PET Metrics Research Articles

Reproducibility of [18F]MK-6240 kinetics in brain studies with shortened dynamic PET protocol in healthy/cognitively normal subjects

Background[18F]MK-6240 is a neurofibrillary tangles PET radiotracer that has been broadly used in aging and Alzheimer’s disease (AD) studies. Majority of [18F]MK-6240 PET studies use dynamic acquisitions longer than 60 min to assess the tracer kinetic parameters. As of today, no consensus has been established on the optimum dynamic PET scan time. In this study, we assess the reproducibility of [18F]MK-6240 quantitative metrics using shortest dynamic PET protocols in cognitively normal subjects. PET metrics were measured through two-tissue compartment model (2TCM) and Logan model to estimate VT and DVR, as well as SUVR from 90 to 120 min (SUVR90 − 120 min) post-tracer injection for brain regions. 2TCM was carried out using the 120 min dynamic coffee break dataset (first scan from 0 to 60 min p.i., second scan from 90 to 120 min p.i.) and then repeated after stepwise shortening it by 5 min. The dynamic scan length that reproduced the 120 min dynamic scans-based VT to within 10% error was defined as the shortest acquisition time (SAT). The SAT SUVR90 − 120 min was deduced from the SAT dataset by extrapolation of each image pixel time-activity curve to 120 min. The reproducibility of the 120 min dynamic scans-based VT2TCM, DVR2TCM, DVRLogan, and SUVR using the SAT was assessed using Passing-Bablock analysis. The limits of reproducibility of each PET metrics were determined using Bland-Altman analysis.ResultsA dynamic SAT of 40 min yielded < 10% error in [18F]MK-6240 VT2TCM’s for all brain regions, compared to those measured using the 120 min datasets. SAT-based analysis did not show statistically significant systemic or proportional biases in VT2TCM, DVR2TCM, DVRLogan, or SUVR compared to those deduced from the full dynamic dataset of 120 min. A mean difference between the 120 min- and SAT-based analysis of less than 4%, 10%, 15%, and 20% existed in the VT2TCM, DVR2TCM, DVRLogan, and SUVR respectively.ConclusionKinetic modeling of [18F]MK-6240 PET can be accurately performed using dynamic scan times as short as 40 min. This can facilitate studies with [18F]MK-6240 PET and improve patients accrual. Further work would be necessary to confirm the reproducibility of these results for patients in dementia spectra.

Interpreting Baseline PET Metrics and PET-Based Response in Lymphoma

Interpreting Baseline PET Metrics and PET-Based Response in Lymphoma

Outcome prediction based on [18F]FDG PET/CT in patients with pleural mesothelioma treated with ipilimumab and nivolumab +/- UV1 telomerase vaccine.

The introduction of immunotherapy in pleural mesothelioma (PM) has highlighted the need for effective outcome predictors. This study explores the role of [18F]FDG PET/CT in predicting outcomes in PM treated with immunotherapy. Patients from the NIPU trial, receiving ipilimumab and nivolumab +/- telomerase vaccine in second-line, were included. [18F]FDG PET/CT was obtained at baseline (n = 100) and at week-5 (n = 76). Metabolic tumour volume (MTV) and peak standardised uptake value (SUVpeak) were evaluated in relation to survival outcomes. Wilcoxon rank-sum test was used to assess differences in MTV, total lesion glycolysis (TLG), maximum standardised uptake value (SUVmax) and SUVpeak between patients exhibiting an objective response, defined as either partial response or complete response according to the modified Response Criteria in Solid Tumours (mRECIST) and immune RECIST (iRECIST), and non-responders, defined as either stable disease or progressive disease as their best overall response. Univariate Cox regression revealed significant associations of MTV with OS (HR 1.36, CI: 1.14, 1.62, p < 0.001) and PFS (HR 1.18, CI: 1.03, 1.34, p = 0.02), while multivariate analysis showed a significant association with OS only (HR 1.35, CI: 1.09, 1.68, p = 0.007). While SUVpeak was not significantly associated with OS or PFS in univariate analyses, it was significantly associated with OS in multivariate analysis (HR 0.43, CI: 0.23, 0.80, p = 0.008). Objective responders had significant reductions in TLG, SUVmax and SUVpeak at week-5. MTV provides prognostic value in PM treated with immunotherapy. High SUVpeak was not associated with inferior outcomes, which could be attributed to the distinct mechanisms of immunotherapy. Early reductions in PET metrics correlated with treatment response. The NIPU trial (NCT04300244) is registered at clinicaltrials.gov. https://classic. gov/ct2/show/NCT04300244?cond=Pleural+Mesothelioma&cntry=NO&draw=2&rank=4.

Association of aggressive prostate cancer features on whole-mount histopathology and quantitative measures on PSMA PET.

289 Background: The intraductal carcinoma (IDC) and the large cribriform growth pattern (LCP) are two architectural patterns of prostate cancer (PC) associated to more aggressive disease, high Gleason scores, advanced tumor stage, biochemical relapse, and distant metastasis. Predicting the presence of these pathology features could be of significant help in case whole-mount pathology (WMHP) is not available. The goal of this analysis was to assess the distribution of quantitative parameters from 68Ga-PSMA-11 PET/CT (PSMA PET) in lesions with and without LCP/IDC patterns on WMHP. We assessed the ability of pre-surgical PSMA PET imaging to predict the presence of aggressive pathology features. Methods: With IRB approval and HIPAA compliance, we derived a study cohort of PC patients who underwent PSMA PET prior to robotic radical prostatectomy (RALP). WMHP analysis described presence/absence of LCP and IDC patterns in each identified PC lesion. Board-certified physicians contoured all PC lesions on PSMA PET. Only lesions matching with WMHP were included in the analysis. PSMA PET metrics (SUVmax, SUVmean and PSMA-volume) were extracted. All lesions were categorized in sub-cohorts as LCP+/IDC+, LCP+/IDC-, LCP-/IDC-, and LCP-/IDC+. One way-ANOVA assessed significant differences among the imaging parameters in the sub-cohorts. The area under the curve (AUC) from ROC analysis was used to assess the ability of imaging metrics to predict the presence of aggressive PC features on WMHP. Results: The final cohort comprised 155 patients and 177 lesions. The median (IQR) PSA at time of RALP was 9.2 (5.55-15.05). 73/177 lesions (41.2%) were categorized as LCP+/IDC+, 63/177 (35.6%) as LCP-/IDC-, 37/177 (20.9%) as LCP+/IDC-, and 4 (2.3%) as LCP-/IDC-. SUVmax (p=0.007), SUVmean (p=0.048) and lesion size on PSMA PET (p=0.003) were significantly higher in lesions showing LCP, whereas only lesion size was significantly higher in lesions showing IDC (p=0.003). Lesions showing LCP+/IDC- had significantly higher SUVmax (p=0.002) and SUVmean (p=0.001) than lesions showing LCP-/IDC-. SUVmean was significantly higher in LCP+/IDC- than in LCP+/IDC+ (0.043). SUVmax and SUVmean were not significantly different among other sub-cohorts. Lesion size on PSMA PET was significantly higher in LCP+/IDC+ than in LCP-/IDC- (0.009). A logistic regression model analysis showed that PSMA PET quantitative measures predict the presence of LCP and/or IDC with moderate accuracy (AUC= 0.69; p=0.001). Conclusions: Higher SUVmax and SUVmean are found in lesions showing LCP, but not in those showing IDC. A linear regression model including SUVmax, SUVmean and PSMA PET lesion volume was able to predict with moderate accuracy the presence of pathology features of aggressive prostate cancer (AUC: 0.69).

The spatial extent of tauopathy on [18F]MK-6240 tau PET shows stronger association with cognitive performances than the standard uptake value ratio in Alzheimer’s disease

Purpose[18F]MK-6240, a second-generation tau PET tracer, is increasingly used for the detection and the quantification of in vivo cerebral tauopathy in Alzheimer’s disease (AD). Given that neurological symptoms are better explained by the topography rather than by the nature of brain lesions, our study aimed to evaluate whether cognitive impairment would be more closely associated with the spatial extent than with the intensity of tau-PET signal, as measured by the standard uptake value ratio (SUVr).Methods[18F]MK6240 tau-PET data from 82 participants in the AD spectrum were quantified in three different brain regions (Braak ≤ 2, Braak ≤ 4, and Braak ≤ 6) using SUVr and the extent of tauopathy (EOT, percentage of voxels with SUVr ≥ 1.3). PET data were first compared between diagnostic categories, and ROC curves were computed to evaluate sensitivity and specificity. PET data were then correlated to cognitive performances and cerebrospinal fluid (CSF) tau values.ResultsThe EOT in the Braak ≤ 2 region provided the highest diagnostic accuracies, distinguishing between amyloid-negative and positive clinically unimpaired individuals (threshold = 9%, sensitivity = 79%, specificity = 82%) as well as between prodromal AD and preclinical AD (threshold = 38%, sensitivity = 81%, specificity = 93%). The EOT better correlated with cognition than SUVr (∆R2 + 0.08–0.09) with the best correlation observed for EOT in the Braak ≤ 4 region (R2 = 0.64). Cognitive performances were more closely associated with PET metrics than with CSF values.ConclusionsQuantifying [18F]MK-6240 tau PET in terms of EOT rather than SUVr significantly increases the correlation with cognitive performances. Quantification in the mesiotemporal lobe is the most useful to diagnose preclinical AD or prodromal AD.

68Ga-labeled fibroblast activation protein inhibitor (FAPI) PET/CT for locally advanced or recurrent pancreatic cancer staging and restaging after chemoradiotherapy.

Purpose: 68Ga-labeled fibroblast activation protein inhibitor (FAPI) is a novel PET tracer with great potential for staging pancreatic cancer. Data on locally advanced or recurrent disease is sparse, especially on tracer uptake before and after high dose chemoradiotherapy (CRT). The aim of this study was to evaluate [68Ga]Ga-FAPI-46 PET/CT staging in this setting. Methods: Twenty-seven patients with locally recurrent or locally advanced pancreatic adenocarcinoma (LRPAC n = 15, LAPAC n = 12) in stable disease or partial remission after chemotherapy underwent FAPI PET/CT and received consolidation CRT in stage M0 with follow-up FAPI PET/CT every three months until systemic progression. Quantitative PET parameters SUVmax, SUVmean, FAPI-derived tumor volume and total lesion FAPI-uptake were measured in baseline and follow-up PET/CT scans. Contrast-enhanced CT (ceCT) and PET/CT data were evaluated blinded and staged according to TNM classification. Results: FAPI PET/CT modified staging compared to ceCT alone in 23 of 27 patients in baseline, resulting in major treatment alterations in 52% of all patients (30%: target volume adjustment due to N downstaging, 15%: switch to palliative systemic chemotherapy only due to diffuse metastases, 7%: abortion of radiotherapy due to other reasons). Regarding follow-up scans, major treatment alterations after performing FAPI PET/CT were noted in eleven of 24 follow-up scans (46%) with switch to systemic chemotherapy or best supportive care due to M upstaging and ablative radiotherapy of distant lymph node and oligometastasis. Unexpectedly, in more than 90 % of the follow-up scans, radiotherapy did not induce local fibrosis related FAPI uptake. During the first follow-up, all quantitative PET metrics decreased, and irradiated lesions showed significantly lower FAPI uptake in locally controlled disease (SUVmax p = 0.047, SUVmean p = 0.0092) compared to local failure. Conclusion: Compared to ceCT, FAPI PET/CT led to major therapeutic alterations in patients with LRPAC and LAPAC prior to and after radiotherapy, which might help identify patients benefiting from adjustments in every treatment stage. FAPI PET/CT should be considered a useful diagnostic tool in LRPAC or LAPAC before and after CRT.

Predictive Value of Pre-Infusion FDG‐PET/CT Parameters for Clinical Outcomes and Toxicities in Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL) Following CAR-T Cell Therapy

Introduction: CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant efficacy in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma but is associated with serious adverse effects such CRS and ICANS. Pre-infusion disease burden has been investigated as a potential predictor of clinical outcome and toxicity. FDG-PET/CT derived metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are quantitative indicators of this baseline tumor load. We aim to assess the predictive value of pre-CART PET metrics on outcome and toxicity in R/R large B-Cell Lymphoma (LBCL) following CAR-T cell therapy. Method: We conducted a retrospective single site study of 25 consecutive patients with R/R LBCL treated with CAR-T therapy in our institution between May 2020 and October 2022, All patients underwent FDG-PET/CT imaging pre-CAR-T infusion (PET-0) and at day 30 post infusion (PET-1). The images were reviewed by two expert lymphoma PET physicians. Metabolic parameters including MTV, TLG (both calculated using a relative threshold of 40%), SUVmax and Deauville score were calculated. PET-1 was classified as complete metabolic response (CMR, Deauville score 1-3) or non-CMR (Deauville score 4-5) as per the Lugano classification. Results: 25 patients were analyzed , Based on the median MTV (74,6 mL), TLG (379,4), SUVmax (11,8) values, patients were divided into two groups “low” and “high”. The median follow-up was 12 months. Patients with low pre-infusion MTV and TLG had significantly superior day 30 CMR rates (84,6% vs 25%, p= 0.001 &amp; 80% vs 20%, p = 0.001 respectively). Pre-infusion SUVmax ( p = 0.29 ) and Deauville score ( p = 0.103), however, did not predict response to treatment. In our population, pre-infusion PET parameters were not associated with CRS or ICANS . Patients with low pre-infusion MTV and TLG had significantly superior PFS (MTV: p=0.02; TLG: p=0.019) and OS (MTV: p=0.017; TLG: p=0.05), Pre-infusion SUVmax had no statistical significant impact on OS ( p = 0.61) or PFS ( p = 0.37) Conclusion: In our study, pre-infusion quantitative PET metrics, TLG and MTV, predict response and outcomes of CART therapy in R/R LBCL. Our results highlight the importance of adequate disease control before CAR-T administration and the value of pre-infusion FDG-PET/CT as a predictor of outcomes in R/R LBCL patients treated by CAR-T-therapy.

The Nature of High-Risk Defining Events in Follicular Lymphoma Determines Overall Survival

Background: A subset of follicular lymphoma (FL) patients will experience a ‘high-risk defining event’ (HRDE) that portends poor survival due to early progression of disease or transformation to diffuse large B cell lymphoma (TFL). Progression of disease within 24 months (POD24) from front-line immunochemotherapy (ICT) identifies patients with a subsequent five-year OS of 50% compared to a reference group of 90% (Casulo et al. JCO 2015). Although a robust surrogate endpoint for OS in clinical trials (Casulo et al. Blood 2022), it remains to be established if the OS of patents is influenced by the nature of the HRDE. In this study, we examined whether characteristics and clinical trajectory of those with relapsed/progressive FL is the same as that of patients experiencing TFL. Methods: We conducted an international retrospective analysis of newly diagnosed FL patients requiring treatment across 14 academic centres between 2002 and 2021 in the era of rituximab and PET-CT staging. Patients were included with grade 1-3A FL requiring first-line (1L) treatment (ICT, rituximab monotherapy or radiotherapy). We excluded patients with untreated FL, de novo TFL and those with &amp;lt;24 months follow up provided they did not experience a HRDE. Baseline clinical, imaging and laboratory values, treatment details and outcomes were collected. We defined HRDE groups as persistent (relapse or progression) FL within 24 months of 1L treatment (FL24), early TFL (&amp;lt;24 months of 1L treatment) or late TFL (&amp;gt;24 months of 1L treatment). Patients not experiencing a HRDE formed the FL reference group. Landmark overall survival (OS) analysis was performed by Cox regression using risk status as a time-varying covariate for time of HRDE. For the FL reference group, landmark was defined at 24 months after 1L treatment. Results: 501 patients met the inclusion criteria and were categorised as: reference FL (n=378), FL24 (n=50), early TFL (n=28), late TFL (n=15). 24 patients who died within 24 months of 1L treatment without documentation of preceding HRDE and were omitted. Median follow up for patients alive beyond 24 months was 5.1 years. Median age at diagnosis was 60 years, 91% had ECOG performance status 0-1 and 38% were high-risk (&amp;gt;3) FLIPI. 1L chemotherapy regimens included: bendamustine (59%), CHOP (24%), CVP (8%), other (9%); a majority received rituximab (80%) vs obinutuzumab (20%). Maintenance therapy was used in 54% of pts. Expectedly, those experiencing HRDE had an inferior OS compared to the reference group (HR 5.23, p&amp;lt;0.001)(Figure 1). However, among HRDE group, median OS significantly differed: early TFL patients (3.0 yrs) and FL24 (12.6yrs)(HR 2.27, p=0.02) (Table 1). There was no difference in OS after HRDE between early TFL and late TFL ( p=0.81). Biopsy was performed in 84% of TFL cases with no difference in OS between biopsy-proven vs clinically suspected cases ( p=0.23). Multivariate OS analysis assessing HRDE and treatment demonstrated no significant interaction between HRDE group and 1L chemotherapy ( p=0.52), monoclonal antibody ( p=0.29) or maintenance therapy ( p=0.27). Several established prognostic features at baseline were enriched in patients who went on to experience HRDE including: ECOG &amp;gt;1 ( p&amp;lt;0.001), raised LDH ( p&amp;lt;0.001), advanced-stage disease (( p&amp;lt;0.011) and high risk FLIPI ( p=0.005). Baseline FDG-PET was available in 259 patients. Adverse PET metrics were enriched in only early TFL, and not FL24 or late TFL patients, including high SUV max( p=0.009), total metabolic tumor volume ( p=0.015) and total lesional glycolysis ( p=0.01). Conclusions: HRDEs after 1L treatment are associated with inferior OS in FL compared with standard-risk patients. Unlike POD24, this study demonstrates disparate clinical outcomes between patients experiencing early progression with persistent FL and those experiencing TFL. Adverse metabolic characteristics on baseline FDG-PET also suggest biological distinction between HRDE subsets. These findings have important implications for epidemiological studies, biomarker development and clinical trials aiming to improve outcomes in this underserved high-risk FL cohort.

IMMU-05. CD8 IMMUNOPET IMAGING IS ABLE TO MONITOR THE IMMUNE RESPONSE SENSITIVELY AND SPECIFICALLY IN GBM PATIENTS FOLLOWING NEOADJUVANT CHECKPOINT BLOCKADE IMMUNOTHERAPY

Abstract The sensitive and specific evaluation of treatment response in glioblastoma (GBM) patients following immunotherapy is a clinical dilemma. Traditional MRI assessments to visualize and quantify intracranial tumor burden following immunotherapy cannot reliably differentiate tumor progression and pseudo progression remains a complicating factor. In this study, we provide an early report on the use of an investigational new functional imaging PET tracer (CD8 ImmunoPET, 89Zr-crefmirlimab berdoxam, ImaginAb) prior to and immediately following neoadjuvant checkpoint blockade immunotherapy in five patients with recurrent GBM. Tumor samples were collected from each patient at surgery following a two-week neoadjuvant checkpoint blockade to assess gene expression changes and TIL density. We then evaluated how such tumor measurements correlated with PET metrics obtained at baseline and within 2 weeks after treatment initiation which included standardized uptake values (SUVmax, SUVpeak, and SUVmean), and two proposed new metrics indicating the Volume of Immunometabolism (VIM), and the Total Lesion or Lymph nodes’ T cells called TLTc (TLTc = VI x SUVmean) in the tumor bed and lymph node basins (neck, axillae, and inguinal regions). CD8 ImmunoPET demonstrated tracer uptake in the intracranial tumor at both time points, as well as specific physiologic uptake in lymph node basins, spleen, liver, and bone marrow. Neoadjuvant checkpoint blockade with PD-1 +/- CTLA-4 mAb (Nivolumab, Ipilimumab, BMS) at 2 weeks induced variable changes in SUV, but in four of the five initial patients studied in this clinical trial, an increase in VI and TLTc was observed within the tumor bed. Tracer uptake was associated with elevated T cell infiltration into the tumor bed and gene expression changes indicative of interferon signaling and immune cells in these same patients. Our early findings identify a noninvasive functional imaging platform to evaluate the immunometabolism secondary to T cell infiltration and/or activation changes following immunotherapy in GBM patients.

Multimodal prediction of neoadjuvant treatment outcome by serial FDG PET and MRI in women with locally advanced breast cancer

PurposeTo investigate combined MRI and 18F-FDG PET for assessing breast tumor metabolism/perfusion mismatch and predicting pathological response and recurrence-free survival (RFS) in women treated for breast cancer.MethodsPatients undergoing neoadjuvant chemotherapy (NAC) for locally-advanced breast cancer were imaged at three timepoints (pre, mid, and post-NAC), prior to surgery. Imaging included diffusion-weighted and dynamic contrast-enhanced (DCE-) MRI and quantitative 18F-FDG PET. Tumor imaging measures included apparent diffusion coefficient, peak percent enhancement (PE), peak signal enhancement ratio (SER), functional tumor volume, and washout volume on MRI and standardized uptake value (SUVmax), glucose delivery (K1) and FDG metabolic rate (MRFDG) on PET, with percentage changes from baseline calculated at mid- and post-NAC. Associations of imaging measures with pathological response (residual cancer burden [RCB] 0/I vs. II/III) and RFS were evaluated.ResultsThirty-five patients with stage II/III invasive breast cancer were enrolled in the prospective study (median age: 43, range: 31–66 years, RCB 0/I: N = 11/35, 31%). Baseline imaging metrics were not significantly associated with pathologic response or RFS (p > 0.05). Greater mid-treatment decreases in peak PE, along with greater post-treatment decreases in several DCE-MRI and 18F-FDG PET measures were associated with RCB 0/I after NAC (p < 0.05). Additionally, greater mid- and post-treatment decreases in DCE-MRI (peak SER, washout volume) and 18F-FDG PET (K1) were predictive of prolonged RFS. Mid-treatment decreases in metabolism/perfusion ratios (MRFDG/peak PE, MRFDG/peak SER) were associated with improved RFS.ConclusionMid-treatment changes in both PET and MRI measures were predictive of RCB status and RFS following NAC. Specifically, our results indicate a complementary relationship between DCE-MRI and 18F-FDG PET metrics and potential value of metabolism/perfusion mismatch as a marker of patient outcome.

CD20low/CD68high a Promising Microenvironnement Profile Identifying Classical Hodgkin Lymphoma Patients with Poor Outcome a Lysa Study

Introduction Although progression free survival and overall survival of patients with Hodgkin lymphoma (HL) has improved in the past 10 years, 15 % of patients will fail to conventional therapy and die of their lymphoma. The search of new prognostic factors for identifying these high risk patients at diagnosis of HL remains challenging in PET-guided strategies developed to improve the outcome HL patients while reducing treatment toxicity The aim of this study was therefore to assess the impact of baseline tumor microenvironnement in a large cohort of HL patients prospectively treated with upfront escalated BEACOPP in a randomized phase III clinical trial evaluating a PET-driven strategy (AHL 2011, NCT01358747) and to compare its prognostic value with other clinicopathological markers. Material and Methods Tumoral material was collected from HL patients prospectively enrolled in the AHL2011 study from LYSA centers in France and Belgium. The AHL2011 study was designed to evaluate in 16-60y HL patients with Ann Arbor stage III, IV or high risk IIB, a de-escalade PET-driven strategy after 2 cycles of BEACOPPesc (PET2) randomly compared to a standard treatment not driven by PET delivering 6 cycles of BEACOPPesc. The AHL2011 strategy was shown to safely guide treatment of advanced HL patients allowing using ABVD in early responders to BEACOPPesc (PET2 negative) reducing toxicities without impairing disease control (Casasnovas et al, Lancet Oncol 2019, JCO 2022). The tumor microenvironnement (TME) was analyzed on formalin fixed paraffin embedded diagnostic tissue biopsy obtained before treatment by morphological evaluation on standard staining on whole slides (% polynuclear eosinophils, % lymphocytes, % plasmocytes, % histiocytes), and immunohistochemistry (IHC) scoring (score 0-1-2-3) for CD20, CD3, CD4, CD8, CD68-TAMs (tumor-associated macrophages), CD163 (n=680) and EBERS (n= 634). Additional staining were done on Tissue microarray (TMA n=409) for PD-1, PD-L1, TIM3, GATA3, CD45R0, TBET and were centrally reviewed. Computational analysis was used for the TMA analysis using Tissu Studio software (Definiens). For each marker, a H-score was calculated (stained cells x 1, 2 or 3 according to the intensity of staining divided by the total number of cells x100) Results 680 patients were included on the whole slides analyses and 409 for those on the TMA analyses. Patients included had similar characteristics to the remaining patients of AHL2011 not included here. Among all the microenvironnement biomarkers tested only CD20 and CD68 had prognosis value. In univariate analysis, high CD20 H-score was associated with a favorable PFS (HR=0.43, 95%CI 0.22-0.86), while patients having high CD68 H-score had unfavorable PFS (HR=2.29, 95%CI 1.29-4.05). Then, the patients with a combined CD20 low/CD68high TME (n= 239, 47%) had a significant lower PFS compared to other groups (HR=2.46, 95%CI 1.48-4.09; p=0.004) (figure 1). In multivariate analysis including all relevant variables (Bulky disease / IPS / TMTV (total metabolic volume) / PET2 /PET4 / combination CD20 CD68 / % of tumor cells /EBV status / B symptoms), only High TMTV &amp;gt;220ml (HR = 2.09, p =0.017), PET4 positivity (HR= 7.06 ; p &amp;lt; 0.0001) and the CD20 low/CD68high profile (HR=1.95, p=0.025) had an independant prognosis value on PFS. Patients harboring both a TME depleted in CD20 and enriched in CD68, had peculiarities. Indeed, they had significantly more B symptoms (78.2% vs 64.2%, p&amp;lt;0.001), higher median TMTV (270 vs 163ml, p&amp;lt;0.001), were more frequently EBERs positive (23.6 vs 12.7%, p=0.002), had more frequently lymphopenia (38.5 vs 18.2%, p&amp;lt;0.001) and high IPS (69.2 vs 53%, p&amp;lt;0.001). Finally, patients with a CD20low/CD68high profile, had a higher median tumor cells PD-L1 H-score compared to other patients (39.7 vs 7.4, p&amp;lt;0.001). Conclusion Altogether these results demonstrate in a large PET-guided phase III trial (AHL2011), the interest of analyzing CD20 and CD68 expressions within the tumor microenvironnement to better evaluate the risk of treatment failure prior to therapy in patients with advanced HL. The prognosis value of the CD20/CD68 profile is independant of those of the baseline PET metrics (TMTV), and the early reponse to treatment. The enrichment of highly positive PD-L1 tumor cells in patients with CD20 low/CD68high TME suggests that PD-1 blockers could be a good therapeutic option in frontline treatment of this poor prognosis group.

Survival Patterns of Non-Randomized Patients in the IELSG37 Study: Deauville Score 4 Is Not Necessarily Associated with Poor Outcome in Primary Mediastinal Lymphoma

Background:Primary mediastinal B-cell lymphoma (PMBCL) is clinically and biologically distinct from other types of aggressive lymphoma, it is characterized by a bulky mediastinal mass and most commonly occurs in women between 30 and 40 years of age. Although consolidation radiotherapy (RT) has yielded extremely positive outcomes in PMBCL, it carries a higher risk of long-term complications. Consequently, there has been an ongoing debate regarding the necessity of RT in patients responding to frontline immunochemotherapy. Methods:In the IELSG37 study, PMBCL 530 patients were treated with rituximab- and doxorubicin-containing regimens; 98% had stage I-II. Their response was assessed by positron emission computed tomography (PET/CT); 268 achieved a complete metabolic remission (CMR) defined as Deauville score (DS) 1 to 3 according to the Lugano classification and were randomly allocated to observation or mediastinal RT. The primary analysis [Zucca et al. J Clin Oncol 2023; 41 (suppl 17): abs. LBA7505] has shown that patients in CMR can safely forgo RT. The 3-year overall survival (OS) rate was 99% irrespective of irradiation. RT provided only minimal benefit on progression-free survival (PFS), which was over 96% at 3 years in both arms. Here we present the outcome of the 262 patients who were not randomized and were managed according to the preference of their treating physician. Results:Median follow-up was 64 months (interquartile range [IQR], 49-69). Besides 230 patients failing frontline treatment (174 DS4 and 56 DS5), the non-randomized cohort also included 1 patient with DS2 (who refused randomization and received RT) and 31 patients with DS3 who were initially considered as partial responders before a protocol amendment that changed the definition of CMR from DS 1-2 to DS 1-3. Among these non-randomized patients with DS3, 27 had RT consolidation, 1 was only observed, 2 had salvage chemotherapy ± RT, and 1 had missing data due to consent withdrawal; their 3-year PFS was very close to the one of the randomized patients with DS3 (90 vs 92%, p=0.99). In the DS4 group, 12 patients were observed, 149 had only RT, and 13 had second-line chemotherapy, with (12) or without (1) autologous stem cell rescue, 8 of 13 also had RT. Among the patients with DS5, only 2 were observed, 32 had only RT, and 22 had second-line chemotherapy, with (15) or without (7) autologous stem cell rescue; 12 of them also had RT. The outcome of patients with DS4 was overlapping the one of the patients achieving a CMR, with 3-year PFS of 97.1% (95%CI 93-99) and 97.4% (95%CI 95-99), respectively, while patients with DS5 had a significantly poorer 3-year PFS (62.4%, 95%CI 48-74) [Figure1A]. The 3-year OS showed a similar trend (98% in patients with DS4, 99% in those randomized, and 78% in the DS5 group). Notably, compared to patients receiving consolidation RT alone or only observed, the residual lesions on post-immunochemotherapy PET/CT scans of patients with DS4 and DS5 who were treated more aggressively (with salvage chemotherapy ± autologous transplant and/or RT) displayed significantly higher tracer maximum standardized uptake value (SUVmax, median: 8.2, IQR 4.6-16.5 vs. 3.8, IQR 3.1-4.9; p&amp;lt;0.0001) and larger residual metabolic tumor volume (MTV, median: 18 ml, IQR 3-95 vs. 3.6, ml, IQR 1-10; p&amp;lt;0.0001). These patients had significantly worse outcomes compared to those who received consolidation RT or were observed only [Figure 1B]. Conclusions:Patients with DS4 had outcomes similar to those of patients achieving a CMR, indicating that this group may either include a significant number of “false-positive” cases with inflammatory uptake or that their residual disease is limited and can potentially be cured with consolidation RT. Patients with DS5 had a significantly poorer outcome, although nearly half of them did well with RT alone. It seems plausible that clinical condition of the patient and/or imaging features of the residual disease have influenced treatment choices in patients without CMR after frontline immunochemotherapy. Further studies are needed to investigate whether PET metrics and/or liquid biopsies can aid in personalizing treatment and identifying patients who could potentially avoid irradiation.

Diagnostic Accuracy of MR Spectroscopic Imaging and 18F-FET PET for Identifying Glioma: A Biopsy-Controlled Hybrid PET/MRI Study.

Contrast-enhanced MRI is the method of choice for brain tumor diagnostics, despite its low specificity for tumor tissue. This study compared the contribution of MR spectroscopic imaging (MRSI) and amino acid PET to improve the detection of tumor tissue. Methods: In 30 untreated patients with suspected glioma, O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) PET; 3-T MRSI with a short echo time; and fluid-attenuated inversion recovery, T2-weighted, and contrast-enhanced T1-weighted MRI were performed for stereotactic biopsy planning. Serial samples were taken along the needle trajectory, and their masks were projected to the preoperative imaging data. Each sample was individually evaluated neuropathologically. 18F-FET uptake and the MRSI signals choline (Cho), N-acetyl-aspartate (NAA), creatine, myoinositol, and derived ratios were evaluated for each sample and classified using logistic regression. The diagnostic accuracy was evaluated by receiver operating characteristic analysis. Results: On the basis of the neuropathologic evaluation of tissue from 88 stereotactic biopsies, supplemented with 18F-FET PET and MRSI metrics from 20 areas on the healthy-appearing contralateral hemisphere to balance the glioma/nonglioma groups, 18F-FET PET identified glioma with the highest accuracy (area under the receiver operating characteristic curve, 0.89; 95% CI, 0.81-0.93; threshold, 1.4 × background uptake). Among the MR spectroscopic metabolites, Cho/NAA normalized to normal brain tissue showed the highest diagnostic accuracy (area under the receiver operating characteristic curve, 0.81; 95% CI, 0.71-0.88; threshold, 2.2). The combination of 18F-FET PET and normalized Cho/NAA did not improve the diagnostic performance. Conclusion: MRI-based delineation of gliomas should preferably be supplemented by 18F-FET PET.

Prospective inter- and intra-tracer repeatability analysis of radiomics features in [68Ga]Ga-PSMA-11 and [18F]F-PSMA-1007 PET scans in metastatic prostate cancer.

This study aimed to quantify both the intra- and intertracer repeatability of lesion-level radiomics features in [68Ga]Ga-prostate-specific membrane antigen (PSMA)-11 and [18F]F-PSMA-1007 positron emission tomography (PET) scans. Eighteen patients with metastatic prostate cancer (mPCa) were prospectively recruited for the study and randomised to one of three test-retest groups: (i) intratracer [68Ga]Ga-PSMA-11 PET, (ii) intratracer [18F]F-PSMA-1007 PET or (iii) intertracer between [68Ga]Ga-PSMA-11 and [18F]F-PSMA-1007 PET. Four conventional PET metrics (standardised uptake value (SUV)max, SUVmean, SUVtotal and volume) and 107 radiomics features were extracted from 75 lesions and assessed using the repeatability coefficient (RC) and the ICC. Radiomic feature repeatability was also quantified after the application of 16 filters to the PET image. Test-retest scans were taken a median of 5 days apart (range: 2-7 days). SUVmean demonstrated the lowest RC limits of the conventional features, with RCs of 7.9%, 14.2% and 24.7% for the [68Ga]Ga-PSMA-11 PET, [18F]F-PSMA-1007 PET, and intertracer groups, respectively. 69%, 66% and 9% of all radiomics features had good or excellent ICC values (ICC ≥ 0.75) for the same groups. Feature repeatability therefore diminished considerably for the intertracer group relative to intratracer groups. In this study, robust biomarkers for each tracer group that can be used in subsequent clinical studies were identified. Overall, the repeatability of conventional and radiomic features were found to be substantially lower for the intertracer group relative to both intratracer groups, suggesting that assessing patient response quantitatively should be done using the same radiotracer where possible. Intertracer biomarker repeatability limits are significantly larger than intratracer limits.

Characterization of Large Brain Metastases with 18F-Fluciclovine PET/CT Treated with Staged Stereotactic Radiosurgery (SSRS): Phase 1 Proof-of-Concept Interim Analysis

Single-session stereotactic radiosurgery (SRS) for large brain metastases (>2cm) results in modest local control. Temporally staged SRS (SSRS), whereby 2 stages of SRS are delivered over a time interval of several weeks, is a novel strategy associated with improved control rates and acceptable radiation necrosis rates. Biomarkers for response are lacking. Here, we report interim results of a phase 1, proof-of-concept study (NCT04689048) to assess the potential clinical utility of amino acid radiotracer 18F-fluciclovine PET/CT as a functional integral biomarker for patients with large brain metastases treated with SSRS. Patients with previously untreated large brain metastases (≥1 lesion; >2cm) underwent a baseline (pre-treatment) 18F-fluciclovine PET/CT and contrast-enhanced treatment planning brain MRI immediately before first SSRS (15 Gy), an interim PET/CT + MRI (4 weeks after the 1st SSRS, immediately prior the 2nd SSRS [15 Gy]), and post-treatment PET/CT + MRI (8 weeks after 2nd SSRS). This interim analysis reviewed the imaging characteristics from static PET images acquired 10-25 minutes after 18F-fluciclovine injection, for the first 7 enrolled patients who completed baseline imaging and 5 who completed the entire treatment course. Seven patients completed baseline imaging and were treated with SSRS for 9 protocol-eligible target lesions, and an additional 25 bystander lesions were treated with SRS. The median age was 72 years and 57% were female. All lesions > 5 mm exhibited baseline increased 18F-fluciclovine uptake compared to the normal contralateral brain. The median baseline target lesion diameters and volumes were 2.16 cm (1.76-3.22 cm) and 4.71cc (2.24-10.21 cc). The median baseline SUVmax, SUVpeak, and SUVmean values were 5.78 (2.16-8.79), 3.33 (0.5-2.72), and 1.75 (1.22-5.16), respectively. The median relative reduction in diameter and volume were both 2% (-13% to 23% and -30% to 60%, respectively) at the interim scans, and at the first follow-up were 30% (-0.2% to 44%) and 43% (-13% to 94%), respectively. Corresponding median relative reduction values for SUVmax, SUVpeak, and SUVmean at interim scans were 20% (-174%-73%), 9% (-99% to 75%), and 14% (-36% to 69%), and at first follow-up 59% (21% to 87%), 41% (-11% to 86%), and 21% (-44% to 79%), respectively. Bystander lesions (< 2 cm) treated with SRS had a median baseline lesion diameter and volume of 0.5 cm (Range: 0.20-1.64 cm) and 0.06 cc (Range: 0.01-1.94 cc). Corresponding median reductions for SUVmax were 5% at interim and 63% at follow-up scans. This proof-of-concept interim study reports baseline 18F-fluciclovine metrics for patients with brain metastases of varying lesion diameters and volumes. Target lesions appear to demonstrate interval reduction in PET metrics after SSRS, more than dimensional measurements alone.

Machine Learning CT-Based Automatic Nodal Segmentation and PET Semi-Quantification of Intraoperative 68Ga-PSMA-11 PET/CT Images in High-Risk Prostate Cancer: A Pilot Study.

High-resolution intraoperative PET/CT specimen imaging, coupled with prostate-specific membrane antigen (PSMA) molecular targeting, holds great potential for the rapid ex vivo identification of disease localizations in high-risk prostate cancer patients undergoing surgery. However, the accurate analysis of radiotracer uptake would require time-consuming manual volumetric segmentation of 3D images. The aim of this study was to test the feasibility of using machine learning to perform automatic nodal segmentation of intraoperative 68Ga-PSMA-11 PET/CT specimen images. Six (n = 6) lymph-nodal specimens were imaged in the operating room after an e.v. injection of 2.1 MBq/kg of 68Ga-PSMA-11. A machine learning-based approach for automatic lymph-nodal segmentation was developed using only open-source Python libraries (Scikit-learn, SciPy, Scikit-image). The implementation of a k-means clustering algorithm (n = 3 clusters) allowed to identify lymph-nodal structures by leveraging differences in tissue density. Refinement of the segmentation masks was performed using morphological operations and 2D/3D-features filtering. Compared to manual segmentation (ITK-SNAP v4.0.1), the automatic segmentation model showed promising results in terms of weighted average precision (97-99%), recall (68-81%), Dice coefficient (80-88%) and Jaccard index (67-79%). Finally, the ML-based segmentation masks allowed to automatically compute semi-quantitative PET metrics (i.e., SUVmax), thus holding promise for facilitating the semi-quantitative analysis of PET/CT images in the operating room.

Detection of recurrent high-grade glioma using microstructure characteristics of distinct metabolic compartments in a multimodal and integrative 18F-FET PET/fast-DKI approach

ObjectivesDifferentiation between high-grade glioma (HGG) and post-treatment-related effects (PTRE) is challenging, but advanced imaging techniques were shown to provide benefit. We aim to investigate microstructure characteristics of metabolic compartments identified from amino acid PET and to evaluate the diagnostic potential of this multimodal and integrative O-(2-18F-fluoroethyl)-l-tyrosine-(FET)-PET and fast diffusion kurtosis imaging (DKI) approach for the detection of recurrence and IDH genotyping.MethodsFifty-nine participants with neuropathologically confirmed recurrent HGG (n = 39) or PTRE (n = 20) were investigated using static 18F-FET PET and a fast-DKI variant. PET and advanced diffusion metrics of metabolically defined (80–100% and 60–75% areas of 18F-FET uptake) compartments were assessed. Comparative analysis was performed using Mann–Whitney U tests with Holm-Šídák multiple-comparison test and Wilcoxon signed-rank test. Receiver operating characteristic (ROC) curves, regression, and Spearman’s correlation analysis were used for statistical evaluations.ResultsCompared to PTRE, recurrent HGG presented increased 18F-FET uptake and diffusivity (MD60), but lower (relative) mean kurtosis tensor (rMKT60) and fractional anisotropy (FA60) (respectively p < .05). Diffusion metrics determined from the metabolic periphery showed improved diagnostic performance — most pronounced for FA60 (AUC = 0.86, p < .001), which presented similar benefit to 18F-FET PET (AUC = 0.86, p < .001) and was negatively correlated with amino acid uptake (rs = − 0.46, p < .001). When PET and DKI metrics were evaluated in a multimodal biparametric approach, TBRmax + FA60 showed highest diagnostic accuracy (AUC = 0.93, p < .001), which improved the detection of relapse compared to PET alone (difference in AUC = 0.069, p = .04). FA60 and MD60 distinguished the IDH genotype in the post-treatment setting.ConclusionDetection of glioma recurrence benefits from a multimodal and integrative PET/DKI approach, which presented significant diagnostic advantage to the assessment based on PET alone.Clinical relevance statementA multimodal and integrative 18F-FET PET/fast-DKI approach for the non-invasive microstructural characterization of metabolic compartments provided improved diagnostic capability for differentiation between recurrent glioma and post-treatment-related changes, suggesting a role for the diagnostic workup of patients in post-treatment settings.Key Points• Multimodal PET/MRI with integrative analysis of 18F-FET PET and fast-DKI presents clinical benefit for the assessment of CNS cancer, particularly for the detection of recurrent high-grade glioma.• Microstructure markers of the metabolic periphery yielded biologically pertinent estimates characterising the tumour microenvironment, and, thereby, presented improved diagnostic accuracy with similar accuracy to amino acid PET.• Combined 18F-FET PET/fast-DKI achieved the best diagnostic performance for detection of high-grade glioma relapse with significant benefit to the assessment based on PET alone.

NEIM-02 CHARACTERIZATION OF LARGE BRAIN METASTASES WITH18F-FLUCICLOVINE PET/CT TREATED WITH STAGED STEREOTACTIC RADIOSURGERY (SSRS): INTERIM ANALYSIS OF A PILOT STUDY

Abstract We report the interim analysis of a phase 1, proof-of-concept study (NCT04689048), to assess the potential clinical utility of an amino acid radiotracer, 18F-fluciclovine PET/CT, as a functional integral biomarker for previously untreated patients with large brain metastases [BM] (≥1 lesion; &amp;gt;2cm) treated with staged stereotactic radiosurgery (SSRS). We reviewed the imaging characteristics from static PET images acquired 10-25 minutes after 18F-fluciclovine injection for the first seven enrolled patients (9 lesions) who completed baseline imaging, and five patients (7 lesions) who completed the treatment course (SSRS). Patients underwent a baseline (pre-treatment) 18F-fluciclovine PET/CT and contrast-enhanced treatment planning brain MRI before 1st SSRS (15 Gy), repeated after 4 weeks (interim; before 2nd SSRS [15 Gy]), and 8 weeks after treatment completion (first follow-up after 2nd SSRS). The median age was 72 years and 57% were female. All lesions exhibited baseline increased 18F-fluciclovine uptake compared to normal contralateral brain. The median baseline lesion diameters and volumes were 2.16 cm (1.76-3.22 cm) and 4.71cc (2.24-10.21 cc). The median baseline SUVmax, SUVpeak, and SUVmean values were 5.78 (2.16-8.79), 3.33 (0.5-2.72), and 1.75 (1.22-5.16), respectively. The median relative changes in diameter and volume were both -2% (-23% to +13% and -60% to +30%, respectively) at the interim scans, and -30% (-44% to +0.2%) and -43% (-94% to +13%), respectively, at first follow-up. Corresponding median relative changes values for SUVmax, SUVpeak, and SUVmean at interim scan were -20% (-73% to +174%), -9% (-75% to +99%), and -14% (-69% to +36%), and at first follow-up -59% (-87% to -21%), -41% (-86% to +11%), and -21% (-79% to +44%), respectively. In conclusion, this proof-of-concept interim study reports 18F-fluciclovine metrics for patients with large BMs, demonstrating interval reduction in PET metrics after SSRS, more than anatomical measurements alone, highlighting the potential of this as an imaging biomarker.

Information fusion for fully automated segmentation of head and neck tumors from PET and CT images.

PET/CT images combining anatomic and metabolic data provide complementary information that can improve clinical task performance. PET image segmentation algorithms exploiting the multi-modal information available are still lacking. Our study aimed to assess the performance of PET and CT image fusion for gross tumor volume (GTV) segmentations of head and neck cancers (HNCs) utilizing conventional, deep learning (DL), and output-level voting-based fusions. The current study is based on a total of 328 histologically confirmed HNCs from six different centers. The images were automatically cropped to a 200 × 200 head and neck region box, and CT and PET images were normalized for further processing. Eighteen conventional image-level fusions were implemented. In addition, a modified U2-Net architecture as DL fusion model baseline was used. Three different input, layer, and decision-level information fusions were used. Simultaneous truth and performance level estimation (STAPLE) and majority voting to merge different segmentation outputs (from PET and image-level and network-level fusions), that is, output-level information fusion (voting-based fusions) were employed. Different networks were trained in a 2D manner with a batch size of 64. Twenty percent of the dataset with stratification concerning the centers (20% in each center) were used for final result reporting. Different standard segmentation metrics and conventional PET metrics, such as SUV, were calculated. In single modalities, PET had a reasonable performance with a Dice score of 0.77±0.09, while CT did not perform acceptably and reached a Dice score of only 0.38±0.22. Conventional fusion algorithms obtained a Dice score range of [0.76-0.81] with guided-filter-based context enhancement (GFCE) at the low-end, and anisotropic diffusion and Karhunen-Loeve transform fusion (ADF), multi-resolution singular value decomposition (MSVD), and multi-level image decomposition based on latent low-rank representation (MDLatLRR) at the high-end. All DL fusion models achieved Dice scores of 0.80. Output-level voting-based models outperformed all other models, achieving superior results with a Dice score of 0.84 for Majority_ImgFus, Majority_All, and Majority_Fast. A mean error of almost zero was achieved for all fusions using SUVpeak , SUVmean and SUVmedian . PET/CT information fusion adds significant value to segmentation tasks, considerably outperforming PET-only and CT-only methods. In addition, both conventional image-level and DL fusions achieve competitive results. Meanwhile, output-level voting-based fusion using majority voting of several algorithms results in statistically significant improvements in the segmentation of HNC.

64Cu]Cu-DOTATATE PET metrics in the investigation of atherosclerotic inflammation in humans

PurposeThe aim of this study was to assess and compare the arterial uptake of the inflammatory macrophage targeting PET tracer [64Cu]Cu-DOTATATE in patients with no or known cardiovascular disease (CVD) to investigate potential differences in uptake. MethodsSeventy-nine patients who had undergone [64Cu]Cu-DOTATATE PET/CT imaging for neuroendocrine neoplasm disease were retrospectively allocated to three groups: controls with no known CVD risk factors (n = 22), patients with CVD risk factors (n = 24), or patients with known ischemic CVD (n = 33). Both maximum, mean of max and most-diseased segment (mds) standardized uptake value (SUV) and target-to-background ratio (TBR) uptake metrics were measured and reported for the carotid arteries and the aorta. To assess reproducibility between different reviewers, Bland–Altman plots were made. ResultsFor the carotid arteries, SUVmax (P = .03), SUVmds (0.05), TBRmax (P < .01), TBRmds (P < .01), and mean-of-max TBR (P = .01) were overall shown to provide a group-wise difference in uptake. When measuring uptake values in the aorta, a group-wise difference was only observed with TBRmds (P = .04). Overall, reproducibility of the reported uptake metrics was excellent for SUVs and good to excellent for TBRs for both the carotid arteries and the aorta. ConclusionUsing [64Cu]Cu-DOTATATE PET imaging as a marker of atherosclerotic inflammation, we were able to demonstrate differences in some of the most frequently reported uptake metrics in patients with different degrees of CVD. Measurements of the carotid artery as either maximum uptake values or most-diseased segment analysis showed the best ability to discriminate between the groups.