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Total metabolic tumor volume (TMTV) is prognostic in lymphoma. However, cutoff values for risk stratification vary markedly, according to the tumor delineation method used. We aimed to create a standardized TMTV benchmark dataset allowing TMTV to be tested and applied as a reproducible biomarker. Methods: Sixty baseline 18 F-FDG PET/CT scans were identified with a range of disease distributions (20 follicular, 20 Hodgkin, and 20 diffuse large B-cell lymphoma). TMTV was measured by 12 nuclear medicine experts, each analyzing 20 cases split across subtypes, with each case processed by 3-4 readers. LIFEx or ACCURATE software was chosen according to reader preference. Analysis was performed stepwise: TMTV1 with automated preselection of lesions using an SUV of at least 4 and a volume of at least 3 cm 3 with single-click removal of physiologic uptake; TMTV2 with additional removal of reactive bone marrow and spleen with single clicks; TMTV3 with manual editing to remove other physiologic uptake, if required; and TMTV4 with optional addition of lesions using mouse clicks with an SUV of at least 4 (no volume threshold). Results: The final TMTV (TMTV4) ranged from 8 to 2,288 cm 3 , showing excellent agreement among all readers in 87% of cases (52/60) with a difference of less than 10% or less than 10 cm 3 In 70% of the cases, TMTV4 equaled TMTV1, requiring no additional reader interaction. Differences in the TMTV4 were exclusively related to reader interpretation of lesion inclusion or physiologic high-uptake region removal, not to the choice of software. For 5 cases, large TMTV differences (>25%) were due to disagreement about inclusion of diffuse splenic uptake. Conclusion: The proposed segmentation method enabled highly reproducible TMTV measurements, with minimal reader interaction in 70% of the patients. The inclusion or exclusion of diffuse splenic uptake requires definition of specific criteria according to lymphoma subtype. The publicly available proposed benchmark allows comparison of study results and could serve as a reference to test improvements using other segmentation approaches., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Rationale and Objectives: In oncological imaging, the use of metabolic tumor volume (MTV) for further prognostic differentiation and the development of risk adapted strategies appears promising. The aim of this analysis was to evaluate ultra-high definition (UHD) and ordered subset expectation maximization (OSEM) PET/CT reconstructions for their potential impact on different methods of MTV measurement., Materials and Methods: We analyzed positron emission tomography combined with computed tomography (PET/CT) scans of 40 Hodgkin lymphoma patients before first-line treatment who had undergone fluorodeoxyglucose (FDG) PET/CT. The MTVs were determined taking an SUV of 4.0 (MTV4.0) as a fixed threshold or 41% of the single hottest voxel (MTV41%) as an adaptive threshold for automated lymphoma delineation in both UHD and OSEM reconstructions. We then compared the absolute and relative differences between MTV4.0 and MTV41% in UHD and OSEM reconstructions. The relative distribution of MTV4.0 and MTV41% in relation to the reconstruction method applied was recorded and respective differences were tested for statistical significance using the paired sample t-test., Results: A comparison of MTV4.0 and MTV41% showed smaller relative and absolute differences in MTV between different reconstruction settings for the MTV4.0 method. Conversely, the absolute as well as the relative differences between MTVs obtained from different reconstructions settings were significantly greater when the MTV41% method was applied (p < 0001)., Conclusion: MTV4.0 brings higher robustness between different reconstruction settings, while with MTV41% the deviation between volumes obtained with different reconstruction settings is greater. For clinical routine and for multicenter settings, the MTV4.0 therefore appears most promising., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Patients with Richter's transformation of chronic lymphocytic leukemia (CLL) to diffuse large B-cell lymphoma (DLBCL-RT) face a dismal prognosis. A 51-year-old female patient diagnosed with CLL with deletion (17p) in 2009. CLL treatment included chemoimmunotherapy and targeted substances. DLBCL-RT was diagnosed in November 2016. After receiving an allogeneic hematopoietic stem cell transplantation, she relapsed in September 2019 and tisagenlecleucel was infused in December 2019. Cytokine release syndrome grade 2 was treated with two doses of tocilizumab and the patient was started on 140 mg ibrutinib in February 2020. Our patient remains in remission up to 4 years after CAR T-cell treatment., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Purpose: The emergence of chimeric antigen receptor (CAR) T-cell therapy fundamentally changed the management of individuals with relapsed and refractory large B-cell lymphoma (LBCL). However, real-world data have shown divergent outcomes for the approved products. The present study therefore set out to evaluate potential risk factors in a larger cohort., Methods: Our analysis set included 88 patients, treated in four German university hospitals and one Italian center, who had undergone 2-[ 18 F]fluoro-2-deoxy-D-glucose positron emission tomography (PET) before CAR T-cell therapy with tisagenlecleucel or axicabtagene ciloleucel. We first determined the predictive value of conventional risk factors, treatment lines, and response to bridging therapy for progression-free survival (PFS) through forward selection based on Cox regression. In a second step, the additive potential of two common PET parameters was assessed. Their optimal dichotomizing thresholds were calculated individually for each CAR T-cell product., Results: Extra-nodal involvement emerged as the most relevant of the conventional tumor and patient characteristics. Moreover, we found that inclusion of metabolic tumor volume (MTV) further improves outcome prediction. The hazard ratio for a PFS event was 1.68 per unit increase of our proposed risk score (95% confidence interval [1.20, 2.35], P = 0.003), which comprised both extra-nodal disease and lymphoma burden. While the most suitable MTV cut-off among patients receiving tisagenlecleucel was 11 mL, a markedly higher threshold of 259 mL showed optimal predictive performance in those undergoing axicabtagene ciloleucel treatment., Conclusion: Our analysis demonstrates that the presence of more than one extra-nodal lesion and higher MTV in LBCL are associated with inferior outcome after CAR T-cell treatment. Based on an assessment tool including these two factors, patients can be assigned to one of three risk groups. Importantly, as shown by our study, metabolic tumor burden might facilitate CAR T-cell product selection and reflect the individual need for bridging therapy., (© 2023. The Author(s).)

Purpose: Fibroblast activation protein (FAP) detected by positron-emission tomography (PET) using fibroblast activation protein inhibitor (FAPI) appears to be a promising target for cancer imaging, staging, and therapy, providing added value and strength as a complement to [ 18 F]fluorodeoxyglucose (FDG) in cancer imaging. We recently introduced a combined single-session/dual-tracer protocol with [ 18 F]FDG and [ 68 Ga]Ga-FAPI for cancer imaging and staging. Malignant tissue visualization and target-to-background uptake ratios (TBRs) as well as functional tumor volume (FTV) and gross tumor volume (GTV) were assessed in the present study with single-tracer [ 18 F]FDG PET/computed tomography (CT) and with dual-tracer [ 18 F]FDG&[ 68 Ga]Ga-FAPI-46 PET/CT., Methods: A total of 19 patients with head and neck and gastrointestinal cancers received initial [ 18 F]FDG-PET/CT followed by dual-tracer PET/CT after additional injection of [ 68 Ga]Ga-FAPI-46 during the same medical appointment (on average 13.9 ± 12.3 min after injection of [ 18 F]FDG). Two readers visually compared detection rate of malignant tissue, TBR, FTV, and GTV for tumor and metastatic tissue in single- and dual-tracer PET/CT., Results: The diagnostic performance of dual-tracer compared to single-tracer PET/CT was equal in 13 patients and superior in 6 patients. The mean TBRs of tumors and metastases in dual-tracer PET/CTs were mostly higher compared to single-tracer PET/CT using maximal count rates (CRmax). GTV and FTV were significantly larger when measured on dual-tracer compared to single-tracer PET/CT., Conclusion: Dual-tracer PET/CT with [ 18 F]FDG and [ 68 Ga]Ga-FAPI-46 showed better visualization due to a generally higher TBR and larger FTV and GTV compared to [ 18 F]FDG-PET/CT in several tumor entities, suggesting that [ 68 Ga]Ga-FAPI-46 provides added value in pretherapeutic staging., (© 2023. The Author(s).)

Objectives: The prognostic relevance of metabolic tumor volume (MTV) having recently been demonstrated in patients with early-stage favorable and advanced-stage Hodgkin lymphoma. The current study aimed to assess the potential prognostic value of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in early-stage unfavorable Hodgkin lymphoma patients treated within the German Hodgkin Study Group HD17 trial., Methods: 18 F-FDG PET/CT images were available for MTV analysis in 154 cases. We used three different threshold methods (SUV 2.5 , SUV 4.0 , and SUV 41% ) to calculate MTV. Receiver-operating-characteristic analysis was performed to describe the value of these parameters in predicting an adequate therapy response. Therapy response was evaluated as PET negativity after 2 cycles of eBEACOPP followed by 2 cycles of ABVD., Results: All three threshold methods analyzed for MTV showed a positive correlation with the PET response after chemotherapy. Areas under the curve (AUC) were 0.70 (95% CI 0.53-0.87) and 0.65 (0.50-0.80) using the fixed thresholds of SUV 4.0 and SUV 2.5 , respectively, for MTV- calculation. The calculation of MTV using a relative threshold of SUV 41% showed an AUC of 0.63 (0.47-0.79)., Conclusions: MTV does have predictive value after chemotherapy in early-stage unfavorable Hodgkin lymphoma, particularly when the fixed threshold of SUV 4.0 is used for MTV calculation., Trial Registration: ClinicalTrials.gov NCT01356680., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

The introduction of chimeric antigen receptor (CAR) T-cell therapy has led to a fundamental shift in the management of relapsed and refractory large B-cell lymphoma. However, our understanding of risk factors associated with non-response is still insufficient and the search for predictive biomarkers continues. Some parameters measurable on 18 F-fluorodeoxyglucose positron emission tomography (PET) may be of additional value in this context. A total of 47 individuals from three German university centers who underwent re-staging with PET prior to CAR T-cell therapy were enrolled into the present study. After multivariable analysis considering tumor characteristics and patient factors that might affect progression-free survival (PFS), we investigated whether metabolic tumor volume (MTV) or maximum standardized uptake value (SUV max ) further improve risk stratification. Their most suitable cut-offs were determined by Cox and logistic regression. Forward selection identified extra-nodal disease as the most predictive factor of those routinely available, and we found it to be associated with significantly inferior overall survival after CAR T-cell treatment ( P = 0.012). Furthermore, patients with MTV and SUV max higher than the optimal threshold of 11 mL and 16.7, respectively, experienced shorter PFS ( P = 0.016 and 0.002, respectively). Hence, these risk factors might be useful for selection of individuals likely to benefit from CAR T-cell therapy and their management., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Imaging studies with PET tracers acting as fibroblast activation protein inhibitors (FAPIs) show promising results that could usefully complement [ 18 F]-FDG in cancer imaging. Methods: All patients received [ 18 F]-FDG PET/CT and dual-tracer PET/CT after an additional injection of [ 68 Ga]Ga-FAPI-46 after the [ 18 F]-FDG PET/CT. Two readers visually compared detection rate and analyzed target-to-background ratios for tumor and metastatic tissue in single- and dual-tracer PET/CT. Results: Detection rate in dual-tracer PET/CT was visually as good as that in single-tracer PET/CT in 4 patients and superior in 2 patients, whereas target-to-background ratios were significantly higher in dual-tracer PET/CT. Conclusion: Dual-tracer [ 18 F]-FDG/[ 68 Ga]Ga-FAPI-46 PET/CT within a single session is feasible and has potential. The dual-tracer approach may have superior sensitivity to [ 18 F]-FDG PET/CT alone without compromising individual assessment of either scan., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: 18 F -fluorodeoxyglucose (FDG) positron emission tomography (PET) plays an important role in the staging and response assessment of lymphoma patients. Our aim was to explore the predictive relevance of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with early stage Hodgkin lymphoma treated within the German Hodgkin Study Group HD16 trial., Methods: 18 F-FDG PET/CT images were available for MTV and TLG analysis in 107 cases from the HD16 trial. We calculated MTV and TLG using three different threshold methods (SUV 4.0, SUV 41% and SUV 140%L ), and then performed receiver-operating-characteristic analysis to assess the predictive impact of these parameters in predicting an adequate therapy response with PET negativity after 2 cycles of chemotherapy., Results: All three threshold methods analyzed for MTV and TLG calculation showed a positive correlation with the PET response after 2 cycles chemotherapy. The largest area under the curve (AUC) was observed using the fixed threshold of SUV 4.0 for MTV- calculation (AUC 0.69 [95% CI 0.55-0.83]) and for TLG-calculation (AUC 0.69 [0.55-0.82]). The calculations for MTV and TLG with a relative threshold showed a lower AUC: using SUV 140%L AUCs of 0.66 [0.53-0.80] for MTV and 0.67 for TLG [0.54-0.81]) were observed, while with SUV 41% an AUC of 0.61 [0.45-0.76] for MTV, and an AUC 0.64 [0.49-0.80]) for TLG were seen., Conclusions: MTV and TLG do have a predictive value after two cycles ABVD in early stage Hodgkin lymphoma, particularly when using the fixed threshold of SUV 4.0 for MTV and TLG calculation., Trial Registration: ClinicalTrials.gov NCT00736320 ., (© 2022. The Author(s).)