Evaluation of the benefit of gadolinium injection in the follow-up of paediatric optic pathway gliomas

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Soutenue publiquement le : 19/03/2020

2019-2020

THÈSE

pour le

DIPLÔME D’ÉTAT DE DOCTEUR EN MÉDECINE

Qualification en Radiologie Diagnostique et interventionnelle

Evaluation of the benefit of gadolinium injection in the follow-up

of paediatric optic pathway gliomas

Évaluation de l’intérêt de l’injection de gadolinium dans le suivie des gliomes des voies optiques pédiatriques

BISSON Ronan

Né le 24 octobre 1991 à Chambray-lès-Tours (37)

Sous la direction du Dr Louis-Marie LEIBER

Membres du jury

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ENGAGEMENT DE NON PLAGIAT

Je, soussigné Ronan BISSON

Déclare être pleinement conscient que le plagiat de documents ou d’une partie d’un document publiée sur toutes formes de support, y compris l’internet, constitue une violation des droits d’auteur ainsi qu’une fraude caractérisée.

En conséquence, je m’engage à citer toutes les sources que j’ai utilisées pour écrire ce rapport ou mémoire.

Signé par l'étudiant le 28/01/2020

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LISTE DES ENSEIGNANTS DE L’UFR SANTÉ D’ANGERS

Directeur de l'UFR : Pr Nicolas Lerolle

Directeur adjoint de l'UFR et directeur du département de pharmacie : Pr Frédéric Lagarce Directeur du département de médecine : Pr Cédric Annweiller

PROFESSEURS DES UNIVERSITÉS

ABRAHAM Pierre Physiologie Médecine

ANNWEILER Cédric Gériatrie et biologie du vieillissement Médecine

ASFAR Pierre Réanimation Médecine

AUBE Christophe Radiologie et imagerie médicale Médecine

AUGUSTO Jean-François Néphrologie Médecine

AZZOUZI Abdel Rahmène Urologie Médecine

BARON-HAURY Céline Médecine générale Médecine

BAUFRETON Christophe Chirurgie thoracique et cardiovasculaire Médecine

BENOIT Jean-Pierre Pharmacotechnie Pharmacie

BEYDON Laurent Anesthésiologie-réanimation Médecine

BIGOT Pierre Urologie Médecine

BONNEAU Dominique Génétique Médecine

BOUCHARA Jean-Philippe Parasitologie et mycologie Médecine

BOUVARD Béatrice Rhumatologie Médecine

BOURSIER Jérôme Gastroentérologie ; hépatologie Médecine

BRIET Marie Pharmacologie Médecine

CAILLIEZ Eric Médecine générale Médecine

CALES Paul Gastroentérologe ; hépatologie Médecine

CAMPONE Mario Cancérologie ; radiothérapie Médecine

CAROLI-BOSC François-xavier Gastroentérologie ; hépatologie Médecine CHAPPARD Daniel Cytologie, embryologie et cytogénétique Médecine

CONNAN Laurent Médecine générale Médecine

COUTANT Régis Pédiatrie Médecine

COUTURIER Olivier Biophysique et médecine nucléaire Médecine

CUSTAUD Marc-Antoine Physiologie Médecine

DE BRUX Jean-Louis Chirurgie thoracique et cardiovasculaire Médecine

DESCAMPS Philippe Gynécologie-obstétrique Médecine

DINOMAIS Mickaël Médecine physique et de réadaptation Médecine

DIQUET Bertrand Pharmacologie Médecine

DUCANCELLE Alexandra Bactériologie-virologie ; hygiène hospitalière

Médecine

DUVAL Olivier Chimie thérapeutique Pharmacie

DUVERGER Philippe Pédopsychiatrie Médecine

EVEILLARD Mathieu Bactériologie-virologie Pharmacie

FANELLO Serge Épidémiologie ; économie de la santé et prévention

Médecine

FAURE Sébastien Pharmacologie physiologie Pharmacie

FOURNIER Henri-Dominique Anatomie Médecine

FURBER Alain Cardiologie Médecine

GAGNADOUX Frédéric Pneumologie Médecine

GARNIER François Médecine générale Médecine

GASCOIN Géraldine Pédiatrie Médecine

GOHIER Bénédicte Psychiatrie d'adultes Médecine

GRANRY Jean-Claude Anesthésiologie-réanimation Médecine

GUARDIOLA Philippe Hématologie ; transfusion Médecine

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GUILET David Chimie analytique Pharmacie

HAMY Antoine Chirurgie générale Médecine

HUNAULT-BERGER Mathilde Hématologie ; transfusion Médecine

IFRAH Norbert Hématologie ; transfusion Médecine

JEANNIN Pascale Immunologie Médecine

KEMPF Marie Bactériologie-virologie ; hygiène

hospitalière Médecine

LACCOURREYE Laurent Oto-rhino-laryngologie Médecine

LAGARCE Frédéric Biopharmacie Pharmacie

LARCHER Gérald Biochimie et biologie moléculaires Pharmacie LASOCKI Sigismond Anesthésiologie-réanimation Médecine

LEGRAND Erick Rhumatologie Médecine

LERMITE Emilie Chirurgie générale Médecine

LEROLLE Nicolas Réanimation Médecine

LUNEL-FABIANI Françoise Bactériologie-virologie ; hygiène

hospitalière Médecine

MARCHAIS Véronique Bactériologie-virologie Pharmacie

MARTIN Ludovic Dermato-vénéréologie Médecine

MENEI Philippe Neurochirurgie Médecine

MERCAT Alain Réanimation Médecine

MERCIER Philippe Anatomie Médecine

PAPON Nicolas Parasitologie mycologie Pharmacie

PASSIRANI Catherine Chimie générale Pharmacie

PELLIER Isabelle Pédiatrie Médecine

PICQUET Jean Chirurgie vasculaire ; médecine vasculaire Médecine

PODEVIN Guillaume Chirurgie infantile Médecine

PROCACCIO Vincent Génétique Médecine

PRUNIER Fabrice Cardiologie Médecine

REYNIER Pascal Biochimie et biologie moléculaire Médecine RICHARD Isabelle Médecine physique et de réadaptation Médecine

RICHOMME Pascal Pharmacognosie Pharmacie

RODIEN Patrice Endocrinologie, diabète et maladies

métaboliques Médecine

ROHMER Vincent Endocrinologie, diabète et maladies métaboliques

Médecine

ROQUELAURE Yves Médecine et santé au travail Médecine

ROUGE-MAILLART Clotilde Médecine légale et droit de la santé Médecine ROUSSEAU Audrey Anatomie et cytologie pathologiques Médecine ROUSSEAU Pascal Chirurgie plastique, reconstructrice et

esthétique Médecine

ROUSSELET Marie-Christine Anatomie et cytologie pathologiques Médecine

ROY Pierre-Marie Thérapeutique Médecine

SAINT-ANDRE Jean-Paul Anatomie et cytologie pathologiques Médecine SAULNIER Patrick Biophysique pharmaceutique et

biostatistique Pharmacie

SERAPHIN Denis Chimie organique Pharmacie

SUBRA Jean-François Néphrologie Médecine

UGO Valérie Hématologie ; transfusion Médecine

URBAN Thierry Pneumologie Médecine

VAN BOGAERT Patrick Pédiatrie Médecine

VENIER Marie-Claire Pharmacotechnie Pharmacie

VERNY Christophe Neurologie Médecine

WILLOTEAUX Serge Radiologie et imagerie médicale Médecine

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MAÎTRES DE CONFÉRENCES

ANGOULVANT Cécile Médecine Générale Médecine

ANNAIX Véronique Biochimie et biologie moléculaires Pharmacie

BAGLIN Isabelle Pharmaco-chimie Pharmacie

BASTIAT Guillaume Biophysique et biostatistique Pharmacie

BEAUVILLAIN Céline Immunologie Médecine

BELIZNA Cristina Médecine interne Médecine

BELLANGER William Médecine générale Médecine

BELONCLE François Réanimation Médecine

BENOIT Jacqueline Pharmacologie et pharmacocinétique Pharmacie

BIERE Loïc Cardiologie Médecine

BLANCHET Odile Hématologie ; transfusion Médecine

BOISARD Séverine Chimie analytique Pharmacie

CAPITAIN Olivier Cancérologie ; radiothérapie Médecine

CASSEREAU Julien Neurologie Médecine

CHEVAILLER Alain Immunologie Médecine

CHEVALIER Sylvie Biologie cellulaire Médecine

CLERE Nicolas Pharmacologie Pharmacie

COLIN Estelle Génétique Médecine

DE CASABIANCA Catherine Médecine générale Médecine

DERBRE Séverine Pharmacognosie Pharmacie

DESHAYES Caroline Bactériologie virologie Pharmacie

FERRE Marc Biologie moléculaire Médecine

FLEURY Maxime Immunologie Pharmacie

FORTRAT Jacques-Olivier Physiologie Médecine

HAMEL Jean-François Biostatistiques, informatique médicale Médicale

HELESBEUX Jean-Jacques Chimie organique Pharmacie

HINDRE François Biophysique Médecine

JOUSSET-THULLIER Nathalie Médecine légale et droit de la santé Médecine LACOEUILLE Franck Biophysique et médecine nucléaire Médecine

LANDREAU Anne Botanique et Mycologie Pharmacie

LEGEAY Samuel Pharmacologie Pharmacie

LE RAY-RICHOMME Anne-Marie Valorisation des substances naturelles Pharmacie LEPELTIER Elise Chimie générale Nanovectorisation Pharmacie

LETOURNEL Franck Biologie cellulaire Médecine

LIBOUBAN Hélène Histologie Médecine

MABILLEAU Guillaume Histologie, embryologie et cytogénétique Médecine MALLET Sabine Chimie Analytique et bromatologie Pharmacie MAROT Agnès Parasitologie et mycologie médicale Pharmacie MAY-PANLOUP Pascale Biologie et médecine du développement et de

la reproduction

Médecine

MESLIER Nicole Physiologie Médecine

MOUILLIE Jean-Marc Philosophie Médecine

NAIL BILLAUD Sandrine Immunologie Pharmacie

PAPON Xavier Anatomie Médecine

PASCO-PAPON Anne Radiologie et imagerie médicale Médecine

PECH Brigitte Pharmacotechnie Pharmacie

PENCHAUD Anne-Laurence Sociologie Médecine

PETIT Audrey Médecine et santé au travail Médecine

PIHET Marc Parasitologie et mycologie Médecine

PRUNIER Delphine Biochimie et biologie moléculaire Médecine

RIOU Jérémie Biostatistique Pharmacie

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ROGER Emilie Pharmacotechnie Pharmacie

SCHINKOWITZ Andréas Pharmacognosie Pharmacie

SIMARD Gilles Biochimie et biologie moléculaire Médecine

TANGUY-SCHMIDT Aline Hématologie ; transfusion Médecine

TRZEPIZUR Wojciech Pneumologie Médecine

AUTRES ENSEIGNANTS

AUTRET Erwan Anglais Médecine

BARBEROUSSE Michel Informatique Médecine

BRUNOIS-DEBU Isabelle Anglais Pharmacie

CHIKH Yamina Économie-Gestion Médecine

FISBACH Martine Anglais Médecine

O’SULLIVAN Kayleigh Anglais Médecine

PAST

CAVAILLON Pascal Pharmacie Industrielle Pharmacie

LAFFILHE Jean-Louis Officine Pharmacie

MOAL Frédéric Physiologie Pharmacie

ATER

FOUDI Nabil (M) Physiologie et communication cellulaire Pharmacie

HARDONNIERE Kévin Pharmacologie - Toxicologie Pharmacie

WAKIM Jamal (Mme) Biochimie et biomoléculaire Médecine

AHU

BRIS Céline Biochimie et biologie moléculaires Pharmacie

LEROUX Gaël Toxico Pharmacie

BRIOT Thomas Pharmacie Galénique Pharmacie

CHAPPE Marion Pharmacotechnie Pharmacie

CONTRACTUEL

VIAULT Guillaume Chimie Pharmacie

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RE M E RC IE M E N TS

À mon maître et président de jury, Monsieur le Professeur AUBÉ.

Vous me faites l’honneur de juger ce travail.

Je vous remercie pour votre soutien durant ces cinq années.

Veuillez trouver ici l’expression de mon profond respect.

À mon maître et directeur de thèse, Monsieur le Docteur LEIBER.

Merci d’avoir accepté de diriger ce travail.

Merci pour ton envie de transmettre, ta disponibilité et les échanges que nous avons eu.

Sois assuré de ma profonde reconnaissance.

À mon maître et juge,

Madame le Professeur PELLIER.

Merci pour l’intérêt que vous y accordez.

Soyez assurée de ma sincère gratitude.

Monsieur le Professeur WILLOTEAUX.

Merci pour l’intérêt que vous y accorderez.

Merci pour votre disponibilité et pour vos conseils.

Veuillez trouver ici l’expression de mes sincères remerciements.

Monsieur le Docteur LOISEL.

Merci pour votre gentillesse et votre disponibilité au quotidien.

Veuillez trouver ici l’expression de ma respectueuse considération.

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RE M E RC IE M E N TS

À ma formidable famille qui a toujours été là pour moi ; merci pour ces belles années passées et celles à venir.

À mes parents pour leur éducation, leur soutien, leur accompagnement tout au long de ces années. Merci pour toutes ces valeurs, ce sens du devoir et cette envie d’exercer ce métier que vous m'avez inculquée, qui font de moi la personne que je suis

aujourd’hui. Merci pour votre présence qui fait de ce berceau familial un refuge

constant et agréable où j'aimerais passer plus de temps, un peu comme mes parasites de frères.

À mes frères pour ces discussions interminables et houleuses qui sont finalement quand même source de partage de savoir. Merci également à mes belles-sœurs pour le soutien que vous leurs apportez au quotidien, vous avez du mérite.

À mon parrain Bruno et ma marraine Chantal qui m'ont accompagné dans les grands moments de ma vie.

À papy Alain, la relève est enfin assurée : l’histoire radiologique de la famille ne sera pas oubliée.

À ma belle-famille, pour les bons moments passés et ceux à venir qui s'annoncent encore meilleurs.

Aux scouts, aux tourangeaux, aux angevins, aux choletais et aux manceaux que l’heureux hasard a placé sur mon chemin et avec lesquels c'est toujours une joie de se retrouver ensemble.

À tout ce que j'ai rencontré durant mes études de médecine et qui m'ont aidé à être l'interne que je suis et le médecin que je serai.

Au service du Docteur Masson pour m'avoir fait découvrir l'autre côté de la barrière, le point de vue du clinicien.

À tous ces sombres héros qui travaillent dans l’ombre des différents services de radiologie que j'ai pu traverser, aux passionnés, aux pragmatiques. Merci pour le formidable compagnonnage dont certains font preuve. J’espère avoir été à la hauteur et pouvoir à mon tour faire preuve d’autant de pédagogie auprès de mes futurs internes.

À mes co-internes avec qui ce fut un plaisir de travailler et qui, le cas échéant, j'en suis certain, ne manqueront pas de m’apporter des oranges. C’est avec joie que je

continuerai à travailler avec certains d'entre vous ces prochaines années.

À Léon qui m’a enfin fait comprendre ce que répète mon père : “il n’y a pas que médecine dans la vie”. Je tâcherai de t'offrir toutes les chances donc j'ai pu bénéficier pour t'accompagner dans la vie.

Au futur bébé qui me remplit de joie à l'idée d'être papa une seconde fois.

À Charline, pilier de mon existence, pour ta présence, ton soutien indéfectible, ton dynamisme, ta joie de vivre et ton humanité... je ne te remercierai jamais assez pour tout l’amour que tu me donnes. Merci simplement pour ce que tu es ; c’est un bonheur renouvelé chaque jour de vivre à tes cotés.

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Liste des abréviations

OPG Optic pathway glioma NF1 Neurofibromatosis type 1 MRI Magnetic resonance imaging TR Répétition time

TE Echo time

NEX Number of excitations FA Flip angle

FOV Field of view

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Plan

LIST OF ABBREVIATIONS

ABSTRACT

INTRODUCTION

MATERIALS & METHODS

1. Patients 2. Imaging

3. Measurements

4. Tumoral’s contour evaluation 5. Population Characteristics 6. Statistical methods

RESULTS

1. Population Characteristics 2. Interobserver reproductibility

3. Correlation Between Measurements Modalities 4. Tumoral’s contour evaluation

DISCUSSION AND CONCLUSION

BIBLIOGRAPHY

LIST OF FIGURES

LIST OF TABLES

TABLE OF CONTENTS

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1 RESUME

Introduction:

Des études suggèrent que le suivi par neuro-imagerie des patients présentant un gliome des voies optiques (GVO) ne nécessite pas d’injection de gadolinium pour guider les décisions de prise en charge, aucune corrélation n'ayant été observée entre les caractéristiques du rehaussement tumoral et les symptômes cliniques ou la progression.

Afin de diminuer le risque de rétention tissulaire de gadolinium et ses conséquences cliniques potentielles à long terme, l’intérêt de l'injection de gadolinium lors du suivi des patients avec un GVO doit être évaluée. L’objectif de cette étude est d’analyser le bénéfice apporté par l'injection de chélates gadolinium pour la quantification du volume tumoral lors de ce suivi.

Méthodes :

Tous les examens d’imagerie par résonance magnétique (IRM) de surveillance des enfants atteints de GVO suivis entre octobre 2015 et octobre 2018 au CHU d'Angers ont été inclus pour cette étude. Deux radiologues ont réalisé, pour chaque séquence (séquence pondérée T2 en spin- écho rapide, séquence pondérée 3D T1 et séquence pondérée 3D T1 avec injection de chélates de gadolinium), une estimation des volumes selon la formule de l’ellipsoïde -la plus utilisée- et des mesures volumétriques calculées par contourage manuel semi-automatique.

Résultats :

130 IRM ont été analysées sur une population de 30 patients. Les coefficients de corrélation intra- classe appliqués pour comparer la reproductibilité inter-observateurs ont montré un avantage significatif de l'utilisation de l'estimation du volume par contourage par rapport à la méthode de l'ellipsoïde, quelle que soit la séquence IRM. Les mesures de volume présentent une meilleure concordance lorsqu'elles sont effectuées par contourage en T1 (0,9908 IC [0,9870-0,9935]) ou T1G (0,9929 IC [0,9900-0,9950]).

L'analyse a montré une excellente corrélation des mesures par contourage par rapport à la séquence 3DT1 après injection de chélates de gadolinium avec un coefficient de corrélation intra- classe estimé à 0,9985 IC [0,9981-0,9988] pour le volume mesuré en T1 et 0,9912 IC [0,9888- 0,9931] pour celui en T2.

Conclusion :

Afin de diminuer la rétention tissulaire cérébrale de gadolinium et ses potentielles conséquences cliniques à long terme, le suivi par IRM des GVO ne nécessite pas d’injection de chélates de gadolinium pour estimer le volume tumoral.

Mots clés : Gliomes des voies optiques, surveillance, rétention de gadolinium

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2

ABSTRACT

Background and purpose:

Some studies suggest that neuroimaging follow up for optic pathway gliomas (OPG) does not require gadolinium to guide management decisions because no correlation between enhancement characteristics and clinical symptoms or progression has been observed.

With the objective of reducing the risk of brain gadolinium retention and potential long- term clinical consequences, our study questioned the added value provided during follow- up by gadolinium injection for the tumoral volume quantification.

Methods:

Child patients with OPGs followed up with MRI scans between October 2015 and October 2018 at Angers University Hospital Centre, were eligible for this study. 2 radiologists carried out, for each sequence (T2-weighted fast spin-echo, 3D T1-weighted and contrast enhanced 3D T1-weighted sequence), an estimation of volumes according to the most widely used ellipsoid formula and volumetric measurements calculated using semi- automatic manual contouring.

Results:

130 MRI scans from 30 patients were analysed. The Intra-class correlation coefficients applied to compare the inter-observer reproducibility showed a significant benefit of using volume estimation by contouring compared to the ellipsoid method regardless of the MRI sequence. The volume measurements were the more concordant when performed by contouring in T1 (0.9908 IC [0.9870-0.9935]) or T1G (0.9929 IC[0.9900-0.9950]).

Compared to contrast enhanced 3D T1-weighted sequence, analysis showed excellent correlation of the volumes obtained by contouring with an estimated intra-class correlation coefficient of 0.9985 IC [0.9981-0.9988] for 3DT1 without gadolinium and 0.9912 IC [0.9888-0.9931] for T2 sequences.

Conclusion:

In order to reduce the brain gadolinium retention and potential long-term clinical consequences, MRI follow up for optic pathway gliomas do not require gadolinium to estimate volume.

Key words: Optic pathway gliomas, follow up, gadolinium retention

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3

INTRODUCTION

Optic pathway gliomas (OPGs) are rare tumours accounting for 1% of all intracranial tumours and 3% to 5% of childhood brain tumours ^(1–4). OPGs usually occur in childhood with 75 % of patients diagnosed in the first decade of life and 90% become symptomatic before the second decades of life ^(5–7). OPGs are a heterogeneous group of low-grade tumours, the main histologic entity in children is low-grade astrocytoma ^(8,9), classically associated with Type 1 neurofibromatosis (NF1) which is observed in 15% to 20% of patients ^(10–12). OPGs can occur anywhere along the optic pathway, from optic nerves to the visual cortex ^(1,13). These are usually slow-growing tumours that sometimes have prolonged quiescence, regress spontaneously, but can also progress rapidly ^(14,15). Its natural history and clinical course are unpredictable and often present a variety of clinical symptoms, such as unilateral vision loss, proptosis, endocrine disorders, or intracranial hypertension ^(16–18).

Current treatment methods to reduce visual morbidity include chemotherapy, radiotherapy, or surgery ^(3,18,19). Chemotherapy is considered the standard first-line treatment; radiotherapy is an effective treatment, but its use is limited because of significant risks, including neuroendocrine dysfunction, neurodevelopmental delay, visual loss, second malignancy and cerebro-occlusive disease ^(20–22). Surgery is indicated in case of near blindness in an eye or tumour enlargement with intracranial hypertension ^(23,24). In the case of a non-evolving tumour without pejorative evolution of the clinical symptomatology, clinical and radiological surveillance alone is often instituted.

Serial imaging and neuro-ophthalmologic exams are instituted for follow up ^(10,21,23). Contrast-enhanced magnetic resonance imaging (MRI) of the brain is the standard imaging technique to diagnose and monitor progression of OPGs ^(10,25).

There is no consensus on the frequency of neuroimaging for monitoring optic pathway gliomas.

Imaging is performed every 3-6 months in our referral centre to follow up paediatric OPGs and may be influenced by clinical results or tumour characteristics ^(10,21).

However, brain gadolinium retention has been identified in children and adults without severe renal dysfunction ^(26–30), where there is no definitive evidence that accumulated gadolinium leads to clinical pathology.

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4 Furthermore, children’s brains are more sensitive to the neurotoxic effects of heavy metal and rare earth elements, such as gadolinium ⁽²⁶⁾, which leads to greater caution about potential long-term clinical consequences and modifies exploration protocols which are designed to limit exposure to gadolinium in the long-term follow-up of young patients

(31–35).

Some study suggests that neuroimaging follow up for optic pathway gliomas does not require gadolinium to guide management decisions because no strong correlation between enhancement characteristics and clinical symptoms or tumour size has been observed ^(36–39).

In order to reduce the potential risks of brain gadolinium retention and potential long- term clinical consequences, we questioned the added value provided during follow-up by gadolinium injection for the tumoral volume quantification. Our study compare estimated volumes according to the most widely used ellipsoid formula and the volumetric measurements (semi-automatic contouring) on T2-weighted fast spin-echo, 3D T1- weighted and contrast enhanced 3D T1-weighted sequence, for follow-up of paediatric patients with OPGS.

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5

MATERIALS AND METHODS

Patients

All children aged 0 to 18 years who underwent OPGs followed by MRI between October 2015 and October 2018 at Angers University Hospital Centre, were eligible for this study.

The diagnosis of OPGs was based primarily on MRI findings of a tumour involving optic pathways. Whenever possible, a biopsy was obtained to confirm the diagnosis.

Exclusion criteria were artefact or lack of required MRI sequences.

The study was approved by the institutional review committee.

Imaging

Brain MRIs were performed on a 1.5 T Siemens magnetom AREA X5 and a 3T Siemens magnetom SKYRA with a standard quadrature head coil.

Patients received DOTAREM (gadoteric acid) according to weight (0.2 ml/Kg) administered as a bolus by a peripheral venous infusion or an implanted central venous access devices.

Each exam included at least ⁽⁴⁰⁾: (parameter appendix 1) - 3D T1-weighted sequence without contrast.

- contrast enhanced 3D T1-weighted sequence.

- axial fast spin echo T2-weighted sequence.

- sagittal fast spin echo T2-weighted sequence.

Measurements

After a short period of training together, MRIs were analysed by 2 radiologists independently using digital callipers. Volumetric analyses were performed on Synapse 3D software.

3D T1 weighted, contrast-enhanced 3D T1-weighted and fast spin echo T2-weighted sequences were analysed separately by each reader blinded one from the other and from the results obtained with the other sequences.

In order to best assess reproducibility, all the sequences of all the patients were randomized. Then, the measurements were taken with ellipsoid formula for each

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6 sequence. After a second randomisation of all the sequences, the volumetric (semi- automatic contouring) measurements were taken.

These precautions were taken in order to avoid bias when processing images of the same patient in succession.

Overall, the following settings were recorded for each sequence:

- Estimated volumes according to the ellipsoid formula using half of the product of the largest orthogonal diameters in the 3 plans of space (ELIPS).

- Volumetric measurements were calculated using a semi-automatic manual contouring of the lesion on each slice excluding peritumoral oedema (VOL).

Tumoral contour evaluation

We classified the tumoral contours into the following 4 types: indisputable (1), clear (2), inaccurate (3), indeterminable (4).

A different method was used by each operator, on one hand a local contours evaluation based on the most pejorative score found (R1), on the other hand a global contour evaluation method (R2).

Population characteristics

Patients demographic information including age, gender, NF-1 status and histology, was retrieved from medical records and Picture Archiving and Communications system (PACS) of our institution.

Statistical methods

Categorical data were described as sample size and percentages and compared using Chi-square tests, and continuous data were described as mean and standard deviation and compared using ANOVA tests.

The reliability of volume estimates depending on the evaluation process (ellipsoid formula or contouring in the different sequences: T1, T2 and T1G) was assessed through the calculation of intra-class correlation coefficients and their 95% confidence interval, and illustrated using Bland and Altman plots. Reliability was a priori defined as correct when the lower bound of the 95% confidence interval of intra-class correlation coefficients were

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7 between 0.6 and 0.8 and excellent when ≥ 0.8. Intra-class correlation coefficients were compared using Konishi & Gupta's modified Z-tests ^(41-43). A significance correction by Bonferroni's method, was used for taking into account the number of comparisons of intra-class correlation coefficients.

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8

RESULTS

Population Characteristics

During the period of interest, 221 MRIs were performed and 91 were excluded (artefact or absence of necessary MRI sequences).

A total of 130 MRI scans were analysed from 30 patients with OPGs. 103 MRI scans were performed on a 1.5 T Siemens magnetom AREA X5 and 27 on 3T Siemens magnetom SKYRA. There were 16 boys and 14 girls and the median age was 8 years [8 months – 14 years] (Table 1). 33% of the patients had neurofibromatosis type 1.

On average, patients had 3 MRIs during this period (two MRI and less, 40%; between three and five MRI, 23%; and six or more, 37%).

Tumour volumes measurements on the contrast enhanced 3DT1 sequences ranger from 0.3 to 166.7cm3 (median:13.87 cm3).

Table 1. Population’s characteristic

Patient characteristic Study population n= 30

n (%) Median (min – max)

Median age (years) 8

Age range 8 months – 14 years

Male : female 16 :14

NF1 Status 10 (33%)

Histological evidence 11 (36%)

Average MRI per patient 3

<3 MRI 12 (40%)

3< MRI >6 7 (23%)

>6 MRI 11 (37%)

Median tumour volume 13.87 cm³ [0.3-166.7]

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9 Interobserver reproducibility

Analysis of the intra-class correlation coefficient applied to compare the inter-observer reproducibility of the different measurement methods on each MRI sequence shows an excellent reproducibility, greater than 0.94 for all the sequence and measurement method used. (Table 2)

However, a significant benefit of using volume estimation by contouring was highlighted compared to the ellipsoid method regardless of the MRI sequence.

The Intra-class correlation coefficients showed a more concordant volume measurements when performed by contouring in T1 (0.9908 IC [0.9870-0.9935]) or T1G (0.9929 IC[0.9900-0.9950]).

Table 2. Interobserver correlation by sequence and measurement method Sequences Measurements

Methods Interobserver

correlation (95%CI) Difference in reproducibility between measuring

methods P value T2

ELIPS T2 0.9578 [0.9409-0.9700]

0.00395 VOL T2 0.9791 [0.9706-0.9852]

T1 ELIPS T1 0.9730 [0.9621-0.9808]

<0.0001 VOL T1 0.9908 [0.9870-0.9935]

T1G ELIPS T1G 0.9600 [0.9439-0.9715]

<0.0001 VOLT1G 0.9929 [0.9900-0.9950]

Abbreviations: ELIPS, Estimated volumes according to the ellipsoid formula; VOL, Volumetric measurements calculated using a semi-automatic manual contouring of the lesion on each slice

The comparison of reliability of contouring volume measurements highlighted a poorer reliability when performed in T2 rather than in T1 (p=0.0009) or in T1G (p=0.00001) (Table 3). No reliability difference was highlighted between T1 and T1G contouring

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10 methods (p=0.29). However, all of these methods presented a quite satisfactory reliability (intra-class correlation coefficient greater than 0.97)

Table 3. Comparison of reproducibility of the volume measurements by contouring among the different sequences

Comparison of estimated volumes according to

the sequence

Reproducibility difference between measurement methods

P value

VOLT2 vs. VOLT1 0.0009

VOLT2 vs. VOLT1G <0.0001

VOLT1 vs. VOLT1G 0.2951

Abbreviations: VOL, Volumetric measurements calculated using a semi-automatic manual contouring of the lesion on each slice

Correlation Between Measurement Modalities

Intra-class correlation coefficients were calculated for all methods and sequences with respect to the gold standard (VOLT1G) to determine the agreement between each pair of measured modalities (ELIPST2 vs VOLT1G, VOLT2 vs VOLT1G, ELIPST1 vs VOLT1G, VOLT1 vs VOLT1G, ELIPST1G vs VOLT1G) (Table 4).

The analysis showed excellent correlation of the contouring measurements with respect to the gold standard with an estimated intra-class correlation coefficient of 0.9985 (0.9981-0.9988) for VOLT1 and 0.9912 [0.9888-0.9931] for VOLT2.

Measurements made by the ellipsoid method remain satisfactorily correlated to the volume by contouring in T1G between 0.911 and 0.937.

Note that volume measurements by the ellipsoid method, regardless of the sequence, had a lower correlation to volume by T2 contouring although it is a non-volumetric thick- section sequence.

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11 The graphical analysis of Bland and Altman (Fig 1.) comparing the measurement differences in pairs (ELIPST1 vs VOLT1G, VOLT2 vs VOLT1G, ELIPST1 vs VOLT1G, VOLT1 vs VOLT1G) as a function of tumour volume also illustrates these trends.

Table 4. Correlation between the different volumes measurement methods with respect to gold standard (VOLT1G).

Comparison of

Measurements methods

Intra-class correlation coefficients (95% CI)

ELIPST2 vs. VOLT1G 0.9110 [0.8878-0.9296]

ELIPST1 vs. VOLT1G 0.9322 [0.9143-0.9465]

ELIPST1G vs. VOLT1G 0.9371 [0.9204-0.9504]

VOLT2 vs. VOLT1G 0.9912 [0.9888-0.9931]

VOLT1 vs. VOLT1G 0.9985 [0.9981-0.9988]

We studied the distribution of the measured volume depending on the measurement method (VOLT1, VOLT2, VOLT1G, ELIPST1, ELIPST2, ELIPST1G) These volume estimates were significantly different depending on the measurement method (p-val: 0.0125 ), but no difference was highlighted between volumes estimated using the ellipsoid method or between volumes estimated using the volumetric method (respectively p-val : 0.9611 and 0.6038 )(Table 5).

Estimated volumes performed using the ellipsoid approach were systematically greater than those performed using the contouring volumetric approach. On our sample, the ellipsoid approach measures were on average 1.28 times greater than the volume approach measures.

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12

Figure 1. Bland and Altman graph comparing measurement differences in pairs (ET1 vs VT1G, VT2 vs VT1G, ET1 vs VT1G, VT1 vs VT1G) as a function of tumour volume.

-20,00 -10,00 0,00 10,00 20,00 30,00 40,00

0,00 50,00 100,00 150,00

VOLT2/VOLT1G

-10,00 -6,00 -2,00 2,00 6,00 10,00

0,00 50,00 100,00 150,00 200,00

VOLT1/VOLT1G

-40,00 0,00 40,00 80,00 120,00

0,00 50,00 100,00 150,00 200,00

ELIPST2/VOLT1G

-30,00 -20,00 -10,00 0,00 10,00 20,00 30,00 40,00 50,00 60,00

0,00 50,00 100,00 150,00 200,00

ELIPST1G/VOLT1G

-40,00 -20,00 0,00 20,00 40,00 60,00

0,00 50,00 100,00 150,00 200,00

ELIPST1/ELIPST1G

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13 Table 5. Comparison of the means of the estimated volume, according to the sequences and methods of measurement

Measurements Methods and

sequences

Means and standard deviation

overall comparison

P-value

Comparison of averages according to measurement

method P-value

ELIPS T2 44.15 ± 59.84

0.0125

0.9611 ELIPS T1 44.02 ± 57.82

ELIPS T1G 42.85 ± 55.35

VOL T2 36.29 ± 45.24

0.6038

VOL T1 33.17 ± 42.32

VOLT1G 32.85 ± 41.83

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14 Tumoral contour evaluation

Regardless of the method used to evaluate the contour of the tumour, the T2 sequence obtains the highest number of indisputable and clear combined evaluations compared to the T1 and T1G sequences for the evaluation performed by Global contour evaluation: 83% (T2) versus 62%(T1) and 57%(T1G)

The method used by Local contours evaluation based on the most pejorative score shows the same result: 67% (T2) compared to 50%(T1) and 54%(T1G).

Figure 2. Tumoral contour evaluation.

Abbreviations: indisputable (1), clear (2), inaccurate (3), indeterminable (4) R1: Local contours evaluation based on the most pejorative score found R2: Global contour evaluation method

The T2 sequence was the most subjectively adapted sequence for the delimitation of the tumour contours. Moreover, the inter-observer agreement of the estimation of the tumour volume by slice by slice contouring is excellent whatever the quality of the tumour contour (table 6), except for the volume estimated by the T2 ellipsoid method due to an outlier and the small number of indistinguishable contour (4) (n = 14).

0 10 20 30 40 50 60 70 80

T1G T1 T2 T1G T1 T2

R2R1

1 2 3 4

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15 Table 6. Inter-observer correlation based on tumour contour assessment

Sequences Measurements

Methods Interobserver correlation (95%CI)

1 2 3 4

T2

ELIPS T2 0.971

[0.947-0.984] 0.953

[0.918-0.973] 0.970

[0.936-0.986] 0.610

[0.177-0.848]

VOL T2 0.975

[0.954-0.986] 0.981

[0.966-0.989] 0.934

[0.863-0.969] 0.963

[0.897-0.987]

T1 ELIPS T1 0.994

[0.973-0.999] 0.968

[0947.-0.981] 0.969

[0.946-0.982] 0.948

[0.853-0.983]

VOL T1 0.993

[0.964-0.998] 0.990

[0.984-0.994] 0.984

[0.973-0.991] 0.990

[0.970-0.996]

T1G ELIPS T1G 0.952

[0.869-0.983] 0.945

[0.909-0.967] 0.985

[0.972-0.992] 0.949

[0.875-0.979]

VOLT1G 0.989

[0.970-0.996] 0.991

[0.985-0.994] 0.996

[0.993-0.998] 0.985

[0.962-0.994]

indisputable (1), clear (2), inaccurate (3), indeterminable (4)

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16

DISCUSSION and CONCLUSION

Main results

Our study shows an excellent interobserver reproducibility and no significant difference of the volumes estimated with manual semi-automatic contouring between the 3DT1 and 3D T1 sequence after injection of gadolinium chelate.

In addition, the excellent inter-observer reproducibility shows that even with poor contours delimitation the volume measurements are reliable.

Lower inter-radiologist reproducibility and unreliability compared to volumetric measurements (semi-automatic contouring) makes volumetric estimation by ellipsoid method a measurement technique not suitable for OPGs monitoring ⁽⁴⁰⁾. Especially since these tumours are often irregular and asymmetrical with an hourglass shape due to the constraint of vascular structures.

The axial sequence T2 also does not seem relevant for semi-automatic contouring measurement compared to the 3D T1 sequence with or without gadolinium injection. This is probably due to the non-millimetric nature of this sequence. Some teams use millimetric 3D T2 FLAIR volumetric sequences, however, T2 TSE sequences benefit from a better contrast between tumour tissue, peritumoral oedema and cerebral parenchyma, essential for satisfactory contour analysis and follow-up of these tumours.

Finally, the evaluation of tumour contours performed in this study shows a clearer delineation of contours on T2 sequences compared to T1-weighted sequences, in relation to the T2 hypersignal nature of tumour tissue and cystic portions.

The decision to treat OPGs is essentially based on 2 criteria: clinical evaluation (neuro- ophthalmological) and tumour volume (evaluated by MRI) and not on enhancement characteristics ⁽⁴⁴⁾.

In the absence of studies proving a correlation between enhancement characteristics, tumour progression and clinical symptoms, it seems legitimate to question the injection of gadolinium chelate for OPGs monitoring.

Numerous studies over long follow-up periods have shown the randomness of OPGs enhancement without association with clinical symptomatology, partly because it is not possible to determine whether an enhancement is related only to a blood-brain barrier rupture or rather to a neovascularization phenomenon in favour of tumour aggressiveness ^(37,39,45).

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17 Potential clinical application

These results do not call into question the need to carry out an examination with contrast injection for the diagnostic assessment of a suspected tumour involving the optical pathways, thus increasing detectability, especially for small lesions of the optic nerve or chiasma, and not neglecting possible differential diagnoses.

However, concerning the monitoring of OPGs, our results confirm the need to modify current patient monitoring protocols in order to reduce the risk of gadolinium retention and its possible complications.

The axial and sagittal T2 sequences appears to be the most relevant for a satisfactory delimitation of tumour contours and the 3DT1 sequence without contrast injection seems suitable for volumetric evaluation of the tumour.

These two sequences (T2 and T1 without gado) are therefore complementary and sufficient for the standard monitoring of OPGs.

Moreover, in the overall management of the patient and from a practical point of view, the absence of injected sequence allows an examination to be carried out under more favourable conditions: lack of apprehension on the part of the child regarding the placement of the venous catheter, decreased agitation following the perfusion sometimes making the interpretation difficult, reducing the examination time making it more easily bearable for children.

Some studies have also carried out preliminary analyses evaluating the benefit in terms of cost, which is significant in relation to the number of examinations and the number of years of follow-up of his patients ⁽³⁶⁾.

However, some additional sequences remain essential depending on the clinical context.

Contrast injection is necessary in the context of the emergency and post-operatively to investigate for complications and tumour residues.

A study demonstrated the correlation between the decrease of the portion of tumour enhanced after chemotherapy BB-SFOP with a better visual prognosis ⁽⁴⁶⁾.

Injection may also be necessary to look for other glial lesions, particularly in the context of type 1 neurofibromatosis, which is sometimes difficult to detect on T2 sequences alone.

Diffusion and angioMR sequences in time of flight also in the post-radiotherapy context in search of complications of cerebro-occlusive disease (carotid stenosis, ischemic stroke). Other sequences are also feasible, especially 3D T2 sequences, only if this sequence preserve good

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18 tissue contrast for contour evaluation which is not the case in our institution with a marked black or white contrast and is why we did not use it for this study.

The 3D T2 Ciss sequences also seems to be of interest especially for small lesions involving the optic nerves due to a high resolution.

Perspective

Some studies suggest the usefulness of multimodal imaging, particularly diffusion and perfusion sequences as prognostic markers of aggressive lesions and evaluation of therapeutic response, but further study is required to confirm these results due to weak samples ⁽³⁹⁾.

A clinical-radiological study evaluating the impact of the T1 3D sequence after injection of gadolinium chelate on the therapeutic decision in a multidisciplinary meeting compared to the T2 and T1 3D sequence without injection in OPG monitoring will provide additional arguments for reducing injections of contrast products in routine monitoring.

Study limitation

One of the limitations of this study, which reduce its external validity, is the limited number of patients included due to low prevalence. However, compared to other studies, our cohort is in the middle range and has the advantage of using recent imaging data.

In addition, the monocentric nature of the study may induce a centre effect. To overcome this bias, a nationwide study should then be conducted on all OPG reference centres.

No difference was expected in volume measurement between examinations performed on a 1.5 T Siemens magnetom AREA X5 and 3T Siemens magnetom SKYRA as the millimetric resolution was identical.

Conclusion

In order to reduce gadolinium retention in the brain and potential long-term clinical consequences, MRI follow up for optic pathway gliomas do not require gadolinium to estimate volume.

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19

BIBLIOGRAPHY

1. Binning MJ, Liu JK, Kestle JRW, Brockmeyer DL, Walker ML. Optic pathway gliomas: a review. Neurosurg Focus.

2007;23(5):E2.

2. Miller NR. Optic pathway gliomas are tumors! Ophthal Plast Reconstr Surg. 2008 Dec;24(6):433.

3. Jahraus CD, Tarbell NJ. Optic pathway gliomas. Pediatr Blood Cancer. 2006 May 1;46(5):586–96.

4. Dutton JJ. Gliomas of the anterior visual pathway. Surv Ophthalmol. 1994 Apr;38(5):427–52.

5. Dutton JJ. Optic nerve gliomas and meningiomas. Neurol Clin. 1991 Feb;9(1):163–77.

6. King A, Listernick R, Charrow J, Piersall L, Gutmann DH. Optic pathway gliomas in neurofibromatosis type 1: the effect of presenting symptoms on outcome. Am J Med Genet A. 2003 Oct 1;122A(2):95–9.

7. Ahn Y, Cho B-K, Kim S-K, Chung Y-N, Lee CS, Kim IH, et al. Optic pathway glioma: outcome and prognostic factors in a surgical series. Childs Nerv Syst ChNS Off J Int Soc Pediatr Neurosurg. 2006 Sep;22(9):1136–42.

8. Chikai K, Ohnishi A, Kato T, Ikeda J, Sawamura Y, Iwasaki Y, et al. Clinico-pathological features of pilomyxoid astrocytoma of the optic pathway. Acta Neuropathol (Berl). 2004 Aug;108(2):109–14.

9. Bilgiç S, Erbengi A, Tinaztepe B, Onol B. Optic glioma of childhood: clinical, histopathological, and histochemical observations. Br J Ophthalmol. 1989 Oct;73(10):832–7.

10. Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol. 2007 Mar;61(3):189–98.

11. Listernick R, Charrow J, Greenwald MJ, Esterly NB. Optic gliomas in children with neurofibromatosis type 1. J Pediatr. 1989 May;114(5):788–92.

12. Listernick R, Charrow J, Greenwald M, Mets M. Natural history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study. J Pediatr. 1994 Jul;125(1):63–6.

13. Medlock MD, Madsen JR, Barnes PD, Anthony DS, Cohen LE, Scott RM. Optic chiasm astrocytomas of childhood.

1. Long-term follow-up. Pediatr Neurosurg. 1997 Sep;27(3):121–8.

14. Piccirilli M, Lenzi J, Delfinis C, Trasimeni G, Salvati M, Raco A. Spontaneous regression of optic pathways gliomas in three patients with neurofibromatosis type I and critical review of the literature. Childs Nerv Syst ChNS Off J Int Soc Pediatr Neurosurg. 2006 Oct;22(10):1332–7.

15. Parsa CF, Hoyt CS, Lesser RL, Weinstein JM, Strother CM, Muci-Mendoza R, et al. Spontaneous regression of optic gliomas: thirteen cases documented by serial neuroimaging. Arch Ophthalmol Chic Ill 1960. 2001

Apr;119(4):516–29.

16. Nicolin G, Parkin P, Mabbott D, Hargrave D, Bartels U, Tabori U, et al. Natural history and outcome of optic pathway gliomas in children. Pediatr Blood Cancer. 2009 Dec 15;53(7):1231–7.

17. Liu GT. Optic gliomas of the anterior visual pathway. Curr Opin Ophthalmol. 2006 Oct;17(5):427–31.

18. Allen JC. Initial management of children with hypothalamic and thalamic tumors and the modifying role of neurofibromatosis-1. Pediatr Neurosurg. 2000 Mar;32(3):154–62.

19. Pollack IF. The Role of Surgery in Pediatric Gliomas. J Neurooncol. 1999 May 1;42(3):271–88.

20. Rasool N, Odel JG, Kazim M. Optic pathway glioma of childhood. Curr Opin Ophthalmol. 2017 May;28(3):289–

95.

21. de Blank PMK, Fisher MJ, Liu GT, Gutmann DH, Listernick R, Ferner RE, et al. Optic Pathway Gliomas in Neurofibromatosis Type 1: An Update: Surveillance, Treatment Indications, and Biomarkers of Vision. J Neuro- Ophthalmol Off J North Am Neuro-Ophthalmol Soc. 2017 Sep;37 Suppl 1:S23–32.

22. Sievert AJ, Fisher MJ. Pediatric low-grade gliomas. J Child Neurol. 2009 Nov;24(11):1397–408.

23. Avery RA, Fisher MJ, Liu GT. Optic pathway gliomas. J Neuro-Ophthalmol Off J North Am Neuro-Ophthalmol Soc.

2011 Sep;31(3):269–78.

(30)

20

24. Goodden J, Pizer B, Pettorini B, Williams D, Blair J, Didi M, et al. The role of surgery in optic pathway/hypothalamic gliomas in children. J Neurosurg Pediatr. 2014 Jan;13(1):1–12.

25. Haik BG, Saint Louis L, Bierly J, Smith ME, Abramson DA, Ellsworth RM, et al. Magnetic resonance imaging in the evaluation of optic nerve gliomas. Ophthalmology. 1987 Jun;94(6):709–17.

26. McDonald JS, McDonald RJ, Jentoft ME, Paolini MA, Murray DL, Kallmes DF, et al. Intracranial Gadolinium Deposition Following Gadodiamide-Enhanced Magnetic Resonance Imaging in Pediatric Patients: A Case-Control Study.

JAMA Pediatr. 2017 Jul 1;171(7):705–7.

27. Kanda T, Fukusato T, Matsuda M, Toyoda K, Oba H, Kotoku J, et al. Gadolinium-based Contrast Agent

Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction: Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass Spectroscopy. Radiology. 2015 Jul;276(1):228–32.

28. Miller JH, Hu HH, Pokorney A, Cornejo P, Towbin R. MRI Brain Signal Intensity Changes of a Child During the Course of 35 Gadolinium Contrast Examinations. Pediatrics. 2015 Dec;136(6):e1637-1640.

29. Mithal LB, Patel PS, Mithal D, Palac HL, Rozenfeld MN. Use of gadolinium-based magnetic resonance imaging contrast agents and awareness of brain gadolinium deposition among pediatric providers in North America. Pediatr Radiol. 2017 May;47(6):657–64.

30. Roberts DR, Lindhorst SM, Welsh CT, Maravilla KR, Herring MN, Braun KA, et al. High Levels of Gadolinium Deposition in the Skin of a Patient With Normal Renal Function. Invest Radiol. 2016 May;51(5):280–9.

31. Research C for DE and. Drug Safety and Availability - FDA Drug Safety Communication: FDA evaluating the risk of brain deposits with repeated use of gadolinium-based contrast agents for magnetic resonance imaging (MRI) [Internet]. [cited 2018 Aug 3]. Available from: https://www.fda.gov/Drugs/DrugSafety/ucm455386.htm 32. Contrast Manual [Internet]. [cited 2018 Aug 3]. Available from: https://www.acr.org/Clinical- Resources/Contrast-Manual

33. ACR - American College of Radiology (via Public) / ACR Response to the European PRAC Recommendations [Internet]. [cited 2018 Aug 3]. Available from:

http://www.publicnow.com/view/DA714236788989CE92F38E18EA3CCB6FCC9DFDE3?2017-04-04-17:31:30+01:00- xxx935

34. Goischke H-K. Safety assessment of gadolinium-based contrast agents (GBCAs) requires consideration of long- term adverse effects in all human tissues. Mult Scler J - Exp Transl Clin [Internet]. 2017 Apr 12 [cited 2018 Aug 3];3(2). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408503/

35. PRAC concludes assessment of gadolinium agents used in body scans and recommends regulatory actions, including suspension for some marketing authorisations. :2.

36. Maloney E, Stanescu AL, Perez FA, Iyer RS, Otto RK, Leary S, et al. Surveillance magnetic resonance imaging for isolated optic pathway gliomas: is gadolinium necessary? Pediatr Radiol. 2018 May 22;

37. Gaudino S, Quaglio F, Schiarelli C, Martucci M, Tartaglione T, Gualano MR, et al. Spontaneous modifications of contrast enhancement in childhood non-cerebellar pilocytic astrocytomas. Neuroradiology. 2012 Sep;54(9):989–95.

38. Kornreich L, Blaser S, Schwarz M, Shuper A, Vishne TH, Cohen IJ, et al. Optic pathway glioma: correlation of imaging findings with the presence of neurofibromatosis. AJNR Am J Neuroradiol. 2001 Dec;22(10):1963–9.

39. Jittapiromsak N, Hou P, Liu H-L, Sun J, Slopis JM, Chi TL. Prognostic Role of Conventional and Dynamic Contrast- Enhanced MRI in Optic Pathway Gliomas. J Neuroimaging Off J Am Soc Neuroimaging. 2017 Nov;27(6):594–601.

40. Lambron J, Rakotonjanah J, Loisel D, De Carli E, Delion M, Rialland X, Toulgoat F. Can we improve accuracy and reliability of MRI interpretation in children with optic pathway glioma? Neuroradiology 2016 Feb;58(2):197-208.

41 Konishi, S. and Gupta, A. K. (1987) Inferences about interclass and intraclass correlations from familial data. In Advances in the Statistical Sciences, vol. 4, Biostatistics (eds I. B. MacNeil and G. J. Umphrey), p.225-233 Boston:

Reidel

42. Konishi S, Gupta AK. Testing the equality of several intraclass correlation coefficients. Journal of Statistical Planning and Inference. 1989 Jan;21(1):93–105.

43. Donner A, Zou G. Testing the equality of dependent intraclass correlation coefficients. J R Statist Soc D. 2002 Sep;51(3):367–79.

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21

44. Fisher MJ, Loguidice M, Gutmann DH et al (2012) Visual out- comes in children with neurofibromatosis type 1- associated optic pathway glioma following chemotherapy: a multicenter retrospec- tive analysis. Neuro-Oncology 14:790–797

45. Gaudino S, Martucci M, Russo R et al (2017) MR imaging of brain pilocytic astrocytoma: beyond the stereotype of benign astrocyto-ma. Childs Nerv Syst 33:35–54

46. Rakotonjanah J, Gravier N, Lambron J, De Carli E, Delion M, Pellier I, Rialland X, Long-term visual acuity in patients with optic pathway glioma treated during childhood with up-front-BB-SFOP chemotherapy-analysis of a french padiatric historical cohort. PLOS ONE 2019 Mar;14(3)e0212107.

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22

LIST OF FIGURES

Figure 1. Bland and Altman graph comparing measurement differences in pairs (ET1 vs VT1G, VT2 vs VT1G, ET1 vs VT1G, VT1 vs VT1G) as a function of tumour volume.

... 12 Figure 2. Tumoral contour evaluation. ... 14

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23

LIST OF TABLES

Table 1 Population’s characteristic ... 8 Table 2 Interobserver correlation by sequence and measurement method ... 9 Table 3 Comparison of reproducibility of the measurements by contouring among the different sequences ………10 Table 4 Correlation between the different measurement methods with respect to gold standard (VOLT1G)………...……….. 11 Table 5 Comparison of the means of the estimated volume, according to the sequences and methods of measurement………13 Table 6 Inter-observer correlation based on tumour contour assessment ... 15

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24

APPENDIX

Appendix 1. Sequences parameters

1.5T 3T

3D T1-weighet sequence with and without contrast enhanced

TR: 2060 ms TE: 4.34 ms NEX: 1 FA: 15

FOV: 220x242 mm Thickness: 1 mm

TR: 1900 ms TE: 3.43 ms NEX: 1 FA: 8

FOV: 255x280 mm Thickness: 1 mm axial fast spin echo T2-

weighted sequence.

TR: 4100 ms TE: 82 ms NEX: 1 FA: 15

FOV: 220x242 mm Thickness: 4 mm

TR: 8140 ms TE: 118 ms NEX: 1 FA: 120

FOV: 219x240 mm Thickness: 4 mm sagittal fast spin echo T2-

weighted sequence

TR: 4100 ms TE: 89 ms NEX: 2 FA: 15

FOV: 240x263 mm Thickness: 2.5 mm

TR :5180 ms TE: 114 ms NEX: 2 FA: 120

FOV: 240x264 mm Thickness: 2.5 mm

Abbreviations: TR, Repetition time; TE, Echo time; NEX, Number of excitations; FA, Flip angle; FOV, Field of view

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25