The coexistence of a BRCA2 germline and a DICER1 somatic variant in two first-degree cousins suggests their potential synergic effect.

Cancer predisposition syndromes are recognized in about 10% of pediatric malignancies with several genes specifically involved in a subset of pediatric tumors such as DICER1, in pleuropulmonary blastoma, cystic nephroma, and brain sarcomas. By contrast, the role of BRCA1/2 in pediatric cancer predisposition is still under investigation. We present two cases of young first-degree cousins, both carrying a germline BRCA2 variant and developing tumors characterized by somatic DICER1 mutations. Patient 1 presented with a cystic nephroma harboring a somatic DICER1 variant (p.Asp1810Tyr), while patient 2 had a primary intracranial DICER1-mutated sarcoma showing a distinct somatic DICER1 variant (p.Asp1709Glu) as well as biallelic inactivation of TP53 (p.Val173Leu, VAF 91%) and APC (p.Ile1307Lys, VAF 95%) and a pathogenic variant in KRAS (p.Gln61His). Both patients carried the same germline BRCA2 variant (p.Arg2842Cys) of unknown significance. The same variant was found in the mother of patient 2 and in the father of patient 1, who are siblings. A homologous recombination deficiency signature was not identified in any of the two tumors, possibly suggesting a reduction of BRCA2 activity. The association of BRCA2 and DICER1 variants in our cases hints at a potential cooperative role in cancer pathogenesis. Further studies are warranted to elucidate the interplay between BRCA1/2 and DICER1 variants and their implications for cancer predisposition and treatment in pediatric patients.

Machine Learning Analysis in Diffusion Kurtosis Imaging for Discriminating Pediatric Posterior Fossa Tumors: A Repeatability and Accuracy Pilot Study.

Background and purpose: Differentiating pediatric posterior fossa (PF) tumors such as medulloblastoma (MB), ependymoma (EP), and pilocytic astrocytoma (PA) remains relevant, because of important treatment and prognostic implications. Diffusion kurtosis imaging (DKI) has not yet been investigated for discrimination of pediatric PF tumors. Estimating diffusion values from whole-tumor-based (VOI) segmentations may improve diffusion measurement repeatability compared to conventional region-of-interest (ROI) approaches. Our purpose was to compare repeatability between ROI and VOI DKI-derived diffusion measurements and assess DKI accuracy in discriminating among pediatric PF tumors. Materials and methods: We retrospectively analyzed 34 children (M, F, mean age 7.48 years) with PF tumors who underwent preoperative examination on a 3 Tesla magnet, including DKI. For each patient, two neuroradiologists independently segmented the whole solid tumor, the ROI of the area of maximum tumor diameter, and a small 5 mm ROI. The automated analysis pipeline included inter-observer variability, statistical, and machine learning (ML) analyses. We evaluated inter-observer variability with coefficient of variation (COV) and Bland-Altman plots. We estimated DKI metrics accuracy in discriminating among tumor histology with MANOVA analysis. In order to account for class imbalances, we applied SMOTE to balance the dataset. Finally, we performed a Random Forest (RF) machine learning classification analysis based on all DKI metrics from the SMOTE dataset by partitioning 70/30 the training and testing cohort. Results: Tumor histology included medulloblastoma (15), pilocytic astrocytoma (14), and ependymoma (5). VOI-based measurements presented lower variability than ROI-based measurements across all DKI metrics and were used for the analysis. DKI-derived metrics could accurately discriminate between tumor subtypes (Pillai's trace: p < 0.001). SMOTE generated 11 synthetic observations (10 EP and 1 PA), resulting in a balanced dataset with 45 instances (34 original and 11 synthetic). ML analysis yielded an accuracy of 0.928, which correctly predicted all but one lesion in the testing set. Conclusions: VOI-based measurements presented improved repeatability compared to ROI-based measurements across all diffusion metrics. An ML classification algorithm resulted accurate in discriminating PF tumors on a SMOTE-generated dataset. ML techniques based on DKI-derived metrics are useful for the discrimination of pediatric PF tumors.

Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile.

BACKGROUND: The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established. METHODS: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization. RESULTS: Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-year survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n = 49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wild-type (n = 31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n = 19), pedHGG_A/B (n = 6), and pedHGG_MYCN (n = 5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wild-type subgroup, recurrent alterations in EGFR (n = 10) and BCOR (n = 9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wild-type subgroup TP53 alterations had a significant negative effect on OS. CONCLUSIONS: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).

Pediatric torticollis: clinical report and predictors of urgency of 1409 cases.

BACKGROUND: To date, the etiology and risk factors of torticollis are still poorly defined in the pediatric literature. Especially in the Emergency Department (ED) scenario, it is critical to reliably distinguish benign and transient conditions from (potentially) life-threatening disorders. This study describes the clinical characteristics of a large sample of children with torticollis. The aim of our study was to detect epidemiology, etiology and predictive variables associated with a higher risk of life-threatening conditions in acute torticollis. METHODS: We conducted a pediatric retrospective study of acute torticollis over a 13-year period referred to the ED of a tertiary pediatric Hospital. We reported the characteristics in the overall sample and in two subgroups divided according to urgency of the underlying condition. Furthermore, we developed a multivariate model aimed at identifying the main clinical predictors of the need for urgent care. RESULTS: 1409 patients were analyzed (median age 5.7 years, IQR 5.8). A history of trauma was present in 393 patients (27.9%). The symptom most frequently associated with torticollis were pain (83.5%). At least one pathological finding was found in 5.4 to 7.9% of patients undergoing further imaging. Hospitalization was required in 11.1% of cases (median duration 4 days). The most frequent etiologies of torticollis were postural cause (43.1%), traumatic (29.5%), and infective/inflammatory (19.1%). A longer time from onset of torticollis and the presence of headache or vomiting were strongly correlated with an underlying urgent condition, after adjusting for the other clinically and statistically significant variables in the bivariate analysis. CONCLUSION: Our study shows that an urgent condition most commonly occur in patients presenting with history of trauma or headache, vomiting and torticollis for more than 24 h should undergo further diagnostic evaluation and short-term follow-up, restricting invasive or expensive investigations to patients with clinical suspicion of an underlying harmful condition.

Central nervous system tumours in neonates: what should the neonatologist know?

Central nervous system (CNS) tumours in neonates are relatively rare and present differently when compared with those occurring later in childhood in terms of aetiology, clinical features, location, histology and prognosis. The clinical presentation is extremely variable. Even if the most frequent clinical sign is a macrocephaly, there are many other non-specific symptoms associated. The prognosis is usually poor with overall survival of less than 30%. Surgery continues to be the primary treatment for neonatal CNS tumours, aiming for a gross total resection, directly correlated with prognosis and the overall outcome. The chemotherapy is the only adjuvant therapy whereas the radiotherapy is avoided under three years of age because of the severe sequelae. Hence the importance of molecular characterization of these neoplasms in order to improve the accuracy of the diagnosis and identify new therapeutic targets. The aim of this review is to describe the main characteristics of these tumours and the recent advances in their treatment in order to recognize these pathologies in the prenatal period and create a multidisciplinary team providing the best possible treatment while minimising the risk of long-term complications. Neonatologists play a key role in the early detection, diagnostic evaluation, management and supportive care of these neonates.  Conclusion: The aim of this review is to describe the main characteristics of these tumours and the recent advances in their treatment in order to ensure the essential knowledge that will help the neonatologist identify them and create a multidisciplinary team providing the best possible treatment while minimising the risk of long-term complications. What is Known: • Neonatal CNS tumours are relatively rare and their early identification is important to identify the best diagnostic-therapeutic management. • Surgery is the main treatment of neonatal CNS tumours. The extent of surgical resection directly correlates with prognosis and outcome. What is New: • Predisposing conditions such as Cancer Predisposition Syndromes must be considered. • Targeted drugs and other therapeutic strategies can be identified through molecular characterization.

Case Report: A rare form of congenital erythrocytosis due to SLC30A10 biallelic variants-differential diagnosis and recommendation for biochemical and genetic screening.

Congenital erythrocytosis recognizes heterogeneous genetic basis and despite the use of NGS technologies, more than 50% of cases are still classified as idiopathic. Herein, we describe the case of a 3-year-old boy with a rare metabolic disorder due to SLC30A10 bi-allelic mutations and characterized by hypermanganesemia, congenital erythrocytosis and neurodegeneration, also known as hypermanganesemia with dystonia 1 (HMNDYT1). The patient was treated with iron supplementation and chelation therapy with CaNa2EDTA, resulting in a significative reduction of blood manganese levels and erythrocytosis indexes. Although it couldn't be excluded that the patient's developmental impairment was part of the phenotypic spectrum of the disease, after three months from starting treatment no characteristic extrapyramidal sign was detectable. Our findings suggest the importance of assessing serum manganese levels in patients with unexplained polycythemia and increased liver enzymes. Moreover, we highlight the importance of extended genetic testing as a powerful diagnostic tool to uncover rare genetic forms of congenital erythrocytosis. In the described patient, identifying the molecular cause of erythrocytosis has proven essential for proper clinical management and access to therapeutic options.

PATZ1-Rearranged Tumors of the Central Nervous System: Characterization of a Pediatric Series of Seven Cases.

PATZ1-rearranged sarcomas are well-recognized tumors as part of the family of round cell sarcoma with EWSR1-non-ETS fusions. Whether PATZ1-rearranged central nervous system (CNS) tumors are a distinct tumor type is debatable. We thoroughly characterized a pediatric series of PATZ1-rearranged CNS tumors by chromosome microarray analysis (CMA), DNA methylation analysis, gene expression profiling and, when frozen tissue is available, optical genome mapping (OGM). The series consisted of 7 cases (M:F=1.3:1, 1-17 years, median 12). On MRI, the tumors were supratentorial in close relation to the lateral ventricles (intraventricular or iuxtaventricular), preferentially located in the occipital lobe. Two major histologic groups were identified: one (4 cases) with an overall glial appearance, indicated as "neuroepithelial" (NET) by analogy with the corresponding methylation class (MC); the other (3 cases) with a predominant spindle cell sarcoma morphology, indicated as "sarcomatous" (SM). A single distinct methylation cluster encompassing both groups was identified by multidimensional scaling analysis. Despite the epigenetic homogeneity, unsupervised clustering analysis of gene expression profiles revealed 2 distinct transcriptional subgroups correlating with the histologic phenotypes. Interestingly, genes implicated in epithelial-mesenchymal transition and extracellular matrix composition were enriched in the subgroup associated to the SM phenotype. The combined use of CMA and OGM enabled the identification of chromosome 22 chromothripsis in all cases suitable for the analyses, explaining the physical association of PATZ1 to EWSR1 or MN1. Six patients are currently disease-free (median follow-up 30 months, range 12-92). One patient of the SM group developed spinal metastases at 26 months from diagnosis and is currently receiving multimodal therapy (42 months). Our data suggest that PATZ1-CNS tumors are defined by chromosome 22 chromothripsis as causative of PATZ1 fusion, show peculiar MRI features (eg, relation to lateral ventricles, supratentorial frequently posterior site), and, although epigenetically homogenous, encompass 2 distinct histologic and transcriptional subgroups.

A systematic review of data sources for artificial intelligence applications in pediatric brain tumors in Europe: implications for bias and generalizability.

Introduction: Europe works to improve cancer management through the use of artificialintelligence (AI), and there is a need to accelerate the development of AI applications for childhood cancer. However, the current strategies used for algorithm development in childhood cancer may have bias and limited generalizability. This study reviewed existing publications on AI tools for pediatric brain tumors, Europe's most common type of childhood solid tumor, to examine the data sources for developing AI tools. Methods: We performed a bibliometric analysis of the publications on AI tools for pediatric brain tumors, and we examined the type of data used, data sources, and geographic location of cohorts to evaluate the generalizability of the algorithms. Results: We screened 10503 publications, and we selected 45. A total of 34/45 publications developing AI tools focused on glial tumors, while 35/45 used MRI as a source of information to predict the classification and prognosis. The median number of patients for algorithm development was 89 for single-center studies and 120 for multicenter studies. A total of 17/45 publications used pediatric datasets from the UK. Discussion: Since the development of AI tools for pediatric brain tumors is still in its infancy, there is a need to support data exchange and collaboration between centers to increase the number of patients used for algorithm training and improve their generalizability. To this end, there is a need for increased data exchange and collaboration between centers and to explore the applicability of decentralized privacy-preserving technologies consistent with the General Data Protection Regulation (GDPR). This is particularly important in light of using the European Health Data Space and international collaborations.

Unraveling the impact of upfront chemotherapy and proton beam therapy on treatment outcome and follow-up in central nervous system germ cell tumors: a single center experience.

Background: Germ cell tumors (GCT) account for a minority of central nervous system (CNS) malignancies, highly prevalent in adolescents and young adults. Despite their aggressive biological behavior, prognosis is excellent in most cases with risk stratified treatment, consisting in a combination of chemotherapy and radiotherapy. Whole ventricular irradiation (WVI) and craniospinal irradiation, the treatment of choice for localized and metastatic disease, pose significant risk of collateral effects, therefore proton beam radiation (PBT) has been recently proposed for its steep dose fallout. Materials and methods: We report our experience in a consecutive series of 17 patients treated for CNS GCT at our Institution from 2015 to 2021. Results: Most frequent lesion location were sellar/suprasellar (35%) and bifocal germinoma (35%), followed by pineal (18%) and thalamic (12%). Two patients (12%), had evidence of disseminated disease at the time of diagnosis. At the latest follow-up all but one patient showed complete response to treatment. The only relapse was successfully rescued by additional chemotherapy and PBT. PBT was well tolerated in all cases. No visual, neurological or endocrinological worsening was documented during and after treatment. Neuropsychological evaluation demonstrated preservation of cognitive performance after PBT treatment. Conclusions: Our data, albeit preliminary, strongly support the favourable therapeutic profile of PBT for the treatment of CNS germ cell tumors.

SHH medulloblastoma and very early onset of bowel polyps in a child with PTEN hamartoma tumor syndrome.

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a cancer predisposition syndrome characterized by an increased risk of developing benign and malignant tumors, caused by germline pathogenic variants of the PTEN tumour suppressor gene. PTEN gene variants often present in childhood with macrocephaly, developmental delay, and/or autism spectrum disorder while tumors and intestinal polyps are commonly detected in adults. PHTS is rarely associated with childhood brain tumors with only two reported cases of medulloblastoma (MB). We report the exceptional case of an infant carrying a germline and somatic pathogenic variant of PTEN and a germline and somatic pathogenic variant of CHEK2 who developed a MB SHH in addition to intestinal polyposis.

Extra-neural metastases in pediatric diffuse midline gliomas, H3 K27-altered: presentation of two cases and literature review.

Introduction: Pediatric diffuse midline gliomas (DMG), H3 K27- altered, are the most aggressive pediatric central nervous system (CNS) malignancies. Disease outcome is dismal with a median survival of less than one year. Extra-neural metastases are an unusual occurrence in DMG and have been rarely described. Methods and results: Here, we report on two pediatric patients affected by DMG with extra-neural dissemination. Their clinical, imaging, and molecular characteristics are reported here. An 11-year-old male 5 months after the diagnosis of diffuse intrinsic pontine glioma (DIPG) developed metastatic osseous lesions confirmed with computed tomography (CT) guided biopsy of the left iliac bone. The patient died one month after the evidence of metastatic progression. Another 11-year-old female was diagnosed with a cerebellar H3K27- altered DMG. After six months, she developed diffuse sclerotic osseous lesions. A CT-guided biopsy of the right iliac bone was non-diagnostic. She further developed multifocal chest and abdominal lymphadenopathy and pleural effusions. Droplet digital polymerase chain reaction (ddPCR) on pleural effusion revealed the presence of H3.3A mutation (c.83A>T, p.K28M). The patient died 24 months after the diagnosis of DMG and 3 months after the evidence of metastatic pleural effusion. Discussion: Extra-neural metastasis of DMG is a rare event and no standard therapy exists. An accurate and early diagnosis is necessary in order to develop a personalized plan of treatment. Further research is needed to gain further insights into the molecular pathology of DMG, H3K27- altered and improve the quality of life and the final outcome of patients with this deadly disease.

Long-term follow-up in a pediatric patient with Ligneous Conjunctivitis due to PLG gene mutation in topical plasminogen treatment after successful use of ocular prosthesis for aesthetic rehabilitation: a case report.

BACKGROUND: Ligneous Conjunctivitis (LC) is the most common clinical manifestation of Type I Plasminogen deficiency (T1PD; OMIM# 217090), and it is characterized by the formation of pseudomembranes (due to deposition of fibrin) on the conjunctivae leading to progressive vision loss. In past times, patients with LC were treated with surgery, topical anti-inflammatory, cytostatic agents, and systemic immunosuppressive drugs with limited results (Blood 108:3021-3026, 2006, Ophthalmology 129:955-957, 2022, Surv Ophthalmol 48:369-388, 2003, Blood 131:1301-1310, 2018). The surgery can also trigger the development of membranes, as observed in patients needing ocular prosthesis (Surv Ophthalmol 48:369-388, 2003). Treatment with topical purified plasminogen is used to prevent pseudomembranes formation (Blood 108:3021-3026, 2006, Ophthalmology 129:955-957, 2022). CASE PRESENTATION: We present the case of a sixteen-year-old girl with LC with severe left eye involvement. We reported the clinical conditions of the patient before and after the use of topical plasminogen eye drops and described the treatment schedule allowing the surgical procedure for the pseudomembranes debulking and the subsequent use of ocular prosthesis for aesthetic rehabilitation. CONCLUSIONS: The patient showed a progressive response to the topical plasminogen, with a complete absence of pseudomembrane formation at a twelve-year follow-up, despite using an ocular prosthesis.

Safety and Efficacy of Mek Inhibitors in the Treatment of Plexiform Neurofibromas: A Retrospective Study.

INTRODUCTION: Plexiform neurofibromas (PN) represent the main cause of morbidity in patients affected by Neurofibromatosis Type 1 (NF1). Until recently, surgery has been the main treatment option in these patients, but it is burdened with a low efficacy rate and a high incidence of side effects as well as recurrence. In recent years, MEK inhibitors (MEKi) such as selumetinib and trametinib have shown great promise. METHODS: We retrospectively describe a single center cohort of NF1 patients affected by PN1 and treated with MEKi since 2019 to 2021. Patients recruited in the study were affected by PN that were not eligible to complete surgical excision, symptomatic or with major cosmetic deformation or functional neurological deficits. RESULTS: Most patients experienced improvement in clinical symptoms and quality of life, with reduction or stabilization of lesions. However, no complete response was achieved. The most common adverse effects involved the skin, affecting every patient. Importantly, no life-threatening adverse effects occurred. CONCLUSIONS: In our experience, MEKi treatment has been shown to be both safe and effective in improving symptomatology and quality of life.

Diagnostic and Dosimetry Features of [64Cu]CuCl2 in High-Grade Paediatric Infiltrative Gliomas.

PURPOSE OF THE REPORT: Paediatric diffuse high-grade gliomas (PDHGG) are rare central nervous system neoplasms lacking effective therapeutic options. Molecular imaging of tumour metabolism might identify novel diagnostic/therapeutic targets. In this study, we evaluated the distribution and the dosimetry aspects of [64Cu]CuCl2 in PDHGG subjects, as copper is a key element in cellular metabolism whose turnover may be increased in tumour cells. MATERIAL AND METHODS: Paediatric patients with PDHGG were prospectively recruited. [64Cu]CuCl2 PET/CT was performed 1 h after tracer injection; if the scan was positive, it was repeated 24 and 72 h later. Lesion standardised uptake value (SUV) and target-to-background ratio (TBR) were calculated. Tumour and organ dosimetry were computed using the MIRD algorithm. Each patient underwent an MRI scan, including FLAIR, T2-weighted and post-contrast T1-weighted imaging. RESULTS: Ten patients were enrolled (median age 9, range 6-16 years, 6 females). Diagnoses were diffuse midline gliomas (n = 8, 5 of which with H3K27 alterations) and diffuse hemispheric gliomas (n = 2). Six patients had visible tracer uptake (SUV: 1.0 ± 0.6 TBR: 5 ± 3.1). [64Cu]CuCl2 accumulation was always concordant with MRI contrast enhancement and was higher in the presence of radiological signs of necrosis. SUV and TBR progressively increased on the 24- and 72-h acquisitions (p < 0.05 and p < 0.01, respectively). The liver and the abdominal organs received the highest non-target dose. CONCLUSIONS: [64Cu]CuCl2 is a well-tolerated radiotracer with reasonably favourable dosimetric properties, showing selective uptake in tumour areas with visible contrast enhancement and necrosis, thus suggesting that blood-brain barrier damage is a pre-requisite for its distribution to the intracranial structures. Moreover, tracer uptake showed an accumulating trend over time. These characteristics could deserve further analysis, to determine whether this radiopharmaceutical might have a possible therapeutic role as well.

Central Nervous System Metastasis in Neuroblastoma: From Three Decades Clinical Experience to New Considerations in the Immunotherapy Era.

Central nervous system (CNS) metastatic spread in neuroblastoma (NB) is rare and occurs more often at relapse/progression. We report on CNS involvement in high risk (HR) NB over 25 years. For this retrospective study, we reviewed the CNS imaging of all the patients treated at Bambino Gesù Children Hospital from 1 July 1996 to 30 June 2022. A total of 128 patients with HR NB were diagnosed over 26 years. Out of 128 patients, CNS metastatic spread occurred in 6 patients: 3 patients presented a metastatic spread at diagnosis, while in 3 patients, CNS was involved at relapse. Overall, the rate of occurrence of CNS spread is 4.7% with the same distribution at diagnosis and at relapse, namely 2.3%. Interestingly, CNS spread at diagnosis was observed only before 2012, whereas CNS was observed at relapse only after 2012, in the immunotherapy era. CNS metastases presented similar imaging features at diagnosis and at relapse, with a peculiar hemorrhagic aspect and mainly hemispheric localization in patients with bone skull involvement at the time of diagnosis. The outcome is dismal, and 3 out of 6 patients died for progressive disease.

Vascular lesions of the pediatric orbit: A radiological walkthrough.

Vascular anomalies of the pediatric orbit represent a heterogeneous group that include both vascular tumors and vascular malformations. The disorder may initially be silent and then associated with symptoms and/or function damage, depending on the type of vascular anomaly and its extension. Vascular tumors include benign, locally aggressive (or borderline) and malignant forms while vascular malformations are divided into "simple", "combined" and syndromic, or "low flow" or "high flow". Both entities can arise in isolation or as part of syndromes. In this review, we describe the imaging findings of the vascular lesions of the orbit in the pediatric population, which are key to obtain a correct diagnosis and to guide the appropriate treatment in the light of the new genetic and molecular discoveries, and the role of the radiologist in their multidisciplinary management. We will also touch upon the main syndromes associated with orbital vascular abnormalities.