Francesco De Leonardis’s research while affiliated with Policlinico di Bari and other places

Background/Objectives: Chronic non-bacterial osteomyelitis (CNO) is a rare autoinflammatory disease characterized by chronic sterile uni- or multifocal osteomyelitis. The treatment of CNO is mostly empirical and the outcome of the disease has not yet been standardized. The aims of this study were to correlate clinically active lesions with radiological signs of inflammation and to evaluate the outcomes in terms of symptoms and radiological signs with Whole Body Magnetic Resonance Imaging (WB-MRI) based on the treatment line used. Methods: A retrospective, observational cohort study of 20 CNO patients, recruited from a single tertiary center in southern Italy, was conducted. Patients included in the study were treated based on the “step-up” approach and were guided by the “treat-to-target” strategy as well as by the response to therapy. The outcome measure was stratified into four different groups, defined by a “Delphy consensus”, depending on the symptoms and the presence of bone lesions in WB-MRI, compared with the therapy carried out. Results: Pain was the most common presenting symptom of the disease. Only 15% of our patients reported long-term complications. WB-MRI was performed for each patient both at diagnosis and during follow-up. At onset, the site most affected by the disease was the tibia. All patients who reached a 5-year follow-up (30%, n = 6) achieved a complete disease remission. Conclusions: The standardized “step-up” treatment approach in our cohort proved effective in disease management with disease control or remission in nearly 90% of patients at one year from diagnosis.

Purpose Patients with high-risk neuroblastoma (HR NB) frequently present with metastases in the bone marrow and bone. Approximately 15% of these patients are refractory to induction therapy, and 50% relapse. Dinutuximab beta is an anti-GD2 monoclonal antibody approved in Europe for maintenance therapy of pediatric patients with HR NB. Immunotherapy with anti-GD2 antibodies improves the survival of children with HR NB and relapsed or refractory disease. It is associated with adverse events, such as pain, fever, allergic reactions, capillary leak syndrome, and diarrhea. This manuscript aims to propose a practical guide in support and prevention treatment of adverse events. Methods MEDLINE was searched using the terms “GD2,” “ch14.18/CHO,” “anti-GD2 antibody,” “dinutuximab beta,” and “neuroblastoma.” The experts reappraised available evidence discussing different clinical Italian experiences. Results Neuropathic pain is the main toxicity associated with dinutuximab beta and can be prevented with analgesics, including intravenous opioids and gabapentin by mouth. The intensity of the supportive treatment decreases from course to course. Conclusion In the experience of the authors, adverse events associated with dinutuximab beta may be prevented and managed in experienced centers. The supportive therapy may be reduced after the first cycle to improve the quality of life.

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.

RMS is a malignant tumor of soft tissues affecting primarily children and adolescents. Around 6% to 23% RMS patients present bone marrow infiltration but leukemia-like involvement is very rare; in these patients cytomorphology on bone marrow smears can lead to misdiagnosis. Differential diagnosis with alveolar RMS should be kept in mind in every pediatric patient presenting with a marked bone marrow involvement in the absence of typical lymphoproliferative findings.

Nuclear protein of the testis carcinoma is an exceedingly rare and poorly differentiated carcinoma characterized by BDR4::NUTM1 gene translocation. Typically, the tumor affects young adults, and no standardized recommendations for therapeutic management have been available since 2022; the clinical course remains mostly dismal. We report the successful multimodal treatment of a 13-year-old boy affected by a primary chest NUT-carcinoma with a novel NUTM1 rearrangement that remains in complete continuous remission at 30 months from diagnosis.

This study describes two cases of bacteraemia sustained by a new putative Pannonibacter species isolated at the U.O.C. of Microbiology and Virology of the Policlinico of Bari (Bari, Italy) from the blood cultures of two patients admitted to the Paediatric Oncohaematology Unit. Pannonibacter spp. is an environmental Gram-negative bacterium not commonly associated with nosocomial infections. Species identification was performed using Sanger sequencing of the 16S rRNA gene and Whole-Genome Sequencing (WGS) for both strains. Genomic analyses for the two isolates, BLAST similarity search, and phylogeny for the 16S rDNA sequences lead to an assignment to the species Pannonibacter phragmitetus. However, by performing ANIb, ANIm, tetranucleotide correlation, and DNA-DNA digital hybridization, analyses of the two draft genomes showed that they were very different from those of the species P. phragmitetus. MALDI-TOF analysis, assessment of antimicrobial susceptibility by E-test method, and Analytical Profile Index (API) tests were also performed. This result highlights how environmental bacterial species can easily adapt to the human host and, especially in nosocomial environments, also gain pathogenic potential through antimicrobial resistance.

Background Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Although the overall survival of patients with NB has improved in the last years, more than 50% of high-risk patients still undergo a relapse. Thus, in the era of precision/personalized medicine, the need for high-risk NB patient-specific therapies is urgent. Methods Within the PeRsonalizEd Medicine (PREME) program, patient-derived NB tumors and bone marrow (BM)-infiltrating NB cells, derived from either iliac crests or tumor bone lesions, underwent to histological and to flow cytometry immunophenotyping, respectively. BM samples containing a NB cells infiltration from 1 to 50 percent, underwent to a subsequent NB cells enrichment using immune-magnetic manipulation. Then, NB samples were used for the identification of actionable targets and for the generation of 3D/tumor-spheres and Patient-Derived Xenografts (PDX) and Cell PDX (CPDX) preclinical models. Results Eighty-four percent of NB-patients showed potentially therapeutically targetable somatic alterations (including point mutations, copy number variations and mRNA over-expression). Sixty-six percent of samples showed alterations, graded as “very high priority”, that are validated to be directly targetable by an approved drug or an investigational agent. A molecular targeted therapy was applied for four patients, while a genetic counseling was suggested to two patients having one pathogenic germline variant in known cancer predisposition genes. Out of eleven samples implanted in mice, five gave rise to (C)PDX, all preserved in a local PDX Bio-bank. Interestingly, comparing all molecular alterations and histological and immunophenotypic features among the original patient’s tumors and PDX/CPDX up to second generation, a high grade of similarity was observed. Notably, also 3D models conserved immunophenotypic features and molecular alterations of the original tumors. Conclusions PREME confirms the possibility of identifying targetable genomic alterations in NB, indeed, a molecular targeted therapy was applied to four NB patients. PREME paves the way to the creation of clinically relevant repositories of faithful patient-derived (C)PDX and 3D models, on which testing precision, NB standard-of-care and experimental medicines.