Browsing by Subject "non-small cell lung cancer"
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Item Open Access Association of pre-treatment radiomic features with lung cancer recurrence following stereotactic body radiation therapy.(Physics in medicine and biology, 2019-01-08) Lafata, Kyle J; Hong, Julian C; Geng, Ruiqi; Ackerson, Bradley G; Liu, Jian-Guo; Zhou, Zhennan; Torok, Jordan; Kelsey, Chris R; Yin, Fang-FangThe purpose of this work was to investigate the potential relationship between radiomic features extracted from pre-treatment x-ray CT images and clinical outcomes following stereotactic body radiation therapy (SBRT) for non-small-cell lung cancer (NSCLC). Seventy patients who received SBRT for stage-1 NSCLC were retrospectively identified. The tumor was contoured on pre-treatment free-breathing CT images, from which 43 quantitative radiomic features were extracted to collectively capture tumor morphology, intensity, fine-texture, and coarse-texture. Treatment failure was defined based on cancer recurrence, local cancer recurrence, and non-local cancer recurrence following SBRT. The univariate association between each radiomic feature and each clinical endpoint was analyzed using Welch's t-test, and p-values were corrected for multiple hypothesis testing. Multivariate associations were based on regularized logistic regression with a singular value decomposition to reduce the dimensionality of the radiomics data. Two features demonstrated a statistically significant association with local failure: Homogeneity2 (p = 0.022) and Long-Run-High-Gray-Level-Emphasis (p = 0.048). These results indicate that relatively dense tumors with a homogenous coarse texture might be linked to higher rates of local recurrence. Multivariable logistic regression models produced maximum [Formula: see text] values of [Formula: see text], and [Formula: see text], for the recurrence, local recurrence, and non-local recurrence endpoints, respectively. The CT-based radiomic features used in this study may be more associated with local failure than non-local failure following SBRT for stage I NSCLC. This finding is supported by both univariate and multivariate analyses.Item Open Access Crizotinib Inhibits Hyperpolarization-activated Cyclic Nucleotide-Gated Channel 4 Activity.(Cardio-oncology (London, England), 2017-01) Zhang, Zhushan; Huang, Tai-Qin; Nepliouev, Igor; Zhang, Hengtao; Barnett, Adam S; Rosenberg, Paul B; Ou, Sai-Hong I; Stiber, Jonathan ASinus bradycardia is frequently observed in patients treated with crizotinib, a receptor tyrosine kinase inhibitor used for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We investigated whether crizotinib could influence heart rate (HR) through direct cardiac effects. The direct effect of crizotinib on HR was studied using ECG analysis of Langendorff-perfused mouse hearts. The whole-cell patch clamp technique was used to measure the effects of crizotinib on the hyperpolarization-activated funny current, If, in mouse sinoatrial node cells (SANCs) and hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) activity in HEK-293 cells stably expressing human HCN4. Crizotinib resulted in a dose-dependent reduction in HR in isolated intact mouse hearts with a half maximal inhibitory concentration (IC50) of 1.7 ± 0.4 μmol/L. Because ECG analysis revealed that crizotinib (0-5 μmol/L) resulted in significant reductions in HR in isolated mouse hearts without changes in PR, QRS, or QT intervals, we performed whole-cell patch clamp recordings of SANCs which showed that crizotinib inhibited If which regulates cardiac pacemaker activity. Crizotinib resulted in diminished current density of HCN4, the major molecular determinant of If, with an IC50 of 1.4 ± 0.3 μmol/L. Crizotinib also slowed HCN4 activation and shifted the activation curve to the left towards more hyperpolarized potentials. Our results suggest that crizotinib's effects on HCN4 channels play a significant role in mediating its observed effects on HR.Item Open Access Genetic Variants of CLEC4E and BIRC3 in Damage-Associated Molecular Patterns-Related Pathway Genes Predict Non-Small Cell Lung Cancer Survival.(Front Oncol, 2021) Liu, Lihua; Liu, Hongliang; Luo, Sheng; Patz, Edward F; Glass, Carolyn; Su, Li; Lin, Lijuan; Christiani, David C; Wei, QingyiAccumulating evidence supports a role of various damage-associated molecular patterns (DAMPs) in progression of lung cancer, but roles of genetic variants of the DAMPs-related pathway genes in lung cancer survival remain unknown. We investigated associations of 18,588 single-nucleotide polymorphisms (SNPs) in 195 DAMPs-related pathway genes with non-small cell lung cancer (NSCLC) survival in a subset of genotyping data for 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another independent subset of genotyping data for 984 patients from Harvard Lung Cancer Susceptibility Study. We performed multivariate Cox proportional hazards regression analysis, followed by expression quantitative trait loci (eQTL) analysis, Kaplan-Meier survival analysis and bioinformatics functional prediction. We identified that two SNPs (i.e., CLEC4E rs10841847 G>A and BIRC3 rs11225211 G>A) were independently associated with NSCLC overall survival, with adjusted allelic hazards ratios of 0.89 (95% confidence interval=0.82-0.95 and P=0.001) and 0.82 (0.73-0.91 and P=0.0003), respectively; so were their combined predictive alleles from discovery and replication datasets (P trend=0.0002 for overall survival). We also found that the CLEC4E rs10841847 A allele was associated with elevated mRNA expression levels in normal lymphoblastoid cells and whole blood cells, while the BIRC3 rs11225211 A allele was associated with increased mRNA expression levels in normal lung tissues. Collectively, these findings indicated that genetic variants of CLEC4E and BIRC3 in the DAMPs-related pathway genes were associated with NSCLC survival, likely by regulating the mRNA expression of the corresponding genes.Item Open Access Peritumoral CT Radiomic Modelling for Non-local Treatment Failure of Early Stage Non-Small Cell Lung Cancers(2020) Gao, YinBackground: Quantitative medical imaging has been increasingly utilized in modern medicine. The field of radiomics is an emerging subset of quantitative medical imaging. Radiomics can identify a large number of quantitative features as the biomarkers from the radiography images. Subsequent mining and analysis of these features may potentially uncover subclinical tumor characteristics of disease in a non-invasive manner, and provide clinical decision support. Biomarkers on gross tumor regions have been studied for many years for different clinical endpoints. Correlations between the radiomic features and treatment outcomes, disease diagnosis, pathological information, and organ functions can be studied for clinical decision support. Peritumor region is the region around the gross tumor, where may also be used to extract radiomics biomarkers. Currently, limited studies are available in this area. Machine learning is a powerful tool to correlate radiomics features with various clinical endpoints and provide a predictive model to better define tumor characteristics.
Purpose: To investigate the association between CT radiomic data from peritumoral regions and non-local treatment failure recurrence of early stage non-small cell lung cancers (NSCLC) following lung stereotactic body radiation therapy (SBRT), to identify secondary quantitative parameters from the dose-driven peritumoral CT radiomic data, to compare the model performance of using radiomic data with and without secondary quantitative parameters for assessing the non-local treatment failure following lung SBRT.
Materials and Methods: Sixty-three patients who received SBRT for early-stage NSCLC were retrospectively identified by an IRB approved clinical trial with treatment outcome provided. Treatment failure was defined as both local cancer recurrence and non-local cancer recurrence following SBRT. Gross Tumor Volumes (GTVs) were segmented on the pre-treatment free-breathing CT images by radiation oncologists. Two types of peritumoral volumes were defined on pre-treatment free-breathing CT: uniform ring and dose-driven. The uniform ring peritumoral volumes were generated by expanding GTVs at radial distances of 3mm, 6mm, 9mm and 12mm. The dose-driven peritumoral volumes were generated by converting ten isodose volumes (100%, 98%, 95%, 90%, 85%, 80%, 70%, 50%, 30%, and 10%) into structures in the treatment planning system. All peritumoral volumes were then modified using a Boolean process to exclude the GTV and non-lung tissue. Sixty radiomic features (4 Intensity, 21 GLCOM, 11 GLRLM, 13 GLSZM, 5 NGLDM, and 6 Shape) were extracted from GTVs and peritumoral volumes using an in-house radiomics calculation platform as biomarkers for cancer recurrence. A univariate feature selection was used to eliminate highly correlated features. Two multivariate machine learning based feature selection algorithms were followed to find the important features and to avoid overfitting. Machine learning algorithms (Random Forest, LASSO Logistic Regression, Ridge Logistic Regression, Linear Support Vector Machine and Kernel Support Vector Machine) were used to build classification models to predict non-local treatment failure. 63 patients were randomly separated into the training group (75%) and the test group (25%). Model generalization was cross validated using a stratified 10-fold with 50 iterations. The learning curve and grid search were used to find the best hyperparameters to enhance the model performance and avoid the overfitting in the random forest model. The performance of each feature selection and classifier combination was based on the area under the receiver operating characteristic curve (ROC). Pair t-tests with 100 iteration permutation tests were used to evaluate the significant difference between different AUCs.
Results: In uniform expansion ring peritumoral region, from the results, 3mm ring was more predictive of non-local treatment failure than all peritumoral radiomic data and gross tumor radiomic data. In dose-driven peritumoral region, from the results, 80% isodose region was more predictive of non-local treatment failure than all peritumoral radiomic data and gross tumor radiomic data. The model combinations of tree-based feature selection and Random Forest classifier presented the highest AUC values. No significant difference in predictive performance was found before and after adding secondary features in the dataset (p-value > 0.05). However, secondary features may be useful in other studies given that obvious patterns were seen in the clustering heatmap.
Conclusions: This study has demonstrated strong prognostic value of peritumoral radiomics for non-local treatment failure in patients with stage I NSCLC. The presented peritumoral radiomics was shown to have better predictive performance compared to the gross tumor radiomics.
Keywords: Radiomics, peritumoral region, machine learning, stereotactic body radiation therapy, non-small cell lung cancer
Item Open Access Potentially functional genetic variants in the complement-related immunity gene-set are associated with non-small cell lung cancer survival.(International journal of cancer, 2019-04) Qian, Danwen; Liu, Hongliang; Wang, Xiaomeng; Ge, Jie; Luo, Sheng; Patz, Edward F; Moorman, Patricia G; Su, Li; Shen, Sipeng; Christiani, David C; Wei, QingyiThe complement system plays an important role in the innate and adaptive immunity, complement components mediate tumor cytolysis of antibody-based immunotherapy, and complement activation in the tumor microenvironment may promote tumor progression or inhibition, depending on the mechanism of action. In the present study, we conducted a two-phase analysis of two independently published genome-wide association studies (GWASs) for associations between genetic variants in a complement-related immunity gene-set and overall survival of non-small cell lung cancer (NSCLC). The GWAS dataset from Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was used as the discovery, and multivariate Cox proportional hazards regression with false-positive report probability for multiple test corrections were performed to evaluate associations between 14,699 single-nucleotide polymorphisms (SNPs) in 111 genes and survival of 1,185 NSCLC patients. The identified significant SNPs in a single-locus analysis were further validated with 984 NSCLC patients in the GWAS dataset from the Harvard Lung Cancer Susceptibility (HLCS) Study. The results showed that two independent, potentially functional SNPs in two genes (VWF rs73049469 and ITGB2 rs3788142) were significantly associated with NSCLC survival, with a combined hazards ratio (HR) of 1.22 [95% confidence interval (CI) = 1.07-1.40, P = 0.002] and 1.16 (1.07-1.27, 6.45 × 10-4 ), respectively. Finally, we performed expression quantitative trait loci (eQTL) analysis and found that survival-associated genotypes of VWF rs73049469 were also significantly associated with mRNA expression levels of the gene. These results indicated that genetic variants of the complement-related immunity genes might be predictors of NSCLC survival, particularly for the short-term survival, possibly by modulating the expression of genes involved in the host immunity.