deregulated in pancreatic cancer, and changes in amino acid metabolism can affect cancer cell status, systemic metabolism in malignant tumor patients and mistakenly involved in different biological processes including stemness, proliferation and growth, invasion and migration, redox state maintenance, autophagy, apoptosis and even tumor microenvironment interaction. Generally, the above effects are achieved through two pathways, energy metabolism and signal transduction. This review aims to highlight the current research progress on the abnormal alterations of amino acids metabolism in pancreatic cancer, how they affect tumorigenesis and development of pancreatic cancer and the application prospects of them as diagnostic, prognostic and therapeutic targets.     

Validation of low-dose lung cancer PET-CT protocol and PET image improvement using machine learning

PurposeTo conduct a simplified lesion-detection task of a low-dose (LD) PET-CT protocol for frequent lung screening using 30% of the effective PETCT dose and to investigate the feasibility of increasing clinical value of low-statistics scans using machine learning.MethodsWe acquired 33 SD PET images, of which 13 had actual LD (ALD) PET, and simulated LD (SLD) PET images at seven different count levels from the SD PET scans. We employed image quality transfer (IQT), a machine learning algorithm that performs patch-regression to map parameters from low-quality to high-quality images. At each count level, patches extracted from 23 pairs of SD/SLD PET images were used to train three IQT models – global linear, single tree, and random forest regressions with cubic patch sizes of 3 and 5 voxels. The models were then used to estimate SD images from LD images at each count level for 10 unseen subjects. Lesion-detection task was carried out on matched lesion-present and lesion-absent images.ResultsLD PET-CT protocol yielded lesion detectability with sensitivity of 0.98 and specificity of 1. Random forest algorithm with cubic patch size of 5 allowed further 11.7% reduction in the effective PETCT dose without compromising lesion detectability, but underestimated SUV by 30%.ConclusionLD PET-CT protocol was validated for lesion detection using ALD PET scans. Substantial image quality improvement or additional dose reduction while preserving clinical values can be achieved using machine learning methods though SUV quantification may be biased and adjustment of our research protocol is required for clinical use.     

Identification of prognostic biomarkers for breast cancer brain metastases based on the bioinformatics analysis

PurposeThe prognosis of breast cancer (BC) patients who develop into brain metastases (BMs) is very poor. Thus, it is of great significance to explore the etiology of BMs in BC and identify the key genes involved in this process to improve the survival of BC patients with BMs.Patients and methodsThe gene expression data and the clinical information of BC patients were downloaded from TCGA and GEO database. Differentially expressed genes (DEGs) in TCGA-BRCA and GSE12276 were overlapped to find differentially expressed metastatic genes (DEMGs). The protein-protein interaction (PPI) network of DEMGs was constructed via STRING database. ClusterProfiler R package was applied to perform the gene ontology (GO) enrichment analysis of DEMGs. The univariate Cox regression analysis and the Kaplan-Meier (K-M) curves were plotted to screen DEMGs associated with the overall survival and the metastatic recurrence survival, which were identified as the key genes associated with the BMs in BC. The immune infiltration and the expressions of immune checkpoints for BC patients with brain relapses and BC patients with other relapses were analyzed respectively. The correlations among the expressions of key genes and the differently infiltrated immune cells or the differentially expressed immune checkpoints were calculated. The gene set enrichment analysis (GSEA) of each key gene was conducted to investigate the potential mechanisms of key genes involved in BC patients with BMs. Moreover, CTD database was used to predict the drug-gene interaction network of key genes.ResultsA total of 154 DEGs were identified in BC patients at M0 and M1 in TCGA database. A total of 667 DEGs were identified in BC patients with brain relapses and with other relapses. By overlapping these DEGs, 17 DEMGs were identified, which were enriched in the cell proliferation related biological processes and the immune related molecular functions. The univariate Cox regression analysis and the Kaplan-Meier curves revealed that CXCL9 and GPR171 were closely associated with the overall survival and the metastatic recurrence survival and were identified as key genes associated with BMs in BC. The analyses of immune infiltration and immune checkpoint expressions showed that there was a significant difference of the immune microenvironment between brain relapses and other relapses in BC. GSEA indicated that CXCL9 and GPR171 may regulate BMs in BC via the immune-related pathways.ConclusionOur study identified the key genes associated with BMs in BC patients and explore the underlying mechanisms involved in the etiology of BMs in BC. These findings may provide a promising approach for the treatments of BC patients with BMs.     

Synthesis and evaluation of novel radioiodinated PSMA targeting ligands for potential radiotherapy of prostate cancer

Radioligand therapy (RLT) using prostate-specific membrane antigen (PSMA) targeting ligands is an attractive option for the treatment of Prostate cancer (PCa) and its metastases. We report herein a series of radioiodinated glutamate-urea-lysine-phenylalanine derivatives as new PSMA ligands in which l-tyrosine and l-glutamic acid moieties were added to increase hydrophilicity concomitant with improvement of in vivo targeting properties. Compounds 8, 15, 19a/19b and 23a/23b were synthesized and radiolabeled with ¹²⁵I by iododestannylation. All iodinated compounds displayed high binding affinities toward PSMA (IC₅₀ = 1–13 nM). In vitro cell uptake studies demonstrated that compounds containing an l-tyrosine linker moiety (8, 15 and 19a/19b) showed higher internalization than MIP-1095 and 23a/23b, both without the l-tyrosine linker moiety. Biodistribution studies in mice bearing PC3-PIP and PC3 xenografts showed that [¹²⁵I]8 and [¹²⁵I]15 with higher lipophilicity exhibited higher nonspecific accumulations in the liver and intestinal tract, whereas [¹²⁵I]19a/19b and [¹²⁵I]23a/23b containing additional glutamic acid moieties showed higher accumulations in the kidney and implanted PC3-PIP (PSMA+) tumors. [¹²⁵I]23b displayed a promising biodistribution profile with favorable tumor retention, fast clearance from the kidney, and 2–3-fold lower uptake in the liver and blood than that observed for [¹²⁵I]MIP-1095. [^125/131I]23b may serve as an optimal PSMA ligand for radiotherapy treatment of prostate cancer over-expressing PSMA.     

Osimertinib Improves overall survival of EGFR-mutant NSCLC patients with leptomeningeal metastases

ObjectiveOsimertinib is a third-generation, irreversible, small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that can effectively penetrate the blood brain-barrier (BBB). This study mainly explored the factors affecting the prognosis of EGFR-mutant advanced non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM), and whether osimertinib could improve the survival benefit in these patients compared with those not treated with osimertinib.MethodsWe retrospectively analyzed patients who had been admitted with EGFR-mutant NSCLC and cytologically confirmed LM to the Peking Union Medical College Hospital between January 2013 and December 2019. Overall survival (OS) was defined as the primary outcome of interest.ResultsA total of 71 patients with LM were included in this analysis, with a median OS (mOS) of 10.7 months (95% CI [7.6, 13.8]). Among them, 39 patients were treated with osimertinib after LM while 32 patients were untreated. Patients treated with osimertinib had a mOS of 11.3 months (95%CI [0, 23.9]) compared with the untreated patients who had a mOS of 8.1 months (95%CI [2.9, 13.3]), with a significant difference between the groups (hazard ratio [HR]): 0.43, 95%CI:0.22–0.66, p = 0.0009). Multivariate analysis revealed the use of osimertinib were correlated with superior OS with a HR of 0.43 (95%CI [0.25, 0.75]), with a statistically significant difference (p = 0.003).ConclusionsOsimertinib can prolong the overall survival of EGFR-mutant NSCLC patients with LM and improve patient outcomes.     

18F-FDG Micro PET/CT imaging to evaluate the effect of BRCA1 knockdown on MDA-MB231 breast cancer cell radiosensitivity

ObjectiveRadioresistance of tumor cells is a major factor associated with failure of radiotherapy (RT). This study aimed to investigate the effect of BRCA1 knockdown on MDA-MB231 breast cancer cell radiosensitivity.Materials and methodsShort hairpin RNA (shRNA) was used to knockdown BRCA1 gene in MDA-MB231 cells. Cell viability and proliferative capacity were assessed by CCK-8 and colony formation assays, respectively. We established xenograft models in nude mice to evaluate tumor volume and tumor weight. The mice were imaged by ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) before and after RT to evaluate changes in maximum standardized uptake value (SUV_max) and tumor SUV_max/muscle SUV_max (TMR). Changes in HIF-1α, Glut-1 and Ki-67 were analyzed and the correlation between ¹⁸F-FDG uptake and tumor biology was analyzed.ResultsCompared with the control cells, RT significantly reduced cell viability and colony formation capacity in cells with the BRCA1 gene knockdown. In vivo assays showed that there was obvious delay in the tumor growth in the shBRCA1+RT group compared with the control group. ¹⁸F-FDG Micro PET/CT indicated a reduction in glucose metabolism in the shBRCA1+RT group, with statistically significant differences in both the SUV_max and TMR. The data showed the expression of HIF-1α, Glut-1 and Ki-67 was downregulated in the shBRCA1+RT group, and both SUVmax and TMR had significant correlation with tumor biology.ConclusionThese results demonstrated that BRCA1 knockdown improves the sensitivity of MDA-MB231 breast cancer cells to RT. In addition, ¹⁸F-FDG PET/CT imaging allows non-invasive analysis of tumor biology and assessment of radiosensitivity.     

The hidden potential of glycomarkers: Glycosylation studies in the service of cancer diagnosis and treatment

Changes in the glycosylation process appear early in carcinogenesis and evolve with the growth and spread of cancer. The correlation of the characteristic glycosylation signature with the tumor stage and the appropriate therapy choice is an important issue in translational medicine. Oncologists also pay attention to extracellular vesicles as reservoirs of new cancer glycomarkers that can be potent for cancer diagnosis/prognosis. In this review, we recall glycomarkers used in oncology and show their new glycoforms of improved clinical relevance. We summarize current knowledge on the biological functions of glycoepitopes in cancer-derived extracellular vesicles and their potential use in clinical practice. Is glycomics a future of cancer diagnosis? It may be, but in combination with other omics analyses than alone.     

Differential expression patterns of phospholipase D isoforms 1 and 2 in the mammalian brain and retina

Phosphatidic acid is a key signaling molecule heavily implicated in exocytosis due to its protein-binding partners and propensity to induce negative membrane curvature. One phosphatidic acid-producing enzyme, phospholipase D (PLD), has also been implicated in neurotransmission. Unfortunately, due to the unreliability of reagents, there has been confusion in the literature regarding the expression of PLD isoforms in the mammalian brain which has hampered our understanding of their functional roles in neurons. To address this, we generated epitope-tagged PLD1 and PLD2 knockin mice using CRISPR/Cas9. Using these mice, we show that PLD1 and PLD2 are both localized at synapses by adulthood, with PLD2 expression being considerably higher in glial cells and PLD1 expression predominating in neurons. Interestingly, we observed that only PLD1 is expressed in the mouse retina, where it is found in the synaptic plexiform layers. These data provide critical information regarding the localization and potential role of PLDs in the central nervous system.     

MicroRNA-567 inhibits cell proliferation and induces cell apoptosis in A549 NSCLC cells by regulating cyclin-dependent kinase 8

MicroRNA-567 (miR-567) plays a decisive role in cancers whereas its role in non-small cell lung cancer (NSCLC) is still unexplored. This study was therefore planned to explore the regulatory function of miR-567 in A549 NSCLC cells and investigate its possible molecular mechanism that may help in NSCLC treatment. In the current study, miR-567 expression was examined by quantitative real time-polymerase chain reaction (qRT-PCR) in different NSCLC cell lines in addition to normal cell line. A549 NSCLC cells were transfected by miR-567 mimic, miR-567 inhibitor, and negative control siRNA. Cell proliferation was evaluated by MTT and 5-bromo-2′deoxyuridine assays. Cell cycle distribution and apoptosis were studied by flow cytometry. Bioinformatics analysis programs were used to expect the putative target of miR-567. The expression of cyclin-dependent kinase 8 (CDK8) gene at mRNA and protein levels were evaluated by using qRT-PCR and western blotting. Our results found that miR-567 expressions decreased in all the studied NSCLC cells as compared to the normal cell line. A549 cell proliferation was suppressed by miR-567 upregulation while cell apoptosis was promoted. Also, miR-567 upregulation induced cell cycle arrest at sub-G1 and S phases. CDK8 was expected as a target gene of miR-567. MiR-567 upregulation decreased CDK8 mRNA and protein expression while the downregulation of miR-567 increased CDK8 gene expression. These findings revealed that miR-567 may be a tumor suppressor in A549 NSCLC cells through regulating CDK8 gene expression and may serve as a novel therapeutic target for NSCLC treatment.     

The functions of azurin of Pseudomonas aeruginosa and human mammaglobin-A on proapoptotic and cell cycle regulatory genes expression in the MCF-7 breast cancer cell line

Azurin protein of Pseudomonas aeruginosa is an anti-tumor agent against breast cancer and mammaglobin-A (MAM-A) protein is a specific antigen on the surface of MCF-7 for induction of cellular immune. The purpose of the present study was to investigate the effects of simultaneous expression of azurin and human MAM-A genes on the mRNA expression level of apoptosis-related and cell cycle genes in MCF-7 breast cancer cell line. The recombinant or empty plasmids were separately transferred into MCF-7 cells using Lipofectamine reagent. Flow cytometry was done to detect cell death and apoptosis. The expression of azurin and MAM-A genes were evaluated by IF assay, RT-PCR and western blot methods. Finally, apoptosis-related and cell cycle genes expression was examined in transformed and non-transformed MCF-7 cells by qPCR method. The successful expression of azurin and MAM-A genes in the MCF-7 cell were confirmed by RT-PCR, IF and western blotting. The apoptosis assay was showed a statistically significant (p < 0.05) difference after transfection. The expression of BAK, FAS, and BAX genes in transformed cells compare with non-transformed and transformed MCF-7 by pBudCE4.1 were increased statistically significant (p < 0.05) increases. Although, the increase of SURVIVIN and P53 expressions in transformed cells were not statistically significant (p > 0.05). Co-expression of azurin and MAM-A genes could induce apoptosis and necrosis in human MCF-7 breast cancer cells by up-regulation of BAK, FAS, and BAX genes. In future researches, it must be better the immune stimulation of pBudCE4.1-azurin-MAM-A recombinant vector in animal models and therapeutic approaches will be evaluated.     

Prediction of response and adverse drug reaction of pemetrexed plus platinum-based chemotherapy in lung adenocarcinoma by serum metabolomic profiling

BackgroundPemetrexed plus platinum doublet chemotherapy regimen remains to be the standard first-line treatment for lung adenocarcinoma patients. However, few biomarkers can be used to identify potential beneficiaries with maximal efficacy and minimal toxicity. This study aimed to explore potential biomarker models predictive of efficacy and toxicity after pemetrexed plus platinum chemotherapy based on metabolomics profiling.MethodsA total of 144 patients who received at least two cycles of pemetrexed plus platinum chemotherapy were enroled in the study. Serum samples were collected before initial treatment to perform metabolomics profiling analysis. Logistic regression analysis was performed to establish prediction models.Results157 metabolites were found to be differentially expressed between the response group and the nonresponse group. A panel of Phosphatidylserine 20:4/20:1, Sphingomyelin d18:1/18:0, and Phosphatidic Acid 18:1/20:0 could predict pemetrexed and platinum chemotherapy response with an Area Under the Receiver Operating Characteristic curve (AUROC) of 0.7968. 76 metabolites were associated with hematological toxicity of pemetrexed plus platinum chemotherapy. A panel incorporating triglyceride 14:0/22:3/22:5, 3-(3-Hydroxyphenyl) Propionate Acid, and Carnitine C18:0 was the best predictive ability of hematological toxicity with an AUROC of 0.7954. 54 differential expressed metabolites were found to be associated with hepatotoxicity of pemetrexed plus platinum chemotherapy. A model incorporating stearidonic acid, Thromboxane B3, l-Homocitrulline, and phosphoinositide 20:3/18:0 showed the best predictive ability of hepatotoxicity with an AUROC of 0.8186.ConclusionsThis study established effective and convenient models that can predict the efficacy and toxicity of pemetrexed plus platinum chemotherapy in lung adenocarcinoma patients before treatment delivery.     

Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs

The inflammatory hypothesis is one of the most important mechanisms of depression. Fucoidan is a bioactive sulfated polysaccharide abundant in brown seaweeds with anti-inflammatory activity. However, the antidepressant effects of fucoidan on chronic stress-induced depressive-like behaviors have not been well elucidated. Here, we used two different depressive-like mouse models, lipopolysaccharide (LPS) and chronic restraint stress (CRS) models, to explore the detailed molecular mechanism underlying its antidepressant-like effects in C57BL/6J mice by combining multiple behavioral, molecular and immunofluorescence experiments. Adenovirus-mediated overexpression of caspase-1 and pharmacological inhibitors were also used to clarify the antidepressant mechanisms of fucoidan. We found that acute administration of fucoidan did not produce antidepressant effects in the tail suspension test (TST) and forced swim test (FST). Interestingly, chronic fucoidan administration not only dose-dependently reduced stress-induced depressive-like behaviors in the TST, FST, sucrose preference test (SPT), and novelty-suppressed feeding test (NSFT), but also alleviated the downregulation of brain-derived neurotrophic factor (BDNF)-dependent synaptic plasticity via inhibiting caspase-1-mediated inflammation in the hippocampus of mice. Moreover, fucoidan significantly ameliorated behavioral and synaptic plasticity abnormalities in the overexpression of caspase-1 in the hippocampus of mice. Furthermore, blocking BDNF abolished the antidepressant-like effects of fucoidan in mice. Therefore, our findings clearly indicate that fucoidan provides a potential supplementary noninvasive treatment for depression by inhibition of hippocampal inflammation.     

Patterns of treatment failure for PD-(L)1 refractory extensive-stage small cell lung cancer in continued PD-(L)1 treatment

BackgroundAlthough immunotherapy greatly extends overall survival (OS) of patients with extensive-stage small cell lung cancer (ES-SCLC), a number of patients develop immunotherapy resistance (IR). Patterns of failure in ES-SCLC are not clarified. Our study aims to explore the clinical pattern of IR and prognostic factors for these patients.MethodsThe study was conducted from 117 ES-SCLC patients with immunotherapy between 2018 and 2022. Chi-square tests and Fishers' exact tests was used to explore failure patterns in different populations. Survival analyses of different progression patterns and subsequent treatment regimens were conducted by Kaplan–Meier curves and log-rank test.Results86 (73.5%) patients experienced IR. The patients with smoking (never smoker vs. current or ex-smoker, 59.5 % vs. 81.3%, P = 0.010), liver metastasis (extrahepatic metastasis vs. intrahepatic metastasis, 73.6 % vs. 90.9%, P = 0.050), and distant metastasis status (no distant metastasis vs. distant metastasis, 39.1 % vs. 81.9%, P<0.001) were associated with IR rates. Liver progression had a lower incidence in 1st line immunotherapy (1st line vs. ≥2nd lines, 14.0 % vs. 41.7%, P = 0.004) and a higher incidence in multiple progression (multiple progression vs. Oligo-progression, 39.4 % vs. 17.0%, P = 0.021). Cranial (41.7 % vs. 16.1%, P = 0.012) and distant lymph node (16.7 % vs. 3.2%, P = 0.049) progression were the main failure model for acquired IR in comparison to primary IR. Patients with new lesion progression only (17.73 vs. 9.17 months, P = 0.013) and non-hepatic progression (14.23 vs. 11.67 months, P = 0.042) had a longer OS. Patients in cross-line immunotherapy after IR had a favourable prognosis (17.07 vs. 11.93 months, P = 0.007).ConclusionThe most common failure pattern of immunotherapy for ES-SCLC was lung and regional lymph node progression. Brain and liver progression were the most common extra thoracic failure sites for 1st line and 2nd and more lines immunotherapy, respectively. There was a higher probability of primary IR in 2 lines and above immunotherapy. Patients with new only progression site and cross-line rechallenge immunotherapy had a better prognosis.     

Differential diagnosis between progression and radionecrosis in brain metastases after stereotactic radiosurgery using hybrid FDG-PET and MRI coregistered images

IntroductionDual phase 18 FDG brain PET is helpful to assess brain metastases (BM) as tracer will build up in metastases or tumor recurrences while its retention remains stable within normal tissue or inflammatory processes. This is useful when MRI can’t discriminate brain tumor recurrence (TR) rom radionecrosis (RN) after stereotaxic radiosurgery (SRS) for BM. Many studies have sought to improve diagnostic performance by associating FDG-PET and MRI with interesting results but many biases, mostly within image post-processing. Coregistered MRI and dual phase FDG-PET images could alleviate these biases and be used to extract prognostic biomarkers.Materials and methodsWe retrospectively evaluated patients treated with SRS for BM which developed a contrast-enhanced MRI lesion with non-conclusive diagnosis for TR or RN. All patients underwent MRI and FDG-PET at least 3 months after their last SRS session. Dual FDG-PET consisted in an “early” and “delayed” acquisition, respectively 30 minutes and 4 h after injection. MRI included permeability and perfusion sequences. PET and MRI data were all coregistered on the contrast enhanced T1 MRI images. Semi-automated Volumes of Interest (VOI) of the tumor were drawn on the BM and a reference contralateral white-matter ROI (WM) was drawn for standardization; every metric was calculated inside these ROIs, in particular the tumor SUVmax and its variation in time. A 20% increase in the tumor SUVmax was in favor of TR while a modification of less than 100% was in favor of RN. Imaging metrics were then evaluated for their association with TR or RN based on histological, radiological and clinical criteria after at least 6 months follow-up.ResultsNine patients were ruled out as TR and 6 as RN. After standardization, there was a significant difference between groups for VP (P = 0.042), Washin (P = 0.035), Peak Enhancement (P = 0.037), standardized delayed SUVmax (P = 0.008) and RI (P = 0.016). Semi-quantitative analysis found respectively for PET and MRI a Sensitivity of 100% and 87.5% and a Specificity of 100% and 85.71%.ConclusionCoregistered PET-MRI images accurately discriminate between TR and RN. With FDG being the most commonly used PET radiotracer, this protocol remains easily transposable and should be encouraged to obtain non-invasive prognostic and clinically relevant biomarkers.     

Exonic variants in multiple myeloma patients associated with relapsed/ refractory and response to bortezomib regimens

Novel treatment in multiple myeloma represented by proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies have produced a deep response. However, relapses are possible, and all classes of drugs are refractory to patients. Next-generation sequencing has improved our understanding of the multiple myeloma genome related to drug resistance and has discovered many genomic variants. Therefore, this study was conducted to investigate new variants associated with drug resistance in MM patients who relapsed and refractory to bortezomib regimen and daratumumab treatment using next-generation sequencing for whole-exome sequencing. Peripheral blood samples were collected in EDTA tubes from six patients; four were in relapsed and refractory to bortezomib regimens and daratumumab; two patients responded to bortezomib regimens. Whole-exome sequencing was performed by the MGI-DNBSEQ-G400 instrument. We identified 21 variants in multiple myeloma patients. Seventeen variants were found in relapsed and refractory multiple myeloma in 11 genes (GNAQ, PMS1, CREB1, NSUNS2, PIK3CG, ROS1, PMS2, FIT4, KDM5A, STK11 and ZFHX3). And four variants were identified in two patients with response to bortezomib regimens in 4 genes (RAF1, CREB1, ZFHX3 and INSR). We have observed several genetic variants in many genes that may have been associated with the poor prognosis and poor response to treatment in these patients. These values should be further confirmed in large sample studies using the RNA-seq technique to identify genome expression.     

Probability of lung cancer in a population excluded from screening due to low PLCOM2012 risk

BackgroundSeveral randomized trials demonstrated have reduced lung cancer mortality with screening using computed tomography. However, there remains debate about the optimal approach for determining screening eligibility, and no evidence yet exists reporting lung cancer rates in those excluded from screening due to too low of a personalized risk.MethodsThis study was based on the Alberta Lung Cancer Screening Study, which received 1737 applicants and enrolled 850 based on the NLST criteria or a PLCO_M2012 risk ≥ 1.5%. We excluded 887 applicants who were interested in screening but deemed ineligible. We report lung cancer rates in the screened and unscreened cohorts.ResultsWe observed 30 and 8 lung cancers in the screened and unscreened groups, respectively. Only 1 of 8 lung cancers were among those considered too low risk (0.14%), while the remaining 7 were among those excluded for other reasons, including symptoms requiring more immediate workup. No NLST eligible but PLCO risk < 1.5% screened individual had a lung cancer detected as part of the study, so that of all applicants contacting the program with risk estimates less than 1.5%, only 1/857 (0.12%) developed lung cancer.ConclusionOur findings indicate that a risk-based approach for screening eligibility is unlikely to miss many lung cancers.