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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.

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.

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

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).

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.)

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.)

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.)