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Preclinical models are required to study individual therapy responses to improve all cancer treatments, particularly non-small cell lung cancer (NSCLC). Patient-derived explants (PDEs) culture model is of great importance in terms of the possibility of tumor cell culture with the microenvironment, and the development of molecular mechanisms and personalized treatment methods. In our study, primary tumor culture with microenvironment was performed using different methods from tumor tissues obtained from 51 patients with NSCLC. To identify the most efficient method, mechanical, enzymatic, and tumor fluid techniques were applied. While the malignant cell rate was > 95% in 3 of these cases, the cancer-associated fibroblasts (CAF) microenvironment was high in 46 (80-94%) and low in 2 (1-79%). Subtyping of cells obtained from culture was performed using the light microscope and, if necessary, additional immunohistochemical markers. Consequently, using different techniques, here we successfully performed primary cell culture from patients with NSCLC with microenvironment. Depending on the cell type and culture conditions, proliferation rate was shown to be altered., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: In oncological imaging using PET/CT, the standardized uptake value has become the most common parameter used to measure tracer accumulation. The aim of this analysis was to evaluate ultra high definition (UHD) and ordered subset expectation maximization (OSEM) PET/CT reconstructions for their potential impact on quantification., Patients and Methods: We analyzed 40 PET/CT scans of lung cancer patients who had undergone PET/CT. Standardized uptake values corrected for body weight (SUV) and lean body mass (SUL) were determined in the single hottest lesion in the lung and normalized to the liver for UHD and OSEM reconstruction. Quantitative uptake values and their normalized ratios for the two reconstruction settings were compared using the Wilcoxon test. The distribution of quantitative uptake values and their ratios in relation to the reconstruction method used were demonstrated in the form of frequency distribution curves, box-plots and scatter plots. The agreement between OSEM and UHD reconstructions was assessed through Bland-Altman analysis., Results: A significant difference was observed after OSEM and UHD reconstruction for SUV and SUL data tested (p < 0.0005 in all cases). The mean values of the ratios after OSEM and UHD reconstruction showed equally significant differences (p < 0.0005 in all cases). Bland-Altman analysis showed that the SUV and SUL and their normalized values were, on average, up to 60 % higher after UHD reconstruction as compared to OSEM reconstruction., Conclusion: OSEM and HD reconstruction brought a significant difference for SUV and SUL, which remained constantly high after normalization to the liver, indicating that standardization of reconstruction and the use of comparable SUV measurements are crucial when using PET/CT.

Introduction: Pharmacostatistical models can quantify different relationships and improve decision making in personalized medicine and drug development. Our objectives were to develop models describing non-small-cell lung cancer (NSCLC) dynamics during first-line treatment with erlotinib, and survival of the cohort., Methods: Data from patients with advanced NSCLC (n = 39) treated first-line with erlotinib (150 mg/day) were analyzed using nonlinear mixed effects modeling. Exposure-driven disease-drug models were built to describe tumor metabolic and proliferative dynamics evaluated by positron emission tomography (PET) using 2'-deoxy-2'-[F]fluoro-D-glucose (FDG) and 3'-[F]fluoro-3'-deoxy-L-thymidine (FLT), respectively, at baseline, weeks 1 and 6 after starting erlotinib treatment. A parametric time-to-event model was built to describe overall survival (OS). Demographics, histology, mutational, smoking, and baseline performance statuses were tested for their effects on models developed, in addition to tumor dynamics on survival., Results: An exponential relationship described progression, and a concentration-driven drug effect model described erlotinib effect. An activating epidermal growth factor receptor (EGFR) mutation increased the drug effect as assessed using FDG-PET by 2.19-fold (95% confidence interval [CI]:1.35-4.44). An exponential distribution described the times-to-death distribution. Baseline FDG uptake (p=0.0005; hazard ratio [HR] =1.26 for every unit increase, 95%CI: 1.13-1.42) and relative change in FDG uptake after 1 week of treatment (p=0.0073; HR=0.84 for every 10% drop, 95%CI: 0.71-0.91) were significant OS predictors irrespective of the EGFR mutational status. FLT-PET was statistically less significant than FDG-PET for OS prediction., Conclusion: Models describing tumor dynamics and survival of advanced NSCLC patients first-treated with erlotinib were developed. The impacts of different covariates were quantified.

Unlabelled: 3'-deoxy-3'-[(18)F]fluoro-L-thymidine (FLT) and 2'-deoxy-2'-[(18)F]fluoro-D-glucose (FDG) are used to visualize proliferative and metabolic activity of tumors. In this study we aimed at evaluating the prognostic value of FLT and FDG uptake measured by positron emission tomography (PET) in patients with metastatic non-small cell lung cancer (NSCLC) prior to systemic therapy with erlotinib. FLT and FDG maximum standardized uptake (SUVmax) values per patient were analyzed in 40 chemotherapy naive patients with advanced NSCLC (stage IV) before treatment with erlotinib. Prior therapy median SUVmax was 6.6 for FDG and 3.0 for FLT, respectively. In univariate analysis, patients with an FDG SUVmax <6.6 had a significantly better overall survival (16.3 months [95% confidence interval [CI] 7.1-25.4 months]) compared to patients with an FDG SUVmax ≥6.6 (3.1 months [95% CI 0.6-5.5 months]) (p<0.001, log rank). Similarly, low FLT uptake (SUVmax <3.0) was associated with significantly longer survival (10.3 months (0-23.3 months, 95% CI) compared to high FLT uptake (3.4 months (0-8.1 months, 95% CI) (p = 0.027). The independent prognostic value of baseline FDG uptake was demonstrated in multivariate analysis (p = 0.05, Cox regression). These data suggest that baseline SUVmax values for both FDG and FLT PET might be further developed as markers for prognostic stratification of patients in advanced NSCLC treated with tyrosine kinase inhibitors (TKI) directed against the epidermal growth factor receptor (EGFR)., Trial Registration: Clinicaltrials.gov, Identifier: NCT00568841.

Purpose: The aim was to assess the value of tumor lesion glycolysis (TLG) and tumor lesion proliferation (TLP) determined by FDG and 3'-deoxy-3'-F-fluorothymidine (FLT) PET for response prediction and prognostic differentiation in patients with advanced non-small cell lung cancer (NSCLC) treated with erlotinib., Patients and Methods: FDG-PET and FLT-PET were performed in 30 patients with untreated Stage IV NSCLC before start of therapy, 1 (early) and 6 (late) weeks after erlotinib treatment. Functional tumor volume parameters including TLG in FDG-PET and TLP in FLT-PET were measured in the sum of up to 5 lesions per scan. Metabolic response was assessed using different cutoff values for percentage changes of TLG and TLP. Absolute baseline and residual levels of TLG and TLP were used for dichotomizing the patients into 2 groups. Kaplan-Meier analysis and the log-rank test were performed to analyze the association with progression-free survival (PFS)., Results: Patients with a metabolic response measured by early changes of TLP and late changes of TLG and TLP showed a significantly better PFS than metabolically nonresponding patients. A lower cutoff value of 20% or 30% for definition of metabolic response showed better differentiation between metabolically responding and nonresponding patients in cases where the 45% cutoff value revealed no significant results. Furthermore, patients with lower absolute early and late residual TLG and TLP levels had a significantly prolonged PFS. In contrast, absolute baseline TLG and TLP levels showed no significant association with PFS., Conclusions: In patients with advanced NSCLC, percentage changes of TLG and TLP and absolute residual TLG and TLP levels under erlotinib treatment emerged as strong predictive factors for PFS. Our findings indicate that a cutoff value of 20% or 30% for definition of metabolic response measured by percentage changes of TLG and TLP provides suitable results for response prediction, which should be further validated.

Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations benefit from treatment with EGFR-targeted therapy. While first-generation ("reversible") EGFR tyrosine kinase inhibitors (TKIs) are well established in the treatment of these patients, the remarkably lower efficacy of second-generation ("irreversible") EGFR-TKIs after failure of reversible EGFR inhibition is far less understood. Here we describe an EGFR-mutated patient treated sequentially with both reversible (erlotinib) and irreversible (afatinib) EGFR-TKIs monitored by sequential [(18)F]fluorothymidine (FLT-)PET. Our observations confirm the value of molecular imaging for assessment of pharmacodynamics and early prediction of response and relapse in these patients., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To evaluate the predictive value of early and late residual (18)F-fluorodeoxyglucose (FDG) and (18)F-fluorothymidine (FLT) uptake using different SUV measurements in PET in patients with advanced non-small-cell lung cancer (NSCLC) treated with erlotinib., Methods: We retrospectively reviewed data from 30 patients with untreated stage IV NSCLC who had undergone a combined FDG PET and FLT PET scan at 1 week (early) and 6 weeks (late) after the start of erlotinib treatment. Early and late residual FDG and FLT uptake were measured in up to five lesions per scan with different quantitative standardized uptake values (SUV(max), SUV(2Dpeak), SUV(3Dpeak), SUV(50), SUV(A50), SUV(A41)) and compared with short-term outcome (progression vs. nonprogression after 6 weeks of erlotinib treatment). Receiver-operating characteristics (ROC) curve analysis was used to determine the optimal cut-off value for detecting nonprogression after 6 weeks. Kaplan-Meier analysis and the log-rank test were used to evaluate the association between residual uptake and progression-free survival (PFS)., Results: Nonprogression after 6 weeks was associated with a significantly lower early and late residual FDG uptake, measured with different quantitative parameters. In contrast, nonprogression after 6 weeks was not associated with early and late residual FLT uptake. Furthermore, patients with a lower early residual FDG uptake measured in terms of SUV(max) and SUV(2Dpeak) had a significantly prolonged PFS (282 days vs. 118 days; p = 0.022) than patients with higher values. Similarly, lower late residual FDG uptake and early residual FLT uptake measured in terms of SUV(3Dpeak), SUV(A50) and SUV(A41), and late FLT uptake measured in terms of SUV(3Dpeak) and SUV(A50) was associated with an improved PFS., Conclusion: Early and late residual FDG uptake, measured using different quantitative SUV parameters, are predictive factors for short-term outcome in patients with advanced NSCLC treated with erlotinib. Additionally, low residual FDG and FLT uptake early and late in the course of erlotinib treatment is associated with improved PFS.

Unlabelled: The purpose of this study was to evaluate the relevance for the prediction of clinical benefit of first-line treatment with erlotinib using different quantitative parameters for PET with both (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) in patients with advanced non-small cell lung cancer., Methods: Data were used from a prospective trial involving patients with untreated stage IV non-small cell lung cancer. (18)F-FDG PET and (18)F-FLT PET were performed before and 1 (early) and 6 (late) weeks after erlotinib treatment. Several quantitative standardized uptake values (SUVs) using different definitions of volumes of interest with varying isocontours (maximum SUV [SUV(max)], 2-dimensional peak SUV [SUV(2Dpeak)], 3-dimensional [3D] peak SUV [SUV(3Dpeak)], 3D isocontour at 50% of the maximum pixel value [SUV(50)], 3D isocontour at 50% adapted for background [SUV(A50)], 3D isocontour at 41% of the maximum pixel value adapted for background [SUV(A41)], 3D isocontour at 70% of the maximum pixel value [SUV(70)], 3D isocontour at 70% adapted for background [SUV(A70)], and relative SUV threshold level [SUV(RTL)]) and metabolically active volume measurements were obtained in the hottest single tumor lesion and in the sum of up to 5 lesions per scan in 30 patients. Metabolic response was defined as a minimum reduction of 30% in each of the different SUVs and as a minimum reduction of 45% in metabolically active volume. Progression-free survival (PFS) was compared between patients with and without metabolic response measured with each of the different parameters, using Kaplan-Meier statistics and a log-rank test., Results: Patients with a metabolic response on early (18)F-FDG PET and (18)F-FLT PET in the hottest single tumor lesion as well as in the sum of up to 5 lesions per scan had a significantly longer PFS, regardless of the method used to calculate SUV. However, the highest significance was obtained for SUV(max), SUV(50), SUV(A50), and SUV(A41.) Patients with a metabolic response measured by SUV(max) and SUV(3Dpeak) on late (18)F-FDG PET in the hottest single tumor lesion had a significantly longer PFS. Furthermore, Kaplan-Meier analyses showed a strong association between PFS and response seen by metabolically active volume, measured either in early (18)F-FLT or in late (18)F-FDG., Conclusion: Early (18)F-FDG PET and (18)F-FLT PET can predict PFS regardless of the method used for SUV calculation. However, SUV(max), SUV(50), SUV(A50), and SUV(A41) measured with (18)F-FDG might be the best robust SUV to use for early response prediction. Metabolically active volume measurement in early (18)F-FLT PET and late (18)F-FDG PET may have an additional predictive value in monitoring response in patients with advanced non-small cell lung cancer treated with erlotinib.