PET imaging and quantification of small animals using a clinical SiPM-based camera.

BACKGROUND: Small-animal PET imaging is an important tool in preclinical oncology. This study evaluated the ability of a clinical SiPM-PET camera to image several rats simultaneously and to perform quantification data analysis. METHODS: Intrinsic spatial resolution was measured using 18F line sources, and image quality was assessed using a NEMA NU 4-2018 phantom. Quantification was evaluated using a fillable micro-hollow sphere phantom containing 4 spheres of different sizes (ranging from 3.95 to 7.86 mm). Recovery coefficients were computed for the maximum (Amax) and the mean (A50) pixel values measured on a 50% isocontour drawn on each sphere. Measurements were performed first with the phantom placed in the centre of the field of view and then in the off-centre position with the presence of three scattering sources to simulate the acquisition of four animals simultaneously. Quantification accuracy was finally validated using four 3D-printed phantoms mimicking rats with four subcutaneous tumours each. All experiments were performed for both 18F and 68Ga radionuclides. RESULTS: Radial spatial resolutions measured using the PSF reconstruction algorithm were 1.80 mm and 1.78 mm for centred and off-centred acquisitions, respectively. Spill-overs in air and water and uniformity computed with the NEMA phantom centred in the FOV were 0.05, 0.1 and 5.55% for 18F and 0.08, 0.12 and 2.81% for 68Ga, respectively. Recovery coefficients calculated with the 18F-filled micro-hollow sphere phantom for each sphere varied from 0.51 to 1.43 for Amax and from 0.40 to 1.01 for A50. These values decreased from 0.28 to 0.92 for Amax and from 0.22 to 0.66 for A50 for 68 Ga acquisition. The results were not significantly different when imaging phantoms in the off-centre position with 3 scattering sources. Measurements performed with the four 3D-printed phantoms showed a good correlation between theoretical and measured activity in simulated tumours, with r2 values of 0.99 and 0.97 obtained for 18F and 68Ga, respectively. CONCLUSION: We found that the clinical SiPM-based PET system was close to that obtained with a dedicated small-animal PET device. This study showed the ability of such a system to image four rats simultaneously and to perform quantification analysis for radionuclides commonly used in oncology.

Artificial intelligence-based 68Ga-DOTATOC PET denoising for optimizing 68Ge/68Ga generator use throughout its lifetime.

Introduction: The yield per elution of a 68Ge/68Ga generator decreases during its lifespan. This affects the number of patients injected per elution or the injected dose per patient, thereby negatively affecting the cost of examinations and the quality of PET images due to increased image noise. We aimed to investigate whether AI-based PET denoising can offset this decrease in image quality parameters. Methods: All patients addressed to our PET unit for a 68Ga-DOTATOC PET/CT from April 2020 to February 2021 were enrolled. Forty-four patients underwent their PET scans according to Protocol_FixedDose (150 MBq) and 32 according to Protocol_WeightDose (1.5 MBq/kg). Protocol_WeightDose examinations were processed using the Subtle PET software (Protocol_WeightDoseAI). Liver and vascular SUV mean were recorded as well as SUVmax, SUVmean and metabolic tumour volume (MTV) of the most intense tumoural lesion and its background SUVmean. Liver and vascular coefficients of variation (CV), tumour-to-background and tumour-to-liver ratios were calculated. Results: The mean injected dose of 2.1 (0.4) MBq/kg per patient was significantly higher in the Protocol_FixedDose group as compared to 1.5 (0.1) MBq/kg for the Protocol_WeightDose group. Protocol_WeightDose led to noisier images than Protocol_FixedDose with higher CVs for liver (15.57% ± 4.32 vs. 13.04% ± 3.51, p = 0.018) and blood-pool (28.67% ± 8.65 vs. 22.25% ± 10.37, p = 0.0003). Protocol_WeightDoseAI led to less noisy images than Protocol_WeightDose with lower liver CVs (11.42% ± 3.05 vs. 15.57% ± 4.32, p < 0.0001) and vascular CVs (16.62% ± 6.40 vs. 28.67% ± 8.65, p < 0.0001). Tumour-to-background and tumour-to-liver ratios were lower for protocol_WeightDoseAI: 6.78 ± 3.49 vs. 7.57 ± 4.73 (p = 0.01) and 5.96 ± 5.43 vs. 6.77 ± 6.19 (p < 0.0001), respectively. MTVs were higher after denoising whereas tumour SUVmax were lower: the mean% differences in MTV and SUVmax were + 11.14% (95% CI = 4.84-17.43) and -3.92% (95% CI = -6.25 to -1.59). Conclusion: The degradation of PET image quality due to a reduction in injected dose at the end of the 68Ge/68Ga generator lifespan can be effectively counterbalanced by using AI-based PET denoising.

Prediction of the Presence of Targetable Molecular Alteration(s) with Clinico-Metabolic 18 F-FDG PET Radiomics in Non-Asian Lung Adenocarcinoma Patients.

This study aimed to investigate if combining clinical characteristics with pre-therapeutic 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography (PET) radiomics could predict the presence of molecular alteration(s) in key molecular targets in lung adenocarcinoma. This non-interventional monocentric study included patients with newly diagnosed lung adenocarcinoma referred for baseline PET who had tumour molecular analyses. The data were randomly split into training and test datasets. LASSO regression with 100-fold cross-validation was performed, including sex, age, smoking history, AJCC cancer stage and 31 PET variables. In total, 109 patients were analysed, and it was found that 63 (57.8%) patients had at least one molecular alteration. Using the training dataset (n = 87), the model included 10 variables, namely age, sex, smoking history, AJCC stage, excessKustosis_HISTO, sphericity_SHAPE, variance_GLCM, correlation_GLCM, LZE_GLZLM, and GLNU_GLZLM. The ROC analysis for molecular alteration prediction using this model found an AUC equal to 0.866 (p < 0.0001). A cut-off value set to 0.48 led to a sensitivity of 90.6% and a positive likelihood ratio (LR+) value equal to 2.4. After application of this cut-off value in the unseen test dataset of patients (n = 22), the test presented a sensitivity equal to 90.0% and an LR+ value of 1.35. A clinico-metabolic 18 F-FDG PET phenotype allows the detection of key molecular target alterations with high sensitivity and negative predictive value. Hence, it opens the way to the selection of patients for molecular analysis.

Feasibility of Imaging Small Animals on a 360° Whole-Body Cadmium Zinc Telluride SPECT Camera: a Phantom Study.

PURPOSE: Single-photon emission computed tomography has found an important place in preclinical cancer research. Nevertheless, the cameras dedicated to small animals are not widely available. The present study aimed to assess the feasibility of imaging small animals by a newly released 360° cadmium zinc telluride camera (VERITON, Spectrum Dynamics, Israel) dedicated to human patients. PROCEDURES: A cylindrical phantom containing hot spheres was used to evaluate the intrinsic performance of the camera first without the presence of background activity and then with two contrasts between background and hot spheres (1/4 and 1/10). Acquisitions were repeated with different scan durations (10 and 20 min), two tested radioisotopes (Tc-99 m and I-123), and a set of reconstruction parameters (10 iterations [i] 8 subsets [s], 10i16s, 10i32s). A 3D-printed phantom mimicking a rat with four subcutaneous tumours was then used to test the camera under preclinical conditions. RESULTS: The results obtained from the micro-hollow sphere phantom showed that it was possible to visualize spheres with an inner diameter of 3.95 mm without background activity. Moreover, spheres with diameters of 4.95 mm can be seen in the condition of high contrast between background and spheres (1/10) and 7.86 mm with lower contrast (1/4). The rat-sized phantom acquisitions showed that 10- and 8-mm subcutaneous tumours were visible with a good contrast obtained for the two radioisotopes tested in this study. Both Tc-99 m and I-123 measurements demonstrated that a 10-min acquisition reconstructed with an ordered subset expectation maximization algorithm applying 10i32s was optimal to obtain sufficient image quality in terms of noise, resolution, and contrast. CONCLUSION: Phantom results showed the ability of the system to detect sub-centimetre lesions for various radioisotopes. It seemed feasible to image small animals using a 360° cadmium zinc telluride gamma camera for preclinical cancer research purposes.

Diagnostic value of baseline 18FDG PET/CT skeletal textural features in follicular lymphoma.

At present, 18F-fluorodesoxyglucose (18FDG) positron emission tomography (PET)/computed tomography (CT) cannot be used to omit a bone marrow biopsy (BMB) among initial staging procedures in follicular lymphoma (FL). The additional diagnostic value of skeletal textural features on baseline 18FDG-PET/CT in diffuse large B-cell lymphoma (DLBCL) patients has given promising results. The aim of this study is to evaluate the value of 18FDG-PET/CT radiomics for the diagnosis of bone marrow involvement (BMI) in FL patients. This retrospective bicentric study enrolled newly diagnosed FL patients addressed for baseline 18FDG PET/CT. For visual assessment, examinations were considered positive in cases of obvious bone focal uptakes. For textural analysis, the skeleton volumes of interest (VOIs) were automatically extracted from segmented CT images and analysed using LifeX software. BMB and visual assessment were taken as the gold standard: BMB -/PET - patients were considered as bone-NEGATIVE patients, whereas BMB +/PET -, BMB -/PET + and BMB +/PET + patients were considered bone-POSITIVE patients. A LASSO regression algorithm was used to select features of interest and to build a prediction model. Sixty-six consecutive patients were included: 36 bone-NEGATIVE (54.5%) and 30 bone-POSITIVE (45.5%). The LASSO regression found variance_GLCM, correlation_GLCM, joint entropy_GLCM and busyness_NGLDM to have nonzero regression coefficients. Based on ROC analysis, a cut-off equal to - 0.190 was found to be optimal for the diagnosis of BMI using PET pred.score. The corresponding sensitivity, specificity, PPV and NPV values were equal to 70.0%, 83.3%, 77.8% and 76.9%, respectively. When comparing the ROC AUCs with using BMB alone, visual PET assessment or PET pred.score, a significant difference was found between BMB versus visual PET assessments (p = 0.010) but not between BMB and PET pred.score assessments (p = 0.097). Skeleton texture analysis is worth exploring to improve the performance of 18FDG-PET/CT for the diagnosis of BMI at baseline in FL patients.

18F-FDG PET/CT versus Diagnostic Contrast-Enhanced CT for Follow-Up of Stage IV Melanoma Patients Treated by Immune Checkpoint Inhibitors: Frequency and Management of Discordances over a 3-Year Period in a University Hospital.

AIM: To perform a comprehensive analysis of discordances between contrast-enhanced CT (ceCT) and 18F-FDG PET/CT in the evaluation of the extra-cerebral treatment monitoring in patients with stage IV melanoma. MATERIALS AND METHODS: We conducted a retrospective monocentric observational study over a 3-year period in patients referred for 18F-FDG PET/CT and ceCT in the framework of therapy monitoring of immune checkpoint (ICIs) as of January 2017. Imaging reports were analyzed by two physicians in consensus. The anatomical site responsible for discordances, as well as induced changes in treatment were noted. RESULTS: Eighty patients were included and 195 pairs of scans analyzed. Overall, discordances occurred in 65 cases (33%). Eighty percent of the discordances (52/65) were due to 18F-FDG PET/CT scans upstaging the patient. Amongst these discordances, 17/52 (33%) led to change in patient's management, the most frequent being radiotherapy of a progressing site. ceCT represented 13/65 (20%) of discordances and induced changes in patients' management in 2/13 cases (15%). The most frequent anatomical site involved was subcutaneous for 18F-FDG PET/CT findings and lung or liver for ceCT. CONCLUSIONS: Treatment monitoring with 18F-FDG PET/CT is more efficient than ceCT and has a greater impact in patient's management.

End-of-treatment 18F-FDG PET/CT in diffuse large B cell lymphoma patients: ΔSUV outperforms Deauville score.

In DLBCL, the Deauville scoring system (DS) is the standard for PET/CT response assessment. An alternative system, based on the semi-quantitative change in standardized uptake values, namely ΔSUVmax, has been reported to be more objective than the DS. We aimed to compare ΔSUVmax and DS for risk stratification of DLBCL patients on end-of-treatment (EoT) PET. 108 consecutive patients were included. 2-year EFS Kaplan-Meier survival analyses and Cox regression models were performed. 2-year EFS was significantly different between favorable ΔSUVmax (favΔ < -86.5%) and unfavorable ΔSUVmax (unfavΔ ≥ -86.5%) patients: 100.0% ± 0.0 versus 58.3% ± 14.2 (p = 0.001). On Cox multivariable regression, ΔSUVmax status was the only independent predictor of 2-year EFS, outperforming DS. Therefore, ΔSUVmax should be computed for non-responder patients, especially DS4, as the 2-year EFS is not different between responders and non-responders in the case of favΔ. Further studies are needed in order to confirm this hypothesis.

Revisiting detection of in-transit metastases in melanoma patients using digital 18F-FDG PET/CT with small-voxel reconstruction.

AIM: To evaluate the use of digital 18F-FDG PET/CT with small-voxels reconstruction for detecting in-transit metastases in melanoma patients with primary lesion located on the upper or lower limbs, in comparison with standard reconstruction and European Association of Nuclear Medicine Research limited (EARL)-compliant reconstruction mimicking former generation PET systems. METHODS: Forty-six PET examinations acquired in list mode on a Vereos digital PET/CT system were reconstructed with (1) the standard reconstruction [2 iterations, 10 subsets (2i10s), point-spread function (PSF) modelling and time-of-flight enabled, no post-filtering and voxel size of 2 mm], (2) a small-voxel reconstruction using 1 mm voxels otherwise using the same parameters, (3) an EARL-compliant reconstruction mimicking a former generation system. Comparison of results across these reconstructions was made for a blind randomized review using a 3-point scale for the presence of in-transit metastases and image quality as well as for tumour-to-background (T/B) ratios and noise level in reference organs. RESULTS: Seven of the thirty-two EARL-compliant images classified as negative moved to positive on 1mmPSF images, and 5 of the 6 EARL-compliant images classified as indeterminate moved to positive on 1mmPSF images (P = 0.01). Amongst a total of 20 PET examinations classified as positive using the 1mmPSF reconstruction, fifteen were considered true positive, five false positive results occurred. Twenty-four patients with 1 mm PSF images were classified as negative, none of those under active surveillance experienced in-transit metastases during the 17 months following their PET examination. The positive likelihood ratio for the 1 mm reconstruction was much higher than that observed for EARL-compliant images (14.7 vs 7.82). Importantly, negative likelihood ratios for the 1 mm and 1mmPSF reconstruction were almost perfect. Compared to EARL-compliant data, T/B ratios extracted from the 1mmPSF showed a 2.84-fold increase (P < 0.001). A similar pattern of statistically significant increase was observed for noise level in organs of reference. Image quality for the torso was found to be significantly lower for 1mmPSF reconstruction (P = 0.03). Image quality for the limbs was found to be better for 1mmPSF (P < 0.001). CONCLUSION: Digital PET with small-voxel reconstruction brings an additional value for the detection of in-transit metastases by reducing the number of indeterminate findings and making up for falsely negative scans using former generation PET systems. An acquisition encompassing lower or upper limbs as appropriate should be performed.

A PSMA-targeted theranostic approach is unlikely to be efficient in serous ovarian cancers.

PURPOSE: Until now, results evaluating the expression of PSMA in ovarian cancer were sparse and contradictory. The aim was to reinvestigate the feasibility of a PSMA targeted theranostic approach in epithelial ovarian cancers with data from the tumour bank of a referring cancer centre. MATERIALS AND METHODS: The OvaRessources Biological Resources Center database was screened from January 2004 to December 2017 to seek patients referred for the initial management of a serous epithelial ovarian cancer and for whom peritoneal histological samples were available in the tumour bank. Immunodetection of PSMA was performed to assess its cellular and neovascular expression. Slides were controlled by a certified pathologist, recorded as tiled tiff images and processed to compute the proportion of DAB stained surface. RESULTS: Of the 51 patients identified by the database screening, 32 patients were included resulting in 57 samples (32 pre-chemotherapy and 25 post-chemotherapy histological samples). Nine patients were chemo-sensitive, 10 were partially chemo-sensitive and 13 were chemo-resistant/refractory. In the entire dataset, the expression of PSMA was quasi-inexistent: %DABPSMA = 0.04 (± 0.12) %. There was no significant difference in the %DABPSMA of sensitive, partially sensitive and resistant/refractory patients. There was also no significant difference in %DABPSMA in tumours before and after chemotherapy in the 25 patients for whom both samples were available. CONCLUSION: The present work demonstrates that PSMA expression is negligible and a fortiori non-sufficient to ensure its usefulness as a prognosticator or a target for a theranostic strategy in ovarian cancers.

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.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Upfront F18-choline PET/CT versus Tc99m-sestaMIBI SPECT/CT guided surgery in primary hyperparathyroidism: the randomized phase III diagnostic trial APACH2.

BACKGROUND: The common endocrine disorder primary hyperparathyroidism (PHPT) can be cured by surgery. Preoperative localization of parathyroid adenoma (PTA) by imaging is a prerequisite for outpatient minimally invasive parathyroidectomy (MIP). Compared to inpatient bilateral cervical exploration (BCE) which is performed if imaging is inconclusive, MIP is superior in terms of cure and complication rates and less costly. The imaging procedure F18-choline (FCH) PET/CT outperforms Tc99m-sestaMIBI (MIBI) SPECT/CT for PTA localization, but it is much costlier. The aim of this study is to identify the most efficient first-line imaging modality for optimal patient care in PHPT without added cost to society. METHODS: We will conduct a multicenter open diagnostic intervention randomized phase III trial comparing two diagnostic strategies in patients with PHPT: upfront FCH PET/CT versus MIBI SPECT/CT. The primary endpoint is the proportion of patients in whom the first-line imaging method results in successful MIP and cure. Follow-up including biological tests will be performed 1 and 6 months after surgery. The main secondary endpoint is the social cost of both strategies. Other secondary endpoints are as follows: FCH PET/CT and MIBI SPECT/CT diagnostic performance, performance of surgical procedure and complication rate, FCH PET/CT inter- and intra-observer variability and optimization of FCH PET/CT procedure. Fifty-eight patients will be enrolled and randomized 1:1. DISCUSSION: FCH PET/CT is a highly efficient but expensive imaging test for preoperative PTA localization and costs three to four times more than MIBI SPECT/CT. Whether FCH PET/CT improves patient outcomes compared to the reference standard MIBI SPECT/CT is unknown. To justify its added cost, FCH PET/CT-guided parathyroid surgery should lead to improved patient management, resulting in higher cure rates and fewer BCEs and surgical complications. In the previous phase II APACH1 study, we showed that second-line FCH PET/CT led to a cure in 88% of patients with negative or inconclusive MIBI SPECT/CT. BCE could be avoided in 75% of patients and surgical complication rates were low. We therefore hypothesize that upfront FCH PET/CT would improve patient care in PHPT and that the reduction in clinical costs would offset the increase in imaging costs. TRIAL REGISTRATION: NCT04040946 , registered August 1, 2019.  Protocol version Version 2.1 dated from 2020/04/23.

How fast can we scan patients with modern (digital) PET/CT systems?

PURPOSE: To seek for the minimal duration per bed position with a digital PET system without compromising image quality and lesion detection in patients requiring fast 18F-FDG PET imaging. MATERIALS AND METHODS: 19 cancer patients experiencing pain or dyspnea and 9 pediatric patients were scanned on a Vereos system. List mode data were reconstructed with decreasing time frame down to 10 s per bed position. Noise was evaluated in the liver, blood pool and muscle, and using target-to-background ratios. Five PET readers recorded image quality, number of clinically relevant foci and of involved anatomical sites in reconstructions ranging from 60 to 10 s per bed position, compared to the standard 90 s reconstruction. RESULTS: The following reconstructions, which harboured a noise not significantly higher than that of the standard reconstruction, were selected for clinical evaluation: 1iterations/10 subsets/20sec (1i10 s20sec), 1i10 s30sec, and 2i10 sPSF60sec. Only the 60 s per bed acquisition displayed similar target-to-background ratios compared to the standard reconstruction, but mean ratios were still higher than 2.0 for the 30 s reconstruction. Inter-rater agreement for the number of involved anatomical sites and detected lesion was good or almost perfect (Kappa: 0.64-0.91) for all acquisitions. In particular, kappa for the 30 s per bed acquisition was 0.78 and 0.91 for lesion and anatomical sites number, respectively. Intra-rater agreement was also excellent for the 30 s reconstruction (kappa = 0.72). Median estimated total PET acquisition time for the 1i10 s30sec, and the standard reconstruction were 4 and 12 min, respectively. CONCLUSIONS: Fast imaging is feasible with state-of-the-art PET systems. Acquisitions of 30 s per bed position are feasible with the Vereos system, requiring optimization of reconstruction parameters.

Baseline 18F-FDG PET radiomic features as predictors of 2-year event-free survival in diffuse large B cell lymphomas treated with immunochemotherapy.

OBJECTIVES: To explore the prognostic value of positron emission tomography (PET) radiomic features in the field of diffuse large B cell lymphoma (DLBCL) treated with a first-line immunochemotherapy. METHODS: One-hundred thirty-two patients newly diagnosed with DLBCL were retrospectively included. PET studies were reconstructed using an ordered subset expectation maximisation algorithm with point spread function modelling. The total metabolic tumour volume (MTV) was recorded for each patient, and the volume of interest structure of the largest target lesion was used to compute 18F-FDG textural parameters. Data was randomly split into training and validation datasets. Optimal cutoff values were determined by means of 2-year event-free survival (EFS) ROC analyses. Two-year EFS analyses were performed using Kaplan-Meier survival analyses and univariable and multivariable Cox regression models. RESULTS: The median follow-up was 27 months, and the 2-year event-free survival (2y-EFS) was 77.3% in the entire population. ROC analyses for the 2y-EFS reached statistical significance for total MTV as well as four second-order metrics (homogeneity, contrast, correlation, dissimilarity) and five third-order metrics (LZE (Long-Zone Emphasis), LZLGE (Long-Zone Low-Grey Level Emphasis), LZHGE (Long-Zone High-Grey Level Emphasis), GLNU (Grey-Level Non-Uniformity) and ZP (Zone Percentage)). LZHGE displayed the highest ROC analysis accuracy (acc. = 0.76) and the best discriminant value on univariable Kaplan-Meier analysis (p < 0.0001, HR = 4.54). On multivariable analysis, including IPIaa, total MTV and LZHGE, LZHGE was the only independent predictor of 2y-EFS. These results were confirmed on the validation dataset. CONCLUSIONS: Baseline 18F-FDG PET heterogeneity of the largest lymphoma lesion is a promising predictor of 2y-EFS in newly diagnosed DLBCL treated with immunochemotherapy. KEY POINTS: •18F-FDG metabolic heterogeneity emerges as a new tool for survival prognostication of patients and has been explored in many solid tumours with promising results. • Baseline18F-FDG PET heterogeneity of the largest lymphoma lesion is an independent predictor of 2y-EFS in newly diagnosed DLBCL treated with immunochemotherapy. • DLBCL patients presenting with a heterogeneous tumour displayed a worse prognosis.

HYPHYCA: a prospective study in 613 patients conducting a comprehensive analysis for predictive factors of physiological 18F-FDG anal uptake.

BACKGROUND: Anal cancer is a relatively rare tumor of which incidence increases in developed countries. 18F-FDG PET has been increasingly used for its post radio-chemotherapy evaluation. However, several authors have reported the risk of local false-positive findings leading to low specificity and positive predictive values. These false-positive results could be due to post-radiotherapy inflammation or infection but certainly also to physiological anal canal uptake that is observed on a regular basis in clinical practice. The purpose of this prospective study (NCT03506529; HYPHYCA) was therefore to seek predictive factors of physiological anal canal hypermetabolism. MATERIALS AND METHODS: Over a 2-month period, patients aged 18 years old and more, referred for 18F-FDG PET-CT at two EARL-accredited PET centers were included, after obtaining their informed and written consent. They were asked to fill in a questionnaire including seven closed questions about usual intestinal transit, ongoing medications relative to intestinal transit, history of digestive, and anal and/or pelvic diseases. Age, gender, and body mass index (BMI) were recorded. A single nuclear medicine physician visually and quantitatively analyzed anal canal uptake (SUVmax_EARL) and assessed visual rectal content (air, feces, or both) and the largest rectal diameter (mm). RESULTS: Six hundred and thirteen patients were included (sex ratio F/M = 0.99) and 545 (89%) questionnaires were entirely completed. Significantly more males presented anal canal hypermetabolism (sex ratio (M/F) = 1.18 versus 0.85, p = 0.048). Moreover, patients with anal canal hypermetabolism had higher BMI (27.6 (5.7) kg/m2 versus 23.9 (4.5) kg/m2, p < 0.0001), higher rate of hemorrhoid history (43% versus 27%, p = 0.016), and higher rate of rectum filled with only feces (21% versus 12%, p = 0.019) as compared to patients with no anal canal uptake. On logistic regression, all these variables were found to be independent predictors of the occurrence of an anal canal hypermetabolism. Odds ratio were 1.16 (1.12-1.20) per unit of BMI (kg/m2) (p < 0.0001), 1.48 (1.04-2.11) for males (p = 0.030), 1.64 (1.10-2.45) for hemorrhoids history (p = 0.016), and 1.94 (1.147-3.22) for the rectum filled with only feces (p = 0.010). CONCLUSION: According to our study, the predictive factors of physiological anal canal hypermetabolism are high BMI, male gender, hemorrhoid history, and rectum filled with only feces. This may pave the way to a more specific interpretation of post radio-chemotherapy PET evaluations of anal canal cancer, provided that other studies are conducted in this specific population. TRIAL REGISTRATION: This prospective study was registered at Clinicaltrial.gov: NCT03506529; HYPHYCA on April 24, 2018.

Hormonal Receptor Immunochemistry Heterogeneity and 18F-FDG Metabolic Heterogeneity: Preliminary Results of Their Relationship and Prognostic Value in Luminal Non-Metastatic Breast Cancers.

INTRODUCTION: We aimed to investigate whether 18F-FDG PET metabolic heterogeneity reflects the heterogeneity of estrogen receptor (ER) and progesterone receptor (PR) expressions within luminal non-metastatic breast tumors and if it could help in identifying patients with worst event-free survival (EFS). MATERIALS AND METHODS: On 38 PET high-resolution breast bed positions, a single physician drew volumes of interest encompassing the breast tumors to extract SUVmax, histogram parameters and textural features. High-resolution immunochemistry (IHC) scans were analyzed to extract Haralick parameters and descriptors of the distribution shape. Correlation between IHC and PET parameters were explored using Spearman tests. Variables of interest to predict the EFS status at 8 years (EFS-8y) were sought by means of a random forest classification. EFS-8y analyses were then performed using univariable Kaplan-Meier analyses and Cox regression analysis. When appropriate, Mann-Whitney tests and Spearman correlations were used to explore the relationship between clinical data and tumoral PET heterogeneity variables. RESULTS: For ER expression, correlations were mainly observed with 18F-FDG histogram parameters, whereas for PR expression correlations were mainly observed with gray-level co-occurrence matrix (GLCM) parameters. The strongest correlations were observed between skewness_ER and uniformity_HISTO (ρ = -0.386, p = 0.017) and correlation_PR and entropy_GLCM (ρ = 0.540, p = 0.001), respectively. The median follow-up was 6.5 years and the 8y-EFS was 71.0%. Random forest classification found age, clinical stage, SUVmax, skewness_ER, kurtosis_ER, entropy_HISTO, and uniformity_HISTO to be variables of importance to predict the 8y-EFS. Univariable Kaplan-Meier survival analyses showed that skewness_ER was a predictor of 8y-EFS (66.7 ± 27.2 versus 19.1 ± 15.2, p = 0.018 with a cut-off value set to 0.163) whereas other IHC and PET parameters were not. On multivariable analysis including age, clinical stage and skewness_ER, none of the parameters were independent predictors. Indeed, skewness_ER was significantly higher in youngest patients (ρ = -0.351, p = 0.031) and in clinical stage III tumors (p = 0.023). CONCLUSION: A heterogeneous distribution of ER within the tumor in IHC appeared as an EFS-8y prognosticator in luminal non-metastatic breast cancers. Interestingly, it appeared to be correlated with PET histogram parameters which could therefore become potential non-invasive prognosticator tools, provided these results are confirmed by further larger and prospective studies.

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 METHODS: Retrospectively 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. RESULTS: Mean (± 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. CONCLUSIONS: Neither 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.

Why harmonization is needed when using FDG PET/CT as a prognosticator: demonstration with EARL-compliant SUV as an independent prognostic factor in lung cancer.

BACKGROUND: To determine EARL-compliant prognostic SUV thresholds in a mature cohort of patients with locally advanced NSCLC, and to demonstrate how detrimental it is to use a threshold determined on an older-generation PET system with a newer PET/CT machine, and vice versa, or to use such a threshold with non-harmonized multicentre pooled data. MATERIALS AND METHODS: This was a single-centre retrospective study including 139 consecutive stage IIIA-IIIB patients. PET data were acquired as per the EANM guidelines and reconstructed with unfiltered point spread function (PSF) reconstruction. Subsequently, a 6.3 mm Gaussian filter was applied using the EQ.PET (Siemens Healthineers) methodology to meet the EANM/EARL harmonizing standards (PSFEARL). A multicentre study including non-EARL-compliant systems was simulated by randomly creating four groups of patients whose images were reconstructed with unfiltered PSF and PSF with Gaussian post-filtering of 3, 5, and 10 mm. Identification of optimal SUV thresholds was based on a two-fold cross-validation process that partitioned the overall sample into learning and validation subsamples. Proportional Cox hazards models were used to estimate age-adjusted and multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals. Kaplan-Meier curves were compared using the log rank test. RESULTS: Median follow-up was 28 months (1-104 months). For the whole population, the estimated overall survival rate at 36 months was 0.39 [0.31-0.47]. The optimal SUVmax cutoff value was 25.43 (95% CI: 23.41-26.31) and 8.47 (95% CI: 7.23-9.31) for the PSF and for the EARL-compliant dataset respectively. These SUVmax cutoff values were both significantly and independently associated with lung cancer mortality; HRs were 1.73 (1.05-2.84) and 1.92 (1.16-3.19) for the PSF and the EARL-compliant dataset respectively. When (i) applying the optimal PSF SUVmax cutoff on an EARL-compliant dataset and the optimal EARL SUVmax cutoff on a PSF dataset or (ii) applying the optimal EARL compliant SUVmax cutoff to a simulated multicentre dataset, the tumour SUVmax was no longer significantly associated with lung cancer mortality. CONCLUSION: The present study provides the PET community with an EARL-compliant SUVmax as an independent prognosticator for advanced NSCLC that should be confirmed in a larger cohort, ideally at other EARL accredited centres, and highlights the need to harmonize PET quantitative metrics when using them for risk stratification of patients.

Correction to: Why harmonization is needed when using FDG PET/CT as a prognosticator: demonstration with EARL-compliant SUV as an independent prognostic factor in lung cancer.

An error occurred in the labelling of Fig. 3, where math symbols for SUV thresholds were inverted in panel b when the EARL threshold was applied to the PSF dataset and vice versa. This figure should read as follows: Fig. 3: Prognostic value of tumour SUVmax.

Implications of reconstruction protocol for histo-biological characterisation of breast cancers using FDG-PET radiomics.

BACKGROUND: The aim of this study is to determine if the choice of the 18F-FDG-PET protocol, especially matrix size and reconstruction algorithm, is of importance to discriminate between immunohistochemical subtypes (luminal versus non-luminal) in breast cancer with textural features (TFs). PROCEDURES: Forty-seven patients referred for breast cancer staging in the framework of a prospective study were reviewed as part of an ancillary study. In addition to standard PET imaging (PSFWholeBody), a high-resolution breast acquisition was performed and reconstructed with OSEM and PSF (OSEMbreast/PSFbreast). PET standard metrics and TFs were extracted. For each reconstruction protocol, a prediction model for tumour classification was built using a random forests method. Spearman coefficients were used to seek correlation between PET metrics. RESULTS: PSFWholeBody showed lower numbers of voxels within VOIs than OSEMbreast and PSFbreast with median (interquartile range) equal to 130 (43-271), 316 (167-1042), 367 (107-1221), respectively (p < 0.0001). Therefore, using LifeX software, 28 (59%), 46 (98%) and 42 (89%) patients were exploitable with PSFWholeBody, OSEMbreast and PSFbreast, respectively. On matched comparisons, PSFbreast reconstruction presented better abilities than PSFwholeBody and OSEMbreast for the classification of luminal versus non-luminal breast tumours with an accuracy reaching 85.7% as compared to 67.8% for PSFwholeBody and 73.8% for OSEMbreast. PSFbreast accuracy, sensitivity, specificity, PPV and NPV were equal to 85.7%, 94.3%, 42.9%, 89.2%, 60.0%, respectively. Coarseness and ZLNU were found to be main variables of importance, appearing in all three prediction models. Coarseness was correlated with SUVmax on PSFwholeBody images (ρ = - 0.526, p = 0.005), whereas it was not on OSEMbreast (ρ = - 0.183, p = 0.244) and PSFbreast (ρ = - 0.244, p = 0.119) images. Moreover, the range of its values was higher on PSFbreast images as compared to OSEMbreast, especially in small lesions (MTV < 3 ml). CONCLUSIONS: High-resolution breast PET acquisitions, applying both small-voxel matrix and PSF modelling, appeared to improve the characterisation of breast tumours.