Clinical Outcomes and Toxicity of First-Line Intensive Chemotherapy in Infant Medulloblastoma: A Single-Center Cohort Study Following AIEOP Recommendations

Clinical Outcomes and Toxicity of First-Line Intensive Chemotherapy in Infant Medulloblastoma: A Single-Center Cohort Study Following AIEOP Recommendations | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Clinical Outcomes and Toxicity of First-Line Intensive Chemotherapy in Infant Medulloblastoma: A Single-Center Cohort Study Following AIEOP Recommendations Giada Del Baldo¹, Valentina Ruscio¹, Antonella Cacchione¹, Annalisa Lo Sasso², and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7366809/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Oct, 2025 Read the published version in Journal of Neuro-Oncology → Version 1 posted 17 You are reading this latest preprint version Abstract Purpose: The long-term neurocognitive impact of craniospinal irradiation (CSI) in young children with medulloblastoma (MB) has driven the development of alternative strategies aimed at improving survival while delaying or avoiding CSI. Methods: We retrospectively analyzed a cohort of patients under 5 years of age with MB treated at Bambino Gesù Children’s Hospital between 2007–2023 with intensive chemotherapy regimens according to AIEOP recommendation. Clinical, radiological, histopathological, molecular, neurocognitive, and toxicity data were collected. Survival was estimated using the Kaplan–Meier method, with group comparisons by log-rank test. Results : Among 42 patients under 5 years, 25 met inclusion criteria (median age 25.3 months). Histology included classic (52%), desmoplastic/nodular (24%), extensive nodularity (16%), and large cell/anaplastic (8%). SHH was the most common molecular subgroup (52%), followed by Group 3 (32%) and Group 4 (16%). At a median follow-up of 95.7 months, 68% of patients were alive and in complete remission. Two- and 5-year OS were 80.0% and 65.9%, respectively; PFS was 72.0% and 67.8%. All patients experienced grade 3–4 hematological toxicity; late endocrine effects occurred in four patients and no other long-term toxicities were reported. Mean IQ was stable from diagnosis (85.3) to last follow up (83.4). Conclusion : Our retrospective study of infants MB treated with first-line intensive chemotherapy shows encouraging survival rates, better than reported in the literature to date. Importantly, neurocognitive function was preserved over time, supporting radiation-sparing strategies, and toxicity was manageable in all cases. medulloblastoma young children intensive chemotherapy neurocognitive outcome radiation-sparing strategies Figures Figure 1 Figure 2 INTRODUCTION Young children diagnosed with medulloblastoma (MB) present a significant clinical challenge due to the heightened sensitivity of the developing brain to neurotoxic treatments. Although craniospinal irradiation (CSI) remains a cornerstone of therapy, its long-term neurocognitive side effects ( 1 , 2 ) have driven the development of alternative strategies aimed at improving survival while delaying or avoiding CSI. The role of focal radiotherapy, with or without chemotherapy, remains debated (COGP9934, SJYC07), and early chemotherapy-based attempts to defer radiotherapy led to poor survival ( 3 , 4 ). Intensive regimens with high-dose chemotherapy (HDC) and stem cell rescue (ASTC) improved survival ( 5 , 6 ) such as intraventricular or high-dose methotrexate (MTX) ( 7 , 8 ). Therefore, CSI is generally avoided before the age of 3 years, and radiation-sparing techniques such as intensity-modulated radiation therapy (IMRT) and proton beam therapy (PBT) have been developed to minimize neurocognitive damage ( 9 ). In selected cases, and following multidisciplinary tumor board consensus, CSI deferral beyond the age of 5 years may be considered ( 10 ). Furthermore, over the past 15 years, molecular and histopathological advances have redefined MB as four distinct subgroups (WNT, SHH, Group 3, and Group 4) each with unique biological and clinical profiles. In early childhood, most cases are SHH or Group 3: Group 3 often shows MYC amplification, high metastatic risk, and poor prognosis, whereas infant SHH-MB, typically linked to SUFU or PTCH1 mutations, generally has a favourable outcome. Moreover, several studies have explored the molecular heterogeneity of SHH MB. Integrated analysis of DNA methylation and gene expression profiles has identified four subtypes: SHH-1 (β), SHH-2 (ɣ), SHH-3 (α), and SHH-4 (δ) ( 11 ), each associated with distinct clinical outcomes, with SHH-2 (ɣ) and SHH-4 (δ) generally exhibiting a more favorable prognosis ( 11 ). These findings challenge the traditional view that younger age alone is a negative prognostic factor and underscore the critical role of molecular stratification to tailor personalized, effective, and less toxic therapeutic approaches ( 12 – 14 ). This study evaluates the outcomes of intensive chemotherapy regimen administered according to AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) guidelines for infant MB patients, analyzing survival, clinical characteristics, cognitive function, and treatment-related toxicities within this cohort. MATERIAL AND METHODS Patients Data were retrospectively collected from 42 children (23 females, 19 males) diagnosed with MB before age 5 and treated at Bambino Gesù Children’s Hospital between 2007 and 2023. The inclusion criteria for this study were as follows: patients younger than 5 years at diagnosis, not eligible for active clinical trials, with histologically confirmed MB, who had received frontline treatment in accordance with the AIEOP recommendations (15). Medical records were reviewed for demographics, neuroimaging, surgery, hydrocephalus management, histological/molecular data, cancer predisposition syndromes, chemotherapy details, and neuropsychological assessments. Data on outcomes, last follow-up, status at follow-up, and relapse treatments (if any) were also collected. The study was approved by the Institutional Review Board of Bambino Gesù Children’s Hospital and conducted in accordance with the Helsinki Declaration. Radiological assessment: diagnosis and treatment response All patients eligible for the analysis underwent a magnetic resonance imaging (MRI) protocol on a 3 Tesla scanner (Siemens, Erlangen, Germany) under sedation. The protocol involved study of the brain and spine in the same session with the following sequences: T2 TSE (slice thickness 3 mm), DWI with ADC maps (b = 0,1000, 3 mm), SWI (1,5 mm) and volumetric FLAIR (1 mm) and T1 SPACE (< 1 mm). The study of the spine was performed with sagittal T1 and T2 TSE (2 mm) and axial T1 (2 mm). Regarding MRI analysis, two neuroradiologists evaluated in consensus the conventional tumor parameters according to RAPNO (Response Evaluation in Pediatric Neuro-Oncology) guidelines for MB and leptomeningeal seeding tumors (16). Histopathological and molecular characterization For the analysis, all cases were reclassified according to the updated 2021 WHO classification of pediatric brain tumors (17). Immunoistochemistry was carried out on formalin-fixed paraffin-embedded sections using an automated immunostainer (Dako Omnis, Agilent, Santa Clara, CA USA). P53 was interpreted as overexpressed when nuclear staining was seen in 50% of the neoplastic cells or more. Ki67 was expressed as percentage of positive neoplastic cells. For NGS analysis, DNA was extracted from formalin-fixed paraffin-embedded tumor tissue using the Maxwell CSC instrument (Promega, Madison, USA) with the Maxwell RSC DNA FFPE kit (Promega, Madison, USA) according to the manufacturer’s protocol. DNA concentrations were measured using a Qubit 2.0 Fluorometer (Thermo Fisher Scientific, Waltham, USA) using the Qubit dsDNA High Sensitivity. A comprehensive genomic profiling was performed in NGS, targeting 523 cancer-related genes. NGS data were analyzed with the Illumina TruSight Oncology 500 Local App v2.1, and variant report files were uploaded to the Pierian Clinical Genomics Workspace cloud (Pierian DX software CGW_V6.21.1). The status of TP53 was assessed using immunohistochemistry; diffuse expression of the protein was considered indicative of a somatic mutation. The amplification status of MYC and NMYC was evaluated in all patients at diagnosis using Fluorescent in Situ Hybridization (FISH) by a central re-viewer. All cases underwent histological evaluation by the Department of Anatomical Pathology at the Sapienza University of Rome. Methylation profile The methylation profile was prospectively studied starting in 2017 and retrospectively in all cases predating the implementation of the technique in Italy. Methylation profiling was assessed using the Illumina Infinium Human Methylation EPIC Bead Chip (EPIC) arrays. Tumor areas with the highest number of neoplastic cells (>70%) were chosen for DNA extraction (approximately 500 ng), using both fresh frozen tissue samples and FFPE (formalin-fixed paraffin-embedded) samples. The technique requires 4 days to be processed and is divided into 8 phases: DNA quantification; Bisulfite conversion; DNA amplification; DNA fragmentation; Precipitation and Resuspension; Hybridization on the HumanMethylation800 BeadChip; Xstain (Extension and Staining); HumanMethylation800 BeadChip scanning. Cancer predisposition syndrome Genomic DNA was extracted, using the DNA Blood Mini Kit (Qiagen, Hilden, NW, Germany) according to the manufacturer's instructions, from circulating leukocytes of peripheral blood samples, after obtaining informed consent. DNA quantification was performed by Qubit fluorimeter (Life Technologies, Carlsbad, California, USA) with the dsDNA HS Assay kit following the manufacturer's instructions. The genetic analysis was performed through Next Generation Sequencing (NGS) by using a custom clinical exome panel containing more than 8,500 genes, including those involved in DNA cancer-predisposition syndromes (Twist Bioscience, South San Francisco, CA, USA) on a NovaSeq 6000 platform (Illumina, San Diego, CA, USA). Surgery Maximal safe microsurgical resection, whenever feasible, was performed at the time of first diagnosis by occipital craniotomy in prone position. Instead, biopsy was considered if resection of the principal posterior fossa lesion would not significantly reduce local mass effect and disease load due to massively disseminated disease. Our institutional policy included navigation assistance and intraoperative monitoring in all cases. Symptomatic hydrocephalus was treated before surgical resection by endoscopic third ventriculostomy (ETV). Ventriculo-peritoneal (VP) shunt was considered only after documented failure of ETV or in presence of documented cisternal blockage by disseminated disease. If extensive spinal dissemination was present an intraventricular access device was positioned to overcome the need for therapeutic spinal taps. Treatment All 25 patients included in the study received chemotherapy regimens based on the AIEOP indications. It consisted of three courses of chemotherapy: methotrexate (8000 mg/m2) and vincristine (1,5 mg/m2) on day 1, etoposide (2400 mg/m2) on day 8, cyclophosphamide (4000 mg/m2) and vincristine (1,5 mg/m2) on day 28. Based on radiological response and histopathological/molecular characteristics, the treatment was continued with two cycles of high-dose chemotherapy with Thiotepa 900 mg/m2 and ASCT. If residual disease and/or metastases persist after two high-dose chemotherapy cycles and the patient is not eligible for second-look surgery, or if residual disease persists after a second surgery, a third cycle of high-dose chemotherapy with thiotepa (750 mg/m²) and carboplatin (1 g/m²) was planned (15). As second-line treatment, chemotherapy and/or radiation therapy were administered. CSI consisted of a dose of 36 Gy, with a boost of 18 Gy to the posterior fossa and disease sites, for a total dose of 54 Gy. PBT became available in Italy starting in June 2015. In PBT, a uniform vertebral dose was delivered, with the Clinical Target Volume including the whole brain (cribriform plate and proximal optic nerves) and the entire spine (subarachnoid space, vertebral body, nerve roots) down to the thecal sac end (S2–S3). Neurocognitive assessment Cognitive assessments were conducted at multiple time points: at diagnosis, at one year from diagnosis and during follow-up one year after the last evaluation. Age-appropriate, validated tools were used, including the Griffiths Mental Development Scales (GMDS) and the Wechsler Intelligence Scale for Children – Fourth Edition (WISC-IV) (18). The GMDS evaluates overall development in children from birth to 8 years across five domains: gross motor skills, personal-social behavior, language development, fine motor coordination, and performance abilities (19). The WISC-IV provides a full-scale IQ and four composite indices; for this study, only the overall cognitive level was considered (20). Toxicity evaluation All patients underwent regular follow-up during and after treatment, per institutional protocols. Hematologic toxicity was monitored throughout therapy and follow-up. Endocrine evaluations (ACTH, Cortisol, IGF-1, GH, FSH, LH, TSH, FT4, testosterone, 17β-estradiol) were performed at baseline, 12, and 24 months post stop-therapy. Cardiac function (ECG, echocardiogram, clinical exam) was assessed at baseline and 18–24 months. Pulmonary toxicity was evaluated by spirometry at baseline and 18–24 months, with lung diffusion tests if indicated. Audiometric exams were done at baseline and 18–24 months post-treatment to assess ototoxicity. Toxicities were graded according to CTCAE v5.0 criteria (19). Statistical analysis Data entry and cleaning processes were conducted using Microsoft Excel. Descriptive statistics were reported as counts and percentages for categorical variables and median and interquartile range (IQR) for continuous variables. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method. OS was defined as the time from the date of diagnosis to death from any cause or last follow-up. EFS was defined as the time from the date of diagnosis to the date of the first progression, to the date of death from any cause, or the date of the last follow-up. The Logrank non-parametric test for comparison of survival distributions was used to compare survival differences between groups. The alpha risk was set to 5.0%. Data analyses were performed utilizing Prism GraphPad 10.0 version software. RESULTS During the 16-year period, we identified a total of 42 patients with infant MB, with a median age at diagnosis of 31.67 months (range 5.10–58.03). Twenty-five patients matched the inclusion criteria and were enrolled in the study, including 12 male and a 13 female with a median age at diagnosis of 25.27 months (range 5–51.33 months). Forty-four percent of patient were metastatic at diagnosis. Patient' characteristics are detailed in Table 1 . Table 1 Patient’s charcteristics Variable N Mean (SD) Count (%) 95% CI Min Max Q1 Q3 Median IQ diagnosis 19 85.32 (24.43) 73.54 97.09 40 130 72.5 103.5 88 IQ 1 year 19 78.47 (21.74) 67.99 88.95 30 115 65.5 92.5 82 IQ last FU 10 83.35 (28.12) 63.23 103.47 22.5 111 68.25 104.75 92.5 Surgical management At diagnosis, 17/25 patients had hydrocephalus; 15 underwent endoscopic third ventriculostomy (ETV), one received a VP shunt, and one a ventricular access device. All patients had surgery: 15 gross total resections (GTR), 2 near-total (NTR), 6 subtotal (STR), and 2 biopsies. One patient experienced severe postoperative complications requiring tracheostomy and gastrostomy; two had transient neurological deficits that improved. Cerebellar Mutism Syndrome (CMS) occurred in 5 of 18 evaluable patients and was fully reversible. Pathology and molecular findings At histological examination 13/25 cases were classified as classic, 6/25 desmoplastic nodular (DNMB), 4/25 with extensive nodularity (MBEN), and 2/25 large cell/anaplastic (LCA). DNA methylation profile highlighted the SHH subgroup as the most representative (13/25) with TP53 status wild type in all cases, followed by group 3 (8/25) and group 4 (4/25). MYC amplification was detected in only 3 cases of group 3 MB. Cancer predisposition syndrome Five patients carried likely pathogenic or pathogenic variants. P5 and P20 were diagnosed with Gorlin syndrome, both carrying heterozygous SUFU variants: c.16delC (P5) and c.364delT (P20), the latter with a maternal history of basal cell carcinomas. P6 had a likely pathogenic POLE variant (c.2584_2585delGA); her family history included breast cancer. P13 carried a GPR161 variant (c.714dupG) inherited from her father, with limited cancer history but a report of macrocrania in a paternal uncle. P18 was diagnosed with Tatton-Brown-Rahman syndrome due to a DNMT3A variant (c.427C > T), inherited from the father. P23 had Cowden syndrome with a de novo PTEN alteration (c.79T > A) and clinical features including MB, intestinal polyposis, and macrocrania. P24 carried biallelic MUTYH variants (c.1353_1355delCCT and c.228G > T), with familial history of gastrointestinal and gynecological cancers. Molecular and histological details are reported in supplementary table. Survival an outcome Median OS for the whole population was 58 months (range 8.70-173.9). Seventeen out of 25 patients are alive and in complete remission with a median follow-up of 95.7 months (range 28.2-173.9). Three patients progressed during first-line treatment, and five relapsed after achieving complete remission at a median time of 7.6 months (range 2-24.2) after stop therapy. Chemotherapy was administered in all but one case. Four patients received CSI: 2 with standard radiotherapy and 2 with PBT. Of the relapsed/progressed patients, only one remained alive and he is the patient re-irradiated with PBT. All other patients died after a median of 5.2 months after relapse/progression. One patient died of treatment-related toxicity. At 2 years, OS was 80.0% (95% CI: 58.4–91.1) and PFS was 72.0% (95% CI: 50.1–85.5); at 5 years, OS was 65.9% (95% CI: 42.8–81.4) and PFS was 67.8% (95% CI: 45.7–82.4) (Fig. 1 a-b). No statistically significant differences in survival were observed by histotype (p = 0.462), molecular subgroup (p = 0.09), disease status (p = 0.139), or extent of resection (p = 0.37) (Fig. 1 c-f). Nonetheless, MBEN cases showed better outcomes compared to other histotypes, SHH cases tended toward improved survival, localized disease showed a favorable trend, and GTR/NTR resections were associated with better outcomes than STR/biopsy. Patients who developed CMS had worse outcomes than those without CMS (p = 0.35) (Fig. 1 g). All five patients with CPS and infant MB were alive at the last follow-up. Cognitive assessment Mean IQ at diagnosis was 85.32 ± 23.78; 78.47 ± 21.16 at one year from diagnosis and 83.35 ± 26.68 at the last follow-up, without difference between different time points (Table 2 and Fig. 2 ). Importantly, even in the single surviving patient who underwent CSI with PBT, no significant change in IQ was observed. Table 2. Descriptive statistics of IQ scores at diagnosis, 1 year after diagnosis, and at last follow-up. Variable N Mean (SD) Count (%) 95% CI Min Max Q1 Q3 Median IQ diagnosis 19 85.32 (24.43) 73.54 97.09 40 130 72.5 103.5 88 IQ 1 year 19 78.47 (21.74) 67.99 88.95 30 115 65.5 92.5 82 IQ last FU 10 83.35 (28.12) 63.23 103.47 22.5 111 68.25 104.75 92.5 Toxicity In our cohort, all patients experienced hematological toxicity during standard chemotherapy regimen, especially of grade 3–4 according to CTCAE v5.0. In particular, grade 3–4 neutropenia was detected in all 25 patients, in 14 cases with fever associated. Grade 3–4 thrombocytopenia and grade 3 anemia were assessed in 18 and 11 patients, respectively. No grade 5 toxicities have been detected. Twenty-two patients experienced liver toxicity, with elevated transaminase levels, although only half of them showed a moderate-severe grade toxicity. Regarding endocrinological toxicities, the majority of patients (22 out of 25) did not show any hormonal impairment during follow-up evaluations. Four out of 25 patients presented endocrinological sequelae, including: growth hormone deficiency associated with delayed puberty (1/4) and hypothyroidism (1/4), delayed pubertal development requiring hormone replacement therapy (1/4), and suspected primary ovarian insufficiency currently under investigation (1/4). Median time of onset of endocrinological sequelae is 55.5 months after the end of therapy (range 37–91 months). The patient with growth retardation and hypothyroidism had been treated with PBT, while the other three had not received radiation therapy. No audiological, renal, cardiac or pulmonary toxicities have been reported. No life-threatening events were observed. Discussion Young children diagnosed with MB present a significant clinical challenge due to the vulnerability of the developing brain to neurotoxic treatments. Historically, CSI has been the standard of care for MB, but its use in very young children is limited by the risk of severe long-term neurocognitive impairment. This concern has driven adoption of alternative strategies, such as intensive chemotherapy regimens to improve survival while minimizing late effects. In the 1980s early collaborative trials using conventional chemotherapy to defer radiotherapy resulted in high progression rates and poor survival outcomes ( 3 , 4 ). Subsequently, more intensive approaches were introduced, including chemotherapy followed by HDC/ASCT ( 5 , 6 ), as well as regimens incorporating intraventricular or high-dose MTX ( 7 , 8 ); both resulted in increased survival. This retrospective study aims to describe the clinical features, treatment outcomes, and toxicities in a cohort of patients under 5 years of age with MB, treated with a first-line intensive chemotherapy according to AIEOP recommendations. In our cohort of infants with MB, the 2- and 5-year survival rates were encouraging albeit in a relatively small patient population, with an OS of 80.0% (95% CI: 58.4–91.1) at 2 years and 65.9% (95% CI: 42.8–81.4) at 5 years. Similarly, PFS was 72.0% (95% CI: 50.1–85.5) at 2 years and 67.8% (95% CI: 45.7–82.4) at 5 years. Although comparative studies are few and heterogeneous, our survival outcomes exceed those reported by Robinson et al., who observed, in their cohort, a 5-year OS of 59.4% (95% CI, 45.7–73.1) and an event-free survival of 31.3% (95% CI, 19.3–43.3) ( 10 ). Notably, the curves at 5 years for PFS and OS are nearly superimposable, strongly indicating that relapse remains the principal determinant of mortality in this population. In fact, all patients but one who experienced relapse or progression died of their disease, with a median post-relapse survival of just 5.2 months, including 3 of 4 patients who received CSI as second-line treatment. Salvage therapy, which often includes CSI radiotherapy, does not always improve outcomes after relapse and can increase treatment-related morbidities from successive therapies ( 21 ). Moreover, there was no statistically significant difference in survival distributions by histotype, molecular subtype, status of disease, entity of resection and CMS. However, consistent with previous reports ( 10 ), MBEN cases showed better survival outcomes compared to other histotypes, such as SHH-subgroup, localized disease, GTR or NTR. Patients who did not develop CMS also appeared to have better outcomes. These findings suggest potential differences that could not reach statistical significance likely because of the small cohort size, highlighting the need for studies with larger samples to confirm these trends. Notably all 5 patients with CPS are alive at last follow-up. Neurocognitive outcomes in our cohort were overall reassuring. The mean IQ at diagnosis was 85.32 ± 23.78, and remained stable over time. In the only relapsed patient who survived and who received proton CSI, treatment was well tolerated and was not associated with any long-term neurocognitive impairments. These findings suggest that, in the context of treatment strategies aimed at minimizing neurotoxicity, cognitive function can be preserved in long-term survivors. Our data are in line with previous studies reporting better neurocognitive profiles in patients treated with chemotherapy-based approaches and radiation-sparing techniques ( 22 ). Hematological toxicity was common as expected ( 10 ), with all patients experiencing grade 3–4 neutropenia, and frequent thrombocytopenia and anemia. Endocrinological toxicities were rare, affecting 4 patients, mostly as delayed growth or pubertal issues. Of them, only one of these patients had received CSI PBT. No cardiac, renal, pulmonary, auditory, or ocular toxicities were reported. Furthermore, several studies have shown that risk stratification in MB identifies patient groups with distinct outcomes, enabling treatment de-escalation to reduce toxicity and side effects in low-risk groups ( 23 , 24 ). In the SJYC07 trial, 5-year progression-free survival was 27.8% for iSHH-I and 75.4% for iSHH-II, suggesting that patients with iSHH-II may benefit from reduced-intensity therapy ( 10 ). Last but not least, ongoing research is exploring innovative therapeutic strategies that may improve the prognosis of these patients. Among these, immunotherapy has recently gained increasing attention. For instance, Donovan et al. investigated locoregional delivery of CAR T cells targeting MB-associated antigens (EPHA2, HER2, IL-13), demonstrating efficacy in metastatic Group 3 MB mouse models ( 18 ). Similarly, Ciccone et al. showed that, in orthotopic mouse models, systemic administration of CAR.GD2 T-cells markedly inhibited tumor growth and significantly prolonged OS ( 25 ). Nevertheless, optimizing tumor immunogenicity remains a critical step for the successful clinical translation of these approaches ( 9 ). Conclusions Medulloblastoma in young children poses significant treatment challenges due to the risks of neurotoxicity from CSI irradiation. Our retrospective study of infants MB treated with intensive first-line chemotherapy shows encouraging survival rates, better than reported in the literature to date. Importantly, neurocognitive function was preserved over time, supporting radiation-sparing strategies. Toxicities were manageable, and proton therapy at relapse showed promising safety. These findings support chemotherapy-based strategies and underscore the need for collaborative studies, ongoing research in targeted and immunotherapies, and long-term monitoring to enhance survival and quality of life. Declarations Author contributions GDB, ACar, AM, contributed to the study conception and design. Material preparation and data collection were performed by GDB, VDR, ACac, ALS, LC, CD, ADS, GA, SC, EM, IG, SR, GSC, SV, AC. Data analysis was performed by GDB. The first draft of the manuscript was written by GDB and VDR; all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Data availability All data generated or analysed during this study are included in the published article, its tables, and the supplementary material. The authors have nothing to declare. Competing interests The authors declare no competing interests. Ethics approval The study was conducted by the Declaration of Helsinki and approved by the Institutional Review Board of Bambino Gesù Children’s. Code of Approval: RAP-2025-002. Acknowledgments The authors thank the association “Il Laboratorio di Chiara” for the support. References Walker DA, Liu J, Kieran M, et al (2013) A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method. 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Rutkowski S, von Hoff K, Emser A, et al (2010) Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol 28(33):4961–4968. doi: 10.1200/JCO.2010.30.2299. Ciccone R, Quintarelli C, Camera A, et al (2024) GD2-Targeting CAR T-cell Therapy for Patients with GD2+ Medulloblastoma. Clin Cancer Res 30(11):2545–2557. doi: 10.1158/1078-0432.CCR-23-1880. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7366809","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":503655802,"identity":"a30ddc4f-5b1d-41ab-a18f-833c5f5de81a","order_by":0,"name":"Giada Del Baldo¹","email":"","orcid":"","institution":"Bambino Gesù Children's Hospital, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Giada","middleName":"Del","lastName":"Baldo¹","suffix":""},{"id":503655803,"identity":"a7f84908-82dc-4df1-83a5-9647e4e25177","order_by":1,"name":"Valentina Ruscio¹","email":"","orcid":"","institution":"Bambino Gesù Children's Hospital, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Valentina","middleName":"","lastName":"Ruscio¹","suffix":""},{"id":503655804,"identity":"2b562b69-f592-4931-8b80-a45e3d758fbe","order_by":2,"name":"Antonella Cacchione¹","email":"","orcid":"","institution":"Bambino Gesù Children's Hospital, IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Antonella","middleName":"","lastName":"Cacchione¹","suffix":""},{"id":503655805,"identity":"1ab41478-ba1f-478b-8f0c-d5f8d5c0ca50","order_by":3,"name":"Annalisa Lo Sasso²","email":"","orcid":"","institution":"University of Udine","correspondingAuthor":false,"prefix":"","firstName":"Annalisa","middleName":"Lo","lastName":"Sasso²","suffix":""},{"id":503655806,"identity":"8e0e8389-f036-45f0-ae80-8be22621b2b2","order_by":4,"name":"Ludovica Corvino³","email":"","orcid":"","institution":"UniCamillus – Saint Camillus International University of Health 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Mastronuzzi¹","email":"data:image/png;base64,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","orcid":"","institution":"Bambino Gesù Children's Hospital, IRCCS","correspondingAuthor":true,"prefix":"","firstName":"Angela","middleName":"","lastName":"Mastronuzzi¹","suffix":""}],"badges":[],"createdAt":"2025-08-13 16:23:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7366809/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7366809/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11060-025-05301-9","type":"published","date":"2025-10-29T15:57:57+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89657437,"identity":"e0cfd7a7-46a5-4777-affe-1460b701f5d5","added_by":"auto","created_at":"2025-08-22 10:34:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":216336,"visible":true,"origin":"","legend":"\u003cp\u003ea. Kaplan–Meier curve showing OS over time.\u003c/p\u003e\n\u003cp\u003eb. Kaplan–Meier curve showing PFS over time.\u003c/p\u003e\n\u003cp\u003ec. Kaplan–Meier curves showing OS stratified by histological subtype.\u003c/p\u003e\n\u003cp\u003ed. Kaplan–Meier curves showing OS stratified by molecular subtype.\u003c/p\u003e\n\u003cp\u003ee. Kaplan–Meier curves showing OS stratified by disease status.\u003c/p\u003e\n\u003cp\u003ef. Kaplan–Meier curves showing OS stratified by entity of resection\u003c/p\u003e\n\u003cp\u003eg. Kaplan–Meier curves showing OS stratified by CMS.\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7366809/v1/96ae99a8f761dbf817f5ddbf.png"},{"id":89657436,"identity":"752490b1-62f7-4613-a69c-dd68a94a2afd","added_by":"auto","created_at":"2025-08-22 10:34:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":47627,"visible":true,"origin":"","legend":"\u003cp\u003eBoxplots showing the distribution of IQ scores at three timepoints: at diagnosis, 1 year after diagnosis, and at last follow-up.\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7366809/v1/cf5934d5e76f68a8657db21e.png"},{"id":95041366,"identity":"51280bc2-f563-40a4-829a-f9ddd14dbd84","added_by":"auto","created_at":"2025-11-03 16:11:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1021885,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7366809/v1/9c923d2c-0d01-48a1-8b09-fc85409c3fe0.pdf"},{"id":89655833,"identity":"55edf808-cc69-4781-a295-d8546e8ea4ac","added_by":"auto","created_at":"2025-08-22 10:26:43","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19274,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarytable.docx","url":"https://assets-eu.researchsquare.com/files/rs-7366809/v1/bdfe761ee48f7b302e6def22.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical Outcomes and Toxicity of First-Line Intensive Chemotherapy in Infant Medulloblastoma: A Single-Center Cohort Study Following AIEOP Recommendations","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eYoung children diagnosed with medulloblastoma (MB) present a significant clinical challenge due to the heightened sensitivity of the developing brain to neurotoxic treatments. Although craniospinal irradiation (CSI) remains a cornerstone of therapy, its long-term neurocognitive side effects (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) have driven the development of alternative strategies aimed at improving survival while delaying or avoiding CSI.\u003c/p\u003e\u003cp\u003eThe role of focal radiotherapy, with or without chemotherapy, remains debated (COGP9934, SJYC07), and early chemotherapy-based attempts to defer radiotherapy led to poor survival (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Intensive regimens with high-dose chemotherapy (HDC) and stem cell rescue (ASTC) improved survival (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) such as intraventricular or high-dose methotrexate (MTX) (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Therefore, CSI is generally avoided before the age of 3 years, and radiation-sparing techniques such as intensity-modulated radiation therapy (IMRT) and proton beam therapy (PBT) have been developed to minimize neurocognitive damage (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In selected cases, and following multidisciplinary tumor board consensus, CSI deferral beyond the age of 5 years may be considered (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eFurthermore, over the past 15 years, molecular and histopathological advances have redefined MB as four distinct subgroups (WNT, SHH, Group 3, and Group 4) each with unique biological and clinical profiles. In early childhood, most cases are SHH or Group 3: Group 3 often shows MYC amplification, high metastatic risk, and poor prognosis, whereas infant SHH-MB, typically linked to SUFU or PTCH1 mutations, generally has a favourable outcome. Moreover, several studies have explored the molecular heterogeneity of SHH MB. Integrated analysis of DNA methylation and gene expression profiles has identified four subtypes: SHH-1 (β), SHH-2 (ɣ), SHH-3 (α), and SHH-4 (δ) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), each associated with distinct clinical outcomes, with SHH-2 (ɣ) and SHH-4 (δ) generally exhibiting a more favorable prognosis (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). These findings challenge the traditional view that younger age alone is a negative prognostic factor and underscore the critical role of molecular stratification to tailor personalized, effective, and less toxic therapeutic approaches (\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e This study evaluates the outcomes of intensive chemotherapy regimen administered according to AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) guidelines for infant MB patients, analyzing survival, clinical characteristics, cognitive function, and treatment-related toxicities within this cohort.\u003c/p\u003e"},{"header":"MATERIAL AND METHODS","content":"\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were retrospectively collected from 42 children (23 females, 19 males) diagnosed with MB before age 5 and treated at Bambino Gesù Children’s Hospital between 2007 and 2023.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria for this study were as follows: patients younger than 5 years at diagnosis, not eligible for active clinical trials, with histologically confirmed MB, who had received frontline treatment in accordance with the AIEOP recommendations (15).\u003c/p\u003e\n\u003cp\u003eMedical records were reviewed for demographics, neuroimaging, surgery, hydrocephalus management, histological/molecular data, cancer predisposition syndromes, chemotherapy details, and neuropsychological assessments. Data on outcomes, last follow-up, status at follow-up, and relapse treatments (if any) were also collected.\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Institutional Review Board of Bambino Gesù Children’s Hospital and conducted in accordance with the Helsinki Declaration.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRadiological assessment: diagnosis and treatment response\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients eligible for the analysis underwent a magnetic resonance imaging (MRI) protocol on a 3 Tesla scanner (Siemens, Erlangen, Germany) under sedation. The protocol involved study of the brain and spine in the same session with the following sequences: T2 TSE (slice thickness 3 mm), DWI with ADC maps (b = 0,1000, 3 mm), SWI (1,5 mm) and volumetric FLAIR (1 mm) and T1 SPACE (\u0026lt; 1 mm). The study of the spine was performed with sagittal T1 and T2 TSE (2 mm) and axial T1 (2 mm).\u003c/p\u003e\n\u003cp\u003eRegarding MRI analysis, two neuroradiologists evaluated in consensus the conventional tumor parameters according to RAPNO (Response Evaluation in Pediatric Neuro-Oncology) guidelines for MB and leptomeningeal seeding tumors (16).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHistopathological and molecular characterization \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the analysis, all cases were reclassified according to the updated 2021 WHO classification of pediatric brain tumors (17). Immunoistochemistry was carried out on formalin-fixed paraffin-embedded sections using an automated immunostainer (Dako Omnis, Agilent, Santa Clara, CA USA). P53 was interpreted as overexpressed when nuclear staining was seen in 50% of the neoplastic cells or more. Ki67 was expressed as percentage of positive neoplastic cells. For NGS analysis, DNA was extracted from formalin-fixed paraffin-embedded tumor tissue using the Maxwell CSC instrument (Promega, Madison, USA) with the Maxwell RSC DNA FFPE kit (Promega, Madison, USA) according to the manufacturer’s protocol. DNA concentrations were measured using a Qubit 2.0 Fluorometer (Thermo Fisher Scientific, Waltham, USA) using the Qubit dsDNA High Sensitivity. A comprehensive genomic profiling was performed in NGS, targeting 523 cancer-related genes. NGS data were analyzed with the Illumina TruSight Oncology 500 Local App v2.1, and variant report files were uploaded to the Pierian Clinical Genomics Workspace cloud (Pierian DX software CGW_V6.21.1). The status of TP53 was assessed using immunohistochemistry; diffuse expression of the protein was considered indicative of a somatic mutation. The amplification status of MYC and NMYC was evaluated in all patients at diagnosis using Fluorescent in Situ Hybridization (FISH) by a central re-viewer. All cases underwent histological evaluation by the Department of Anatomical Pathology at the Sapienza University of Rome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethylation profile\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe methylation profile was prospectively studied starting in 2017 and retrospectively in all cases predating the implementation of the technique in Italy. Methylation profiling was assessed using the Illumina Infinium Human Methylation EPIC Bead Chip (EPIC) arrays. Tumor areas with the highest number of neoplastic cells (\u0026gt;70%) were chosen for DNA extraction (approximately 500 ng), using both fresh frozen tissue samples and FFPE (formalin-fixed paraffin-embedded) samples. The technique requires 4 days to be processed and is divided into 8 phases: DNA quantification; Bisulfite conversion; DNA amplification; DNA fragmentation; Precipitation and Resuspension; Hybridization on the HumanMethylation800 BeadChip; Xstain (Extension and Staining); HumanMethylation800 BeadChip scanning.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCancer predisposition syndrome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGenomic DNA was extracted, using the DNA Blood Mini Kit (Qiagen, Hilden, NW, Germany) according to the manufacturer's instructions, from circulating leukocytes of peripheral blood samples, after obtaining informed consent. DNA quantification was performed by Qubit fluorimeter (Life Technologies, Carlsbad, California, USA) with the dsDNA HS Assay kit following the manufacturer's instructions.\u003c/p\u003e\n\u003cp\u003eThe genetic analysis was performed through Next Generation Sequencing (NGS) by using a custom clinical exome panel containing more than 8,500 genes, including those involved in DNA cancer-predisposition syndromes (Twist Bioscience, South San Francisco, CA, USA) on a NovaSeq 6000 platform (Illumina, San Diego, CA, USA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurgery\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMaximal safe microsurgical resection, whenever feasible, was performed at the time of first diagnosis by occipital craniotomy in prone position. Instead, biopsy was considered if resection of the principal posterior fossa lesion would not significantly reduce local mass effect and disease load due to massively disseminated disease. Our institutional policy included navigation assistance and intraoperative monitoring in all cases. Symptomatic hydrocephalus was treated before surgical resection by endoscopic third ventriculostomy (ETV). Ventriculo-peritoneal (VP) shunt was considered only after documented failure of ETV or in presence of documented cisternal blockage by disseminated disease. If extensive spinal dissemination was present an intraventricular access device was positioned to overcome the need for therapeutic spinal taps.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll 25 patients included in the study received chemotherapy regimens based on the AIEOP indications. It consisted of three courses of chemotherapy: methotrexate (8000 mg/m2) and vincristine (1,5 mg/m2) on day 1, etoposide (2400 mg/m2) on day 8, cyclophosphamide (4000 mg/m2) and vincristine (1,5 mg/m2) on day 28. Based on radiological response and histopathological/molecular characteristics, the treatment was continued with two cycles of high-dose chemotherapy with Thiotepa 900 mg/m2 and ASCT. If residual disease and/or metastases persist after two high-dose chemotherapy cycles and the patient is not eligible for second-look surgery, or if residual disease persists after a second surgery, a third cycle of high-dose chemotherapy with thiotepa (750 mg/m²) and carboplatin (1 g/m²) was planned (15).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs second-line treatment, chemotherapy and/or radiation therapy were administered. CSI consisted of a dose of 36 Gy, with a boost of 18 Gy to the posterior fossa and disease sites, for a total dose of 54 Gy. PBT became available in Italy starting in June 2015. In PBT, a uniform vertebral dose was delivered, with the Clinical Target Volume including the whole brain (cribriform plate and proximal optic nerves) and the entire spine (subarachnoid space, vertebral body, nerve roots) down to the thecal sac end (S2–S3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNeurocognitive assessment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCognitive assessments were conducted at multiple time points: at diagnosis, at one year from diagnosis\u0026nbsp;and during follow-up one year after the last evaluation. Age-appropriate, validated tools were used, including the Griffiths Mental Development Scales (GMDS) and the Wechsler Intelligence Scale for Children – Fourth Edition (WISC-IV) (18).\u003c/p\u003e\n\u003cp\u003eThe GMDS evaluates overall development in children from birth to 8 years across five domains: gross motor skills, personal-social behavior, language development, fine motor coordination, and performance abilities (19). The WISC-IV provides a full-scale IQ and four composite indices; for this study, only the overall cognitive level was considered (20).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eToxicity evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients underwent regular follow-up during and after treatment, per institutional protocols. Hematologic toxicity was monitored throughout therapy and follow-up. Endocrine evaluations (ACTH, Cortisol, IGF-1, GH, FSH, LH, TSH, FT4, testosterone, 17β-estradiol) were performed at baseline, 12, and 24 months post stop-therapy. Cardiac function (ECG, echocardiogram, clinical exam) was assessed at baseline and 18–24 months. Pulmonary toxicity was evaluated by spirometry at baseline and 18–24 months, with lung diffusion tests if indicated. Audiometric exams were done at baseline and 18–24 months post-treatment to assess ototoxicity. Toxicities were graded according to CTCAE v5.0 criteria (19).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData entry and cleaning processes were conducted using Microsoft Excel. Descriptive statistics were reported as counts and percentages for categorical variables and median and interquartile range (IQR) for continuous variables.\u003c/p\u003e\n\u003cp\u003eOverall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method. OS was defined as the time from the date of diagnosis to death from any cause or last follow-up. EFS was defined as the time from the date of diagnosis to the date of the first progression, to the date of death from any cause, or the date of the last follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe Logrank non-parametric test for comparison of survival distributions was used to compare survival differences between groups. The alpha risk was set to 5.0%.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData analyses were performed utilizing Prism GraphPad 10.0 version software. \u0026nbsp;\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eDuring the 16-year period, we identified a total of 42 patients with infant MB, with a median age at diagnosis of 31.67 months (range 5.10\u0026ndash;58.03). Twenty-five patients matched the inclusion criteria and were enrolled in the study, including 12 male and a 13 female with a median age at diagnosis of 25.27 months (range 5\u0026ndash;51.33 months). Forty-four percent of patient were metastatic at diagnosis. Patient\u0026apos; characteristics are detailed in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatient\u0026rsquo;s charcteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003cp\u003eCount (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMin\u003c/p\u003e\n \u003cp\u003eMax\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eQ1\u003c/p\u003e\n \u003cp\u003eQ3\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eIQ diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e85.32 (24.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73.54\u003c/p\u003e\n \u003cp\u003e97.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003cp\u003e130\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72.5\u003c/p\u003e\n \u003cp\u003e103.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eIQ 1 year\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e78.47 (21.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67.99\u003c/p\u003e\n \u003cp\u003e88.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003cp\u003e115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65.5\u003c/p\u003e\n \u003cp\u003e92.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eIQ last FU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e83.35 (28.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63.23\u003c/p\u003e\n \u003cp\u003e103.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.5\u003c/p\u003e\n \u003cp\u003e111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68.25\u003c/p\u003e\n \u003cp\u003e104.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e92.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eSurgical management\u003c/h2\u003e\n \u003cp\u003eAt diagnosis, 17/25 patients had hydrocephalus; 15 underwent endoscopic third ventriculostomy (ETV), one received a VP shunt, and one a ventricular access device. All patients had surgery: 15 gross total resections (GTR), 2 near-total (NTR), 6 subtotal (STR), and 2 biopsies. One patient experienced severe postoperative complications requiring tracheostomy and gastrostomy; two had transient neurological deficits that improved. Cerebellar Mutism Syndrome (CMS) occurred in 5 of 18 evaluable patients and was fully reversible.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003ePathology and molecular findings\u003c/h2\u003e\n \u003cp\u003eAt histological examination 13/25 cases were classified as classic, 6/25 desmoplastic nodular (DNMB), 4/25 with extensive nodularity (MBEN), and 2/25 large cell/anaplastic (LCA). DNA methylation profile highlighted the SHH subgroup as the most representative (13/25) with TP53 status wild type in all cases, followed by group 3 (8/25) and group 4 (4/25). MYC amplification was detected in only 3 cases of group 3 MB.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eCancer predisposition syndrome\u003c/h2\u003e\n \u003cp\u003eFive patients carried likely pathogenic or pathogenic variants. P5 and P20 were diagnosed with Gorlin syndrome, both carrying heterozygous SUFU variants: c.16delC (P5) and c.364delT (P20), the latter with a maternal history of basal cell carcinomas. P6 had a likely pathogenic POLE variant (c.2584_2585delGA); her family history included breast cancer. P13 carried a GPR161 variant (c.714dupG) inherited from her father, with limited cancer history but a report of macrocrania in a paternal uncle. P18 was diagnosed with Tatton-Brown-Rahman syndrome due to a DNMT3A variant (c.427C\u0026thinsp;\u0026gt;\u0026thinsp;T), inherited from the father. P23 had Cowden syndrome with a de novo PTEN alteration (c.79T\u0026thinsp;\u0026gt;\u0026thinsp;A) and clinical features including MB, intestinal polyposis, and macrocrania. P24 carried biallelic MUTYH variants (c.1353_1355delCCT and c.228G\u0026thinsp;\u0026gt;\u0026thinsp;T), with familial history of gastrointestinal and gynecological cancers. Molecular and histological details are reported in supplementary table.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eSurvival an outcome\u003c/h2\u003e\n \u003cp\u003eMedian OS for the whole population was 58 months (range 8.70-173.9). Seventeen out of 25 patients are alive and in complete remission with a median follow-up of 95.7 months (range 28.2-173.9).\u003c/p\u003e\n \u003cp\u003eThree patients progressed during first-line treatment, and five relapsed after achieving complete remission at a median time of 7.6 months (range 2-24.2) after stop therapy. Chemotherapy was administered in all but one case. Four patients received CSI: 2 with standard radiotherapy and 2 with PBT. Of the relapsed/progressed patients, only one remained alive and he is the patient re-irradiated with PBT. All other patients died after a median of 5.2 months after relapse/progression. One patient died of treatment-related toxicity.\u003c/p\u003e\n \u003cp\u003eAt 2 years, OS was 80.0% (95% CI: 58.4\u0026ndash;91.1) and PFS was 72.0% (95% CI: 50.1\u0026ndash;85.5); at 5 years, OS was 65.9% (95% CI: 42.8\u0026ndash;81.4) and PFS was 67.8% (95% CI: 45.7\u0026ndash;82.4) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea-b).\u003c/p\u003e\n \u003cp\u003eNo statistically significant differences in survival were observed by histotype (p\u0026thinsp;=\u0026thinsp;0.462), molecular subgroup (p\u0026thinsp;=\u0026thinsp;0.09), disease status (p\u0026thinsp;=\u0026thinsp;0.139), or extent of resection (p\u0026thinsp;=\u0026thinsp;0.37) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ec-f). Nonetheless, MBEN cases showed better outcomes compared to other histotypes, SHH cases tended toward improved survival, localized disease showed a favorable trend, and GTR/NTR resections were associated with better outcomes than STR/biopsy. Patients who developed CMS had worse outcomes than those without CMS (p\u0026thinsp;=\u0026thinsp;0.35) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eg). All five patients with CPS and infant MB were alive at the last follow-up.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003eCognitive assessment\u003c/h2\u003e\n \u003cp\u003eMean IQ at diagnosis was 85.32\u0026thinsp;\u0026plusmn;\u0026thinsp;23.78; 78.47\u0026thinsp;\u0026plusmn;\u0026thinsp;21.16 at one year from diagnosis and 83.35\u0026thinsp;\u0026plusmn;\u0026thinsp;26.68 at the last follow-up, without difference between different time points (Table\u0026nbsp;2 and Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Importantly, even in the single surviving patient who underwent CSI with PBT, no significant change in IQ was observed.\u003c/p\u003e\n \u003cp\u003eTable 2. Descriptive statistics of IQ scores at diagnosis, 1 year after diagnosis, and at last follow-up.\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"567\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMean (SD)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eCount (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMin\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMax\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eQ1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eQ3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMedian\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eIQ diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e85.32 (24.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e73.54\u003c/p\u003e\n \u003cp\u003e97.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003cp\u003e130\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e72.5\u003c/p\u003e\n \u003cp\u003e103.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eIQ 1 year\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e78.47 (21.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e67.99\u003c/p\u003e\n \u003cp\u003e88.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003cp\u003e115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e65.5\u003c/p\u003e\n \u003cp\u003e92.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e82\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eIQ last FU\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e83.35 (28.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e63.23\u003c/p\u003e\n \u003cp\u003e103.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22.5\u003c/p\u003e\n \u003cp\u003e111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e68.25\u003c/p\u003e\n \u003cp\u003e104.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e92.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003eToxicity\u003c/h2\u003e\n \u003cp\u003eIn our cohort, all patients experienced hematological toxicity during standard chemotherapy regimen, especially of grade 3\u0026ndash;4 according to CTCAE v5.0. In particular, grade 3\u0026ndash;4 neutropenia was detected in all 25 patients, in 14 cases with fever associated. Grade 3\u0026ndash;4 thrombocytopenia and grade 3 anemia were assessed in 18 and 11 patients, respectively. No grade 5 toxicities have been detected. Twenty-two patients experienced liver toxicity, with elevated transaminase levels, although only half of them showed a moderate-severe grade toxicity.\u003c/p\u003e\n \u003cp\u003eRegarding endocrinological toxicities, the majority of patients (22 out of 25) did not show any hormonal impairment during follow-up evaluations. Four out of 25 patients presented endocrinological sequelae, including: growth hormone deficiency associated with delayed puberty (1/4) and hypothyroidism (1/4), delayed pubertal development requiring hormone replacement therapy (1/4), and suspected primary ovarian insufficiency currently under investigation (1/4). Median time of onset of endocrinological sequelae is 55.5 months after the end of therapy (range 37\u0026ndash;91 months). The patient with growth retardation and hypothyroidism had been treated with PBT, while the other three had not received radiation therapy.\u003c/p\u003e\n \u003cp\u003eNo audiological, renal, cardiac or pulmonary toxicities have been reported. No life-threatening events were observed.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eYoung children diagnosed with MB present a significant clinical challenge due to the vulnerability of the developing brain to neurotoxic treatments. Historically, CSI has been the standard of care for MB, but its use in very young children is limited by the risk of severe long-term neurocognitive impairment. This concern has driven adoption of alternative strategies, such as intensive chemotherapy regimens to improve survival while minimizing late effects. In the 1980s early collaborative trials using conventional chemotherapy to defer radiotherapy resulted in high progression rates and poor survival outcomes (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Subsequently, more intensive approaches were introduced, including chemotherapy followed by HDC/ASCT (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), as well as regimens incorporating intraventricular or high-dose MTX (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e); both resulted in increased survival.\u003c/p\u003e\u003cp\u003eThis retrospective study aims to describe the clinical features, treatment outcomes, and toxicities in a cohort of patients under 5 years of age with MB, treated with a first-line intensive chemotherapy according to AIEOP recommendations.\u003c/p\u003e\u003cp\u003eIn our cohort of infants with MB, the 2- and 5-year survival rates were encouraging albeit in a relatively small patient population, with an OS of 80.0% (95% CI: 58.4\u0026ndash;91.1) at 2 years and 65.9% (95% CI: 42.8\u0026ndash;81.4) at 5 years. Similarly, PFS was 72.0% (95% CI: 50.1\u0026ndash;85.5) at 2 years and 67.8% (95% CI: 45.7\u0026ndash;82.4) at 5 years. Although comparative studies are few and heterogeneous, our survival outcomes exceed those reported by Robinson et al., who observed, in their cohort, a 5-year OS of 59.4% (95% CI, 45.7\u0026ndash;73.1) and an event-free survival of 31.3% (95% CI, 19.3\u0026ndash;43.3) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eNotably, the curves at 5 years for PFS and OS are nearly superimposable, strongly indicating that relapse remains the principal determinant of mortality in this population. In fact, all patients but one who experienced relapse or progression died of their disease, with a median post-relapse survival of just 5.2 months, including 3 of 4 patients who received CSI as second-line treatment. Salvage therapy, which often includes CSI radiotherapy, does not always improve outcomes after relapse and can increase treatment-related morbidities from successive therapies (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eMoreover, there was no statistically significant difference in survival distributions by histotype, molecular subtype, status of disease, entity of resection and CMS. However, consistent with previous reports (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), MBEN cases showed better survival outcomes compared to other histotypes, such as SHH-subgroup, localized disease, GTR or NTR. Patients who did not develop CMS also appeared to have better outcomes. These findings suggest potential differences that could not reach statistical significance likely because of the small cohort size, highlighting the need for studies with larger samples to confirm these trends. Notably all 5 patients with CPS are alive at last follow-up.\u003c/p\u003e\u003cp\u003eNeurocognitive outcomes in our cohort were overall reassuring. The mean IQ at diagnosis was 85.32\u0026thinsp;\u0026plusmn;\u0026thinsp;23.78, and remained stable over time. In the only relapsed patient who survived and who received proton CSI, treatment was well tolerated and was not associated with any long-term neurocognitive impairments. These findings suggest that, in the context of treatment strategies aimed at minimizing neurotoxicity, cognitive function can be preserved in long-term survivors. Our data are in line with previous studies reporting better neurocognitive profiles in patients treated with chemotherapy-based approaches and radiation-sparing techniques (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eHematological toxicity was common as expected (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), with all patients experiencing grade 3\u0026ndash;4 neutropenia, and frequent thrombocytopenia and anemia. Endocrinological toxicities were rare, affecting 4 patients, mostly as delayed growth or pubertal issues. Of them, only one of these patients had received CSI PBT. No cardiac, renal, pulmonary, auditory, or ocular toxicities were reported.\u003c/p\u003e\u003cp\u003eFurthermore, several studies have shown that risk stratification in MB identifies patient groups with distinct outcomes, enabling treatment de-escalation to reduce toxicity and side effects in low-risk groups (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). In the SJYC07 trial, 5-year progression-free survival was 27.8% for iSHH-I and 75.4% for iSHH-II, suggesting that patients with iSHH-II may benefit from reduced-intensity therapy (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eLast but not least, ongoing research is exploring innovative therapeutic strategies that may improve the prognosis of these patients. Among these, immunotherapy has recently gained increasing attention. For instance, Donovan et al. investigated locoregional delivery of CAR T cells targeting MB-associated antigens (EPHA2, HER2, IL-13), demonstrating efficacy in metastatic Group 3 MB mouse models (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Similarly, Ciccone et al. showed that, in orthotopic mouse models, systemic administration of CAR.GD2 T-cells markedly inhibited tumor growth and significantly prolonged OS (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Nevertheless, optimizing tumor immunogenicity remains a critical step for the successful clinical translation of these approaches (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eMedulloblastoma in young children poses significant treatment challenges due to the risks of neurotoxicity from CSI irradiation. Our retrospective study of infants MB treated with intensive first-line chemotherapy shows encouraging survival rates, better than reported in the literature to date. Importantly, neurocognitive function was preserved over time, supporting radiation-sparing strategies. Toxicities were manageable, and proton therapy at relapse showed promising safety. These findings support chemotherapy-based strategies and underscore the need for collaborative studies, ongoing research in targeted and immunotherapies, and long-term monitoring to enhance survival and quality of life.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGDB, ACar, AM, contributed to the study conception and design. Material preparation and data collection were performed by GDB, VDR, ACac, ALS, LC, CD, ADS, GA, SC, EM, IG, SR, GSC, SV, AC. Data analysis was performed by GDB. The first draft of the manuscript was written by GDB and VDR; all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in the published article, its tables, and the supplementary material.\u003c/p\u003e\n\u003cp\u003eThe authors have nothing to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was conducted by the Declaration of Helsinki and approved by the Institutional Review Board of Bambino Ges\u0026ugrave; Children\u0026rsquo;s. Code of Approval: RAP-2025-002.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the association \u0026ldquo;Il Laboratorio di Chiara\u0026rdquo; for the support.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eWalker DA, Liu J, Kieran M, et al (2013) A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method. Neuro Oncol 15(4):462\u0026ndash;468. doi: 10.1093/neuonc/nos330.\u003c/li\u003e\n \u003cli\u003eJohnston DL, Keene D, Bartels U, et al (2009) Medulloblastoma in children under the age of three years: a retrospective Canadian review. J Neurooncol 94(1):51\u0026ndash;56. doi: 10.1007/s11060-009-9799-2.\u003c/li\u003e\n \u003cli\u003eDuffner PK, Horowitz ME, Krischer JP, et al (1993) Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328(24):1725\u0026ndash;1731. doi: 10.1056/NEJM199306173282401.\u003c/li\u003e\n \u003cli\u003eStrother DR, Lafay-Cousin L, Boyett JM, et al (2014) Benefit from prolonged dose-intensive chemotherapy for infants with malignant brain tumors is restricted to patients with ependymoma: a report of the Pediatric Oncology Group randomized controlled trial 9233/34. Neuro Oncol 16(3):457\u0026ndash;465. doi: 10.1093/neuonc/not163.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eJackson K, Packer RJ. (2023) Recent Advances in Pediatric Medulloblastoma. Curr Neurol Neurosci Rep 23(12):841\u0026ndash;848. doi: 10.1007/s11910-023-01316-9.\u003c/li\u003e\n \u003cli\u003eChoi JY. (2023) Medulloblastoma: Current Perspectives and Recent Advances. Brain Tumor Res Treat 11(1):28\u0026ndash;38. doi: 10.14791/btrt.2022.0046.\u003c/li\u003e\n \u003cli\u003eCohen BH, Geyer JR, Miller DC, et al (2015) Pilot Study of Intensive Chemotherapy With Peripheral Hematopoietic Cell Support for Children Less Than 3 Years of Age With Malignant Brain Tumors, the CCG-99703 Phase I/II Study. Pediatric Neurology 53(1):31\u0026ndash;46. doi: 10.1016/j.pediatrneurol.2015.03.019.\u003c/li\u003e\n \u003cli\u003eDhall G, O\u0026rsquo;Neil SH, Ji L, et al (2020) Excellent outcome of young children with nodular desmoplastic medulloblastoma treated on \u0026laquo;Head Start\u0026raquo; III: a multi-institutional, prospective clinical trial. Neuro Oncol 22(12):1862\u0026ndash;1872. doi: 10.1093/neuonc/noaa102.\u003c/li\u003e\n \u003cli\u003eLazow MA, Palmer JD, Fouladi M, et al (2022) Medulloblastoma in the Modern Era: Review of Contemporary Trials, Molecular Advances, and Updates in Management. Neurotherapeutics 19(6):1733\u0026ndash;1751. doi: 10.1007/s13311-022-01273-0.\u003c/li\u003e\n \u003cli\u003eRobinson GW, Rudneva VA, Buchhalter I, et al (2018) Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial. Lancet Oncol 19(6):768\u0026ndash;784. doi: 10.1016/S1470-2045(18)30204-3.\u003c/li\u003e\n \u003cli\u003eCavalli FMG, Remke M, Rampasek L, et al (2017) Intertumoral Heterogeneity within Medulloblastoma Subgroups et al (2017) Cancer Cell 31(6):737-754.e6. doi: 10.1016/j.ccell.2017.05.005.\u003c/li\u003e\n \u003cli\u003eGuerrini-Rousseau L, Grill J, Dufour C. (2018) New stratification for early childhood medulloblastoma. Pediatric Medicine 1(0). doi: 10.21037/pm.2018.12.01\u003c/li\u003e\n \u003cli\u003eSursal T, Ronecker JS, Dicpinigaitis AJ, et al (2022) Molecular Stratification of Medulloblastoma: Clinical Outcomes and Therapeutic Interventions. Anticancer Res 42(5):2225\u0026ndash;2239. doi: 10.21873/anticanres.15703.\u003c/li\u003e\n \u003cli\u003eBagchi A, Dhanda SK, Dunphy P, et al (2023) Molecular Classification Improves Therapeutic Options for Infants and Young Children With Medulloblastoma. J Natl Compr Canc Netw 21(10):1097\u0026ndash;1105. doi: 10.6004/jnccn.2023.7024.\u003c/li\u003e\n \u003cli\u003eAntonelli M, Korshunov A, Mastronuzzi A, et al (2015) Long-term survival in a case of ETANTR with histological features of neuronal maturation after therapy. Virchows Arch 466(5):603\u0026ndash;607. doi: 10.1007/s00428-015-1736-5.\u003c/li\u003e\n \u003cli\u003ePeng J, Zhou H, Tang O, et al (2020) Evaluation of RAPNO criteria in medulloblastoma and other leptomeningeal seeding tumors using MRI and clinical data. Neuro-Oncol 22(10):1536\u0026ndash;1544. doi: 10.1093/neuonc/noaa072.\u003c/li\u003e\n \u003cli\u003eLouis DN, Perry A, Wesseling P, et al (2021) The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-Oncol 23(8):1231\u0026ndash;1251. doi: 10.1093/neuonc/noab106.\u003c/li\u003e\n \u003cli\u003eGrizzle R (2011) Wechsler Intelligence Scale for Children, Fourth Edition. In: Goldstein S, Naglieri JA, curatori. Encyclopedia of Child Behavior and Development. Boston, MA: Springer US; p. 1553\u0026ndash;1555.\u003c/li\u003e\n \u003cli\u003eGriffiths R, Huntley M. (2011) Griffiths Mental Development Scales-Revised: Birth to 2 years.\u003c/li\u003e\n \u003cli\u003eWarschausky S, Raiford SE. (2018) Wechsler Preschool and Primary Scale of Intelligence. In: Kreutzer JS, DeLuca J, Caplan B, curatori. Encyclopedia of Clinical Neuropsychology. Cham: Springer International Publishing; p. 3705\u0026ndash;3709.\u003c/li\u003e\n \u003cli\u003eErker C, Mynarek M, Bailey S, et al (2023) Outcomes of Infants and Young Children With Relapsed Medulloblastoma After Initial Craniospinal Irradiation\u0026ndash;Sparing Approaches: An International Cohort Study. JCO 41(10):1921\u0026ndash;1932. doi: 10.1200/JCO.21.02968.\u003c/li\u003e\n \u003cli\u003eFay-McClymont TB, Ploetz DM, Mabbott D, et al (2017) Long-term neuropsychological follow-up of young children with medulloblastoma treated with sequential high-dose chemotherapy and irradiation sparing approach. J Neurooncol 133(1):119\u0026ndash;128. doi: 10.1007/s11060-017-2409-9.\u003c/li\u003e\n \u003cli\u003eBailey S, Jacobs S, Kourti M, et al (2025) Medulloblastoma therapy: Consensus treatment recommendations from SIOP-Europe and the European Reference Network. EJC Paediatric Oncology 5:100205. https://doi.org/10.1016/j.ejcped.2024.100205.\u003c/li\u003e\n \u003cli\u003eRutkowski S, von Hoff K, Emser A, et al (2010) Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol 28(33):4961\u0026ndash;4968. doi: 10.1200/JCO.2010.30.2299.\u003c/li\u003e\n \u003cli\u003eCiccone R, Quintarelli C, Camera A, et al (2024) GD2-Targeting CAR T-cell Therapy for Patients with GD2+ Medulloblastoma. Clin Cancer Res 30(11):2545\u0026ndash;2557. doi: 10.1158/1078-0432.CCR-23-1880.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"medulloblastoma, young children, intensive chemotherapy, neurocognitive outcome, radiation-sparing strategies","lastPublishedDoi":"10.21203/rs.3.rs-7366809/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7366809/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe long-term neurocognitive impact of craniospinal irradiation (CSI) in young children with medulloblastoma (MB) has driven the development of alternative strategies aimed at improving survival while delaying or avoiding CSI.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe retrospectively analyzed a cohort of patients under 5 years of age with MB treated at Bambino Gesù Children’s Hospital between 2007–2023 with intensive chemotherapy regimens according to AIEOP recommendation. Clinical, radiological, histopathological, molecular, neurocognitive, and toxicity data were collected. Survival was estimated using the Kaplan–Meier method, with group comparisons by log-rank test.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eAmong 42 patients under 5 years, 25 met inclusion criteria (median age 25.3 months). Histology included classic (52%), desmoplastic/nodular (24%), extensive nodularity (16%), and large cell/anaplastic (8%). SHH was the most common molecular subgroup (52%), followed by Group 3 (32%) and Group 4 (16%). At a median follow-up of 95.7 months, 68% of patients were alive and in complete remission. Two- and 5-year OS were 80.0% and 65.9%, respectively; PFS was 72.0% and 67.8%. All patients experienced grade 3–4 hematological toxicity; late endocrine effects occurred in four patients and no other long-term toxicities were reported. Mean IQ was stable from diagnosis (85.3) to last follow up (83.4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eOur retrospective study of infants MB treated with first-line intensive chemotherapy shows encouraging survival rates, better than reported in the literature to date. Importantly, neurocognitive function was preserved over time, supporting radiation-sparing strategies, and toxicity was manageable in all cases.\u003c/p\u003e","manuscriptTitle":"Clinical Outcomes and Toxicity of First-Line Intensive Chemotherapy in Infant Medulloblastoma: A Single-Center Cohort Study Following AIEOP Recommendations","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-22 10:26:38","doi":"10.21203/rs.3.rs-7366809/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-04T10:53:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-31T20:04:25+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-29T20:09:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-25T20:09:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-25T18:09:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"78354762992294354702988529723011469863","date":"2025-08-23T05:20:50+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-22T17:51:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"310192995299963773008095715128392024912","date":"2025-08-22T14:58:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"98278653132559959244185216821043332589","date":"2025-08-20T03:10:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"323873378028306915592426216951811432745","date":"2025-08-18T16:08:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"182101944942430119258044503805061523469","date":"2025-08-18T14:10:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"66165694484156589010036442076893171866","date":"2025-08-18T08:59:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"164682808272687227687104904338151544548","date":"2025-08-17T19:25:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-14T14:08:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-14T13:55:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-14T13:54:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2025-08-13T16:07:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f98c65c0-7bbd-484c-9edc-0742fd89fe45","owner":[],"postedDate":"August 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-03T16:10:32+00:00","versionOfRecord":{"articleIdentity":"rs-7366809","link":"https://doi.org/10.1007/s11060-025-05301-9","journal":{"identity":"journal-of-neuro-oncology","isVorOnly":false,"title":"Journal of Neuro-Oncology"},"publishedOn":"2025-10-29 15:57:57","publishedOnDateReadable":"October 29th, 2025"},"versionCreatedAt":"2025-08-22 10:26:38","video":"","vorDoi":"10.1007/s11060-025-05301-9","vorDoiUrl":"https://doi.org/10.1007/s11060-025-05301-9","workflowStages":[]},"version":"v1","identity":"rs-7366809","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7366809","identity":"rs-7366809","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}