Background and Objectives:Disease-causing variants in the syntaxin-binding protein 1 (STXBP1) gene are among the most common genetic causes of developmental and epileptic encephalopathies and are associated with a wide phenotypic spectrum. Qualitative neuroimaging studies are usually unrevealing or uncover variable MRI findings, including cortical atrophy, thin/dysmorphic corpus callosum (CC), hypo/delayed myelination, and focal cortical dysplasia (FCD). Methods:We used quantitative MRI methods to estimate abnormal brain properties of the cortical mantle and volume of subcortical structures in patients with STXBP1 encephalopathy and age- and sex-matched controls.We performed a region-of-interest group statistical analysis between patients with STXBP1 encephalopathy and controls by multivariable linear regression models to identify morphometric patterns and to evaluate the effect of the group (patients/controls) on morphometric features. We conducted a longitudinal analysis to estimate the volumetric changes in 4 patients with serial MRI scans at different ages. We calculated the association between the structural alterations and the known STXBP1 expression levels and explored associations between morphometric and volumetric features and clinical findings (age at seizure onset, intellectual disability [ID]) and genetic variants. Results:Our analysis included 24 patients and 48 controls and revealed widespread cortical thickening, reduced frontal and occipital surface area, and reduced white matter (left/right hemisphere p value = 0.005/0.022) and CC (p value < 0.050) volumes. The longitudinal analysis highlighted that brain growth trends were lower than the average trend in the control cohort. In patients with more severe ID, we observed a significantly increased volume of the lateral ventricles (left/right p value = 0.049/0.030) and CSF (p value = 0.019). Patients with missense variants exhibited more altered morphometric values and more severe reductions of white-matter volumes, possibly because of a dominant negative effect of variants. Two patients were operated for intractable focal seizures, and the histopathologic substrate was FCD-I. Discussion:The altered cortical patterns and WM reductions we observed in STXBP1 encephalopathy might be the structural counterpart of the widespread impaired neurotransmitter release caused by a dysfunctional syntaxin-binding protein. The 2 histopathologic observations we describe, bring to 4 the number of reported patients with STXBP1 encephalopathy and FCD-I, suggesting cortical dyslamination as the architectural substrate for the abnormal morphometric parameters and reduced surface areas.

Focal cortical dysplasia (FCD) type II is a major cause of drug-resistant epilepsy, often curable only by surgery. Despite its clinical importance, the diagnosis of FCD is very difficult in MRI because of subtle abnormalities, leading to misdiagnosis. This study investigates the use of 3D convolutional neural networks (3D-CNNs) for FCD detection, using a dataset of 170 subjects (85 FCD patients and 85 controls) composed of T1-weighted and FLAIR MRI scans. In particular, it investigates the benefits obtained from cross-modality transfer learning and explainable artificial intelligence (XAI) techniques, in particular Gradient-weighted Class Activation Mapping (Grad-CAM). ResNet architectures (ResNet-18, -34, and -50) were implemented, employing transfer learning strategies that used pre-trained weights from segmentation tasks. Results indicate that transfer learning significantly enhances classification accuracy (up to 80.3 metric, which evaluates the model's focus on clinically relevant regions. Improvements in the Heat-Score metric underscore the model's seizure zone localization capabilities, bringing AI predictions and clinical insights closer together. These results highlight the importance of transfer learning, including cross-modality, and XAI in advancing AI-based medical diagnostics, especially for difficult-to-diagnose pathologies such as FCD.

There are no specific guidelines for posterior cranial fossa decompression (PCFD) in asymptomatic Chiari Malformation Type I (CM-I) patients with autism spectrum disorder (ASD). However, some studies suggest that surgery for symptomatic CM-I may improve ASD symptoms. This study aims to identify skull and brain morphometric parameters that could predict surgical outcomes in symptomatic CM-I with ASD, using artificial intelligence (AI). This study included pediatric patients diagnosed with both symptomatic CM-I and ASD who underwent posterior cranial fossa (PCF) surgery. Eleven morphometric parameters were measured using computed tomography (CT) and magnetic resonance imaging (MRI) scans, including cerebellar tonsil descent, tentorium length and angle, cerebellum-to-PCF area ratio, PCF-to-cerebrum area ratio, PCF height and diameter, and various distances involving the corpus callosum, pons, fastigium, foramen magnum, and clivus length. ASD symptom changes were assessed through phone interviews and outpatient evaluations. A binary tree classifier AI model was used to identify patients who improved post-surgically. Our analysis showed that patients with a larger tentorium angle experienced some improvements in ASD symptoms after surgery, whereas those with a significantly smaller tentorium angle showed no improvement. AI identified a tentorium angle of 89.55° as a potential cut-off for distinguishing between outcome groups. No other morphometric parameters significantly influenced ASD symptom outcomes. This study evaluates the relevance of the tentorium angle width as a potentially valuable MRI-based morphometric parameter that could guide neurosurgeons in the decision-making process for this unique patient population. These findings may contribute to a more tailored approach for managing patients with CM-I and coexistent ASD.

Methylation of CpG islands plays a crucial role in the regulation of gene expression. The study of DNA methylation profiles offers deep insights into key oncogenic processes and facilitates the differentiation of tumor entities at the epigenetic level. Methylation profiling was performed on 8 CNS tumors (6 children, 1 adolescent, 1 young adult) with inconclusive diagnoses, available frozen tissue, and surgeries dating back over 5 years. Our goal was to correlate the resulting methylation classes with the clinical-radiological data and to evaluate the diagnostic and prognostic power of this analysis. The resulting molecularly defined diagnoses were: pilocytic astrocytoma (3 cases), pilocytic astrocytoma subclass FGFR1 altered (1 case), ganglioglioma (2 cases), diffuse leptomeningeal glioneuronal tumor subtype 1 (1 case), and diffuse midline glioma H3.3K27-altered, subtype H3K27 mutant or EZHIP-expressing (1 case). Clinico-pathological features of each tumor in our series are discussed. The clinical behavior was consistent with the molecular diagnosis in all cases but one that was lost to follow-up. In our series, the initial diagnostic failure in 3 of the 8 cases was due to the fact that the pathological entities-diffuse midline glioma, H3 K27-altered, pilocytic astrocytoma with FGFR1 alteration and diffuse leptomeningeal glioneuronal tumor -had not yet been fully characterized or widely recognized in the literature at the time of diagnosis. In the remaining cases, the lack of distinctive histopathological features hindered a definitive diagnosis. In conclusion, according to our experience, DNA methylation profile analysis represents a very attractive diagnostic tool and provides important support for the diagnosis and classification of CNS tumors.

Pediatric high-grade gliomas (pHGGs) are aggressive central nervous system (CNS) tumors with poor prognosis and limited effective treatments. Doxorubicin (Dox), a widely used anthracycline, is rarely applied in CNS tumors due to blood-brain barrier (BBB) impermeability and dose-dependent cardiotoxicity. However, preclinical studies have demonstrated the efficacy of Dox against glioma cells, especially with prolonged exposure. Furthermore, it is known that radiotherapy transiently increases BBB permeability, allowing enhanced drug delivery. This is a monocentric, non-randomized, phase II trial (EudraCT 2015-002307-28) conducted at Meyer Children’s Hospital IRCCS in Florence. Twenty-one patients aged 3-22 years with newly diagnosed pHGGs received standard treatment (surgery if feasible, radiotherapy, temozolomide) in addition to valproic acid. 12 out of the 21 patients received 96-hour Dox infusion (100 mg/m²), for 1-3 cycles, 9 out of the 21 patients withdrew from the study because of disease progression or non-permissive clinical conditions before Dox administration.The primary endpoint was safety; the secondary endpoints included overall survival (OS) and response. No cases of Dox-induced cardiotoxicity, nephrotoxicity, or neurotoxicity were observed. Adverse events were predominantly hematologic. No Dox related study withdrawals or deaths occurred. The median OS was 13.7 months in the Dox one cycle treated patients. Prolonged infusion of Dox in pHGGs appears to be a safe and feasible therapeutic strategy, showing good overall tolerability. Notably, no signs of cardiotoxicity, nephrotoxicity, or neurotoxicity were observed, even in a high-risk pediatric population. These findings support the potential of this approach as a safe add-on regimen.

In Disorders of Consciousness, 18F-fluorodeoxyglucose PET (FDG-PET) is known to be effective in distinguishing vegetative state/unresponsive wakefulness syndrome from minimally conscious state, and when combined with MRI techniques, the risk of misdiagnosis decreases. However, FDG-PET studies on chronic patients with different etiologies (traumatic, vascular, and anoxic brain injury) are limited, and the association between metabolic activity and resting-state functional MRI (fMRI) networks remains unclear. This study combined FDG-PET with resting-state functional MRI and MRI to assess: i) the diagnostic accuracy of FDG-PET metabolism in different etiological groups of patients; ii) whether resting-state fMRI networks presence or absence was associated with higher versus lower FDG-PET metabolism. A group of 84 chronic patients underwent FDG-PET (47 vegetative state/unresponsive wakefulness syndrome, 31 minimally conscious state, and six emerged from a minimally conscious state), equally distributed in traumatic, vascular, and anoxic etiologies. Eight cases of covert cortical processing were identified. A subgroup of 68 patients also underwent resting-state fMRI. Standardized uptake values were calculated for these areas of interest: 10 resting-state fMRI networks, the precuneus, and a whole-brain mask. Patients in a vegetative state/unresponsive wakefulness syndrome exhibited a significant decrease in metabolism compared to patients in a minimally conscious state across all areas of interest. Patients with covert cortical processing showed intermediate metabolic levels between the two diagnostic categories. The anoxic group displayed a severe decrease in metabolism compared to patients with traumatic and vascular etiologies. The highest diagnostic accuracy among the areas of interest was reached in the precuneus and medial visual network (Area Under the Curve, AUC = 0.82-0.83). However, when anoxic patients were excluded, the diagnostic accuracy did not reach statistical significance, although the medial visual network and precuneus retained a trend of gradually increasing metabolism as clinical conditions improved. Identification of resting-state functional MRI networks was associated with increased metabolism in all networks at the group level, even excluding patients with severe structural damage. FDG-PET proves to be a technique capable of distinguishing vegetative state/unresponsive wakefulness syndrome from minimally conscious state even in chronic patients, although its diagnostic accuracy can be significantly affected by the etiology. There is a concordance between the metabolism level and the presence of resting-state fMRI networks.

BACKGROUND:Preserved resting-state functional MRI (rs-fMRI) networks are typically observed in Disorders of Consciousness (DOC). Despite the widespread use of rs-fMRI in DOC, a systematic assessment of networks is needed to improve the interpretability of data in clinical practice. We investigated functional connectivity of the main networks, combining structural MRI to obtain a description of the most observed networks in DOC, their diagnostic ability, and whether they can be related to clinical assessment. METHODS:A group of 109 chronic patients [65 vegetative state/unresponsive wakefulness state (VS/UWS), 34 minimally conscious state (MCS), and 10 emerged from MCS (eMCS)], with different etiologies, and 34 control subjects underwent multimodal assessment. Rs-fMRI data were analyzed with a semi-automatic pipeline to assess residual functional activity in terms of number, type, mean intensity, and structural preservation of networks. RESULTS:The more networks observed, the better the patient's clinical condition is likely to be. VS/UWS patients display 0-9, MCS 5-9, and eMCS 8-10 networks. Both the presence and intensity of 5 networks (visual networks, temporal, left fronto-parietal and default mode network) are relevant to distinguish VS/UWS from MCS, with AUCs of 0.64-0.69 (95% confidence interval). Etiology and disease duration have an impact on the number and type of preserved networks. High residual functional connectivity observed in VS/UWS patients, as in MCS, is in agreement with neurophysiological and metabolic evaluations. CONCLUSIONS:This systematic assessment of the main rs-fMRI networks in DOC provides basic measures of functional connectivity that can enhance their interpretability in clinical practice.

Introduction:In neuro-oncological pediatric patients under 3 years of age, chemotherapy intensified to high doses (high-dose chemotherapy, HDC) represents the cornerstone to avoid the potential toxicity of radiotherapy. Combination treatment with gemcitabine-oxaliplatin (GemOx) was administered for infant- type cerebral tumors as a bridge toward autologous hematopoietic transplantation to achieve clinical and neuroradiological permissiveness to HDC and to raise the possibility of second-look neurosurgery. Methods:From May 2017 to May 2023, at Meyer Children's Hospital IRCSS in Florence (Italy), four patients, with a median age of 19 months (with two high- grade gliomas, a metastatic medulloblastoma, and a choroid plexus carcinoma CNS WHO grade 3), were subjected to partial neurosurgical removal and induction therapy delivered according to the Italian program for malignant cerebral tumors under 3 years. To delay HDC, either for disease reassessment or for temporary unfitness, GemOx cycles were administered. Gemcitabine 1,000 mg/m2 and oxaliplatin 100 mg/m2 were given on day 1 every 21-28 days for one to six cycles. Results:The treatment was well tolerated overall, except for severe platelet hematological toxicity in a patient, which required dose reduction to 75%. After GemOx, one patient was also subjected to further neurosurgery. Bridge therapy made it possible to submit patients to HDC in safety, in permissive clinical conditions, and after assessment of disease stability. Conclusion:In infant-type cerebral tumors eligible for HDC, GemOx could be a possible strategy in the case of post-induction residual disease to exclude uncertain evolution or when waiting for clinical suitability for second surgery and intensified treatment. The therapy was overall safe and well tolerated. This approach resulted incisive in the therapeutic or palliative choice for extremely young patients with aggressive brain tumors.

Low-Grade Gliomas (LGG) are the most common primary brain tumors in pediatric patients, presenting diagnostic and therapeutic challenges due to their heterogeneity. Radiomics and Machine Learning (ML) can support classification of histological grades, according to WHO-2021 criteria, and prediction of molecular alterations such as BRAF mutations. A robust pipeline was developed and tested on both a public dataset (BRATS-2020) and a private dataset from Meyer Children’s Hospital IRCCS, including pediatric patients with known BRAF-V600E and KIAA1549 alterations, as well as BRAF wild type cases. T1w, T2w and FLAIR images were analyzed using Python 3.6 and Pyradiomics. Brainstem was extracted using Synthseg for normalization. To enhance robustness, each original ROI was artificially augmented to generate two additional ROIs. Feature selection was performed to retain only robust features. Random Forest and XGBoost models were trained using stratified 5-fold cross-validation. The pipeline was applied for both histologic grade and BRAF mutation classification. Explainability was achieved using LORE and SHAP algorithms. On the BRATS-2020 (n=369) test set, the pipeline achieved a mean accuracy of 0.91 and an AUC of 0.93. On the private dataset from Meyer Children’s Hospital IRCCS (n=46; 14 BRAF-V600E, 11 KIAA1549, 21 BRAF-wildtype), the pipeline achieved an accuracy of 0.76 and an AUC of 0.75 for KIAA1549 prediction, for BRAF-V600E an accuracy of 0.63 and an AUC of 0.66. This study presents a reproducible and interpretable radiomics pipeline validated on both public and private pediatric datasets. The integration of voxel normalization, multi-ROI enhancement, and explainability tools supports accurate LGG subtyping and BRAF mutation status prediction. The model’s consistent performance across datasets underscores its potential generalizability in clinical applications. All code used in the pipeline is available on GitHub to facilitate accessible and reproducible radiomic analysis of MRI images.

Abstract BACKGROUND Pediatric high-grade gliomas (pHGGs) comprise a very poor prognosis. Current treatment consists of maximal surgical resection followed by radiotherapy plus concomitant and adjuvant temozolomide (Stupp’s regimen). Despite innovative approaches, outcome remains dismal. Based on the results of previous in vitro and in vivo assays, also considering the wide experience in other pediatric tumors, we aimed to introduce doxorubicin (DOX) as add-on therapy to the standard of care. METHODS For testing safety and efficacy of add-on doxorubicin treatment in newly-diagnosed pHGGs, two open-label monocentric not-randomized phase II studies were consequently opened at our institution: GBM TMZ/DOX 2015 (EudraCT 2015-002307-28) and pGBM-WBRT/DOX2020 (EudraCT 2020-005131-74). GBM TMZ/DOX 2015 consisted of DOX 100 mg/mq in 96 hours infusion for 1-3 cycles at 8 week after radiotherapy. pGBM-WBRT/DOX2020 study introduced pan-encephalic radiotherapy followed by DOX 75 mg/mq in 48 hours for 4 cycles starting at week 12 after irradiation, to reduce metastatic relapse rate and to facilitate radiotherapy-induced blood brain barrier opening. Concomitant and adjuvant temozolomide were preserved. RESULTS Twenty-one heterogeneous malignant glioma patients (12 hystological diagnosis, 12 males and 8 females, mean age 9.1 ± 4.2 years, age range 2-22 years) were enrolled in the first study. However, for study exiting or for no clinical permissiveness at the time of DOX treatment, only 12 patients were treated with DOX: 2 received three DOX courses and 10 a single course, reducing hematological toxicities. DOX-group showed a longer progression free survival (PFS) compared to standard of care group (median PFS 9 versus 6 months respectively), although this trend was not statistically significative. The second study is on course. CONCLUSIONS The adjuvant DOX use in addition to the standard treatment in pHHGs is a practicable option, although to be consolidated, in terms of effectiveness on outcome.

Deep brain stimulation (DBS) of nucleus ventralis intermedius thalami (Vim) is a validated technique for the treatment of essential tremor (ET) in adults. Conversely, its use for post traumatic tremor (PTT) and in paediatric patients is still debated. We evaluated the efficacy of Vim-DBS for lesional tremor in three paediatric patients with drug-resistant post-traumatic unilateral tremor. We retrospectively collected data regarding three patients with unilateral tremor due to severe head injury, with no MRI evidence of basal ganglia lesions. The three patients underwent stereotactic frame-based robot-assisted DBS of Vim contralateral to the tremor side. Mean follow-up was 48 months (range: 36–60 months). Tremor was reduced in all patients with a better control of voluntary movements and improvement of functional status (mean FIM scale improvement + 7 points). No surgical complications occurred. Unilateral contralateral DBS of Vim could be efficacious in post-traumatic tremor, even in paediatric patients and should be offered in PTT drug-resistant patients.

Abstract INTRODUCTION Chemotherapy remains the cornerstone in case of incompletely resected pedatric Low Grade Glioma (pLGGs) and for recurrent tumors in unfavorable locations. Based on previous cisplatin etoposide regimen (INT Milan strategy), we tried to reduce toxicity and achieve a similar tumor control using a modified regimen composed of CBCDA-etoposide. METHODS From August 2012 to December 2023 we treated 79 pLGGS (45 F (57%), 34 M (43%)) with carboplatin (400 mg/m2 day 1) and etoposide (100 mg/2 day 1-3) at 4-6 weeks interval with 10 cycles in one year or until disease progression. Median age at diagnosis is 7 years. Seventeen patients were affected by neurofibromatosis type 1 (21.5%). 28 pLGGS affected visual pathway (35.4%). Treatment was delivered for clinical symptoms and/or radiological evidence of progression. RESULTS According to RAPNO criteria, on brain magentic resonance imaging (MRI) at the end of treatment 40 patients had stable disease (50.6%), 10 had partial response (12.7%), 7 had major response (8.9%), 5 had minor response (6.3%), 2 presented complete remission (2.5%), 13 patient had disease progression (16.5%). 2 patients are undergoing treatment (2.5%). Acute toxicity was unremarkable. During follow up (median time 59,5 months) 9 children (11,4%) developed audiological alterations but 2 of them also received radiotherapy. 14 patients presented hematological toxicity CTCAE grade 3 or 4 (17,7%). During follow up 30 patients developed a progressive disease (38%) and require further treatments and only one patients died because of progressive disease. Overall survival was 98,7% (78/79). CONCLUSIONS The combination of low doses CBCDA-etoposide seems equally effective with a lower hematological and audiological toxicity compared to other regimens.

Protocadherin-19 (PCDH19) developmental and epileptic encephalopathy causes an early-onset epilepsy syndrome with limbic seizures, typically occurring in clusters and variably associated with intellectual disability and a range of psychiatric disorders including hyperactive, obsessive-compulsive and autistic features. Previous quantitative neuroimaging studies revealed abnormal cortical areas in the limbic formation (parahippocampal and fusiform gyri) and underlying white-matter fibers. In this study, we adopted morphometric, network-based and multivariate statistical methods to examine the cortex and substructure of the hippocampus and amygdala in a cohort of 20 PCDH19-mutated patients and evaluated the relation between structural patterns and clinical variables at individual level. We also correlated morphometric alterations with known patterns of PCDH19 expression levels. We found patients to exhibit high-significant reductions of cortical surface area at a whole-brain level (left/right pvalue = 0.045/0.084), and particularly in the regions of the limbic network (left/right parahippocampal gyri pvalue = 0.230/0.016; left/right entorhinal gyri pvalue = 0.002/0.327), and bilateral atrophy of several subunits of the amygdala and hippocampus, particularly in the CA regions (head of the left CA3 pvalue = 0.002; body of the right CA3 pvalue = 0.004), and differences in the shape of hippocampal structures. More severe psychiatric comorbidities correlated with more significant altered patterns, with the entorhinal gyrus (pvalue = 0.013) and body of hippocampus (pvalue = 0.048) being more severely affected. Morphometric alterations correlated significantly with the known expression patterns of PCDH19 (rvalue = -0.26, pspin = 0.092). PCDH19 encephalopathy represents a model of genetically determined neural network based neuropsychiatric disease in which quantitative MRI-based findings correlate with the severity of clinical manifestations and had have a potential predictive value if analyzed early.

In the past 2 decades, several attempts have been made to promote a correct diagnosis and possible restorative interventions in patients suffering from disorders of consciousness. Sensory stimulation has been proved to be useful in sustaining the level of arousal/awareness and to improve behavioural responsiveness with a significant effect on oro-motor functions. Recently, action observation has been proposed as a stimulation strategy in patients with disorders of consciousness, based on neurophysiological evidence that the motor cortex can be activated not only during action execution but also when actions are merely observed in the absence of motor output, or during listening to action sounds and speech. This mechanism is provided by the activity of mirror neurons. In the present study, a group of patients with disorders of consciousness (11 males, 4 females; median age: 55 years; age range: 19-74 years) underwent task-based functional MRI in which they had, in one condition, to observe and listen to the sound of mouth actions, and in another condition, to listen to verbs with motor or abstract content. In order to verify the presence of residual activation of the mirror neuron system, the brain activations of patients were compared with that of a group of healthy individuals (seven males, eight females; median age: 33.4 years; age range: 24-65 years) performing the same tasks. The results show that brain activations were lower in patients with disorders of consciousness compared with controls, except for primary auditory areas. During the audiovisual task, 5 out of 15 patients with disorders of consciousness showed only residual activation of low-level visual and auditory areas. Activation of high-level parieto-premotor areas was present in six patients. During the listening task, three patients showed only low-level activations, and six patients activated also high-level areas. Interestingly, in both tasks, one patient with a clinical diagnosis of vegetative state showed activations of high-level areas. Region of interest analysis on blood oxygen level dependent signal change in temporal, parietal and premotor cortex revealed a significant linear relation with the level of clinical functioning, assessed with coma recovery scale-revised. We propose a classification of the patient's response based on the presence of low-level and high-level activations, combined with the patient's functional level. These findings support the use of action observation and listening as possible stimulation strategies in patients with disorders of consciousness and highlight the relevance of combined methods based on functional assessment and brain imaging to provide more detailed neuroanatomical specificity about residual activated areas at both cortical and subcortical levels. Errante et al. have studied the activation of the mirror neuron system (MNS) in patients with disorders of consciousness. Their findings demonstrate a spared activation of the MNS, thus suggesting the potential use of observation of actions and listening to their sound as stimulation programme in this challenging condition. Graphical Abstract

Abstract BACKGROUND Gemcitabine plus oxaliplatin chemotherapy (GemOx) represents a possible option in advanced hepatocholangiocarcinoma and pancreatic cancer of adulthood. Considering the pediatric population, it was evaluated in recurrent solid tumors and in children with non-Hodgkin lymphoma unable to tolerate intensive therapy. We report our single-center experience on the applicability of GemOx in infant type brain tumors. MATERIAL AND METHODS At the Meyer Children’s Hospital IRCCS in Florence (Italy), from May 2017 to April 2024, seven children received GemOx after induction chemotherapy delivered according to Italian program for malignant brain tumors under 3 years (AIEOP SNC INFANT). The median age at diagnosis was 14 months, the female/male ratio was 1.3, histology was: three high-grade gliomas, a metastatic medulloblastoma MM, a pineoblastoma, a choroid plexus carcinoma CPC, a pilomyxoid astrocytoma progressed during first line chemotherapy. GemOx was administered to ascertain a more stable disease control and to allow a better recovery from the induction chemotherapy, especially in prevision of high-dose chemotherapy, but also to consider the possibility of a second look neurosurgery. Response was evaluated maximum every four cycles and assessed according to RECIST criteria. RESULTS Gemcitabine 1000 mg/m2 and Oxaliplatin 100 mg/m2 were administered every 14-28 days for 1-11 cycles. Five patients presented stable diseases and two partial responses. GemOx treatment allowed further neurosurgery in one patient (MM). The treatment was overall well tolerated. The most common toxicities were hematological (reaching neutropenia and thrombocytopenia Common Terminology Criteria for Adverse Events grade 4). Six patients were safely exposed to HDC (1-2 courses), another patient is on GemOx treatment. Two patients (MM and CPC) progressed respectively 4 ad 19 months after the end of GemOx: considering the achievement of permissive age also through the bridge therapy, it was possible to expose both to radiotherapy (the latter after a second look neurosurgery). To date all patients are alive and in good clinical condition. CONCLUSION Infant brain tumors represent an extremely challenging subgroup, due to the vulnerable age, with subsequently major risk of therapy-related sequelae and limitation of therapeutic instruments. In the event that a bridge strategy is temporarily warranted, GemOx add on should be considered as a safe option. In our limited and heterogenous cohort, it permitted disease control during the awaiting period, and it was crucial for the patients’ course, especially when a palliative perspective emerged to the lack of other feasible strategies expecting induction therapy recovery.

Abstract BACKGROUND Combined gemcitabine and oxaliplatin (GemOx) was evaluated in recurrent pediatric solid tumors, showing safety but limited activity. In neuro-oncological infant patients, chemotherapy intensified to high doses (HDC) represents the cornerstone, avoiding radiotherapy toxicities. We describe the roles of GemOx towards autologous transplantation in infant-type brain tumors. METHODS From May 2017 to January 2024, at the Meyer Children’s Hospital IRCCS in Florence, six children (median age 19 months, sex equally distributed, three high-grade gliomas, a metastatic medulloblastoma MM, a pineoblastoma, a choroid plexus carcinoma CPC) completed GemOx after induction chemotherapy delivered according to Italian program for malignant brain tumors under 3 years. GemOx was administered to achieve clinical and neuroradiological permissiveness to HDC and to raise the possibility of second look neurosurgery. RESULTS Gemcitabine 1000 mg/m2 and Oxaliplatin 100 mg/m2 were given every 14-28 days for 1-6 cycles. At re-assessment, maximum every four cycles, disease control was optimal (five stable diseases and one partial response according to RECIST criteria). After GemOx, one patient was also subjected to further neurosurgery. The treatment was overall well tolerated, except for Common Terminology Criteria for Adverse Events (CTCAE) grade 4 platelet toxicity in two patients (one of whom also developed hydrocephalus CTCAE 3 and hyponatremia CTCAE 4 during treatment). All patients were safely exposed to HDC (1-2 courses). MM and CPC patients progressed respectively 4 ad 19 months after the end of GemOx. The latter underwent second look neurosurgery, and a radiotherapy course was delivered to both, considering the achievement of permissive age. To date all patients are alive. CONCLUSIONS In brain infant-type malignant tumors strategies are limited due to the extremely vulnerable age. GemOx treatment should be considered a reasonable and safe option waiting for intensified treatment, especially in radiotherapy delaying programs, and it should result incisive in the therapeutic or palliative choice.

Abstract BACKGROUND Optic pathway gliomas (OPG) are low-grade tumors (LGG) that affect the precortical visual pathway, representing 3-5% of pediatric brain tumors, more often diagnosed before the age of 5 years. Although histologically benign, due to their location and thus their unresectability, they carry considerable morbidity, bringing to progressive visual loss. In up to 20% of cases they are detected in patients with neurofibromatosis type 1 (NF1). Consolidated chemotherapy regimen with or without biopsy or debulking, if feasible, remains so far the standard management, moving to new personalized frontiers. MATERIAL AND METHODS In Meyer Children’s Hospital IRCCS Neuro-oncology Unit in Florence (Italy), from February 2013 to April 2024, for visual impairment at diagnosis or for disease progression, thirty-seven OPG patients (female/male ratio 1.3, median age at onset 4 years) completed the first line LGG chemotherapy (carboplatin-etoposide scheme adopted in our institution, built upon the INT Milan strategy and the standard SIOP LGG trial). Fourteen patients (37.8%) presented NF1-related OPG diagnosis, mostly made on a clinical/neuroradiological data. Response was assessed according to RAPNO criteria. RESULTS Non-NF1 OPG patients debuted at a lower median age (3 years) and mostly in a chiasmatic-hypothalamic location, predominantly with a pilocytic astrocytoma histology and manifested with nystagmus, secondarily with visual impairment. Despite the most frequent pre-chiasmatic involvement, during follow-up NF1 patients surprisingly presented a mean and median higher thickness (μm) of the retinal nerve fiber layer (RNFL) on optic coherence tomography (OCT) compared to non-NF1 patients, tested in the majority of patients (mean right RNFL 74.4 versus 58.0, median 66.0 versus 50.0, mean left RNFL 77.2 versus 55.3, median 73.0 versus 49.5). Four non-NF1 patients progressed during treatment or immediately afterwards. Considering the whole follow-up from the stop therapy (median time 5 years), non-NF1 patients progressed by far much more (15/23, 65.2% with one death versus 2/14, 14.3%). Overall survival was 97.3%. CONCLUSION NF1-related and not related pediatric OPG represent two distinct subgroups, with different clinical and prognostic characteristics. In agreement to other series our data show that non-NF1 OPG are less chemotherapy responsive than NF1-related OPG, surely due to the molecular landscape at the basis of tumor growth, warranting the needing of precision medicine directed to targets also in first- line treatment. A worse OCT outcome was found in the former cohort.