Evaluation of elastix-based propagated align algorithm for VOI- and voxel-based analysis of longitudinal F-18-FDG PET/CT data from patients with non-small cell lung cancer (NSCLC)

Background: Deformable image registration allows volume of interest (VOI)- and voxel-based analysis of longitudinal changes in fluorodeoxyglucose (FDG) tumor uptake in patients with non-small cell lung cancer (NSCLC). This study evaluates the performance of the elastix toolbox deformable image registration algorithm for VOI and voxel-wise assessment of longitudinal variations in FDG tumor uptake in NSCLC patients. Methods: Evaluation of the elastix toolbox was performed using F-18-FDG PET/CT at baseline and after 2 cycles of therapy (follow-up) data in advanced NSCLC patients. The elastix toolbox, an integrated part of the IMALYTICS workstation, was used to apply a CT-based non-linear image registration of follow-up PET/CT data using the baseline PET/CT data as reference. Lesion statistics were compared to assess the impact on therapy response assessment. Next, CT-based deformable image registration was performed anew on the deformed follow-up PET/CT data using the original follow-up PET/CT data as reference, yielding a realigned follow-up PET dataset. Performance was evaluated by determining the correlation coefficient between original and realigned follow-up PET datasets. The intra-and extra-thoracic tumors were automatically delineated on the original PET using a 41% of maximum standardized uptake value (SUVmax) adaptive threshold. Equivalence between reference and realigned images was tested (determining 95% range of the difference) and estimating the percentage of voxel values that fell within that range. Results: Thirty-nine patients with 191 tumor lesions were included. In 37/39 and 12/39 patients, respectively, thoracic and non-thoracic lesions were evaluable for response assessment. Using the EORTC/SUVmax-based criteria, 5/37 patients had a discordant response of thoracic, and 2/12 a discordant response of non-thoracic lesions between the reference and the realigned image. FDG uptake values of corresponding tumor voxels in the original and realigned reference PET correlated well (R-2=0.98). Using equivalence testing, 94% of all the voxel values fell within the 95% range of the difference between original and realigned reference PET. Conclusions: The elastix toolbox impacts lesion statistics and therefore therapy response assessment in a clinically significant way. The elastix toolbox is therefore not applicable in its current form and/or standard settings for PET response evaluation. Further optimization and validation of this technique is necessary prior to clinical implementation

Generalizations of Yang-Mills Theory with Nonlinear Constitutive Equations

We generalize classical Yang-Mills theory by extending nonlinear constitutive equations for Maxwell fields to non-Abelian gauge groups. Such theories may or may not be Lagrangian. We obtain conditions on the constitutive equations specifying the Lagrangian case, of which recently-discussed non-Abelian Born-Infeld theories are particular examples. Some models in our class possess nontrivial Galilean (c goes to infinity) limits; we determine when such limits exist, and obtain them explicitly.Comment: Submitted to the Proceedings of the 3rd Symposium on Quantum Theory and Symmetries (QTS3) 10-14 September 2003. Preprint 9 pages including reference

Total Body Metabolic Tumor Response in ALK Positive Non-Small Cell Lung Cancer Patients Treated with ALK Inhibition

In ALK-positive advanced NSCLC, crizotinib has a high response rate and effectively increases quality of life and survival. CT measurement of the tumor may insufficiently reflect the actual tumor load changes during targeted therapy with crizotinib. We explored whether 18F-FDG PET measured metabolic changes are different from CT based changes and studied the impact of these changes on disease progression.18F-FDG PET/CT was performed prior to and after 6 weeks of crizotinib treatment. Tumor response on CT was classified with RECIST 1.1, while 18F-FDG PET response was assessed according to the 1999 EORTC recommendations and PERCIST criteria. Agreement was assessed using McNemars test. During follow-up, patients received additional PET/CT during crizotinib treatment and second generation ALK inhibition. We assessed whether PET was able to detect progression earlier then CT.In this exploratory study 15 patients were analyzed who were treated with crizotinib. There was a good agreement in the applicability of CT and 18F-FDG PET/CT using the EORTC recommendations. During first line crizotinib and subsequent second line ALK inhibitors, PET was able to detect progression earlier then CT in 10/22 (45%) events of progression and in the others disease progression was detected simultaneously.In advanced ALK positive NSCLC PET was able to detect progressive disease earlier than with CT in nearly half of the assessments while both imaging tests performed similar in the others

Chronic Obstructive Pulmonary Disease Is Not Associated with KRAS Mutations in Non-Small Cell Lung Cancer

Mutations in epithelial growth factor receptor (EGFR), as well as in the EGFR downstream target KRAS are frequently observed in non-small cell lung cancer (NSCLC). Chronic obstructive pulmonary disease (COPD), an independent risk factor for developing NSCLC, is associated with an increased activation of EGFR. In this study we determined presence of EGFR and KRAS hotspot mutations in 325 consecutive NSCLC patients subjected to EGFR and KRAS mutation analysis in the diagnostic setting and for whom the pulmonary function has been determined at time of NSCLC diagnosis. Information about age at diagnosis, sex, smoking status, forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV1) was collected. Chronic obstructive pulmonary disease(COPD) was defined according to 2013 GOLD criteria. Chi-Square, student t-test and multivariate logistic regression were used to analyze the data. A total of 325 NSCLC patients were included, 193 with COPD and 132 without COPD. COPD was not associated with presence of KRAS hotspot mutations, while EGFR mutations were significantly higher in non-COPD NSCLC patients. Both female gender (HR 2.61; 95% CI: 1.56-4.39; pT and G>C transversions were significantly more frequent in females (86.2%) than in males (61.5%) (p = 0.008). The exon 19del mutation was more frequent in non-smokers (90%) compared to current or past smokers (36.8%). In conclusion, KRAS mutations are more common in females and smokers, but are not associated with COPD-status in NSCLC patients. EGFR mutations are more common in non-smoking NSCLC patients

An exploratory study of volumetric analysis for assessing tumor response with 18F-FAZA PET/CT in patients with advanced non-small-cell lung cancer (NSCLC)

Background: Hypoxia is associated with resistance to chemotherapy and radiotherapy and is randomly distributed within malignancies. Characterization of changes in intratumoral hypoxic regions is possible with specially developed PET tracers such as F-18-fluoroazomycin arabinoside (F-18-FAZA) while tumor metabolism can be measured with 2-deoxy-2-[F-18] fluoro-D-glucose (F-18-FDG). The purpose of this study was to study the effects of chemotherapy on F-18-FAZA and F-18-FDG uptake simultaneously in non-small-cell lung cancer (NSCLC) patients Methods: At baseline and after the second chemotherapy cycle, both PET/CT with F-18-FDG and F-18-FAZA was performed in seven patients with metastasized NSCLC. F-18-FAZA and F-18-FDG scans were aligned with deformable image registration using Mirada DBx. The primary tumors were contoured, and on the F-18-FDG scan, volumes of interest (VOI) were drawn using a 41 % adaptive threshold technique. Subsequently, the resulting VOI was transferred to the F-18-FAZA scan. F-18-FAZA maximum tumor-to-background (T/Bg(max)) ratio and the fractional hypoxic volume (FHV) were assessed. Measurements were corrected for partial volume effects. Finally, a voxel-by-voxel analysis of the primary tumor was performed to assess regional uptake differences. Results: In the primary tumor of all seven patients, median F-18-FDG standard uptake value (SUVmax) decreased significantly (p = 0.03). There was no significant decrease in F-18-FAZA uptake as measured with T/Bg(max) (p = 0.24) or the FHV (p = 0.35). Additionally, volumetric voxel-by-voxel analysis showed that low hypoxic tumors did not significantly change in hypoxic status between baseline and two cycles of chemotherapy, whereas highly hypoxic tumors did. Individualized volumetric voxel-by-voxel analysis revealed that hypoxia and metabolism were not associated before and after 2 cycles of chemotherapy. Conclusions: Tumor hypoxia and metabolism are independent dynamic events as measured by F-18-FAZA PET and F-18-FDG PET, both prior to and after treatment with chemotherapy in NSCLC patients

Baseline ¹⁸F-FDG PET and CT tumor response measurements with PERCIST and EORTC criteria and progression-free survival per patient with ALK positive NSCLC.

<p>Baseline ¹⁸F-FDG PET and CT tumor response measurements with PERCIST and EORTC criteria and progression-free survival per patient with ALK positive NSCLC.</p

Baseline patient characteristics.

<p>Baseline patient characteristics.</p

¹⁸F-FDG maximum intensity projection of patient 2 and 8 prior to (A, B) and after 6 weeks of treatment with crizotinib (C, D).

<p>Scale is from 0–15 SUV. These images illustrate the clinically dramatic decrease in ¹⁸F-FDG uptake, with both patients having a PMR according to both PERCIST criteria and the EORTC recommendations.</p

PET Imaging of Tumor Hypoxia Using F-18-Fluoroazomycin Arabinoside in Stage III-IV Non-Small Cell Lung Cancer Patients

<p>Tumor hypoxia hampers the efficacy of radiotherapy because of its increased resistance to ionizing radiation. The aim of the present study was to estimate the potential added clinical value of the specific hypoxia tracer F-18-fluoroazomycin arabinoside (F-18-FAZA) over commonly used F-18-FDG in the treatment of advanced-stage non-small cell lung cancer (NSCLC). Methods: Eleven patients with stage Ill or stage IV NSCLC underwent F-18-FDG and F-18-FAZA PET before chemoradiotherapy. The maximum standardized uptake value (SUVmax) was used to depict F-18-FDG uptake, and the tumor-to-background (T/B) ratio and tumor fractional hypoxic volume (FHV) were used to quantify hypoxia. The spatial correlation between F-18-FDG and F-18-FAZA uptake values was investigated using voxel-based analysis. Partial-volume correction was applied. Results: All 11 patients showed clear uptake of F-18-FAZA in the primary tumor. However, different patterns of F-18-FDG and F-18-FAZA uptake distributions were observed and varied widely among different tumors. No significant correlation was observed between F-18-FDG SUVmax and F-18-FAZA T/B ratio (P = 0.055). The median FHV of 1.4 was 48.4% (range, 5.0-91.5). A significant positive correlation was found between the F-18-FAZA T/B ratio and FHV of 1.4 (P <0.001). There was no correlation between the lesion size and FHV or between the F-18-FDG SUVmax and FHV. The pattern of tumoral F-18-FDG uptake was rather homogeneous, whereas F-18-FAZA uptake was more heterogeneous, suggesting that F-18-FAZA identifies hypoxic areas within metabolically active areas of tumor. A significant correlation between F-18-FDG SUVmax and lesion size (P = 0.002) was observed. Conclusion: F-18-FAZA PET imaging is able to detect heterogeneous distributions of hypoxic subvolumes out of homogeneous F-18-FDG background in a clinical setting. Therefore, F-18-FAZA might be considered a tool for guiding dose escalation to the hypoxic fraction of the tumor.</p>