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Overexpression of G protein-coupled receptors (GPCRs) in tumours is widely used to develop GPCR-targeting radioligands for solid tumour imaging in the context of diagnosis and even treatment. The human vasoactive neuropeptide urotensin II (hUII), which shares structural analogies with somatostatin, interacts with a single high affinity GPCR named UT. High expression of UT has been reported in several types of human solid tumours from lung, gut, prostate, or breast, suggesting that UT is a valuable novel target to design radiolabelled hUII analogues for cancer diagnosis. In this study, two original urotensinergic analogues were first conjugated to a DOTA chelator via an aminohexanoic acid (Ahx) hydrocarbon linker and then -hUII and DOTA-urantide, complexed to the radioactive metal indium isotope to successfully lead to radiolabelled DOTA-Ahx-hUII and DOTA-Ahx-urantide. The 111 In-DOTA-hUII in human plasma revealed that only 30% of the radioligand was degraded after a 3-h period. DOTA-hUII and DOTA-urantide exhibited similar binding affinities as native peptides and relayed calcium mobilization in HEK293 cells expressing recombinant human UT. DOTA-hUII, not DOTA-urantide, was able to promote UT internalization in UT-expressing HEK293 cells, thus indicating that radiolabelled 111 In-DOTA-hUII would allow sufficient retention of radioactivity within tumour cells or radiolabelled DOTA-urantide may lead to a persistent binding on UT at the plasma membrane. The potential of these radioligands as candidates to target UT was investigated in adenocarcinoma. We showed that hUII stimulated the migration and proliferation of both human lung A549 and colorectal DLD-1 adenocarcinoma cell lines endogenously expressing UT. In vivo intravenous injection of 111 In-DOTA-hUII in C57BL/6 mice revealed modest organ signals, with important retention in kidney. 111 In-DOTA-hUII or 111 In-DOTA-urantide were also injected in nude mice bearing heterotopic xenografts of lung A549 cells or colorectal DLD-1 cells both expressing UT. The observed significant renal uptake and low tumour/muscle ratio (around 2.5) suggest fast tracer clearance from the organism. Together, DOTA-hUII and DOTA-urantide were successfully radiolabelled with 111 Indium, the first one functioning as a UT agonist and the second one as a UT-biased ligand/antagonist. To allow tumour-specific targeting and prolong body distribution in preclinical models bearing some solid tumours, these radiolabelled urotensinergic analogues should be optimized for being used as potential molecular tools for diagnosis imaging or even treatment tools., Competing Interests: The authors declare no conflict of interest.

PET/CT has become a standard examination in oncology but is probably still underused for radiotherapy planning. However, except for the clinical research data that shows the interest of this examination in considering personalized and adaptive radiotherapy, it is also important in defining target volumes. However, before using it in clinical practice, a few prerequisites are required to know the acquisition and segmentation methods. Ideally, PET/CT should become a standard examination for radiotherapy departments in the same way as planning CT and tomorrow as MRI., (Copyright © 2019 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

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. 18 F-Fluoromisonidazole ( 18 F-FMISO) PET/CT was used to determine the hypoxic profile of the patients. 18 F-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 18 F-FMISO-positive patients was 25.8 months and was not reached in the 18 F-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 18 F-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: 18 F-FMISO uptake in NSCLC patients is strongly associated with features indicating a poor prognosis. In 18 F-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.

Background and Aims: Changes in body composition have been described in patients with Crohn's disease, but their predictive performances on disease evolution remain undefined. The aims of our study were to assess, in patients with Crohn's disease requiring abdominal computed tomography, body composition by computed tomography, and to study the outcome according to various body composition parameters at the time of the computed tomography., Methods: Patients with Crohn's disease who underwent abdominal computed tomography for suspected complications were retrospectively included. The definition of adverse outcome included death or need for surgery within 6 months of the computed tomography. Skeletal muscle index and visceral and subcutaneous adiposity indexes were calculated from tissue surface areas measured at the third lumbar vertebra, divided by the height squared., Results: The prevalence of underweight was 26.8% and the prevalence of sarcopenia was 33.6%. After gender adjustment, skeletal muscle index tended to be reduced in patients with adverse outcome, compared with patients without surgery or death [p = 0.07]. Moreover, subcutaneous adiposity index and visceral adiposity index were significantly lower in patients with surgery or death [p = 0.009 and p < 0.001, respectively]. These differences were almost equivalent in both genders for the subcutaneous adiposity index but were clearly stronger in men for the visceral adiposity index., Conclusions: Subcutaneous and visceral adiposity indexes correlate inversely with adverse outcome in patients with Crohn's disease. Alteration of body composition assessed by computed tomography in these patients appears to be a marker of disease severity.

Objectives: To propose an easily applicable segmentation method (perPET-RT) for delineation of tumour volume during radiotherapy on interim fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in patients with non-small cell lung cancer (NSCLC)., Material and Methods: Sixty-seven patients (51 primary tumours, 60 lymph nodes), from 4 prospective studies, underwent an FDG PET/CT scan during the fifth week of radiation therapy, using different generations of PET/CT. Per-therapeutic PET/CT scans were delineated in consensus by two experienced physicians leading to the gold standard threshold to be applied. The mathematical expression of Th opt , the optimal threshold to be applied as a function of the maximum standard uptake value (SUV max ), was determined. The performance of this method (perPET-RT) was assessed by computing the DICE similarity coefficient (DSC) and was compared with 8 fixed threshold values and 3 adaptive thresholding methods., Results: Th opt verified the following expression: Th opt  = A.ln(1/SUV max ) + B where A and B were 2 constants. A and B were independent from the generation of PET/CT, but depended on the type of lesions (primary lung tumours vs. lymph nodes). PerPET-RT showed good to very good agreement in comparison to the gold standard. The mean and standard deviation of DSC value was 0.81 ± 0.13 for lung lesions and 0.78 ± 0.15 for lymph nodes. PerPET-RT showed a significant better agreement than the other segmentation methods (p < 0.001), except for one of the adaptive thresholding method ADT (p = 0.11)., Conclusion: On the database used, perPET-RT has proven its reliability and accuracy for tumour delineation on per-therapeutic FDG PET/CT using only SUV max measurement. This method may be used to delineate tumour volume for dose-escalation planning., Trial Registration: NCT01261598 , NCT01261585 , NCT01576796 .

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 18 FDG and 18 F-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 18 FDG- and 18 F-miso PET/CT before the start of radiotherapy and 18 FDG 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 18 FDG hotspot (70% of SUV max ) (plan 2), pre-treatment 18 F-miso target (SUV max  > 1.4) (plan 3) and per-treatment 18 FDG residual (40% of SUV max ). (plan 4)., Results: The mean target volumes were 4.8 cc (± 1.1) for 18 FDG hotspot, 38.9 cc (± 14.5) for 18 F-miso and 36.0 cc (± 10.1) for per-treatment 18 FDG. 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 18 FDG hotspot, 18 F-miso and per-treatment 18 FDG. In scenario 2, the mean D95% was 72.5 (± 0.25) Gy in 18 FDG hotspot versus 67.9 (± 0.49) and 67.9 Gy (± 0.52) in 18 F-miso and per-treatment 18 FDG, respectively. In scenario 3, the mean D95% was 72.2 (± 0.27) Gy to 18 F-miso versus 70.4 (± 0.74) and 69.5Gy (± 0.74) for 18 FDG hotspot and per-treatment 18 FDG, respectively. In scenario 4, the mean D95% was 73.1 (± 0.3) Gy to 18 FDG per-treatment versus 71.9 (± 0.61) and 69.8 (± 0.61) Gy for 18 FDG hotspot and 18 F-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 18 FDG and 18 F-miso PET/CT functional images. The most relevant strategy should be investigated in clinical trials., Trial Registration: (RTEP5, NCT01576796 , registered 15 june 2012).

In this article, we present a complete automated system for spotting a particular slice in a complete 3D Computed Tomography exam (CT scan). Our approach does not require any assumptions on which part of the patient's body is covered by the scan. It relies on an original machine learning regression approach. Our models are learned using the transfer learning trick by exploiting deep architectures that have been pre-trained on imageNet database, and therefore it requires very little annotation for its training. The whole pipeline consists of three steps: i) conversion of the CT scans into Maximum Intensity Projection (MIP) images, ii) prediction from a Convolutional Neural Network (CNN) applied in a sliding window fashion over the MIP image, and iii) robust analysis of the prediction sequence to predict the height of the desired slice within the whole CT scan. Our approach is applied to the detection of the third lumbar vertebra (L3) slice that has been found to be representative to the whole body composition. Our system is evaluated on a database collected in our clinical center, containing 642 CT scans from different patients. We obtained an average localization error of 1.91±2.69 slices (less than 5 mm) in an average time of less than 2.5 s/CT scan, allowing integration of the proposed system into daily clinical routines., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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 18 F-misonidazole ( 18 F-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 18 F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In 18 F-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-β = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were 18 F-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 18 F-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 18 F-FMISO-negative patients ( P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the 18 F-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. 18 F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The potential benefits of 18 F-fluoro-2-deoxy-D-glucose-positron emission tomography/CT (FDG-PET/CT) imaging for radiotherapy (RT) treatment planning of head and neck squamous cell carcinoma (HNSCC) are increasingly being recognized. It has been suggested that intratumoral subvolumes with high FDG avidity ("hotspots") are potential targets for selected dose escalation. The purposes of this study were to demonstrate that pre-RT FDG-PET/CT can identify intratumoral sites at increased risk of local relapse after RT and to determine an optimal threshold to delineate smaller RT target volumes that would facilitate RT dose escalation without impaired tolerance., Methods: Seventy-two consecutive patients with locally advanced HNSCC treated by RT ± chemotherapy were included in this study. All patients underwent FDG-PET/CT at initial staging (PET A ) and during systematic follow-up (PET R ). FDG-PET/CT was coregistered on the initial CT scan with a rigid method. Various subvolumes (A X ; × = 30%, 40%, 50%, 60%, 70%, 80%, and 90% standardized uptake value maximum [SUVmax] thresholds) within the primary tumor and in the subsequent local relapse (R X ; × = 40% and 70% SUVmax thresholds) were compared together (Dice, Jaccard, overlap fraction, common volume/baseline volume, and common volume/recurrent volume)., Results: Nineteen patients (26%) had local relapses. Using a 40% SUVmax threshold, the initial metabolic tumor volume was significantly higher in patients with local relapses than in controlled patients (10.4 ± 8.6 vs 5.1 ± 4.9 cc; p = .002) as well as total lesion glycolysis (117.9 ± 88.6 vs 60.6 ± 80.4; p = .013). For both methods, the overlap index among A 30 , A 40 , and A 50 subvolumes on PET A and the whole metabolic volume of recurrence R 40 and R 70 on PET R showed a moderate agreement (0.52 to 0.43)., Conclusion: Our study does not find high overlap index values between the initial tumor and recurrence subvolumes, probably because of a suboptimal coregistration. Our results also confirm that metabolic tumor volume and total lesion glycolysis are independently correlated with recurrence-free survival in patients with HNSCC. Further larger prospective studies with FDG-PET/CT performed in the same RT position and with a validated elastic registration method are needed. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1155-1165, 2017., (© 2017 Wiley Periodicals, Inc.)

Purpose: In oncology, texture features extracted from positron emission tomography with 18-fluorodeoxyglucose images (FDG-PET) are of increasing interest for predictive and prognostic studies, leading to several tens of features per tumor. To select the best features, the use of a random forest (RF) classifier was investigated., Methods: Sixty-five patients with an esophageal cancer treated with a combined chemo-radiation therapy were retrospectively included. All patients underwent a pretreatment whole-body FDG-PET. The patients were followed for 3 years after the end of the treatment. The response assessment was performed 1 month after the end of the therapy. Patients were classified as complete responders and non-complete responders. Sixty-one features were extracted from medical records and PET images. First, Spearman's analysis was performed to eliminate correlated features. Then, the best predictive and prognostic subsets of features were selected using a RF algorithm. These results were compared to those obtained by a Mann-Whitney U test (predictive study) and a univariate Kaplan-Meier analysis (prognostic study)., Results: Among the 61 initial features, 28 were not correlated. From these 28 features, the best subset of complementary features found using the RF classifier to predict response was composed of 2 features: metabolic tumor volume (MTV) and homogeneity from the co-occurrence matrix. The corresponding predictive value (AUC = 0.836 ± 0.105, Se = 82 ± 9%, Sp = 91 ± 12%) was higher than the best predictive results found using the Mann-Whitney test: busyness from the gray level difference matrix (P < 0.0001, AUC = 0.810, Se = 66%, Sp = 88%). The best prognostic subset found using RF was composed of 3 features: MTV and 2 clinical features (WHO status and nutritional risk index) (AUC = 0.822 ± 0.059, Se = 79 ± 9%, Sp = 95 ± 6%), while no feature was significantly prognostic according to the Kaplan-Meier analysis., Conclusions: The RF classifier can improve predictive and prognostic values compared to the Mann-Whitney U test and the univariate Kaplan-Meier survival analysis when applied to several tens of features in a limited patient database.

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 18 F-FDG PET/CT with adaptive thresholding methods with TMTV measured with a fixed 41% SUV max 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% SUV max 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 SUV max The TMTV values obtained with each adaptive method were compared with those obtained with the 41% SUV max 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 TMTV 41% , TMTV Da , TMTV Ns , TMTV Fit , and TMTV Bl were, respectively, 231 cm 3 (range, 5-3,824), 175 cm 3 (range, 8-3,510), 198 cm 3 (range, 3-3,934), 175 cm 3 (range, 8-3,512), and 333 cm 3 (range, 3-5,113). The intraclass correlation coefficients were excellent, from 0.972 to 0.988, for TMTV Da , TMTV Fit , and TMTV Ns , and less good for TMTV Bl (0.856). The mean differences obtained from the Bland-Altman plots were 48.5, 47.2, 19.5, and -253.3 cm 3 , 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% SUV max , 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., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Aim: To assess the feasibility of SPECT-computed tomography (CT) in rats with trinitrobenzene sulfonic acid (TNBS)-induced acute colitis and confront it with model inflammatory characteristics., Methods: Colitis was induced in Sprague-Dawley rats by intrarectal injection of TNBS ( n = 10) while controls received vehicle ( n = 10). SPECT-CT with intravenous injection of 10 MBq of 67Ga-Citrate was performed at day 2. SPECT-CT criteria were colon wall thickness and maximal wall signal intensity. Laboratory parameters were assessed: colon weight:length ratio, colon cyclooxygenase-2 expression by western blot and histological inflammatory score., Results: Colon weight/length ratio, colon COX-2 expression and histological inflammatory score were significantly higher in the TNBS group than in the control group ( P = 0.0296, P < 0.0001, P = 0.0007 respectively). Pixel max tend to be higher in the TNBS group than in the control group but did not reach statistical significance ( P = 0.0662). Maximal thickness is significantly increased in the TNBS group compared to the control group ( P = 0.0016) while colon diameter is not ( P = 0.1904). Maximal thickness and colon diameter were correlated to colon COX-2 expression ( P = 0.0093, P = 0.009 respectively) while pixel max was not ( P = 0.22). Maximal thickness was significantly increased when inflammation was histologically observed ( P = 0.0043) while pixel max and colon diameter did not ( P = 0.2452, P = 0.3541, respectively)., Conclusion: SPECT-CT is feasible and easily distinguished control from colitic rats., Competing Interests: Conflict-of-interest statement: We declare that we have no financial and personal relationships with other people or organizations that could inappropriately influence our work.

Purpose: The aim of this study was to evaluate the impact of consensus algorithms on segmentation results when applied to clinical PET images. In particular, whether the use of the majority vote or STAPLE algorithm could improve the accuracy and reproducibility of the segmentation provided by the combination of three semiautomatic segmentation algorithms was investigated., Methods: Three published segmentation methods (contrast-oriented, possibility theory and adaptive thresholding) and two consensus algorithms (majority vote and STAPLE) were implemented in a single software platform (Artiview®). Four clinical datasets including different locations (thorax, breast, abdomen) or pathologies (primary NSCLC tumours, metastasis, lymphoma) were used to evaluate accuracy and reproducibility of the consensus approach in comparison with pathology as the ground truth or CT as a ground truth surrogate., Results: Variability in the performance of the individual segmentation algorithms for lesions of different tumour entities reflected the variability in PET images in terms of resolution, contrast and noise. Independent of location and pathology of the lesion, however, the consensus method resulted in improved accuracy in volume segmentation compared with the worst-performing individual method in the majority of cases and was close to the best-performing method in many cases. In addition, the implementation revealed high reproducibility in the segmentation results with small changes in the respective starting conditions. There were no significant differences in the results with the STAPLE algorithm and the majority vote algorithm., Conclusion: This study showed that combining different PET segmentation methods by the use of a consensus algorithm offers robustness against the variable performance of individual segmentation methods and this approach would therefore be useful in radiation oncology. It might also be relevant for other scenarios such as the merging of expert recommendations in clinical routine and trials or the multiobserver generation of contours for standardization of automatic contouring.

Introduction: Earlier studies indicated that bevacizumab could favorably be combined with radiation. However excessive damage to tumor vasculature can result in radioresistance and clinical data suggest that treatment sequencing may be important when combining bevacizumab with radiation. The aim of this study was to evaluate whether αvβ3 scintigraphic imaging could provide information to determine the optimal combination schedule of bevacizumab and radiotherapy on a lung adenocarcinoma model in mice., Methods: The tumor volume and angiogenesis changes induced after bevacizumab and radiation treatment were evaluated using (99m)Tc-RGD on a microSPECT/CT. First, we determined the optimal dose regimen for bevacizumab and radiotherapy alone. Second, the combined effects of bevacizumab and radiation were evaluated according to the combination timing (radiation 2, 24, 48 hours after bevacizumab and 48 hours before bevacizumab)., Results: The optimal dose regimen is 20mg/kg for bevacizumab and 12.5 Gy for radiotherapy with a significant decrease of tumoral uptake and volume at day 9 compared to the controls (+8.8%, +7.7%, and +44% volume, respectively, and +9.8%, +3.8%, and +207% uptake, respectively). Scintigraphic imaging showed a significant increased RGD tumor uptake two hours after bevacizumab treatment compared to 24 hours and controls (p=0.02). When bevacizumab treatment was combined with radiation, the best combination appears to be the administration of bevacizumab two hours prior to radiation with better results than single treatments (p < 0.05). On the contrary, bevacizumab given 24 hours prior to radiation led to less tumor growth delay compared to a single agent, without significant difference compared to the controls. Histological results confirmed these data with an increased percentage of necrosis (p=0.04) and a decrease of angiogenesis (p=0.04) in the optimal combination group., Conclusions: The RGD tracer helps us identify the vascular normalization window and it shows a supra-additive effect of bevacizumab when administered two hours before radiotherapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: The high failure rates in the radiotherapy (RT) target volume suggest that patients with locally advanced oesophageal cancer (LAOC) would benefit from increased total RT doses. High 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) uptake (hotspot) on pre-RT FDG positron emission tomography (PET)/CT has been reported to identify intra-tumour sites at increased risk of relapse after RT in non-small cell lung cancer and in rectal cancer. Our aim was to confirm these observations in patients with LAOC and to determine the optimal maximum standardized uptake value (SUVmax) threshold to delineate smaller RT target volumes that would facilitate RT dose escalation without impaired tolerance., Methods: The study included 98 consecutive patients with LAOC treated by chemoradiotherapy (CRT). All patients underwent FDG PET/CT at initial staging and during systematic follow-up in a single institution. FDG PET/CT acquisitions were coregistered on the initial CT scan. Various subvolumes within the initial tumour (30, 40, 50, 60, 70, 80 and 90% SUVmax thresholds) and in the subsequent local recurrence (LR, 40 and 90% SUVmax thresholds) were pasted on the initial CT scan and compared[Dice, Jaccard, overlap fraction (OF), common volume/baseline volume, common volume/recurrent volume]., Results: Thirty-five patients had LR. The initial metabolic tumour volume was significantly higher in LR tumours than in the locally controlled tumours (mean 25.4 vs 14.2 cc; p = 0.002). The subvolumes delineated on initial PET/CT with a 30-60% SUVmax threshold were in good agreement with the recurrent volume at 40% SUVmax (OF = 0.60-0.80). The subvolumes delineated on initial PET/CT with a 30-60% SUVmax threshold were in good to excellent agreement with the core volume (90% SUVmax) of the relapse (common volume/recurrent volume and OF indices 0.61-0.89)., Conclusion: High FDG uptake on pretreatment PET/CT identifies tumour subvolumes that are at greater risk of recurrence after CRT in patients with LAOC. We propose a 60% SUVmax threshold to delineate high FDG uptake areas on initial PET/CT as reduced target volumes for RT dose escalation.

Unlabelled: The high rates of failure in the radiotherapy target volume suggest that patients with stage II or III non-small cell lung cancer (NSCLC) should receive an increased total dose of radiotherapy. Areas of high (18)F-FDG uptake on preradiotherapy (18)F-FDG PET/CT have been reported to identify intratumor subvolumes at high risk of relapse after radiotherapy. We wanted to confirm these observations on a cohort of patients included in 3 sequential prospective studies. Our aim was to assess an appropriate threshold (percentage of maximum standardized uptake value [SUVmax]) to delineate subvolumes on staging (18)F-FDG PET/CT scans assuming that a smaller target volume would facilitate isotoxic radiotherapy dose escalation., Methods: Thirty-nine patients with inoperable stage II or III NSCLC, treated with chemoradiation or with radiotherapy alone, were extracted from 3 prospective studies (ClinicalTrials.gov identifiers NCT01261585, NCT01261598, and RECF0645). All patients underwent (18)F-FDG PET/CT at initial staging, before radiotherapy, during radiotherapy, and during systematic follow-up in a single institution. All (18)F-FDG PET/CT acquisitions were coregistered on the initial scan. Various subvolumes in the initial acquisition (30%, 40%, 50%, 60%, 70%, 80%, and 90% SUVmax thresholds) and in the 3 subsequent acquisitions (40% and 90% SUVmax thresholds) were pasted on the initial scan and compared., Results: Seventeen patients had a local relapse. The SUVmax measured during radiotherapy was significantly higher in locally relapsed tumors than in locally controlled tumors (mean, 6.8 vs. 4.6; P = 0.02). The subvolumes delineated on initial PET/CT scans with 70%-90% SUVmax thresholds were in good agreement with the recurrent volume at a 40% SUVmax threshold (common volume/baseline volume, 0.60-0.80). The subvolumes delineated on initial PET/CT scans with 30%-60% SUVmax thresholds were in good to excellent agreement with the core volume of the relapse (90% SUVmax threshold) (common volume/recurrent volume and overlap fraction indices, 0.60-0.93). The agreement was moderate (>0.51) when a 70% SUVmax threshold was used to delineate on initial PET/CT scans., Conclusion: High (18)F-FDG uptake areas on pretreatment PET/CT scans identify tumor subvolumes at greater risk of relapse in patients with NSCLC treated by concomitant chemoradiation. We propose a 70% SUVmax threshold to delineate areas of high (18)F-FDG uptake on initial PET/CT scans as the target volumes for potential radiotherapy dose escalation., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

A segmentation algorithm based on the random walk (RW) method, called 3D-LARW, has been developed to delineate small tumors or tumors with a heterogeneous distribution of FDG on PET images. Based on the original algorithm of RW [1], we propose an improved approach using new parameters depending on the Euclidean distance between two adjacent voxels instead of a fixed one and integrating probability densities of labels into the system of linear equations used in the RW. These improvements were evaluated and compared with the original RW method, a thresholding with a fixed value (40% of the maximum in the lesion), an adaptive thresholding algorithm on uniform spheres filled with FDG and FLAB method, on simulated heterogeneous spheres and on clinical data (14 patients). On these three different data, 3D-LARW has shown better segmentation results than the original RW algorithm and the three other methods. As expected, these improvements are more pronounced for the segmentation of small or tumors having heterogeneous FDG uptake., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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.

Purpose: Various segmentation methods for 18F-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT) images were correlated with pathological volume in breast cancer patients as a model of small mobile tumours., Methods: Thirty women with T2-T3/M0 breast invasive ductal carcinoma (IDC) were included prospectively. A FDG-PET/CT was acquired 4 ± 3d before surgery in prone and supine positions, with/without respiratory gating. The segmentation methods were as follows: manual (Vm), relative (Vt%) and adaptive (Va) standard uptake value (SUV) threshold and semi-automatic on CT (Vct). Pathological volumes (Vpath) were measured for 26 lesions., Results: The mean (±SD) Vpath was 4.1 ± 2.9 mL, and the lesion displacements were 3.9 ± 2.8 mm (median value: 3 mm). The delineated VOIs did not vary with the acquisition position nor with respiration, regardless of the segmentation method. The Vm, Va, Vct and Vt% methods, except Vt30%, were correlated with Vpath (0.5

Objectives: Approximately 30% of DLBCL patients are older than 70 yr. This study evaluated the prognostic impact of a cachexia score (CS) including fat tissue loss (adipopenia) and sarcopenia as assessed by computed tomography (CT scan) in elderly DLBCL patients treated with chemotherapy and rituximab (R)., Methods: This retrospective analysis included 80 DLBCL patients older than 70 yr treated with R-CHOP or R-miniCHOP. Skeletal muscle (SM) and visceral (V) and subcutaneous (S) adipose (A) tissues were measured by analysing CT images at the third lumbar (L3) level., Results: The median age of the patients was 78 yr. Forty-four and 46 patients were considered sarcopenic and adipopenic, respectively. The median progression-free survival (PFS) was 13.6 months in the adipopenic group and 49.4 months in the non-adipopenic group [hazard ratio (HR) = 2.27; 95% confidence interval (CI): 1.3-4; P = 0.0042]. The median overall survival (OS) was 25.7 months in the adipopenic group and 57.1 months in the non-adipopenic group (HR = 1.93; 95% CI: 1.05-3.55; P = 0.0342). A two-point CS including adipopenia and sarcopenia was created and defined two distinct risk groups with differences in outcomes that were highly significant. The CS was predictive of the prognosis in a multivariate analysis including body mass index (BMI) (< or ≥ 25 kg/m(2) ), age (< or ≥ 80 yr), international prognostic index (IPI) and albuminaemia (HR = 3.67; 95% CI = 1.93-6.97; P < 0.0001)., Conclusion: A CS including sarcopenia and adipopenia, assessed by a single CT scan slice, predicts outcome independent of BMI and the IPI., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To assess prospectively the prognostic value of FDG PET/CT during curative-intent radiotherapy (RT) with or without concomitant chemotherapy in patients with non-small-cell lung cancer (NSCLC)., Methods: Patients with histological proof of invasive localized NSCLC and evaluable tumour, and who were candidates for curative-intent radiochemotherapy (RCT) or RT were preincluded after providing written informed consent. Definitive inclusion was conditional upon significant FDG uptake before RT (PET₁). All included patients had a FDG PET/CT scan during RT (PET₂, mean dose 43 Gy) and were evaluated by FDG PET/CT at 3 months and 1 year after RT. The main endpoint was death (from whatever cause) or tumour progression at 1 year., Results: Of 77 patients preincluded, 52 were evaluable. Among the evaluable patients, 77% received RT with induction chemotherapy and 73% RT with concomitant chemotherapy. At 1 year, 40 patients (77 %) had died or had tumour progression. No statistically significant association was found between stage (IIIB vs. other), histology (squamous cell carcinoma vs. other), induction or concomitant chemotherapy, and death/tumour progression at 1 year. The SUVmax in the PET2 scan was the single variable predictive of death or tumour progression at 1 year (odds ratio 1.97, 95% CI 1.25 - 3.09, p = 0.003) in multivariate analysis. The area under the receiver operating characteristic curve was 0.85 (95% CI 0.73 - 0.94, p < 10(-4)). A SUVmax value of 5.3 in the PET₂ scan yielded a sensitivity of 70% and a specificity of 92% for predicting tumour progression or death at 1 year., Conclusion: This prospective multicentre study demonstrated the prognostic value in terms of disease-free survival of SUVmax assessed during the 5th week of curative-intent RT or RCT in NSCLC patients (NCT01261598; RTEP2 study).

Approximately 25-35% of patients with diffuse large B-cell lymphoma (DLBCL) are older than 70 years. The aim of this study was to investigate the prognostic impact of depletion of skeletal muscle (sarcopenia) in elderly patients with DLBCL. This retrospective analysis included 82 patients with DLBCL older than 70 years and treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin, prednisone) or R-miniCHOP. Sarcopenia was measured by the analysis of stored computed tomography (CT) images at the L3 level at baseline. The surface of the muscular tissues was selected according to the CT Hounsfield unit. This value was normalized for stature in order to calculate the lumbar L3 skeletal muscle index (LSMI, in cm(2)/m(2)). The mean age of the population was 78 years. According to the defined cut-offs for LSMI, 45 patients with DLBCL were considered sarcopenic. Sarcopenic patients displayed a higher revised International Prognostic Index (R-IPI) compared with patients without sarcopenia, and were older, with a mean age of 80 years and 77 years, respectively (p = 0.006). With a median follow-up of 39 months, the 2-year overall survival in the sarcopenic population was 46% compared with 84% in the non-sarcopenic group (HR = 3.22; 95% CI = 1.73-5.98; p = 0.0002). In a multivariate analysis, sarcopenia remained predictive of outcome (p = 0.005). Sarcopenia is a relevant and predictive factor in elderly patients with DLBCL treated with rituximab plus chemotherapy.

Background: The objective of this study is to investigate the feasibility and the additional interest of a parametric imaging (PI) method to monitor the early tumour metabolic response in a prospective series of oesophageal cancer patients who underwent positron emission tomography with fluoro-2-deoxy-d-glucose (FDG-PET/CT) before and during curative-intent chemo-radiotherapy., Methods: Fifty-seven patients with squamous cell carcinoma (SCC) of the oesophagus prospectively underwent FDG-PET/CT before chemo-radiotherapy (CRT) (PET1) and at 21 ± 3 days after the beginning of CRT (PET2). The outcome was assessed at 3 months and 1 year after the completion of CRT (clinical examination, CT scan or FDG-PET/CT, biopsy). For each patient, PET1 and PET2 were registered using CT images. The 2 PET image sets were subtracted, so the voxels with significant changes in FDG uptake were identified. A model-based analysis of this graph was used to identify the tumour voxels in which significant changes occurred between the two scans and yielded indices characterising these changes (green and red clusters). Quantitative parameters were compared with clinical outcome at 3 months and at 1 year., Results: The baseline tumour FDG uptake decreased significantly at PET2 (p < 0.0001). The tumour volume significantly decreased between PET1 and PET2 (p < 0.02). The initial functional volume of the lesion (TV1) was significantly lower (p < 0.02) in patients in clinical response (CR) at 3 months and 1 year. The volume of the lesion during the treatment (TV2) was significantly lower in patients identified as in CR at 3 months (p < 0.03), but did not predict the outcome at 1 year. Multivariate analyses of outcome at 3 months showed that the risk of failure/death increased with younger age (p = 0.001), larger metabolic volume on PET1 (p = 0.009) and larger volume with decreased FDG uptake (p = 0.047). As for outcome at 1 year, the risk of failure/death increased with younger age (p = 0.006), nodal involvement (p = 0.08) and larger volumes with increased uptake (p = 0.03)., Conclusion: A parametric method to assess tumour response on serial FDG-PET performed during chemo-radiotherapy was evaluated. Early metabolic changes, i.e. variations in FDG uptake, provided additional prognostic information in multivariate analyses ClinicalTrials.gov NCT 00934505., Trial Registration: Current Controlled Trials ISRCTN7824458.

Background: Few data are published on docetaxel toxicity in obese patients., Patients and Methods: All obese patients (n=100) treated for early breast cancer during three consecutive years at our Institution, were retrospectively investigated. The same number of non-obese patients was randomly selected and used as controls. We assessed the factors predictive of the relative dose intesity (RDI) reduction, including body composition., Results: A total of 18% (n=18) of obese patients and 5% (n=5) of non-obese patients required reduction of docetaxel RDI due to toxicity (p=0.008). In a multivariate analysis, body mass index (BMI) and age were predictive of a reduction in RDI. Among the 89 patients with a determination of body composition, patients with a higher fat mass more frequently had a reduction in docetaxel RDI (p=0.002). In multivariate analysis, fat mass was the only independent factor predictive of a reduction in docetaxel RDI., Conclusion: Obese patients treated for early breast cancer more frequently required a reduction in docetaxel RDI. Fat mass seems to be the best factor predictive of a reduction in docetaxel RDI.

Unlabelled: As the preparation phase of a multicenter clinical trial using (18)F-fluoro-2-deoxy-d-glucose ((18)F-FDG), (18)F-fluoromisonidazole ((18)F-FMISO), and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) in non-small cell lung cancer (NSCLC) patients, we investigated whether 18 nuclear medicine centers would score tracer uptake intensity similarly and define hypoxic and proliferative volumes for 1 patient and we compared different segmentation methods., Methods: Ten (18)F-FDG, ten (18)F-FMISO, and ten (18)F-FLT PET/CT examinations were performed before and during curative-intent radiotherapy in 5 patients with NSCLC. The gold standards for uptake intensity and volume delineation were defined by experts. The between-center agreement (18 nuclear medicine departments connected with a dedicated network, SFMN-net [French Society of Nuclear Medicine]) in the scoring of uptake intensity (5-level scale, then divided into 2 levels: 0, normal; 1, abnormal) was quantified by κ-coefficients (κ). The volumes defined by different physicians were compared by overlap and κ. The uptake areas were delineated with 22 different methods of segmentation, based on fixed or adaptive thresholds of standardized uptake value (SUV)., Results: For uptake intensity, the κ values between centers were, respectively, 0.59 for (18)F-FDG, 0.43 for (18)F-FMISO, and 0.44 for (18)F-FLT using the 5-level scale; the values were 0.81 for (18)F-FDG and 0.77 for both (18)F-FMISO and (18)F-FLT using the 2-level scale. The mean overlap and mean κ between observers were 0.13 and 0.19, respectively, for (18)F-FMISO and 0.2 and 0.3, respectively, for (18)F-FLT. The segmentation methods yielded significantly different volumes for (18)F-FMISO and (18)F-FLT (P < 0.001). In comparison with physicians, the best method found was 1.5 × maximum SUV (SUVmax) of the aorta for (18)F-FMISO and 1.3 × SUVmax of the muscle for (18)F-FLT. The methods using the SUV of 1.4 and the method using 1.5 × the SUVmax of the aorta could be used for (18)F-FMISO and (18)F-FLT. Moreover, for (18)F-FLT, 2 other methods (adaptive threshold based on 1.5 or 1.6 × muscle SUVmax) could be used., Conclusion: The reproducibility of the visual analyses of (18)F-FMISO and (18)F-FLT PET/CT images was demonstrated using a 2-level scale across 18 centers, but the interobserver agreement was low for the (18)F-FMISO and (18)F-FLT volume measurements. Our data support the use of a fixed threshold (1.4) or an adaptive threshold using the aorta background to delineate the volume of increased (18)F-FMISO or (18)F-FLT uptake. With respect to the low tumor-on-background ratio of these tracers, we suggest the use of a fixed threshold (1.4).

Purpose: Increased expression of αvβ3 integrins is involved in tumour angiogenesis. Targeting these receptors with a dedicated peptide containing the RGD sequence may provide information about the receptor status in and around the tumour and about the angiogenesis process involved. The aim of this study was to compare the uptake of [Tc]-HYNIC-RGD in two types of tumours that either express or do not express the αvβ3 receptor (NTERA-2 and MDA-MB-231, respectively) and discuss the use of this tracer in experimental models of angiogenesis., Procedures: Uptake of intravenously injected [Tc]-HYNIC-RGD was studied ex vivo and in vivo. Histological analysis of excised tumours was carried out. Percentages of the injected dose uptake per gram of tissue were compared between the two types of tumours and in the periphery and centre of each tumour., Results: [Tc]-HYNIC-RGD was rapidly cleared from blood circulation and excreted through the kidneys. Residual activity was retained in the intestine. Tumour uptake of [Tc]-HYNIC-RGD was high and homogeneous for αvβ3-positive cell lines (1.94±0.26%ID/g). Tumour uptake was weak and distributed only in the tumour periphery for αvβ3-negative cell lines (0.10±0.02%ID/g, tumour periphery; 0.06±0.01%ID/g, tumour core; P=0.01). These results correlated with vessel distribution., Conclusion: Uptake of [Tc]-HYNIC-RGD was more intense in αvβ3-positive cell lines than in αvβ3-negative cell lines, but tracer distribution was more representative of angiogenic locations in αvβ3-negative cell lines. Further clinical and preclinical studies are needed on the use of RGD-related tracers.

Objectives: To test the influence of media injection in PET/CT on the functional or gross tumour volume measurement., Patients and Methods: Thirty-three patients (56 ± 19 years) with non-Hodgkin's lymphoma (n=22) or Hodgkin's disease (n=11) were prospectively studied at staging. PET/CTs were performed 60 min after injection of FDG. Iopamiron 300 (Iopamidol, 1.5cc/kg) was injected immediately after, followed 50s later by a second craniocaudal CT (CT+). PET images were successively reconstructed using the unenhanced CT (PET-) and the CT+ (PET+) for attenuation correction using iterative reconstruction (4 iterations, 8 subsets, 5mm post-filtering). The SUVmax, SUVmean, SUVpeak and functional tumoural volume were measured in tumoural lymphadenopathies or malignant tissues (n=56 VOIs) using 5 3D-thresholding methods on PET- and PET+ images: absolute SUV value of 2.5; 40% of SUVmax, and 3 adaptative thresholding methods (Vauclin, Black and Schaefer methods)., Results: The SUVmean and the volume measurement were significantly different (p<0.001) for the five segmentation methods for PET- (p<0.001) and PET+ (p<0.001). The SUVmax, SUVmean and SUVpeak increased significantly in PET+ compared to PET- (2-5%). The SUVpeak was not significantly different for the five segmentation methods. The functional volume measurements were significantly different between PET- and PET+ only for the 2.5 segmentation method (+3%; p=0.001), but not for the 40%, Vauclin, Black and Schaefer methods., Conclusion: The functional volume could be measured in PET/CT when CT was performed with enhanced media. Caution should be taken when using the volume delineation method. Volume delineation methods using absolute threshold may artefactually increase the functional volume when enhanced CT is used for attenuation correction. The delineation volume using the relative or adaptative method should be preferred when contrast media are used for PET/CT., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Several algorithms from the literature were compared with the original random walk (RW) algorithm for brain perfusion heterogeneity quantification purposes. Algorithms are compared on a set of 210 brain single photon emission computed tomography (SPECT) simulations and 40 patient exams., Methods: Five algorithms were tested on numerical phantoms. The numerical anthropomorphic Zubal head phantom was used to generate 42 (6 × 7) different brain SPECT simulations. Seven diffuse cortical heterogeneity levels were simulated with an adjustable Gaussian noise function and six focal perfusion defect levels with temporoparietal (TP) defects. The phantoms were successively projected and smoothed with Gaussian kernel with full width at half maximum (FWHM = 5 mm), and Poisson noise was added to the 64 projections. For each simulation, 5 Poisson noise realizations were performed yielding a total of 210 datasets. The SPECT images were reconstructed using filtered black projection (Hamming filter: α = 0.5).The five algorithms or measures tested were the following: the coefficient of variation, the entropy and local entropy, fractal dimension (FD) (box counting and Fourier power spectrum methods), the gray-level co-occurrence matrix (GLCM), and the new RW.The heterogeneity discrimination power was obtained with a linear regression for each algorithm. This regression line is a mean function of the measure of heterogeneity compared to the different diffuse heterogeneity and focal defect levels generated in the phantoms. A greater slope denotes a larger separation between the levels of diffuse heterogeneity.The five algorithms were computed using 40 99mTc-ethyl-cysteinate-dimer (ECD) SPECT images of patients referred for memory impairment. Scans were blindly ranked by two physicians according to the level of heterogeneity, and a consensus was obtained. The rankings obtained by the algorithms were compared with the physicians' consensus ranking., Results: The GLCM method (slope = 58.5), the fractal dimension (35.9), and the RW method (31.6) can differentiate the different levels of diffuse heterogeneity. The GLCM contrast parameter method is not influenced by a focal defect contrary to the FD and RW methods. A significant correlation was found between the RW method and the physicians' classification (r = 0.86; F = 137; p < 0.0001)., Conclusions: The GLCM method can quantify the different levels of diffuse heterogeneity in brain-simulated SPECT images without an influence from the focal cortical defects. However, GLCM classification was not correlated with the physicians' classification (Rho = -0.099). The RW method was significantly correlated with the physicians' heterogeneity perception but is influenced by the existence of a focal defect.

Objectives: The objectives were (i) to confirm that diagnostic FDG-PET images could be obtained during thoracic radiotherapy, (ii) to verify that significant changes in FDG uptake or volume could be measured early enough to adapt the radiotherapy plan and (iii) to determine an optimal time window during the radiotherapy course to acquire a single FDG-PET examination that would be representative of tumour response., Methods: Ten non-small cell lung carcinoma (NSCLC) patients with significant PET/CT-FDG tumour radioactivity uptake (versus the background level), candidates for curative radiotherapy (RT, n=4; 60-70 Gy, 2 Gray per fraction, 5 fractions per week) or RT plus chemotherapy (CT-RT, n=6), were prospectively evaluated. Using a Siemens Biograph, 5 or 6 PET/CT scans (PET(n), n=0-5) were performed for each patient. Each acquisition included a 15-min thoracic PET with respiratory gating (RG) 60±5 min post-injection of the FDG (3.5 MBq/kg), followed by a standard, 5-min non-gated (STD) thoracic PET. PET(0) was performed before the first RT fraction. During RT, PET(1-5) were performed every 7 fractions, i.e., at 14 Gy total dose increment. FDG uptake was measured as the variation of SUV(max,PETn) versus SUV(max,PET0). Each lesions' volume was measured by (i) visual delineation by an experienced nuclear physician, (ii) 40% SUV(max) fixed threshold and (iii) a semi-automatic adaptive threshold method., Results: A total of 53 FDG-PET scans were acquired. Seventeen lesions (6 tumours and 11 nodes) were visible on PET(0) in the 10 patients. The lesions were located either in or near the mediastinum or in the apex, without significant respiratory displacements at visual inspection of the gated images. Healthy lung did not cause motion artefacts in the PET images. As measured on 89 lesions, both the absolute and relative SUV(max) values decreased as the RT dose increased. A 50% SUV(max) decrease was obtained around a total dose of 45 Gy. Out of the 89 lesions, 75 remained visually identifiable during the entire course of treatment. The 40% fixed threshold and adaptive threshold methods failed to delineate otherwise visible lesions in 16/33 (48%) and 3/33 (9%) lesions, respectively. The failure rate increased with increasing RT doses. Restricting the analysis to the manually-defined volumes in 89 visible lesions, the relative volumes decreased with increased dose., Conclusions: FDG-PET images can be analysed during thoracic RT, given either alone or with chemotherapy, without disturbing radiation-induced artefacts. An average 50% decrease in SUV(max) was observed around 40-45 Gy (i.e., during week 5 of RT). The three delineation methods yielded consistent volume measurements before RT and during the first week of RT, while manual delineation appeared to be more reliable later on during RT., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The recent advances in medical imaging have profoundly altered the radiotherapy of non-small cell lung cancers (NSCLC). A meta-analysis has confirmed the superiority of FDG PET-CT over CT for initial staging. FDG PET-CT improves the reproducibility of target volume delineation, especially close to the mediastinum or in the presence of atelectasia. Although not formally validated by a randomized trial, the reduction of the mediastinal target volume, by restricting the irradiation to FDG-avid nodes, is widely accepted. The optimal method of delineation still remains to be defined. The role of FDG PET-CT in monitoring tumor response during radiotherapy is under investigation, potentially opening the way to adapting the treatment modalities to tumor radiation sensitivity. Other tracers, such as F-miso (hypoxia), are also under clinical investigation. To avoid excessive delays, the integration of PET-CT in routine practice requires quick access to the imaging equipment, technical support (fusion and image processing) and multidisciplinary delineation of target volumes., (Copyright © 2011 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Purpose: High-dose (HD) cytosine arabinoside (ara-C) is a major treatment in acute myeloblastic leukemia (AML) that can lead to cerebellar complications, although electroencephalogram, computed tomography, and magnetic resonance imaging remain normal. We conducted a prospective study to evaluate brain perfusion with single-photon emission computed tomography (SPECT) in adult patients before and after receiving ara-C., Procedures: Forty-three patients were pre-included, and 20 reached a complete remission. These 20 patients were definitively included and underwent three technetium-99m hexamethyl-propylene-amine oxime (HMPAO) SPECT acquisitions with a double-head camera: SPECT1 at AML diagnosis, SPECT2 after induction (conventional ara-C dose), and SPECT3 during HD ara-C treatment. All the included patients underwent six series of neurological and cognitive examinations: N1, N2, and N3 at the time of SPECT1, SPECT2, and SPECT3, respectively; N4 during HD ara-C treatment; N5 (at 10 days); and N6 during follow-up (at 6 months). Statistical parametric mapping (SPM2) was used to test perfusion changes. A specific method based on random walk (RW) was used to analyze diffuse brain perfusion heterogeneity., Results: No neurological adverse effect was observed, and all neurological and cognitive examinations remained normal. Between SPECT1 and SPECT2, SPM2 analysis showed a decrease in cerebral blood flow, i.e., in the cerebellum, in the occipitoparietal cortex, and in the thalamus. No significant difference was observed between SPECT2 and SPECT3 or between SPECT1 and SPECT3. RW analysis showed no significant difference in perfusion heterogeneity between the three SPECTs., Conclusions: HMPAO SPECT demonstrated a decrease in thalamus, cerebellar, and parieto-occipital perfusion after conventional doses of ara-C in AML patients, although the neurological examinations were normal and the patients had no neurological adverse effects.

Aim: We assessed in this study the influence of contrast-enhanced CT (ceCT) on PET/CT interpretation and PET/CT on ceCT interpretation in patients with lymphoma, before and after chemotherapy., Methods: Fifty patients with Hodgkin disease (N.=17) or non-Hodgkin lymphomas (N.=33) were assessed before and after chemotherapy. PET/CT were performed 60 minutes after injection of FDG. Iopamidol was then injected and followed, 50 seconds later, by another CT. PET images were successively reconstructed using non-enhanced CT (PET-) and ceCT (PET+). Four nuclear physicians rated PET- and PET+ in random order. Three radiologists initially rated ceCT alone and then ceCT along with PET+., Results: Before chemotherapy, global agreement (GA) was 99% (k=0.96) when PET- was compared to PET+. Nine (5%) lesions were discordant, 5 according to PET- and 4 to PET+. After chemotherapy, GA was 99% (k=0.91). Eight (15%) lesions were discordant, 3 according to PET- and 5 to PET+. Before chemotherapy, GA was 97% (k=0.91) when ceCT was compared to ceCT with PET+. Twenty-one (12%) lesions were discordant, 16 when ceCT were analyzed alone and 5 when ceCT was analyzed with PET+. After chemotherapy, GA was 95% (k=0.76). All 30 (35%) discordant lesions were positive according to ceCT alone. A significant difference between the 2 procedures was found in the pelvis and in the groin (P<0.05)., Conclusion: PET+ did not differ from PET-, before and after chemotherapy. Fewer abnormalities were observed, when ceCT was analyzed with PET+, particularly after chemotherapy, due to residual masses that are better analyzed with functional imaging.

Purpose: We assessed whether imaging α(v)β(3) integrin could distinguish mature teratoma from necrosis in human non-seminomatous germ cell tumour (NSGCT) post-chemotherapy residual masses., Methods: Human embryonal carcinoma xenografts (six/rat) were untreated (controls) or treated to form mature teratomas with low-dose cisplatin and all-trans retinoic acid (ATRA) over a period of 8 weeks. In another group, necrosis was induced in xenografts with high-dose cisplatin plus etoposide (two cycles). (18)F-Fluorodeoxyglucose ((18)F-FDG) small animal positron emission tomography (SA PET) imaging was performed in three rats (one control and two treated for 4 and 8 weeks with cisplatin+ATRA). Imaging of α(v)β(3) expression was performed in six rats bearing mature teratomas and two rats with necrotic lesions on a microSPECT/CT device after injection of the tracer [(99m)Tc]HYNIC-RGD [6-hydrazinonicotinic acid conjugated to cyclo(Arg-Gly-Asp-D-Phe-Lys)]. Correlative immunohistochemistry studies of human and mouse α(v)β(3) expression were performed., Results: Cisplatin+ATRA induced differentiation of the xenografts. After 8 weeks, some glandular structures and mesenchymal cells were visible; in contrast, control tumours showed undifferentiated tissues. SA PET imaging showed that mature teratoma had very low avidity for (18)F-FDG [mean standardised uptake value (SUV(mean)) = 0.48 ± 0.05] compared to untreated embryonal carcinoma (SUV(mean) = 0.92 ± 0.13) (p = 0.005). α(v)β(3) imaging accurately distinguished mature teratoma (tumour to muscle ratio = 4.29 ± 1.57) from necrosis (tumour to muscle ratio = 1.3 ± 0.26) (p = 0.0002). Immunohistochemistry studies showed that α(v)β(3) integrin expression was strong in the glandular structures of mature teratoma lesions and negative in host stroma., Conclusion: Imaging α(v)β(3) integrin accurately distinguished mature teratoma from necrosis following cisplatin-based treatment in human NSGCT xenografts.

Objectives: To investigate the changes in tumour proliferation (using FLT), metabolism (using FDG), and hypoxia (using F-miso) during curative (chemo-) radiotherapy (RT) in patients with non-small-cell lung cancer (NSCLC)., Patients and Methods: Thirty PET scans were performed in five patients (4 males, 1 female) that had histological proof of NSCLC and were candidates for curative-intent RT. Three PET-CT (Biograph S16, Siemens) scans were performed before (t(0)) and during (around dose 46 Gy, t(46)) RT with minimal intervals of 48 h between each PET-CT scan. The tracers used were (18)fluoro-2deoxyglucose (FDG) for metabolism, (18)fluorothymidine (FLT) for proliferation, and (18)F-misonidasole (F-miso) for hypoxia. The 3 image sets obtained at each time point were co-registered (rigid: n=9, elastic: n=1, Leonardo, TrueD, Siemens) using FDG PET-CT as reference. VOIs were delineated (40% SUV(max) values were used as a threshold) for tumours and lymph nodes on FDG PET-CT, and they were automatically pasted on FLT and F-miso PET-CT images. ANOVA and correlation analyses were used for comparison of SUV(max) values., Results: Four tumours and twelve nodes were identified on initial FDG PET-CT images. FLT SUV(max) values were significantly lower (p<0.0006) at t(46) in both tumours and nodes. The decrease in FDG SUV(max) values had a trend towards significance (p=0.048). F-Miso SUV(max) values were significantly higher in tumours than in nodes (p=0.02) and did not change during radiotherapy (p=0.39). A significant correlation was observed between FLT and FDG uptake (r=0.56, p<10(-4)) when all data were pooled together, and they remained similar when the before and during RT data were analysed separately. FDG and F-miso uptakes were significantly correlated (r=0.59, p=0.0004) when all data were analysed together. The best fit was obtained after adjusting for lesion type (tumour vs. node). This correlation was observed for the SUV(max) measured during RT (r=0.70, p=0.008) but not for the pre-RT data (r=0.19, p=0.35). The weak correlation between FLT and F-miso uptakes only became significant (r=0.66, p=0.002) when the analysis was restricted to the data acquired during RT., Conclusion: Three different PET acquisitions can be performed quasi-simultaneously (4-7 days) before and during radiotherapy in patients with NSCLC. Our results at 46 Gy suggest that a fast decrease in the proliferation of both tumours and nodes exists during radiotherapy with differences in metabolism (borderline significant decrease) and hypoxia (stable)., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: A Random Walk (RW) algorithm was designed to quantify the level of diffuse heterogeneous perfusion in brain SPECT images in patients suffering from systemic brain disease or from drug-induced therapy. The goal of the present paper is to understand the behavior of the RW method on different kinds of images (extrinsic parameters) and also to understand how to choose the right parameters of the RW (intrinsic parameters) depending on the image characteristics (i.e. SPECT images). "Extrinsic parameters" are related to the image characteristics (level/size of defect and diffuse heterogeneity) and "intrinsic" parameters are related to the parameters of the method (number (N(rw)) and length of walk (L(rw)), temperature (T) and slowing parameter (S)). Two successive studies were conducted to test the influence of these parameters on the RW result. In the first study, calibrated checkerboard images are used to test the influence of "extrinsic parameters" (i.e. image characteristics) on the RW result (R-value). The R-value was tested as a function of (i) the size of black & white (B&W) squares simulating the size of a cortical defect, (ii) the intensity level gaps between the B&W squares simulating the intensity of the cortical defect and (iii) intensity (=variance) of noise, simulating the diffuse heterogeneity. The second study was constructed with simulated representative brain SPECT images, to test the "intrinsic" parameters. The R-value was tested regarding the influence of four parameters: S, T, N(rw) and L(rw). The third study is constructed so as to see if the classification by diffuse heterogeneity of real brain SPECT images is the same if it's made by senior clinicians or by RW algorithm., Results: Study 1: the RW was strongly influenced by all the characteristics of the images. Moreover, these characteristics interact with each other. The RW is influenced most by diffuse heterogeneity, then by intensity and finally by the size of a defect. Study 2: N(rw) and L(rw) values of 1000 give an optimal reproducibility of the measurement (mean standard deviation<0.1), a fast computation time (time<0.5s/image) and have a maximum difference in terms of R-value between the two extreme images corresponding to the range of the population studied. The best S and T values for SPECT images are 3 and 15, respectively. Study 3: A significant correlation was found between RW ranking and the physicians' consensus (rho=0.789; p<0.0001)., Conclusion: This study confirms that the RW method is able to measure the heterogeneity of brain SPECT images even in the presence of a large defect. However, the result of the method is strongly influenced by the "intrinsic" parameters, so the program should be calibrated for each different type of image., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Background: Thyrotropin (TSH) stimulates thyrocyte metabolism, glucose transport, and glycolysis. The interest in using recombinant human TSH (rhTSH) stimulation of fluoro-2-deoxy-D-glucose (FDG) with positron emission tomography (PET) has been shown, but mainly for patients with high serum thyroglobulin (Tg) concentration. We evaluated the use of rhTSH-stimulated PET-FDG in patients with low serum Tg concentration., Methods: Sixty-one PET/computed tomography (CT)-FDG (Biograph Sensation 16; Siemens Medical Solutions, Knoxville, TN) were performed in 44 patients (28 women and 16 men; 51 +/- 16 years) with positive Tg levels, negative or no contributive iodine-131 whole-body scintigraphy results, and no contributive morphological imaging results (ultrasound, magnetic resonance imaging, and CT). Thirty-eight patients had papillary carcinoma and six had follicular thyroid carcinoma. All patients had previously undergone total thyroidectomy and postoperative iodine ablation of thyroid bed remnant tissue. The rhTSH-stimulated PET/CT-FDG (5 MBq/kg) was performed after two 0.9 mg intramuscular doses of rhTSH (Thyrogen; Genzyme) which were administered 48 and 24 hours before imaging, while patients continued levothyroxine (LT(4)). Blood sampling was performed immediately before FDG injection for measurement of serum TSH and Tg concentrations (TSH(1) and Tg(1)) and after 48 hours (TSH(2) and Tg(2)). PET/CT-FDG findings were compared with the Tg: (i) at the initial iodine treatment during T(4) withdrawal (Tg(ini)), (ii) under T(4) (Tg(T4)) within 3 months before the PET/CT-FDG, (iii) with Tg(1), and (iv) with Tg(2). PET/CT-FDG findings were correlated with the findings of histology, iodine-131 whole-body scintigraphy, morphological imaging, or clinical follow-up., Results: The mean Tg(ini) was 785 +/- 2707 microg/L for a TSH of 73 +/- 64 mU/L. The mean Tg(T4) was 7 +/- 15 microg/L (T(4) = 195 +/- 59 microg/day; mean TSH of 0.24 +/- 0.57 mU/L). Among the 44 patients, PET/CT-FDG findings were positive in 20 and negative in 24. Among the 61 PET/CT-FDG, 25 PET/CT-FDG were positive (41%). Among the 25 positive PET, the Tg(T4) values were less than 10 microg/L for 19, including 9 true-positive patients (20% of the 44 patients). There was no difference of PET/CT-FDG results (positive vs. negative) as related to the serum Tg concentrations (p = 0.99 for Tg(ini), p = 0.95 for Tg(T4), p = 0.07 for Tg(1), and p = 0.42 for Tg(2)). No relation was observed with PET/CT-FDG results and initial tumor size (p = 0.52) or node metastasis (p = 0.14)., Conclusion: In the diagnosis of recurrent disease in patients with differentiated thyroid carcinoma and low Tg level, the sensitivity of rhTSH-stimulated PET/CT-FDG seems to be low and no correlation was observed between PET/CT-FDG findings and Tg level. However, positive PET-FDG results have been found in 9/44 (20%) patients with serum Tg levels lower than 10 microg/L. Therefore, this series shows that a cutoff value of 10 microg/L for the Tg under T(4) is probably not the best criteria to select patient candidates for PET/CT-FDG examination to detect the recurrence of differentiated thyroid carcinoma.

Unlabelled: Heterogeneity analysis has been studied for radiological imaging, but few methods have been developed for functional images. Diffuse heterogeneous perfusion frequently appears in brain single photon emission computed tomography (SPECT) images, but objective quantification is lacking. An automatic method, based on random walk (RW) theory, has been developed to quantify perfusion heterogeneity. We assess the robustness of our algorithm in differentiating levels of diffuse heterogeneity even when focal defects are present., Methods: Heterogeneity is quantified by counting R (percentage), the mean rate of visited pixels in a fixed number of steps of the stochastic RW process. The algorithm has been tested on the numerical anthropomorphic Zubal head phantom. Seven diffuse cortical heterogeneity levels were simulated with an adjustable Gaussian function and 6 temporoparietal focal defects simulating Alzheimer Disease, leading to 42 phantoms. Data were projected and smoothed (full width at half maximum, 5.5 mm), and Poisson noise was added to the 64 projections. The SPECT data were reconstructed using filtered backprojection (Hamming filter, 0.5 c/p). R values for different levels of perfusion defect and diffuse heterogeneity were evaluated on 3 parameters: the number of slices studied (20 vs 40), the use of Talairach normalization versus original space, and the use of a cortical mask within the Talairach space. For each parameter, regression lines for heterogeneity and temporoparietal defect quantification were analyzed by covariance statistics. R values were also evaluated on SPECT images performed on 25 subjects with suspected focal dementia and on 15 normal controls. Scans were blindly ranked by 2 experienced nuclear physicians according to the degree of diffuse heterogeneity., Results: Variability of R was smaller than 0.17% for repeated measurements. R was more particularly influenced by diffuse heterogeneity compared with focal perfusion defect. The Talairach normalization had a significant influence on the heterogeneity quantification. The number of slices visited by the RW and the cortical masking have a weak influence on the heterogeneity quantification but only for very low heterogeneity levels. The Spearman coefficient between physicians' consensus and RW automatic ranking is 0.85, in the same order of magnitude as the Spearman coefficient between the rankings of the 2 senior physicians (0.86)., Conclusions: Random walk is an original and objective method and is able to quantify heterogeneous brain perfusion, even in presence of cortical defects. This method is repeatable, robust, and mainly influenced by spatial normalization.