*2.2. 2-[18F]-FDG PET/CT Imaging and Interpretation*

All patients underwent a baseline 2-[18F]-FDG PET/CT scan before any kind of therapy and, if available, an eotPET/CT. Then, 2-[18F]-FDG PET/CT was acquired after at least 4 h fasting and with glucose blood level <150 mg/dL. An activity of 3.5–4.5 MBq/Kg of radiotracer was injected intravenously and scans began about 60 ± 10 min after the injection. The scan was performed from the skull base to the mid-thigh on two PET/CT scanners: Discovery ST and Discovery 690 PET/CT tomographs (General Electric Company—GE® —Milwaukee, WI, USA) with standard parameters (CT: 80 mA, 120 kV without contrast; 2.5–4 min per bed-PET-step of 15 cm). The matrix of reconstruction was 256 × 256 and the field of view was 60 cm. For both tomographs a standard non-contrast free-breathing helical low-dose CT was obtained for morphologic correlation and attenuation correction. The D-STE acquisition parameters were: 120 kV, fixed tube current ~73 mAs (40–160 mAs), 4 slices × 3.75 mm and 3.27 mm interval, pitch 1.5:1, tube rotation 0.8 s. The D690 acquisition parameters were: 120 kV, fixed tube current ~60 mAs (40–100 mAs), 64 slices × 3.75 mm and 3.27 mm interval, pitch 0.984:1, tube rotation 0.5 s. For D690, time-of-flight (TOF) and point spread function (PSF) were used as reconstruction algorithms; filter cutoff 5 mm, 18 subsets; three iterations. For D-STE, ordered subset expectation maximization (OSEM) was applied; filter cutoff 5 mm; 21 subsets, two iterations.

When available, eotPET/CT were performed at least three weeks after the last cycle of chemotherapy.

All PET images were analyzed visually and semi-quantitatively by a nuclear medicine physician with experience (DA) with the measurements of the maximum standardized uptake value body weight (SUVbw), the SUVmax corrected for the lean body mass (SU-Vlbm), the SUVmax corrected for body surface area (SUVbsa), lesion to liver SUVmax ratio (L-L SUV R), lesion to blood-pool SUVmax ratio (L-BP SUV R), MTV and TLG. Eot PET/CT was interpreted visually by the same nuclear medicine physician with more than 10 years of experience (DA) applying the Deauville scores. According to Deauville criteria [18], 2-[18F]-FDG PET/CT was interpreted as follows: 1 = no uptake above background, 2 = uptake equal to or lower than mediastinum, 3 = uptake higher than mediastinum and lower than liver, 4 = uptake moderately increased compared to the liver and 5 = uptake markedly increased compared to the liver. After therapy, patients with a score of 1–3 were judged as having complete metabolic response, while patients with score 4–5 as not complete metabolic response. For the measurements of SUV, a region of interest (ROI) was drawn over the area of maximum activity of the lesion with highest uptake and the SUVmax was derived as the highest SUV of the pixels within the ROI. SUVmax of the liver was calculated at the VIII hepatic segment of axial PET images using a round-shape ROI of 10 mm; SUVmax of the blood-pool was calculated at the aortic arch by use not involving the vessel wall in a similar way. MTV was measured from attenuation-corrected PET images using an SUV-based automated contouring program (Advantage Workstation 4.6, GE HealthCare) with an isocounter threshold method based on 41% of the SUVmax, as previously recommended by European Association of Nuclear Medicine because of its high inter-observer reproducibility [19]. Total MTV (tMTV) was obtained by the sum

of all nodal and extranodal lesions. Bone marrow involvement was included in volume measurement only if there was focal uptake; splenic involvement was considered if there was focal uptake in spleen or diffuse uptake higher than 150% in the liver background. Total TLG (tTLG) was calculated as the sum of the product of MTV of each lesion and its SUVmean. Semiquantitative analyses were performed by the same nuclear medicine physicians with long experience in lymphoma and in the use of Advantage Workstation 4.6, GE HealthCare for contouring.

### *2.3. Sarcopenia Analysis*

Low-dose CT of 2-[18F]-FDG PET/CT scans were analyzed by a researcher for the estimation of muscular and adipose tissues using Slice-O-Matic software V4.2 (Montreal, QC, Canada Tomovision). A transaxial slice with a multiplanar reconstruction at the third lumbar (L3) level was considered for the measurement of skeletal muscle area (SMA) considering psoas, paraspinal, abdominal transverse rectum, internal and external oblique, because the skeletal muscle in this area has been shown to represent the whole-body tissue quantities [11]. To measure the SMA (cm2), CT Hounsfield unit thresholds were –29 to 150. If necessary, the tissue margins were manually corrected. Subsequently SMA was normalized for the height to obtain the skeletal muscle index (SMI) expressed in cm2/m2.
