Respiratory gated multistatic PET reconstructions to delineate radiotherapy target volume in patients with mobile lung tumors.

BACKGROUND: PET-CT with 18F-FDG or other radiopharmaceuticals is a recommended tool to help the delineation of lung cancers candidate to radiotherapy. The motion artifacts caused by respiratory movements are reduced by 4D acquisitions. We introduced an extended reconstruction algorithm (multiple reconstruct register and average [multi-RRA]) which requires much shorter acquisition times than standard 4D PET-CT. Our aim was to evaluate the interest on multi-RRA images as an alternative of 3D and 4D PET-CT for the delineation of lung lesion. METHODS: PET acquisitions synchronized to the respiratory signal were obtained in 18 patients with mobile lung tumors. We compared the tumor volumes delineated on Multi-RRA images to 3D and 4D PET-CT, considering the 4D CT as a reference. The tumor volumes were delineated and compared with topologic similarity indexes (Dice, Jaccard and overlap). RESULTS: Twenty tumors were delineated. The volumes delineated with multi-RRA and 4D PET were not significantly different (mean difference of 0.2±0.7 mL). Comparison by pairs (Tukey-Kramer test) showed that 3D-PET volumes were significantly smaller than 4D-PET and multi-RRA volumes (P<0.001). Topologic similarity indexes with 4D-PET were slightly statistically higher with multi-RRA than with 3D-PET (Dice and Jaccard) or 4D-CT (Dice, Jaccard and Overlap). CONCLUSIONS: The tumor volumes delineated on multi-RRA are similar to the volumes obtained with 4D PET, with shorter acquisition time.

Radiotherapy boost in patients with hypoxic lesions identified by 18F-FMISO PET/CT in non-small-cell lung carcinoma: can we expect a better survival outcome without toxicity? [RTEP5 long-term follow-up].

PURPOSE: Chemoradiotherapy is the reference curative-intent treatment for nonresectable locally advanced non-small-cell lung carcinoma (NSCLC), with unsatisfactory survival, partially due to radiation resistance in hypoxic tissues. The objective was to update survival and toxicity at 3 years following radiotherapy boost to hypoxic tumours in NSCLC patients treated with curative-intent chemoradiotherapy. METHODS: This was an open-label, nonrandomized, multicentre, phase II clinical trial. 18F-Fluoromisonidazole (18F-FMISO) PET/CT was used to determine the hypoxic profile of the patients. 18F-FMISO-positive patients and those without organ-at-risk constraints received a radiotherapy boost (70-84 Gy); the others received standard radiotherapy (66 Gy). Overall survival (OS), progression-free survival (PFS) and safety were assessed. RESULTS: A total of 54 patients were evaluated. OS and PFS rates at 3 years were 48.5% and 28.8%, respectively. The median OS in the 18F-FMISO-positive patients was 25.8 months and was not reached in the 18F-FMISO-negative patients (p = 0.01). A difference between the groups was also observed for PFS (12 months vs. 26.2 months, p = 0.048). In 18F-FMISO-positive patients, no difference was observed in OS in relation to dose, probably because of the small sample size (p = 0.30). However, the median OS seemed to be in favour of patients who received the radiotherapy boost (26.5 vs. 15.3 months, p = 0.71). In patients who received the radiotherapy boost, no significant late toxicities were observed. CONCLUSION: 18F-FMISO uptake in NSCLC patients is strongly associated with features indicating a poor prognosis. In 18F-FMISO-positive patients, the radiotherapy boost seemed to improve the OS by 11.2 months. A further clinical trial is needed to investigate the efficacy of a radiotherapy boost in patients with hypoxic tumours.

18F-FDG-PET partial volume effect correction using a modified recovery coefficient approach based on functional volume and local contrast: physical validation and clinical feasibility in oncology.

BACKGROUND: 2-deoxy-2-[18F]fluoro-D-glucose 18F-FDG uptake within tumors reflects the glucose consumption of malignant tumors, i.e., the tumor activity. Thus, 18F-FDG uptake measurements enable improved therapeutic monitoring of patients in chemo- or radiotherapy treatment through the detection of changes in tumor uptake via quantitative measurements of the lesion standard uptake values (SUVs) or activity concentrations. A major bias that affects positron emission tomography (PET) image quantitation is the partial volume effect (PVE), which most strongly affects the smallest structures due to the poor spatial resolution of PET. Thus, PVE corrections are important when 18F-FDG-PET images are used as a quantitative tool for monitoring responses to therapy. The aim of this paper was to propose a PVE correction based on a modified recovery coefficient method (termed FARCAS) that considers the functional volumes and local contrasts of lesions that are automatically determined using a semi-automatic iterative segmentation algorithm. METHODS: The FARCAS method consists of establishing a set of calibration curves based on the mathematical fitting of the RC values as a function of the automatically determined functional lesion volume and local lesion contrast. We set up our method using data from a cylindrical phantom that included spheres of different volumes (range: 0.43 to 97.8 mL) and contrasts (range: 1.7 to 22.9), and we assessed the method using both cylindrical and anthropomorphic phantom data that also included spheres of different volumes and contrasts. FARCAS was also compared with conventional RC methods that only considered the lesion functional volume, either automatically determined (RCVa) or using the ground truth volume (RCVgt). Finally, the clinical feasibility of FARCAS and its evaluation on tumor classification were also assessed on 24 NSCLC lesions. RESULTS: Whatever the phantom considered, for the spheres with contrast <5, FARCAS obtained comparable results to RCVgt and better than RCVa. For the spheres with contrast >5, FARCAS and RCVa were not statistically different, neither for the cylindrical and nor the anthropomorphic phantom. For the cylindrical phantom FARCAS yielded corrections that were not statistically different to those of RCVa for the smallest spheres (V<2 mL), but statistically superior for the larger spheres (V≥2 mL). RCVgt maintained a non-statistically superior accuracy. Regarding the anthropomorphic data, FARCAS was statistically more accurate than RCVa but not RCVgt. As main findings regarding the clinical data, FARCAS modified the classifications of five of 24 NSCLC lesions based on quantitative PERCIST criteria. CONCLUSIONS: The PVE correction proposed in this paper allows the accurate quantification of the PVE-corrected SUV, allowing also an automatic definition of the Metabolic Target Volume (MTV). Our results revealed that the PVE correction based on FARCAS is a better approach than conventional RC to significantly reduce the impact of PVE on lesion quantification, thus improving the evaluation of tumor response to treatment based on PET-CT images.

Pretreatment metabolic tumour volume is predictive of disease-free survival and overall survival in patients with oesophageal squamous cell carcinoma.

PURPOSE: It has been suggested that FDG PET has predictive value for the prognosis of treated oesophageal carcinoma. However, the studies reported in the literature have shown discordant results. The aim of this study was to determine whether pretherapy quantitative metabolic parameters correlate with patient outcomes. METHODS: Included in the study were 67 patients with a histological diagnosis of oesophageal squamous cell carcinoma. Each patient underwent (18)F-FDG PET (4.5 MBq/kg) before chemoradiotherapy. Quantitative analysis was performed using the following parameters: age, weight loss, location, N stage, OMS performance status, MTVp and MTVp' (metabolic tumour volume determined by two different physicians), MTV40% (volume for a threshold of 40 % of SUVmax), MTVa (volume automatically determined with a contrast-based adaptive threshold method), SUVmax, SUVmean and TLG (total lesion glycolysis). RESULTS: MTVp and MTV40% were highly correlated (Pearson's index 0.92). SUVmeanp and SUVmean40% were also correlated (Pearson's index 0.86), as were TLGp and TLG40% (Pearson's index 0.98). Similarly, the parameters obtained with the adaptive threshold method (MTVa, SUVmeana and TLGa) were correlated with those obtained manually (MTVp, SUVmeanp and TLGp). The manual metabolic tumour volume determination (MTVp and MTVp') was reproducible. Multivariate analysis for disease-free survival (DFS) showed that a larger MTVp was associated with a shorter DFS (p = 0.004) and that a higher SUVmax was associated with a longer DFS (p = 0.02). Multivariate analysis for overall survival (OS) showed that a larger MTVp was associated with a shorter OS (p = 0.01) and that a tumour in the distal oesophagus was associated with a longer OS (p = 0.005). The associations among the other parameters were not statistically significant. CONCLUSION: Metabolic tumour volume is a major prognostic factor for DFS and OS in patients with oesophageal squamous cell carcinoma. Higher SUVmax values were paradoxically associated with longer survival. The location of the tumour also appeared to affect prognosis.

Quantitative MRI to Characterize Hypoxic Tumors in Comparison to FMISO PET/CT for Radiotherapy in Oropharynx Cancers.

Intratumoral hypoxia is associated with a poor prognosis and poor response to treatment in head and neck cancers. Its identification would allow for increasing the radiation dose to hypoxic tumor subvolumes. 18F-FMISO PET imaging is the gold standard; however, quantitative multiparametric MRI could show the presence of intratumoral hypoxia. Thus, 16 patients were prospectively included and underwent 18F-FDG PET/CT, 18F-FMISO PET/CT, and multiparametric quantitative MRI (DCE, diffusion and relaxometry T1 and T2 techniques) in the same position before treatment. PET and MRI sub-volumes were segmented and classified as hypoxic or non-hypoxic volumes to compare quantitative MRI parameters between normoxic and hypoxic volumes. In total, 13 patients had hypoxic lesions. The Dice, Jaccard, and overlap fraction similarity indices were 0.43, 0.28, and 0.71, respectively, between the FDG PET and MRI-measured lesion volumes, showing that the FDG PET tumor volume is partially contained within the MRI tumor volume. The results showed significant differences in the parameters of SUV in FDG and FMISO PET between patients with and without measurable hypoxic lesions. The quantitative MRI parameters of ADC, T1 max mapping and T2 max mapping were different between hypoxic and normoxic subvolumes. Quantitative MRI, based on free water diffusion and T1 and T2 mapping, seems to be able to identify intra-tumoral hypoxic sub-volumes for additional radiotherapy doses.

Evaluation of the capability and reproducibility of RECIST 1.1. measurements by technologists in breast cancer follow-up: a pilot study.

The evaluation of tumor follow-up according to RECIST 1.1 has become essential in clinical practice given its role in therapeutic decision making. At the same time, radiologists are facing an increase in activity while facing a shortage. Radiographic technologists could contribute to the follow-up of these measures, but no studies have evaluated their ability to perform them. Ninety breast cancer patients were performed three CT follow-ups between September 2017 and August 2021. 270 follow-up treatment CT scans were analyzed including 445 target lesions. The rate of agreement of classifications RECIST 1.1 between five technologists and radiologists yielded moderate (k value between 0.47 and 0.52) and substantial (k value = 0.62 and k = 0.67) agreement values. 112 CT were classified as progressive disease (PD) by the radiologists, and 414 new lesions were identified. The analysis showed a percentage of strict agreement of progressive disease classification between reader-technologists and radiologists ranging from substantial to almost perfect agreement (range 73-97%). Analysis of intra-observer agreement was strong at almost perfect (k > 0.78) for 3 technologists. These results are encouraging regarding the ability of selected technologists to perform measurements according to RECIST 1.1 criteria by CT scan with good identification of disease progression.

Synthetic MRI for Radiotherapy Planning for Brain and Prostate Cancers: Phantom Validation and Patient Evaluation.

Purpose: We aimed to evaluate the accuracy of T 1 and T 2 mappings derived from a multispectral pulse sequence (magnetic resonance image compilation, MAGiC®) on 1.5-T MRI and with conventional sequences [gradient echo with variable flip angle (GRE-VFA) and multi-echo spin echo (ME-SE)] compared to the reference values for the purpose of radiotherapy treatment planning. Methods: The accuracy of T 1 and T 2 measurements was evaluated with 2 coils [head and neck unit (HNU) and BODY coils] on phantoms using descriptive statistics and Bland-Altman analysis. The reproducibility and repeatability of T 1 and T 2 measurements were performed on 15 sessions with the HNU coil. The T 1 and T 2 synthetic sequences obtained by both methods were evaluated according to quality assurance (QA) requirements for radiotherapy. T 1 and T 2 in vivo measurements of the brain or prostate tissues of two groups of five subjects were also compared. Results: The phantom results showed good agreement (mean bias, 8.4%) between the two measurement methods for T 1 values between 490 and 2,385 ms and T 2 values between 25 and 400 ms. MAGiC® gave discordant results for T 1 values below 220 ms (bias with the reference values, from 38% to 1,620%). T 2 measurements were accurately estimated below 400 ms (mean bias, 8.5%) by both methods. The QA assessments are in agreement with the recommendations of imaging for contouring purposes for radiotherapy planning. On patient data of the brain and prostate, the measurements of T 1 and T 2 by the two quantitative MRI (qMRI) methods were comparable (max difference, <7%). Conclusion: This study shows that the accuracy, reproducibility, and repeatability of the multispectral pulse sequence (MAGiC®) were compatible with its use for radiotherapy treatment planning in a range of values corresponding to soft tissues. Even validated for brain imaging, MAGiC® could potentially be used for prostate qMRI.

Clinical and phantom validation of a deep learning based denoising algorithm for F-18-FDG PET images from lower detection counting in comparison with the standard acquisition.

BACKGROUND: PET/CT image quality is directly influenced by the F-18-FDG injected activity. The higher the injected activity, the less noise in the reconstructed images but the more radioactive staff exposition. A new FDA cleared software has been introduced to obtain clinical PET images, acquired at 25% of the count statistics considering US practices. Our aim is to determine the limits of a deep learning based denoising algorithm (SubtlePET) applied to statistically reduced PET raw data from 3 different last generation PET scanners in comparison to the regular acquisition in phantom and patients, considering the European guidelines for radiotracer injection activities. Images of low and high contrasted (SBR = 2 and 5) spheres of the IEC phantom and high contrast (SBR = 5) of micro-spheres of Jaszczak phantom were acquired on 3 different PET devices. 110 patients with different pathologies were included. The data was acquired in list-mode and retrospectively reconstructed with the regular acquisition count statistic (PET100), 50% reduction in counts (PET50) and 66% reduction in counts (PET33). These count reduced images were post-processed with SubtlePET to obtain PET50 + SP and PET33 + SP images. Patient image quality was scored by 2 senior nuclear physicians. Peak-signal-to-Noise and Structural similarity metrics were computed to compare the low count images to regular acquisition (PET100). RESULTS: SubtlePET reliably denoised the images and maintained the SUVmax values in PET50 + SP. SubtlePET enhanced images (PET33 + SP) had slightly increased noise compared to PET100 and could lead to a potential loss of information in terms of lesion detectability. Regarding the patient datasets, the PET100 and PET50 + SP were qualitatively comparable. The SubtlePET algorithm was able to correctly recover the SUVmax values of the lesions and maintain a noise level equivalent to full-time images. CONCLUSION: Based on our results, SubtlePET is adapted in clinical practice for half-time or half-dose acquisitions based on European recommended injected dose of 3 MBq/kg without diagnostic confidence loss.

First Comparison between [18f]-FMISO and [18f]-Faza for Preoperative Pet Imaging of Hypoxia in Lung Cancer.

Hypoxic areas are typically resistant to treatment. However, the fluorine-18-fluoroazomycin-arabinoside (FAZA) and fluorine 18 misonidazole (FMISO) tracers have never been compared in non small cell lung cancer (NSCLC). This study compares the capability of 18F-FAZA PET/CT with that of 18F-FMISO PET/CT for detecting hypoxic tumour regions in early and locally advanced NSCLC patients. We prospectively evaluated patients who underwent preoperative PET scans before surgery for localised NSCLC (i.e., fluorodeoxyglucose (FDG)-PET, FMISO-PET, and FAZA-PET). The PET data of the three tracers were compared with each other and then compared to immunohistochemical analysis (GLUT-1, CAIX, LDH-5, and HIF1-Alpha) after tumour resection. Overall, 19 patients with a mean age of 68.2 ± 8 years were included. There were 18 lesions with significant uptake (i.e., SUVmax >1.4) for the F-MISO and 17 for FAZA. The mean SUVmax was 3 (±1.4) with a mean volume of 25.8 cc (±25.8) for FMISO and 2.2 (±0.7) with a mean volume of 13.06 cc (±13.76) for FAZA. The SUVmax of F-MISO was greater than that of FAZA (p = 0.0003). The SUVmax of F-MISO shows a good correlation with that of FAZA at 0.86 (0.66-0.94). Immunohistochemical results are not correlated to hypoxia PET regardless of the staining. The two tracers show a good correlation with hypoxia, with FMISO being superior to FAZA. FMISO, therefore, remains the reference tracer for defining hypoxic volumes.

Uptake of Pineal Gland Visible on 18F-DOPA PET/CT With Last Generation of SiPM PET/CT.

A 17-year-old girl underwent an F-DOPA brain PET/CT on a new high-resolution digital SiPM PET/CT (Vision600 Siemens) to explore a suspicion of recurrence of a pilocytic astrocytoma. This study showed a local recurrence, but a second intense focal uptake was visible above, more intense than striata. On fused MRI, this was the pineal gland considered as physiological. This physiological uptake, due to a pineal DOPA decarboxylase activity, has also been observed with this PET system in other patients with F-DOPA to explore movement disorders. New high-resolution PET can show uptake of small structures by being less dependent to partial volume effect.

Impact of the Bayesian penalized likelihood algorithm (Q.Clear®) in comparison with the OSEM reconstruction on low contrast PET hypoxic images.

PURPOSE: To determine the impact of the Bayesian penalized likelihood (BPL) reconstruction algorithm in comparison to OSEM on hypoxia PET/CT images of NSCLC using 18F-MIZO and 18F-FAZA. MATERIALS AND METHODS: Images of low-contrasted (SBR = 3) micro-spheres of Jaszczak phantom were acquired. Twenty patients with lung neoplasia were included. Each patient benefitted from 18F-MISO and/or 18F-FAZA PET/CT exams, reconstructed with OSEM and BPL. Lesion was considered as hypoxic if the lesion SUVmax > 1.4. A blind evaluation of lesion detectability and image quality was performed on a set of 78 randomized BPL and OSEM images by 10 nuclear physicians. SUVmax, SUVmean, and hypoxic volumes using 3 thresholding approaches were measured and compared for each reconstruction. RESULTS: The phantom and patient datasets showed a significant increase of quantitative parameters using BPL compared to OSEM but had no impact on detectability. The optimal beta parameter determined by the phantom analysis was ß350. Regarding patient data, there was no clear trend of image quality improvement using BPL. There was no correlation between SUVmax increase with BPL and either SUV or hypoxic volume from the initial OSEM reconstruction. Hypoxic volume obtained by a SUV > 1.4 thresholding was not impacted by the BPL reconstruction parameter. CONCLUSION: BPL allows a significant increase in quantitative parameters and contrast without significantly improving the lesion detectability or image quality. The variation in hypoxic volume by BPL depends on the method used but SUV > 1.4 thresholding seems to be the more robust method, not impacted by the reconstruction method (BPL or OSEM). TRIAL REGISTRATION: ClinicalTrials.gov, NCT02490696. Registered 1 June 2015.

Correlations between baseline 18F-FDG PET tumour parameters and circulating DNA in diffuse large B cell lymphoma and Hodgkin lymphoma.

BACKGROUND: 18F-FDG PET/CT is a standard for many B cell malignancies, while blood DNA measurements are emerging tools. Our objective was to evaluate the correlations between baseline PET parameters and circulating DNA in diffuse large B cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). METHODS: Twenty-seven DLBCL and forty-eight cHL were prospectively included. Twelve PET parameters were analysed. Spearman's correlations were used to compare PET parameters each other and to circulating cell-free DNA ([cfDNA]) and circulating tumour DNA ([ctDNA]). p values were controlled by Benjamini-Hochberg correction. RESULTS: Among the PET parameters, three different clusters for tumour burden, fragmentation/massiveness and dispersion parameters were observed. Some PET parameters were significantly correlated with blood DNA parameters, including the total metabolic tumour surface (TMTS) describing the tumour-host interface (e.g. ρ = 0.81 p < 0.001 for [ctDNA] of DLBLC), the tumour median distance between the periphery and the centroid (medPCD) describing the tumour's massiveness (e.g. ρ = 0.81 p < 0.001 for [ctDNA] of DLBLC) and the volume of the bounding box including tumours (TumBB) describing the disease's dispersion (e.g. ρ = 0.83 p < 0.001 for [ctDNA] of DLBLC). CONCLUSIONS: Some PET parameters describing tumour burden, fragmentation/massiveness and dispersion are significantly correlated with circulating DNA parameters of DLBCL and cHL patients. These results could help to understand the pathophysiology of B cell malignancies.

FDG and FMISO PET-guided dose escalation with intensity-modulated radiotherapy in lung cancer.

BACKGROUND: Concomitant chemo-radiotherapy is the reference treatment for non-resectable locally-advanced Non-Small Cell Lung Cancer (NSCLC). Increasing radiotherapy total dose in the whole tumour volume has been shown to be deleterious. Functional imaging with positron emission tomography (PET/CT) offers the potential to identify smaller and biologically meaningful target volumes that could be irradiated with larger doses without compromising Organs At Risk (OAR) tolerance. This study investigated four scenarios, based on 18FDG and 18F-miso PET/CT, to delineate the target volumes and derive radiotherapy plans delivering up to 74Gy. METHOD: Twenty-one NSCLC patients, selected from a prospective phase II trial, had 18FDG- and 18F-miso PET/CT before the start of radiotherapy and 18FDG PET/CT during the radiotherapy (42Gy). The plans were based planned on a standard plan delivering 66 Gy (plan 1) and on three different boost strategies to deliver 74Gy total dose in pre-treatment 18FDG hotspot (70% of SUVmax) (plan 2), pre-treatment 18F-miso target (SUVmax > 1.4) (plan 3) and per-treatment 18FDG residual (40% of SUVmax). (plan 4). RESULTS: The mean target volumes were 4.8 cc (± 1.1) for 18FDG hotspot, 38.9 cc (± 14.5) for 18F-miso and 36.0 cc (± 10.1) for per-treatment 18FDG. In standard plan (66 Gy), the mean dose covering 95% of the PTV (D95%) were 66.5 (± 0.33), 66.1 (± 0.32) and 66.1 (± 0.32) Gy for 18FDG hotspot, 18F-miso and per-treatment 18FDG. In scenario 2, the mean D95% was 72.5 (± 0.25) Gy in 18FDG hotspot versus 67.9 (± 0.49) and 67.9 Gy (± 0.52) in 18F-miso and per-treatment 18FDG, respectively. In scenario 3, the mean D95% was 72.2 (± 0.27) Gy to 18F-miso versus 70.4 (± 0.74) and 69.5Gy (± 0.74) for 18FDG hotspot and per-treatment 18FDG, respectively. In scenario 4, the mean D95% was 73.1 (± 0.3) Gy to 18FDG per-treatment versus 71.9 (± 0.61) and 69.8 (± 0.61) Gy for 18FDG hotspot and 18F-miso, respectively. The dose/volume constraints to OARs were matched in all scenarios. CONCLUSION: Escalated doses can be selectively planned in NSCLC target volumes delineated on 18FDG and 18F-miso PET/CT functional images. The most relevant strategy should be investigated in clinical trials. TRIAL REGISTRATION: (RTEP5, NCT01576796 , registered 15 june 2012).

A new methodology to derive 3D kinetic parametric FDG PET images based on a mathematical approach integrating an error model of measurement.

BACKGROUND: In FDG-PET, SUV images are hampered by large potential biases. Our aim was to develop an alternative method (ParaPET) to generate 3D kinetic parametric FDG-PET images easy to perform in clinical oncology. METHODS: The key points of our method are the use of a new error model of PET measurement extracted from a late dynamic PET acquisition of 15 min, centered over the lesion and an image-derived input function (IDIF). The 15-min acquisition is reconstructed to obtain five images of FDG mean activity concentration and images of its variance to model errors of PET measurement. Our approach is carried out on each voxel to derive 3D kinetic parameter images. ParaPET was evaluated and compared to Patlak analysis as a reference. Hunter and Barbolosi methods (Barbolosi-Bl: with blood samples or Barbolosi-Im: with IDIF) were also investigated and compared to Patlak. Our evaluation was carried on Ki index, the net influx rate and its maximum value in the lesion (Ki,max). RESULTS: This parameter was obtained from 41 non-small cell lung cancer lesions associated with 4 to 5 blood samples per patient, required for the Patlak analysis. Compare to Patlak, the median relative difference and associated range (median; [min;max]) in Ki,max estimates were not statistically significant (Wilcoxon test) for ParaPET (- 3.0%; [- 31.9%; 47.3%]; p = 0.08) but statistically significant for Barbolosi-Bl (- 8.0%; [- 30.8%; 53.7%]; p = 0.001), Barbolosi-Im (- 7.9%; [- 38.4%; 30.6%]; p = 0.007) or Hunter (32.8%; [- 14.6%; 132.2%]; p < 10- 5). In the Bland-Altman plots, the ratios between the four methods and Patlak are not dependent of the Ki magnitude, except for Hunter. The 95% limits of agreement are comparable for ParaPET (34.7%), Barbolosi-Bl (30.1%) and Barbolosi-Im (30.8%), lower to Hunter (81.1%). In the 25 lesions imaged before and during the radio-chemotherapy, the decrease in the FDG uptake (ΔSUVmax or ΔKi,max) is statistically more important (p < 0.02, Wilcoxon one-tailed test) when estimated from the Ki images than from the SUV images (additional median variation of - 2.3% [- 52.6%; + 19.1%] for ΔKi,max compared to ΔSUVmax). CONCLUSION: None of the four methodologies is yet ready to replace the Patlak approach, and further improvements are still required. Nevertheless, ParaPET remains a promising approach, offering a non-invasive alternative to methods based on multiple blood samples and only requiring a late PET acquisition. It allows deriving Ki values, highly correlated and presenting the lowest relative bias with Patlak estimates, in comparison to the other methods we evaluated. Moreover, ParaPET gives access to quantitative information at the pixel level, which needs to be evaluated in the perspective of radiomic and tumour response. TRIAL REGISTRATION: NCT 02821936 ; May 2016.

Clinical respiratory motion correction software (reconstruct, register and averaged-RRA), for 18F-FDG-PET-CT: phantom validation, practical implications and patient evaluation.

OBJECTIVE: On fluorine-18 fludeoxyglucose (18F-FDG) positron emission tomography (PET) CT of pulmonary or hepatic lesions, standard uptake value (SUV) is often underestimated due to patient breathing. The aim of this study is to validate, on phantom and patient data, a motion correction algorithm [reconstruct, register and averaged (RRA)] implemented on a PET-CT system. METHODS: Three phantoms containing five spheres filled with 18F-FDG and suspended in a water or Styrofoam®18F-FDG-filled tank to create different contrasts and attenuation environment were acquired on a Discovery GE710. The spheres were animated with a 2-cm longitudinal respiratory-based movement. Respiratory-gated (RRA) and ungated PET images were compared with static reference images (without movement). The optimal acquisition time, number of phases and the best phase within the respiratory cycle were investigated. The impact of irregular motion was also investigated. Quantification impact was computed on each sphere. Quantification improvement on 28 lung lesions was also investigated. RESULTS: Phantoms: 4 min was required to obtain a stable quantification with the RRA method. The reference phase and the number of phases used for RRA did not affect the quantification which was similar on static acquisitions but different on ungated images. The results showed that the maximum standard uptake value (SUVmax) restoration is majored for the smallest spheres (≤2.1 ml). PATIENTS: SUVmax on RRA and ungated acquisitions were statistically different to the SUVmax on whole-body images (p = 0.05) but not different from each other (mean SUVmax: 7.0 ± 7.8 vs 6.9 ± 7.8, p = 0.23 on RRA and ungated images, respectively). We observed a statistically significant correlation between SUV restoration and lesion displacement, with a real SUV quantitation improvement for lesion with movement >1.2 mm. CONCLUSION: According to the results obtained using phantoms, RRA method is promising, showing a real impact on the lesion quantification on phantom data. With regard to the patient study, our results showed a trend towards an increase in the SUVs and a decrease in the volume between the ungated and RRA data. We also noticed a statistically significant correlation between the quantitative restoration obtained with RRA compared with ungated data and lesion displacement, indicating that the RRA approach should be reserved to patients with small lesions or nodes moving with a displacement larger than 1.2 cm. Advances in knowledge: This article investigates the performances of motion correction software recently introduced in PET. The conclusion revealed that such respiratory motion correction approach shows a real impact on the lesion quantification but must be reserved to the patient for whom lesion displacement was confirmed and high enough to clearly impact lesion evaluation.

Baseline Total Metabolic Tumor Volume Measured with Fixed or Different Adaptive Thresholding Methods Equally Predicts Outcome in Peripheral T Cell Lymphoma.

The purpose of this study was to compare in a large series of peripheral T cell lymphoma, as a model of diffuse disease, the prognostic value of baseline total metabolic tumor volume (TMTV) measured on 18F-FDG PET/CT with adaptive thresholding methods with TMTV measured with a fixed 41% SUVmax threshold method. METHODS: One hundred six patients with peripheral T cell lymphoma, staged with PET/CT, were enrolled from 5 Lymphoma Study Association centers. In this series, TMTV computed with the 41% SUVmax threshold is a strong predictor of outcome. On a dedicated workstation, we measured the TMTV with 4 adaptive thresholding methods based on characteristic image parameters: Daisne (Da) modified, based on signal-to-background ratio; Nestle (Ns), based on tumor and background intensities; Fit, including a 3-dimensional geometric model based on spatial resolution (Fit); and Black (Bl), based on mean SUVmax The TMTV values obtained with each adaptive method were compared with those obtained with the 41% SUVmax method. Their respective prognostic impacts on outcome prediction were compared using receiver-operating-characteristic (ROC) curve analysis and Kaplan-Meier survival curves. RESULTS: The median value of TMTV41%, TMTVDa, TMTVNs, TMTVFit, and TMTVBl were, respectively, 231 cm3 (range, 5-3,824), 175 cm3 (range, 8-3,510), 198 cm3 (range, 3-3,934), 175 cm3 (range, 8-3,512), and 333 cm3 (range, 3-5,113). The intraclass correlation coefficients were excellent, from 0.972 to 0.988, for TMTVDa, TMTVFit, and TMTVNs, and less good for TMTVBl (0.856). The mean differences obtained from the Bland-Altman plots were 48.5, 47.2, 19.5, and -253.3 cm3, respectively. Except for Black, there was no significant difference within the methods between the ROC curves (P > 0.4) for progression-free survival and overall survival. Survival curves with the ROC optimal cutoff for each method separated the same groups of low-risk (volume ≤ cutoff) from high-risk patients (volume > cutoff), with similar 2-y progression-free survival (range, 66%-72% vs. 26%-29%; hazard ratio, 3.7-4.1) and 2-y overall survival (79%-83% vs. 50%-53%; hazard ratio, 3.0-3.5). CONCLUSION: The prognostic value of TMTV remained quite similar whatever the methods, adaptive or 41% SUVmax, supporting its use as a strong prognosticator in lymphoma. However, for implementation of TMTV in clinical trials 1 single method easily applicable in a multicentric PET review must be selected and kept all along the trial.

Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by 18F-Misonidazole PET/CT in Patients with Non-Small Cell Lung Carcinoma (RTEP5 Study).

See an invited perspective on this article on page 1043.This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant 18F-misonidazole (18F-FMISO) uptake in patients with non-small cell lung carcinoma (NSCLC). Methods: Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The 18F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In 18F-FMISO-positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral α = 0.05, power 1-ß = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were 18F-FMISO-positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%-71%) using RECIST 1.1 (17/34 responders in the 18F-FMISO-positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77-0.96) and 0.63 (95% CI, 0.49-0.74), respectively. DFS was longer in the 18F-FMISO-negative patients (P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the 18F-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (>66 Gy) were reported. Conclusion: Our approach results in a response rate of 40% or more, with acceptable toxicity. 18F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy.

Quantification in simultaneous (99m)Tc/(123)I brain SPECT using generalized spectral factor analysis: a Monte Carlo study.

In SPECT, simultaneous (99m)Tc/(123)I acquisitions allow comparison of the distribution of two radiotracers in the same physiological state, without any image misregistration, but images can be severely distorted due to cross-talk between the two isotopes. We propose a generalized spectral factor analysis (GSFA) method for solving the cross-talk issue in simultaneous (99m)Tc/(123)I SPECT. In GSFA, the energy spectrum of the photons in any pixel is expressed as a linear combination of five common spectra: (99m)Tc and (123)I photopeaks and three scatter spectra. These basis spectra are estimated from a factor analysis of all spectra using physical priors (e.g. Klein-Nishina distributions). GSFA was evaluated on (99m)Tc/(123)I Monte Carlo simulated data and compared to images obtained using recommended spectral windows (WIN) and to the gold standard (GS) images (scatter-free, cross-talk-free and noise-free). Using GSFA, activity concentration differed by less than 9% compared to GS values against differences from -23% to 110% with WIN in the (123)I and (99m)Tc images respectively. Using GSFA, simultaneous (99m)Tc/(123)I imaging can yield images of similar quantitative accuracy as when using sequential and scatter-free (99m)Tc/(123)I imaging in brain SPECT.

Determination of the unmetabolised (18)F-FDG fraction by using an extension of simplified kinetic analysis method: clinical evaluation in paragangliomas.

Tumours with high (18)F-FDG uptake values on static late PET images do not always exhibit high proliferation indices. These discrepancies might be related to high proportion of unmetabolised (18)F-FDG components in the tissues. We propose a method that enables to calculate different (18)F-FDG kinetic parameters based on a new mathematical approach that integrates a measurement error model. Six patients with diagnosed non-metastatic paragangliomas (PGLs) and six control patients with different types of lesions were investigated in this pilot study using (18)F-FDG PET/CT. In all cases, a whole-body acquisition was followed by four static acquisitions centred over the target lesions, associated with venous blood samplings. We used an extension of the Hunter's method to calculate the net influx rate constant (K H). The exact net influx rate constant and vascular volume fraction (K i and V, respectively) were subsequently obtained by the method of least squares. Next, we calculated the mean percentages of metabolised (PM) and unmetabolised (PUM) (18)F-FDG components, and the times required to reach 80 % of the amount of metabolised (18)F-FDG (T80%). A test-retest evaluation indicated that the repeatability of our approach was accurate; the coefficients of variation were below 2 % regardless of the kinetic parameters considered. We observed that the PGLs were characterised by high dispersions of the maximum standardised uptake value SUVmax (9.7 ± 11, coefficient of variation CV = 114 %), K i (0.0137 ± 0.0119, CV = 87 %), and V (0.292 ± 0.306, CV = 105 %) values. The PGLs were associated with higher PUM (p = 0.02) and T80% (p = 0.02) values and lower k 3 (p = 0.02) values compared to the malignant lesions despite the similar SUVmax values (p = 0.55). The estimations of these new kinetic parameters are more accurate than SUVmax or K i for in vivo metabolic assessment of PGLs at the molecular level.