# DIPG-23. Artificial intelligence for detecting ACVR1 mutations in patients with DIPG using MRI and clinical data

Fahad Khalid, Thibault Escobar, Jessica Goya-Outi, Vincent Frouin, Nathalie Boddaert, Jacques Grill, Frederique Frouin

<figure><img src="image_1.png" /></figure>

To cite this version:

Fahad Khalid, Thibault Escobar, Jessica Goya-Outi, Vincent Frouin, Nathalie Boddaert, et al., DIPG-23. Artificial intelligence for detecting ACVR1 mutations in patients with DIPG using MRI and clinical data. 24 (Supplement 1), pp.i23-i23, 2022, Neuro-Oncology, 10.1093/neuonc/noac079.080. [https://hal.science/hal-04248823v1](https://hal.science/hal-04248823v1) .

hal-04248823

HAL Id: hal-04248823

https://hal.science/hal-04248823v1

Submitted on 18 Oct 2023

**HAL** is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons CC BY 4.0 - Attribution - International License
munoglobulin and mucin domain protein family. It is expressed on multiple immune cell types, including T cells, NK cells, myeloid populations, and microglia, regulating adaptive and innate immunity. In silico assessment of TIM-3 expression in DIPG datasets showed a robust expression of this gene. Single-cell sequencing analyses of DIPG biopsies uncover TIM-3 expression, especially in microglia. In vivo efficacy studies showed that treatment with AbTIM-3 significantly increased overall survival in two DIPG immunocompetent orthotopic models, led to long-term survivors (50%), and showed immune memory. TIM-3 treatment led to a significant increase in the tumor microenvironment of microglia, granulocytes, NK, and CD8+ cells and higher levels of IFNγ, GrzB and TNFα corresponding with an NK and T-cell activate phenotypes. Interestingly, there was a decrease in the Treg population which causes an increase in the pro-inflammatory CD8/Treg ratio. CD4, CD8 or NK cell depletion leads to a significant but not a total loss of treatment efficacy. CD4+ and CD8+ cells were augmented in treated draining lymph nodes and expressed higher amounts of pro-inflammatory cytokines than control-mice. Population analysis and depletion experiments demonstrated the relevance of NK, CD4, CD8 and myeloid populations in the response to anti-TIM-3 therapy. Interestingly, the depletion of the different immune populations combined or using immunodeficient Rag2 mice, did not completely abrogate the treatment efficacy. These results suggest the concurrence of an additional mechanism of action that together with the immune response leads to a robust anti-DIPG effect. In conclusion, these data demonstrate that TIM-3 is a potential target for the treatment of DIPG.

### DIPG-23. ARTIFICIAL INTELLIGENCE FOR DETECTING ACVR1 MUTATIONS IN PATIENTS WITH DIPG USING MRI AND CLINICAL DATA

Eahad Khalid¹, Thibault Escobar¹, Jessica Goya-Outi¹, Vincent Frouin², Nathalie Boddaert³, Jacques Grill³, Frederique Frouin¹; ¹LITO U¹²⁸⁸, Inserm, Institut Curie - Centre de recherche, Université Paris-Saclay, Orsay, France. ²GAIA, Neurospin, CEA, Gif-sur-Yvette, France. ³Hôpital Necker Enfants Malades, AP-HP, IMAGINE Institute, Inserm, Université de Paris, Paris, France. ⁴Gustave Roussy, Inserm, Villejuif, France

**INTRODUCTION:** ACVR1 mutations are found in about 25% of patients with diffuse intrinsic pontine glioma (DIPG). Recent work has identified the combination of vandetanib and everolimus as a promising therapeutic approach for these patients. We investigate the predictive power of an AI model integrating clinical and radiomic information to predict ACVR1 mutation. **METHODS:** This retrospective monocentric study includes 65 patients with known ACVR1 status. Patients were scanned at the diagnosis time with at least one of the four structural MRI modalities (pre- and post-contrast T1, T2, FLAIR) and basic clinical information (age and sex) was collected. Radiomic features were extracted within the tumor region from each modality. For each modality, a recursive feature elimination method was used to select the most relevant features. Inside a leave-one-out framework, up to five logistic regression models were built: one per MRI modality and one for the clinical information. The final prediction for each patient was computed as the mean of the probabilities of ACVR1 mutation for the up to 5 different models. Assigning a different weight to clinical data according to age, (more or less than 10 years old) was also tested. **RESULTS:** Out of the 65 patients (mean age 7.9±3.7, 15 patients older then 10 years), ACVR1 mutations were identified with a 78% accuracy (sensitivity = 92% and specificity = 75%) in the leave-out-out process. Accounting for the clinical data in the model increase the accuracy to 82% (resp. sensitivity = 86% and specificity = 80%). **CONCLUSION:** The proposed multi model approach compensates for missing MR modalities while taking advantage of all the available information. Our first results suggest that a dedicated model could be developed for younger patients to improve the prediction. The different models will now be tested using additional data coming from the ongoing multicentric BIOMEDE trials.

### DIPG-24. NEUROLOGICAL SYMPTOM IMPROVEMENT AFTER RE-IRRADIATION IN PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): A RETROSPECTIVE ANALYSIS OF THE SIOP-E-HGG/DIPG PROJECT.

Lara Chavaz¹,², Geert O. Janssens³,⁴, Stephanie Bolle⁵, Henry Mandeville⁶, Monica Ramos-Albiac⁷, Karen van Beek⁸, Helen Benghiat⁹, Bianca Hoeben³,⁴, Andres Morales La Madrid¹⁰, Clemens Seidel¹¹, Rolf-Dieter Kortmann¹¹, Darren Hargrave¹², Lorenza Gandola¹³, Emilia Pecori¹³, Dannis G. van Vuurden¹⁴,⁴, Veronica Biassoni¹⁵, Maura Massimino¹⁵, Christof Kramm¹⁶, Andre O. von Bueren¹,²; ¹Department of Pediatrics, Gynecology and Obstetrics, Division of Pediatric Hematology and Oncology, University Hospital of Geneva, Geneva, Switzerland. ²Cansearch Research platform for pediatric oncology and hematology, Faculty of Medicine, Department of Pediatrics, Gynecology and Obstetrics, Geneva, Switzerland. ³Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, Netherlands. ⁴Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands. ⁵Department of Radiation Oncology, Gustave Roussy Cancer Institute, Paris Saclay University, Villejuif, France. ⁶Department of Radiotherapy, The Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom. ⁷Department of Radiation Oncology, Hospital Vall d'Hebron, Barcelona, Spain. ⁸Department of Radiation Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium. ⁹Department of Clinical Oncology, University Hospital Birmingham, Birmingham, United Kingdom. ¹⁰Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Barcelona, Spain. ¹¹Department of Radiation-Oncology, University Hospital Leipzig, Leipzig, Germany. ¹²Pediatric Oncology Unit, Great Ormond Street Hospital for Children, London, United Kingdom. ¹³Pediatric Radiotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. ¹⁴Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pediatric Oncology, Amsterdam, Netherlands. ¹⁵Pediatrics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. ¹⁶Division of Pediatric Hematology and Oncology, University Hospital Goettingen, Goettingen, Germany

**PURPOSE:** To investigate the spectrum of neurological triad improvement in patients with diffuse intrinsic pontine glioma (DIPG) treated by re-irradiation (re-RT) at first progression. **METHODS:** Re-analysis of the SIOP-E retrospective DIPG cohort by investigating clinical benefits after re-RT with focus on the neurological triad. Patients were divided as "responding" or "non-responding" to re-RT. To assess the interdependence between patients' characteristics and clinical benefits we used a Chi-Square or Fisher's Exact test. Survival according to clinical response to re-RT was calculated by the Kaplan-Meier method. **RESULTS:** As earlier reported, 77% (n = 24/31) of patients had any clinical benefit after re-RT. Among 25/31 well documented patients, 44% (n=11/25) had improvement in cranial nerve palsies, 40% (n=10/25) in long-tract signs, 44% (11/25) in cerebellar signs. Clinical benefits were observed in at least 1, 2 or 3 out of 3 symptoms of the DIPG triad, in 64%, 40% and 24% respectively. Patients irradiated with a dose ≥ 20 Gy versus < 20 Gy may improve slightly better with regards of ataxia (67% versus 23%; *P*-value = 0.028). The survival from the start of re-RT to death was not different between responding and non-responding DIPG patients (*P*-value = 0.871). **CONCLUSION:** A median re-irradiation dose of 20 Gy provides a neurological benefit in two-third of patients with an improvement of at least one symptom of the triad. DIPG patients receiving ≥20 Gy appear to improve slightly better with regards of ataxia, however we need more data to determine whether dose escalation up to 30 Gy provides additional benefit.

### DIPG-25. PATTERNS OF CEREBROSPINAL FLUID DIVERSION AND SURVIVAL IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA: A REPORT FROM THE INTERNATIONAL DIFFUSE INTRINSIC PONTINE GLIOMA REGISTRY

Tabitha Cooney¹, Mariko DeWire-Schottmiller², Adam Lane², Raya Saab³, Pratiti Bandopadhyay¹, Kathleen Dorris⁴, Roger Packer⁵, Lindsay Kilburn⁵, Jane Minturn⁶, Andrew Dodgshun⁷, Sara Parkin⁷, Stewart Goldman⁸, Eric Sandler⁹, Robert Greiner¹⁰, Nicholas Gottardo¹¹, Hetal Dholaria¹¹, Scott Coven¹², Tim Hassall¹³, Jordan Hansford¹⁴, Yvan Samson¹⁵, Sarah Leary¹⁶, Ute Bartels¹⁷, Adriana Fonseca³, Eric Bouffet¹⁷, Christopher Tinkle¹⁸, Michelle Monje¹⁹, Paul Fisher¹⁹, David Ziegler²⁰, Murali Chintagumpala²¹, Lars Wagner²², Carl Koschmann²³, James Leach², Blaise Jones², Elisa Carrasquedo Benito², Hailey Bond², Brooklyn Chaney²⁴, Katie Black², Anthony Asher², Maryam Fouladi²⁴, Lindsey Hoffman⁸, Katherine Warren¹; ¹dana farber cancer institute, boston, ma, USA. ²Cincinnati Children's Hospital, Cincinnati, OH, USA. ³American University of Beirut, Beirut, Lebanon. ⁴Children's Colorado, Denver, CO, USA. ⁵Children's National, D.C., D.C., USA. ⁶Children's Hospital of Philadelphia, Philadelphia, PA, USA. ⁷Christchurch Hospital, Christchurch, New Zealand. ⁸Phoenix Children's, Phoenix, AZ, USA. ⁹Nemour Children's Hospital, Orlando, FL, USA. ¹⁰Penn State Children's Hospital, Hershey, PA, USA. ¹¹Perth Children's Hospital, Nedlands, Australia. ¹²Riley Children's Hospital, Indianapolis, IN, USA. ¹³Queensland Children's Hospital, South Brisbane, Australia. ¹⁴Royal Children's Hospital Melbourne, Melbourne, Australia. ¹⁵CHU Sainte Justine, Montreal, Canada. ¹⁶Seattle Children's, Seattle, WA, USA. ¹⁷Sick Kids, Toronto, Canada. ¹⁸St Jude, Memphis, TN, USA. ¹⁹Stanford University, Stanford, CA, USA. ²⁰Sydney Children's Hospital, Sydney, Australia. ²¹Texas Children's, Dallas, TX, USA. ²²Duke University, Durham, NC, USA. ²³University of Michigan, Detroit, MI, USA. ²⁴Nationwide, Columbus, OH, USA

**BACKGROUND:** There are no standard practice guidelines for cerebrospinal (CSF) diversion for diffuse intrinsic pontine glioma (DIPG), nor clear understanding of potential for palliation and life-prolongation. We evaluated CSF diversion characteristics in children with DIPG to determine incidence, indications, symptom effects, and survival. **METHODS:** Data