Metabolically Active Tumor Volume Research Articles

Reducing and controlling metabolic active tumor volume prior to CAR T-cell infusion can improve survival outcomes in patients with large B-cell lymphoma

Bridging therapy before CD19-directed chimeric antigen receptor (CAR) T-cell infusion is frequently applied in patients with relapsed or refractory Large B-cell lymphoma (r/r LBCL). This study aimed to assess the influence of quantified MATV and MATV-dynamics, between pre-apheresis (baseline) and pre-lymphodepleting chemotherapy (pre-LD) MATV, on CAR T-cell outcomes and toxicities in patients with r/r LBCL. MATVs were calculated semi-automatically at baseline (n = 74) and pre-LD (n = 68) in patients with r/r LBCL who received axicabtagene ciloleucel. At baseline, patients with a low MATV (< 190 cc) had a better time to progression (TTP) and overall survival (OS) compared to high MATV patients (p < 0.001). High MATV patients who remained stable or reduced upon bridging therapy showed a significant improvement in TTP (p = 0.041) and OS (p = 0.015), compared to patients with a high pre-LD MATV (> 480 cc). Furthermore, high MATV baseline was associated with severe cytokine release syndrome (CRS, p = 0.001). In conclusion, patients with low baseline MATV had the best TTP/OS and effective reduction or controlling MATV during bridging improved survival outcomes in patients with a high baseline MATV, providing rationale for the use of more aggressive bridging regimens.

Reduction of Metabolic Active Tumor Volume Prior to CAR T-Cell Therapy Improves Survival Outcomes in Patients with Large B-Cell Lymphoma

Introduction CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become the standard 2 nd or 3 rd line therapy for patients with relapsed or refractory Large B-cell lymphoma (r/r LBCL). As part of this treatment bridging therapy is frequently used between T-cell apheresis and CAR T-cell infusion in order to limit disease progression, diminish lymphoma-related symptoms and/or reduce tumor volume. Bridging therapy has shown to be feasible, safe and effective in patients prior to infusion. In addition, a lower tumor volume is associated with better treatment outcomes and less toxicity. However, the exact reduction and dynamics in metabolic active tumor volume (MATV) are unknown. Here we investigated the relation of changes in pre-apheresis (baseline) MATV, based on 18F-FDG PET scans, and pre-lymphodepleting chemotherapy (pre-LD) MATV with CAR T-cell outcomes and toxicities in patients with r/r LBCL. Methods Baseline and pre-LD MATVs and PET characteristics were calculated semi-automatically of patients who were treated with CAR T-cell therapy. A Standardized Uptake Value (SUV) threshold of 2.5 was used to maintain robustness and avoid MATV underestimation. Bridging strategies consisted of radiotherapy, chemotherapy, or a combination of both. Primary endpoints were duration of response (DOR) and overall survival (OS). Secondary endpoints included cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The Youden index was used to identify the optimal cut-off for dividing patients into low- and high-MATV groups to predict DOR at 2 years. Two-year DOR and OS rates were estimated using Kaplan-Meier curves and the log-rank test was utilized to compare the differences among low- and high-MATV patient groups. Univariable analysis was performed with Cox regression for DOR and OS, and with logistic regression for CRS and ICANS. Results Seventy-four patients with LBCL and treated with CAR T-cell therapy were included in the study. For all patients baseline 18F-FDG PET scans were available, whereof in 68 patients the pre-LD scans. The median baseline MATV was 180 cc (IQR 64 - 426) with a median SUV max of 18.8 (IQR 11.9 - 28.1) and increased to 241 cc (IQR 75 - 525) at pre-LD, with a median SUV max of 21.0 (IQR 12.8 - 31.3). The optimal cut-offs for low- and high-MATV patient groups at baseline and pre-LD were 190 cc and 480 cc, respectively. Patients with a low MATV baseline had a better DOR (Figure 1A) and OS compared to high MATV baseline patients (both p &amp;lt; 0.001). Patients with a high MATV baseline that was reduced to a low MATV pre-LD showed a significant improvement in DOR (Figure 1B) and OS, compared to patients with a high MATV pre-LD ( p = 0.036 for DOR; p = 0.015 for OS). Univariable analysis showed that a high baseline MATV was associated with a worse DOR (HR 6.43 CI [2.15 - 19.20]; p &amp;lt; 0.001) and OS (HR 6.97 CI [2.33 - 20.80]; p &amp;lt; 0.001). A high pre-LD MATV was also associated with a worse DOR (HR 4.86 CI [1.98 - 12.00]; p &amp;lt; 0.001) and OS (HR 5.87 [2.41 - 14.30]; p &amp;lt; 0.001). Other significant associations with DOR and OS were observed for pre-LD lactate dehydrogenase (LDH), the IPI score for DOR exclusively, and gender and bridging therapy for OS exclusively. Conclusions We showed that patients with a low MATV compared to a high MATV at baseline have better survival outcomes and less toxicity. Additionally, reducing tumor volume by applying bridging therapy in patients with a high baseline MATV, results in a significant better DOR and OS. Reducing the MATV before CAR T-cell infusion is therefore essential in CAR T-cell therapy patient care and provides a rationale for the use of more intensive bridging therapies.

Does consensus contours improve robustness and accuracy on ^{18}F-FDG PET imaging tumor delineation?

Purpose:The aim of this study is to explore the robustness and accuracy of consensus contours with 225 nasopharyngeal carcinoma (NPC) clinical cases and 13 extended cardio-torso simulated lung tumors (XCAT) based on 2-deoxy-2-[^{18}F]fluoro-D-glucose (^{18}F-FDG) PET imaging.Methods:Primary tumor segmentation was performed with two different initial masks on 225 NPC ^{18}F-FDG PET datasets and 13 XCAT simulations using methods of automatic segmentation with active contour, affinity propagation (AP), contrast-oriented thresholding (ST), and 41% maximum tumor value (41MAX), respectively. Consensus contours (ConSeg) were subsequently generated based on the majority vote rule. The metabolically active tumor volume (MATV), relative volume error (RE), Dice similarity coefficient (DSC) and their respective test–retest (TRT) metrics between different masks were adopted to analyze the results quantitatively. The nonparametric Friedman and post hoc Wilcoxon tests with Bonferroni adjustment for multiple comparisons were performed with P< 0.05 considered to be significant.Results:AP presented the highest variability for MATV in different masks, and ConSeg presented much better TRT performances in MATV compared with AP, and slightly poorer TRT in MATV compared with ST or 41MAXin most cases. Similar trends were also found in RE and DSC with the simulated data. The average of four segmentation results (AveSeg) showed better or comparable results in accuracy for most cases with respect to ConSeg. AP, AveSeg and ConSeg presented better RE and DSC in irregular masks as compared with rectangle masks. Additionally, all methods underestimated the tumour boundaries in relation to the ground truth for XCAT including respiratory motion.Conclusions:The consensus method could be a robust approach to alleviate segmentation variabilities, but did not seem to improve the accuracy of segmentation results on average. Irregular initial masks might be at least in some cases attributable to mitigate the segmentation variability as well.

Semi-automated 18F-FDG PET segmentation methods for tumor volume determination in Non-Hodgkin lymphoma patients: a literature review, implementation and multi-threshold evaluation

In the treatment of Non-Hodgkin lymphoma (NHL), multiple therapeutic options are available. Improving outcome predictions are essential to optimize treatment. The metabolic active tumor volume (MATV) has shown to be a prognostic factor in NHL. It is usually retrieved using semi-automated thresholding methods based on standardized uptake values (SUV), calculated from 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG PET) images. However, there is currently no consensus method for NHL. The aim of this study was to review literature on different segmentation methods used, and to evaluate selected methods by using an in house created software tool.A software tool, MUltiple SUV Threshold (MUST)-segmenter was developed where tumor locations are identified by placing seed-points on the PET images, followed by subsequent region growing. Based on a literature review, 9 SUV thresholding methods were selected and MATVs were extracted. The MUST-segmenter was utilized in a cohort of 68 patients with NHL. Differences in MATVs were assessed with paired t-tests, and correlations and distributions figures.High variability and significant differences between the MATVs based on different segmentation methods (p < 0.05) were observed in the NHL patients. Median MATVs ranged from 35 to 211 cc.No consensus for determining MATV is available based on the literature. Using the MUST-segmenter with 9 selected SUV thresholding methods, we demonstrated a large and significant variation in MATVs. Identifying the most optimal segmentation method for patients with NHL is essential to further improve predictions of toxicity, response, and treatment outcomes, which can be facilitated by the MUST-segmenter.

Early Response Prediction of Multiparametric Functional MRI and 18F-FDG-PET in Patients with Head and Neck Squamous Cell Carcinoma Treated with (Chemo)Radiation.

Simple SummaryPatients with locally-advanced head and neck squamous cell carcinoma (HNSCC) have variable responses to (chemo)radiotherapy. A reliable early prediction of outcomes allows for enhancing treatment efficacy and follow-up monitoring. Early tumoral changes can be captured by functional imaging (DWI/IVIM/DCE/18F-FDG-PET-CT) parameters, which allow for the construction of accurate patient-specific prognostic models for locoregional recurrence-free survival, distant metastasis-free survival and overall survival. We also present clinical applicable risk stratification in high/medium/low risks for these patient outcomes. This can enable personalized treatment (adaptation) management early on during treatment, improve counseling and enhance patient-specific post-therapy monitoring.Background: Patients with locally-advanced head and neck squamous cell carcinoma (HNSCC) have variable responses to (chemo)radiotherapy. A reliable prediction of outcomes allows for enhancing treatment efficacy and follow-up monitoring. Methods: Fifty-seven histopathologically-proven HNSCC patients with curative (chemo)radiotherapy were prospectively included. All patients had an MRI (DW,-IVIM, DCE-MRI) and 18F-FDG-PET/CT before and 10 days after start-treatment (intratreatment). Primary tumor functional imaging parameters were extracted. Univariate and multivariate analysis were performed to construct prognostic models and risk stratification for 2 year locoregional recurrence-free survival (LRFFS), distant metastasis-free survival (DMFS) and overall survival (OS). Model performance was measured by the cross-validated area under the receiver operating characteristic curve (AUC). Results: The best LRFFS model contained the pretreatment imaging parameters ADC_kurtosis, Kep and SUV_peak, and intratreatment imaging parameters change (Δ) Δ-ADC_skewness, Δ-f, Δ-SUV_peak and Δ-total lesion glycolysis (TLG) (AUC = 0.81). Clinical parameters did not enhance LRFFS prediction. The best DMFS model contained pretreatment ADC_kurtosis and SUV_peak (AUC = 0.88). The best OS model contained gender, HPV-status, N-stage, pretreatment ADC_skewness, D, f, metabolic-active tumor volume (MATV), SUV_mean and SUV_peak (AUC = 0.82). Risk stratification in high/medium/low risk was significantly prognostic for LRFFS (p = 0.002), DMFS (p < 0.001) and OS (p = 0.003). Conclusions: Intratreatment functional imaging parameters capture early tumoral changes that only provide prognostic information regarding LRFFS. The best LRFFS model consisted of pretreatment, intratreatment and Δ functional imaging parameters; the DMFS model consisted of only pretreatment functional imaging parameters, and the OS model consisted ofHPV-status, gender and only pretreatment functional imaging parameters. Accurate clinically applicable risk stratification calculators can enable personalized treatment (adaptation) management, early on during treatment, improve counseling and enhance patient-specific post-therapy monitoring.

Metabolic active tumour volume quantified on [18F]FDG PET/CT further stratifies TNM stage IV non-small cell lung cancer patients.

This study aimed to assess whether the whole body metabolic active tumour volume (MTVWB), quantified on staging [18F]FDG PET/CT, could further stratify stage IV non-small cell lung cancer (NSCLC) patients. A group of 160 stage IV NSCLC patients, submitted to staging [18F]FDG PET/CT between July 2010 and May 2020, were retrospectively evaluated. MTVWB was quantified. Univariate and multivariate Cox regressions were carried out to assess correlation with overall survival (OS). C-statistic was used to test predictive power. Kaplan-Meier survival curves with Log-Rank tests were performed to compute statistical differences between strata from dichotomized variables and to calculate the estimated mean survival times (EMST). Survival rates at 1 and 5 years were calculated. MTVWB was a statistically significant predictor of OS on univariate (p < 0.0001) and multivariate analyses (p < 0.0001). The multivariate model with MTVWB (Cindex ± SE = 0.657 ± 0.024) worked significantly better as an OS predictor than the cTNM model (Cindex ± SE = 0.544 ± 0.028) (p = 0.003). An EMST of 29.207 ± 3.627(95% CI 22.099-36.316) months and an EMST of 10.904 ± 1.171(95% CI 8.609-13.199) months (Log-Rank p < 0.0001) were determined for patients with MTVWB < 104.3 and MTVWB ≥ 104.3, respectively. In subsamples of stage IVA (cut-off point = 114.5) and IVB patients (cut-off point = 191.1), statistically significant differences between EMST were also reported, with p-values of 0.0001 and 0.0002, respectively. In both substages and in the entire cohort, patients with MTVWB ≥ cut-off points had lower EMST and survival rates. Baseline MTVWB, measured on staging [18F]FDG PET/CT, further stratifies stage IV NSCLC patients. This parameter is an independent predictor of OS and provides valuable prognostic information over the 8th edition of cTNM staging.

PET-Derived Tumor Metrics Predict DLBCL Response and Progression-Free Survival

Background:Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoid malignancy with heterogeneous clinical outcomes following treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). [18F] fluorodeoxyglucose (FDG) - positron emission tomography (PET)/computed tomography (CT) imaging is routinely used in staging and response assessment for DLBCL at diagnosis and after treatment. However, the prognostic value of PET during treatment (interim) and of PET-derived metrics measuring tumor burden and metabolism remains unresolved. Such PET-derived metrics include tumor maximum standardized uptake value (SUV); metabolically active tumor volume (MTV), calculated as the total volume of tumor with FDG uptake; and total lesion glycolysis (TLG), the sum of tumor volume weighted by the intensity of FDG uptake. We investigated the predictive value of pre-treatment, interim and end-of-treatment (EOT) MTV and TLG on progression-free survival at 24 months (PFS24) in patients with DLBCL treated with R-CHOP.Methods:Patients with DLBCL treated at Emory University between 2005-2016 were eligible. Cases were included if there was a diagnosis of DLBCL confirmed by record review, available information on date of diagnosis, date of last contact or date of death. Analyses were restricted to patients who received R-CHOP and had PET/CT scans available before, during, and after treatment. Maximum SUV, MTV, and TLG were calculated using MIM software for tumor with an SUV threshold > 4. Univariate analysis was used to examine the relationship between interim MTV and post-treatment MTV, DLBCL subtype (classified as either germinal center B-cell (GCB) or non-GCB by the Hans algorithm), and LDH (defined as high > 200 or low < 200) at time of diagnosis. Logistic regression was used to examine the predictive value of pre-treatment and interim MTV on EOT PET results as well as the relationship between LDH and pretreatment MTV. Cox proportional hazard models were used to estimate PFS24 hazard ratios (HR) and 95% confidence intervals (CI) for positive pre-treatment MTV, interim MTV, EOT MTV, subtype and LDH at diagnosis.Results:Pre-treatment PET/CT scans for 55 patients were identified. The mean pre-treatment MTV was 304 ml (range 4.26 - 1,488 ml) and mean TLG was 3068 ml*SUVbw (range 24.48 - 16,180 ml*SUVbw). The mean pre-treatment MTV was 261 ml (range 4.26 - 1,327 ml) and mean TLG was 2033.768 ml*SUVbw (range 24.48-8,783 ml*SUVbw) for GCB DLBCL and were 383 ml (range 12.82 - 1,488 ml) and 4344.058 ml*SUVbw (range 85.29 - 16,180 ml*SUVbw) for non-GCB DLBCL, respectively. MTV and TLG were undetectable in 79% of interim scans and 74% of post-treatment scans. Receiver operating characteristic curve analysis determined optimal cutoffs of pre-treatment MTV at 121 ml, interim MTV at 0 ml and EOT MTV at 4.68 ml for predicting PFS. Elevated LDH was strongly associated with a high pre-treatment MTV (p = 0.0006). Controlling for pre-treatment MTV, a positive interim MTV was highly correlated with (0.86) and a significant predictor of a positive EOT MTV (p = 0.03). Interim MTV > 0 (HR 5.51, CI 1.13, 26.79) and EOT MTV > 4.68 (HR 10.75, CI 1.31, 105.48) were significant predictors of PFS24, controlling for pre-treatment MTV.Conclusions:PET-derived metrics of pre-treatment and interim MTV offer significant predictive value for end of treatment response and progression-free survival, and can guide future response-adapted treatment approaches for DLBCL patients that build on the R-CHOP backbone. Interim and EOT MTV provide value in DLBCL risk stratification and can be incorporated into new integrative prognostic models. Larger outcomes studies based on secondary analyses of clinical trials data or large observational cohort studies are needed to confirm these findings. [Display omitted] DisclosuresFlowers:Clinical Care Options: Research Funding; V Foundation: Research Funding; Burroughs Welcome Fund: Research Funding; Janssen Pharmaceutical: Research Funding; Educational Concepts: Research Funding; Acerta: Research Funding; Gilead: Consultancy; Seattle Genetics: Consultancy; Research to Practice: Research Funding; Prime Oncology: Research Funding; Bayer: Consultancy; Pharmacyclics LLC, an AbbVie Company: Research Funding; National Cancer Institute: Research Funding; National Institutes Of Health: Research Funding; OptumRx: Consultancy; Millennium/Takeda: Research Funding; Abbvie: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Research Funding; Infinity: Research Funding; Spectrum: Consultancy; Genentech/Roche: Consultancy, Research Funding; TG Therapeutics: Research Funding; Eastern Cooperative Oncology Group: Research Funding.

Assessing immune organs on 18F-FDG PET/CT imaging for therapy monitoring of immune checkpoint inhibitors: inter-observer variability, prognostic value and evolution during the treatment course of melanoma patients.

Immune checkpoint inhibitors (ICIs) have significantly improved survival in advanced melanoma. There is a need for robust biomarkers to identify patients who do not respond. We analysed 14 baseline 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) metrics and their evolution to assess their correlation with patient outcome, compared with 7 established biological markers and 7 clinical variables. We conducted a retrospective monocentric observational study of 29 patients with advanced melanoma who underwent baseline 18F-FDG PET/CT, followed by an early monitoring PET/CT (iPET) scan after 1 month of treatment and follow-up studies at 3rd (M3PET) and 6th month (M6PET). 18F-FDG uptake in immune organs (spleen, bone marrow, ileocecal valve) and derived spleen-to-liver (SLR) and bone-to-liver (BLR) ratios were reviewed by two PET readers for reproducibility analysis purposes including 14 PET variables. The most reproducible indexes were used for evaluation as predictors of overall survival (OS) in comparison with PET response using imPERCIST5, whole-body metabolic active tumour volume (WB-MATV) and biological parameters (lactate dehydrogenases (LDH), reactive protein c (CRP), white blood count (WBC), absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR) and derived neutrophils to lymphocyte ratio). Strong reproducibility's (intraclass coefficients of correlation (ICC) > 0.90) were observed for spleen anterior SUVpeak, spleen MV, spleen TLG, spleen length and BLRmean. ICC for SLRmean and ileocecal SUVmean were 0.86 and 0.65, respectively. In the 1-year OS 1 group, SLRmean tended to increase at each time point to reach a significant difference at M6-PET (p = 0.019). The same trends were observed with spleen SUVpeak anterior and spleen length. In the 1-year OS 0 group, a significative increase of spleen length was found at iPET, as compared with baseline PET (p = 0.014) and M3-PET (p = 0.0239). Univariable Kaplan-Meier survival analysis found that i%var spleen length, M3%var SLRmean, baseline LDH, i%var NLR and response at M6PET were all predictors of 1-year OS. SLRmean is recommended as a prognosticator in melanoma patients under immunotherapy: its increase greater than 25% at 3 months, compared with baseline, was associated with poor outcome after ICIs.

Repeatability of two semi-automatic artificial intelligence approaches for tumor segmentation in PET

BackgroundPositron emission tomography (PET) is routinely used for cancer staging and treatment follow-up. Metabolic active tumor volume (MATV) as well as total MATV (TMATV—including primary tumor, lymph nodes and metastasis) and/or total lesion glycolysis derived from PET images have been identified as prognostic factor or for the evaluation of treatment efficacy in cancer patients. To this end, a segmentation approach with high precision and repeatability is important. However, the implementation of a repeatable and accurate segmentation algorithm remains an ongoing challenge.MethodsIn this study, we compare two semi-automatic artificial intelligence (AI)-based segmentation methods with conventional semi-automatic segmentation approaches in terms of repeatability. One segmentation approach is based on a textural feature (TF) segmentation approach designed for accurate and repeatable segmentation of primary tumors and metastasis. Moreover, a convolutional neural network (CNN) is trained. The algorithms are trained, validated and tested using a lung cancer PET dataset. The segmentation accuracy of both segmentation approaches is compared using the Jaccard coefficient (JC). Additionally, the approaches are externally tested on a fully independent test–retest dataset. The repeatability of the methods is compared with those of two majority vote (MV2, MV3) approaches, 41%SUVMAX, and a SUV > 4 segmentation (SUV4). Repeatability is assessed with test–retest coefficients (TRT%) and intraclass correlation coefficient (ICC). An ICC > 0.9 was regarded as representing excellent repeatability.ResultsThe accuracy of the segmentations with the reference segmentation was good (JC median TF: 0.7, CNN: 0.73). Both segmentation approaches outperformed most other conventional segmentation methods in terms of test–retest coefficient (TRT% mean: TF: 13.0%, CNN: 13.9%, MV2: 14.1%, MV3: 28.1%, 41%SUVMAX: 28.1%, SUV4: 18.1%) and ICC (TF: 0.98, MV2: 0.97, CNN: 0.99, MV3: 0.73, SUV4: 0.81, and 41%SUVMAX: 0.68).ConclusionThe semi-automatic AI-based segmentation approaches used in this study provided better repeatability than conventional segmentation approaches. Moreover, both algorithms lead to accurate segmentations for both primary tumors as well as metastasis and are therefore good candidates for PET tumor segmentation.

Predicting tumor response and outcome of second-look surgery with 18F-FDG PET/CT: insights from the GINECO CHIVA phase II trial of neoadjuvant chemotherapy plus nintedanib in stage IIIc-IV FIGO ovarian cancer

BackgroundThis ancillary study aimed to evaluate 18F-FDG PET parameter changes after one cycle of treatment compared to baseline in patients receiving first-line neoadjuvant anti-angiogenic nintedanib combined to paclitaxel-carboplatin chemotherapy or chemotherapy plus placebo and to evaluate the ability of 18F-FDG PET parameters to predict progression-free survival (PFS), overall survival (OS), and success of second-look surgery.Materials and methodsCentral review was performed by two readers blinded to the received treatment and to the patients’ outcome, in consensus, by computing percentage change in PET metrics within a volume of interest encompassing the entire tumor burden. EORTC and PERCIST criteria were applied to classify patients as responders (partial metabolic response and complete metabolic response) or non-responders (stable metabolic disease and progressive metabolic disease). Also analyzed was the percentage change in metabolic active tumor volume (MATV) and total lesion glycolysis (TLG).ResultsTwenty-four patients were included in this ancillary study: 10 received chemotherapy + placebo and 14 chemotherapy + nintedanib. PERCIST and EORTC criteria showed similar discriminative power in predicting PSF and OS. Variation in MATV/TLG did not predict PFS or OS, and no optimal threshold could be found for MATV/TLG for predicting survival. Complete cytoreductive surgery (no residual disease versus residual disease < 0.25 cm/0.25–2.5 cm/> 2.5 cm) was more frequent in responders versus non-responders (P = 0.002 for PERCIST and P = 0.02 for EORTC criteria). No correlation was observed between the variation of PET data and the variation of CA-125 blood level between baseline sample and that performed contemporary to the interim PET, but a statistically significant correlation was observed between ΔSULpeak and ΔCA-125 between baseline sample and that performed after the second cycle.Conclusion18F-FDG PET using EORTC or PERCIST criteria appeared to be a useful tool in ovarian cancer trials to analyze early tumor response, and predict second-look surgery outcome and survival. An advantage of PERCIST is the correlation of ΔSULpeak and ΔCA-125, PET response preceding tumor markers response by 1 month. Neither MATV nor TLG was useful in predicting survival.Trial registrationNCT01583322 ARCAGY/ GINECO GROUP GINECO-OV119, 24 April 2012

Predictive value of quantitative 18F-FDG-PET radiomics analysis in patients with head and neck squamous cell carcinoma

BackgroundRadiomics is aimed at image-based tumor phenotyping, enabling application within clinical-decision-support-systems to improve diagnostic accuracy and allow for personalized treatment. The purpose was to identify predictive 18-fluor-fluoro-2-deoxyglucose (18F-FDG) positron-emission tomography (PET) radiomic features to predict recurrence, distant metastasis, and overall survival in patients with head and neck squamous cell carcinoma treated with chemoradiotherapy.MethodsBetween 2012 and 2018, 103 retrospectively (training cohort) and 71 consecutively included patients (validation cohort) underwent 18F-FDG-PET/CT imaging. The 434 extracted radiomic features were subjected, after redundancy filtering, to a projection resulting in outcome-independent meta-features (factors). Correlations between clinical, first-order 18F-FDG-PET parameters (e.g., SUVmean), and factors were assessed. Factors were combined with 18F-FDG-PET and clinical parameters in a multivariable survival regression and validated. A clinically applicable risk-stratification was constructed for patients’ outcome.ResultsBased on 124 retained radiomic features from 103 patients, 8 factors were constructed. Recurrence prediction was significantly most accurate by combining HPV-status, SUVmean, SUVpeak, factor 3 (histogram gradient and long-run-low-grey-level-emphasis), factor 4 (volume-difference, coarseness, and grey-level-non-uniformity), and factor 6 (histogram variation coefficient) (CI = 0.645). Distant metastasis prediction was most accurate assessing metabolic-active tumor volume (MATV)(CI = 0.627). Overall survival prediction was most accurate using HPV-status, SUVmean, SUVmax, factor 1 (least-axis-length, non-uniformity, high-dependence-of-high grey-levels), and factor 5 (aspherity, major-axis-length, inversed-compactness and, inversed-flatness) (CI = 0.764).ConclusionsCombining HPV-status, first-order 18F-FDG-PET parameters, and complementary radiomic factors was most accurate for time-to-event prediction. Predictive phenotype-specific tumor characteristics and interactions might be captured and retained using radiomic factors, which allows for personalized risk stratification and optimizing personalized cancer care.Trial registrationTrial NL3946 (NTR4111), local ethics commission reference: Prediction 2013.191 and 2016.498. Registered 7 August 2013, https://www.trialregister.nl/trial/3946

The association between active tumor volume, total lesion glycolysis and levels of S-100B and LDH in stage IV melanoma patients

IntroductionThe Standardized Uptake Value (SUV) in single lesions on 18F-FDG PET/CT scans and serum S-100B concentrations are inversely associated with disease-free survival in stage IV melanoma. The aim of this study was to assess the association between biomarkers (S-100B, LDH) and the PET-derived metrics SUVmean/max, metabolic active tumor volume (MATV), and total lesion glycolysis (TLG) in stage IV melanoma in order to understand what these biomarkers reflect and their possible utility for follow-up. MethodsIn 52 stage IV patients the association between PET-derived metrics and the biomarkers S-100B and LDH was assessed and the impact on survival analyzed. ResultsS-100B was elevated (>0.15 μg/l) in 37 patients (71%), LDH in 11 (21%). There was a correlation between S-100B and LDH (R2 = 0.19). S-100B was correlated to both MATV (R2 = 0.375) and TLG (R2 = 0.352), but LDH was not. Higher MATV and TLG levels were found in patients with elevated S-100B (p < 0.001) and also in patients with elevated LDH (>250 U/l) (p < 0.001). There was no association between the biomarkers and SUVmean/max. Survival analysis indicated that LDH was the only predictor of melanoma-specific survival. ConclusionIn newly diagnosed stage IV melanoma patients S-100B correlates with 18F-FDG PET/CT derived MATV and TLG in contrast to LDH, is more often elevated than LDH (71% vs. 21%) and seems to be a better predictor of disease load and disease progression. However, elevated LDH is the only predictor for survival. The biomarkers, S-100B and LDH appear to describe different aspects of the extent of metastatic disease and of tumornecrosis.

Heterogeneity in tumours: Validating the use of radiomic features on 18F-FDG PET/CT scans of lung cancer patients as a prognostic tool

AimThe aim was to validate promising radiomic features (RFs)1 on 18F-flourodeoxyglucose positron emission tomography/computed tomography-scans (18F-FDG PET/CT) of non-small cell lung cancer (NSCLC) patients undergoing definitive chemo-radiotherapy. Methods18F-FDG PET/CT scans performed for radiotherapy (RT) planning were retrieved. Auto-segmentation with visual adaption was used to define the primary tumour on PET images. Six pre-selected prognostic and reproducible PET texture -and shape-features were calculated using texture respectively shape analysis. The correlation between these RFs and metabolic active tumour volume (MTV)3, gross tumour volume (GTV)4 and maximum and mean of standardized uptake value (SUV)5 was tested with a Spearman's Rank test. The prognostic value of RFs was tested in a univariate cox regression analysis and a multivariate cox regression analysis with GTV, clinical stage and histology. P-value ≤ 0.05 were considered significant. ResultsImage analysis was performed for 233 patients: 145 males and 88 females, mean age of 65.7 and clinical stage II-IV. Mean GTV was 129.87 cm3 (SD 130.30 cm3). Texture and shape-features correlated more strongly to MTV and GTV compared to SUV-measurements. Four RFs predicted PFS in the univariate analysis. No RFs predicted PFS in the multivariate analysis, whereas GTV and clinical stage predicted PFS (p = 0.001 and p = 0.008 respectively). ConclusionThe pre-selected RFs were insignificant in predicting PFS in combination with GTV, clinical stage and histology. These results might be due to variations in technical parameters. However, it is relevant to question whether RFs are stable enough to provide clinically useful information.

5966Whole-vessel coronary 18F-sodium fluoride coronary microcalfication activity is associated with Low density plaque

Abstract Background 18F-sodium fluoride (18F-NaF) showed promise in imaging vulnerable coronary plaques. To date reporting of the highest per patient target to background ratio (TBR), total number of lesions with visual uptake and whole-heart tracer activity have been proposed. Unfortunately, each of these approaches has limitations which become especially prominent in patients with multiple foci of uptake, where reproducible global per-vessel measures are required. In oncology, the total metabolic active tumor volume has been found to be a significant prognostic factor for disease progression, recurrence and death. We evaluated if such methodology could be applied to coronary PET imaging. Purpose To quantify whole-vessel coronary 18F-NaF PET activity by utilizing automatically derived coronary vessel regions of interest (ROI) from CT angiography and assess the relationship between coronary microcalcification activity (CMA) and per vessel quantitative plaque characteristics on coronary CT angiography (CTA). Methods Twenty patients (68±6 years old, 70% males) with multivessel coronary artery disease underwent a 30 min single bed position PET 1h after a 250mB injection of 18F-NaF and CTA on a hybrid PET/CT scanner. We assessed coronary 18F-NaF uptake using novel whole-vessel tubular and tortuous 3D ROIs which were automatically extracted from CTA datasets. Within such ROIs we measured mean standard uptake value (SUV), maximum TBR (TBRmax) and the activity of voxels (CMA) above 1.25 the background SUV (left atrium activity). We used a previously established 1.25 TBRmax threshold to distinguish vessels positive and negative for 18F-NaF uptake. Coronary CTA datasets were analyzed by semi-automated software to quantify volumes and percentage lesion content of non-calcified plaque (NCP), low-density non-calcified plaque (LD-NCP, attenuation &lt;30 Hounsfield units) and calcified plaque (CP). Results 13 (65%) patients and 24 (40%) out of 60 main epicardial vessels presented with 18F-NaF uptake exceeding the 1.25 TBRmax threshold. While coronaries positive for uptake had higher CMA 0.92 [0.17, 2.03] vs 0.0, p&lt;0.001 and TBRmax 1.42 [1.35, 1.74] vs 1.09 [1.0, 1.19], there was no difference in whole-vessel SUVmean 0.90 [0.77, 1.17] vs 0.87 [0.78, 0.96], p=0.33 compared to 18F-NaF negative arteries. Of the quantitative plaque characteristics vessels positive for uptake had higher NCP 278.4 [145.6, 576.9] vs 184.6 [63.8, 367.0]mm3, p=0.030; and LD-NCP 8.4 [0.3, 11.0] vs 2.7 [12.1, 43.5]mm3, p=0.01. CMA showed a stronger correlation with LD-NCP (r=0.70, p&lt;0.001) than TBRmax (r=0.52, p&lt;0.001). On regression analysis LD-NCP acted as an independent predictor of CMA after adjustments for CP and vessel SUVmean (p&lt;0.001). Figure 1 Conclusions Whole-vessel 18F-NaF coronary microcalcification activity assessment with CT angiography automatically derived 3-dimensional ROIs is feasible and the measured coronary microcalcification burden correlates well with low density plaque. Acknowledgement/Funding This research was supported by grants R01HL135557 and R01HL133616 from the NHLBI/NIH and a grant from the Dr. Miriam &amp; Sheldon G. Adelson MRF

Comprehensive analysis of the influence of G-CSF on the biodistribution of 18F-FDG in lymphoma patients: insights for PET/CT scheduling

Aims(1) To perform a comprehensive analysis of the time elapsed between the last G-CSF injection and the PET/CT examination on the biodistribution of 18F-FDG, with emphasis on liver, spleen, and bone marrow uptake, and (2) to investigate whether an inversion of the liver to spleen ratio affects the Deauville scoring.Materials and methodsRetrospectively included were 74 consecutive diffuse large B cell lymphoma (DLBCL) patients referred for baseline and interim examinations and receiving immunochemotherapy with various G-CSF regimens. A comprehensive evaluation considering baseline metabolic active tumour volume (MATV), factors affecting liver uptake, the type of G-CSF, and the time elapsed between chemotherapy/G-CSF and interim PET/CTs was performed.ResultsMean (± SD) percentage variations between baseline and interim PET/CTs (i-PET/CT) for bone marrow (%Variation_BONE), liver (%Variation_LIVER) and spleen (%Variation_SPLEEN) were equal to 32.0 ± 46.9%, 16.1 ± 42.8%, and 10.6 ± 51.1 %, respectively. %Variation_LIVER and %Variation_SPLEEN were higher in patients using lenograstim, but this was linked to lower uptakes at baseline and was therefore likely not due to G-CSF itself. The mean delay between G-CSF injection and i-PET/CT acquisition was not an independent explanatory variable for %Variation_BONE, %Variation_LIVER, and %Variation_SPLEEN. On the contrary, %Variation_BONE and %Variation_SPLEEN were negatively correlated to the time-lapse between the end of chemotherapy and i-PET/CT: ρ = − 0.342 (p = 0.010) and ρ = − 0.529 (p < 0.0001), respectively. Patients with a time-lapse since the last injection of chemotherapy < 17 days displayed higher bone and spleen SUVmaxEARL. %Variation_LIVER was positively correlated to baseline MATV: ρ = 0.243 (p = 0.039). Patients displaying a high baseline MATV ≥ 177 cc had significantly lower liver SUVmaxEARL at baseline. This difference was no longer observed at i-PET/CT, after tumours had shrunk.ConclusionsNeither the type of G-CSF used nor the time elapsed between its last injection and i-PET/CT examination independently influences bone, hepatic, or splenic uptakes at i-PET/CT. The major determinant for the occurrence of a bone or spleen hypermetabolism on i-PET/CT is the time elapsed between the chemotherapy and the examination, which should be maintained above 15 days. Inversion of the liver to spleen ratio appeared to be due to increased spleen hypermetabolism on i-PET/CT, making unlikely an impact on the Deauville scoring.

Development and validation of a prognostic score for overall survival integrating baseline metabolically active tumor volume measured by 18F-FDG PET/CT and clinical factors for metastatic colorectal cancer patients.

3543 Background: This study aimed to develop and validate a prognostic score integrating baseline metabolically active tumor volume (MATV) and clinical factors in metastatic colorectal cancer (mCRC) patients. Methods: The development cohort included chemorefractory mCRC patients enrolled in two prospective multicenter non-randomized trials evaluating sorafenib/regorafenib as last line therapy. The validation cohort included mCRC patients from another center, treated with chemotherapy and bevacizumab as first line. Baseline MATV was defined as the sum of metabolically active volumes of all target lesions identified on the baseline 18F-FDG PET/CT. MATV optimal cutoff for OS prediction was determined from the development cohort with Contal and O’Quigley’s method. MATV, age, gender, BMI, ECOG PS, years since diagnosis, and KRAS status were included in a multivariate analysis. A prognostic score to predict OS was developed from the development cohort using Cox proportional hazards model. Results: MATV and clinical factors were evaluable respectively in 155 and 122 patients of the development and validation cohorts. In univariate analysis, MATV with cutoff set at 100 cm³ identified two risk groups with different median OS (mOS) in both the development (4.5 vs 10.9 months, HR: 2.64; p &lt; 0.001) and validation cohorts (20.9 vs 42.9 months, HR: 2.39; p &lt; 0.001). A multivariate analysis identified four independent negative predictors of OS (high MATV, short time since diagnosis, poor PS, BMI &lt; 25). Combining these factors in a prognostic score for OS (best cutoff:-2) allowed to identify two risk groups with different mOS in the development (4.4 vs 13.4 months, HR: 3.67; p &lt; 0.001) and validation cohorts (25 vs 63.8 months, HR: 2.5; p = 0.001). Conclusions: In mCRC patients, the high prognostic value of baseline MATV found in the development cohort was confirmed by external validation, independently of patients’ treatment. In both the development and validation cohorts the prognostic score for OS allowed to identify two risk groups of mCRC patients with significantly different mOS. MATV and our prognostic score for OS should provide a firm basis for risk stratification, in clinical practice and research trials.

Tumour necrosis as assessed with 18F-FDG PET is a potential prognostic marker in diffuse large B cell lymphoma independent of MYC rearrangements

ObjectivesMYC gene rearrangements in diffuse large B cell lymphomas (DLBCLs) result in high proliferation rates and are associated with a poor prognosis. Strong proliferation is associated with high metabolic demand and tumour necrosis. The aim of this study was to investigate differences in the presence of necrosis and semiquantitative 18F-FDG PET metrics between DLBCL cases with or without a MYC rearrangement. The prognostic impact of necrosis and semiquantitative 18F-FDG PET parameters was investigated in an explorative survival analysis.MethodsFluorescence in situ hybridisation analysis for MYC rearrangements, visual assesment, semiquantitative analysis of 18F-FDG PET scans and patient survival analysis were performed in 61 DLBCL patients, treated at a single referral hospital between 2008 and 2015.ResultsOf 61 tumours, 21 (34%) had a MYC rearrangement (MYC+). MYC status was neither associated with the presence of necrosis on 18F-FDG PET scans (necrosisPET; p = 1.0) nor associated with the investigated semiquantitative parameters maximum standard uptake value (SUVmax; p = 0.43), single highest SUVmax (p = 0.49), metabolic active tumour volume (MATV; p = 0.68) or total lesion glycolysis (TLG; p = 0.62). A multivariate patient survival analysis of the entire cohort showed necrosisPET as an independent prognostic marker for disease-specific survival (DSS) (HR = 13.9; 95% CI 3.0–65; p = 0.001).ConclusionsMYC rearrangements in DLBCL have no influence on the visual parameter necrosisPET or the semi-quantiative parameters SUVmax, MATV and TLG. Irrespective of MYC rearrangements, necrosisPET is an independent, adverse prognostic factor for DSS.Key Points• Retrospective analysis indicates that MYC rearrangement is not associated with necrosis on18F-FDG PET (necrosisPET) scans or semiquantitative18F-FDG PET parameters.• NecrosisPETis a potential independent adverse prognostic factor for disease-specific survival in patients with DLBCL and is not influenced by the presence of MYC rearrangements.

Prognostic Value of 18F-Fluorocholine PET Parameters in Metastatic Castrate-Resistant Prostate Cancer Patients Treated with Docetaxel.

Background and Aim The availability of new treatments for metastatic castrate-resistant prostate cancer (mCRPC) patients increases the need for reliable biomarkers to help clinicians to choose the better sequence strategy. The aim of the present retrospective and observational work is to investigate the prognostic value of 18F-fluorocholine (18F-FCH) positron emission tomography (PET) parameters in mCRPC. Materials and Methods Between March 2013 and August 2016, 29 patients with mCRPC were included. They all received three-weekly docetaxel after androgen deprivation therapy, and they underwent 18F-FCH PET/computed tomography (CT) before and after the therapy. Semi-quantitative indices such as maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) with partial volume effect (PVC-SUV) correction, metabolically active tumour volume (MATV), and total lesion activity (TLA) with partial volume effect (PVC-TLA) correction were measured both in pre-treatment and post-treatment 18F-FCH PET/CT scans for each lesion. Whole-body indices were calculated as sum of values measured for each lesion (SSUVmax, SPVC-SUV, SMATV, and STLA). Progression-free survival (PFS) and overall survival (OS) were considered as clinical endpoints. Univariate and multivariate hazard ratios for whole-body 18F-FCH PET indices were performed, and p < 0.05 was considered as significant. Results Cox regression analysis showed a statistically significant correlation between PFS, SMATV, and STLA. No correlations between OS and 18F-FCH PET parameters were defined probably due to the small sample size. Conclusions Semi-quantitative indices such as SMATV and STLA at baseline have a prognostic role in patients treated with docetaxel for mCRPC, suggesting a potential role of 18F-FCH PET/CT imaging in clinical decision-making.

Impact of Tissue Classification in MRI-Guided Attenuation Correction on Whole-Body Patlak PET/MRI.

The aim of this work is to investigate the impact of tissue classification in magnetic resonance imaging (MRI)-guided positron emission tomography (PET) attenuation correction (AC) for whole-body (WB) Patlak net uptake rate constant (Ki) imaging in PET/MRI studies. WB dynamic PET/CT data were acquired for 14 patients. The CT images were utilized to generate attenuation maps (μ-mapCTAC) of continuous attenuation coefficient values (Acoeff). The μ-mapCTAC were then segmented into four tissue classes (μ-map4-classes), namely background (air), lung, fat, and soft tissue, where a predefined Acoeff was assigned to each class. To assess the impact of bone for AC, the bones in the μ-mapCTAC were then assigned a predefined soft tissue Acoeff (0.1cm-1) to produce an AC μ-map without bones (μ-mapno-bones). Thereafter, both WB static SUV and dynamic PET images were reconstructed using μ-mapCTAC, μ-map4-classes, and μ-mapno-bones (PETCTAC, PET4-classes, and PETno-bones), respectively. WB indirect and direct parametric Ki images were generated using Patlak graphical analysis. Malignant lesions were delineated on PET images with an automatic segmentation method that uses an active contour model (MASAC). Then, the quantitative metrics of the metabolically active tumor volume (MATV), target-to-background (TBR), contrast-to-noise ratio (CNR), peak region-of-interest (ROIpeak), maximum region-of-interest (ROImax), mean region-of-interest (ROImean), and metabolic volume product (MVP) were analyzed. The Wilcoxon test was conducted to assess the difference between PET4-classes and PETno-bones against PETCTAC for all images. The same test was also adopted to compare the differences between SUV, indirect Ki, and direct Ki images for each evaluated AC method. No significant differences in MATV, TBR, and CNR were observed between PET4-classes and PETCTAC for either SUV or Ki images. PET4-classes significantly overestimated ROIpeak, ROImax, ROImean, as well as MVP scores compared with PETCTAC in both SUV and Ki images. SUV images exhibited the highest median relative errors for PET4-classes with respect to PETCTAC (RE4-classes): 6.91%, 6.55%, 5.90%, and 6.56% for ROIpeak, ROImax, ROImean, and MVP, respectively. On the contrary, Ki images showed slightly reduced RE4-classes (indirect 5.52%, 5.95%, 4.43%, and 5.70%, direct 6.61%, 6.33%, 5.53%, and 4.96%) for ROIpeak, ROImax, ROImean, and MVP, respectively. A higher TBR was observed on indirect and direct Ki images relative to SUV, while direct Ki images demonstrated the highest CNR. Four-tissue class AC may impact SUV and Ki parameter estimation but only to a limited extent, thereby suggesting that WB Patlak Ki imaging for dynamic WB PET/MRI studies is feasible. Patlak Ki imaging can enhance TBR, thereby facilitating lesion segmentation and quantification. However, patient-specific Acoeff for each tissue class should be used when possible to address the high inter-patient variability of Acoeff distributions.

Repeatability of [18F]FDG PET/CT total metabolic active tumour volume and total tumour burden in NSCLC patients

BackgroundTotal metabolic active tumour volume (TMATV) and total tumour burden (TTB) are increasingly studied as prognostic and predictive factors in non-small cell lung cancer (NSCLC) patients. In this study, we investigated the repeatability of TMATV and TTB as function of uptake interval, positron emission tomography/computed tomography (PET/CT) image reconstruction settings, and lesion delineation method. We used six lesion delineation methods, four direct PET image-derived delineations and two based on a majority vote approach, i.e. intersection between two or more delineations (MV2) and between three or more delineations (MV3). To evaluate the accuracy of those methods, they were compared with a reference delineation obtained from the consensus of the segmentations performed by three experienced observers. Ten NSCLC patients underwent two baseline whole-body [18F]2-Fluoro-2-deoxy-2-D-glucose ([18F]FDG) PET/CT studies on separate days, within 3 days. Two scans were obtained on each day at 60 and 90 min post-injection to assess the influence of tracer uptake interval. PET/CT images were reconstructed following the European Association of Nuclear Medicine Research Ltd. (EARL) compliant settings and with point-spread-function (PSF) modelling. Repeatability between the measurements of each day was determined and the influence of uptake interval, reconstruction settings, and lesion delineation method was assessed using the generalized estimating equations model.ResultsBased on the Jaccard index with the reference delineation, the MV2 lesion delineation method was the most successful method for automated lesion segmentation. The best overall repeatability (lowest repeatability coefficient, RC) was found for TTB from 90 min of tracer uptake scans reconstructed with EARL compliant settings and delineated with 41% of lesion’s maximum SUV method (RC = 11%). In most cases, TMATV and TTB repeatability were not significantly affected by changes in tracer uptake time or reconstruction settings. However, some lesion delineation methods had significantly different repeatability when applied to the same images.ConclusionsThis study suggests that under some circumstances TMATV and TTB repeatability are significantly affected by the lesion delineation method used. Performing the delineation with a majority vote approach improves reliability and does not hamper repeatability, regardless of acquisition and reconstruction settings. It is therefore concluded that by using a majority vote based tumour segmentation approach, TMATV and TTB in NSCLC patients can be measured with high reliability and precision.