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Purpose: Three prospective observational studies (Italy, the Netherlands, and France) on active surveillance (AS) in patients with extra-abdominal desmoid-type fibromatosis support AS as a first-line approach. Identifying prognostic factors for the failure of AS will help determine the strategy. The aim of this study was to investigate the prognostic impact of clinical and molecular variables in a larger series., Experimental Design: Data available as of January 31, 2024, from the three studies, in which patients were followed for ≥3 years, were pooled. Patients ≥18 years of age, with primary sporadic desmoid-type fibromatosis, and with CTNNB1 mutations available were eligible. The primary study endpoint was treatment-free survival (TFS). Secondary endpoints included the incidence of RECIST progression, spontaneous RECIST regression, and regression post-RECIST progression., Results: Patients (n = 282) with a median follow-up of 53 months (IQR, 39-63) were included. The 3- and 5-year TFS rates were 67% and 66%, respectively; the 3- and 5-year crude cumulative incidences were 33% and 34% for RECIST progression, 26% and 34% for RECIST regression, and 33% and 38% for regression post-RECIST progression, respectively. In multivariable analysis, larger tumor size, mutation type, and tumor locations were associated with lower TFS. The specific mutation (S45F), larger tumor size, and extremity and trunk locations were all associated with a lower probability of spontaneous RECIST regression., Conclusions: This study confirms that spontaneous regression occurs in a significant proportion of patients and that two-thirds are treatment free at 5 years. Initial tumor size, CTNNB1 mutation, and location should be factored into the initial decision-making process., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Newborn screening (NBS) is a simple, non-invasive test that allows for the early identification of genetic diseases within the first days of a newborn's life. The aim of NBS is to detect potentially fatal or disabling conditions in newborns as early as possible, before the onset of disease symptoms. Early diagnosis enables timely treatments and improves the quality of life for affected patients., Results: A pilot project for dried blood spot (DBS) NBS of lysosomal storage diseases (LSDs), including Mucopolysaccharidosis I (MPSI, IDUA α-L-iduronidase deficiency), Pompe disease (GAA α-glucosidase acid deficiency), Gaucher disease (GBA β-glucosidase deficiency) and Fabry disease (GLA α-galactosidase deficiency), was conducted using the digital microfluidic (DMF) technique. DBS were analyzed in a multiplexed assays for the enzymatic activities of four lysosomal enzymes (IDUA, GAA, GBA, GLA), and subjects identified as deficient in any of these enzymes were referred to the clinical reference center for diagnosis confirmation. From June 6th, 2022, to May 12th, 2023, a total of 7650 newborns were analyzed and 1 subject affected by Pompe disease was identified together with two additional subjects, suspected of Pompe and Fabry disease respectively, for whom continued follow-up is mandatory to determine the phenotype., Conclusions: The pilot project for DBS NBS of four LSDs in Campania Region validated the effectiveness of DMF method, established enzymatic activity cut-offs, and identified newborns referred to the clinical center for integrated diagnostics, including genetic analyses. The results suggest that this technique can effectively detect potentially affected newborns, who will require further diagnostic confirmation and clinical follow-up. This diagnostic flow chart provides the opportunity to initiate early treatments and improve LSD patients' life span., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Background: Newborn screening (NBS) programs have significantly improved the health and outcomes of patients with inherited metabolic disorders (IMDs). Methods based on liquid chromatography/mass spectrometry (LC-MS/MS) analysis are viewed worldwide as the gold standard procedure for the expanded NBS programs for these disorders. Advanced molecular technologies point to genomic sequencing as an alternative and feasible strategy for the screening of genetic diseases, including IMDs. However, each of the two approaches has potential limitations when used as a first-tier analysis. In this study, we tested a workflow-based parallel biochemical and sequencing analyses to determine whether this approach could improve the diagnostic outcome., Results: For each patient identified by LC-MS/MS as positive, we performed both the biochemical confirmatory tests and next-generation sequencing (NGS) procedures from the same Dried Blood Spot (DBS). NGS analysis was based on applying Exome Sequencing libraries, limiting the analysis to 105 actionable genes involved in IMDs. This allows overtaking the actual limitations of NBS on DBS, enhancing our capacity to identify variants that can drive a genetic disease. Through this approach, we could reach 100% of cases solved, with 37.9% of cases (41/108) for which the combination of the biochemical and NGS analysis was indispensable for a correct diagnosis. In total, we could identify 17 affected, 34 false positives, 12 individuals referred to us for maternal conditions. In 45 newborns the molecular analysis showed heterozygosity for mutations in one or more of the genes analyzed, with results compatible with the biochemical profile indicative of NBS positivity., Conclusions: In this study, we validated the performance of the proposed workflow. The advantage of this approach is limiting molecular analysis only to positive newborns and using a restricted panel of 105 genes relevant for the expanded NBS, with a 100% rate of diagnosis and potential reduction of the costs related to NBS procedures and reduced impact on patients and families., Competing Interests: Declarations. Ethics approval and consent to participate: NBS for both biochemistry and genetics was performed according the Italian national law 167/2016 [9] Ethics approval from the local ethical committee (Campania 3) was also obtained: GENOMED study (nr. 3/2023). The research conformed to the principle of the Helsinki Declaration. Consent for publication: Not applicable. Competing interests: Davide Cacchiarelli is the founder, shareholder, and consultant of NEGEDIA Srl. Sara Riccardo, Patrizia Annunziata, and Chiara Colantuono are employees of NEGEDIA Srl. The other authors declare that they have no competing interests., (© 2025. The Author(s).)

Background: Several studies have shown that the intensity of treatment in Ewing sarcoma has an impact on outcome. The present trial tested the non-inferiority of intensive, shorter, induction chemotherapy (25 weeks total treatment time) compared to the standard treatment (37 weeks) in non-metastatic Ewing sarcoma (ES) at onset., Procedure: This national, multicenter, parallel, randomized, controlled, open-label, non-inferiority, phase III trial was conducted in 14 specialized hospitals in Italy. Patients aged 2-40 years with newly diagnosed localized ES were randomized to receive four courses of induction therapy (one every 21 days) either with a standard arm (Arm A) or with an intensive arm (Arm B). For consolidation therapy, good responders (GRs) in Arm A received nine courses (37 weeks), while Arm B patients received five courses (25 weeks). Poor responders for both arms received four courses followed by high-dose busulfan/melphalan + autologous stem cell rescue. Follow-up was 5 years., Results: In the study period 2009-2018, 274 patients with ES at onset were screened, 248 were eligible, 15 refused randomization, and 233 were randomized (Arm A: 113; Arm B: 120). Median age was 14 years. Arm B was not inferior to Arm A: 5-year EFS was 77.5% and 71.6%, respectively (HR vs. Arm A: 0.74, 90% CI: 0.49-1.14). GRs were 54.9% in Arm A and 62.5% in Arm B. Hematological, gastrointestinal, and cardiovascular Grade ≥3 toxicities had higher frequencies in Arm B., Conclusions: Intensive induction therapy showed non-inferiority in 5-year EFS when compared with the standard induction therapy. Higher toxicity was reported in Arm B with similar outcome, counterbalanced in GRs with a shorter treatment plan., Clinicaltrials: gov Identifier: NCT02063022., (© 2025 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: We applied the strategy for M+ medulloblastoma across all high-risk subgroups, including LC/A histology, TP53 mutations, and MYC/MYCN amplification., Methods: Patients over 3 years old received, after surgery, staging and histo-biological analysis, sequential high-dose-methotrexate(HD-MTX), high-dose-etoposide(HD-VP16), high-dose-cyclophosphamide(HD-Cyclo), and high-dose-carboplatin(HD-Carbo). Hyperfractionated-accelerated-radiotherapy-craniospinal(HART-CSI), administered twice daily 1.3 Gy-fractions reached a total dose tailored to the patients' age and pre-radiation response to chemotherapy(CT): 31.2 Gy if under 10-years-old and complete response(CR) or partial response(PR) obtained or absence of metastatic disease, 39 Gy in other/older patients. Boosts to posterior fossa/residual metastatic(M+) deposits were given up to a total dose of 60 Gy/9 Gy, respectively, but avoided if metastatic nodules were very big or patients were very young. Two courses of high-dose-thiotepa were delivered in case of not CR/PR after the pre-radiotherapy (RT) phase and in all M0 patients either-pre/post-HART. Subgrouping was performed where the tissue was available., Results: Eighty-nine patients were enrolled, with a median age of 8.8 years, and a median follow-up of 136 months. Overall survival (OS) and event-free survival (EFS) at 5/15 years were 75.9/66.5% and 68.2/65.3%, respectively; 5/28 fatal events were not related to relapse(3 developed secondary malignancies). Sex, age less than 10 years, histological subtype, presence of MYC/MYCN amplification, reduction in CSI dose, omission of RT-boosts, implementation of myeloablative therapy, presence-absence of metastases did not impact prognosis.Patients progressing after pre-HART CT(14/89) and stable-disease(SD)+PD after HART(10/89) negatively affected outcome(P < .001).Subgrouping in 66/89 patients' samples demonstrated a significantly worse EFS for patients with Sonic Hedgehog(SHH)-tumors(#15, 2 with constitutional TP53-mutations) versus groups 3 and 4(15 and 29 patients, respectively, group3/4 in 7).Patients younger than 10 received lower CSI doses if stratified according to CT response., Conclusions: This strategy, partly adopted in the ongoing SIOPE protocol, confirmed improved EFS and OS over previously reported outcomes in all high-risk categories; SHH tumors appeared the most aggressive., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)