Metabolic Active Volume Research Articles

MRI and [18F]FET PET for early response assessment of Nivolumab and Bevacizumab in patients with recurrent high grade astrocytic glioma

Abstract Background In the present study early response assessment by O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) and contrast enhanced magnetic resonance imaging (MRI) were investigated in a phase II open-label single-centre study of nivolumab plus bevacizumab for recurrent high grade astrocytic glioma Methods Twenty patients with non-resectable first recurrence of high grade astrocytic glioma after EORTC/NCIC protocol underwent [18F]FET PET/MRI at baseline and after 2 cycles of treatment. Whole brain values of contrast enhancing volume on MRI (CEV), of mean (TBRmean) and maximal tumour-to-background ratio (TBRmax) and of metabolically active volume (MTV) on [18F]FET PET were obtained. Regional changes in [18F]FET uptake were assessed by parametric response mapping (PRM). Prediction of overall survival (OS) and response (OS>11 months) were assessed by Cox and receiver operating characteristic (ROC) analysis, respectively. Also, MRI (RANO 2.0) and PET based (PET RANO 1.0) response assessment criteria were compared. Results In ROC analysis responders were separated (p<0.05) from non-responders by lower MTV at follow-up (AUC 0.771, cut-off 18.3 ml), larger decrease in MTV (AUC 0.757, cut-off -5.3 ml), larger decrease in both TBRmax (AUC 0.814, cut-off -0.53) and relative TBRmax (AUC 0.829, cut-off -11%) and smaller PRM progressive volume (AUC 0.843, cut-off 4.0 ml). Change in CEV did not predict response. RANO 2.0 and PET RANO response assessment criteria had similar and only borderline prognostic value. Conclusion The study indicates that [18F]FET PET is superior to contrast enhanced MRI for early response assessment in patients with recurrent high grade astrocytic glioma treated with nivolumab and bevacizumab.

Baseline FDG PET/CT in free breathing versus deep inspiration breath-hold for pediatric patients with mediastinal lymphoma

Introduction The prospective TEDDI protocol investigates the feasibility of radiotherapy delivery in deep inspiration breath-hold (DIBH) for pediatric patients. To secure optimal radiotherapy planning, a diagnostic baseline FDG PET/CT in free breathing (FB) and DIBH was acquired. The anatomical changes in the mediastinum and the effect on PET metrics between the two breathing conditions were assessed for pediatric patients with mediastinal lymphoma. Material and methods Ten patients aged 5–17 were included and had a PET/CT in FB and DIBH. Metabolic active lymphoma volumes were manually delineated with a visually based segmentation method and the PET metrics were extracted. The anatomical lymphoma, lung and heart volumes were delineated on CT. Results The lung volume increased while the heart was displaced caudally and separated from the lymphoma in DIBH compared to FB. Both the anatomical and the metabolically active lymphoma volumes appeared different regarding shape and configuration in the two breathing conditions. The image quality of the DIBH PET was equal to the FB PET regarding interpretation and delineation of lymphoma lesions. All PET metrics increased on the DIBH PET compared to the FB PET with the highest increase observed for the maximum standardized uptake value (33%, range 7–56%). Conclusion Diminished respiratory motion together with anatomical changes within the lymphoma increased all PET metrics in DIBH compared to FB. The anatomical changes observed in DIBH compared to FB are expected to reduce radiation doses to the heart and lungs in pediatric patients with mediastinal lymphoma referred for radiotherapy delivery in DIBH and, thereby, reduce their risk of late effects. Trial registration The Danish Ethical Committee (H-16035870, approved November 24th 2016), the Danish Data Protection Agency (2012-58-0004, approved 1 January 2017). Registered retrospectively at clinicaltrials.gov (NCT03315546, 20 October 2017).

Assessing the effects of body weight on subchondral bone formation with quantitative 18F-sodium fluoride PET.

The aim of this study was to quantify subchondral bone remodeling in the elbows, hands, knees, and feet using volumetric and metabolic parameters derived from 18F-sodium fluoride positron emission tomography (NaF-PET) and to assess the convergent validity of these parameters as an index of joint degeneration and preclinical osteoarthritis. A retrospective analysis was conducted in 34 subjects (32 males, 2 females) with metastatic bone disease who underwent full-body NaF-PET/CT scans. An adaptive contrast-oriented thresholding algorithm was applied to segment NaF-avid regions in the bilateral elbows, hands, knees, and feet of each subject, and metabolically active volume (MAV), maximum standardized uptake value (SUVmax), mean metabolic volumetric product (MVPmean), and partial volume-corrected MVPmean (cMVPmean) of the segmented regions were calculated. Global parameters for MAV, SUVmax, MVPmean, and cMVPmean were defined as the sum of the corresponding values in all the joints of a subject. Inter-rater reliability was determined with Lin's concordance correlation, and associations of global values with subject body weight and age were assessed with Pearson correlation and Spearman correlation analyses. Inter-rater reliability was observed to be the highest in SUVmax (ρc = 0.99), followed by MVPmean (ρc = 0.96), cMVPmean (ρc = 0.93), and MAV (ρc = 0.93). MAV, MVPmean, and cMVPmean were observed to significantly increase with weight (all p < 0.0001) determined by Pearson correlation. In addition, Spearman rank-order analysis demonstrated a significant correlation between SUVmax and weight in addition to MAV, MVPmean, and cMVPmean and weight (all p < 0.01). No significant association between age and any PET parameter was observed. These preliminary data demonstrate the feasibility and reliability of assessing bone turnover at the joints using quantitative NaF-PET. Our findings corroborate the fact that biomechanical factors including mechanical loading and weight-bearing are contributors to osteoarthritis disease progression.

Noise reduction using a Bayesian penalized-likelihood reconstruction algorithm on a time-of-flight PET-CT scanner

PurposeQ.Clear is a block sequential regularized expectation maximization (BSREM) penalized-likelihood reconstruction algorithm for PET. It tries to improve image quality by controlling noise amplification during image reconstruction. In this study, the noise properties of this BSREM were compared to the ordered-subset expectation maximization (OSEM) algorithm for both phantom and patient data acquired on a state-of-the-art PET/CT.MethodsThe NEMA IQ phantom and a whole-body patient study were acquired on a GE DMI 3-rings system in list mode and different datasets with varying noise levels were generated. Phantom data was evaluated using four different contrast ratios. These were reconstructed using BSREM with different β-factors of 300–3000 and with a clinical setting used for OSEM including point spread function (PSF) and time-of-flight (TOF) information. Contrast recovery (CR), background noise levels (coefficient of variation, COV), and contrast-to-noise ratio (CNR) were used to determine the performance in the phantom data. Findings based on the phantom data were compared with clinical data. For the patient study, the SUV ratio, metabolic active tumor volumes (MATVs), and the signal-to-noise ratio (SNR) were evaluated using the liver as the background region.ResultsBased on the phantom data for the same count statistics, BSREM resulted in higher CR and CNR and lower COV than OSEM. The CR of OSEM matches to the CR of BSREM with β = 750 at high count statistics for 8:1. A similar trend was observed for the ratios 6:1 and 4:1. A dependence on sphere size, counting statistics, and contrast ratio was confirmed by the CNR of the ratio 2:1. BSREM with β = 750 for 2.5 and 1.0 min acquisition has comparable COV to the 10 and 5.0 min acquisitions using OSEM. This resulted in a noise reduction by a factor of 2–4 when using BSREM instead of OSEM. For the patient data, a similar trend was observed, and SNR was reduced by at least a factor of 2 while preserving contrast.ConclusionThe BSREM reconstruction algorithm allowed a noise reduction without a loss of contrast by a factor of 2–4 compared to OSEM reconstructions for all data evaluated. This reduction can be used to lower the injected dose or shorten the acquisition time.

Correlations between the metabolic profile and 18F-FDG-Positron Emission Tomography-Computed Tomography parameters reveal the complexity of the metabolic reprogramming within lung cancer patients

Several studies have demonstrated that the metabolite composition of plasma may indicate the presence of lung cancer. The metabolism of cancer is characterized by an enhanced glucose uptake and glycolysis which is exploited by 18F-FDG positron emission tomography (PET) in the work-up and management of cancer. This study aims to explore relationships between 1H-NMR spectroscopy derived plasma metabolite concentrations and the uptake of labeled glucose (18F-FDG) in lung cancer tissue. PET parameters of interest are standard maximal uptake values (SUVmax), total body metabolic active tumor volumes (MATVWTB) and total body total lesion glycolysis (TLGWTB) values. Patients with high values of these parameters have higher plasma concentrations of N-acetylated glycoproteins which suggest an upregulation of the hexosamines biosynthesis. High MATVWTB and TLGWTB values are associated with higher concentrations of glucose, glycerol, N-acetylated glycoproteins, threonine, aspartate and valine and lower levels of sphingomyelins and phosphatidylcholines appearing at the surface of lipoproteins. These higher concentrations of glucose and non-carbohydrate glucose precursors such as amino acids and glycerol suggests involvement of the gluconeogenesis pathway. The lower plasma concentration of those phospholipids points to a higher need for membrane synthesis. Our results indicate that the metabolic reprogramming in cancer is more complex than the initially described Warburg effect.

Axillary lymph-node metabolic activity assessment on 18F-FDG-PET/CT in rheumatoid arthritis patients treated with biologic therapies

Objective: Recent studies have provided new insights into the role of lymph nodes (LNs) in rheumatoid arthritis (RA). The aim of this study was to evaluate the metabolic activity of the axillary LNs in relation to that of the upper limb joints and the clinical assessment of disease activity in RA patients treated with biologic therapies.Method: 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) scans were acquired for 64 patients with RA at baseline and after 6 months of biologic therapy, and the patients’ clinical status was evaluated. The maximum standardized uptake value (SUVmax), metabolic active volume, and total lesion glycolysis (TLG) were used to assess glucose metabolism in the LNs and 12 joints. Clinical evaluations included serum markers and the Disease Activity Score based on 28-joint count–erythrocyte sedimentation rate (DAS28-ESR).Results: Changes in the SUVmax and TLG for the axillary LNs correlated significantly with those of the ipsilateral wrist joints. There was a positive correlation between the changes in the three metabolic parameters of the axillary LNs and the changes in disease activity after treatment. After 6 months of biologic therapy, all metabolic parameters for the axillary LNs in patients with a DAS28-ESR < 3.2 were significantly lower than those of patients with a DAS28-ESR ≥ 3.2.Conclusion: A relationship between the glucose metabolism of the axillary LNs and the ipsilateral wrist joints was demonstrated by the 18F-FDG-PET/CT parameters. The metabolic activity and active volume of axillary LNs may reflect the therapeutic response to the biologic treatment of RA.

Noninvasive assessment and quantification of tumor vascularization using [18F]FDG-PET/CT and CE-CT in a tumor model with modifiable angiogenesis\u2014an animal experimental prospective cohort study

BackgroundThis study investigated the noninvasive assessment of tumor vascularization with clinical F-18-fluorodeoxyglucose positron emission tomography/computed tomography and contrast-enhanced computed tomography ([18F]FDG-PET/CT and CE-CT) in experimental human xenograft tumors with modifiable vascularization and compared results to histology. Tumor xenografts with modifiable vascularization were established in 71 athymic nude rats by subcutaneous transplantation of human non-small-cell lung cancer (NSCLC) cells. Four different groups were transplanted with two different tumor cell lines (either A549 or H1299) alone or tumors co-transplanted with rat glomerular endothelial (RGE) cells, the latter to increase vascularization. Tumors were assessed noninvasively by [18F]FDG PET/CT and contrast-enhanced CT (CE-CT) using clinical scanners. This was followed by histological examinations evaluating tumor vasculature (CD-31 and intravascular fluorescent beads).ResultsIn both tumor lines (A549 and H1299), co-transplantation of RGE cells resulted in faster growth rates [maximal tumor diameter of 20 mm after 22 (± 1.2) as compared to 45 (± 1.8) days, p < 0.001], higher microvessel density (MVD) determined histologically after CD-31 staining [171.4 (± 18.9) as compared to 110.8 (± 11) vessels per mm2, p = 0.002], and higher perfusion as indicated by the number of beads [1.3 (± 0.1) as compared to 1.1 (± 0.04) beads per field of view, p = 0.001]. In [18F]FDG-PET/CT, co-transplanted tumors revealed significantly higher standardized uptake values [SUVmax, 2.8 (± 0.2) as compared to 1.1 (± 0.1), p < 0.001] and larger metabolic active volumes [2.4 (± 0.2) as compared to 0.4 (± 0.2) cm3, p < 0.001] than non-co-transplanted tumors. There were significant correlations for vascularization parameters derived from histology and [18F]FDG PET/CT [beads and SUVmax, r = 0.353, p = 0.005; CD-31 and SUVmax, r = 0.294, p = 0.036] as well as between CE-CT and [18F]FDG PET/CT [contrast enhancement and SUVmax, r = 0.63, p < 0.001; vital CT tumor volume and metabolic PET tumor volume, r = 0.919, p < 0.001].ConclusionsIn this study, a human xenograft tumor model with modifiable vascularization implementable for imaging, pharmacological, and radiation therapy studies was successfully established. Both [18F]FDG-PET/CT and CE-CT are capable to detect parameters closely connected to the degree of tumor vascularization, thus they can help to evaluate vascularization in tumors noninvasively. [18F]FDG-PET may be considered for characterization of tumors beyond pure glucose metabolism and have much greater contribution to diagnostics in oncology.

Confirmation of the prognostic value of pretherapeutic tumor SUR and MTV in patients with esophageal squamous cell carcinoma.

The prognosis for patients with inoperable esophageal carcinoma is still poor and the reliability of individual therapy outcome prediction based on clinical parameters is not convincing. In a recent publication, we were able to show that PET can provide independent prognostic information in such a patient group and that the tumor-to-blood standard uptake ratio (SUR) can improve the prognostic value of tracer uptake values. The present investigation addresses the question of whether the distinctly improved prognostic value of SUR can be confirmed in a similar patient group that was examined and treated at a different site. 18F-FDG PET/CT was performed in 147 consecutive patients (115 male, 32 female, mean age: 62 years) with newly diagnosed esophageal squamous cell carcinoma prior to definitive radiochemotherapy. In the PET images, the metabolic active volume (MTV) of the primary tumor was delineated with an adaptive threshold method. For the resulting ROIs, SUVmax and total lesion glycolysis (TLG = MTV × SUVmean) were computed. The blood SUV was determined by manually delineating the aorta in the low-dose CT. SUR values were computed as ratio of tumor SUV and blood SUV. Univariate Cox regression and Kaplan-Meier analysis with respect to overall survival (OS), distant-metastases-free survival (DM), and locoregional control (LRC) was performed. Additionally, a multivariate Cox regression including clinically relevant parameters was performed. Univariate Cox regression revealed MTV, TLG, and SURmax as significant prognostic factors for OS. MTV as well as TLG were significant prognostic factors for LRC while SURmax showed only a trend for significance. None of the PET parameters was prognostic for DM. In univariate analysis, SUVmax was not prognostic for any of the investigated clinical endpoints. In multivariate analysis (T-stage, N-stage, MTV, and SURmax), MTV was an independent prognostic factor for OS and showed a trend for significance for LRC. SURmax was not an independent predictor for OS or LRC. When including the PET parameters separately in multivariate analysis, MTV as well as SURmax were prognostic factors for OS indicating that SURmax is independent from the clinical parameters but not from MTV. In addition, MTV was an independent prognostic factor for LRC in this separate analysis. Our study revealed a clearly improved prognostic value of tumor SUR compared to tumor SUV and confirms our previously published findings regarding OS. Furthermore, SUR delivers prognostic information beyond that provided by the clinical parameters alone, but does not add prognostic information beyond that provided by MTV in this patient group. Therefore, our results suggest that pretherapeutic MTV is the parameter of choice for PET-based risk stratification in the considered setting but further investigations are necessary to demonstrate that this suggestion is correct.

Prognostic value of SUR in patients with trimodality treatment of locally advanced esophageal carcinoma.

The prognosis of patients with esophageal carcinoma remains dismal despite ongoing efforts to improve treatment options. For locally advanced tumors, several randomized trials have shown the benefit of neoadjuvant chemoradiation followed by surgery compared to surgery alone. The aim of this exploratory study was to evaluate the prognostic value of different baseline positron emission tomography (PET) parameters and their potentially additional prognostic impact at the end of neoadjuvant radiochemotherapy. Furthermore, the standard uptake ratio (SUR) as a new parameter for quantification of tumor metabolism was compared to the conventional PET parameters metabolic active volume (MTV), total lesion glycolysis (TLG), and standardized uptake value (SUV) taking into account known basic parameters. Methods:18F-FDG-PET/CT was performed in 76 consecutive patients ((60±10) years, 71 males) with newly diagnosed esophageal cancer before and during the last week of neoadjuvant radiochemotherapy. MTV of the primary tumor was delineated with an adaptive threshold method. The blood SUV was determined by manually delineating the aorta in the low dose CT. SUR values were computed as scan time corrected ratio of tumor SUVmax and mean blood SUV. Univariate Cox regression and Kaplan-Meier analysis with respect to locoregional control (LRC), freedom from distant metastases (FFDM), and overall survival (OS) was performed. Additionally, independence of PET parameters from standard clinical factors was analyzed with multivariate Cox regression. Results: In multivariate analysis two parameters showed a significant correlation with all endpoints: restaging MTV and restaging SUR. Furthermore, restaging TLG was prognostic for LCR and FFDM. For all endpoints the largest effect size was found for restaging SUR. The only basic factors remaining significant in multivariate analyses were histology for OS and FFDM and age for LRC. Conclusion: PET provides independent prognostic information for OS, LRC, and FFDM in addition to standard clinical parameters in this patient cohort. Our results suggest that the prognostic value of tracer uptake can be improved when characterized by SUR rather than by SUV. Overall, our investigation revealed a higher prognostic value of restaging parameters compared to baseline PET; therapy-adjustments would still be possible at this point of time. Further investigations are required to confirm these hypothesis-generating results.

Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial

Pancreatic ductal adenocarcinoma (PDAC) is resistant to T-cell-mediated immunotherapy. We engineered T cells to transiently express a messenger RNA encoding a chimeric antigen receptor (CAR) specific for mesothelin, a protein that is overexpressed by PDAC cells. We performed a phase I study to evaluate the safety and efficacy of adoptive cell therapy with autologous mesothelin-specific CAR T cells (CARTmeso cells) in 6 patients with chemotherapy-refractory metastatic PDAC. Patients were given intravenous CARTmeso cells 3 times weekly for 3 weeks. None of the patients developed cytokine release syndrome or neurologic symptoms and there were no dose-limiting toxicities. Disease stabilized in 2 patients, with progression-free survival times of 3.8 and 5.4 months. We used 18F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography imaging to monitor the metabolic active volume (MAV) of individual tumor lesions. The total MAV remained stable in 3 patients and decreased by 69.2% in 1 patient with biopsy-proven mesothelin expression; in this patient, all liver lesions had a complete reduction in FDG uptake at 1 month compared with baseline, although there was no effect on the primary PDAC. Transient CAR expression was detected in patients' blood after infusion and led to expansion of new immunoglobulin G proteins. Our results provide evidence for the potential antitumor activity of messenger RNA CARTmeso cells, as well as PDAC resistance to the immune response.

Prognostic value of total lesion glycolysis and metabolic active tumor volume in non-small cell lung cancer

IntroductionTo predict the outcome of patients with non-small cell lung cancer (NSCLC) the currently used prognostic system (TNM) is not accurate enough. The prognostic significance of the SUVmax measured by PET remains controversial. This study aims to evaluate the prognostic value in overall survival and progression free survival of SUVmax, the total lesion glycolysis (TLG) and the mean metabolic active volume (MATV) in NSCLC. MethodsWe retrospectively reviewed 105 patients (72 males, 33 females) with a new diagnosis of NSCLC (TNM stage I: 27.6%, II: 10.5%, III: 40.9% and IV: 21.0%) who underwent scanning with a PET/CT. For VOI definition a semi-automatic delineation tool was used. On PET images SUVmax, SUVmean and MATV of the primary tumor and the whole tumor burden were measured. TLG and MATV were measured by using a threshold of 50% of SUVmax. ResultsOS and PFS are found to be higher in patients with low-SUVTmax and low-TLGT values. OS and PFS were significantly higher for low-SUVWTBmax, low-MATVWTB and low-TLGWTB values of the whole-tumor burden.Multivariate analysis of the whole-tumor burden revealed that the most important prognostic factors for OS are high MATVWTB and TLGWTB values, increasing stage and male gender. TLGWTB and stage are also independent prognosticators in PFS. ConclusionOnly whole-body TLG is of prognostic value in NSCLC for both OS and PFS. Stratification of patients by TLGWTB might complement outcome prediction but the TNM stage remains the most important determinant of prognosis. MicroabstractIn order to predict the outcome of patients with non-small cell lung cancer (NSCLC) the currently used prognostic system (TNM) is not accurate enough. The prognostic significance of the standard uptake value (SUV) measured by PET remains controversial. This study aims to evaluate the prognostic value in overall survival (OS) and progression free survival (PFS) of the standard uptake value (SUV), the total lesion glycolysis (TLG) and the mean metabolic active volume (MATV) in NSCLC. The study reveals that TLG of the whole-tumor burden is an independent prognostic factor for OS and PFS in patients with NSCLC.

Can semiquantitative measurements of SUVmax and cut-off values differentiate colorectal malignant from benign lessions?

We investigated maximum standardized uptake value (SUVmax) and cut-off values for differentiation of malignant and benign lesions in colorectal cancer (CC) as multiple studies have questioned their validity. We also investigated more extended indices using common semi-quantification analysis in incidental colorectal findings (ICF). Fluorine-18-fluoro deoxy glucose positron emission tomography/computed tomography in 25 patients with a total of 30 focal ICF was retrospectively analysed using dedicated software. Method variability was tested through application of three common threshold-based lesion delineation techniques as well as a partial-volume correction (PVC). Lesion SUVmax, SUVmean, metabolically active volume (MAV) and mean total lesion glycolysis (TLG) were thereby extracted along with PVC corrected values (cSUVmean, cTLG) and SUVpeak. In all lesions, SUVmax was >5 and SUVmean≥2.7. Malignant SUVmax values (mean±SD: 16.5±6.2) were overall significantly higher than benign levels (9.8±3.6). There was a substantial overlap with values in polyps/adenomas (14.4±7.7). Both SUVpeak and SUVmean showed similar characteristics. Malignant MAV and TLG showed more distinct levels. Though different segmentation methods introduced variations, largest in MAV (-58.6%-141.5%), and PVC generally increased measures significantly by a factor of 1.2-2.7, neither changed relative levels much. SUVmax values were inadequate for aetiological differentiation of ICF, which also precludes a clinically significant cut-off value. The same applies to SUVpeak and SUVmean while TLG measures may be more indicative. Semi-quantitative measurements of SUVmax and cut-off values proved inadequate for differentiating colorectal malignancies from benign findings. While integrated measures, e.g. cTLG, are potentially better indicators of disease severity and extent, more optimal segmentation and PVC methods are required.

Identification of low variability textural features for heterogeneity quantification of 18F-FDG PET/CT imaging

ObjectiveTo identify those textural features that are insensitive to both technical and biological factors in order to standardise heterogeneity studies on 18F-FDG PET imaging. Materials and methodsTwo different studies were performed. First, nineteen series from a cylindrical phantom filled with different 18F-FDG activity concentration were acquired and reconstructed using three different protocols. Seventy-two texture features were calculated inside a circular region of interest. The variability of each feature was obtained. Second, the data for 15 patients showing non-pathological liver were acquired. Anatomical and physiological features such as patient's weight, height, body mass index, metabolic active volume, blood glucose level, SUV and SUV standard deviation were also recorded. A liver covering region of interest was delineated and low variability textural features calculated in each patient. Finally, a multivariate Spearman's correlation analysis between biological factors and texture features was performed. ResultsOnly eight texture features analysed show small variability (<5%) with activity concentration and reconstruction protocol making them suitable for heterogeneity quantification. On the other hand, there is a high statistically significant correlation between MAV and entropy (P<0.05). Entropy feature is, indeed, correlated (P<0.05) with all patient parameters, except body mass index. ConclusionsThe textural features that are correlated with neither technical nor biological factors are run percentage, short-zone emphasis and intensity, making them suitable for quantifying functional changes or classifying patients. Other textural features are correlated with technical and biological factors and are, therefore, a source of errors if used for this purpose.

MO-DE-207B-11: Reliability of PET/CT Radiomics Features in Functional and Morphological Components of NSCLC Lesions: A Repeatability Analysis in a Prospective Multicenter Cohort

Purpose: The goal of this study was to evaluate the repeatability of radiomics features (intensity, shape and heterogeneity) in both PET and low-dose CT components of test-retest FDG-PET/CT images in a prospective multicenter cohort of 74 NSCLC patients from ACRIN 6678 and a similar Merck trial. Methods: Seventy-four patients with stage III-IV NCSLC were prospectively included. The primary tumor and up to 3 additional lesions per patient were analyzed. The Fuzzy Locally Adaptive Bayesian algorithm was used to automatically delineate metabolically active volume (MAV) in PET. The 3D SlicerTM software was exploited to delineate anatomical volumes (AV) in CT. Ten intensity first-order features, as well as 26 textural features and four 3D shape descriptors were calculated from tumour volumes in both modalities. The repeatability of each metric was assessed by Bland-Altman analysis. Results: One hundred and five lesions (primary tumors and nodal or distant metastases) were delineated and characterized. The MAV and AV determination had a repeatability of −1.4±11.0% and −1.2±18.7% respectively. Several shape and heterogeneity features were found to be highly or moderately repeatable (e.g., sphericity, co-occurrence entropy or intensity size-zone matrix zone percentage), whereas others were confirmed as unreliable with much higher variability (more than twice that of the corresponding volume determination). Conclusion: Our results in this large multicenter cohort with more than 100 measurements confirm the PET findings in previous studies (with <30 lesions). In addition, our study is the first to explore the repeatability of radiomics features in the low-dose CT component of PET/CT acquisitions (previous studies considered dosimetry CT, CE-CT or CBCT). Several features were identified as reliable in both PET and CT components and could be used to build prognostic models. This work has received a French government support granted to the CominLabs excellence laboratory and managed by the National Research Agency in the “Investing for the Future” program under reference ANR-10-LABX-07-01, and support from the city of Brest.

Identification of low variability textural features for heterogeneity quantification of 18F-FDG PET/CT imaging.

To identify those textural features that are insensitive to both technical and biological factors in order to standardise heterogeneity studies on 18F-FDG PET imaging. Two different studies were performed. First, nineteen series from a cylindrical phantom filled with different 18F-FDG activity concentration were acquired and reconstructed using three different protocols. Seventy-two texture features were calculated inside a circular region of interest. The variability of each feature was obtained. Second, the data for 15 patients showing non-pathological liver were acquired. Anatomical and physiological features such as patient's weight, height, body mass index, metabolic active volume, blood glucose level, SUV and SUV standard deviation were also recorded. A liver covering region of interest was delineated and low variability textural features calculated in each patient. Finally, a multivariate Spearman's correlation analysis between biological factors and texture features was performed. Only eight texture features analysed show small variability (<5%) with activity concentration and reconstruction protocol making them suitable for heterogeneity quantification. On the other hand, there is a high statistically significant correlation between MAV and entropy (P<0.05). Entropy feature is, indeed, correlated (P<0.05) with all patient parameters, except body mass index. The textural features that are correlated with neither technical nor biological factors are run percentage, short-zone emphasis and intensity, making them suitable for quantifying functional changes or classifying patients. Other textural features are correlated with technical and biological factors and are, therefore, a source of errors if used for this purpose.

Interaction of quantitative (18)F-FDG-PET-CT imaging parameters and human papillomavirus status in oropharyngeal squamous cell carcinoma.

Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) have a better survival than with HPV-negative oropharyngeal SCC. An (18) F-fluorodeoxyglucose positron emission tomography-CT ((18) F-FDG-PET-CT) may also provide prognostic information. We evaluated glycolytic characteristics in HPV-negative and HPV-positive oropharyngeal SCC. Forty-four patients underwent pretreatment (18) F-FDG-PET-CT. Standardized uptake values (SUVs) and metabolic active tumor volumes (MATVs) were determined for primary tumors. HPV status was determined with p16 immunostaining, followed by high-risk HPV DNA detection on the positive cases. Twenty-seven patients were HPV-positive (61.4%). Median MATV was 2.8 mL (range = 1.6-5.1 mL) for HPV-positive and 6.0 mL (range = 4.4-18.7 mL) for HPV-negative tumors (p < .001). SUV values are volume dependent (partial volume effect), therefore, MATV was included as covariate in multivariate analysis. In this multivariate analysis, the maximum SUV in HPV-positive tumors was 3.9 units lower than in HPV-negative tumors (p = .01). The (18) F-FDG-PET-CT parameters are lower in HPV-positive than in HPV-negative patients. Low pretreatment SUV values in HPV-positive oropharyngeal SCC may be at least partly explained by HPV-induced tumor changes.

Y90 radioembolization of colorectal cancer liver metastases: response assessment by contrast-enhanced computed tomography with or without PET-CT guidance

PurposeTo compare various computed tomography (CT) parameters to the positron emission tomography with computed tomography (PET-CT) response, with or without PET guidance for the response assessment of colorectal cancer (CRC) metastases treated by Y90 radioembolization. MethodsThirty-six CRC metastases were retrospectively evaluated on 18F-Fluoro-Deoxy-Glucose PET-CT and contrast-enhanced computed tomography (CECT) performed at baseline and 2–3 months after Y90 radioembolization. ResultsMedian SUVmax values decreased from 11.39 to 6.71 after radioembolization (P<.001), and 23/36 (64%) metastases were categorized metabolic responses according to European Organisation for Research and Treatment of Cancer criteria. Only a decrease of the mean attenuation in the structural (P<.001) and metabolic active volume (P<.001) was observed. The change in these criteria was correlated with the change of SUVmax.

In vivo quantification of hypoxic and metabolic status of NSCLC tumors using [18F]HX4 and [18F]FDG-PET/CT imaging.

Increased tumor metabolism and hypoxia are related to poor prognosis in solid tumors, including non-small cell lung cancer (NSCLC). PET imaging is a noninvasive technique that is frequently used to visualize and quantify tumor metabolism and hypoxia. The aim of this study was to perform an extensive comparison of tumor metabolism using 2[(18)F]fluoro-2-deoxy-d-glucose (FDG)-PET and hypoxia using HX4-PET imaging. FDG- and HX4-PET/CT images of 25 patients with NSCLC were coregistered. At a global tumor level, HX4 and FDG parameters were extracted from the gross tumor volume (GTV). The HX4 high-fraction (HX4-HF) and HX4 high-volume (HX4-HV) were defined using a tumor-to-blood ratio > 1.4. For FDG high-fraction (FDG-HF) and FDG high-volume (FDG-HV), a standardized uptake value (SUV) > 50% of SUVmax was used. We evaluated the spatial correlation between HX4 and FDG uptake within the tumor, to quantify the (mis)match between volumes with a high FDG and high HX4 uptake. At a tumor level, significant correlations were observed between FDG and HX4 parameters. For the primary GTV, the HX4-HF was three times smaller compared with the FDG-HF. In 53% of the primary lesions, less than 1 cm(3) of the HX4-HV was outside the FDG-HV; for 37%, this volume was 1.9 to 12 cm(3). Remarkably, a distinct uptake pattern was observed in 11%, with large hypoxic volumes localized outside the FDG-HV. Hypoxic tumor volumes are smaller than metabolic active volumes. Approximately half of the lesions showed a good spatial correlation between the PET tracers. In the other cases, a (partial) mismatch was observed. The addition of HX4-PET imaging has the potential to individualize patient treatment.

Dual Time Point FDG-PET/CT Imaging Can Distinguish Between Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma

▪Introduction: 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) has become a standard of care imaging modality for multiple types of lymphoma, including Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL). However, many applications of PET/CT in lymphomas have not yet been explored. We investigated whether dual time point (DT) PET/CT would detect more sites of disease due to improved tumor to background ratio. It has also been reported that inflammatory lesions have decreased FDG accumulation over time, whereas malignant lesions accumulate FDG over time, becoming more FDG-avid. Histologically, HL lesions are predominantly composed of inflammatory cells and relatively few tumor cells. This tumor composition calls into question whether HL will behave as a malignancy or as an inflammatory lesion on DT PET/CT imaging compared to DLBCL and whether changes in FDG accumulation over time on DT PET/CT imaging will differ between HL and DLBCL.Methods: Patients (pts) with untreated, biopsy-confirmed, nodular sclerosing HL and DLBCL were prospectively enrolled on this clinical trial (clinicaltrials.gov NCT01004718). Pts with uncontrolled diabetes, active infection, and primary mediastinal large B-cell lymphoma were excluded. Following injection of FDG, pts underwent PET/CT at 60 minutes (DT60) and 180 minutes (DT180). Any lesion with a Deauville Score of 4-5 was considered positive (i.e. FDG uptake > liver at any site) (Meignan, Leuk Lymphoma 2012). SUVmax, SUVmean, and tumor to background ratio, defined as lesion SUVmax / liver SUVmean, were calculated for each lesion. Software using an automatic adaptive thresholding method (ROVER, ABX GmbH) was also used to measure the metabolically active volume (MAV) of lesions on PET images. Mean metabolic volumetric product (MVPmean) was calculated as MVPmean = SUVmean * MAV for each lesion, and total MVPmean for a given pt was calculated as the sum of MVPmean for all lesions.Results: 160 total lesions (78 lesions with DT60 and 82 lesions with DT180 images) were evaluated in this prospective study of 20 paired PET/CT scans in 10 pts. Five pts had HL and 5 had DLBCL. Median age was 51; 5 pts were men. Pts with DLBCL had higher SUVmax values at both 60 and 180 minutes than HL (DT60: DLBCL 22.4 v HL 10.8, p = 0.0007, t test; DT180: DLBCL 31.6 v HL 14.6, p = 0.0006, t test) as well as a higher average SUVmean than HL at both time points (DT60: DLBCL 9.2 v 4.5, p = 0.009 t test; DT180: DLBCL 12.7 v 5.8, p = 0.02 t test). We also observed that the average %change in tumor to background ratio for HL increased from DT60 to D180 by 75% whereas the %change in tumor to background ratio for DLBCL increased by 34% (p = 0.0001, t-test). DT180 detected 4 additional lesions that were not apparent on DT60; 3 lesions were in HL and 1 in DLBCL. The locations of these lesions were mesenteric, lung, external iliac, and subclavian regions. For each pt, %change in total MVPmean between DT60 and DT180 was higher in DLBCL (p=0.02, rank sum). Of interest, the %change in MAV between DT60 and DT180 decreased in HL compared to slight increase in DLBCL (HL 12% decrease v. DLBCL 2% increase in MAV). Thus, changes in MAV accounted for the difference detected in %change in total MVPmean between these histologies. There was no difference between HL and DLBCL in %change in SUVmean or %change in SUVmax.Conclusions: We report the first prospective study of dual time point PET/CT imaging of lymphomas, as well as the first study to specifically compare dual time point imaging of DLBCL and HL. Our results indicate that lesions of DLBCL are generally more FDG-avid than HL when measured as either SUVmax or SUVmean at 60 and 180 minutes. When measured as %change in total MVPmean, DLBCL accumulates significantly more FDG than HL, consistent with the differences in histologic composition of these tumors. Computerized algorithms for generation of MAV and SUVmean add additional information not reflected in measurement of SUVmax alone that may be useful for distinguishing between tumor histologies. Given variation between histologies, optimal timing of image acquisition for detection of lesions may be improved by choosing an imaging time point that optimizes tumor to background ratio. Tumor to background ratio is improved, especially for HL, with use of imaging that occurs at 180 minutes, and we demonstrate the ability to detect additional lesions not detected at 60 minutes. DisclosuresNo relevant conflicts of interest to declare.

FDG PET/CT in Crohn’s disease: correlation of quantitative FDG PET/CT parameters with clinical and endoscopic surrogate markers of disease activity

The aim of this study was to determine the feasibility and potential clinical utility of assessment of Crohn's disease (CD) activity by (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT employing a new quantitative approach. A total of 22 subjects (mean age 37) with CD who had undergone FDG PET/CT followed by ileocolonoscopy within 1 week were included in this analysis. The CD endoscopy index of severity (CDEIS) for various bowel segments was calculated. The CD activity index (CDAI) was evaluated, and fecal calprotectin was measured. On PET, regions with increased FDG uptake in large bowel were segmented with an adaptive contrast-oriented thresholding algorithm, and metabolically active volume (MAV), uncorrected mean standardized uptake value (SUV(mean)), partial volume-corrected SUV(mean) (PVC-SUV(mean)), SUV(max), uncorrected total lesion glycolysis (TLG = MAV × SUV(mean)), and PVC total lesion glycolysis (PVC-TLG = MAV × PVC-SUV(mean)) were measured. Global CD activity score (GCDAS) was calculated as the sum of PVC-TLG over all clinically significant FDG-avid regions in each subject. Correlations between regional PET quantification measures (SUVs, TLGs) and CDEIS were calculated. Correlations between the global PET quantification measure (GCDAS, global SUVs) with CDAI, fecal calprotectin, CDEIS, and CRP level were also calculated. SUV(max), PVC-SUV(mean), and PVC-TLG significantly correlated with segment CDEIS subscores (r = 0.50, r = 0.69, and r = 0.31, respectively; p < 0.05). GCDAS significantly correlated with CDAI and fecal calprotectin (r = 0.64 and r = 0.51, respectively; p < 0.05). By employing this new quantitative approach, we were able to calculate indices of regional and global CD activity, which correlated well with both clinical and pathological disease activity surrogate markers. This approach may be of clinical importance in measuring both global disease activity and treatment response in patients with CD.