applied sciences  
The Impact of Segmentation Method and Target Lesion Selection on Radionic Analysis of \({}^{18}\)F-FDG PET Images in Diffuse Large B-Cell Lymphoma  
[PERSON] \({}^{1}\)\({}^{\copyright}\), [PERSON] \({}^{1}\), [PERSON] \({}^{2,*}\)\({}^{\copyright}\), [PERSON] \({}^{2}\)\({}^{\copyright}\), [PERSON] \({}^{2}\), [PERSON] \({}^{3}\), [PERSON] \({}^{4,5}\)\({}^{\copyright}\), [PERSON] \({}^{3}\), [PERSON] \({}^{3}\)\({}^{\copyright}\), [PERSON] \({}^{3,6}\), [PERSON] \({}^{4}\) and [PERSON] \({}^{4,5}\)\({}^{\copyright}\)  
\({}^{1}\) Medical Physics Unit, IEO European Institute of Oncology IRCCS, 20141 Milan, Italy  
\({}^{2}\) Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, 20141 Milan, Italy  
\({}^{3}\) Onco-Hematology Division, IEO European Institute of Oncology IRCCS, 20141 Milan, Italy  
\({}^{4}\) Division of Nuclear Medicine, IEO European Institute of Oncology IRCCS, 20141 Milan, Italy  
\({}^{5}\) Department of Oncology and Hemato-Onology, University of Milan, 20122 Milan, Italy  
\({}^{6}\) Department of Health Sciences, University of Milan, 20146 Milan, Italy  
\({}^{*}\) Correspondence: [EMAIL_ADDRESS]  
Featured Application: The present work contributes to the investigation on the robustness and reproducibility of radiomic studies, a fundamental step for bringing radiomics towards clinical implementation.  
**Abstract:** Radionic analysis of \({}^{18}\)F[FDG] PET/CT images might identify predictive imaging biomarkers, however, the reproducibility of this quantitative approach might depend on the methodology adopted for image analysis. This retrospective study investigates the impact of PET segmentation method and the selection of different target lesions on the radiomic analysis of baseline \({}^{18}\)F[FDG] PET/CT images in a population of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients. The whole tumor burden was segmented on PET images applying six methods: (1) 2.5 standardized uptake value (SUV) threshold; (2) 25% maximum SUV (SUVmax) threshold; (3) 42% SUVmax threshold; (4) 1.3-liver uptake threshold; (5) intersection among 1, 2, 4; and (6) intersection among 1, 3, 4. For each method, total metabolic tumor volume (TMTV) and whole-body total lesion glycolysis (WTLG) were assessed, and their association with survival outcomes (progression-free survival PFS and overall survival OS) was investigated. Methods 1 and 2 provided stronger associations and were selected for the next steps. Radionic analysis was then performed on two target lesions for each patient: the one with the highest SUV and the largest one. Fifty-three radiomic features were extracted, and radiomic scores to predict PFS and OS were obtained. Two proportional-hazard regression Cox models for PFS and OS were developed: (1) univariate radiomic models based on radiomic score; and (2) multivariable clinical-radiomic model including radiomic score and clinical/diagnostic parameters (IPI score, SUVmax, TMTV, WTLG, lesion volume). The models were created in the four scenarios obtained by varying the segmentation method and/or the target lesion; the models' performances were compared (C-index). In all scenarios, the radiomic score was significantly associated with PFS and OS both at univariate and multivariable analysis (\(p<0.001\)), in the latter case in association with the IPI score. When comparing the models' performances in the four scenarios, the C-indexes agreed within the confidence interval. C-index ranges were 0.79-0.81 and 0.80-0.83 for PFS radiomic and clinical-radiomic models; 0.82-0.87 and 0.83-0.90 for OS radiomic and clinical-radiomic models. In conclusion, the selection of either between two PET segmentation methods and two target lesions for radiomic analysis did not significantly affect the performance of the prognostic models built on radiomic and clinical data of DLBCL patients. These results prompt further investigation of the proposed methodology on a validation dataset.  
PET; radiomics; lymphoma; biomarkers; prognosis; methodology; reproducibility