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Telomere length appears to correlate with survival in early non-small-cell lung cancer (NSCLC), but the prognostic impact of telomere status in advanced NSCLC remains undetermined. Our purpose was to evaluate telomere parameters as prognostic and predictive biomarkers in advanced NSCLC. In 79 biopsies obtained before treatment, we analyzed the telomere length and expression of TERT and shelterin complex genes (TRF1, TRF2, POT1, TPP1, RAP1, and TIN2), using quantitative PCR. Non-responders to first-line chemotherapy were characterized by shorter telomeres and low RAP1 expression (p = 0.0035 and p = 0.0069), and tended to show higher TERT levels (p = 0.058). In multivariate analysis, short telomeres were associated with reduced event-free (EFS, p = 0.0023) and overall survival (OS, p = 0.00041). TERT and TRF2 overexpression correlated with poor EFS (p = 0.0069 and p = 0.00041) and OS (p = 0.0051 and p = 0.007). Low RAP1 and TIN2 expression-levels were linked to reduced EFS (p = 0.00032 and p = 0.0069) and OS (p = 0.000051 and p = 0.02). Short telomeres were also associated with decreased survival after nivolumab therapy (p = 0.097). Evaluation of telomere status in advanced NSCLC emerges as a useful biomarker that allows for the selection of patient groups with different clinical evolutions, to establish personalized treatment.

International audience; An increasing number of studies concerning solid cancers, including prostate cancer, are tending to demonstrate the predominant role of the interactions of tumor cells with their microenvironment, and underlining the relevance of therapeutic approaches co-targeting these two components. Artificial in vitro 3D culture models, such as spheroids, are therefore being designed to allow intercellular interactions between tumor cells and the matrix, under hypoxic conditions mimicking a microtumor. This project aims to develop and characterize a multicellular tumor spheroid (MCTS) model of human prostate cancer cells expressing PSMA, for in vitro drug screening. To this end, 1,000 cells/well were seeded in 100 µl of culture medium with 0.5% of methylcellulose in 96-well, non-adherent, V-shaped bottom plates. Bioluminescent imaging of the spheroids enabled the measurement of spheroid growth. From Day 7 of growth, immunofluorescence studies showed cellular proliferation (Ki-67), mainly located in the periphery of the spheroid section, associated with the formation of an apoptotic core (TUNEL). Scanning electron microscopy and fluorescent imaging (Lox-1 probe) showed the presence of an extracellular matrix and the installation of an oxygen gradient leading to the formation of a hypoxic area during growth. This hypoxia was correlated with increased VEGF excretion. Drug sensitivity was assessed on 2D and 3D cultures. The LNCaP-Luc spheroids are more resistant to docetaxel and TH-302, a hypoxia-activated prodrug, compared with cells grown in a monolayer. For docetaxel, this resistance increased with the spheroid growth stage, whereas the activity of TH-302 was potentiated by the hypoxic environment. In conclusion, the development of LNCaP-Luc cell MCTS provides a simple model mimicking a microtumor; it appears to be particularly well-suited to the validation of new therapeutic approaches targeting proliferation and the microenvironment.

As the clinical development of this radiotracer would be oriented toward the functional imaging of joint pathologies, we have chosen to include patients with healthy joints (unilateral osteoarthritis of the knee or breast cancer with indication of AI treatment). This phase I study will be an open-label, multicenter, dose-escalation trial of a radiopharmaceutical orientation to determine the recommended level of activity ofThis first in-human phase I trial will be proof-of-concept of the relevance ofClinicaltrials.gov: NCT04481230. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2020-000495-37.

Introduction Dual phase 18 FDG brain PET is helpful to assess brain metastases (BM) as tracer will build up in metastases or tumor recurrences while its retention remains stable within normal tissue or inflammatory processes. This is useful when MRI can’t discriminate brain tumor recurrence (TR) rom radionecrosis (RN) after stereotaxic radiosurgery (SRS) for BM. Many studies have sought to improve diagnostic performance by associating FDG-PET and MRI with interesting results but many biases, mostly within image post-processing. Coregistered MRI and dual phase FDG-PET images could alleviate these biases and be used to extract prognostic biomarkers. Materials and methods We retrospectively evaluated patients treated with SRS for BM which developed a contrast-enhanced MRI lesion with non-conclusive diagnosis for TR or RN. All patients underwent MRI and FDG-PET at least 3 months after their last SRS session. Dual FDG-PET consisted in an “early” and “delayed” acquisition, respectively 30 minutes and 4 h after injection. MRI included permeability and perfusion sequences. PET and MRI data were all coregistered on the contrast enhanced T1 MRI images. Semi-automated Volumes of Interest (VOI) of the tumor were drawn on the BM and a reference contralateral white-matter ROI (WM) was drawn for standardization; every metric was calculated inside these ROIs, in particular the tumor SUVmax and its variation in time. A 20% increase in the tumor SUVmax was in favor of TR while a modification of less than 100% was in favor of RN. Imaging metrics were then evaluated for their association with TR or RN based on histological, radiological and clinical criteria after at least 6 months follow-up. Results Nine patients were ruled out as TR and 6 as RN. After standardization, there was a significant difference between groups for VP (P = 0.042), Washin (P = 0.035), Peak Enhancement (P = 0.037), standardized delayed SUVmax (P = 0.008) and RI (P = 0.016). Semi-quantitative analysis found respectively for PET and MRI a Sensitivity of 100% and 87.5% and a Specificity of 100% and 85.71%. Conclusion Coregistered PET-MRI images accurately discriminate between TR and RN. With FDG being the most commonly used PET radiotracer, this protocol remains easily transposable and should be encouraged to obtain non-invasive prognostic and clinically relevant biomarkers.

18F-FDG PET is recommended for the initial staging of locally advanced breast cancer. Studies have shown the prognostic value of 18F-FDG PET for staging, but its ability to predict pathological complete response remains uncertain. Our objective was to determine the predictive value of early therapeutic evaluation by 18F-FDG PET for HER2-positive breast cancer patients. We studied a subpopulation of the prospective and multicentric French NeoTOP trial, at interim analysis. All patients were eligible for neoadjuvant chemotherapy. A 18F-FDG PET was performed at baseline and then after one cycle of neoadjuvant treatment. 18F-FDG PET were studied by three conventional methods (two visuals and one quantitative) and by textural analysis. Complete pathological response on surgical samples corresponded to grades 1/2 of Chevallier's classification and no responders corresponded to grades 3/4 of Chevallier. Pathological results were available for 21 patients. SUVmax decreased by 55% after one cycle of chemotherapy. No difference between groups was found with visuals, conventional quantitative and textural analysis of tumour uptake evaluations. Early therapeutic evaluation by 18F-FDG PET for HER2-positive breast cancer was not predictive of pathological therapeutic response after neoadjuvant treatment, with conventional study or textural analyses in this interim analysis.

International audience

Since the beginning of the year 2020, the coronavirus-19 disease (COVID-19) pandemic has undoubtedly posed significant challenges to healthcare systems worldwide. It has also affected, in a way previously unimaginable, our lifestyle and the way we relate to each other, not only at work, but also in the community and in the family setting. Healthcare systems worldwide have been forced to make huge alterations to be able to handle the different stages of the pandemic. [...]

L’[131I]ICF01012, benzamide developpee par notre equipe, presente une forte affinite pour la melanine. L’objectif principal de cette phase I est de determiner la dose recommandee (GBq/m2) d’[131I]ICF01012 administree pour le traitement de patients atteints de melanomes de stade IV. Les objectifs secondaires rapportes ici sont l’evaluation de la pharmacocinetique, biodistribution et dosimetrie. Methodologie Un maximum de 36 patients sera inclus. Quatre paliers seront explores : 0,8 ; 1,6 ; 2,7 ; 4 GBq/m2. Chaque patient beneficie au prealable d’un examen diagnostique (185 MBq) pour confirmer la presence de lesions positives, verifier que les doses absorbees sont inferieures aux doses limitantes pour le foie, la retine et les poumons, et pour l’etude de pharmacocinetique. Sont realisees des imageries corps entiers et TEMP/TDM de 30 min a J4 p.i. diagnostique et de J4 a J21 p.i therapeutique. Les doses absorbees par les organes a risque (OAR) et les lesions secondaires sont calculees par le formalisme du MIRD : produit de l’activite cumulee et des facteurs S personnalises. Les pharmacocinetiques sanguines et urinaires sont evaluees respectivement jusqu’a 166 et 72 h p.i. La tolerance est cotee selon la methode NCI-CTC. Resultats Nous rapportons les resultats obtenus chez les deux premiers patients traites respectivement par 0,8 et 1,6 GBq/m2. La pharmacocinetique sanguine presente un aspect biphasique avec 3,2 ± 0,2 % et 5,1 ± 2,4 % de l’activite injectee (AI) mesuree dans le sang total 5 min et 24 h p.i dont 33,5 ± 2,1 et 89 ± 4,2 % liees aux proteines. 53 ± 17 % de l’AI est eliminee par voie urinaire dans les 3 jours p.i. L’analyse visuelle des scintigraphies a montre une fixation tres intense et stable jusqu’a J21 sur les lesions secondaires pulmonaires, osseuses et peritoneales, une fixation faible et stable sur la retine, une fixation intense rapidement decroissante sur les lesions benignes inflammatoires, le foie et les reins. Les doses absorbees ont ete mesurees a 3,9 ± 1,9 ; 1,3 ± 0,4 ; 0,8 ± 0,2 ; 0,3 ± 0,1 Gy/GBq respectivement sur les lesions secondaires, la retine, le foie et les reins. Une toxicite neurologique grade I a ete rapportee au palier 2. La prochaine inclusion est prevue au palier 3. Conclusion Les resultats preliminaires montrent un ratio dose absorbee metastases/OAR tres favorable, positionnant ainsi l’[131I]ICF01012 comme une nouvelle strategie theranostique pertinente pour le traitement du melanome metastatique. Grant : PRTK INCA/DGOS tranla 12-143.

Le 99mTc-NTP-15-5, radiotraceur developpe par notre UMR 1240 INSERM, possede une fonction ammonium quaternaire ciblant les proteoglycanes du cartilage articulaire. L’objectif principal de cette phase I est de determiner la dose recommandee (MBq/kg) de 99mTc-NTP 15-5 permettant d’obtenir le meilleur contraste visuel de fixation articulaire sur le cartilage sain, sans toxicite. Les objectifs secondaires rapportes ici sont les analyses quantitatives de la fixation sur le cartilage sain et arthrosique, les donnees de biodistribution et de pharmacocinetique du 99mTc-NTP-15-5. Materiels et methodes Un maximum de 6 patients presentant une arthrose unilaterale du genou ou un cancer du sein traite par antiaromatase sera a terme inclus. Trois paliers d’activites sont etudies (5, 10 et 15 MBq/kg). Un score visuel (1 a 3) mesure la fixation du traceur sur 31 articulations/disques intervertebraux a 30 min, 1 h, 2 h, 4 h et 6 h p.i : 1 : fixation fixation diaphysaire. Le palier selectionne sera celui pour lequel 80 % des articulations presenteront un score egal a 3 a 2 h p.i. Pharmacocinetiques et biodistributions sont analysees sur materiel urinaire, sanguin et scintigraphique. La quantification 3D de la fixation sur l’articulation du genou est mesuree par le ratio epiphyse/diaphyse (E/D). La tolerance est cotee par l’echelle NCICTC 4.0. Resultats Nous rapportons les resultats obtenus chez le premier patient inclus (cancer du sein). La fixation a ete cotee a 3 a 2 h p.i, sur moins de 80 % des sites etudies, respectivement sur la capsule synoviale et le cartilage des articulations glenohumerale, radiocarpienne, radiohumerale, coxofemorale et femorotibiale. L’analyse des scintigraphies a montre une elimination urinaire et entero-hepatique du traceur des la 30eme minute. Le ratio E/D a ete evalue a 1,23. 11 % de l’activite injectee a ete mesuree dans le sang total a 2 h p.i, 30 % etant lies aux proteines plasmatiques. 70 % du traceur a ete elimine dans les urines a 8 h p.i. Aucune toxicite n’a ete rapportee. La prochaine inclusion est prevue au palier 10 MBq/kg. Conclusion La scintigraphie au 99mTc-NTP15-5 est une imagerie moleculaire innovante potentiellement pertinente pour l’exploration des pathologies benignes du cartilage. Les resultats preliminaires demontrent une accumulation specifique du 99mTc-NTP-15-5 sur la capsule synoviale et le cartilage articulaire. Grant : I-Site CAP 20-25.

Introduction Dual phase 18[F]-FDG brain PET (dual-PET) is useful to distinguish tumor recurrence (TR) from radionecrosis (RN) after stereotaxic radiosurgery (SRS) of brain metastases, when contrast-enhanced MRI is inconclusive. We aimed to compare six different visual and quantitative interpretation criteria to enhance diagnostic performances. Materials and methods In this retrospective french multicentric study (Clermont-Ferrand, Montpellier, Rennes), we evaluated 45 patients previously treated with SRS for BM, addressed for a dual-PET by the local neuro-oncological committees for an evolving lesion on MRI inconclusive between TR and RN, at least 3 months after the last SRS session. Dual-PET included both an “early” and a “delayed” acquisition, respectively 30 to 60 minutes and 4 to 5 hours after 18[F]-FDG injection. After measuring SUVmax values of both lesion (L) and mirror contralateral grey matter (GM) at early (1) and delayed (2) acquisitions, three quantitative metrics were calculated: ratios of L SUVmax to GM SUVmax at “early” (L1/GM1) and “delayed” (L2/GM2) acquisitions and the retention index which is the variation over time of the standardized SUVmax ratio (RI = [(Delayed-Early)/Early]). Visual analysis was also conducted using a subjective 6 points visual scale of the lesion uptake at both acquisitions. The five interpretation criteria were compared according to their area under the ROC curve (AUC), and to their diagnostic accuracy applying the best cut off value (maximizing the Youden's index) by the Cochran Q test. The final diagnosis was based on pathology, or by default radiological and clinical follow-up criteria after at least 6 months. Results Final diagnoses were TR for 24 patients and RN for 21 patients. There was no statistically significant difference regarding AUC between the different interpretation methods. AUC ranged from 0,78 [95 %CI 0,63; 0,89] with the L1/GM1 Ratio, to 0.85 [95 %CI 0.72; 0.94] with the L2/GM2 ratio. Visual analyses AUC were excellent at both early (0.835 [95 %CI 0.7; 0.93]) and delayed acquisitions (0.83 [95 %CI 0.69; 0.92]). There was no statistically significant difference between accuracies (p = 0.87) ranging from 0.71 with the RI ratio to 0.80 with both the “delayed” visual and quantitative analyses. Conclusion Dual-PET protocol distinguishes RN and TR after SRS with robust diagnostic performances in case of doubtful MR, with an accuracy up to 80 %.

Le cancer du sein triple-negatif (CSTN) est le sous-type le plus agressif. L’identification precoce des patientes resistantes a la chimiotherapie neoadjuvante peut permettre une readaptation therapeutique et ainsi ameliorer leur pronostic. Depuis plusieurs annees, les nanobodies (VHHs) sont apparus comme une alternative aux anticorps conventionnels et montrent un fort potentiel pour l’imagerie nucleaire. L’objectif de ce projet est de developper un nouveau radioligand de type nanobody, radiomarque par le Technetium-99 m, ciblant l’Human Epidermal growth factor Receptor 3 (HER3), recepteur implique dans les mecanismes de resistance des CSTN a la chimiotherapie neoadjuvante. La production des VHHs a ete realisee par la societe Caminnov. L’immunisation des camelides a ete induite par injection de proteine recombinante HER3-Fc (R&D Systems) ou de fragments membranaires de cellules HEK293 transfectees avec la proteine recombinante HER3-Fc. La selection des VHHs a ete realisee sur cinq lignees cellulaires avec differents niveaux d’expression du recepteur HER3 : MCF-7, MDA-MB-468, MDA-MB-231, SkBr3 et CHO. L’affinite des VHHs pour HER3 a ete mesuree par cytometrie de flux (CMF) et par test ELISA avec presence ou non de neureguline (R&D systems). En parallele, la faisabilite du radiomarquage des tags histidines, presents sur l’extremite C-terminale des VHHs, par le Technetium-99 m a ete realisee grâce a l’utilisation du complexe [99mTc(H2O)3(CO)3]+. Sur 13 VHHs produits, un seul a montre une affinite pour les cellules exprimant HER3 en presence ou non de la neureguline par CMF. L’analyse des tests ELISA realises sur ce VHH a mis en evidence une affinite plus importante pour la lignee cellulaire exprimant HER3 (KDMCF-7 = 0,027) comparativement a la lignee n’exprimant pas HER3 (KDCHO = 0,078). Les etudes de radiomarquage avec le [99mTc(H2O)3(CO)3]+ ont permis d’obtenir 2 VHHs avec des rendements d’environ 90 % sans purification et 2 VHHs avec des rendements de 20 et 25 % avec purification sur colonne d’exclusion sterique NAP-5. Ils ont tous ete obtenus avec une purete radiochimique > 90 %. Ces resultats preliminaires confirment la possibilite de produire et de radiomarquer des naonobodies ciblant HER3. Des etudes complementaires de resonnance plasmonique de surface sont en cours pour evaluer la specificite du VHH selectionne par rapport aux autres membres de la famille HER. Support : Ligue regionale contre le cancer, I-site Clermont.

Positron Emission Tomography (PET) is a functional nuclear medicine imaging technique which clinical value in oncology has been demonstrated. PET indications are constantly evolving, thanks to the contribution of research. The use of PET in oncology has been the subject of recommendations according to the Standard-Options-Recommendations methodology from the Federation Nationale des Centres de Lutte Contre le Cancer in 2002, updated in 2003. However, many scientific works have been published since 2003 and new tracers have also obtained a marketing authorization in France. The objective of this work was therefore to update the recommendations established in 2003. In this context, in collaboration with the Societe francaise de medecine nucleaire, a working group was set up for the development of good clinical practice recommendations under the HAS-INCA methodological label. The present document is issued from a comprehensive review of the literature and rigorous appraisal by a panel of national experts, organ specialists, clinical oncologists, surgeons, and imaging specialists. It is intended to be used as a guide to decision-making for those oncology teams that are able to manage patients in various situations in which the AMM label is not sufficiently precise.

International audience; Cutaneous melanoma arises from proliferating melanocytes, cells specialized in the production of melanin. This property means melanin can be considered as a target for monitoring melanoma patients using nuclear imaging or targeted radionuclide therapy (TRT). Since the 1970s, many researchers have shown that specific molecules can interfere with melanin. This paper reviews some such molecules: benzamide structures improved to increase their pharmacokinetics for imaging or TRT. We first describe the characteristics and biosynthesis of melanin, and the main features of melanin tracers. The second part summarizes the preclinical and corresponding clinical studies on imaging. The last section presents TRT results from ongoing protocols and discusses combinations with other therapies as an opportunity for melanoma non-responders or patients resistant to treatments.

Introduction/Materiels Le marquage au 99mTc-HMPAO des leucocytes, indique dans la recherche d’infections, necessite le developpement d’une technique optimale de separation des cellules sanguines. L’etape de sedimentation du sang preleve sur le patient est une des etapes decisives pour assurer la qualite de la preparation. Certains parametres biologiques du patient tels que la Vitesse de Sedimentation (VS) conditionnent cette qualite de marquage en augmentant le volume de surnageant et donc le nombre de leucocytes marques. L’utilisation d’agents de sedimentation de type Hydroxyethylamidon (HEA) selon les recommandations de l’EANM permet d’augmenter ce volume. Cependant, l’utilisation de tels agents est-elle justifiee lorsque la VS du patient est suffisamment elevee ? Methodes/Resultats/Conclusion Nous avons compare a l’issue de l’etape de sedimentation le volume de surnageant et le nombre de leucocytes recueillis en utilisant ou non de l’HEA, sur le sang de 37 patients. Un ratio volume de surnageant (Vs)/volume de sang total (Vt) a ete determine pour chaque tube de sedimentation et les cellules recueillies ont ete comptees a l’aide de Kova Slide®. Les patients ont ete discrimines en fonction de leur classe de VS et nous avons compare les resultats a l’aide d’un test de Mann-Whitney au risque 5 %. A faible vitesse de sedimentation (VS≤ 7 mm), le ratio Vs/Vt est significativement superieur en utilisant l’HEA (p = 0,02). Cependant, des que la VS > 7 mm, l’utilisation d’HEA ne permet plus d’augmenter significativement le ratio Vs/Vt. Sur l’ensemble des prelevements, le nombre de leucocytes comptes dans chacun des surnageant n’est pas significativement different en utilisant ou non l’HEA. Nous avons, par ailleurs, remarque que le ratio nombre de globules rouges sur nombre de cellules total est significativement inferieur dans le surnageant recueilli sans HEA, mettant en evidence une meilleure qualite de ce dernier. Selon ces resultats, l’utilite de l’HEA serait discutable chez des patients presentant une VS > 7 mm pour l’etape de sedimentation. S’affranchir d’HEA a VS > 7 mm permettrait un gain de temps sur le marquage et une reduction du cout, non negligeable au regard du nombre d’examens sur une annee. Par ailleurs, les globules rouges recueillis retrouves en nombre significativement inferieur, lorsque l’HEA n’est pas utilise, pourraient avoir un impact sur la qualite de l’image en reduisant le bruit de fond.

PURPOSE This study aims to perform dosimetry for [99m Tc]NTP15-5 radiotracer used in imaging of articular cartilage in rabbits and humans. The radiotracer (covered by a world patent WO 01/00621 A1) has been proposed in the previous years for the study of cartilage in osteoarthritis diseases. A sensitive imaging approach is essential to quantify osteoarthritis progression and monitor response to new therapies. [99m Tc]NTP15-5 binds to cartilage proteoglycans whose decreased content is associated to a loss of biomedical function of cartilage. We have implemented the whole dosimetry study concerning this new radiotracer for rabbits and humans using the GATE Monte Carlo platform. MATERIALS AND METHODS Absorbed doses to critical organs are determined using the MIRD formalism. Biodistribution data are obtained by organ sampling, measuring the activity in organs for three rabbits sacrificed at various times postadministration, and by SPECT/CT imaging at different times after injection. Most important sources are cartilages (in knees and intervertebral discs), due to localization together with the liver and kidneys due to excretion of the agent. S-values are calculated from rabbit's CT scan and human CT scan using the GATE v8.0 Monte Carlo platform. Cumulated activity in humans is extrapolated from animals using the %kg-dose/g method. Particular attention is given to dose calculation in bones, bone marrow and organs at risk. RESULTS The dosimetry performed in rabbits shows highest absorbed doses for liver and kidneys with respectively 22.5 and 43.8 µGy per MBq of injected activity. In humans, we found absorbed doses for a maximum injected activity of 15 MBq/kg, that is, 1050 MBq for an adult of 70 kgs of 9.03 mGy for kidneys and 4.16 mGy for knee cartilages. Effective dose is 2.69 µSv/MBq. CONCLUSIONS The dosimetry profile of [99m Tc]NTP15-5 in the context of preclinical trials is of major importance in order to make sure that organs at risk are not overexposed. GATE provides all the capability needed to calculate dose profiles for internal dosimetry. The extrapolation of the dose for a human model is a first step towards clinical trials.

Background A surveillance program was performed in colorectal cancer (CRC) patients after surgery, to diagnose asymptomatic recurrence. Aims To assess whether 18-FDG positron emission tomography/CT (PET/CT) improved the detection of recurrence during a 3-year follow-up. Methods A multicentre, two-arm randomised prospective trial comparing different 36-month follow-up strategies. Complete colonoscopy was performed at baseline and after 3 years and clinical exams with imaging every 3 months. The conventional arm (A) received carcinoembryonic antigen, liver echography, and alternated between lung radiography and computed tomography (CT) scans. The experimental arm (B) received PET/CT. Results A total of 365 patients with colon (79.4%) or rectal cancer (20.6%), stages II (48.2%) or III (50.8%), were enroled in this study. At 36 months, intention-to-treat analysis revealed recurrence in 31 (17.2%) patients in arm A and 47 (25.4%) in arm B (p = 0.063). At 3 years, 7 of 31 relapses (22.5%) in arm A were surgically treated with curative intent, compared to 17 of 47 (36.2%) in arm B (p = 0.25). The rates of recurrence and new cancers were higher in arm B than arm A (p = 0.038). Conclusions PET/CT follow-up every 6 months did not increase the rate of recurrence at 3 years or the rate of surgically treated recurrence compared with conventional follow-up.

This study aims to perform dosimetry for [Absorbed doses to critical organs are determined using the MIRD formalism. Biodistribution data are obtained by organ sampling, measuring the activity in organs for three rabbits sacrificed at various times postadministration, and by SPECT/CT imaging at different times after injection. Most important sources are cartilages (in knees and intervertebral discs), due to localization together with the liver and kidneys due to excretion of the agent. S-values are calculated from rabbit's CT scan and human CT scan using the GATE v8.0 Monte Carlo platform. Cumulated activity in humans is extrapolated from animals using the %kg-dose/g method. Particular attention is given to dose calculation in bones, bone marrow and organs at risk.The dosimetry performed in rabbits shows highest absorbed doses for liver and kidneys with respectively 22.5 and 43.8 µGy per MBq of injected activity. In humans, we found absorbed doses for a maximum injected activity of 15 MBq/kg, that is, 1050 MBq for an adult of 70 kgs of 9.03 mGy for kidneys and 4.16 mGy for knee cartilages. Effective dose is 2.69 µSv/MBq.The dosimetry profile of [

Purpose Pathological complete response to the neoadjuvant therapy (NAT) for triple negative breast cancer (TNBC) is predictive of prolonged patient survival. Methods for early evaluation of NAT efficiency are still needed, in order to rapidly adjust the therapeutic strategy in case of initial non-response. One option for this is molecular imaging of apoptosis induced by chemotherapy. Therefore, we investigated the capacity of [18F]ML-10 PET imaging, an apoptosis radiotracer, to detect tumor cell apoptosis and early predict the therapeutic response of human TNBC. Results Initially, the induction of apoptosis by different therapies was quantified. We confirmed, in vitro, that paclitaxel or epirubicin, the fundamental cytotoxic drugs for breast cancer, induce apoptosis in TNBC cell lines. Exposure of TNBC models MDA-MB-231 and MDA-MB-468 to these drugs induced a significant increase (p < 0.01) of the apoptotic hallmarks: DNA fragmentation, membrane phospholipid scrambling, and PARP activation. Secondarily, apoptotic fraction was compared to the intracellular accumulation of the radiotracer. [18F]ML-10 accumulated in the apoptotic cells after 72 h of treatment by paclitaxel in vitro; this accumulation positively correlated with the apoptotic fraction. In vivo, [18F]ML-10 was rapidly cleared from the nontarget organs and mainly eliminated by the kidneys. Comparison of the in vivo [18F]FDG, [18F]FMISO, and [18F]ML-10 uptakes revealed that the tumor accumulation of [18F]ML-10 was directly related to the tumor hypoxia level. Finally, after the in vivo treatment of TNBC murine xenografts by paclitaxel, apoptosis was well induced, as demonstrated by the cleaved caspase-3 levels; however, no significant increase of [18F]ML-10 accumulation in the tumors was observed, either on day 3 or day 6 after the end of the treatment. Conclusions These results highlighted that PET imaging using [18F]ML-10 allows the visualization of apoptotic cells in TNBC models. Nevertheless, the increase of the chemotherapy-induced apoptotic response when using paclitaxel could not be assessed using this radiotracer in our mouse model.

Positron emission tomography/computed tomography (PET/CT) is a nuclear medicine functional imaging technique with proven clinical value in oncology. PET/CT indications are continually evolving with fresh advances made through research. French practice on the use of PET in oncology was framed in recommendations based on Standards-Options-Recommendations methodology and coordinated by the French federation of Comprehensive Cancer Centres (FNLCC). The recommendations were originally issued in 2002 followed by an update in 2003, but since then, a huge number of scientific papers have been published and new tracers have been licenced for market release. The aim of this work is to bring the 2003 version recommendations up to date. For this purpose, a focus group was set up in collaboration with the French Society for Nuclear Medicine (SFMN) to work on developing good clinical practice recommendations. These good clinical practice recommendations have been awarded joint French National Heath Authority (HAS) and French Cancer Institute (INCa) label status-the stamp of methodological approval. The present document is the outcome of comprehensive literature review and rigorous appraisal by a panel of experts, organ specialists, clinical oncologists, surgeons and imaging specialists. These data were also used for the EANM referral guidelines.

Purpose: The objective of this study was to evaluate periarticular FDG uptake scores from 18F-FDG-PET/CT to identify polymyalgia rheumatica (PMR) within a population presenting rheumatic diseases. Methods: A French retrospective study from 2011 to 2015 was conducted. Patients who underwent 18F-FDG-PET/CT for diagnosis or follow-up of a rheumatism or an unexplained biological inflammatory syndrome were included. Clinical data and final diagnosis were reviewed. Seventeen periarticular sites were sorted by a visual reading enabling us to calculate two scores: mean FDG visual uptake score, number of sites with significant uptake same as that or higher than liver uptake intensity and by a semi-quantitative analysis using mean maximum standardized uptake value (SUVmax). Optimal cutoffs of visual score and SUVmax to diagnose PMR were determined using receiver operating characteristics curves. Results: Among 222 18F-FDG PET/CT selected for 215 patients, 161 18F-FDG PET/CT were performed in patients who presented inflammatory rheumatism as a final diagnosis (of whom 57 PMR). The presence of at least three sites with significant uptake identified PMR with a sensitivity of 86% and a specificity of 85.5% (AUC 0.872, 95% CI [0.81-0.93]). The mean FDG visual score cutoff to diagnose a PMR was 0.765 with a sensitivity of 82.5% and a specificity of 75.8% (AUC 0.854; 95% CI [0.80-0.91]). The mean SUVmax cutoff to diagnose PMR was 2.168 with a sensitivity of 77.2% and a specificity of 77.6% (AUC 0.842; 95% CI [0.79-0.89]). Conclusions: This study suggests that 18F-FDG PET/CT had good performances to identify PMR within a population presenting rheumatic diseases.

Purpose For differentiating tumor from inflammation and normal tissues, fluorodeoxyglucose ([18F]FDG) dual time point PET could be helpful. Albeit [18F]FLT is more specific for tumors than [18F]FDG; we explored the role of dual time point [18F]FLT-PET for discriminating benign from malignant tissues. Methods Before any treatment, 85 womens with de novo unifocal breast cancer underwent three PET acquisitions at 33.94 ± 8.01 min (PET30), 61.45 ± 8.30 min (PET60), and 81.06 ± 12.12 min (PET80) after [18F]FLT injection. Semiquantitative analyses of [18F]FLT uptake (SUV) were carried out on tumors, liver, bone marrow (4th thoracic vertebra (T4) and humeral head), descending thoracic aorta, muscle (deltoid), and contralateral normal breast. Repeated measures ANOVA tests and Tukey’s posttests were used to compare SUVmax of each site at the three time points. Results There was a significant increase in SUVmax over time for breast lesions (5.58 ± 3.80; 5.97 ± 4.56; 6.19 ± 4.42; p < 0.0001) (m ± SD for PET30, PET60, and PET80, respectively), and bone marrow (for T4, 8.21 ± 3.17, 9.64 ± 3.66, 10.85 ± 3.63, p < 0.0001; for humeral head, 3.36 ± 1.79, 3.87 ± 1.89, 4.39 ± 2.00, p < 0.0001). A significant decrease in SUVmax over time was observed for liver (6.79 ± 2.03; 6.24 ± 1.99; 5.57 ± 1.74; p < 0.0001), muscle (0.95 ± 0.28; 0.93 ± 0.29; 0.86 ± 0.20; p < 0.027), and aorta (1.18 ± 0.34; 1.01 ± 0.32; 0.97 ± 0.30; p < 0.0001). No significant difference was observed for SUVmax in contralateral breast (0.8364 ± 0.40; 0.78 ± 0.38; 0.80 ± 0.35). Conclusion [18F]FLT-SUVmax increased between 30 and 80 min only in proliferating tissues. This could be helpful for discriminating between residual tumor and scar tissue.

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International audience; Purpose of the report: This study aimed at assessing an original low-dose dual-isotope procedure in which the abnormal stress Tc-99m Sestamibi SPECT is followed by rest Tl-201 SPECT, along with a head-to-head comparison with a single-isotope procedure.Methods and results: One hundred two patients, referred for a low-dose stress-SPECT with Sestamibi (123 ± 20 MBq) on a CZT camera and for whom a rest Sestamibi SPECT was warranted, had an additional Tl-201 rest-SPECT (52 ± 5 MBq) between stress and rest Sestamibi SPECT recordings. Tl-201 images were processed for spill-over and scatter corrections, and uptake differences with stress Sestamibi SPECT were analyzed: (1) for rest acquisitions from Tl-201 (dual-isotope procedure) and from Sestamibi (single-isotope procedure) and (2) in segments for which a diagnosis of ischemia, infarct, or normal perfusion was achieved. Mean effective dose was 8.3 mSv for dual-isotope but would decrease to 5.7 mSv for an expected rate of 37% of patients for whom rest-SPECT is not warranted. After a further background correction of Tl-201 images, the rest-stress difference in myocardial uptake was equivalent between dual- and single-procedures for identifying ischemic segments (respective areas-under-curves: 0.83 ± 0.03 and 0.81 ± 0.03).Conclusion: This original dual-isotope procedure provides acceptable radiation doses and consistent results, as compared with conventional single-isotope.

Resume L’imagerie est desormais un outil pivot pour la prise en charge des patients en cancerologie solide. Elle permet d’apprecier, le plus objectivement possible, l’efficacite du traitement. Du fait du developpement et de la generalisation des TEP couplees au TDM, il semblait important de refaire le point sur les differents outils accessibles, morphologiques et metaboliques, pour la pratique quotidienne en medecine nucleaire cancerologique. Les criteres morphologiques les plus utilises aujourd’hui en cancerologie generale sont les criteres RECIST 1.1, bases sur une evaluation par TDM. Mais ceux-ci ont certaines limites. D’autres criteres ont donc ete developpes comme les criteres d’Immune-Related Response Criteria pour les immunotherapies. Concernant l’evaluation metabolique, des criteres d’interpretation sont egalement disponibles depuis 1999 (criteres EORTC) et 2009 (criteres PERCIST), avec leurs methodologies propres. Enfin, des criteres specifiques sont utilises pour le cancer de la prostate, bases sur la scintigraphie osseuse. Cet article permet de refaire le point sur ces differents outils et leurs complementarites.

Purpose For differentiating tumor from inflammation and normal tissues, fluorodeoxyglucose ([18F]FDG) dual time point PET could be helpful. Albeit [18F]FLT is more specific for tumors than [18F]FDG; we explored the role of dual time point [18F]FLT-PET for discriminating benign from malignant tissues. Methods Before any treatment, 85 womens with de novo unifocal breast cancer underwent three PET acquisitions at 33.94 ± 8.01 min (PET30), 61.45 ± 8.30 min (PET60), and 81.06 ± 12.12 min (PET80) after [18F]FLT injection. Semiquantitative analyses of [18F]FLT uptake (SUV) were carried out on tumors, liver, bone marrow (4th thoracic vertebra (T4) and humeral head), descending thoracic aorta, muscle (deltoid), and contralateral normal breast. Repeated measures ANOVA tests and Tukey’s posttests were used to compare SUVmax of each site at the three time points. Results There was a significant increase in SUVmax over time for breast lesions (5.58 ± 3.80; 5.97 ± 4.56; 6.19 ± 4.42; p < 0.0001) (m ± SD for PET30, PET60, and PET80, respectively), and bone marrow (for T4, 8.21 ± 3.17, 9.64 ± 3.66, 10.85 ± 3.63, p < 0.0001; for humeral head, 3.36 ± 1.79, 3.87 ± 1.89, 4.39 ± 2.00, p < 0.0001). A significant decrease in SUVmax over time was observed for liver (6.79 ± 2.03; 6.24 ± 1.99; 5.57 ± 1.74; p < 0.0001), muscle (0.95 ± 0.28; 0.93 ± 0.29; 0.86 ± 0.20; p < 0.027), and aorta (1.18 ± 0.34; 1.01 ± 0.32; 0.97 ± 0.30; p < 0.0001). No significant difference was observed for SUVmax in contralateral breast (0.8364 ± 0.40; 0.78 ± 0.38; 0.80 ± 0.35). Conclusion [18F]FLT-SUVmax increased between 30 and 80 min only in proliferating tissues. This could be helpful for discriminating between residual tumor and scar tissue.

International audience; Positron Emission Tomography (PET) is a functional nuclear medicine imaging technique which clinical value in oncology has been demonstrated. PET indications are constantly evolving, thanks to the contribution of research. The use of PET in oncology has been the subject of recommendations according to the Standard-Options-Recommendations methodology from the Fédération Nationale des Centres de Lutte Contre le Cancer in 2002, updated in 2003. However, many scientific works have been published since 2003 and new tracers have also obtained a marketing authorization in France. The objective of this work was therefore to update the recommendations established in 2003. In this context, in collaboration with the Société française de médecine nucléaire, a working group was set up for the development of good clinical practice recommendations under the HAS-INCA methodological label. The present document is issued from a comprehensive review of the literature and rigorous appraisal by a panel of national experts, organ specialists, clinical oncologists, surgeons, and imaging specialists. It is intended to be used as a guide to decision-making for those oncology teams that are able to manage patients in various situations in which the AMM label is not sufficiently precise.

Objectives Dual phase 18 FDG-PET has been proven helpful to assess FDG-avid cerebral tumors as tracer will build up in metastases or tumor recurrences while its retention remains stable within normal tissue or inflammatory process. This is useful when MRI can’t discriminate brain tumor recurrence (TR) from radionecrosis (RN) after stereotaxic radiosurgery (SRS) for brain metastases (BM). Many studies sought to improve diagnostic performance by associating FDG-PET and MRI with interesting results but many bias, mostly within image post-processing. Coregistered MRI and dual phase FDG-PET images could alleviate these biases and be used to extract prognostic biomarkers. Methods We retrospectively evaluated patients treated with SRS for BM which developed a contrast-enhanced MRI lesion with non-conclusive diagnosis for TR or RN. All patients underwent MRI and FDG-PET at least 3 months after their last SRS session. Dual FDG-PET comprised a one hour “based image” (H1) followed by a 4 hours “delayed image” (H4). MRI included contrast enhanced T1 (T1), FLAIR, ASL (BAT,CBF), T1 Perfusion (ktrans, SER) and T2* Permeability (k2, rBF, rBV). PET and MRI data were all coregistered on the T1 images. Semi-automated Regions of Interest (ROI) of the tumor were drawn on the T1 MRI, H1 and H4 FDG-PET images; a reference contralateral white-matter ROI (WM) was drawn for standardization. Imaging metrics were then evaluated for their association with TR or RN based on histological, radiological and clinical criteria after at least 6 months follow-up. Results Eleven patients matched the inclusion criteria; 7 with TR and 4 with RN; no additional treatment was introduced. On visual analysis, FDG-PET and MRI respectively obtained 100% and 83% Sensitivity and 100% and 80% Specificity. The two MRI-false negative diagnoses were subsequently identified on follow-up (1 patient, RN) and histology (1 patient, TR). When standardized on WM, PET SUVmax values were significantly different across groups at H1 (P Conclusion Coregistered PET-MRI images accurately discriminates between TR and RN. With FDG being the most commonly used PET radiotracer, this protocol remains easily transposable and should be encouraged to obtain non-invasive prognostic and clinically relevant biomarkers.

La TEP au 18FDG est recommandee lors du bilan d’extension initial des neoplasies mammaires localement avancees. Plusieurs etudes ont demontre sa valeur pronostique dans cette indication. Sa valeur pour predire la reponse complete histologique reste en revanche incertaine. Notre objectif a ete d’evaluer la valeur predictive de l’evaluation therapeutique precoce par TEP au 18FDG chez les patientes presentant une neoplasie mammaire HER2+. Ce travail est une analyse intermediaire des imageries TEP realisees dans le cadre de l’etude prospective et multicentrique francaise NeoTOP. Les patientes incluses etaient eligibles a une chimiotherapie neoadjuvante. Elles ont beneficie d’une TEP au 18FDG avant et apres la premiere cure de traitement. L’evolution de la fixation tumorale entre les deux examens TEP a ete mesuree par trois methodes conventionnelles (deux visuelles et une quantitative) et par une analyse texturale. Les parametres des quatre methodes ont ete compares entre le groupe de patients repondeurs (reponse complete histologique : grades 1 et 2 de Chevallier) et celui non repondeur (grades 3 et 4 de Chevallier). Les resultats histologiques etaient disponibles chez 21 patientes. Le SUVmax a diminue en moyenne de 55 % apres une cure. Il n’a pas ete retrouve de difference significative entre les groupes repondeurs et non repondeur lorsque la fixation tumorale etait evaluee par methodes visuelles, quantitative conventionnelle ou par analyse texturale. L’evaluation precoce de la reponse therapeutique par TEP au 18FDG pour les neoplasies mammaires HER2+ n’est pas predictive de la reponse anatomopathologique apres traitement neoadjuvant.

To compare, vs CMR, four softwares: quantitative gated SPECT (QGS), myometrix (MX), corridor 4DM (4DM), and Emory toolbox (ECTb) to evaluate left ventricular ejection fraction (LVEF), end-systolic (ESV), and end-diastolic volumes (EDVs) by gated MPI CZT-SPECT. 48 patients underwent MPI CZT-SPECT and CMR 6 weeks after STEMI, LV parameters were measured with four softwares at MPI CZT-SPECT vs CMR. We evaluated (i) concordance and correlation between MPI CZT-SPECT and CMR, (ii) concordance MPI CZT-SPECT/CMR for the categorical evaluation of the left ventricular dysfunction, and (iii) impacts of perfusion defects > 3 segments on concordance. LVEF: LCC QGS/CMR = 0.81 [+ 2.2% (± 18%)], LCC MX/CMR = 0.83 [+ 1% (± 17.5%)], LCC 4DM/CMR = 0.73 [+ 3.9% (± 21%)], LCC ECTb/CMR = 0.69 [+ 6.6% (± 21.1%)]. ESV: LCC QGS/CMR = 0.90 [− 8 mL (± 40 mL)], LCC MX/CMR = 0.90 [− 9 mL (± 36 mL)], LCC 4DM/CMR = 0.89 [+ 4 mL (± 45 mL)], LCC ECTb/CMR = 0.87 [− 3 mL (± 45 mL)]. EDV: LCC QGS/CMR = 0.70 [− 16 mL (± 67 mL)], LCC MX/CMR = 0.68 [− 21 mL (± 63 mL], LCC 4DM/CMR = 0.72 [+ 9 mL (± 73 mL)], LCC ECTb/CMR = 0.69 [+ 10 mL (± 70 mL)]. QGS and MX were the two best-performing softwares to evaluate LVEF after recent STEMI.

Purpose Dosimetry for melanoma-targeted radionuclide therapy (TRT) with [131 I]ICF01012, a melanin ligand, has been previously evaluated in mice bearing melanomas. In this study, activity distribution and dosimetry are performed on healthy rabbits (Fauve de Bourgogne) using SPECT-CT imaging and ex vivo measurements. Material and methods Ex vivo biodistribution (i.v. injection: 370 kBq/kg, n = 2 per point) is performed on blood, eyes, brain, lung, liver, kidneys, heart, stomach, and spleen. Dosimetry calculations follow the MIRD formalism: S values are calculated from CT images using the GATE Monte Carlo platform and activity distributions are obtained from SPECT-CT imaging (i.v. injection: 37 MBq/kg n = 3 per point). A specific study is presented to assess dose to human retina. Results Time-integrated activities based on SPECT-CT are in accordance with ex vivo measurements except for spleen. Doses to liver and eyes are the most significant, with respectively, 6.38 ± 0.50 Gy/GBq (evaluated through SPECT-CT imaging) and 45.8 ± 7.9 Gy/GBq (evaluated through ex vivo measurements). Characterization of ocular [131 I]ICF01012 biodistribution in rabbits and quantification of melanin allowed to assess a dose of 3.07 ± 0.70 Gy/GBq to human retina. Conclusion This study sustains [131 I]ICF01012 as a good candidate for melanoma TRT and open perspectives for personalized dosimetry calculation during phase I clinical transfer.

Dosimetry for melanoma-targeted radionuclide therapy (TRT) with [Ex vivo biodistribution (i.v. injection: 370 kBq/kg, n = 2 per point) is performed on blood, eyes, brain, lung, liver, kidneys, heart, stomach, and spleen. Dosimetry calculations follow the MIRD formalism: S values are calculated from CT images using the GATE Monte Carlo platform and activity distributions are obtained from SPECT-CT imaging (i.v. injection: 37 MBq/kg n = 3 per point). A specific study is presented to assess dose to human retina.Time-integrated activities based on SPECT-CT are in accordance with ex vivo measurements except for spleen. Doses to liver and eyes are the most significant, with respectively, 6.38 ± 0.50 Gy/GBq (evaluated through SPECT-CT imaging) and 45.8 ± 7.9 Gy/GBq (evaluated through ex vivo measurements). Characterization of ocular [This study sustains [

Introduction Les algorithmes de reconstruction iterative utilises en TEP de type OSEM offrent de bonnes performances pour la quantification des lesions. Cependant, la convergence ne pouvant etre menee a terme afin de limiter l’augmentation du bruit, ces algorithmes sont suboptimales pour la restitution du contraste des lesions. Pour pallier a ce biais, General Electrics a implemente l’algorithme Q.Clear utilisant un terme de regularisation du bruit base sur une approche bayesienne. Ce terme, caracterise par une valeur β, permet de controler le bruit et assure ainsi la convergence totale de l’algorithme. L’objectif de ce travail a ete de caracteriser differentes methodes de segmentation standards en comparant les reconstructions Q.Clear et OSEM sur fantome puis sur patient dans le cas de cancers pulmonaires CPNPC. Methodes Les acquisitions ont ete realisees sur une TEP/TDM MIDR (GE). L’etude sur fantome a ete menee avec l’objet test NEMA IEC pour des rapports de concentration sphere :fond de 2 :1, 5:1, 10:1 et 20:1. Les algorithmes OSEM VPFX et Q.Clear (β : 300, 400 et 500) ont ete compares pour differentes methodes de segmentation de volume (volume anatomique, SUV40 % et seuillage adaptatif) afin de mesurer l’impact de Q.Clear sur le volume segmente ainsi que sur la quantification des spheres. Une methode de seuillage adaptatif (Nestle, 2007) a ensuite ete caracterisee en fonction de la taille de la lesion et du contraste avec Q.Clear. L’etude a ensuite ete menee sur 12 patients CPNPC afin d’evaluer l’influence de Q.Clear sur la quantification des volumes tumoraux. Resultats Les acquisitions sur fantome montrent que Q.Clear semble moins adapte que VPFX pour les methodes de segmentation standards a seuillage fixe type SUV40 %. Q.Clear influence sensiblement les valeurs de SUVmax et SUVpeak par rapport a VPFX, en revanche les variations selon la valeur de β pour Q.Clear sont moins prononcees. Ainsi, le parametre β ne semble pas impacter sensiblement la determination du volume segmente. A partir des mesures realisees sur fantome, une methode de seuillage adaptatif specifique aux reconstructions Q.Clear a ete caracterisee selon la methode decrite par Nestle. Conclusions Cette etude a permis de caracteriser une methode de seuillage adaptatif en fonction du parametre β et du rapport de contraste lesion/fond pour l’algorithme Q.Clear pouvant etre appliquee lors de la segmentation de lesions sur des patients presentant des lesions pulmonaires.

Le traitement standard du cancer du sein triple negatif (CSTN) repose sur une chimiotherapie neoadjuvante (CTNA). La reponse complete histologique suite a la CTNA est un facteur predictif de la survie, d’ou la necessite de posseder des methodes d’evaluation precoce de cette reponse, pour readapter au plus tot le traitement. L’apoptose etant la mort cellulaire principalement induite par la CTNA, nous avons etudie le potentiel du radiotraceur 18F-ML10 (acide 2-(5-[18F]fluoropentyl)-2-methylmalonique) a detecter les cellules en apoptose dans les modeles precliniques du CSTN exposes a differentes drogues cytotoxiques. Une cinetique de traitement (paclitaxel et TH-302) a ete realisee sur deux lignees cellulaires humaines de CSTN : MDA-MB-468 et MDA-MB-231. L’apoptose induite a ete caracterisee par western blot (PARP), cytometrie de flux (annexine V/iodure de propidium) et par TUNEL immunofluorescent. L’etude de captation cellulaire du radiotraceur a ete realisee sur les modeles cellulaires a differents temps de traitement. In vivo, la fixation du radiotraceur a ete evaluee sur deux modeles murins de xenogreffe MDA-MB-468 et MDA-MB-231. Les souris ont recu une dose de paclitaxel (20 mg/kg) ou de TH-302 (50 mg/kg). Une imagerie TEP au 18F-ML10 a ete realisee avant traitement et 72 h apres permettant de determiner le rapport de fixation entre la tumeur et le muscle pour calculer le ΔT/M = (T/Mbaseline-T/M72 h/T/Mbaseline)×100. Ex vivo, l’apoptose a ete caracterisee par immunofluorescence (TUNEL) et western blot (PARP). Les resultats in vitro montre une augmentation significative (p