Role of PET/CT in initial evaluation of lymphoma patients

Background Accurate radiologic assessment of treatment response in lymphoma patients is important to evaluate the effectiveness of treatment and consequently predict the relapse; the value of PET/CT for post-treatment prognosis prediction has been recently investigated. The aim of this study is to highlight the prognostic value of PET-CT metabolic volumetric parameters in the evaluation of lymphoma patients. Results Among the included 40 patients, post-treatment SUV, MTV, and TLG were significantly lower in a responsive group than the non-responsive group. % changes of all quantitative PET/CT parameters were significantly higher in the responsive group than the non-responsive group. Conclusions This study suggests that pre-treatment PET/CT quantitative measures (except baseline SUVmax) are not conclusive in the prediction of patient response to treatment; however, the ΔSUVmax, ΔMTV, and ΔTLG% from the baseline to the end of therapy could be used in predicting patient response to treatment, determining patient prognosis, and suggesting the relapse.

Harmonization of PET image reconstruction parameters in simultaneous PET/MRI

Objective Simultaneous PET/MRIs vary in their quantitative PET performance due to inherent differences in the physical systems and differences in the image reconstruction implementation. This variability in quantitative accuracy confounds the ability to meaningfully combine and compare data across scanners. In this work, we define image reconstruction parameters that lead to comparable contrast recovery curves across simultaneous PET/MRI systems. Method The NEMA NU-2 image quality phantom was imaged on one GE Signa and on one Siemens mMR PET/MRI scanner. The phantom was imaged at 9.7:1 contrast with standard spheres (diameter 10, 13, 17, 22, 28, 37 mm) and with custom spheres (diameter: 8.5, 11.5, 15, 25, 32.5, 44 mm) using a standardized methodology. Analysis was performed on a 30 min listmode data acquisition and on 6 realizations of 5 min from the listmode data. Images were reconstructed with the manufacturer provided iterative image reconstruction algorithms with and without point spread function (PSF) modeling. For both scanners, a post-reconstruction Gaussian filter of 3–7 mm in steps of 1 mm was applied. Attenuation correction was provided from a scaled computed tomography (CT) image of the phantom registered to the MR-based attenuation images and verified to align on the non-attenuation corrected PET images. For each of these image reconstruction parameter sets, contrast recovery coefficients (CRCs) were determined for the SUVmean, SUVmax and SUVpeak for each sphere. A hybrid metric combining the root-mean-squared discrepancy (RMSD) and the absolute CRC values was used to simultaneously optimize for best match in CRC between the two scanners while simultaneously weighting toward higher resolution reconstructions. The image reconstruction parameter set was identified as the best candidate reconstruction for each vendor for harmonized PET image reconstruction. Results The range of clinically relevant image reconstruction parameters demonstrated widely different quantitative performance across cameras. The best match of CRC curves was obtained at the lowest RMSD values with: for CRCmean, 2 iterations-7 mm filter on the GE Signa and 4 iterations-6 mm filter on the Siemens mMR, for CRCmax, 4 iterations-6 mm filter on the GE Signa, 4 iterations-5 mm filter on the Siemens mMR and for CRCpeak, 4 iterations-7 mm filter with PSF on the GE Signa and 4 iterations-7 mm filter on the Siemens mMR. Over all reconstructions, the RMSD between CRCs was 1.8%, 3.6% and 2.9% for CRC mean, max and peak, respectively. The solution of 2 iterations-3 mm on the GE Signa and 4 iterations-3 mm on Siemens mMR, both with PSF, led to simultaneous harmonization and with high CRC and low RMSD for CRC mean, max and peak with RMSD values of 2.8%, 5.8% and 3.2%, respectively. Conclusions For two commercially available PET/MRI scanners, user-selectable parameters that control iterative updates, image smoothing and PSF modeling provide a range of contrast recovery curves that allow harmonization in harmonization strategies of optimal match in CRC or high CRC values. This work demonstrates that nearly identical CRC curves can be obtained on different commercially available scanners by selecting appropriate image reconstruction parameters.

PET-CT Quantitative Parameter Delta Suvmax As a Predictor of Early Relapse in Patients with Difuse Large B-Cell Lymphoma

Introduction: About one third of patients with diffuse large B-cell lymphoma (DLBCL) fail frontline treatment or have early relapse. Baseline quantitative parameters derived from positron emission computed tomography (PET/CT) at baseline may predict outcome in DLBCL patients. However, their prognostic value in interim scans is unclear. Recently, the role delta maximum standardized uptake value (ΔSUVmax) has been tested as a predictor of PFS. In this retrospective study we aimed to analyze the role of ΔSUVmax between baseline and interim PET-CT as a predictor of progression of disease within 1 year in DLBCL patients and, to compare this parameter to the standard validated method to evaluate disease response: Deauville scale (DS). Methods: This is a single-center retrospective cohort study from São Paulo, Brazil. We included patients with DLBCL who had baseline (b-PET) and interim (i-PET, after 2-3 cycles of treatment) PET-CTs and who have been treated with 6 cycles of R-CHOP given every 21 days. All PET-CTs were analyzed by the same physician and blinded for the clinical features. Delta maximum standardized uptake value (ΔSUVmax) was calculated by the difference in % between initial PET SUVmax and iPET SUVmax. The objective was to assess if ΔSUV performed better than Deauville scale (DS) in predicting early disease progression. Cut-off values were defined by receiver operating characteristic (ROC) analysis. Analysis was performed with Cox model. Model comparison was based on the lowest AIC. Results: A total of 83 patients with DLBCL were available for analyses. The median age was 60 years and 66% of patients had a germinal center B-Cell (GCB) phenotype. With median follow-up of 15 months, patients with a cut-off ΔSUVmax <85% had a higher risk of disease relapse (49% vs 2%, p<0.001) at 12 months (figure 1). Patients with DS >3 in the iPET were also at a higher risk of disease progression (p<0.001) (figure 2). The model with ΔSUVmax was better adjusted (AIC=86) than the one with DS (AIC=92). The median maximum uptake at baseline PET/CT, MYC and/or BCl2 expression were not predictive of relapse at 12 months. International prognostic index (IPI) was also predictive of relapse (p=0.003), but again performed poorer than ΔSUVmax (AIC=99). Discussion/Conclusion: We showed that ΔSUVmax quantitative PET-CT model has superior discriminatory power than the qualitative DS model and the clinical IPI. Although we have a small sample, this finding corresponds with PETAL trial, which also showed that the ΔSUVmax method is superior to the commonly used Deauville five-point scale to identify patients at high risk of treatment fails. Although, the ΔSUVmax cut-off value calculated in our study was 85%, while in the PETAL study a reduction off 66% in the baseline SUV was the considered cutoff. Maybe, combing ΔSUVmax method in a with DS and IPI can improve prognostic stratification and early identification of high risk DLBCL. The ΔSUVmax is an easily reproducible method, that can be easily assessed by PET-CT, differing from other quantitative measures like the total metabolic tumor volume. In conclusion, further validation in a large sample of patients should be performed before the incorporation of quantitative PET-CT methods in clinical practice however it is a promising prognostic marker. Figure 1 Figure 1. Disclosures Perini: Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau.

68Ga-EMP-100 PET/CT—a novel ligand for visualizing c-MET expression in metastatic renal cell carcinoma—first in-human biodistribution and imaging results

Background 68Ga-EMP-100 is a novel positron emission tomography (PET) ligand that directly targets tumoral c-MET expression. Upregulation of the receptor tyrosin kinase c-MET in renal cell carcinoma (RCC) is correlated with overall survival in metastatic disease (mRCC). Clinicopathological staging of c-MET expression could improve patient management prior to systemic therapy with for instance inhibitors targeting c-MET such as cabozantinib. We present the first in-human data of 68Ga-EMP-100 in mRCC patients evaluating uptake characteristics in metastases and primary RCC. Methods Twelve patients with mRCC prior to anticipated cabozantinib therapy underwent 68Ga-EMP-100 PET/CT imaging. We compared the biodistribution in normal organs and tumor uptake of mRCC lesions by standard uptake value (SUVmean) and SUVmax measurements. Additionally, metastatic sites on PET were compared to contrast-enhanced computed tomography (CT) and the respective, quantitative PET parameters were assessed and then compared inter- and intra-individually. Results Overall, 87 tumor lesions were analyzed. Of these, 68/87 (79.3%) were visually rated c-MET-positive comprising a median SUVmax of 4.35 and SUVmean of 2.52. Comparing different tumor sites, the highest uptake intensity was found in tumor burden at the primary site (SUVmax 9.05 (4.86–29.16)), followed by bone metastases (SUVmax 5.56 (0.97–15.85)), and lymph node metastases (SUVmax 3.90 (2.13–6.28)) and visceral metastases (SUVmax 3.82 (0.11–16.18)). The occurrence of visually PET-negative lesions (20.7%) was distributed heterogeneously on an intra- and inter-individual level; the largest proportion of PET-negative metastatic lesions were lung and liver metastases. The highest physiological 68Ga-EMP-100 accumulation besides the urinary bladder content was seen in the kidneys, followed by moderate uptake in the liver and the spleen, whereas significantly lower uptake intensity was observed in the pancreas and the intestines. Conclusion Targeting c-MET expression, 68Ga-EMP-100 shows distinctly elevated uptake in mRCC patients with partially high inter- and intra-individual differences comprising both c-MET-positive and c-MET-negative lesions. Our first clinical results warrant further systemic studies investigating the clinical use of 68Ga-EMP-100 as a biomarker in mRCC patients.

SAFIR-I: Design and Performance of a High-Rate Preclinical PET Insert for MRI

(1) Background: Small Animal Fast Insert for MRI detector I (SAFIR-I) is a preclinical Positron Emission Tomography (PET) insert for the Bruker BioSpec 70/30 Ultra Shield Refrigerated (USR) preclinical 7T Magnetic Resonance Imaging (MRI) system. It is designed explicitly for high-rate kinetic studies in mice and rats with injected activities reaching 500MBq, enabling truly simultaneous quantitative PET and Magnetic Resonance (MR) imaging with time frames of a few seconds in length. (2) Methods: SAFIR-I has an axial field of view of 54.2mm and an inner diameter of 114mm. It employs Lutetium Yttrium OxyorthoSilicate (LYSO) crystals and Multi Pixel Photon Counter (MPPC) arrays. The Position-Energy-Timing Application Specific Integrated Circuit, version 6, Single Ended (PETA6SE) digitizes the MPPC signals and provides time stamps and energy information. (3) Results: SAFIR-I is MR-compatible. The system’s Coincidence Resolving Time (CRT) and energy resolution are between separate-uncertainty 209.0(3)ps and separate-uncertainty 12.41(02) Full Width at Half Maximum (FWHM) at low activity and separate-uncertainty 326.89(12)ps and separate-uncertainty 20.630(011) FWHM at 550MBq, respectively. The peak sensitivity is ∼1.6. The excellent performance facilitated the successful execution of first in vivo rat studies beyond 300MBq. Based on features visible in the acquired images, we estimate the spatial resolution to be ∼2mm in the center of the Field Of View (FOV). (4) Conclusion: The SAFIR-I PET insert provides excellent performance, permitting simultaneous in vivo small animal PET/MR image acquisitions with time frames of a few seconds in length at activities of up to 500MBq.

Fifty Shades of Scandium: Comparative Study of PET Capabilities Using Sc-43 and Sc-44 with Respect to Conventional Clinical Radionuclides

Scandium-44 has been proposed as a valuable radionuclide for Positron Emission Tomography (PET). Recently, scandium-43 was introduced as a more favorable option, as it does not emit high-energy γ-radiation; however, its currently employed production method results in a mixture of scandium-43 and scandium-44. The interest in new radionuclides for diagnostic nuclear medicine critically depends on the option for image-based quantification. We aimed to evaluate and compare the quantitative capabilities of scandium-43/scandium-44 in a commercial PET/CT device with respect to more conventional clinical radionuclides (fluorine-18 and gallium-68). With this purpose, we characterized and compared quantitative PET data from a mixture of scandium-43/scandium-44 (~68% scandium-43), scandium-44, fluorine-18 and gallium-68, respectively. A NEMA image-quality phantom was filled with the different radionuclides using clinical-relevant lesion-to-background activity concentration ratios; images were acquired in a Siemens Biograph Vision PET/CT. Quantitative accuracy with scandium-43/scandium-44 in the phantom’s background was within 9%, which is in agreement with fluorine-18-based PET standards. Coefficient of variance (COV) was 6.32% and signal recovery in the lesions provided RCmax (recovery coefficient) values of 0.66, 0.90, 1.03, 1.04, 1.12 and 1.11 for lesions of 10-, 13-, 17-, 22-, 28- and 37-mm diameter, respectively. These results are in agreement with EARL reference values for fluorine-18 PET. The results in this work showed that accurate quantitative scandium-43/44 PET/CT is achievable in commercial devices. This may promote the future introduction of scandium-43/44-labelled radiopharmaceuticals into clinical use.

In vivo quantitative assessment of therapeutic response to bortezomib therapy in disseminated animal models of multiple myeloma with [18F]FDG and [64Cu]Cu-LLP2A PET

Background Multiple myeloma (MM) is a disease of cancerous plasma cells in the bone marrow. Imaging-based timely determination of therapeutic response is critical for improving outcomes in MM patients. Very late antigen-4 (VLA4, CD49d/CD29) is overexpressed in MM cells. Here, we evaluated [18F]FDG and VLA4 targeted [64Cu]Cu-LLP2A for quantitative PET imaging in disseminated MM models of variable VLA4 expression, following bortezomib therapy. Methods In vitro and ex vivo VLA4 expression was evaluated by flow cytometry. Human MM cells, MM.1S-CG and U266-CG (C: luciferase and G: green fluorescent protein), were injected intravenously in NOD-SCID gamma mice. Tumor progression was monitored by bioluminescence imaging (BLI). Treatment group received bortezomib (1 mg/kg, twice/week) intraperitoneally. All cohorts (treated, untreated and no tumor) were longitudinally imaged with [18F]FDG (7.4–8.0 MBq) and [64Cu]Cu-LLP2A (2–3 MBq; Molar Activity: 44.14 ± 1.40 MBq/nmol) PET, respectively. Results Flow cytometry confirmed high expression of CD49d in U266 cells (> 99%) and moderate expression in MM.1S cells (~ 52%). BLI showed decrease in total body flux in treated mice. In MM.1S-CG untreated versus treated mice, [64Cu]Cu-LLP2A localized with a significantly higher SUVmean in spine (0.58 versus 0.31, p < 0.01) and femur (0.72 versus 0.39, p < 0.05) at week 4 post-tumor inoculation. There was a four-fold higher uptake of [64Cu]Cu-LLP2A (SUVmean) in untreated U266-CG mice compared to treated mice at 3 weeks post-treatment. Compared to [64Cu]Cu-LLP2A, [18F]FDG PET detected treatment-related changes at later time points. Conclusion [64Cu]Cu-LLP2A is a promising tracer for timely in vivo assessment of therapeutic response in disseminated models of MM.

18F-FDG-PET-MRI for the assessment of acute intestinal graft-versus-host-disease (GvHD)

Background Graft versus host disease (GvHD) is a frequent complication of allogeneic stem cell transplantation (alloSCT), significantly increasing mortality. Previous imaging studies focused on the assessment of intestinal GvHD with contrast-enhanced MRI/CT or 18F-FDG-PET imaging alone. The objective of this retrospective study was to elucidate the diagnostic value of a combined 18F-FDG-PET-MRI protocol in patients with acute intestinal GvHD. Methods Between 2/2015 and 8/2019, 21 patients with acute intestinal GvHD underwent 18F-FDG-PET-MRI. PET, MRI and PET-MRI datasets were independently reviewed. Readers assessed the number of affected segments of the lower gastrointestinal tract and the reliability of the diagnosis on a 5-point Likert scale and quantitative PET (SUVmax, SUVpeak, metabolic volume (MV)) and MRI parameter (wall thickness), were correlated to clinical staging of acute intestinal GvHD. Results The detection rate for acute intestinal GvHD was 56.8% for PET, 61.4% for MRI and 100% for PET-MRI. PET-MRI (median Likert-scale value: 5; range: 4–5) offers a significantly higher reliability of the diagnosis compared to PET (median: 4; range: 2–5; p = 0.01) and MRI alone (median: 4; range: 3–5; p = 0.03). The number of affected segments in PET-MRI (rs = 0.677; p < 0.001) and the MV (rs = 0.703; p < 0.001) correlated significantly with the clinical stage. SUVmax (rs = 0.345; p = 0.14), SUVpeak (rs = 0.276; p = 0.24) and wall thickening (rs = 0.174; p = 0.17) did not show a significant correlation to clinical stage. Conclusion 18F-FDG-PET-MRI allows for highly reliable assessment of acute intestinal GvHD and adds information indicating clinical severity.