tbuckley/cabot-search huggingface dataset:
GCT-12. OUTCOMES OF INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMOURS (NGGCT) TREATED AT A SINGLE UK PROTON CENTRE ACCORDING TO UK CHILDREN’S CANCER AND LEUKAEMIA GROUP (CCLG) GUIDANCE, INCLUDING EARLY IMPROVED OUTCOMES USING WHOLE VENTRICULAR RADIOTHERAPY (WVRT) FOR LOCALISED DISEASE
Authors: Love Goyal, Anna France, Simona Gaito, Rovel J Colaco, Shermaine Pan, Daniel Saunders, Nicola Thorp, Matthew J Murray, James C Nicholson, Thankamma V Ajithkumar, Gillian A Whitfield
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND After SIOP-CNS-GCT-II closed in 2018, the CCLG recommended, with caveats, following standard trial arms: 4 Cisplatin-Etoposide-Ifosfamide (PEI) cycles, then focal radiotherapy (FRT) (54Gy/30fractions) to primary site(s) for localised NGGCT and craniospinal-irradiation (CSI) (30Gy/20fr) + boosts (24Gy/15fr cranial, 20.8Gy/13fr spinal) for metastatic disease. Since 04/2021, the CCLG formally recommended adding WVRT (24Gy/15fr) for localised NGGCT, and considering 2x standard, 2x high-dose PEI for high-risk (HR) cases (diagnostic AFP&amp;gt;1000ng/ml). METHODS Retrospective review of all CNS-NGGCT patients referred 12/2018-06/2023. We collected patient, tumour and treatment factors, acute toxicities (CTCAE grade≥3), and event-free survival (EFS) from radiotherapy until 09/2023. RESULTS Twenty-four patients (21M:3F) included, 14 localised (4xHR), 10 (including 2 incompletely staged) treated as metastatic (3xHR). Median age 11 years, median follow-up 16 months (m). Primary sites: 13 pineal, 5 pituitary/suprasellar, 6 bifocal. Patients were treated according to CCLG guidance. One received FRT without WVRT. One incompletely staged bifocal standard-risk (SR) NGGCT after partial response to PEI had surgery, local+metastatic progression, then second-line chemotherapy before CSI. All seven HR patients received intensified chemotherapy. Nine had post-chemotherapy surgery for residual, two showing necrosis/inflammation, three mature teratoma, two mixed viable GCT. Three relapses (1/17 SR, 2/7 HR) made early EFS 0.875. Of 13 localised patients receiving WVRT, 2 progressed. One bifocal SR patient developed spinal metastases at 5.0m and died despite chemotherapy+spinal irradiation. One unifocal HR patient developed posterior parafalcine metastasis at 3.9m, received GemPOx (Gemcitabine-Paclitaxel-Oxaliplatin), surgery, high dose Carboplatin-Etoposide-Thiotepa with stem-cell rescue, and photon CSI and remains disease-free at 13.2m. One metastatic HR patient progressed at 0.9m and died at 3.0m despite chemotherapy. Acute toxicities were grade 3 lymphopenia in two CSI patients. CONCLUSIONS Despite short follow-up, initial EFS is excellent in SR disease. No localised WRVT-receiving NGGCT patient progressed within the ventricular volume, suggesting benefit of low-dose WVRT.
DIPG-43. CHARACTERIZATION OF THE BLOOD BRAIN BARRIER IN DIPG MURINE MODELS AND EFFECT OF ULTRASOUND ON ITS SPECIFICITIES AND PERMEABILITY TO ASIDNA™
Authors: adam BIARD, DRET LE Ludivine, DUTREIX Marie, CARPENTIER Alexandre, LANCIEN Manon, PELLISSIER Alexandre, Debily Marie-Anne, CASTEL David, GRILL Jacques, BECCARIA Kevin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The poor prognosis of pediatric diffuse midline gliomas, including diffuse intrinsic pontine gliomas (DIPGs), is partly due to the blood-brain barrier (BBB). The BBB can be opened by ultrasound (US), but few studies have focused on its characteristics in DIPGs, especially when submitted to US. We aimed to characterize the BBB in DIPGs and the influence of US on its characteristics, and to evaluate the effect of US-induced BBB opening on the kinetics of AsiDNA™ in DIPG murine models. METHODS US-induced BBB opening was performed with the SonoCloud® device and controlled with Evans blue dye. Permeability of DIPGs’ BBB was assessed with fluorescent dextrans. A histological evaluation of BBB markers was carried out by immunohistochemistry and immunofluorescence, including endothelial markers (CD34, GLUT1, PLAVP), tight junctions proteins (claudin 5, Zona occludens 1), and the efflux transporter ABCB1. An in vivo and ex vivo kinetic study of AsiDNA™ was performed with fluorescence. RESULTS We could repeatedly open the BBB with low intensity US (acoustic pressure 0.4 Mpa). In vivo, 3 kDa and 70 kDa dextrans delivery to DIPG tissue was increased by US-induced opening of the BBB, while 500 kDa dextrans did not cross the BBB spontaneously or after US. ABCB1 gene expression was variable at baseline in different DIPGs but was downregulated after US-induced BBB opening. The spontaneous passage of AsiDNA™ through the BBB was limited but could be increased after US-induced BBB opening. CONCLUSIONS We have shown that the BBB was specific in DIPG murine models, particularly in the expression of ABCB1. This BBB can be modulated and permeabilized by US, a technique that could allow for an improved delivery of AsiDNA. This study is a preliminary step before the introduction of a such technique and treatment in future clinical trials in children and adolescents with DMGs.
DIPG-54. PREDICTING EARLY DEATH IN DIFFUSE MIDLINE GLIOMA
Authors: Sam Moloney, Vickyanne Carruthers, Melissa J Davis, Dharmesh D Bhuva, Cristina Mignone, Susan Singh, Rebecca E Gardiner, Santosh Valvi, David D Eisenstat, Jordan R Hansford
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline glioma (DMG) is an invariably fatal diagnosis with a median survival of 9-11 months. While early death is uncommon, such cases do exist. Identification of children at risk of short-term survival can support clinicians to provide informed counselling to families regarding important treatment decisions. METHODS We identified patients with a radiological diagnosis of DMG at the Royal Children’s Hospital (Melbourne) and the Women’s and Children’s Hospital (Adelaide) between 2001-2023. Clinical, imaging, and histopathological data were abstracted and compared between short-term survivors (STSs) and longer survivors (LSs). RESULTS Among 89 patients included, 21 (24%) had an overall survival (OS) of &amp;lt; 6 months of which 7 (8%) had an OS &amp;lt; 3 months. 5 of these cases had dramatic early death with &amp;lt; 1 month since diagnosis. While neither the pattern nor presence of contrast enhancement were predictive of poor survival, STSs were found to have a larger volume of contrast enhancement on T1-weighted imaging compared to LSs (1.3 cm3 vs 0.2 cm3, p &amp;lt; 0.01). Evaluation of the presence and extent of intratumoural susceptibility signals (ITSS) on susceptibility weighted imaging (SWI) demonstrated higher grades of ITSS (&amp;gt; 5 foci) were strongly associated with poor survival (p = 0.01, median OS = 5.5 months). Furthermore, 50% (6/12) of STSs had ≥ 11 dot-like or fine linear ITSSs in a maximum tumour cross section. From a treatment standpoint, as expected, patients who did not receive upfront radiotherapy experienced significantly worse OS (3.4 months vs 10.4 months, p &amp;lt; 0.01). Notably, a number of STSs did not receive palliative therapy in the context of their rapid and unforeseen disease progression. CONCLUSIONS The preliminary findings from this multi-centre study provide the foundation for future exploratory analysis alongside international collaborators at the DMG/DIPG registry to improve prognostication for patients with high-risk features of early death.
MODL-16. CRANIOSPINAL RADIOTHERAPY IN COMBINATION WITH DNA-DAMAGE RESPONSE INHIBITORS IN PATIENT-DERIVED ORTHOTOPIC XENOGRAFT MODELS OF MEDULLOBLASTOMA
Authors: Hilary Hii, Meegan Howlett, Jessica Buck, Hetal Dholaria, Mani Kuchibhotla, Ranjith Palanisamy, Sally Larder, Jacqueline P Whitehouse, Brooke Carline, Martin A Ebert, Nicholas G Gottardo, Raelene Endersby
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite treatment intensification, survival for high-risk subgroups of medulloblastoma (MB) such as MYC-amplified Group 3 (Gr3-II) and p53-mutant SHH (SHH-3p53mut) have remained dismal with overall survival around 40% and 20% respectively. Our previous studies have shown that the DNA-damage response inhibitors (DDRis) prexasertib and ceralasertib enhance the effects of CSI using medulloblastoma cell line-derived orthotopic mouse models. However, patient-derived orthotopic xenografts (PDOXs) are considered superior models for preclinical testing compared to immortalised cell lines. Here, we developed a CSI protocol for multiple PDOX models of high-risk medulloblastoma and tested the optimal protocol with concurrent DDRis. METHOD For our CSI optimisation studies, MED211FH (Gr3-II) or MED813FH (SHH-3p53mut) tumour-bearing mice were monitored for clinical symptoms of tumour before commencing treatment. Multiple, fractionated CSI dosing schedules using a 5-days-on, 2-days-off treatment cycle were trialled based on our lab’s previously established CSI protocols before a schedule of 10 x 0.5 Gy fractions (5.0 Gy total) proved optimal. This schedule was then used in both PDOX models plus an additional SHH-3p53mut model (MED314mCLFH), either alone or in combination with concurrent prexasertib or ceralasertib. RESULTS MED211FH and MED813FH mice treated with 5.0 Gy CSI alone resulted in significantly improved median survival compared to control mice (p&amp;lt;0.0001 and p&amp;lt;0.005 respectively) While 5.0 Gy CSI plus concurrent prexasertib or ceralasertib showed significantly improved survival when compared to CSI alone for each model used. MED211FH: p&amp;lt;0.01 and p&amp;lt;0.001 respectively, MED813FH: p&amp;lt;0.05 and p&amp;lt;0.01 respectively and MED314mCLFH: p&amp;lt;0.05 for both DDRi combination groups. CONCLUSION Remarkably, concurrent use of prexasertib or ceralasertib with CSI significantly improved survival in fatal Gr3-II and SHH-3p53mut models. With these results, we provide robust preclinical evidence for radiosensitising use of DDRi in paediatric high-risk MB and recommend swift clinical translation.
TRLS-16. RESULTS FROM SJDAWN: A ST JUDE CHILDREN’S RESEARCH HOSPITAL PHASE 1 STUDY EVALUATING MOLECULARLY DRIVEN DOUBLET THERAPIES FOR ALL CHILDREN WITH REFRACTORY OR RECURRENT CENTRAL NERVOUS SYSTEM (CNS) MALIGNANT NEOPLASMS AND YOUNG ADULTS WITH SHH MEDULLOBLASTOMA
Authors: Giles W Robinson, Brent A Orr, Sandeep K Dhanda, Tong Lin, Noah D Sabin, Katie Han, Anna Kostecka, Arzu Onar-Thomas, Martine F Roussel, Clinton Stewart, Amar Gajjar, Paul A Northcott
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric CNS tumors have recurring molecular aberrations that modulate the cell cycle. We hypothesized that ribociclib, a brain-penetrant CDK4/6 inhibitor, given in doublet combinations could benefit patients with CNS malignancies. SJDAWN (NCT03434262) was launched to determine the recommended phase 2 dose (RP2D), safety, pharmacokinetics, and early efficacy of doublets. METHODS Patients &amp;gt;1 and &amp;lt;40 years with recurrent/refractory CNS malignancy were stratified into 3 strata. Escalating dose-levels in 28-day cycles were evaluated in each stratum by rolling-6 design with an expansion cohort at the highest tolerated dose-level. RP2D was declared if ≤3 dose-limiting toxicities (DLTs) occurred in 12 patients. Stratum A evaluated ribociclib/gemcitabine in group3/group4 (Grp3/4) MB and ependymoma (EPN). Stratum B evaluated ribociclib/trametinib in malignancies not eligible for stratum A or C. Stratum C evaluated ribociclib/sonidegib in skeletally mature patients with SHH-MB, TP53 wildtype with chr9q loss and/or PTCH1 mutation. Tumor, blood, and CSF samples were analyzed. RESULTS From 2018-2022, 68 patients enrolled: 33 in A (22 Grp3/4-MB, 11 EPN); 28 in B (15 HGG, 13 other); 7 SHH-MB in C. The RP2D was gemcitabine 1250mg/m2 IV day 1, 15 and ribociclib 350mg/m2 PO 1-21 days for A; trametinib 0.025mg/kg PO days 1-14 and ribociclib 280mg/m2 PO days 7-21 for B; and not established for C. DLTs included neutropenia (A), thrombocytopenia (B), mucositis (B), and rash (C). The 6-, 12-, and 24-month progression-free survival (PFS) was 42%(26%-58%), 18%(8%-33%), and 12%(4%-26%) in A, 18%(7%-34%), 4%(1%-15%), and 0% in B, 71%(30%-92%), 43%(13%-73%), and 0% in C. PFS beyond 2-years was observed in 3 Grp3/4-Subgroup3 MBs and 1 EPN. Amplification of CDK6, CCND2, and MYCN in serial CSF samples suggested a mechanism of resistance. CONCLUSIONS Ribociclib doublets are tolerated, and the lengthy survival of some patients suggests a selective benefit.
EPEN-12. EZHIP IMPACTS CELLULAR DIFFERENTIATION IN POSTERIOR FOSSA GROUP A EPENDYMOMA
Authors: Carola Jaunecker, Anne Jenseit, Theresa Zehetbauer, Natalia Stepien, Shanzheng Wang, Katharina Bruckner, Jens-Martin Hübner, Lisa Gabler, Alexandra Lang, Sibylle Madlener, Leah Mager, Christine Haberler, Walter Berger, Christian Dorfer, Mariella Filbin, Marcel Kool, Johannes Gojo, Daniela Lötsch-Gojo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND High-risk ependymomas are central nervous system tumors comprising ten molecular groups with posterior fossa group A (PFA) and supratentorial ependymoma with zinc finger translocation associated (ST-ZFTA) fusions being among the most aggressive subgroups in children. Loss of H3K27 trimethylation maintained by Enhancer of Zeste homologs Inhibitory Protein (EZHIP) overexpression in PFA or ZFTA-RELA oncofusions in ST-ZFTA ependymoma are known as important driver events. Additionally, we uncovered that high-risk ependymomas arise from undifferentiated cell populations, while more differentiated ependymal-like signatures (e.g. ciliogenic programs) are enriched in prognostically favourable subtypes. METHODS We investigated presence of “ependymal-like” signatures by analysing mRNA expression of selected genes (RSPH1, DNAAF1, SLC47A2, CAPS, CAPS-L) in ependymoma bulk samples (n=90). Gene expression was correlated to clinicopathological characteristics (EZHIP expression, 1q-gain/6q-loss, DNA methylation subtype). Impact on mRNA levels of ependymal-like markers was investigated upon an inducible EZHIP knockdown using lentiviral vectors in EPD210FH PFA cells. RESULTS Ependymal-like markers were significantly lower expressed in ST-ZFTA as compared to spinal and PFB ependymoma. In PFA ependymoma two distinct groups showing either low or high expression of these ependymal-like genes were present. In detail, “ependymal-like-high” PFA were assigned to the PFA-2 subtype which was also confirmed in an independent cohort. EZHIP was strongly negative prognostic in our cohort and the expression was distinctly induced during PFA progression accompanied by increased ependymal-like signature genes. This suggests an impact of EZHIP on cell differentiation processes particularly during PFA progression. Knock-down of EZHIP in EPD210FH PFA cells increased expression of ependymal signature genes associated with ciliogenesis. Next, we will spatially dissect the correlation between EZHIP and ependymal-like genes in primary and recurrent PFA and investigate DNA methylation, histone marks and EZHIP binding at these gene loci. CONCLUSION Overall, our data indicate that ependymal-like cell differentiation is deregulated by EZHIP particularly in progressive PF-A ependymoma.
NFS-24. TUMOR VOLUME IN NEWLY DIAGNOSED OPTIC PATHWAY GLIOMAS ASSOCIATED WITH NF1 (NF1-OPG): PRELIMINARY RESULTS FROM THE INTERNATIONAL MULTICENTER NF1-OPG NATURAL HISTORY STUDY
Authors: Robert Avery, Zhifan Jiang, Abhijeet Parida, Robert Listernick, Grant Liu, Rosalie Ferner, David Gutmann, Peter de Blank, Janice Lasky-Zeid, Nicole Ullrich, Gena Heidary, Miriam Bornhorst, Steven Stasheff, Teena Rosser, Mark Borchert, Simone Arden-Holmes, Maree Flaherty, Trent Hummel, Walker Motley, Kevin Bielamowicz, Paul Phillips, Eric Bouffet, Arun Reginald, David Wolf, Jason Peragallo, David Van Mater, Mays El-Diari, Aimee Sato, Kristina Tarczy-Hornoch, Laura Klesse, Nick Hogan, Nicholas Foreman, Emily McCourt, Jeffrey Allen, Milan Ranka, Cynthia Campen, Shannon Beres, Christopher Moertel, Ray Areaux, Duncan Stearns, Faruk Orge, John Crawford, Henry O’Halloran, Michael Brodsky, Adam Esbenshade, Sean Donahue, Julius Oattes, Alyssa Reddy, Gary Cutter, Marius Linguraru, Michael Fisher
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND NF1-OPGs are amorphous tumors involving either single or multiple locations (optic nerve, chiasm, tract) along the anterior visual pathway (AVP). In this prospective study, we investigated how volumetric MRI measures of the AVP as well as other clinical variables are associated with treatment decisions in children with newly diagnosed NF1-OPGs. METHODS Children with newly diagnosed NF1-OPG whose MRI included a T1-weighted volumetric sequence without significant artifact at their enrollment visit were eligible for inclusion. All subjects underwent a quantitative ophthalmic exam to determine if visual acuity (VA) was normal. The neuro-oncologist/NF1 expert determined whether the subject would be observed or undergo treatment at that baseline visit. Volumetric MRI analysis was automatically performed using a deep learning network that measured AVP volume (mm3). Non-parametric group comparisons and multivariable logistic regression models evaluated the impact of age at enrollment, sex, NF1 inheritance type, AVP volume, and VA on the decision for immediate treatment with chemotherapy versus observation. RESULTS One-hundred twenty-three subjects met inclusion criteria. Subjects assigned to observation (N=112, 44% female) and subjects immediately treated with chemotherapy (N=11, 80% female) at enrollment were of similar age (2.7 and 2.8 years, respectively) and inheritance (p &amp;gt; 0.05). Abnormal VA was present more often in the treatment group (46%) compared to the observation group (17%, p &amp;lt;0.001). AVP volume was significantly greater in the treatment group (4,181.1mm3) compared to the observation group (1,819.8mm3, p &amp;lt;0.001). AVP volume, sex, and VA reached significance in univariable regression, however, in the multivariable regression model only the AVP volume (p &amp;lt; 0.001) was significantly associated with treatment initiation. DISCUSSION Children with greater NF1-OPG AVP volumes are treated more often compared with those with lower volumes. Volumetric measures of NF1-OPGs are a valuable metric in understanding treatment patterns and are positioned to help inform clinical decision making.
MODL-12. REPURPOSING SSRI/SNRI TARGETING NEUROTRANSMITTER SIGNALING TO SENSITIZE DMG TO CDK9 INHIBITORS
Authors: Rebecca L Murdaugh, Brittany R Eberl, Rosemary U Richard, Jack R Tremblay, Alfred Dei-Ampeh, Calla M Olson, Jamie N Anastas
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse Midline Glioma (DMG) comprise a subset of aggressive pediatric brain tumors with few effective therapies. Cyclin-dependent kinase 9 inhibitors (CDK9i) like zotiraciclib (ZTR) are in clinical trials for adult and pediatric glioma, but resistance frequently develops. In this study, we find that co-treatment with CDK9i and brain penetrant, FDA-approved drugs targeting neurotransmitter signaling alters DMG transcription and reduces DMG growth and tumorigenesis. METHODS We conducted drug screens to assess DMG response to a sub-threshold dose of ZTR combined with a library of ~220 bioactive and FDA-approved compounds. Combinatorial effects of CDK9i+SSRI/SNRI treatment were confirmed through in vitro dose curve studies and in orthotopic DMG xenograft models. We identified downstream targets of CDK9i+SSRI/SNRI treatment through phospho-proteomic profiling, RNAseq analysis, immunofluorescence staining, and Western blotting. RESULTS Our targeted drug screens identified SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin and norepinephrine reuptake inhibitors) that increase DMG sensitivity to a low dose of zotiraciclib (ZTR). Follow-up studies confirm that combinations of structurally distinct CDK9i (ZTR, AZD4573) and SSRI/SNRI (sertraline, duloxetine) synergistically reduce DMG growth in neurospheres, induce the apoptotic marker cleaved caspase 3, and reduce the expression of proliferation markers. Additional proteogenomic analyses define downstream targets of CDK9i+SSRI co-treatment, including differential phosphorylation of chromatin regulators and RNA Polymerase 2 (Pol2)-associated elongation factors and splicing machinery. Further RNAseq studies reveal robust transcriptional changes induced by CDK9i+SSRI treatment characterized by altered expression of developmental and synaptic signaling genes. Finally, pilot pre-clinical studies find that CDK9i+SSRI treatment reduces tumor growth and increases progression free survival in a DMG xenograft model. CONCLUSIONS We have identified synergistic CDK9i+SSRI drug combinations that can be applied to alter malignant gene regulation and reduce DMG growth in vitro and in xenografts. These studies provide a basis for a drug-repurposing strategy to combine SSRI/SNRI and CDK9 inhibitors for DMG treatment.
RADT-06. ENCOURAGING OUTCOMES AFTER CRANIO-SPINAL IRRADIATION (CSI) WITH MODERN IMAGE GUIDED INTENSITY MODULATED PROTON THERAPY (IMPT) (IMPT-CSI) IN CHILDREN AND YOUNG ADULTS (AYA)- AN INSTITUTION EXPERIENCE
Authors: UDAY KRISHNA AS, Ganapathy KC, Anindita Das, Preethi S, Manoj Wakde, Dayananda S, Srinivas C, Rakesh Jalali
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Outcomes of IMPT-CSI in children and adolescent-young adults (AYA) treated at our institute over a period of 5 years was analyzed MATERIALS AND METHODS 92 children/AYA were treated by IMPT-CSI. PTV definition of the spine for skeletally immature patients was modified to only the vertebral body without isotropic margins. All plans were multifield optimized for 5 mm robustness (cranio-caudal) &amp; 2.5% range uncertainty. The treatment set-up was confirmed by both orthogonal radiograph and CBCT. Toxicity was graded as per RTOG criteria. RESULTS Median CSI dose of 35GyE in 21 fractions was given to cohort with 74% males, median age of 7 years (2-39 years), consisting of Medulloblastoma (58%), other Embryonal tumours (20%), recurrent Ependymoma (10%), GCT (10%) and others (2%) with 18% being reirradiation and under sedation in 25%. Concurrent chemotherapy was given in 40%. The median V98% for clinical target volumes and V95% for PTVs of the brain, spine and craniospinal were &amp;gt;97%. Isodose 95% covered the cribriform plate completely and optic nerves keeping Dmax to the lens &amp;lt;3.9 GyRBE, critical OARs (mean of the cohort- Cochlea Dmax 28GyE, midline mucosa 23.2GyE, Esophagus 23.2GyE and gonads (testes and ovaries- 0GyE and 0.4GyE). The online set-up verification showed translational and rotational deviation within 2 mm and 0.5 in 94% and 97% of the cases. Radiation dermatitis was Grade 2-40%; Gr3-10%. Neutropenia was Grade 3 in 30%; few needed G-CSF. Less than 10% developed &amp;gt;grade 3 significant weight loss/ anorexia/ mucositis. At median F/U 20 months (6–60m), 12 patients have progressed with PFS of 78% &amp; OS of 87%, best in GCT and worst in Ependymoma (recurrent), 100% vs. 55% (p&amp;lt;0.014) CONCLUSION Outcomes of IMPT-CSI in children and young adults, showed very encouraging dosimetry, toxicity profile and long-term survival.