Le Lutétium 177 est un émetteur β- d'énergie maximale 498 keV avec un trajet moyen de 0,7 mm. Les interactions avec la matière à favoriser, pour entraîner la mort cellulaire, sont celles au niveau de l'ADN afin d'entrainer des cassures simple- ou double-brins. L'internalisation du vecteur dans la cellule après fixation à la membrane permet une proximité du radioisotope et du noyau lors de l'émission de ces particules ionisantes. Le lutétium 177 est également émetteur de photons y d'énergie 113 keV (avec une faible probabilité d'émission 6,3%) et 208 keV avec une probabilité d'émission de 10,4% permettant ainsi de réaliser une imagerie après administration du médicament radiopharmaceutique (post-thérapie).

La RTIV donne également naissance au concept de « **théranostique** » (ou « radiothéranostique »), néologisme construit à partir des termes **thérapie** et **diagnostic**, et permettant une approche personnalisée dans le traitement du cancer. Le diagnostic de la maladie est effectué à partir de l'imagerie réalisée après administration d'un médicament radiopharmaceutique (vecteur + isotope radioactif émetteur de photons gammas). Si le patient est éligible au traitement (bon ciblage), l'isotope radioactif est remplacé par un isotope radioactif utilisé en thérapie et émetteur de particules α ou β-. C'est par exemple le cas du <sup>68</sup>Ga-PSMA utilisé en imagerie TEP diagnostique des cancers prostatiques avec le <sup>68</sup>Ga, émetteur β+ avec une demi-vie de 68 minutes, alors que le <sup>177</sup>Lu-PSMA utilisé pour le traitement de ces cancers.

L'imagerie réalisée au cours de cette prise en charge permet : (i) de diagnostiquer ces tumeurs, (ii) d'assurer leur éligibilité au traitement par RTIV par le concept de théranostique (association isotope radioactif diagnostic/thérapie), et (iii) assurer le monitoring du traitement par RTIV à travers des images quantitatives, pour suivre l'évolution de la pathologie et sa réponse au traitement.

Le service de médecine nucléaire du CHRU de Nancy dispose des équipements de pointe avec notamment deux caméras CZT grand-champ permettant de réaliser des enregistrements TEMP/TDM rapides. Ainsi, la figure 33 illustre l'intérêt d'un suivi par imagerie chez un homme de 90 ans, atteint d'un adénocarcinome de la prostate métastatique et ayant bénéficié de 6 injections de <sup>177</sup>Lu-PSMA d'activité 7400 MBq à des intervalles d'environ 6 semaines. Les images TEP de <sup>68</sup>Ga-PSMA sont réalisées dans le cadre du diagnostic et du suivi inter-cure (après la 4ème cure de <sup>177</sup>Lu-PSMA). Les images corps entier de <sup>177</sup>Lu-PSMA ont été obtenues sur une caméra CZT grand champ (géométrie 3D) grâce notamment à l'amélioration de la sensibilité de détection, permettant alors des enregistrements rapides et d'extraire une information quantitative (89).
<figure><img src="image_34.png" /><figcaption>Figure 33 : Images MIP (Maximum Intensity Projection) des enregistrements TEMP corps entier obtenus 24 heures après injection de ¹⁷⁷Lu-PSMA avec la caméra CZT **Veriton 200series** (A). Ces images montrent une réduction de l'activité des lésions osseuses et ganglionnaires (TLA), parallèlement à une diminution du taux de l'antigène prostatique spécifique (PSA) plasmatique (B). Les activités lésionnelles (LA) ont été obtenues avec le produit du SUV_moyen et du volume déterminé avec un seuil SUV de 3 sur les enregistrements de ¹⁷⁷Lu-PSMA et deux enregistrements de ⁶⁸Ga-PSMA (C). Les LA déterminées sur les enregistrements de ¹⁷⁷Lu-PSMA et ⁶⁸Ga-PSMA étaient corrélées (R² = 0,985 pour les 24 plus grandes lésions, (D). L'activité totale de toutes les lésions (TLA) de chaque enregistrement TEMP était directement corrélé au taux de PSA (R² = 0,996, (E)).</figcaption></figure>
L'objectif principal du projet est de développer une méthodologie de dosimétrie personnalisée pour la RTIV. En effet, le radiotraceur utilisé en RTIV se fixe dans la zone tumorale ciblée, mais aussi dans des organes à risque. A l'heure actuelle, une activité forfaitaire de 7400 MBq est délivrée, quelque ce soient le patient et l'indication (tumeurs neuroendocrines, méningiomes, cancer prostatique). L'imagerie permet de suivre et de quantifier, pour chaque patient, la distribution du radiotraceur dans la cible tumorale et dans les organes à risque, et d'adapter l'activité au cours du traitement. A terme, l'objectif est de proposer une activité individuelle adaptée à chaque patient, afin d'augmenter l'efficacité thérapeutique par le biais de la dosimétrie tumorale, et de diminuer les effets secondaires en limitant la dose aux organes à risque. Les principaux verrous technologiques sont liés à : i) la quantification des activités volumiques moyennes, ii) la méthodologie de segmentation (manuelle ou semi-automatique) des organes à risque et des lésions tumorales et iii) la modélisation pharmacocinétique liée à la fixation et l'élimination du radiopharmaceutique.

Des développements méthodologiques importants seront menés pour obtenir une quantification précise tout au long du traitement. Le projet s'appuiera sur les expertises du laboratoire en traitement d'images (segmentation d'image par deep-learning, radiomique etc...) et en analyse quantitative et dynamique.

Ce projet fait l'objet d'une thèse d'Université intitulée « Implémentation clinique d'une approche dosimétrique en Radiothérapie Interne Vectorisée ».

**Encadrement de la thèse d'Université** de Caroline Boursier (en cours, thèse d'Université 2022-2025, Ecole Doctorale BioSE, laboratoire IADI INSERM U1254)

Demande d'Autorisation à codiriger la thèse obtenue le 24 janvier 2023

**Objectifs** : (1) optimiser une approche dosimétrique systématique pour tous les examens de radiothérapie interne vectorisée dans les trois indications principales (méningiome, tumeur neuroendocrine et cancer prostatique), (2) corréler les données dosimétriques tumorales avec les données cliniques (survie sans progression et survie globale), (3) corréler les données dosimétriques des organes à risque avec la survenue d'effets secondaires et (4) corréler les paramètres quantitatifs (SUV : standardized Uptake Value) des imageries pré thérapeutiques TEP avec les données dosimétriques obtenues à partir des imageries TEMP.
Ce travail fait suite à un stage de Master 2, réalisée par Mme Caroline Boursier (médecin nucléaire), qui portait sur la quantification absolue en ¹⁷⁷Lu et la dosimétrie des méningiomes. Nous avons montré, à partir d'une étude sur fantôme, que la caméra CZT grand-champ **Veriton 200series** (enregistrement des photons gammas de basse énergie (113 keV avec une probabilité d'émission de 6,3%)) permettait d'obtenir une quantification acceptable pour des objets de diamètre supérieur à 50 mm, celle-ci étant impactée pour des objets de petites tailles du fait de l'effet de volume partiel. Enfin, l'étude clinique portait sur 22 lésions de méningiome traitées par Lutathera® pour lesquelles la dose moyenne absorbée a été déterminée à partir de trois enregistrements rapides TEMP/TDM corps entier réalisés le lendemain de l'injection (J1), puis à 4 jours (J4) et 7 jours après (J7). Après correction de l'effet de volume partiel, les valeurs obtenues étaient proches des valeurs déjà publiées dans la littérature (91), montrant ainsi la faisabilité de ces enregistrements rapides avec une quantification possible sur le corps entier.

Une quantification absolue fiable est un prérequis indispensable au calcul de dosimétrie. Une autre problématique concerne les méthodes de segmentation. En effet, la dose moyenne à l'organe ou à une lésion donnée va dépendre du volume considéré. Il est donc important de déterminer ce volume avec précision. Que ce soit pour les traitements par Lutathera® ou ¹⁷⁷Lu-PSMA, les organes à risque sont généralement déterminés sur l'acquisition TDM couplée à la scintigraphie au ¹⁷⁷Lu. Des méthodes de segmentation anatomique par IA sont proposées et déjà utilisées en routine clinique. La segmentation des lésions reste quant à elle discutable. Certaines équipes utilisent la TDM associée à la scintigraphie pour contourer anatomiquement le volume tumoral (92) alors que d'autres équipes s'appuient sur l'imagerie TEMP ou TEP pour déterminer un volume métaboliquement actif (93).

Une première étude rétrospective, menée dans le service de médecine nucléaire et incluant 20 patients (39 lésions méningiomateuses) a montré qu'une segmentation semi-automatisée réalisée sur les images TEP pré-thérapeutiques de ⁶⁸Ga-DOTATOC était faisable en routine (94). De plus, les valeurs de SUVmoyen obtenus sur ces images TEP étaient prédictives des doses absorbées par les tumeurs dans le cadre de méningiomes réfractaires traités par ¹⁷⁷Lu-DOTATATE. Des études complémentaires sont nécessaires pour évaluer la robustesse de cette méthode de segmentation : i) dans le cas d'études multicentriques pour lesquelles les images TEP et TEMP sont acquises sur des caméras différentes et ii) d'élargir cette méthode de segmentation à d'autres indications cliniques avec dans un premier temps, les tumeurs neuroendocrines.
L'harmonisation des pratiques devrait permettre une évaluation de la dosimétrie à plus grande échelle, notamment pour des essais cliniques multicentriques et plus particulièrement en vue d'une médecine personnalisée avec adaptation des doses des thérapies au ¹⁷⁷Lu. L'objectif final est d'améliorer l'efficacité du traitement (dosimétrie tumorale) et de diminuer les effets secondaires (dosimétrie aux organes à risque).

Différentes étapes sont prévues pour la réalisation de ce projet :

**A court terme :**

- Collaboration scientifique avec l'IRSN, le groupe Unicancer et le comité « Radiothérapie Interne Vectorisée » de la Société Française de Médecine Nucléaire sur des aspects méthodologiques de quantification absolue en ¹⁷⁷Lu et dosimétrie.

- Co-encadrement d'une thèse de médecine avec Mme Caroline Boursier portant sur la détermination du volume métabolique en ⁶⁸Ga-PSMA vs ¹⁷⁷Lu-PSMA chez des patients atteints d'un cancer prostatique. Ce travail fait suite au cas clinique accepté au journal *Clin. Nucl. Med* pour lequel, la diminution du volume métabolique de ¹⁷⁷Lu-PSMA était corrélaté à la diminution du taux de PSA (95).

- Travail méthodologique sur fantôme permettant de valider la quantification absolue en ¹⁷⁷Lu sur la caméra **Veriton 400series**.

**A moyen terme :**

- Optimisation des enregistrements corps entier au ¹⁷⁷Lu sur la caméra **Veriton 400series**. L'utilisation de cette caméra permet de détecter à la fois les photons gammas de basse et haute énergie (113 et 208 keV), permettant alors d'augmenter la sensibilité de détection et ainsi, de diminuer le temps d'acquisition.

- Réalisation et analyse des dosimétries obtenues dans le cadre de l'étude clinique **EVADOVE** « Optimisation d'une méthode d'évaluation dosimétrique à l'aide d'une caméra CZT grand-champ VERITON-CT™ chez des patients traités par Lutathera® ». Il s'agit d'une étude pilote monocentrique incluant 15 patients ayant bénéficié d'un enregistrement sur caméra conventionnelle et sur caméra CZT Veriton 200series. Le dernier patient a été inclus en juillet 2023. Les premiers résultats de cette étude (dosimétrie déterminée au niveau des reins et de la moelle) seront présentés lors du congrès européen de médecine nucléaire EANM à Vienne en septembre 2023 (Eposter presentation).
- Evaluation de la méthode de segmentation semi-automatisée obtenue sur des images de ⁶⁸Ga-DOTATOC pré-thérapeutiques dans le cadre de tumeurs neuroendocrines, la méthode étant initialement développée et validée sur des lésions méningiomateuses (94).

A long terme :

- Optimisation des enregistrements TEMP corps entier réalisés sur la caméra **Veriton 400series** après administration d'une gélule d'Iode 131 dans le cadre des cancers thyroïdiens. Une étude clinique prospective incluant 77 patients est en cours. Actuellement 10 patients ont été inclus. Il s'agit de l'étude **VERICATH** : Évaluation d'une procédure d'enregistrement corps entier 3D en caméra CZT « VERITON-CT™ » : Comparaison à la procédure classique d'enregistrement 2D corps entier associée à des tomoscintigraphies complémentaires chez des patients ayant reçu un traitement par Iode 131 pour un CAncer Thyroïdien.

- Un financement de 344 K€ a été obtenu en 2023 dans le cadre de l'appel à projet national PHRC-K-2022 pour l'étude clinique multicentrique **ELUMEN** (Association de l'évérolimus et ¹⁷⁷Lu-DOTATATE dans le traitement des méningiomes réfractaires de grades II-III : une étude de phase II) ;

- D'autres études cliniques en collaboration avec des industriels sont en projet avec l'utilisation notamment de particules alphas comme l'Actinium 225 (²²⁵Ac). Il s'agit de nouvelles molécules radiopharmaceutiques, jusqu'ici non utilisées chez l'homme. Des études de cinétique, dosimétrie, toxicité... seront à envisager.
# 3. Développement de nouvelles méthodes d'analyse

Le second axe de recherche identifié dans le quinquennat 2024-2028 concerne l'analyse et le traitement des images en i) **neurologie**, application clinique largement développée au cours de ce rapport mais également en ii) **scintigraphie osseuse**. Il s'agit d'un domaine d'expertise plus récent mais pour lequel des projets sont à venir.

## a) Neurologie

Les perspectives de recherche dans ce domaine sont nombreuses, que ce soit en TEP ou plus récemment en TEMP compte tenu de l'amélioration des performances des caméras CZT grand-champ par rapport à une technologie conventionnelle.

### A court terme :

- Intégration d'une analyse radiomique à l'échelle individuelle en routine clinique à partir d'enregistrements de ¹⁸F-FDOPA en neuro-oncologie (30 patients). Il s'agit de l'objectif n°3 de la thèse d'Université de Mme Shamim Ahrari dont la soutenance est prévue en 2024 ;

### A moyen terme :

- Développement de la connectivité métabolique en TEP cérébrale au ¹⁸F-FDG dans des pathologies aussi diverses que les démences et les épilepsies (96). Cette thématique de recherche est portée par Antoine Verger (PU-PH, médecin nucléaire) et Matthieu Doyen (ingénieur de recherche) du laboratoire IADI. Cette nouvelle méthode d'analyse quantitative permet de prendre en compte les relations existantes entre les modifications de différentes régions cérébrales.

Compte tenu de leur sensibilité de détection, les caméras CZT à géométrie 3D permettent de réaliser des acquisitions dynamiques avec un échantillonnage temporel minimal de 3 sec/frame (97). Le développement de la connectivité métabolique en TEMP cérébrale au ⁹⁹mTc-HMPAO pourrait donc constituer une nouvelle application clinique rendue possible par cette évolution technologique, ce traceur étant particulièrement adapté à la perfusion cérébrale compte tenu de sa cinétique rapide. Ce sujet constitue un autre axe de recherche dans lequel je suis impliquée en collaboration avec Messieurs Antoine Verger et Matthieu Doyen.

La faisabilité d'une étude de connectivité métabolique à partir d'un enregistrement de ⁹⁹mTc-HMPAO a été démontré, ce cas clinique fait l'objet d'une publication dans la revue Frontiers in Human Neuroscience (77).
<figure><img src="image_35.png" /><figcaption>Figure 34 : Résultats des analyses de corrélation TEMP projetées sur des coupes axiales IRM avec pour chacun des 5 réseaux définis (par défaut, exécutif, insulaire, moteur et visuel), la région d'origine étant représentée par un cercle bleu, les coordonnées sont données dans le référentiel MNI – extraite (77).</figcaption></figure>

Une étude de connectivité métabolique en TEMP cérébrale au ⁹⁹mTc-HMPAO à plus grande échelle, sera réalisée à partir d'une sélection rétrospective de patients. La connectivité obtenue à l'échelle de groupe, sera comparée aux informations de connectivité extraites à partir d'autres modalités telles que l'électroencéphalographie et l'IRMf, des thématiques développées au sein du laboratoire dans l'axe electro-imaging.

## A long terme :

Concernant la thématique centrée sur la caractérisation des gliomes à partir d'enregistrements de ¹⁸F-FDOPA, de nouvelles méthodes s'intéressant à la dynamique temporelle de l'étude radiomique dans les tumeurs cérébrales seront développées au travers d'un PHRC-K national (KING, 500 k€) accepté en 2022 pour la période 2023-2026. L'étude clinique multicentrique est en cours (6 centres actuellement ouverts sur 12 initialement prévus).
b) Scintigraphie osseuse

Cette thématique est développée dans le cadre de la thèse d'Université de Mr Achraf Bahloul, médecin nucléaire. L'utilisation de caméras CZT grand-champ permet d'envisager de nouvelles procédures d'enregistrements corps-entier « rapides », non réalisables avec une caméra conventionnelle. Ainsi, nous avons développé des protocoles de scintigraphie osseuse en temps précoce (enregistrement quelques minutes après injection du MRP) et en temps tardif (enregistrement 3 à 6 heures après injection du MRP) selon les indications cliniques : i) oncologie et ii) rhumatologie (cf. Figure 35). Le travail réalisé dans le cadre du Master 2 a permis de valider l'utilisation de la quantification absolue en routine clinique en temps tardif (85). Un travail équivalent sur fantôme a été réalisé pour le temps précoce (statistique de comptage, temps d'acquisition et paramètres de reconstruction différents). Ces résultats feront prochainement l'objet d'une publication scientifique.

<figure><img src="image_36.png" /></figure>

Figure 35 : Acquisitions TEMP corps entier en phases précoce (< 8 minutes d'enregistrement) et tardive (~ 18 minutes d'enregistrement) obtenues sur les caméras VERITON-CT (Spectrum Dynamics Medical) du service de médecine nucléaire du CHRU de Nancy : patiente de 25 ans ne présentant pas de fixation pathologique et pour laquelle l'examen est considéré comme normal après injection de 522 MBq de ⁹⁹mTc-HDP (à gauche), patiente de 59 ans présentant une fixation de l'aile sacro-iliaque gauche, visible sur les enregistrements TEMP en temps précoce et en temps tardif après injection de 548 MBq (au milieu) et patiente de 30 ans présentant des fixations diffuses au niveau des articulations (poignets, mains, chevilles) après injection de 589 MBq de ⁹⁹mTc-HDP. Les images sont affichées en échelle SUV pour les temps précoce (de 0 à 6 SUV) et tardif (de 0 à 13 SUV).
De nombreux projets sont en cours ou à venir dans le domaine de la scintigraphie osseuse. Ceux-ci intègrent à la fois des études méthodologiques réalisées sur fantôme(s) pour optimiser des paramètres d'acquisition et de reconstruction, et également des études sur des images de patients, de manière à pouvoir répondre à des problématique cliniques. Ces projets cliniques sont rendus possibles grâce à l'amélioration des performances des caméras CZT grand-champ.

**A court terme :**

- Etude clinique rétrospective **ASOCE** (78 patients) en collaboration avec le service de rhumatologie du CHRU de Nancy sur l'apport de la scintigraphie osseuse précoce et tardive en TEMP/TDM du corps entier dans le diagnostic des atteintes rhumatismales atteintes et périphériques ;

- Etude clinique rétrospective **IATOS** (20 patients) portant sur l'évaluation d'un algorithme d'intelligence artificielle réduisant le bruit sur des acquisitions tomoscintigraphiques osseuses rapides du corps entier enregistrées par une caméra CZT 360° ;

- Des études méthodologiques réalisées à partir d'expérience sur fantômes sont en cours afin d'évaluer l'influence des paramètres de reconstruction y compris d'un filtre de réduction de bruit développé à partir d'un algorithme d'intelligence artificielle, sur la qualité des images obtenues en scintigraphie osseuse précoce et tardive.

**A moyen terme :**

- Etude clinique prospective **OSS** (126 patients inclus de 2020 à 2022) portant sur l'évaluation d'une procédure d'enregistrement corps-entier accélérée des tomoscintigraphies osseuses avec la caméra CZT « VERITON-CTTM » : comparaison à la procédure classique d'enregistrement 2D corps entier associé ou non à des tomoscintigraphies complémentaires. Un travail de reconstruction est nécessaire pour : i) optimiser la qualité d'image et ii) avoir une quantification absolue précise.

- Etude clinique prospective **PERQUAL** (12 patients inclus sur 70) en collaboration avec le service de neurochirurgie du CHRU de Nancy : Performance prédictive de la quantification en scintigraphie osseuse TEMP/TDM avant une chirurgie d'arthrodèse lombaire.
A long terme :

- Etude clinique prospective MUSIC (68 patients à inclure, mise en place de l'étude effectuée en juillet 2023, en attente d'inclusion) en collaboration avec les services de radiologie Guilloz et de biopathologie du CHRU de Nancy. Le but est d'analyser l'apport d'une analyse multiparamétrique en scintigraphie osseuse pour la caractérisation des lésions osseuses dont l'origine maligne ne peut être exclue en imagerie conventionnelle. L'hypothèse de l'étude est que la scintigraphie osseuse SPECT-CT, non invasive permet de mieux caractériser les lésions osseuses solitaires, notamment l'exclusion de leur caractère malin afin d'éviter une biopsie inutile et des complications éventuelles au patient. Pour cette étude, les patients bénéficieront de 3 séries d'images réalisées aux temps vasculaire, précoce et tardif comme l'illustre la figure suivante :

<figure><img src="image_37.png" /></figure>

Figure 36 : Lésion osseuse solitaire de la 10ème côté droite de nature indéterminée à l'imagerie conventionnelle. Rendu volumique 3D de l'acquisition TDM (A), courbe activité-temps correspondant au temps vasculaire (la lésion osseuse est représentée en vert, l'activité vasculaire mesurée au niveau du cœur est représentée en rouge) (B), acquisition TEMP/TDM au temps précoce (C) et acquisition TEMP/TDM au temps tardif (D). Analyse multiparamétrique : TTP = 90 secondes, SUVmax lésion en temps précoce = 2,6 et SUVmax lésion en temps tardif = 9,8. Biopsie en faveur d'une lésion osseuse bénigne de dysplasie fibreuse.
L'objectif est d'évaluer les performances diagnostiques du paramètre Time To Peak (TTP) de la courbe de perfusion en scintigraphie osseuse (temps vasculaire) dans l'évaluation du caractère bénin des lésions osseuses solitaires indéterminées à l'imagerie conventionnelle. On s'appuiera pour cette analyse, des méthodes développées pour l'imagerie TEP à la ¹⁸F-FDOPA en neuro-oncologie (54).
IV. Conclusion

La médecine nucléaire est une discipline en plein essor que ce soit pour le diagnostic avec les évolutions technologiques des systèmes d'imagerie TEMP et TEP ou pour la thérapie avec l'arrivée de la radiothérapie interne vectorisée (RTIV) au ¹⁷⁷Lu. J'ai la chance d'évoluer dans un environnement me permettant de mener à bien des projets de recherche tels que ceux présentés dans ce manuscrit.

L'un des enjeux majeurs de la RTIV est de proposer une thérapie personnalisée, où les activités injectées et le nombre d'injections pourraient être moduler pour augmenter l'efficacité et la tolérance de ces traitements. Ces développements méthodologiques importants font partie intégrante de la thématique « Optimiser les traitements de RTIV » identifiée pour le prochain contrat quinquennal du laboratoire IADI.

En tant que physicienne médicale au sein du service de médecine nucléaire du CHRU de Nancy, je souhaite poursuivre mes activités de recherche avec autant de dynamisme et de motivation que ces 10 dernières années.
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13. Perrin M, Djaballah W, Moulin F, Claudin M, Veran N, Imbert L, et al. Stress-first protocol for myocardial perfusion SPECT imaging with semiconductor cameras: high diagnostic performances with significant reduction in patient radiation doses. Eur J Nucl Med Mol Imaging. 2015 Jun;42(7):1004-11.
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35. Salvadori J, Odille F, Karcher G, Marie PY, Imbert L. Fully digital PET is unaffected by any deterioration in TOF resolution and TOF image quality in the wide range of routine PET count rates. EJNMMI Phys. 2021 Jan 6;8(1):1.

36. Salvadori J, Imbert L, Perrin M, Karcher G, Lamiral Z, Marie PY, et al. Head-to-head comparison of image quality between brain 18F-FDG images recorded with a fully digital versus a last-generation analog PET camera. EJNMMI Res. 2019 Jul 12;9(1):6.

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54. Ginet M, Zaragori T, Marie PY, Roch V, Gauchotte G, Rech F, et al. Integration of dynamic parameters in the analysis of 18F-FDopa PET imaging improves the prediction of molecular features of gliomas. Eur J Nucl Med Mol Imaging. 2020 Jun;47(6):1381-1390.
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56. Zhou W, Huang Q, Wen J, Li M, Zhu Y, Liu Y, et al. Integrated CT Radiomics Features Could Enhance the Efficacy of 18F-FET PET for Non-Invasive Isocitrate Dehydrogenase Genotype Prediction in Adult Untreated Gliomas: A Retrospective Cohort Study. Front Oncol. 2021;11:772703.

57. Li Z, Kaiser L, Holzgreve A, Ruf VC, Suchorska B, Wenter V, et al. Prediction of TERTp-mutation status in IDH-wildtype high-grade gliomas using pre-treatment dynamic 18F-FET PET radiomics. Eur J Nucl Med Mol Imaging. 2021 Dec;48(13):4415-4425.

58. Carles M, Popp I, Starke MM, Mix M, Urbach H, Schimek-Jasch T, et al. FET-PET radiomics in recurrent glioblastoma: prognostic value for outcome after re-irradiation? Radiat Oncol. 2021;16:46.

59. Li Z, Holzgreve A, Unterrainer LM, Ruf VC, Quach S, Bartos LM, et al. Combination of pre-treatment dynamic [18F]FET PET radiomics and conventional clinical parameters for the survival stratification in patients with IDH-wildtype glioblastoma. Eur J Nucl Med Mol Imaging. 2023;50:535-45.

60. Müller M, Winz O, Gutsche R, Leijenaar RTH, Kocher M, Lerche C, et al. Static FET PET radiomics for the differentiation of treatment-related changes from glioma progression. J Neurooncol. 2022;159:519-29.

61. Qian J, Herman MG, Brinkmann DH, Laack NN, Kemp BJ, Hunt CH, et al. Prediction of MGMT Status for Glioblastoma Patients Using Radiomics Feature Extraction From 18F-DOPA-PET Imaging. Int J Radiat Oncol. 2020;108:1339-46.

62. Zaragori T, Oster J, Roch V, Hossu G, Chawki MB, Grignon R, et al. 18F-FDOPA PET for the Noninvasive Prediction of Glioma Molecular Parameters: A Radiomics Study. J Nucl Med Off Publ Soc Nucl Med. 2022;63:147-57.

63. Ahrari S, Zaragori T, Rozenblum L, Oster J, Imbert L, Kas A, et al. Relevance of Dynamic 18F-DOPA PET Radiomics for Differentiation of High-Grade Glioma Progression from Treatment-Related Changes. Biomedicines. 2021;9:1924.

64. Bros M, Zaragori T, Rech F, Blonski M, Hossu G, Taillandier L, et al. Effects of Carbidopa Premedication on 18F-FDOPA PET Imaging of Glioma: A Multiparametric Analysis. Cancers. 2021;13:5340.

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67. Doyen M, Mairal E, Bordonne M, Zaragori T, Roch V, Imbert L, et al. Effect of Point Spread Function Deconvolution in Reconstruction of Brain 18F-FDG PET Images on the Diagnostic Thinking Efficacy in Alzheimer's Disease. Front Med (Lausanne). 2021 Jul 29;8:721551.
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69. Agostini D, Roule V, Nganoa C, Roth N, Baavour R, Parienti JJ, et al. First validation of myocardial flow reserve assessed by dynamic 99mTc-sestamibi CZT-SPECT camera: head to head comparison with 15O-water PET and fractional flow reserve in patients with suspected coronary artery disease. The WATERDAY study. Eur J Nucl Med Mol Imaging. 2018 Jul;45(7):1079-1090.

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95. Boursier C, Olivier P, Claudin M, Marie PY, Imbert L. 177Lu-PSMA treatment monitoring through serial fast whole-body tomoscintigraphies recorded with a latest-generation CZT-camera. Clin Nucl Med. 2023 (accepted)

96. Doyen M, Chawki MB, Heyer S, Guedj E, Roch V, Marie PY, et al. Metabolic connectivity is associated with seizure outcome in surgically treated temporal lobe epilepsies: A 18F-FDG PET seed correlation analysis. Neuroimage Clin. 2022;36:103210.

97. Mairal E, Imbert L, Marie PY, Bahloul A. Three-phase bone quantitative-SPECT of navicular bones with a high-sensitivity whole-body CZT-camera in a Müller-Weiss syndrome. Eur J Nucl Med Mol Imaging. 2022 Jul;49(9):3295-3296.
# VI. Annexe A

## a) Communications orales internationales

<table><tr><td>2023</td><td>EANM Effects of medications on dopamine transporter imaging using <sup>123</sup>I-FP-CIT SPECT in routine practice. Piatkova Y, Doyen M, Frismand S, Hopes L, <b>Imbert L</b>, Verger A. Vienna (Austria)<br>EANM SUV-Based Assessment of Known or Suspected Polyarthritis on Double-Phase Whole-Body Bone Tomoscintigraphies Provided by a High-Speed CZT Camera. Bahloul A, Rajadhas F, Morizot C, Loeuille D, Chary-Valckenaere I, Roch V, Marie PY, <b>Imbert L</b>. Vienna (Austria)<br>EANM Quantification of <sup>177</sup>Lu-DOTATATE uptake in neuroendocrine tumors using a fast whole-body 360° CZT-SPECT/CT camera for monitoring and prediction of treatment response (<i>ePoster presentation</i>). Boursier C, Grangeret J, Chevalier E, Karcher G, <b>Imbert L</b>, Marie PY. Vienna (Austria)</td></tr><tr><td>2022</td><td>EANM Dual high-speed whole-body SPECT-CT recordings of the blood-pool and delayed phases of bone scintigraphy in patients with known or suspected chronic inflammatory arthritis. Bahloul A, Rajadhas F, Loeuille D, Chary-Valckenaere I, Marie PY, <b>Imbert L</b>. Barcelona (Spain)<br>EANM Semi-automated segmentation method of <sup>68</sup>Ga-DOTATOC PET for dosimetry prediction in refractory meningiomas treated by <sup>177</sup>Lu-DOTATATE (<i>ePoster presentation</i>). Boursier C, Zaragori T, Bros M, Bordonne M, Melki S, Taillandier L, Blonski M, Roch V, Marie PY, Karcher G, <b>Imbert L</b>, Verger A. Barcelona (Spain)</td></tr><tr><td>2021</td><td>EANM Dynamic <sup>18</sup>F-FDopa PET imaging for newly diagnosed gliomas: is a semiquantitative model sufficient? (Virtual meeting). Zaragori T, Doyen M, Rech F, Blonski M, Taillandier L, <b>Imbert L</b>, Verger A.</td></tr><tr><td>2020</td><td>EANM Assessment of high-speed recording lung perfusion images provided by a high sensitivity 360° whole-body CZT camera in the pre-operative workup of lung cancer (Virtual meeting). Melki S, Verger A, Karcher G, Marie PY, <b>Imbert L</b>.<br>EANM DMSA renal investigations performed with a 360° whole-body CZT SPECT camera as compared with the conventional method based on planar images from an Anger camera (Virtual meeting). Bahloul A, <b>Imbert L</b>, Karcher G, Marie PY, Verger A.<br>EANM Bone metabolism may be monitored through the absolute quantification provided by a whole-body 360° CZT SPECT/CT camera during the healing period of vertebral fractures (Virtual meeting). Bahloul A, <b>Imbert L</b>, Blum A, Karcher G, Verger A, Marie PY.<br>EANM Signs of a diffuse and intense tracheobronchitis are commonly observed on ventilation scans obtained with <sup>99m</sup>Tc-labelled aerosols during the disease progression of coronavirus 2019 (Virtual meeting). Marie PY, Bahloul A, Melki S, Karcher G, Selton C, Goheringer F, <b>Imbert L</b>, Verger A.<br>EANM Compared visual analyses of whole-body planar bone scintigraphies obtained from conventional Anger camera and from retro-projections after CT-based corrections of a high-speed SPECT recording using a 360° CZT-camera (Virtual meeting). Bahloul A, Verger A, Perrin M, Claudin M, Karcher G, Marie PY, <b>Imbert L</b>.</td></tr></table>
<table><tr><td></td><td>SNMMI DMSA renal investigations performed with a 360°whole-body CZT SPECT camera as compared with the conventional method based on planar images from an Anger camera (Virtual meeting). Bahloul A, Imbert L, Karcher G, Marie PY, Verger A.</td></tr><tr><td></td><td>ECCN Use of static and dynamic <sup>18</sup>F-FDopa PET parameters for detecting patients with glioma recurrence or progression. Zaragori T, Roch V, Karcher G, Marie PY, Imbert L, Verger A. Paris</td></tr><tr><td rowspan="4">2018</td><td>EANM Assessment of myocardial CZT-SPECT recording in a forward-leaning "bicker-like" position: head-to-head comparisons with the more conventional supine and semi-upright positions. Perrin M, Roch V, Claudin M, Verger A, Boutley H, Karcher G, Baumann C, Djaballah W, Veran N, Marie PY, Imbert L. Düsseldorf (Germany)</td></tr><tr><td>EANM Radionuclide left ventricular ejection fraction may be determined with a dramatic reduction in recording times with the very high sensitivity "DSPECT" CZT-camera. Tissot H, Djaballah W, Veran N, Roch V, Perrin M, Claudin M, Verger A, Boutley H, Karcher G, Marie PY, Imbert L. Düsseldorf (Germany)</td></tr><tr><td>SNMMI Head-to-head comparisons of the PET performance measured using the NEMA standard between digital and analogic last-generation cameras. Salvadori J, Verger A, Chevalier E, Perrin M, Tissot H, Claudin M, Olivier P, Karcher G, Marie PY, Imbert L. Philadelphia (United States)</td></tr><tr><td>SNMMI Is image quality really improved with a digital PET camera, when compared with a last-generation analogic PET camera, on the FDG brain images recorded in clinical routine? Verger A, Salvadori J, Imbert L, Karcher G, Marie PY. Philadelphia (United States)</td></tr><tr><td>2016</td><td>EANM Routine evaluation of left ventricular function using CZT-SPECT, with low injected activities and limited recording times. Claudin M, Imbert L, Djaballah W, Veran N, Poussier S, Roch V, Perrin M, Verger A, Boutley H, Karcher G, Marie PY. Barcelona (Spain)</td></tr></table>

b) Communications affichées internationales

<table><tr><td>2023</td><td>EANM, Assessment of a Deep Learning-Based Noise Reduction Algorithm on the Ultra-Fast Whole-Body Bone Tomoscintigraphies Recorded by a 360° CZT Camera. Bahloul A, Lamash Y, Roth N, Dari A, Marie PY, Imbert L. Vienna (Austria)</td></tr><tr><td>2022</td><td>EANM, An Original Segmentation Method for Dosimetry of Refractory Meningiomas Treated by <sup>177</sup>Lu-DOTATATE based on Quantitative SPECT 360° Whole-body CZT-camera Imaging. Zaragori T, Boursier C, Bros M, Mairal E, Verger A, Imbert L. Barcelona (Spain)</td></tr><tr><td>2021</td><td>EANM Variations of myocardial uptake suppression and endocarditis detectability between a first conventional fasting-based FDG-PET and a second one scheduled on the next day after an Atkins diet (Virtual meeting). Germaini M, Boursier C, Goehringer F, Selton-Suty C, Lefevre B, Roch V, Imbert L, Claudin M, Chevalier E, Marie PY.</td></tr><tr><td></td><td>SNMMI Absolute quantification of bone scintigraphy provided by a whole-body 360°CZT SPECT/CT camera in patients with vertebral fractures (Virtual Meeting). Bahloul A, Verger A, Karcher G, Marie PY, Imbert L.</td></tr></table>
<table><tr><td>2020</td><td>SNMMI Assessment of multi-view planar imaging provided by a high-speed 360° whole-body CZT camera in patients undergoing pre-surgical assessment of a lung cancer (Virtual meeting). Melki S, Verger A, Karcher G, Marie PY, Imbert L.</td></tr><tr><td>2019</td><td>EANM Comparison of the quality of brain images obtained with 99mTc-HMPAO acquired using either the Veriton™ 360° CZT camera or a conventional Anger camera, and with an 18FDG analog PET system. Bordonné M, Chawki MB, Zaragori T, Roch V, Grignon R, Karcher G, Marie PY, Imbert L, Verger A. Barcelona (Spain)<br>EANM Comparison of 123I-iodupane SPECT imaging between the Veriton™ 360° CZT camera with striatum focusing and a conventional gamma-camera. Chawki MB, Bordonné M, Zaragori T, Karcher G, Marie PY, Imbert L, Verger A. Barcelona (Spain)<br>EANM Integration of dynamic parameters in the analysis of 18F-FDopa PET imaging improves the prediction of molecular features of gliomas. Zaragori T, Ginet M, Gauchotte G, Taillandier L, Blonski M, Grignon R, Roch V, Marie PY, Imbert L, Verger A. Barcelona (Spain)<br>EANM Assessment of a Monte Carlo simulation of PET recordings from the fully digital Vereos camera. Salvadori J, Odille F, Verger A, Karcher G, Marie PY, Imbert L. Barcelona (Spain)</td></tr><tr><td>2018</td><td>EANM Static and dynamic 18F-FDOPAPET for the characterization of gliomas defined by IDH and 1p/19q status Zaragori T, Ginet M, Gauchotte G, Taillandier L, Blonski M, Grignon R, Roch V, Marie PY, Imbert L, Verger A. Düsseldorf (Germany)<br>EANM Is image quality really improved with a digital PET camera, when compared with a last-generation analogic PET camera, on the FDG brain images recorded in clinical routine? Salvadori J, Imbert L, Karcher G, Marie PY, Verger A. Düsseldorf (Germany)<br>EANM A French multicenter comparative study of 3D dosimetry software used in therapeutic Nuclear Medicine. Badel JN, Jamain C, Santoro L, Imbert L, Vrigneaud JM, Martin A, Ferrer L, Belly-Poinsigny A, Caselles O, Guendouzen S, Billoux T, Wagner A, Berejny P, Ricard M, Laffont S, Mognetti T, Gardin I. Düsseldorf (Germany)<br>EANM Comparison of timing and energy resolutions between digital and analogic last-generation PET cameras. Salvadori J, Odille F, Verger A, Karcher G, Marie PY, Imbert L. Düsseldorf (Germany)</td></tr><tr><td>2015</td><td>EANM Dual radionuclide myocardial perfusion SPECT may be planned with much lower radiation doses on CZT cameras. Roch V, Imbert L, Djaballah W, Perrin M, Verger A, Boutley H, Karcher G, Marie PY. Hamburg (Germany)</td></tr></table>

c) *Communications orales nationales*

<table><tr><td>2023</td><td>JFMN Utilisation en routine clinique du VERITON 360° CZT TEMP-CT en imagerie 3D corps entier, symposium Spectrum Dynamics. Marie PY, Imbert L, Bahloul A et coll. Paris<br>SFPM Semi-automated segmentation methods of SSTR PET for dosimetry prediction in refractory meningioma patients treated by SSTR-targeted peptide receptor radionuclide therapy. Zaragori T, Boursier C, Bros M, Bordonne M, Melki S, Imbert L, Verger A. Nancy</td></tr></table>
<table><tr><td>2022</td><td>SFPM Retour du groupe de travail Gamma cameras CZT grand champ. Doyeux K, Le Rouzic G, Serre D, Barrau C, Hapdey S, Tylski P, Cassol E, Imbert L. Avignon</td></tr><tr><td>2021</td><td>JFMN Apport des caméras CZT grand champ 2D et 3D dans l'évolution des pratiques cliniques. Doyeux K, Le Rouzic G, Serre D, Barrau C, Hapdey S, Tylski P, Cassol E, Imbert L. Paris<br>JFMN 18F-FDOPA PET for the non-invasive prediction of glioma molecular parameters: a radiomics study. Zaragori T, Oster J, Roch V, Hossu G, Chawki MB, Grignon R, Pouget C, Gauchotte G, Rech F, Blonski M, Taillandier L, Imbert L, Verger A. Paris</td></tr><tr><td>2018</td><td>JFMN Impact de l'utilisation d'un TEP numérique, par comparaison à un TEP analogique, sur la qualité des images de TEP cérébrale au <sup>18</sup>F-FDG. Salvadori J, Verger A, Chevalier E, Perrin M, Tissot H, Claudin M, Olivier P, Karcher G, Marie PY, Imbert L. Paris<br>JFMN Integration fo dynamic parameters in the analysis of <sup>18</sup>F-FDopa PET imaging improves the prediction of molecular features of gliomas. Ginet M, Zaragori T, Marie PY, Roch V, Gauchotte G, Rech F, Blonski M, Lamiral Z, Taillandier L, Imbert L, Verger A. Paris</td></tr><tr><td>2016</td><td>SFPM Comparaison de la sensibilité aux déplacements cardiaques de différentes caméras de cardiologie nucléaire. Salvadori J, Imbert L, Petegnief Y, Sabbah R, Boulahdour H, Karcher G, Marie PY. Nancy<br>JFMN Evaluation d'un protocole en double isotope <sup>99m</sup>Tc-Sestamibi / <sup>201</sup>Thallium pour l'étude de la perfusion myocardique sur une caméra à semi-conducteurs. Roch V, Imbert L, Djaballah W, Perrin M, Verger A, Boutley H, Karcher G, Marie PY. Grenoble.</td></tr><tr><td>2012</td><td>SFMN Résultats d'une étude multicentrique avec la caméra DSPECT. Verger A, Djaballah W, Fourquet N, Rouzet F, Koehl G, Imbert L, Poussier S, Ray R, Roch V, Le Guludec D, Karcher G, Marie PY. Montpellier</td></tr></table>

d) Communications affichées nationales

<table><tr><td>2016</td><td>SFPM Impact de la modélisation des collections de charges pour la simulation des enregistrements par gamma-caméras à semi-conducteurs. Jurczak J, Imbert L, Karcher G, Marie PY. Nancy</td></tr><tr><td>2015</td><td>SFMN Evaluation d'un protocole en double isotope 99mTc-Sestamibi / 201Thallium pour l'étude de la perfusion myocardique sur une caméra à semi-conducteurs. Roch V, Imbert L, Djaballah W, Perrin M, Verger A, Boutley H, Karcher G, Marie PY. La Rochelle</td></tr></table>
# VII. Annexe B

Reproduction des 5 publications les plus significatives.
# Compared Performance of High-Sensitivity Cameras Dedicated to Myocardial Perfusion SPECT: A Comprehensive Analysis of Phantom and Human Images

Laetitia Imbert¹⁻⁴, Sylvain Poussier³,⁵, Philippe R. Franken⁶, Bernard Songy⁷, Antoine Verger³⁻⁵, Olivier Morel⁴, Didier Wolf¹, Alain Noel¹, Gilles Karcher³⁻⁵, and Pierre-Yves Marie³,⁴,⁸

¹CRAN-UMR 7039, Université de Lorraine-CNRS, Vandoeuvre, France; ²Department of Radiotherapy, Centre Alexis Vautrin, Vandoeuvre, France; ³Nancycлотep Experimental Imaging Platform, Nancy, France; ⁴Department of Nuclear Medicine, CHU-Nancy, Nancy, France; ⁵INSERM, U947, Nancy, France; ⁶Department of Nuclear Medicine, Centre Antoine Lacassagne, Nice, France; ⁷Department of Nuclear Medicine, Centre Cardiologique du Nord, Saint-Denis, France; and ⁸INSERM, U961, Nancy, France

Differences in the performance of cadmium-zinc-telluride (CZT) cameras or collimation systems that have recently been commercialized for myocardial SPECT remain unclear. In the present study, the performance of 3 of these systems was compared by a comprehensive analysis of phantom and human SPECT images. **Methods:** We evaluated the Discovery NM 530c and DSPECT CZT cameras, as well as the Symbia Anger camera equipped with an astigmatic (IQ-SPECT) or parallel-hole (conventional SPECT) collimator. Physical performance was compared on reconstructed SPECT images from a phantom and from comparable groups of healthy subjects. **Results:** Classifications were as follows, in order of performance. For count sensitivity on cardiac phantom images (counts·s⁻¹·MBq⁻¹), DSPECT had a sensitivity of 850; Discovery NM 530c, 460; IQ-SPECT, 390; and conventional SPECT, 130. This classification was similar to that of myocardial counts normalized to injected activities from human images (respective mean values, in counts·s⁻¹·MBq⁻¹: 11.4 ± 2.6, 5.6 ± 1.4, 2.7 ± 0.7, and 0.6 ± 0.1). For central spatial resolution: Discovery NM 530c was 6.7 mm; DSPECT, 8.6 mm; IQ-SPECT, 15.0 mm; and conventional SPECT, 15.3 mm, also in accordance with the analysis of the sharpness of myocardial contours on human images (in cm⁻¹: 1.02 ± 0.17, 0.92 ± 0.11, 0.64 ± 0.12, and 0.65 ± 0.06, respectively). For contrast-to-noise ratio on the phantom: Discovery NM 530c had a ratio of 4.6; DSPECT, 4.1; IQ-SPECT, 3.9; and conventional SPECT, 3.5, similar to ratios documented on human images (5.2 ± 1.0, 4.5 ± 0.5, 3.9 ± 0.6, and 3.4 ± 0.3, respectively). **Conclusion:** The performance of CZT cameras is dramatically higher than that of Anger cameras, even for human SPECT images. However, CZT cameras differ in that spatial resolution and contrast-to-noise ratio are better with the Discovery NM 530c, whereas count sensitivity is markedly higher with the DSPECT.

**Key Words:** CZT-cameras; high-speed SPECT; myocardial perfusion imaging; count sensitivity

J Nucl Med 2012; 53:1-7

DOI: 10.2967/jnumed.112.107417

Stress myocardial SPECT has been markedly enhanced by the recent commercialization of cameras with semiconductor (cadmium-zinc-telluride [CZT]) detectors or new collimation systems. These improved systems enhance the sensitivity of count detection and thereby enable recording times or tracer doses to be reduced, a property that has highly favorable consequences on patient comfort and radiation exposure (1-4). This enhancement is based mainly on acquisitions that are heart-centric but obtained with very different technologies: first, for the IQ-SPECT system (Siemens Medical Solutions (5-8)), an Anger camera equipped with collimators convergent on the image center (astigmatic collimators); second, for the DSPECT system (Spectrum Dynamics (9-13)), mobile columns of CZT detectors with wide parallel-hole collimators; and third, for the Discovery NM 530c system (GE Healthcare (14-21)), fixed CZT detectors with multipinhole collimators.

The respective performance of these new cameras and collimation systems has been analyzed, but only separately (6,11,14). To our knowledge, there has been no direct head-to-head comparison of the performance of the IQ-SPECT, DSPECT, and Discovery NM 530c systems. In addition, their performance was never compared for human SPECT images and, thus, with the additional confusing influence of breathing and cardiac motion, along with body attenuation and diffusion.

This study directly compared the performance of IQ-SPECT, DSPECT, and Discovery NM 530c in routine conditions of SPECT recording and reconstruction and by a comprehensive analysis of SPECT images from phantoms and from healthy subjects.

<footnote>Received Apr. 18, 2012; revision accepted Jul. 17, 2012.
For correspondence contact: Laetitia Imbert, Médecine Nucléaire, Hôpital de Brabois, CHU-Nancy, Allée du Morvan, 54500 Vandoeuvre-lès-Nancy, France.
E-mail: l.imbert@nancy.unicancer.fr
Published online ■■■.
COPYRIGHT © 2012 by the Society of Nuclear Medicine and Molecular Imaging, Inc.</footnote>
<table><caption>**TABLE 1**

Parameters Commonly Used for SPECT Recording and Reconstruction</caption><thead><tr><th>Parameter</th><th>Discovery NM 530c</th><th>DSPECT</th><th>IQ SPECT</th><th>Conventional SPECT</th></tr></thead><tbody><tr><td><strong>Recording</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Collimator</td><td></td><td>Wide-angle parallel hole</td><td>Astigmatic</td><td>LEHR or parallel hole</td></tr><tr><td>Energy window</td><td>Multipinhole</td><td>140 keV ± 10%</td><td>140 keV ± 7.5%</td><td>140 keV ± 7.5%</td></tr><tr><td>Number of projections</td><td>19</td><td>120 (x9 blocks)</td><td>17 (x2 heads)</td><td>16 (x2 heads)</td></tr><tr><td>Detector angle between consecutive projections</td><td>None (fixed detector)</td><td>0.4°-7°*</td><td>6°</td><td>3°</td></tr><tr><td><strong>Reconstruction</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Method</td><td>Iterative 3D</td><td>Iterative 3D</td><td>Iterative 3D</td><td>Iterative 3D</td></tr><tr><td>Number of iterations</td><td>60</td><td>7</td><td>10</td><td>8</td></tr><tr><td>Number of subsets</td><td>1</td><td>32</td><td>3</td><td>4</td></tr><tr><td>Interiteration filter</td><td>—</td><td>Kernel (0.125)</td><td>—</td><td>—</td></tr><tr><td>Final filter</td><td>Butterworth (order, 7; cutoff, 0.37 cm<sup>-1</sup>)</td><td>Normalizing filter<sup>†</sup></td><td>Gaussian (10 mm FWHM)</td><td>Gaussian (10 mm FWHM)</td></tr><tr><td>Pixel size (mm)</td><td>4.0</td><td>4.92</td><td>4.8</td><td>6.6</td></tr></tbody><tfoot><tr><td colspan="5"><sup>*</sup>Angles are approximately 0.4° for projections passing through cardiac region (as defined by adjusted region of interest on prescan images) and up to 7° for other projections.<br><sup>†</sup>Way in which normalizing filter works is proprietary information of Spectrum Dynamics.<br>LEHR = low-energy high-resolution; 3D = 3-dimensional; FWHM = full width at half maximum.</td></tr></tfoot></table>

## MATERIALS AND METHODS

### γ-Cameras and Collimation Systems

Table 1 summarizes the conventional recording and reconstruction parameters that were used for the 4 cameras. [Table 1]

The DSPECT camera was analyzed at the University Hospital of Nancy. As previously described (9–11), this camera operates with 9 mobile blocks of pixelated CZT detectors (pixel size, 2.5 × 2.5 mm) associated with a wide-angle square-hole tungsten collimator. A total of 120 projections are recorded by each block by means of a region-centric acquisition that maximizes counts emanating from the heart area, which was previously defined on a short prescan acquisition. A specific algorithm of iterative reconstruction is used to compensate for the collimator-related loss in spatial resolution (9–11). All the reconstruction parameters currently recommended for clinical routine (Table 1) were used, except for the cardiac anatomic model of the DSPECT camera, which constrains the shape and thickness of left ventricular walls (12).

The Discovery NM 530c camera was analyzed at the North Cardiology Centre in Saint-Denis, France. This camera operates with 19 fixed detectors, which are placed over an arc of 180° and orientated to focus on the heart area (15,16). Each detector involves 4 modules of 32 × 32 CZT pixels (pixel size, 2.5 × 2.5 mm) and is associated with a tungsten pinhole collimator with an effective aperture of 5.1 mm (19,20). Nineteen projections are thus recorded, and an iterative reconstruction allows modeling for collimator geometry.

The Symbia camera (Siemens Medical Solutions) is a dual-head Anger camera for which cardiac imaging can be performed either with a low-energy high-resolution collimator (for conventional SPECT) or with a high-sensitivity astigmatic collimator involving a convergent geometry for the image center and parallel holes for the edges (for IQ-SPECT) (6). Conventional SPECT and IQ-SPECT were assessed in the University Hospitals of Nice and Nancy, respectively. For conventional SPECT, the detectors were placed close to the patient in a body-contour mode, whereas for IQ-SPECT, rotation of the detectors was circular with a 28-cm radius and centered on the heart (12). SPECT images are routinely reconstructed with 3-dimensional iterative algorithms (22) and with an additional correction for the geometry of the astigmatic collimator for IQ-SPECT (23,24).

### Selection of Human SPECT Images

Presumably healthy male subjects were retrospectively selected for 4 groups, up to a total of 12 in each group, if they fulfilled the following criteria: first, had been routinely referred for exercise myocardial SPECT with ⁹⁹mTc-sestamibi on the Discovery NM 530c (first group in Saint-Denis), the DSPECT (second group in Nancy), or the Symbia equipped for IQ-SPECT (third group in Nancy) or conventional SPECT (fourth group in Nice); second, were between 50 and 70 y old; third, weighed less than 100 kg; fourth, had no history of coronary artery disease and less than a 10% pretest likelihood of coronary artery disease, according to the Diamond and Forster tables; fifth, had achieved maximal exercise on testing (≥85% of predicted maximal heart rate (220 – age)); and finally, had exercise test results and SPECT images that were considered normal by experienced observers. Images were rendered anonymous, and no approval of any ethical committee was required for this retrospective analysis of routinely recorded human SPECT images.
Phantom SPECT Images

A commercially available phantom mimicking the shape of a normal heart was used (cardiac insert; Biodex Medical Systems) [Fig. 1] (Fig. 1). The left ventricular cavity was filled with water, and the left ventricular walls were filled with a solution containing only 10 MBq of ⁹⁹mTc to avoid any saturation-related loss in counts. This phantom was placed at the center of the field of view and orientated in 45° left-anterior and 45° caudal directions. SPECT images were obtained using the parameters listed in Table 1. Time per projection was modulated to obtain a total recorded activity of approximately 500 kilocounts.

Performance Parameters

The selection of 3 major performance parameters—tomographic count sensitivity, spatial resolution, and contrast-to-noise ratio—was based on their ability to be determined on phantoms and to be assessed at least indirectly on human SPECT images.

*Tomographic Count Sensitivity.* Tomographic count sensitivity was measured on the reconstructed SPECT images of the phantom. The total number of recorded counts was determined with a manually adjusted elliptic region of interest, and count sensitivity was calculated using the following formula:

Total recording counts/[recording time (s) × left ventricular activity (MBq)].

This count sensitivity could not be directly determined for the human SPECT images. The actual left ventricular activities were unknown and thus replaced in the formula by the activities that were injected intravenously at peak exercise. Thereby, intergroup comparisons were made with the myocardial counts normalized to recording times (s) and injected activities (MBq). However, it is likely that these comparisons were dependent mainly on the differences in count sensitivity between the 4 camera groups. These groups were indeed constituted in such a way as to standardize factors that can affect cardiac uptake of tracer (exclusion of subjects with submaximal testing) or that clearly change the conditions of body attenuation and diffusion (inclusion of male-only subjects weighing < 100 kg).

The measurements were corrected for decay, and further corrections were needed for the conventional SPECT protocol in which exercise SPECT was performed after rest SPECT. Myocardial activity, corresponding to exercise-only injection, was then obtained after subtraction of residual myocardial activity from rest injection. This residual activity was obtained with the myocardial activity that was measured on the previous rest SPECT (in counts·s⁻¹) and corrected for decay.

RGB

<figure><img src="image_38.png" /><figcaption>FIGURE 1. Images of cardiac phantom provided by CT and by DSPECT camera, as well as representation of background (blue) and myocardial (yellow) regions of interest, which were used for determining contrast-to-noise ratio.</figcaption></figure>

*Reconstructed Spatial Resolution.* Reconstructed spatial resolution was determined according to the National Electrical Manufacturers Association NU-1 2001 protocol, with the exception that the reconstruction SPECT parameters were those recommended for clinical routine (Table 1). SPECT images were obtained from an insert with 3 linear sources of 1.5-mm internal diameter. These sources were filled with a 2 MBq/mL solution of ⁹⁹mTc and placed in the longitudinal direction. Horizontal and vertical profiles were generated for each line source on a median axial reconstructed slice. Central, tangential, and radial resolutions were determined with the open-source AMIDE software as the full width at half maximum of gaussian fit (19).

Spatial resolution could not be directly measured on human SPECT images but could be estimated through a quantitative sharpness profile, a parameter that is dramatically influenced by spatial resolution (25–27). As illustrated in Figure 2, a sharpness index [Fig. 2] was determined on the horizontal profile of the midventricular short-axis slice. This index was computed as the maximal slope of the decrease in myocardial counts (cm⁻¹) on the epicardial border of the lateral wall and after exclusion of the low-count part of the profile (activities < 25% of the maximal value).

*Contrast-to-Noise Ratio.* Contrast-to-noise ratio reflects the ability to generate an image contrast that may not be due to noise fluctuations yet is clinically useful (28,29). This ratio was determined on the midventricular short-axis slice of each SPECT recording (Fig. 1). Mean myocardial counts and corresponding SD were determined on a ring-shaped region of interest encompassing the endocardial and epicardial borders. Mean background counts and corresponding SD were determined on a half-moon-shaped region of interest, at 15 mm from the lateral wall. Contrast-to-noise ratio was estimated with the following formula:

$$ (M_{My} - M_{BG}) / \sqrt{[SD_{My}]^2 + [SD_{BG}]^2}, $$

where M<sub>My</sub> is mean myocardial counts, M<sub>BG</sub> is mean background counts, SD<sub>My</sub> is mean myocardial SD, and SD<sub>BG</sub> is mean background SD.

RESULTS

Characteristics of the Study Groups

Four groups of 12 presumably healthy subjects, corresponding to each of the 4 cameras, were created. As detailed in Table 2, age, body weight, and maximal heart rate at [Table 2] exercise were comparable in all 4 groups.

<figure><img src="image_39.png" /><figcaption>FIGURE 2. Example, on median short-axis slice, of determination of maximal slope of epicardial border of left lateral wall, representing sharpness index. Distance is expressed in centimeters, and voxel intensity is expressed in percentage of maximal myocardial voxel value.</figcaption></figure>
<table><caption>TABLE 2
Main Characteristics of the 4 Camera Groups Involved in Clinical Study</caption><thead><tr><th>Characteristic</th><th>Discovery NM 530c</th><th>DSPECT</th><th>IQ·SPECT</th><th>Conventional SPECT</th></tr></thead><tbody><tr><td>Number of subjects</td><td>12</td><td>12</td><td>12</td><td>12</td></tr><tr><td>Age (y)</td><td>53 ± 10</td><td>56 ± 10</td><td>53 ± 8</td><td>57 ± 7</td></tr><tr><td>Body weight (kg)</td><td>80 ± 10</td><td>80 ± 7</td><td>84 ± 13</td><td>83 ± 13</td></tr><tr><td>Study protocol</td><td>1-d stress-rest</td><td>1-d stress-rest</td><td>1-d stress-rest</td><td>1-d rest-stress</td></tr><tr><td>Tracer</td><td>Sestamibi</td><td>Sestamibi</td><td>Sestamibi</td><td>Sestamibi</td></tr><tr><td>Activity injected at exercise (MBq)*</td><td>132 ± 22</td><td>168 ± 62</td><td>318 ± 34</td><td>1,073 ± 177</td></tr><tr><td>Maximal heart rate at exercise (%†)</td><td>93 ± 8</td><td>95 ± 4</td><td>91 ± 7</td><td>91 ± 4</td></tr><tr><td>Recording time (min)</td><td>10</td><td>6</td><td>4.5</td><td>16</td></tr><tr><td>Patient position</td><td>Prone</td><td>Semireclining</td><td>Prone</td><td>Supine</td></tr><tr><td>Total myocardial counts (×10³)</td><td>447 ± 96</td><td>625 ± 198</td><td>214 ± 60</td><td>1,019 ± 190</td></tr></tbody></table>

However, there were substantial differences in the conditions under which SPECT was recorded, especially with regard to patient position (prone for IQ·SPECT and Discovery NM 530c, supine for conventional SPECT, and semireclining on a dedicated chair for DSPECT (9)), the 1-d study protocols (starting with rest SPECT for the conventional SPECT group and with exercise SPECT for the other groups), and the injected activities and recording times (Table 2). Therefore, the total myocardial counts were different in the 4 groups. The lowest values were in the IQ·SPECT group, and the highest values were in the conventional SPECT group (Table 2).

## Performance Parameters

Tomographic count sensitivities were determined with the phantom for total recording counts, which were near or slightly higher than 500 kilocounts for conventional SPECT (578 kilocounts), IQ·SPECT (581 kilocounts), DSPECT (580 kilocounts), and Discovery NM 530c (497 kilocounts).

[Fig. 3] As illustrated in Figure 3, this count sensitivity was 130 counts·s⁻¹·MBq⁻¹ with conventional SPECT and was improved 3-fold with IQ·SPECT (390 counts·s⁻¹·MBq⁻¹), about 4-fold with Discovery NM 530c (460 counts·s⁻¹·MBq⁻¹), and nearly 7-fold with DSPECT (850 counts·s⁻¹·MBq⁻¹).

Concordant results were also achieved for myocardial counts normalized to injected activities from human examinations (in counts·s⁻¹·MBq⁻¹: conventional SPECT, 0.6 ± 0.1; IQ·SPECT, 2.7 ± 0.7; Discovery NM 530c, 5.6 ± 1.4; and DSPECT, 11.4 ± 2.6) (Fig. 3).

The best spatial resolution was achieved with the Discovery NM 530c (6.7 mm for central spatial resolution, Fig. 3). Documented values were higher for the DSPECT (8.6 mm for central spatial resolution) and higher still for IQ·SPECT (15.0 mm) and conventional SPECT (15.3 mm). In addition, a concordant classification was obtained for the sharpness index of myocardial contours on human images (in cm⁻¹: Discovery NM 530c, 1.02 ± 0.17; DSPECT, 0.92 ± 0.11; IQ·SPECT, 0.64 ± 0.12; and conventional SPECT, 0.65 ± 0.06) (Fig. 3).

Figure 4 displays representative SPECT images obtained [Fig. 4] with the 4 cameras for human images from our study population and for the phantom after simulation of a small parietal defect (insertion of a small solid cube 15 mm in length).

<figure><img src="image_40.png" /><figcaption>FIGURE 3. Comparison of the 4 cameras. Count sensitivity was determined for phantom (top left) and indirectly assessed for human (top right) SPECT images by normalizing counts to recording time and injected activity. Spatial resolution was determined for phantom insert (middle left) and indirectly assessed for human (middle right) SPECT images using sharpness index for myocardial contours. Contrast-to-noise ratio was determined for phantom (bottom left) and human (bottom right) SPECT images. Conv = conventional SPECT; DSP = DSPECT; IQ = IQ·SPECT; NM = Discovery NM 530c; c = central resolution; r = radial resolution; t = tangential resolution.</figcaption></figure>

<footnote>*Corrected for physical decay at half-time of SPECT recording.</footnote>

<footnote>†Expressed in percentage of maximal predicted value (220 – age).</footnote>
<figure><img src="image_41.png" /><figcaption>FIGURE 4. Representative SPECT images obtained with 4 different cameras: with phantom after simulation of small parietal defect (insertion of small solid cube 15 mm in length) (left) and in subjects involved in clinical part of study (right).</figcaption></figure>

The contrast-to-noise ratios obtained for the phantom (Fig. 3) were higher for Discovery NM 530c (4.6) and lower for DSPECT (4.1), IQ-SPECT (3.9), and conventional SPECT (3.5). In addition, an equivalent order of classification was documented for human images: 5.2 ± 1.0 for Discovery NM 530c, 4.5 ± 0.5 for DSPECT, 3.9 ± 0.6 for IQ-SPECT, and 3.4 ± 0.3 for conventional SPECT (Fig. 3).

## DISCUSSION

Objective measurements reflecting performance have already been described for the Discovery NM 530c and DSPECT cameras, as well as for the IQ-SPECT collimation system (6,11,14). However, the differences in count sensitivity, as well as in image quality, remain unclear, especially in routine patient SPECT.

In the present study, head-to-head comparisons were conducted by analyzing global performance parameters that could be at least indirectly assessed on human SPECT images, that is, count sensitivity, spatial resolution, and contrast-to-noise ratio. Tomographic count sensitivities were determined on a cardiac phantom rather than on point sources to better reflect the conditions of routine SPECT. These count sensitivities were nevertheless close to those previously published for point sources placed at the center of the field of view (Discovery NM 530c (20), DSPECT (11), IQ-SPECT (12)). Of greater significance is the fact that head-to-head comparisons gave evidence of a dramatic superiority for the DSPECT camera. The count sensitivity provided by this camera was indeed around 7-fold higher than that from conventional SPECT and nearly 2-fold higher than those from Discovery NM 350c and from IQ-SPECT.

However, these differences could not be directly extrapolated to the conditions for human SPECT because of several

interfering factors such as breathing and cardiac motion, as well as body attenuation and diffusion. Hence, tomographic count sensitivity was also indirectly assessed on human SPECT images. For this purpose, myocardial counts normalized to recording times and injected activities were compared among groups of presumably healthy subjects (low pretest likelihoods and normal test results) who had undergone exercise SPECT on each of the 4 cameras and who had comparable characteristics (exclusion of subjects with submaximal testing, inclusion of male-only subjects weighing < 100 kg).

The normalized myocardial activities thus obtained represented approximately 1% of the count sensitivities obtained on the cardiac phantom. This low percentage can be explained by several factors: that only about 5% of the injected activity is likely to pass through coronary vessels (coronary flow expressed as percentage of cardiac flow) (30), that less than 40% of this amount will be retained within the myocardial tissue (retention fractions of sestamibi under high-flow conditions (31,32)), and that the addition of body attenuation further decreases the number of detected photons.

Finally, the results provided by these normalized activities were highly coherent with the count sensitivities from the phantom—in particular, 2-fold higher values for DSPECT than for Discovery NM 530c—possibly because of the differences in collimation systems between the Discovery NM 530c (pinholes) and the DSPECT (wide parallel holes). In addition, the heart-centric methods of collimation for these 2 CZT cameras are likely to explain most of their enhanced count sensitivity, when compared with conventional SPECT (11,13,14).

Spatial resolution was analyzed with a National Electrical Manufacturers Association-defined insert but with routine reconstruction parameters and, thus, in a different manner from that recommended in the National Electrical Manufacturers Association procedures (large voxel size, iterative methods of reconstruction). Therefore, our values of full width at half maximum were not the same as those already published (11,14) but were nevertheless highly coherent while showing much better results with CZT cameras and especially with the Discovery NM 530c. Furthermore, equivalent differences were observed with regard to the sharpness of the myocardial contours from human images (Fig. 3), a parameter strongly linked to spatial resolution (25,26,33). This finding provides evidence that the improvement in spatial resolution from CZT cameras has a true impact on patients’ SPECT images.

These differences in spatial resolution among the 4 cameras also correlated with corresponding differences in contrast-to-noise ratio (Fig. 3). This observation illustrates the general consideration that the contrast of myocardial SPECT images depends mainly on the level of reconstructed resolution. In addition, the difference in collimation systems herein is also a likely explanation for much of
the difference in spatial resolution and contrast between the Discovery NM 530c (pinholes) and the DSPECT (wide parallel holes). However, it is the pixelated organization of CZT detectors that is the most likely explanation of the enhancement in spatial resolution and contrast between CZT and Anger SPECT (13,14).

As a function of reconstruction parameters, there is a balance between reconstructed noise on the one hand and contrast and spatial resolution on the other. Our analyses were performed with routine reconstruction parameters and, thus, at a balance level that is considered to be well adapted to clinical routine. However, the choice of other reconstruction parameters could have affected our results. In particular, it is likely that the image quality parameters of the CZT cameras could have been enhanced using smaller energy windows, with only a limited loss in count sensitivity, but further studies are required to determine the optimal energy windows for CZT SPECT. Additional enhancements might be achieved using cardiac models, such as that available and recommended for the DSPECT camera; by new low-dose protocols (34); and by triggering breathing, especially when using the stationery detectors of the Discovery NM 530c (17).

As recommended by the manufacturers, thresholds of ±10% were applied for the ⁹⁹mTc energy windows of the DSPECT and Discovery NM 530c cameras as opposed to ±7.5% for the Symbia Anger camera. However, this difference is unlikely to have any significant impact on our results, particularly for the recording counts, which increase no more than 10% when a ±10% energy window is used on the Symbia camera instead of a ±7.5% window.

In addition, human SPECT images were analyzed here only in small subgroups of highly selected healthy subjects. Therefore, it is likely that the further analysis of larger groups with more varied characteristics would be informative.

## CONCLUSION

By a comprehensive analysis of phantom and human SPECT images, this study provided evidence that the physical performance of CZT cameras is dramatically higher than that of Anger cameras, even when equipped with astigmatic collimators. However, the 2 CZT cameras are inherently different; spatial resolution and contrast-to-noise ratio are better with the Discovery NM 530c, whereas detection sensitivity is markedly higher with the DSPECT.

## DISCLOSURE STATEMENT

The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. No other potential conflict of interest relevant to this article was reported.

## ACKNOWLEDGMENTS

We thank the Nancy University Hospital for organizational support, the French Research Ministry for financial support (a 2009 grant from CIFRE), and the staffs of General Electric France, Siemens France, and Spectrum Dynamics for technical support.

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# Comparison between stress myocardial perfusion SPECT recorded with cadmium-zinc-telluride and Anger cameras in various study protocols

Antoine Verger · Wassila Djaballah · Nicolas Fourquet · François Rouzet · Grégoire Koehl · Laetitia Imbert · Sylvain Poussier · Renaud Fay · Véronique Roch · Dominique Le Guludec · Gilles Karcher · Pierre-Yves Marie

Received: 29 May 2012 / Accepted: 6 November 2012
© Springer-Verlag Berlin Heidelberg 2012

## Abstract

*Purpose* The results of stress myocardial perfusion SPECT could be enhanced by new cadmium-zinc-telluride (CZT) cameras, although differences compared to the results with conventional Anger cameras remain poorly known for most study protocols. This study was aimed at comparing the results of CZT and Anger SPECT according to various study protocols while taking into account the influence of obesity.

*Methods* The study population, which was from three different institutions equipped with identical CZT cameras, comprised 276 patients referred for study using protocols involving ²⁰¹Tl (n=120) or ⁹⁹mTc-sestamibi injected at low dose at stress (⁹⁹mTc-Low; stress/rest 1-day protocol; n=110)

or at high dose at stress (⁹⁹mTc-High; rest/stress 1-day or 2-day protocol; n=46). Each Anger SPECT scan was followed by a high-speed CZT SPECT scan (2 to 4 min).

*Results* Agreement rates between CZT and Anger SPECT were good irrespective of the study protocol (for abnormal SPECT, ²⁰¹Tl 92 %, ⁹⁹mTc-Low 86 %, ⁹⁹mTc-High 98 %), although quality scores were much higher for CZT SPECT with all study protocols. Overall correlations were high for the extent of myocardial infarction (r=0.80) and a little lower for ischaemic areas (r=0.72), the latter being larger on Anger SPECT (p<0.001). This larger extent was mainly observed in 50 obese patients who were in the ²⁰¹Tl or ⁹⁹mTc-Low group and in whom stress myocardial counts

A. Verger · W. Djaballah · G. Koehl · L. Imbert · V. Roch · G. Karcher · P.-Y. Marie
Department of Nuclear Medicine, CHU-Nancy, Nancy 54000, France

A. Verger · W. Djaballah · S. Poussier · G. Karcher
INSERM U947, Nancy 54000, France

A. Verger · G. Koehl · L. Imbert · S. Poussier · V. Roch · G. Karcher · P.-Y. Marie
Nancyclotep Experimental Imaging Platform, Nancy 54000, France

N. Fourquet
Clinique Pasteur, Toulouse 31000, France

F. Rouzet · D. Le Guludec
Department of Nuclear Medicine, AP-HP, Hôpital Bichat, Paris 75018, France

F. Rouzet · D. Le Guludec
INSERM U 773 Inserm and Denis Diderot University, Paris 75018, France

L. Imbert
Department of Radiotherapy, Centre Alexis Vautrin, Vandoeuvre 54500, France

R. Fav
Centre d'Investigation Clinique CIC-P 9501, INSERM, Nancy 54000, France

P.-Y. Marie
INSERM U961, Nancy 54000, France

P.-Y. Marie (✉)
Médecine Nucléaire, Hôpital de Brabois, CHU-Nancy, Allée du Morvan, 54500 Vandoeuvre-les-Nancy, France
e-mail: py.marie@chu-nancy.fr
were particularly low with Anger SPECT (228±101 kcounts) and dramatically enhanced with CZT SPECT (+279±251 %).

*Conclusion* Concordance between the results of CZT and Anger SPECT is good regardless of study protocol and especially when excluding obese patients who have low-count Anger SPECT and for whom myocardial counts are dramatically enhanced on CZT SPECT.

**Keywords** Myocardial perfusion SPECT · Thallium-201 · Sestamibi · Obesity · Low-count artefacts · CZT camera

## Introduction

Stress myocardial perfusion SPECT could be markedly enhanced by the use of cadmium-zinc-telluride (CZT) semiconductor cameras that have recently become commercially available. These new cameras offer higher energy resolution and higher count sensitivity, thereby allowing image quality to be improved and recording times and/or tracer doses to be reduced [1–7], even in obese patients [5], while maintaining efficient detection of coronary stenosis [5, 6]. The new DSPECT CZT camera (Spectrum Dynamics, Caesarea, Israel) is equipped with a wide parallel-hole collimator and provides a tomographic count sensitivity approximately eight times higher than that achieved with Anger cameras, without affecting spatial resolution [8–10].

A previous multicentre study has already shown good concordance between the results obtained from high-speed recording with the DSPECT camera and conventional SPECT recording with an Anger camera [11]. However, this latter study was designed with the injection of high doses of ⁹⁹mTc-labelled tracers at stress, whereas lower doses are currently used at stress (e.g. ²⁰¹Tl protocol or stress/rest 1-day protocol with ⁹⁹mTc perfusion tracers). The use of such low-count stress protocols and especially the use of ²⁰¹Tl are likely to lower image quality and to increase the rates of low-count or attenuation artefacts at stress [12, 13]. It is not yet known how CZT SPECT cameras “handle” such differences in study protocols, especially in obese subjects, in whom low image quality and artefacts with Anger SPECT are also frequently documented [14–17]. CZT SPECT has been considered to provide a lower rate of attenuation artefacts [7] and better ischaemia detection [5] in obese subjects, although this remains to be confirmed.

This prospective multicentre study was aimed at comparing the results of CZT and Anger SPECT imaging according to study protocol designed for Anger SPECT while taking into account the influence of obesity.

## Materials and methods

The study was conducted in three different French institutions which had recently been equipped with the same model of CZT SPECT camera: (1) the University Hospital in Nancy, (2) the Pasteur Clinic in Toulouse, and (3) the Bichat Hospital in Paris. In each of these three centres, stress myocardial SPECT was performed with ²⁰¹Tl at fixed times of the week and with ⁹⁹mTc-sestamibi at the other times. Sestamibi was injected either at low dose at stress (⁹⁹mTc-Low) in a 1-day stress/rest protocol (Nancy and Bichat), or at high dose at stress (⁹⁹mTc-High) in a 1-day rest/stress protocol (Toulouse) or in a 2-day protocol (Bichat).

Patients who were routinely referred for stress myocardial SPECT in these three centres could be prospectively included, depending on the availability of cameras, physicians and technicians and on patient consent. According to the study protocol, a high-speed recording with a CZT SPECT camera was scheduled after each rest and stress conventional SPECT recording (Anger SPECT). The study protocol was approved by the local ethics committee (CPP agreement no. 2009-A00422-55) and all study subjects gave signed informed consent to participate.

### Conventional stress and rest Anger SPECT

The stress tests and Anger SPECT recording protocols were close to those recommended by the French societies of nuclear medicine and of cardiology [18], that is: (1) injected ²⁰¹Tl activities of 1.5 MBq kg⁻¹ at stress and 0.5 MBq kg⁻¹ at rest, and injected ⁹⁹mTc-sestamibi activities of 3.7 MBq kg⁻¹ for low-activity SPECT and 11 MBq kg⁻¹ for high-activity SPECT, and (2) times per projection of ≥50 s for low-activity SPECT and ≥30 s for high-activity SPECT, for a total of 32 projections over 180 °. Patients were referred for an exercise test on a bicycle ergometer, except in patients in whom it was contraindicated or with poor physical capacity, in which case a dipyridamole test was conducted with or without exercise.

Table 1 summarizes the main parameters of Anger SPECT recording, as well as the injected tracer activities for each protocol. The Anger SPECT scans were recorded on four different dual-head gamma cameras, which were all equipped with low-energy high-resolution collimators. They included two DST-XL gamma cameras (General Electric Healthcare, Buc, France), an Infinia camera (General Electric Healthcare) and a Cardio MD camera (Philips Medical Systems, Da Best, The Netherlands). Similar to clinical routine, the patients were positioned in the prone position in Nancy and Toulouse and in the supine position in Paris.

All SPECT and gated-SPECT acquisitions were reconstructed with an OSEM reconstruction method (two iterations for gated-SPECT, four for SPECT, and eight subsets
<table><caption>**Table 1** Main parameters used for conventional Anger SPECT recording in patients referred for study using a protocol involving <sup>201</sup>Tl or <sup>99m</sup>Tc-sestamibi with a low dose (<sup>99m</sup>Tc-Low) or a high dose (<sup>99m</sup>Tc-High) at stress</caption><thead><tr><th></th><th colspan="3"><sup>201</sup>Tl</th><th colspan="2"><sup>99m</sup>Tc-Low</th><th colspan="2"><sup>99m</sup>Tc-High</th></tr><tr><th></th><th>(n=52)</th><th>(n=16)</th><th>(n=52)</th><th>(n=100)</th><th>(n=10)</th><th>(n=43)</th><th>(n=3)</th></tr></thead><tbody><tr><td>Gamma camera (manufacturer)</td><td>DST-XL (GE)</td><td>DST-XL (GE)</td><td>Infinia (GE)</td><td>DST-XL (GE)</td><td>Infinia (GE)</td><td>Cardio MD (Philips)</td><td>Infinia (GE)</td></tr><tr><td>Site</td><td>Toulouse</td><td>Nancy</td><td>Paris</td><td>Nancy</td><td>Paris</td><td>Toulouse</td><td>Paris</td></tr><tr><td>Injected activities (MBq.kg<sup>-1</sup>)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>At stress</td><td>1.5</td><td>1.5</td><td>1.5</td><td>4</td><td>3.7</td><td>10</td><td>11</td></tr><tr><td>At rest</td><td>0.3</td><td>0.5</td><td>0.5</td><td>12</td><td>11</td><td>5</td><td>11</td></tr><tr><td>Injection-acquisition delay (min)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>At stress</td><td>10</td><td>10</td><td>5</td><td>45</td><td>10</td><td>20</td><td>45</td></tr><tr><td>At rest</td><td>60</td><td>60</td><td>20</td><td>60</td><td>60</td><td>30</td><td>60</td></tr><tr><td>Patient position</td><td>Prone</td><td>Prone</td><td>Supine</td><td>Prone</td><td>Supine</td><td>Prone</td><td>Supine</td></tr><tr><td>Energy window (keV)</td><td>30 %</td><td>30 %</td><td>30 %</td><td>20 %</td><td>20 %</td><td>20 %</td><td>20 %</td></tr><tr><td>Orbit</td><td>Circular 180°</td><td>Circular 180°</td><td>Circular 180°</td><td>Circular 180°</td><td>Circular 180°</td><td>Circular 180°</td><td>Circular 180°</td></tr><tr><td>Total no. of projections</td><td>32</td><td>32</td><td>30</td><td>32</td><td>30</td><td>32</td><td>30</td></tr><tr><td>Time per projection (s)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>At stress</td><td>50</td><td>60</td><td>60</td><td>50</td><td>50</td><td>45</td><td>50</td></tr><tr><td>At rest</td><td>50</td><td>60</td><td>60</td><td>30</td><td>50</td><td>50</td><td>50</td></tr><tr><td>No. of ECG-triggered intervals</td><td>8</td><td>8</td><td>8</td><td>8</td><td>8</td><td>12</td><td>8</td></tr><tr><td>Voxel size (mm)</td><td>6.8</td><td>6.8</td><td>6.6</td><td>6.8</td><td>6.6</td><td>6.4</td><td>6.6</td></tr></tbody></table>

GE General Electric Healthcare.

for both [19]), with a postreconstruction 9-mm gaussian filter and no attenuation correction.

## Recording and reconstruction of CZT SPECT images

The CZT SPECT recordings were obtained immediately after each rest or stress Anger SPECT scan, the patients being fitted with three ECG leads and placed in a semi-reclining position, with their back at 55° to the vertical.

The DSPECT system has been previously described in detail [8, 9]. Briefly, it involves nine mobile blocks of pixelated CZT detectors (2.46×2.46 mm) associated with a wide-angle square-hole tungsten collimator. A total of 120 projections are recorded by each block by means of a ‘region-centric’ acquisition that maximizes counts arising from the heart area, this area being defined on a short prescan acquisition [8, 9]. A specific algorithm for iterative reconstruction is used to compensate for the collimator-related loss in spatial resolution [8, 9].

Energy windows were set at 20% around the 140 keV photopeak for <sup>99m</sup>Tc and at 30% around the 70 keV photopeak for <sup>201</sup>Tl. The recording times were set to: (1) 2 min for the high-dose acquisitions with <sup>99m</sup>Tc-sestamibi, and (2) 4 min for the acquisitions with <sup>201</sup>Tl and the low-dose acquisitions with <sup>99m</sup>Tc-sestamibi. Parameters for reconstructing the SPECT images were as follows: 32 subsets and four iterations, a 0.3 kernel inter-iteration filter and a

final 5-mm gaussian filter. These parameters provided images of an equivalent spatial resolution to those from Anger SPECT (14 mm of full-width at half-maximum for a point source placed at the centre of the field of view). For gated SPECT, there were eight ECG-triggered intervals, 32 subsets, three iterations, a 0.5 kernel inter-iteration filter and a 7-mm gaussian filter.

## Image analysis

SPECT and gated SPECT images were rendered anonymous and were analysed visually by two experienced observers (W.D. and P.Y.M.) 1 month apart for CZT and Anger SPECT. Image quality was scored visually according to the level of background noise, the myocardial-to-background contrast and the presence of adjacent abdominal foci using a five-point scale: excellent (4), good (3), moderate (2), or low quality leading to a difficult (1) or impossible (0) analysis. Scores from the two observers were averaged for further analyses.

Myocardial perfusion was assessed visually by the two observers in consensus on a 17-segment division of the left ventricle [20] and using a four-point grading system: 0, normal uptake; 1, equivocal; 2, moderate and 3, severe reduction of uptake [21–23]. Only segments with an uptake score ≥2 at stress were considered to have a definite uptake reduction at stress. Of these, segments with reversible
defects (ischaemic segments) were defined as those with a decrease in uptake score of 1 point or more at rest [21–23], and the remainder were considered to have a fixed defect (myocardial infarction segments) except for those with a definitely normal contractility on gated SPECT and for which the final diagnosis was attenuation artefact [18, 23]. The segments with attenuation artefact were also excluded from the final definition of the stress defects area. Finally, only areas involving more than one segment with stress defects, myocardial ischaemia or myocardial infarction were considered significant for the definitions of the presence of abnormal SPECT, myocardial ischaemia or myocardial infarction, respectively.

Total myocardial counts were determined in each acquisition with a manually adjusted elliptical region of interest.

## Statistical analysis

Continuous variables are reported as means±SD and discrete variables as percentages. All quantitative variables were analysed with nonparametric tests: Kruskal-Wallis test for unpaired three-group comparisons, Wilcoxon rank sum test for paired comparisons between data from CZT SPECT and Anger SPECT, and Spearman rank method for assessing the correlations of continuous variables between CZT and Anger SPECT. For discrete variables, unpaired data were compared with the chi-squared test (or Fisher exact test when more appropriate) and paired data with the McNemar test. Diagnostic concordance between CZT and Anger SPECT was assessed through agreement rates and kappa scores.

The best independent predictors of the changes between CZT and Anger SPECT results were determined by an ANOVA model. Variables were entered into the models and removed at *p* values of <0.05 and >0.1, respectively.

## Results

### Patient characteristics

The initial study population comprised 292 patients representing approximately 20 % of the overall population who underwent stress SPECT at the three institutions during the same period. However, 16 were excluded because of patient motion during SPECT recording (*n*=6), inadequate heart centring with CZT SPECT (*n*=5) or very poor quality of Anger SPECT images (quality score 0; *n*=5). Therefore, the final population comprised 276 patients. Their mean age was 63±10 years, 21 % were women, 22 % were obese (body mass index >30 kg m⁻²), 55 % had a previous history of coronary artery disease (myocardial infarction 26 %), 59 % had taken antianginal medications in the preceding 24 h and 37 % had an abnormal Anger SPECT.

Study protocols included $^{201}$Tl in 120 patients, $^{99m}$Tc-Low in 110 patients and a $^{99m}$Tc-High in 46 patients. As detailed in Table 2, significant differences were found between patients studied using these three protocols, mainly because a smaller proportion of the $^{99m}$Tc-High group had a history of coronary artery disease and thereby antianginal medications and abnormal SPECT. In addition, most SPECT scans were acquired in the prone position, especially in $^{99m}$Tc-Low and $^{99m}$Tc-High groups (Table 1).

### Image quality and myocardial counts

As shown in Table 3, there were differences in quality scores and myocardial counts among the three study protocols with both Anger and CZT SPECT. The lower quality scores were always found in the $^{201}$Tl group, while the lower myocardial counts were found in the $^{99m}$Tc-Low group at stress and in the $^{201}$Tl group at rest. Furthermore, there were marked enhancements between Anger and CZT SPECT for both myocardial counts and quality scores. The enhancement in myocardial counts ranged from +72 % to +273 % according to study protocol (Table 3). SPECT images were difficult to analyse (quality score 1) in 14 % of the overall population undergoing Anger SPECT and in only 2.5 % undergoing CZT SPECT (*p*<0.001).

### Comparison between Anger and CZT SPECT abnormalities

Agreement rates between Anger and CZT SPECT were higher than 85 % in the overall population (see Table 4 for corresponding values and kappa scores) as well as in each of the three groups. High agreement rates were also observed for the detection of abnormal SPECT ($^{201}$Tl 92 %, $^{99m}$Tc-Low 86 %, $^{99m}$Tc-High 98 %), myocardial ischaemia ($^{201}$Tl 88.3 %, $^{99m}$Tc-Low 88.2 %, $^{99m}$Tc-High 95.7 %) and myocardial infarction ($^{201}$Tl 90.8 %, $^{99m}$Tc-Low 93.6 %, $^{99m}$Tc-High 100 %). No statistically significant association was apparent between these rates and corresponding kappa scores on the one hand, and study protocols as well as prone or supine position of patients during SPECT recording on the other.

As detailed in Fig. 1, overall correlations between Anger and CZT SPECT were high with regard to extent of stress defects (*r*=0.86) and infarction area (*r*=0.80), and slightly lower for the extent of the ischaemic area (*r*=0.72). In addition, the extent of infarction area was not significantly different between Anger and CZT SPECT (mean number of segments 0.72±1.63 vs. 0.68±1.62). However, ischaemic areas were larger on Anger SPECT than on CZT SPECT (0.73±1.31 vs. 0.52±1.08, *p*<0.001) and thus the total extent of stress defects was also larger on Anger SPECT (1.45±2.12 vs. 1.20±1.98 for CZT SPECT, *p*<0.001).
<table><caption>**Table 2** Characteristics of the three groups of patients referred for stress SPECT performed with ²⁰¹Tl, a low dose of ⁹⁹mTc-sestamibi at stress (⁹⁹mTc-Low) or a high dose of ⁹⁹mTc-sestamibi at stress (⁹⁹mTc-High)</caption><thead><tr><th>Characteristic</th><th>²⁰¹Tl (n=120)</th><th>⁹⁹mTc-Low (n=110)</th><th>⁹⁹mTc-High (n=46)</th><th>p value</th></tr></thead><tbody><tr><td>Age (years)</td><td>64±10</td><td>63±10</td><td>59±11</td><td>0.008</td></tr><tr><td>Women</td><td>26 (22 %)</td><td>20 (18 %)</td><td>13 (28 %)</td><td>NS</td></tr><tr><td>Body mass index (kg m<sup>-2</sup>)</td><td>26±4</td><td>26±4</td><td>27±6</td><td>NS</td></tr><tr><td>Cardiovascular risk factors</td><td></td><td></td><td></td><td></td></tr><tr><td>Hypertension</td><td>85 (71 %)</td><td>71 (64 %)</td><td>35 (76 %)</td><td>NS</td></tr><tr><td>Diabetes mellitus</td><td>28 (23 %)</td><td>32 (29 %)</td><td>12 (26 %)</td><td>NS</td></tr><tr><td>Obesity</td><td>19 (16 %)</td><td>31 (28 %)</td><td>11 (24 %)</td><td>NS</td></tr><tr><td>Active smoking</td><td>20 (39 %)</td><td>19 (37 %)</td><td>12 (24 %)</td><td>NS</td></tr><tr><td>History of coronary artery disease</td><td>80 (67 %)</td><td>60 (55 %)</td><td>11 (24 %)</td><td>&lt;0.001</td></tr><tr><td>Myocardial infarction</td><td>34 (47 %)</td><td>36 (49 %)</td><td>3 (4 %)</td><td>0.003</td></tr><tr><td>Coronary angioplasty</td><td>65 (54 %)</td><td>42 (38 %)</td><td>10 (22 %)</td><td>&lt;0.001</td></tr><tr><td>Coronary artery bypass grafting</td><td>19 (16 %)</td><td>18 (16 %)</td><td>1 (2 %)</td><td>0.04</td></tr><tr><td>Left bundle branch block</td><td>3 (3 %)</td><td>5 (5 %)</td><td>2 (4 %)</td><td>NS</td></tr><tr><td>Pacemaker</td><td>1 (1 %)</td><td>6 (6 %)</td><td>2 (4 %)</td><td>NS</td></tr><tr><td>Antianginal medications (&lt;24 h)</td><td>78 (65 %)</td><td>71 (65 %)</td><td>14 (30 %)</td><td>&lt;0.001</td></tr><tr><td>Beta-blockers</td><td>54 (45 %)</td><td>52 (47 %)</td><td>7 (15 %)</td><td>&lt;0.001</td></tr><tr><td>Calcium antagonists</td><td>27 (23 %)</td><td>33 (30 %)</td><td>9 (20 %)</td><td>NS</td></tr><tr><td>Nitrates or molsidomine</td><td>11 (9 %)</td><td>9 (8 %)</td><td>3 (7 %)</td><td>NS</td></tr><tr><td>Stress technique</td><td></td><td></td><td></td><td></td></tr><tr><td>Exercise</td><td>84 (70 %)</td><td>88 (80 %)</td><td>38 (83 %)</td><td>NS</td></tr><tr><td>Dipyridamole</td><td>8 (7 %)</td><td>8 (7 %)</td><td>3 (6 %)</td><td>NS</td></tr><tr><td>Dipyridamole and exercise</td><td>28 (23 %)</td><td>14 (13 %)</td><td>5 (11 %)</td><td>NS</td></tr><tr><td>Supine position for Anger SPECT</td><td>52 (30 %)</td><td>10 (9 %)</td><td>3 (7 %)</td><td>&lt;0.001</td></tr><tr><td>Abnormal Anger SPECT</td><td>45 (38 %)</td><td>48 (44 %)</td><td>8 (17 %)</td><td>0.008</td></tr></tbody></table>

### Predictors of differences in extent of SPECT abnormalities

While the differences between Anger and CZT SPECT determinations of the extent of SPECT abnormalities were

small, as shown in Fig. 1, they were influenced by study protocol. The ischaemic area was significantly larger in the ⁹⁹mTc-Low group than in the two other groups (mean number of segments 0.29±0.87 vs. 0.08±0.85, *p*=0.045), but

<table><caption>**Table 3** Comparison of image quality scores and total myocardial counts between Anger SPECT and CZT SPECT and between the three groups of patients referred for stress SPECT performed with ²⁰¹Tl, a</caption><thead><tr><th></th><th></th><th>²⁰¹Tl (n=120)</th><th>⁹⁹mTc-Low (n=110)</th><th>⁹⁹mTc-High (n=46)</th><th>p values<sup>a</sup></th></tr></thead><tbody><tr><td>Quality score</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Anger SPECT</td><td></td><td>2.51±0.46</td><td>2.88±0.44</td><td>2.97±0.50</td><td>&lt;0.001</td></tr><tr><td>CZT SPECT</td><td></td><td>3.39±0.62*</td><td>3.68±0.56*</td><td>3.65±0.52*</td><td>&lt;0.001</td></tr><tr><td>Myocardial counts (×10<sup>3</sup>)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Anger SPECT</td><td>Stress</td><td>330±86</td><td>207±63</td><td>1,236±348</td><td>&lt;0.001</td></tr><tr><td></td><td>Rest</td><td>269±71</td><td>404±118</td><td>369±111</td><td>&lt;0.001</td></tr><tr><td>CZT SPECT</td><td>Stress</td><td>740±216*</td><td>738±244*</td><td>2,100±638*</td><td>&lt;0.001</td></tr><tr><td></td><td>Rest</td><td>743±208*</td><td>1,238±435*</td><td>969±415*</td><td>&lt;0.001</td></tr><tr><td>Myocardial count enhancement (%)</td><td>Stress</td><td>157±99</td><td>273±87</td><td>72±57</td><td>&lt;0.001</td></tr><tr><td>between Anger and CZT SPECT</td><td>Rest</td><td>216±109</td><td>208±78</td><td>172±66</td><td>0.028</td></tr></tbody></table>

low dose of ⁹⁹mTc-sestamibi at stress (⁹⁹mTc-Low) or a high dose of ⁹⁹mTc-sestamibi at stress (⁹⁹mTc-High)

<footnote>*p*<0.05 for paired comparisons CZT SPECT vs. Anger SPECT.</footnote>

<footnote><sup>a</sup>Unpaired multigroup comparisons.</footnote>
<table><caption>**Table 4** Concordances between Anger SPECT and CZT SPECT in the overall population for the detection of abnormal SPECT, ischaemia and infarction</caption><thead><tr><th rowspan="2">Anger SPECT</th><th colspan="3">CZT SPECT</th></tr><tr><th>Absence</th><th>Presence</th><th>Total</th></tr></thead><tbody><tr><td><strong>Abnormal SPECT<sup>a</sup></strong></td><td></td><td></td><td></td></tr><tr><td>Absence</td><td>171</td><td>4</td><td>175</td></tr><tr><td>Presence</td><td>21</td><td>80</td><td>101</td></tr><tr><td>Total</td><td>192</td><td>84</td><td>276</td></tr><tr><td><strong>Ischaemic area<sup>b</sup></strong></td><td></td><td></td><td></td></tr><tr><td>Absence</td><td>207</td><td>7</td><td>214</td></tr><tr><td>Presence</td><td>22</td><td>40</td><td>62</td></tr><tr><td>Total</td><td>229</td><td>47</td><td>276</td></tr><tr><td><strong>Infarction area<sup>c</sup></strong></td><td></td><td></td><td></td></tr><tr><td>Absence</td><td>226</td><td>7</td><td>233</td></tr><tr><td>Presence</td><td>11</td><td>32</td><td>43</td></tr><tr><td>Total</td><td>237</td><td>39</td><td>276</td></tr></tbody></table>

the infarction area was not significantly different (0.12±0.65 vs. -0.03±0.63).

Independent correlates of the differences between Anger and CZT SPECT determinations of the extent of ischaemic and infarction areas were subsequently determined among: (1) study protocols (²⁰¹Tl, ⁹⁹mTc-Low, ⁹⁹mTc-High), (2) demographic and anthropometric parameters from Table 2, (3) prone or supine position during SPECT recording, and (4) quality score and count parameters from Table 3. No correlation was found for the difference in infarction area. In contrast, for the difference in ischaemic area, the percentage myocardial count enhancement between Anger SPECT and CZT SPECT at stress was determined as the single best independent correlate (*p*=0.007). When this variable was excluded, two independent correlates were documented: obesity (*p*=0.01) and patients belonging to the ⁹⁹mTc-Low or ²¹⁰Tl group (*p*=0.03). The SPECT quality scores, as well as the supine or prone position at SPECT recording, were not significant univariate predictors.

The multivariate analyses (Fig. 2) showed that the difference in ischaemic areas between Anger and CZT SPECT occurred mainly in a small subgroup of 50 obese patients in whom Anger SPECT was recorded with the ⁹⁹mTc-Low or ²¹⁰Tl protocol. Discordant ischaemic areas were observed in 22 out of these 50 patients (44 %), with the larger ischaemic areas always seen with Anger SPECT. This subgroup was also characterized by stress myocardial counts which were particularly low on Anger SPECT (228±101 kcounts vs. 472±420 kcounts for the other patients, *p*<0.001) but dramatically enhanced on CZT SPECT (+279±251 % vs. +168 ±116 % for the other patients, *p*<0.001).

Stress defects area

Number of segments on CZT-SPECT

p<0.001
r=0.86

<figure><img src="image_42.png" /></figure>

Number of segments on Anger-SPECT

Infarction area

Number of segments on CZT-SPECT

p<0.001
r=0.80

<figure><img src="image_43.png" /></figure>

Number of segments on Anger-SPECT

Ischemic area

Number of segments on CZT-SPECT

p<0.001
r=0.72

<figure><img src="image_44.png" /></figure>

Number of segments on Anger-SPECT

<caption>**Fig. 1** Overall correlations between Anger SPECT and CZT SPECT for the extent of stress defect areas (top) and for the extent of infarction (centre) and ischaemic areas (bottom)</caption>

Figures 3 and 4 show examples of concordant ischaemic and infarction areas between Anger and CZT SPECT, and Fig. 5 shows an example of discordant ischaemic areas.

Discussion

Several studies have already shown good accuracy of stress myocardial-SPECT recorded with CZT cameras for identifying patients with significant coronary stenoses [24, 25], including with low-dose protocols [1–6, 26]. Several

<footnote><sup>a</sup>Agreement 91 %, kappa 0.80 ± 0.04 (SE), *p*<0.001.</footnote>

<footnote><sup>b</sup>Agreement 89 %, kappa 0.67 ± 0.06 (SE), *p*<0.001.</footnote>

<footnote><sup>c</sup>Agreement 93 %, kappa 0.74 ± 0.06 (SE), *p*<0.001.</footnote>
<figure><img src="image_45.png" /><figcaption>**Fig. 2** Differences between Anger and CZT SPECT determinations of the extent of infarction (grey columns in upper panel) and ischaemic areas (black columns in upper panel), as well as percentage myocardial count enhancement between Anger and CZT SPECT (lower panel), in relation to the presence of obesity and $^{201}$Tl or $^{99m}$Tc-Low protocol</figcaption></figure>

clinical trials have also shown good concordance with
results provided by conventional Anger cameras [9–11,
27]. However, it is likely that the physical characteristics
of CZT cameras, such as their enhanced count sensitivity,
have the potential to improve on and therefore modify the
results from Anger SPECT, especially when low myocardial
counts are recorded by Anger SPECT at stress. This situa-
tion was therefore specifically analysed in the present multi-
centre study in which the results provided by a DSPECT
CZT camera were compared with those provided by Anger

cameras in a population the majority of whom were imaged
using a protocol involving the injection of a low-dose of
tracer at stress, namely a $^{201}$Tl protocol or a 1-day protocol
with injection of a low dose of $^{99m}$Tc-sestamibi at stress
($^{99m}$Tc-Low).

The results in the global population were in accordance
with those of previous studies [9–11, 27] while showing
high agreement rates between CZT and Anger SPECT and
high corresponding kappa scores for the identification of an
abnormal SPECT scan, as well as for the detection of myo-
cardial ischaemia and myocardial infarction, and also show-
ing much higher image quality and myocardial counts for
CZT SPECT than for Anger SPECT, in spite of four- to
eightfold lower shorter times. Furthermore, these observa-
tions were made irrespective of the Anger SPECT study
protocol ($^{201}$Tl, $^{99m}$Tc-Low or $^{99m}$Tc-High).

The count enhancement between Anger and CZT SPECT
was highly variable, ranging from +72 % on average for
stress images obtained with high injected doses ($^{99m}$Tc-High
protocol), to up to +273 % on average for stress images
obtained with the $^{99m}$Tc-Low protocol. This enhancement
was inversely related to the myocardial count obtained by
Anger SPECT and, in accordance with previous studies, the
lower counts were found at stress with the $^{99m}$Tc-Low
protocol and not with the $^{201}$Tl protocol [12]. This observa-
tion can be explained mainly by differences in myocardial
kinetics between $^{201}$Tl and $^{99m}$Tc-sestamibi (much higher
extraction fractions for $^{201}$Tl) [28, 29].

Furthermore, the overall concordance between the CZT
and Anger SPECT findings was clearly lower for ischaemic
than for infarction areas, with the additional characteristic
that ischaemic areas in particular were larger on Anger
SPECT. In a previous multicentre study [11], SPECT abnor-
malities were found to be larger by Anger SPECT than with
the DSPECT camera but only for resting SPECT, contrary to
the observations in this study. In the previous study,

<figure><img src="image_46.png" /><figcaption>**Fig. 3** Example of a
concordant ischaemic area
between Anger SPECT and
CZT SPECT in a patient in the
$^{99m}$Tc-Low group. Ischaemia
extends over a large inferior and
lateral area</figcaption></figure>
<figure><img src="image_47.png" /><figcaption>**Fig. 4** Example of a concordant infarction area between Anger SPECT and CZT SPECT in a patient in the ⁹⁹mTc-Low group. Myocardial infarction extends over a large anterior, septal and apical area</figcaption></figure>

however, rest Anger SPECT was recorded with a low-dose of ⁹⁹mTc-sestamibi (1-day rest/stress protocol), contrary to the procedure performed in the present study. Taken together, these observations suggest that low myocardial counts could play a role in the larger defects shown by Anger SPECT, a hypothesis further strengthened by additional observations.

These larger ischaemic areas were indeed mainly predicted by the percentage enhancement of stress myocardial count between Anger and CZT SPECT. Further explanatory analyses allowed the identification of a small subgroup of 50 obese subjects who had undergone a low-dose protocol (⁹⁹mTc-Low or ²¹⁰Tl protocol) and among whom as many as 22 had larger ischaemic areas on Anger SPECT. In addition, the myocardial counts from these 50 subjects were very low

at stress Anger SPECT (228 kcounts on average) but dramatically enhanced on DSPECT (+279 %), as shown in Fig. 2.

However, it should be kept in mind that the patients studied using a low-dose protocols not only had a low tracer activity stress injection when compared with ⁹⁹mTc-High patients but also had different characteristics and especially different Anger SPECT recording conditions (time per projection, type of Anger camera, delay between injection and recording, etc.). Therefore, the respective influences of obesity, injected activities and Anger SPECT recording conditions may not have been fully defined here. However, our results show that larger ischaemic areas are likely to be shown on Anger SPECT when myocardial counts are dramatically enhanced between Anger and CZT SPECT, and

<figure><img src="image_48.png" /><figcaption>**Fig. 5** Example of a discordant ischaemic area between Anger SPECT and CZT SPECT in an obese male patient from the ⁹⁹mTc-Low group and in whom the Anger SPECT imaging was performed in the prone position. The inferior infarction area appears similar on the high-dose rest Anger and CZT SPECT images. However, the low-dose exercise</figcaption></figure>

images exhibit larger defect areas in the apical parts of the inferior and anterior walls in the Anger SPECT images (arrows) and there were much lower myocardial counts on Anger SPECT imaging (202 kcounts) than on CZT SPECT imaging (809 kcounts)
that this situation might mainly occur in obese patients with low-count Anger SPECT. Therefore, as shown in Fig. 5, low count artefacts, which were predominantly seen on stress images, are likely to lead to a pattern of reversible defects and thus to an erroneous identification of an ischaemic area. However, it must be considered that low count artefacts might also predominate in rest images, especially when a low tracer activity is injected at rest ($^{201}$Tl and $^{99m}$Tc-High groups), although we did not find a larger extent of infarction on Anger SPECT, when compared with CZT SPECT. This latter finding was probably because the corresponding pattern was generally that of a reverse redistribution (especially with $^{201}$Tl) and not of the fixed defects which suggest infarction, and the additional observation of a normal contractility at gated SPECT could help exclude the diagnosis of infarction.

Low-count artefacts, enlarging stress SPECT defects, have already been shown to be frequent in $^{201}$Tl studies [12] and when a low $^{99m}$Tc-sestamibi activity is injected at stress, particularly in patients with high body mass index [12, 13]. Obesity is known to affect the accuracy of conventional stress myocardial perfusion imaging when performed with a $^{201}$Tl- or $^{99m}$Tc-labelled tracer [14–16], with a dramatic deterioration in image quality [17] along with an increased rate of low-count artefacts [13]. Our results suggest that the greater count density provided by DSPECT may help prevent low-count artefacts, especially in obese patients. This suggestion is in agreement with previous findings in obese patients whereby highly accurate results are achieved when a stress/rest low-dose protocol is planned on a CZT camera [5], and also the rate of certain artefacts may be lower with a CZT camera [7]. However, no external validation standard was used in the present study. Therefore, further studies are required to determine to what extent the results from CZT cameras are superior to those from Anger cameras, especially in obese patients and in regard to clinical end-points such as the detection of coronary stenosis, assessment of myocardial viability or patient prognosis.

In a similar way, $^{82}$Rb PET has previously been found to provide better image quality than Anger SPECT, especially in obese subjects and mainly because of a higher count density [14, 30]. However, while attenuation correction could be systematically integrated in these PET examinations, this was not the case with our CZT SPECT camera. Gated-SPECT images were extensively used in this study to differentiate attenuation artefacts from infarction SPECT defects, but these artefacts may be better prevented by the additional use of attenuation correction methods, especially in obese subjects [16]. A first study was recently published on hybrid systems involving a CZT camera and CT for attenuation correction [31]. Further studies are required to determine the difference between such hybrid CZT SPECT/CT systems and conventional PET/CT for stress myocardial perfusion imaging.

For a first-step comparison with Anger SPECT, we selected reconstruction parameters providing images comparable to those with DSPECT, especially in terms of central spatial resolution (14 mm). However, spatial resolution may be enhanced with other reconstruction parameters which could further increase the differences with results from Anger SPECT. In addition, different patient positions were used for DSPECT (semireclining position) and Anger SPECT (prone or supine, according to the protocol routinely used in each centre), whereas these positions are likely to provide different rates and locations of attenuation artefacts. The differences between DSPECT and Anger SPECT results were not significantly related to the position used (supine or prone) for Anger SPECT. However, the question could be raised as to whether these differences were influenced by the particular semireclining position used for the DSPECT recording.

In conclusion, the present multicentre study provided evidence that the concordance between the results from CZT and Anger SPECT is good irrespective of the study protocol used and in spite of the variability in tracer protocols, stress tests and types of Anger cameras, reflecting the various modalities in which Anger SPECT is currently performed in clinical routine. However, this concordance is higher if obese patients with low-count Anger SPECT are excluded in whom myocardial counts are dramatically enhanced by the use of a CZT camera.

**Acknowledgments** The authors thank: Henri Boutley for his help in image analysis, Pierre Pothier for critical review of the manuscript and Nancy University Hospital for financial and organizational support.

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12. Kapur A, Latus KA, Davies G, Dhawan RT, Eastick S, Jarritt PH, et al. A comparison of three radionuclide myocardial perfusion tracers in clinical practice: the ROBUST study. Eur J Nucl Med Mol Imaging. 2002;29(12):1608-16.

13. Robinson CN, van Aswegen A, Julious SA, Nunan TO, Thomson WH, Tindale WB, et al. The relationship between administered radiopharmaceutical activity in myocardial perfusion scintigraphy and imaging outcome. Eur J Nucl Med Mol Imaging. 2008;35 (2):329-35.

14. Freedman N, Schechter D, Klein M, Marciano R, Rozenman Y, Chisin R. SPECT attenuation artifacts in normal and overweight persons: insights from a retrospective comparison of Rb-82 positron emission tomography and TI-201 SPECT myocardial perfusion imaging. Clin Nucl Med. 2000;25(12):1019-23.

15. Hansen CL, Woodhouse S, Kramer M. Effect of patient obesity on the accuracy of thallium-201 myocardial perfusion imaging. Am J Cardiol. 2000;85(6):749-52.

16. Thompson RC, Heller GV, Johnson LL, Case JA. Cullom SJ, Garcia EV, et al. Value of attenuation correction on ECG-gated SPECT myocardial perfusion imaging related to body mass index. J Nucl Cardiol. 2005;12(2):195-202.

17. Notghi A, Williams N, Smith N, Goyle S, Harding LK. Relationship between myocardial counts and patient weight: adjusting the injected activity in myocardial perfusion scans. Nucl Med Commun. 2003;24(1):55-9.

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19. Marie PY, Djaballah W, Franken PR, Vanhove C, Muller MA, Boutley H, et al. OSEM reconstruction, associated with temporal fourier and depth-dependant resolution recovery filtering, enhances results from sestamibi and 201Tl 16-interval gated SPECT. J Nucl Med. 2005;46(11):1789-95.

20. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, et al. Standardized myocardial segmentation and

nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation. 2002;105:539-42.

21. Marie PY, Mercennier C, Danchin N, Djaballah K, Gretzinger A, Zannad F, et al. Residual exercise-SPECT ischemia on treatment is a main determinant of outcome in patients with coronary artery disease treated medically at long-term by beta-blockers. J Nucl Cardiol. 2003;10:361-8.

22. Marie PY, Danchin N, Branly F, Angioi M, Brentzinger A, Virion JM, et al. Effects of medical therapy on outcome assessment using exercise thallium-201 single photon emission computed tomography imaging: evidence of a protective effect of beta-blocking antianginal medications. J Am Coll Cardiol. 1999;34(1):113-21.

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24. Nakazato R, Tamarappoo BK, Kang X, Wolak A, Kite F, Hayes SW, et al. Quantitative upright-supine high-speed SPECT myocardial perfusion imaging for detection of coronary artery disease: correlation with invasive coronary angiography. J Nucl Med. 2010;51(11):1724-31.

25. Fiechter M, Ghadri JR, Kuest SM, Pazhenkottil AP, Wolfrum M, Nkoulou RN, et al. Nuclear myocardial perfusion imaging with a novel cadmium-zinc-telluride detector SPECT/CT device: first validation versus invasive coronary angiography. Eur J Nucl Med Mol Imaging. 2011;38(11):2025-30.

26. Duvall WL, Sweeny JM, Croft LB, Barghash MH, Kulkarni NK, Guma KA, et al. Comparison of high efficiency CZT SPECT MPI to coronary angiography. J Nucl Cardiol. 2011;18(4):595-604.

27. Buechel RR, Herzog BA, Husmann L, Burger IA, Pazhenkottil AP, Treyer V, et al. Ultrafast nuclear myocardial perfusion imaging on a new gamma camera with semiconductor detector technique: first clinical validation. Eur J Nucl Med Mol Imaging. 2010;37(4):773-8.

28. Ayalew A, Marie PY, Menu P, Mertes PM, Hassan N, Danchin N, et al. A comparison of the overall first-pass kinetics of thallium-201 and technetium-99m MIBI in normoxic and low-flow ischaemic myocardium. Eur J Nucl Med. 2000;27(11):1632-40.

29. Ayalew A, Marie PY, Menu P, Mertes PM, Audonnet S, Jouan V, et al. (201)Tl and (99 m)Tc-MIBI retention in an isolated heart model of low-flow ischemia and stunning: evidence of negligible impact of myocyte metabolism on tracer kinetics. J Nucl Med. 2002;43 (4):566-74.

30. Bateman TM, Heller GV, McGhie AI, Friedman JD, Case JA, Bryngelson JR, et al. Diagnostic accuracy of rest/stress ECG-gated Rb-82 myocardial perfusion PET: comparison with ECG-gated Tc-99m sestamibi SPECT. J Nucl Cardiol. 2006;13 (1):24-33.

31. Herzog BA, Buechel RR, Husmann L, Pazhenkottil AP, Burger IA, Wolfrum M, et al. Validation of CT attenuation correction for high-speed myocardial perfusion imaging using a novel cadmium-zinc-telluride detector technique. J Nucl Med. 2010;51(10):1539-44.
# Stress-first protocol for myocardial perfusion SPECT imaging with semiconductor cameras: high diagnostic performances with significant reduction in patient radiation doses

Mathieu Perrin · Wassila Djaballah · Frédéric Moulin · Marine Claudin · Nicolas Veran · Laetitia Imbert · Sylvain Poussier · Olivier Morel · Cyril Besseau · Antoine Verger · Henri Boutley · Gilles Karcher · Pierre-Yves Marie

Received: 18 November 2014 / Accepted: 2 February 2015
© Springer-Verlag Berlin Heidelberg 2015

## Abstract

*Purpose* Effective doses of 14 mSv or higher are currently being attained in patients having stress and rest myocardial perfusion imaging (MPI) single photon emission computed tomography (SPECT) performed on the same day with conventional protocols. This study aimed to assess the actual reduction in effective doses as well as diagnostic performances for MPI routinely planned with: (1) high-sensitivity cadmium zinc telluride (CZT) cameras, (2) very low injected activities and (3) a stress-first protocol where the normality of stress images may lead to avoiding rest imaging.

*Methods* During a 1-year period, 2,845 patients had MPI on a CZT camera, a single-day stress-first protocol and low

injected activities (120 MBq of 99mTc-sestamibi at stress for 75 kg body weight and threefold higher at rest). The ability to detect > 50 % coronary stenosis was assessed in a subgroup of 149 patients who also had coronary angiography, while the normalcy rate was assessed in a subgroup of 128 patients with a low pretest likelihood of coronary artery disease (<10 %).

*Results* Overall, 33 % of patients had abnormal MPI of which 34 % were women and 34 % were obese. The mean effective doses and the percentage of exams involving only stress images were: (1) 3.53 ± 2.10 mSv and 37 % in the overall population, (2) 4.83 ± 1.56 mSv and 5 % in the subgroup with angiography and (3) 1.96 ± 1.52 mSv and 71 % in the low-probability subgroup. Sensitivity and global accuracy for identifying the 106 patients with coronary stenosis were 88 and 80 %, respectively, while the normalcy rate was 97 %.

*Conclusion* When planned with a low-dose stress-first protocol on a CZT camera, MPI provides high diagnostic performances and a dramatic reduction in patient radiation doses. This reduction is even greater in low-risk subgroups with high rates of normal stress images, thus allowing the mean radiation dose to be balanced against cardiac risk in targeted populations.

**Keywords** Myocardial SPECT · Sestamibi · Stress-first protocol · CZT camera · Coronary artery disease

## Introduction

There is broad concern regarding the risk of cancer for the growing number of patients who are referred for repeat ionizing cardiac procedures throughout their lifetime [1]. This is

M. Perrin · W. Djaballah · M. Claudin · N. Veran · L. Imbert · S. Poussier · O. Morel · C. Besseau · A. Verger · H. Boutley · G. Karcher · P.-Y. Marie
Department of Nuclear Medicine, CHU-Nancy, Nancy, France

M. Perrin (✉) · W. Djaballah · M. Claudin · N. Veran · L. Imbert · S. Poussier · O. Morel · C. Besseau · A. Verger · H. Boutley · G. Karcher · P.-Y. Marie
Nancyclotep Experimental Imaging Platform, Nancy, France
e-mail: matperrin@yahoo.fr

W. Djaballah · S. Poussier · A. Verger
INSERM U947 and Université de Lorraine, Nancy, France

F. Moulin
Department of Cardiology, CHU-Nancy, Nancy, France

L. Imbert · G. Karcher
UMR 7039 CRAN and Université de Lorraine, Nancy, France

P.-Y. Marie
INSERM U1116 and Université de Lorraine, Nancy, France
particularly critical for those with low risk of cardiac events and for whom the benefits of such procedures are limited [1]. Myocardial perfusion imaging (MPI) single photon emission computed tomography (SPECT) represents a significant part of these repeat radiation doses [1–3]. However, patient radiation may be considerably reduced by high-sensitivity semiconductor cameras, as well as by the planning of stress-first protocols, as stated in a recent European position paper [4].

For logistical reasons, most laboratories perform MPI with ⁹⁹mTc-labelled tracers on a single-day protocol where both rest and stress imaging are completed on the same day. The second imaging procedure requires the injection of a threefold higher activity to overcome the background of the first injection [5, 6]. With stress-first protocols, rest acquisitions may be suppressed when stress images are interpreted as definitely normal, leading to a dramatic reduction in patient radiation doses. However, poor image quality as well as low-count artefacts may be documented at stress, especially in obese subjects [7–9]. Hence, until recently, it was frequently preferred to use rest-first protocols followed by injection of higher doses at stress [10, 11]. However, such image quality problems and low-count artefacts may be overcome by recent cameras equipped with semiconductor [cadmium zinc telluride (CZT)] detectors and new collimation systems [7]. These cameras offer much higher energy resolutions and count sensitivities, allowing image quality to be improved [7, 12] as well as acquisition times and tracer doses to be reduced [13–18]. However, the diagnostic performances of stress-first protocols applied on such CZT cameras remain unclear, especially when acquisition times and tracer doses are dramatically reduced.

This study aimed to assess the actual reduction in effective doses as well as overall diagnostic performances in the detection of obstructive coronary artery disease (CAD) for MPI exams scheduled in routine clinical practice with a CZT camera and a very low-dose stress-first protocol.

## Materials and methods

### Study groups

This study was approved by our institution's Ethics Committee (Comité de Réflexion Ethique Nancéien Hospitalo-Universitaire). All patients from our institution are informed that their medical data can be rendered anonymous and used for scientific purposes. The following sets of all patients were retrospectively analysed: (1) patients referred for stress MPI for a known or suspected CAD in the University Hospital in Nancy throughout the entire year 2012 and (2) patients for whom stress MPI was routinely planned with a low-dose protocol on a CZT camera ("D-SPECT" camera, Spectrum Dynamics [7, 12, 13, 18–20].

The ability to detect obstructive CAD was assessed in a subgroup of patients who: (1) had a coronary angiography at ≤3 months from MPI in our University Hospital and (2) neither had a cardiac event nor myocardial revascularization between these two exams. The normalcy rate was assessed in a subgroup of patients for whom the pretest likelihood of CAD was low (<10% according to the classification provided by the American College of Cardiology/American Heart Association (ACC/AHA) exercise testing guideline [21]). Patients with a known history of congenital heart disease, cardiac transplantation, hypertrophic or idiopathic dilated cardiomyopathy, left bundle branch block or an active pacemaker were excluded from the two subgroups.

### Stress tests and tracer injection

Patients were referred for an exercise test, except in the case of contraindication or poor physical capacity, in which instance a dipyridamole test was conducted with or without exercise. Dipyridamole was injected at a dose of 0.56 mg kg⁻¹ and exercise tests were performed in the upright position on a bicycle ergometer [22–24].

As already described elsewhere [13] and as detailed in Table 1, the injected activities of ⁹⁹mTc-sestamibi were adapted to the high sensitivity of this camera and to body weight. For example, the activities injected at stress were 120 MBq for 75 kg of body weight and more than twofold higher for >110 kg (260 MBq). The activities injected at rest were three times higher than those injected at stress, although no rest injection was routinely scheduled when stress MPI was considered as definitely normal.

Effective doses were determined according to the activity of ⁹⁹mTc-sestamibi, which was measured within the syringe prior to injection with a dedicated dose calibrator (CRC®-15R, Capintec, Inc., Ramsey, NJ, USA) while neglecting the small percentage of activity remaining after injection (<5%, on average, in our experience). Respective ratios of 0.0079 mSv/MBq of ⁹⁹mTc-sestamibi for stress injection and 0.009 mSv/MBq of ⁹⁹mTc-sestamibi for rest injection were

<table><caption>**Table 1** ⁹⁹mTc-Sestamibi activities injected at stress and at rest</caption><thead><tr><td>Body weight (kg)</td><td>Stress activity (MBq)</td><td>Rest activity (MBq)</td></tr></thead><tbody><tr><td>≤60</td><td>80</td><td>240</td></tr><tr><td>61–70</td><td>100</td><td>300</td></tr><tr><td>71–80</td><td>120</td><td>360</td></tr><tr><td>81–90</td><td>140</td><td>420</td></tr><tr><td>91–100</td><td>145</td><td>434</td></tr><tr><td>101–110</td><td>190</td><td>570</td></tr><tr><td>>110</td><td>260</td><td>780</td></tr></tbody></table>
used, according to data provided by the International Commission on Radiological Protection (ICRP) [25].

Acquisitions, reconstruction and analysis of CZT SPECT images

The SPECT acquisitions were initiated approximately 30 min after tracer injection, with the patients set in a semi-reclining prone position (Fig. 1) and the thoracic heart area in contact with the camera head, at 35° from vertical (a surrogate of prone position with this camera). By using the myocardial count rate from the pre-scan acquisition, the time per projection was set to target the recording of 500 myocardial kcounts. Reconstruction was conducted with a specific algorithm of iterative reconstruction using previously described parameters [7, 13].

SPECT and gated SPECT images from both angiography and low-probability subgroups were re-analysed sensually by two blinded experienced observers, whereas results from the other exams were extracted from routine medical reports. Myocardial perfusion was routinely assessed visually by using the 17-segment model of the left ventricle (LV) and a conventional 4-point grading system: 0, normal uptake; 1, equivocal; 2, moderate; and 3, severe reduction of uptake [7, 23, 24]. Only segments with an uptake score≥2 at stress were considered to have a definite uptake reduction. Of these, (1) segments with reversible defects (ischaemic segments) were defined as those with a≥1-point decrease in uptake score on the rest acquisition and (2) the other segments were considered to have a fixed defect (myocardial infarction segments) except for those with a definitely normal contractility on gated SPECT and for which the final diagnosis was attenuation artefact [5, 7]. The segments with attenuation artefact were excluded for the final definition of the stress defects area.

## Coronary angiography

Invasive coronary angiography was routinely conducted according to standard techniques. Coronary angiograms were re-analysed by a blinded experienced observer. Per cent diameter reductions in coronary stenosis were determined visually on end-diastolic frames and with the help of a quantitative angiography software (Medcon analysis software, McKesson Israel Ltd) for those stenoses visually determined to be around the 50 % threshold. All stenoses with >50 % diameter reduction were considered to correspond to a significant obstructive CAD, except when supplied by patent bypass grafts.

## Statistical analysis

Continuous variables are reported as mean±SD and categorical variables as percentages. Unpaired comparisons were performed with analysis of variance (ANOVA) tests for continuous variables and with chi-square tests for categorical variables. For all tests, a *p* value<0.05 was considered to reflect a significant difference.

## Results

### Patient characteristics

A total of 2,845 stress MPI exams were performed with the low-dose protocol using the D-SPECT camera during the year 2012, all of which were considered for the present study. As detailed in Table 2, the mean age of corresponding patients was 62±11 years, of whom 34 % were women, 34 % were obese [body mass index (BMI)>30 kg m⁻²] and 40 % were overweight (BMI>25—to 30 kg m⁻²). The stress test involved only physical exercise in 81 % of cases, while 67 % of stress MPI were considered as normal.

<figure><img src="image_49.png" /><figcaption>**Fig. 1** SPECT recording in semi-reclining prone position with the D-SPECT camera</figcaption></figure>
<table><caption>**Table 2** Main parameters recorded in the overall study population as well as in the angiography and low-probability subgroups</caption><thead><tr><th></th><th>Overall MPI<br>exams<br>n=2,845</th><th>Angiography<br>subgroup<br>n=149</th><th>Low-probability<br>subgroup<br>n=128</th></tr></thead><tbody><tr><td>Age (years)</td><td>62±11</td><td>64±12</td><td>47±8*</td></tr><tr><td>Female gender</td><td>964 (34 %)</td><td>31 (20 %)*</td><td>111 (87 %)*</td></tr><tr><td>Weight (kg)</td><td>82±17</td><td>83±16</td><td>75±20*</td></tr><tr><td>Height (m)</td><td>1.69±0.09</td><td>1.71±0.09*</td><td>1.64±0.08*</td></tr><tr><td>BMI (kg m<sup>-2</sup>)</td><td>29±6</td><td>28±5</td><td>28±8</td></tr><tr><td>Obesity</td><td>959 (34 %)</td><td>48 (30 %)</td><td>43 (33 %)</td></tr><tr><td>Nb. of stress-only MPI</td><td>1,054 (37 %)</td><td>8 (5 %)*</td><td>92 (71 %)*</td></tr><tr><td>Injected activities (MBq)</td><td></td><td></td><td></td></tr><tr><td>Stress</td><td>142±37</td><td>145±40</td><td>131±44*</td></tr><tr><td>Rest <sup>a</sup></td><td>425±106</td><td>428±114</td><td>356±88*</td></tr><tr><td>Total</td><td>410±235</td><td>555±177*</td><td>234±170*</td></tr><tr><td>Effective doses (mSv) <sup>b</sup></td><td></td><td></td><td></td></tr><tr><td>For stress</td><td>1.12±0.29</td><td>1.14±0.31</td><td>1.04±0.33*</td></tr><tr><td>For rest <sup>a</sup></td><td>3.83±0.96</td><td>3.88±3.83</td><td>3.21±0.79*</td></tr><tr><td>Total</td><td>3.53±2.10</td><td>4.83±1.56*</td><td>1.96±1.52*</td></tr><tr><td>Stress test</td><td></td><td></td><td></td></tr><tr><td>Exercise</td><td>2,305 (81 %)</td><td>113 (76 %)</td><td>120 (94 %)*</td></tr><tr><td>Dipyridamole</td><td>540 (19 %)</td><td>36 (24 %)</td><td>8 (6 %)*</td></tr><tr><td>Abnormal MPI</td><td>938 (33 %)</td><td>110 (74 %)*</td><td>4 (3 %)*</td></tr></tbody></table>

BMI body mass index, MPI myocardial perfusion SPECT imaging

*p*<0.05 for comparison between the considered subgroup and the remaining exams from the overall population

<sup>a</sup>The corresponding mean±SD values are determined only in patients having rest imaging

<sup>b</sup>Effective doses were determined, in each patient, by the products of injected activities (MBq) times 0.0079 for stress and times 0.009 mSv for rest [25] and by the sum of stress and rest effective doses for the total effective dose

Among the above 2,845 MPI exams, 128 were placed in the “low-probability” subgroup and 149 were placed in the “angiography” subgroup. As detailed in Table 2, the patients from the low-probability subgroup were younger, more frequently female and had much lower rates of abnormal MPI and of pharmacological stress tests when compared to the others. In contrast, the patients from the angiography subgroup were older, more frequently male and had a much higher rate of abnormal MPI when compared with the others.

Among the 149 patients in the coronary angiography subgroup, 82 (55 %) had a previous history of CAD (63 myocardial infarctions and 68 myocardial revascularizations), while in the 67 remaining patients, the pretest probability of CAD based on age, sex and symptoms [21] was low in 41, intermediate in 20 and high in 6. At coronary angiography, 106 (71 %) had at least one>50 % stenosis, 39 (26 %) had single-vessel disease, 46 (31 %) had double-vessel disease and 21 (14 %)

had triple-vessel disease. Additional details regarding the characteristics of this subgroup are provided in Table 3.

Effective doses

As detailed in Table 2, 37 % of the overall 2,845 exams involved stress MPI only, while the remaining 63 % involved both stress and rest MPI. The total effective dose per patient was 3.53±2.10 mSv, on average. This mean level corresponded to a 29 % reduction when compared with the mean dose of 4.96±1.28 mSv which would have been attained if rest MPI had been prescribed in all patients.

As detailed in Fig. 2, effective doses varied according to the patients’ BMI status and to the prescription of rest MPI. These doses ranged from 0.88±0.16 mSv in normal-weight subjects with only stress images to 6.03±1.37 mSv in obese subjects with both stress and rest images. Forty per cent of the obese subjects had stress-only MPI and their mean effective dose level was limited to 1.36±0.31 mSv.

<table><caption>**Table 3** Additional patient characteristics and results from MPI and coronary angiography in the angiography subgroup (n=149)</caption><thead><tr><th>Characteristic</th><th></th></tr></thead><tbody><tr><td>Chest pain</td><td>60 (40 %)</td></tr><tr><td>Medical history</td><td></td></tr><tr><td>Previous history of CAD</td><td>82 (55 %)</td></tr><tr><td>Myocardial infarction</td><td>63 (42 %)</td></tr><tr><td>Coronary angioplasty</td><td>60 (40 %)</td></tr><tr><td>Bypass grafting</td><td>19 (13 %)</td></tr><tr><td>Hypertension</td><td>94 (63 %)</td></tr><tr><td>Diabetes</td><td>46 (31 %)</td></tr><tr><td>Dyslipidaemia</td><td>87 (58 %)</td></tr><tr><td>Delay D-SPECT<br>angiography (days)</td><td>26±19</td></tr><tr><td>Coronary anatomy</td><td></td></tr><tr><td>0-vessel disease</td><td>43 (29 %)</td></tr><tr><td>1-vessel disease</td><td>39 (26 %)</td></tr><tr><td>2-vessel disease</td><td>46 (31 %)</td></tr><tr><td>3-vessel disease</td><td>21 (14 %)</td></tr><tr><td>LAD artery stenosis</td><td>69 (46 %)</td></tr><tr><td>LCx artery stenosis</td><td>62 (42 %)</td></tr><tr><td>RCA stenosis</td><td>63 (42 %)</td></tr><tr><td>Stress and MPI</td><td></td></tr><tr><td>ST segment depression</td><td>21 (14 %)</td></tr><tr><td>Abnormal stress images</td><td>110<br>(74 %)</td></tr><tr><td>Extent (no. of segments)</td><td>2.9±2.6</td></tr><tr><td>Ischaemic pattern</td><td>89 (60 %)</td></tr><tr><td>Extent (no. of segments)</td><td>1.6±1.8</td></tr><tr><td>Necrotic pattern</td><td>58 (39 %)</td></tr><tr><td>Extent (no. of segments)</td><td>1.3±2.1</td></tr><tr><td>Post-stress LV ejection<br>fraction</td><td>51±14 %</td></tr></tbody></table>
Effective doses (mSv)

<figure><img src="image_50.png" /><figcaption>**Fig. 2** Mean effective doses according to: (1) performance of stress acquisitions only (white columns) or of both stress and rest acquisitions (grey columns) and (2) BMI status, i.e. normal weight (<25 kg/m²), overweight (>25–30 kg/m²) and obesity (>30 kg/m²)</figcaption></figure>

In the low-probability subgroup, as many as 71 % of exams involved only stress MPI, leading to a very limited effective dose level of 1.96±1.52 mSv. In the angiography subgroup, by contrast, the performance of only stress MPI was very uncommon (5 %), leading to a higher effective dose level of 4.83±1.56 mSv.

MPI results and correlation with coronary anatomy

Results of MPI exams in the angiography subgroup are detailed in Table 3 and Fig. 3. Mean recorded myocardial activities were 548±85 kcounts at stress and 581±133 kcounts at

Positive MPI exams (%)

<figure><img src="image_51.png" /><figcaption>**Fig. 3** Percentages of positive MPI exams: (1) in the low-probability subgroup and (2) in the angiography subgroup according to the number of vessel diseases (VD). The black columns represent the results from the overall angiography subgroup and the grey columns the results obtained after exclusion of patients with previous history of CAD</figcaption></figure>

rest. Corresponding recording times were 7.7±1.9 and 2.7±0.9 min, respectively. The rate of detection of abnormal stress MPI was 74 % (110/149); this criterion was associated with a sensitivity of 88 % (93/106) for the detection of patients with >50 % coronary stenosis along with a specificity of 61 % (26/43) and a global accuracy of 80 % (119/149).

Equivalent results were documented when analysing obese subjects (sensitivity 90 %, specificity 69 % and global accuracy 80 %) or women (sensitivity 88 %, specificity 75 % and global accuracy 83 %) separately, two categories considered to provide high rates of attenuation artefacts with conventional cameras.

When the analysis was restricted to those patients who had no previous history of CAD (neither myocardial infarction nor myocardial revascularization), sensitivity was 80 %, specificity 71 % and global accuracy 76 %. As evidenced in Fig. 3, the sensitivity was variable according to the number of vessel diseases. An example of the SPECT images obtained in a patient with single-vessel disease is given in Fig. 4.

Finally, among the 128 patients from the low-probability subgroup, only 4 had an abnormal MPI exam, leading to a normalcy rate of 97 % (Fig. 3). This rate remained very high in the separate analyses of obese subjects (100 %) and women (96 %).

Discussion

Until recently, given the risks associated with cumulative exposure to ionizing radiation, MPI exams have been confronted with the need to provide a lower radiation exposure, although this difficulty can now be overcome by high-sensitivity CZT cameras, especially when associated with low-dose stress-first protocols, as evidenced by results obtained in the present study.

With this latter protocol, only a mean of 142 MBq of sestamibi was routinely injected at stress. Conversely, doses recommended for conventional cameras are three- to fourfold higher according to the European Society of Nuclear Medicine (400–500 MBq [5, 25]) and two- to threefold higher according to the American Society of Nuclear Medicine (300–400 MBq [6]). The present dose reduction was rendered possible by the dramatic increase in sensitivity provided by the D-SPECT CZT camera, a factor of 6 to 10 compared to conventional cameras, along with a concomitant improvement in image quality [7, 12, 13]. Because of this high sensitivity, recording times were also able to be additionally limited to a mean of 7–8 min for stress acquisitions and of 2–3 min for rest acquisitions, leading to enhanced patient tolerance and reduced risk of motion-related artefacts.

Artefacts may also result from a low-count recording when low tracer activity is injected at stress, particularly in patients with a high BMI [8, 9]. In a previous multicentre study, we
**Fig. 4** Example of an ischaemic area (white arrows on left panel) related to stenosis of a diagonal coronary artery branch (red arrow on right panel) in a 69-year-old male patient from the angiography subgroup. Body weight was 65 kg and injected activities were 92 MBq at stress and 277 MBq at rest, leading to a total effective dose of 3.2 mSv. Recorded myocardial activities were 524 kcounts at stress and 629 kcounts at rest, and corresponding recording times were 5 min 42 s and 2 min 43 s, respectively. R rest, S stress

<figure><img src="image_52.png" /></figure>

found that the greater count density provided by the D-SPECT camera helped in preventing such low-count artefacts, especially in obese patients [7]. In the present study, acquisition times were adapted to target the recording of 500 myocardial kcounts in order to prevent these particular artefacts.

Injected activities were slightly increased in our obese subjects but nonetheless remained at a low level, leading to mean effective doses of 6 mSv when both stress and rest imaging were performed and of 1.4 mSv when only stress MPI was performed (Fig. 2). Moreover, obese subjects also had high rates of normal MPI in the low-probability group (100 %), along with concordant results obtained with coronary angiography (80 % global accuracy), providing evidence that this very low-dose protocol is also very efficient in obese subjects.

The high normalcy rate, which was documented in our low-probability group, could be explained by the greater image quality and count density provided by the D-SPECT camera, especially in the obese subjects, as discussed above. In previous studies, image quality was indeed consistently shown to be higher with CZT than with Anger cameras, while the rate of low image quality, leading to difficulties in image analysis, was reduced to only 2.5 % with the D-SPECT camera [7]. This high count density not only helps prevent low-count artefacts on perfusion SPECT images, but is also likely to facilitate the differentiation between attenuation and infarct areas on gated SPECT images.

In the overall study population, correlation with the presence of >50 % stenosis was high, with a global accuracy near 80 %, a value similar to those previously documented in a number of studies performed with comparable methodology and no correction for referral bias [26]. In such retrospective studies, referral biases are likely to favour sensitivity (high prevalence of severe CAD) and moreover to hinder specificity (most true-negative MPIs are not referred for coronary angiography and may not be included) [26]. However, our results demonstrate that sensitivity remained relatively high, even for

the less severely ill patients with only single-vessel disease (≥70 %, see Fig. 3). In addition, specificity was relatively low (from 60 to 70 %, see Fig. 3) but likely to be underestimated, similarly to that commonly observed in a comparable retrospective study [26]. However, the normalcy rate, which may be used as a surrogate for true specificity [26], reached as high as 97 %.

The high quality of the low-dose stress images is likely one of the reasons why rest imaging could be avoided in as many as 37 % of cases in our overall population. Until recently, it was frequently preferred to use the rest-first protocols and to inject the higher doses at stress [10, 11]. These protocols led, on the one hand, to favouring visualization of stress-induced perfusion abnormalities but also to increasing body radiation, when compared with stress-first protocols (rest images are always prescribed). In the present study, the withdrawing of 37 % of rest MPI acquisitions led to an additional 29 % reduction in radiation dose in the overall population, reaching a mean level of 3.53 mSv. This level is four times lower than that attained in a conventional protocol where 400 MBq would be injected at stress along with an additional threefold dose at rest (corresponding effective dose of 14 mSv) [5, 6, 25].

While there are currently no strong data associating ionizing radiation specifically resulting from cardiac imaging to increased risks of cancer, there is nonetheless a concern with regard to the risk of cancer in the long term for the growing number of patients who are referred for repeat ionizing procedures throughout their lifetime [1, 4]. Radiation doses from medical imaging have dramatically increased in the last 2 decades with cardiac imaging being a major contributor to this increase [1, 4]. High cumulative doses of radiation, sometimes higher than 100 mSv, have been documented in certain subgroups of hospitalized patients with ischaemic heart disease [3], but also in patients undergoing repeat MPI [2]. However, although certainly a matter of concern, these radiation doses
should not be viewed in isolation but rather within the clinical
context where radiation risk is balanced against potential
benefits [2, 4].

The present low-dose protocol provides a dramatic de-
crease in radiation dose, with this decrease being even steeper
in the low-risk subgroups, which are likely to exhibit high
rates of normal stress images, a strong indicator of an excellent
prognosis [6, 22, 23]. On a population scale, this ultimately
leads to balance the mean level of radiation against that of
cardiac risk and, thus, with the potential benefit for further
changes in cardiac medical management. This point is best
illustrated by the observation that the mean effective dose
was only 1.96 mSv in our low-risk subgroup as opposed to
2.5-fold higher (4.83 mSv) in the higher-risk subgroup of
patients referred for coronary angiography.

However, the 67 % of normal MPI exams documented in
the overall study population largely exceeded the 37 % of
stress-only MPI. Images from both stress and rest MPI were
frequently required to reach a definite diagnosis of a normal
exam, especially in the cases of attenuation artefacts. It may be
speculated that if no rest MPI had been scheduled in all cases
of normal MPI exams, the mean effective dose would have
averaged 2.32 mSv, leading to an additional 34 % decrease
compared with the actual level of 3.53 mSv.

Therefore, it is likely that patient radiation exposure could
be even lower if image quality were further enhanced and
attenuation artefacts minimized. The development of efficient
attenuation correction methods is highly suitable in this set-
ting. The semi-reclining prone position, which can be used
with the D-SPECT camera, is also likely to lower the rate of
certain artefacts, although the usefulness of other and possibly
additional recording positions needs to be further ascertained.

This pilot study has several limitations. First, effective
doses were determined while neglecting the few percentages
of activity remaining within the syringe after injection. This
percentage, systematically determined in previous series in
our department, was found to be lower than 5 %, on average.
However, it should be recognized that the actual effective
doses may be a few percentages lower than those reported
herein. Second, as already pointed out above, our retrospec-
tive analysis of patients having both coronary angiography
and stress SPECT likely leads to referral biases. Under these
conditions, the actual values of sensitivity and specificity for
detecting significant coronary stenosis may not have been
determined. However, the present study does show that these
diagnostic parameters were as high as those documented in
comparable retrospective studies conducted with conventional
cameras [26] and more recently with CZT cameras [14–17,
27–31], in spite of dramatically lower radiation doses.

Low-dose protocols have already been assessed with an-
other type of CZT camera [14–16, 27–29], although all led to a
mean patient radiation ranging between 5 and 8 mSv and thus
at a much higher mean level than that attained in the present

study (3.5 mSv). Indeed, these previous studies involved a
protocol where rest images were always scheduled in associ-
ation with stress images. While these studies also involved up
to a 50 % reduction in injected doses compared to convention-
al protocols, this reduction was even more substantial in the
present series, in the range of two thirds on average, due to the
twofold higher count sensitivity provided by the D-SPECT
camera [12].

In conclusion, when planned with a low-dose stress-first
protocol on a CZT camera, MPI is likely to provide both high
diagnostic performances and a dramatic reduction in patient
radiation doses. This reduction is even greater in low-risk
subgroups with high rates of normal stress images, thus en-
abling the mean radiation dose to be balanced against cardiac
risk in targeted populations.

**Acknowledgments** The authors thank Pierre Pothier for critical review of the manuscript and the Nancyclotep experimental imaging platform for organizational support.

Compliance with ethical standards

**Conflicts of interest** None.

**Statement of human rights** For this type of study formal consent from participants is not required.

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<figure><img src="image_53.png" /></figure>

# Integration of dynamic parameters in the analysis of ¹⁸F-FDopa PET imaging improves the prediction of molecular features of gliomas

Merwan Ginet<fnref n="1" /> · Timothée Zaragori<fnref n="1" />,<fnref n="2" /> · Pierre-Yves Marie<fnref n="1" />,<fnref n="3" /> · Véronique Roch<fnref n="1" /> · Guillaume Gauchotte<fnref n="4" />,<fnref n="5" /> · Fabien Rech<fnref n="6" />,<fnref n="7" /> · Marie Blonski<fnref n="6" />,<fnref n="7" /> · Zohra Lamiral<fnref n="3" /> · Luc Taillandier<fnref n="7" />,<fnref n="8" /> · Laëtitia Imbert<fnref n="1" />,<fnref n="2" /> · Antoine Verger<fnref n="1" />,<fnref n="2" /> ID

Received: 24 April 2019 / Accepted: 23 August 2019

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

## Abstract

**Purpose** ¹⁸F-FDopa PET imaging of gliomas is routinely interpreted with standardized uptake value (SUV)-derived indices. This study aimed to determine the added value of dynamic ¹⁸F-FDopa PET parameters for predicting the molecular features of newly diagnosed gliomas.

**Methods** We retrospectively included 58 patients having undergone an ¹⁸F-FDopa PET for establishing the initial diagnosis of gliomas, whose molecular features were additionally characterized according to the WHO 2016 classification. Dynamic parameters, involving time-to-peak (TTP) values and curve slopes, were tested for the prediction of glioma types in addition to current static parameters, i.e., tumor-to-normal brain or tumor-to-striatum SUV ratios and metabolic tumor volume (MTV).

**Results** There were 21 IDH mutant without 1p/19q co-deletion (IDH+/1p19q−) gliomas, 16 IDH mutants with 1p/19q co-deletion (IDH+/1p19q+) gliomas, and 21 IDH wildtype (IDH−) gliomas. Dynamic parameters enabled differentiating the gliomas according to these molecular features, whereas static parameters did not. In particular, a longer TTP was the single best independent predictor for identifying (1) IDH mutation status (area under the curve (AUC) of 0.789, global accuracy of 74% for the criterion of a TTP ≥ 5.4 min) and (2) 1p/19q co-deletion status (AUC of 0.679, global accuracy of 69% for the criterion of a TTP ≥ 6.9 min). Moreover, the TTP from IDH− gliomas was significantly shorter than those from both IDH+/1p19q− and IDH+/1p19q+ (*p* ≤ 0.007).

**Conclusion** Prediction of the molecular features of newly diagnosed gliomas with ¹⁸F-FDopa PET and especially of the presence or not of an IDH mutation, may be obtained with dynamic but not with current static uptake parameters.

**Keywords** ¹⁸F-FDopa PET · Dynamic analysis · Glioma · Diagnosis · WHO 2016 classification · IDH mutation

Merwan Ginet and Timothée Zaragori contributed equally to this work.

This article is part of the Topical Collection on Oncology – Brain

**Electronic supplementary material** The online version of this article (https://doi.org/10.1007/s00259-019-04509-y) contains supplementary material, which is available to authorized users.

<figure><img src="image_54.png" /></figure>

Antoine Verger

a.verger@chru-nancy.fr

<figure><img src="image_55.png" /></figure>

<footnote n="1">¹ CHRU-Nancy, Department of Nuclear Medicine & Nancyyclotep Imaging platform, Université de Lorraine, F-54000 Nancy, France</footnote>

<footnote n="2">² IADI, INSERM, UMR 1254, Université de Lorraine, F-54000 Nancy, France</footnote>

<footnote n="3">³ Université de Lorraine, INSERM U1116, F-54000 Nancy, France</footnote>

<footnote n="4">⁴ CHRU-Nancy, Department of Pathology, Université de Lorraine, F-54000 Nancy, France</footnote>

<footnote n="5">⁵ INSERM U1256, Université de Lorraine, F-54000 Nancy, France</footnote>

<footnote n="6">⁶ Department of Neurosurgery, CHU-Nancy, F-54000 Nancy, France</footnote>

<footnote n="7">⁷ Centre de Recherche en Automatique de Nancy CRAN, CNRS UMR 7039, Université de Lorraine, F-54000 Nancy, France</footnote>

<footnote n="8">⁸ CHRU-Nancy, Department of Neuro-oncology, Université de Lorraine, F-54000 Nancy, France</footnote>
**Introduction**

The radiolabeled amino acid positron emission tomography (PET) imaging of gliomas is increasingly used for diagnostic and prognostic purposes, both for treatment planning and for tumor monitoring (whether under oncological treatment or without any treatment), including the specific diagnosis of glioma recurrence [1–5]. The Response Assessment in Neuro-Oncology (RANO) working group has recommended its use in these settings as a complement to standard magnetic resonance imaging (MRI) [6].

Until now, studies with 6-[¹⁸F]fluoro-L-DOPA (¹⁸F-FDopa), an amino acid PET radiotracer approved and currently used in Europe for assessing recurrent brain tumors [7–10], have been mainly performed using standard uptake value (SUV)-derived indices such as tumor-to-brain or tumor-to-striatum ratios [7–9, 11, 12]. Albeit less used in routine practice, the metabolic tumor volume (MTV) has also been shown to be informative in this setting [13]. However, this standard analysis does not take into account the dynamic information previously shown to markedly improve the grading of gliomas, although this improvement was established for PET recorded with O-(2-[¹⁸F]fluoroethyl)-L-tyrosine (¹⁸F-FET), another amino acid radiotracer extensively used in glioma imaging [14, 15]. In these dynamic ¹⁸F-FET studies, low-grade gliomas typically show a continuous increasing slope with a late time-to-peak, as opposed to an early time-to-peak, followed by a steeper slope in high-grade gliomas [14, 15]. Dynamic data of ¹⁸F-FDopa were previously analyzed in only a few pilot studies [16–18], without considering the molecular characteristics involved in the World Health Organization (WHO) 2016 classification of gliomas, and only by modeling tracer kinetics with multi-compartmental models [19]. For routine ¹⁸F-FET PET imaging, it has however been shown that a much more simple analysis of time-activity curves can provide key information for tumor characterization [14, 15].

In addition, the WHO classification of gliomas has recently been upgraded with the introduction of molecular parameters including IDH (isocitrate dehydrogenase enzyme isoform) mutation and 1p/19q co-deletion, leading to improve the link with patient prognosis [19]. In particular, the presence of an IDH mutation at initial diagnosis is strongly associated with an enhanced prognosis [19]. The correspondence with this new glioma classification has since been analyzed for PET performed with amino acids other than ¹⁸F-FDopa [20–23] or more recently with ¹⁸F-FDopa PET using only static parameters and with inconclusive results [24]. Notwithstanding the latter, the potential effect of IDH mutation on ¹⁸F-FDopa uptake has been suggested in diffuse gliomas [25, 26].

In light with the above, this study aimed to determine the added value of dynamic ¹⁸F-FDopa PET parameters for predicting the molecular features of newly diagnosed gliomas according to the WHO 2016 classification.

**Material and methods**

**Patients**

Consecutive patients in whom ¹⁸F-FDopa PET imaging was performed for a newly diagnosed glioma were retrospectively selected, and only those for whom the dynamic PET parameters and the features of IDH mutation and 1p/19q co-deletion status were available according to the WHO 2016 classification [19], were included for the final analysis. In addition, the time window between PET imaging and neuropathological confirmation was 56.0 (9.3; 109.0) days [8]. A flowchart describing patient selection is provided in Supplemental Fig. 1. The local ethics committee (Comité d'Ethique du CHRU de Nancy) approved the retrospective data evaluation on June 7, 2018, and the CNIL (National Commission on Information Technology and Liberties) number authorization was delivered on June 25, 2018 (R2018-11). This research complied with the principles of the Declaration of Helsinki. Informed consent was obtained from all individuals included in the study.

**PET recording and reconstruction**

¹⁸F-FDopa PET-computed tomography (CT) scans were obtained on a Biograph hybrid system involving a six-detector CT for attenuation correction (Biograph 6 True Point, SIEMENS, Erlangen, Germany). Patients were instructed to fast for at least 4 h and certain patients received Carbidopa administration 1 h prior to their exam, the latter having been shown to increase striatal dopaminergic activity [27], as well as brain tumor uptake [16]. The CT scan was first recorded and immediately followed by a 30-min 3D list-mode PET recording initiated during the bolus injection of 3 MBq of ¹⁸F-FDopa per kilogram of body weight. The static PET images were reconstructed with the list-mode data acquired from 10 to 30-min post-injection [9, 28] while the dynamic PET images involved 6 consecutive frames of 20 s each followed by 28 frames of 1 min each [18].

All images were reconstructed with an OSEM 2D algorithm (2 iterations, 21 subsets, 4-mm Gaussian post-reconstruction filter), corrected for attenuation, scatter, and radioactive decay, and displayed in a 256 × 256 matrix with 2.7 × 2.7 × 3.0 mm³ voxels.

**Analyses of PET images**

Different regions of interest (ROIs) were placed on the static PET images using a dedicated software (Oasis, Nicesoft, Paris, France). These consisted of two spherical ROIs of 2-cm diameter each, the first of which was centered on the tumor area of maximum uptake [17] for determining maximal and mean standardized uptake values (SUVmax and SUVmean, respectively) of the tumor, and the second on the contralateral basal ganglia for the computing of tumor-to-striatum (TSR)
ratios. An elliptic ROI (2 × 4 cm) was additionally positioned on the semi-oval center of the unaffected contralateral hemisphere, including white and gray matter [9], for the computing of tumor-to-normal brain (TBR) ratios. TSR and TBR were computed as SUV<sub>mean</sub> or SUV<sub>max</sub> of the tumor divided by the SUV<sub>mean</sub> of the striatum (TSR<sub>mean</sub> and TSR<sub>max</sub>) or of normal brain (TBR<sub>mean</sub> and TBR<sub>max</sub>).

The tumor could not be detected on ¹⁸F-FDopa PET images (TBR<sub>max</sub> < 1.6) in 10 cases where the tumor ROIs were placed at the site of the MRI abnormalities with a fused display of PET and Fluid Attenuation Inversion Recovery (FLAIR) MRI images [9].

As previously described, the metabolic tumor volume (MTV) was obtained through a 3D auto-contouring process with a threshold corresponding to the SUV<sub>mean</sub> of the contralateral striatum [13].

In addition, given that TBR values are likely to be much less influenced by Carbidopa premedication than SUV, time-activity curves, representing the evolution of the TBR<sub>mean</sub> as a function of time (TAC<sub>ratio</sub>), were extracted with the PLANET® Dose software (DOSIsoft, Cachan, France) and with the ROIs previously placed on the static images (see above). Each dynamic frame was previously registered on the CT images, to take into account potential patient movements during acquisitions [29]. Two dynamic parameters were determined from fitted curves to overcome noise effects, using a method already validated for ¹⁸F-FET in the same setting [30], namely (i) time-to-peak (TTP), corresponding to the delay between the beginning of the dynamic acquisition (time of tracer injection) and the time-point of the maximal TBR<sub>mean</sub> value and (ii) the slope from the 10th minute of the TBR<sub>mean</sub>-based curve, calculated through linear regressions applied on the 10th to 30th minute interval.

## Pathological grading of gliomas

Glioma classification according to the WHO 2016 standard was obtained from tumor samples provided by surgery or stereotactic biopsy [19]. IDH mutation status was assessed by immunohistochemistry with IDH1 R132H protein expression (Dianova, clone H09), or Sanger sequencing in case of ATRX immunohistochemical loss without IDH1 R132H staining [31]. Tumors presenting oligodendroglial morphology or showing IDH mutation without ATRX loss were additionally tested for 1p/19q co-deletion using multiplex PCR fragment analysis (loss of heterozygosity), or comparative genomic hybridization [26].

## Statistical analysis

Categorical variables are expressed as percentages and continuous variables as medians (first quartile, third quartile). Intergroup comparisons were performed with Chi-squared tests for categorical variables and Mann-Whitney tests or Kruskal-Wallis tests for continuous variables. In the first step,

Mann-Whitney tests were performed between gliomas with and without IDH mutation and additionally between gliomas with and without a 1p/19q co-deletion. A multivariate model including both static and dynamic parameters was applied for parameters reaching a sufficiently high level of significance at univariate analysis (probability value equal or less than 0.1). In the second step, Kruskal-Wallis tests were performed between the three following glioma groups: IDH mutant without 1p/19q co-deleted gliomas, IDH mutant with 1p/19q co-deleted gliomas, and IDH wildtype gliomas. Probability values of less than 0.05 were considered significant.

Receiver-operating-characteristic (ROC) curves were also tested for the prediction of molecular parameters (i.e., IDH mutation and 1p/19q co-deletion) by static and dynamic PET parameters. Optimal threshold values, extracted from the ROC curves, were considered to be those associated with the maximal value of the product of sensitivity by specificity. Analyses were performed with the SPSS (SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp) software package.

## Results

### Patients

Fifty-eight patients (44.8 (34.2, 59.4) years old, 20 women) were retrospectively selected with histological diagnosis obtained by surgery (n = 34) or biopsy (n = 24): 21 IDH mutant without 1p/19 co-deletion (IDH+/1p19q−) gliomas, 16 IDH mutant with 1p/19q co-deletion (IDH+/1p19q+) gliomas, and 21 with IDH wildtype (IDH−) gliomas, according to the WHO 2016 classification (Table 1). Contrast enhancement on T1-weighted gadolinium-injected MRI was observed in 7 (33.3%) patients with IDH+/1p19q− gliomas, 2 (12.5%) patients with IDH+/1p19q+ gliomas, and 10 (47.6%) patients with IDH− gliomas (Table 1). The 10 tumors that could not be detected with ¹⁸F-FDopa PET (TBR<sub>max</sub> < 1.6) were only diffuse gliomas involving 5 IDH+/1p19q− gliomas (23.8% of this population), 2 IDH+/1p19q+ gliomas (12.5% of this population) and 3 IDH− gliomas (14.3% of this population) (Table 1). No significant difference in Carbidopa premedication (p = 0.27) was noted among the 3 glioma groups (i.e., (i) IDH+/1p19q−, (ii) IDH+/1p19q+, and (iii) IDH− groups). All static and dynamic PET parameters did not significantly differ between anaplastic (grade III WHO 2016) and non-anaplastic gliomas (grade II WHO 2016) (p > 0.54).

### Prediction of the IDH mutation and 1p/19q co-deletion statuses

Results of univariate analyses are depicted in Table 2 and ROC curves in Figs. 1 and 2. As detailed in Table 2, only dynamic parameters (i.e., TTP and slope) were significant univariate PET predictors of the IDH mutation status (for
<table><caption>**Table 1** Patient characteristics</caption><thead><tr><th rowspan="2"></th><th colspan="3">Patients</th><th rowspan="2">Age (years), median (Q1, Q3)</th><th rowspan="2">Female gender, n (%)</th></tr><tr><th>All (n = 58), n (%)</th><th>TBR<sub>max</sub> &lt; 1.6 (n = 10), n (%)</th><th>CE on MRI (n = 19), n (%)</th></tr></thead><tbody><tr><td>IDH+/1p19q- astrocytomas</td><td>12 (20.7%)</td><td>3 (30.0%)</td><td>4 (21.1%)</td><td>IDH+/1p19q- gliomas (n = 21)</td><td>37.3 (30.2, 49.9)</td><td>7 (33.3%)</td></tr><tr><td>Anaplastic IDH+/1p19q- astrocytomas</td><td>8 (13.8%)</td><td>2 (20.0%)</td><td>2 (10.5%)</td><td></td><td></td><td></td></tr><tr><td>IDH+/1p19q- glioblastomas</td><td>1 (1.7%)</td><td>0 (0.0%)</td><td>1 (5.3%)</td><td></td><td></td><td></td></tr><tr><td>IDH+/1p19q+ oligodendrogliomas</td><td>7 (12.1%)</td><td>0 (0.0%)</td><td>1 (5.3%)</td><td>IDH+/1p19q+ gliomas (n = 16)</td><td>38.8 (34.9, 58.2)</td><td>5 (31.3%)</td></tr><tr><td>Anaplastic IDH+/1p19q+ oligodendrogliomas</td><td>9 (15.5%)</td><td>2 (20.0%)</td><td>1 (5.3%)</td><td></td><td></td><td></td></tr><tr><td>IDH- astrocytomas</td><td>6 (10.3%)</td><td>1 (10.0%)</td><td>0 (0.0%)</td><td>IDH- gliomas (n = 21)</td><td>58.6 (40.8, 69.5)†</td><td>8 (38.1%)</td></tr><tr><td>Anaplastic IDH- astrocytomas</td><td>5 (8.6%)</td><td>2 (20.0%)</td><td>1 (5.3%)</td><td></td><td></td><td></td></tr><tr><td>IDH- glioblastomas</td><td>10 (17.2%)</td><td>0 (0.0%)</td><td>9 (47.4%)</td><td></td><td></td><td></td></tr><tr><td></td><td colspan="3">p value</td><td>0.016*</td><td>0.901</td><td></td></tr></tbody></table>

CE, contrast enhancement; *IDH+/1p19q*, IDH mutant without 1p/19q co-deletion gliomas; *IDH+/1p19q+*, IDH mutant with 1p/19q co-deletion gliomas; *IDH-*, IDH wildtype gliomas; *TBR*, tumor-to-brain ratio

TTP *p* < 0.001, area under the curve (AUC) = 0.789, and for slope *p* = 0.013 and AUC = 0.698) whereas TTP was the sole significant predictor of the 1p/19q co-deletion status (*p* = 0.034 and AUC = 0.679). The global accuracies for predicting the IDH mutation status reached 74% (sensitivity 76%, specificity 73%) when using the criterion of a TTP ≥ 5.4 min, and 62% (sensitivity 67%, specificity 59%) when using the criterion of a slope ≥ − 0.39 h⁻¹ (Fig. 1). For the prediction of the 1p/19q co-deletion status, a global diagnostic accuracy of 69% (sensitivity 69%, specificity 69%) was achieved when using

the criterion of a TTP ≥ 6.9 min (Fig. 2). No static parameter reached a sufficiently high level of significance at univariate analysis (Table 2) to be tested in a multivariate model together with the significant univariate dynamic parameters (Fig. 3).

**Prediction of IDH+/1p19q- gliomas, IDH+/1p19q+ gliomas, and IDH- gliomas**

Intergroup comparisons of PET parameters in each of the three glioma groups are given in Table 3. TTP was the only

<table><caption>**Table 2** Results of the univariate analyses for predicting IDH mutation and 1p/19q co-deletion statuses with the considered static and dynamic PET variables</caption><thead><tr><th>Parameter</th><th>p value</th><th>AUC</th><th>Cut-off</th><th>Sensitivity</th><th>Specificity</th><th>Accuracy</th></tr></thead><tbody><tr><td colspan="7">IDH mutation status</td></tr><tr><td>TSR<sub>mean</sub></td><td>0.704</td><td>NS</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>TSR<sub>max</sub></td><td>0.955</td><td>NS</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>TBR<sub>mean</sub></td><td>0.523</td><td>NS</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>TBR<sub>max</sub></td><td>0.734</td><td>NS</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>MTV (mL)</td><td>0.740</td><td>NS</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>TTP (min)</td><td>&lt; 0.001*</td><td>0.789</td><td>≥ 5.4</td><td>76%</td><td>73%</td><td>74%</td></tr><tr><td>Slope (h<sup>-1</sup>)</td><td>0.013*</td><td>0.698</td><td>≥ − 0.39</td><td>67%</td><td>59%</td><td>62%</td></tr><tr><td colspan="7">1p/19q co-deletion status</td></tr><tr><td>TSR<sub>mean</sub></td><td>0.708</td><td>NS</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>TSR<sub>max</sub></td><td>0.429</td><td>NS</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>TBR<sub>mean</sub></td><td>0.931</td><td>NS</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>TBR<sub>max</sub></td><td>0.774</td><td>NS</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>MTV (mL)</td><td>0.531</td><td>NS</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>TTP (min)</td><td>0.034*</td><td>0.679</td><td>≥ 6.9</td><td>69%</td><td>69%</td><td>69%</td></tr><tr><td>Slope (h<sup>-1</sup>)</td><td>0.186</td><td>NS</td><td>—</td><td>—</td><td>—</td><td>—</td></tr></tbody></table>

<footnote>*p < 0.05 for the global 3 groups comparisons</footnote>

<footnote>†p < 0.05 for comparison between IDH mutant and IDH wildtype gliomas</footnote>

<footnote>*p value < 0.05; AUC, area under the curve; *MTV*, metabolic tumor volume; *NS*, non-significant; *TBR*, tumor-to-brain ratio; *TSR*, tumor-to-striatum ratio; *TTP*, time-to-peak</footnote>