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Intra-tumour 18F-FDG uptake heterogeneity decreases the reliability of target volume definition with PET/CT imagingPurpose:The use of Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography(18F-FDG PET/CT)images have been shown to improve the target volume definition for radiotherapy treatment planning.Despite the wide acceptance of PET/CT by the radiotherapy community,the actual integration of PET/CT images into the tumour target contouring process has been problematic,with the most controversial being the segmentation of PET images.Manual contouring with PET/CT is widely used in the clinical setting.However,this method is far from ideal,as it suffers from large intra-and inter-observer variability and is also a tedious and time-consuming procedure.On the other hand,increased accuracy was also reported in target delineation using a threshold function,relative to a constant threshold.However,there was no consensus regarding target volume delineation using PET images.The intra-tumoural heterogeneous uptake of FDG is one of the important factors for the segmentation of PET images.PET image radiomic analysis can be used to evaluate the degree of heterogeneity of 18F-FDG in tumor.To explore whether the intra-tumour 18F-FDG uptake heterogeneity affects the reliability of target volume definition with FDG PET/CT imaging for non-small cell lung cancer(NSCLC)and squamous cell oesophageal cancer(SCEC).Materials and Methods:Patients with NSCLC(n = 50)or SCEC(n = 50)who received 18F-FDG PET/CT scanning before treatments were included in this retrospective study.Intra-tumour FDG uptake heterogeneity was assessed by visual scoring,the coefficient of variation(COV)of the standardised uptake value(SUV)and the image texture feature(entropy).Tumour volumes were delineated on the CT gross tumour volume(GTVCT)images,the fused PET/CT images(GTVPET-CT)and the PET images,using a threshold at 40%SUVmax(GNVPET40%)or the SUV cut-off value of 2.5(GTVPET2.5).The correlation between the FDG uptake heterogeneity parameters and the differences in tumour volumes between GTVCT,GTVPET-CT,GTNPET40%and GTVPET2.5 was analysed.Results:The FDG uptake visual score was 2.22 ± 0.91 and 2.06 ± 0.89 for NSCLC and SCEC,respectively.The COV was 0.57 ± 0.12(0.37?0.86)for NSCLC and 0.56±0.10(0.43-0.86)for SCEC.Entropy was 3.91±0.67(2.52?4.99)for NSCLC and 4.21 ± 0.76(2.72?5.59)for SCEC,respectively.The uptake heterogeneity assessed by COV and PET image texture analysis is consistent with that defined by visual scoring.It was found that COV and entropy were significantly positive correlated with SUVmax and the tumour volume.The tumour volumes delineated on the CT images were significantly different from those defined on PET images.The volumes decreased significantly as GTVCT>GTVPET-CT>GTVPET2.5(35.7 ± 53.8 cm3 for NSCLC and 34.3 ± 32.2 cm3 for SCEC)>GTVPET40%(23.1 ± 23.4 cm3 for NSCLC and 20.9 ± 18.1 cm3 for SCEC).The integration of the GTV differences parameter(Diff)for NSCLC and SCEC is 44%± 13%and 55%±18%,respectively.Linear regression showed a positive correlation between the GTV differences and the visual scores(r = 0.42,P = 0.03),the COV(r =0.53,P = 0.02)or entropy(r = 0.57,P = 0.001).Meanwhile,the relationship between the automatic calculation heterogeneity parameter(COV and entropy)and the GTV differences tend to be more robust and reliable than the visual score system.Colusion:Intra-tumour 18F-FDG uptake heterogeneity decreases the reliability of target volume definition using different PET imaging parameters for both NSCLC and SCEC.Advance image segmentation algorithms dealing with tracer uptake heterogeneity should be incorporated into the treatment planning system.In the clinical setting,more research is warranted to define the uptake heterogeneity,in the best way possible,with either image-histopathology or image-prognosis correlation analysis.Part I I Early Change in Metabolic Tumor Heterogeneity during Chemoradiotherapy and its Prognostic Value for Patients with Locally Advanced Non-Small Cell Lung CancerIntroduction:Non-small cell lung cancer is a malignancy with a high degree of heterogeneity.State-of-the-art treatment of locally advanced-stage non-small cell lung cancer is chemoradiotherapy.Even in the same staging,pathologic type,and treatment mode.Its efficacy,recurrence and survival time have a big difference.Response assessment in the first weeks of radiotherapy would be useful to tailor the optimal treatment strategy for the individual patient.To observe the early change of metabolic tumor heterogeneity during chemoradiotherapy and to determine its prognostic value for patients with locally advanced non-small cell lung cancer(NSCLC).Methods:From January 2007 to March 2010,58 patients with NSCLC were included who were received 18F-fluorodeoxyglucose(18F-FDG)PET/CT before and following 40 Gy radiotherapy with the concurrent cisplatin-based chemotherapy(CCRT).Primary tumor FDG uptake heterogeneity was determined using global and local scale textural features extracted from standardized uptake value(SUV)histogram analysis(coefficient of variation[COV],skewness,kurtosis,area under the curve of the cumulative SUV histogram[AUC-CSH])and normalized gray-level co-occurrence matrix(Contrast,dissimilarity,entropy,homogeneity).SUVmax and metabolic tumor volume(MTV)were also evaluated.Correlations were analyzed between parameters on baseline or during treatments with tumor response,progression-free survival(PFS),and overall survival(OS).Result:Compared with non-responders,responders showed significantly greater pre-treatment COV,Contrast and MTV(AUC=0.781,0.804,0.686,respectively).Receiver-operating-characteristic curve analysis showed that early change of tumor textural analysis serve as a response predictor with higher sensitivity(73.2%?92.1%)and specificity(80.0%?83.6%)than baseline parameters.Change in AUC-CSH and dissimilarity during CCRT could also predictive response with optimal cut-off values(33.0%and 28.7%,respectively).The patients with greater changes in Contrast and AUC-CSH had significantly higher 5-year OS(P=0.008,P =0.034)and PFS(P =0.007,P=0.039).In multivariate analysis,only change in Contrast was found as the independent prognostic factor of PFS(HR 0.476,P=0.021)and OS(HR 0.519,P=0.015).Conclusion:We demonstrated that the metabolic tumor heterogeneity change during CCRT characterized by global and local scale textural features may provide independent information to predict treatment response and survival for patients with locally advanced NSCLC.Change in imaging Contrast is not the only parameter differentiating responders from non-responders.However,it serves as the only independent prognostic factor for OS and PFS.Our results suggest that characterization of FDG PET uptake heterogeneity early during treatment holds the potential to revolutionize the predictive role of PET in personalized treatment for locally advanced NSCLC. 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